Clinical Trials Handbook
Clinical Trials Handbook
DESIGN AND CONDUCT
Curtis L. Meinert
Bloomberg School of Public Health
The Johns Hopkins University
Baltimore, MD
A John Wiley & Sons, Inc., Publication
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Library of Congress Cataloging-in-Publication Data:
Meinert, Curtis L.
Clinical trials handbook : design and conduct / Curtis L. Meinert.
p. cm.
Includes bibliographical references and index.
ISBN 978-1-118-21846-4 (hardback)
1. Drugs–Testing–Handbooks, manuals, etc. 2. Clinical trials–
Handbooks, manuals, etc. I. Title.
RM301.27.M45 2013
615.1072 4–dc23
2012015097
Printed in the United States of America
10 9 8 7 6 5 4 3 2 1
Contents
Acknowledgments xi
Preface xiii
On planning xv
Explanatory notes, focus, and conventions xvii
Abbreviations and designations xxi
I.
General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.
2.
3.
4.
5.
6.
7.
8.
9.
Terminology 3
Definitions 5
Measurement units 7
Trial type 9
Design and flow schematics 13
Design and operating principles 15
Counting and analysis rules 17
Multi-study umbrella name 19
Study name 21
II.
10.
11.
12.
13.
14.
15.
16.
III.
17.
18.
19.
20.
21.
Design Specifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Objective 27
Specific aims 29
Experimental variable 31
Treatment unit 33
Primary outcome 35
Outcome measures 39
Design synopsis 41
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Type of funding initiative 47
Funding: Specifications 49
Funding: Terminology 51
Funding: Type 59
Funding: Initiative 61
v
vi
CONTENTS
22. Funding: Period 63
23. Funding: Budget 65
24. Funding: Mode 67
IV.
Treatment Groups/Treatment Administration . . . . . . . . . . . . . 69
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
Study groups 71
Comparison group 73
Study treatments 75
Test treatments 77
Control/comparison treatment 79
Placebo treatment 87
Sham treatment 91
Treatment modality 93
Treatment schedule 95
Treatment compliance measures 97
Protocol overrides 101
Protocol bailouts 103
V.
Masking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
37.
38.
39.
40.
41.
42.
43.
44.
45.
Mask/masking: Definitions 107
Masking principles 111
Masking, censoring, and shielding specifications 113
Drug masking procedure 115
Drug packaging and labeling 117
Drug supply 121
Masking safeguards 123
Unmasking treatment assignment 125
Results blackouts 127
VI.
46.
47.
48.
49.
VII.
Bias and Variance Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Bias control procedures 131
Stratification 135
Variance control procedures 139
Separations 141
Treatment Assignment/Randomization. . . . . . . . . . . . . . . . . .143
50. Assignment methods: Fixed vs. adaptive 145
51. Treatment assignment: Random vs. nonrandom 147
52. Randomization: Complete vs. restricted 151
Contents
vii
53. Randomization unit 155
54. Randomization: Procedures 157
VIII.
55.
56.
57.
58.
59.
60.
61.
62.
63.
IX.
IRBs and Consents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
IRBs 161
IRBs: Models and procedures 163
Consent 169
Consent: Checklist 177
Consent: Disclaimers and notifications 181
Consent: Principles and purpose 183
Consent: Process 185
Consent: Types 189
Consent: Questions and answers 191
Enrollment and Followup . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
Notation 197
Timing conventions 199
Required approvals, permissions, accesses, and supplies 201
Start-up design 203
Start-up checklist 207
Recruitment design 209
Enrollment goals 211
Enrollment quotas 213
Followup: Terminology 217
Followup: Method 221
Followup: Length 223
Closeout design 225
Missed visit 229
Dropout 231
Loss to followup 235
Study timetable 239
Critical event path analysis 241
Eligibility criteria 243
Exclusions from enrollment 245
Eligibility and exclusions by reason 249
X.
Sample Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
84. Sample size: Design 253
85. Sample size: Specifications 257
viii
86.
87.
88.
89.
CONTENTS
Sample size: Calculation 259
Fixed vs. sequential sample size designs 261
Fixed vs. adaptive designs 263
Designed subgroup comparisons 265
XI.
Data Collection and Processing . . . . . . . . . . . . . . . . . . . . . . . . . 267
90. Contact schedule 269
91. Examinations/visits 271
92. Examination/clinic visit schedule 275
93. Data collection 279
94. Data collection: Schedules and procedures 281
95. Data flow 283
96. Data processing procedures 285
97. Laboratory tests 287
98. Readings 289
99. Tissue repositories 293
100. Form design: Principles and procedures 295
101. Time window specifications 299
102. Data entry design 301
103. Data sharing: Internal 307
104. Data sharing: External 311
XII.
Study Centers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
105. Center types 317
106. Centers 323
107. Center requirements 325
XIII.
Investigators/Study Staff . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
108. Investigator requirements 331
109. Clinic staffing requirements 333
110. Research group/Investigators 335
XIV.
Committees . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
111. Key Committees 339
112. Standing and working committees 341
113. Committee rules and procedures 343
114. Study officers 347
115. Study chair/vice-chair 349
Contents
ix
116. Executive committee 353
117. Executive committee members 357
118. Steering committee 359
119. Steering committee members 361
120. Steering committee: Questions, answers, and observations 363
121. Steering committee representation models 367
XV.
Treatment Effects Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . 371
122. Treatment effects monitoring 373
123. Treatment effects monitoring: Purpose 375
124. Treatment effects monitoring: Approach 377
125. Treatment effects monitoring: Masking 379
126. Stopping rules and guidelines 381
127. Treatment effects monitoring: Questions and answers 383
128. Treatment effects monitoring committee 387
129. Treatment effects monitoring committee: Questions and answers 391
XVI.
Quality Control and Assurance . . . . . . . . . . . . . . . . . . . . . . . . 393
130. Quality control and assurance procedures 395
131. Performance monitoring 399
132. Training procedures 401
133. Assurances and certifications 403
134. Site visiting procedures 405
135. Audit procedures 409
XVII.
Data Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
136. Analysis datasets 415
137. Analysis questions regarding study results publications 417
138. Frequentist vs. Bayesian analysis 419
139. Final analysis 421
140. Subgroup analysis 423
XVIII.
Publication/Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425
141. Publication 427
142. Publication policy 429
143. Authorship 431
144. Credits 435
145. Presentation policy 439
x
XIX.
CONTENTS
Policies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441
146. Policies 443
147. Publicity policy 445
148. Policy on access to study documents 447
149. Policy on access to study data and results 449
150. Policy on advertising for patients 453
151. Policy on incentive payments 455
152. Policy on payment of patient-related travel expenses 457
153. Ancillary study policy 459
154. Policy on patient-care-related payments 461
155. Policy on conflicts of interest 463
156. Substudy policy 467
XX. Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469
157. Adverse events 471
158. Adverse event reporting procedures 475
XXI.
Miscellaneous. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .479
159. Key study documents 481
160. Design synopsis 483
161. Slide sets 485
162. Study CV 487
163. Study website 489
164. Study history log 491
165. Landmark events and dates 493
166. Registration 495
Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
appendix 1. Design summaries for selected finished trials 499
appendix 2. Sample design slide sets 517
appendix 3. Template summary worksheet 537
References 551
Index 557
Acknowledgments
I wish to thank the people of the Johns Hopkins Center for Clinical Trials for help
in producing this document—especially Betty Collison, Jill Meinert, Annette Wagoner,
Karen Collins, Mark Van Natta, and Susan Tonascia.
xi
Preface
The idea underlying randomized trials is deceptively simple: Create comparable groups of
persons by randomization, treat them according to a prescribed protocol, follow them for
the outcome of interest, analyze the results, write up the results, and pass on to the next
trial.
How hard can it be? Decide on the treatment, define who is eligible, calculate a
sample size, recruit and randomize, treat and follow, and wait for fame and fortune, or if
not fortune, then at least fame!
If only it were so.
The difference between success and failure in trials is hundreds of details. Details
of design and conduct to the trialist is what blueprints are to builders. But trials do
not come with blueprints. They have to be developed, almost always in a ‘‘rush.’’ This
handbook is produced in the hope of making that process easier and less error prone.
This handbook is the product of years in trials primarily as a
statistician–methodologist in coordinating centers formulticenter trials. Its roots are
in materials posted to trialsmeinertsway.com. It took the form of a handbook in early
2000 but then lay fallow for several years while I was working on the 2nd edition of my
textbook Clinical Trials: Design, Conduct, and Analysis60 and An Insider’s Guide to Clinical
Trials.53 It came back to life a couple of years back as work on those books ebbed.
This handbook consists of 21 sections, each containing 2 to 20 parts, depending
on the section, three appendices, reference list and index.
Curtis L Meinert
Towson, Maryland
8 March 2012
xiii
On Planning
The traditional classroom paradigm for instructing students in trials is one involving a
series of steps. First, students formulate questions amenable to testing. Next, they design
trials suitable for addressing the questions. After that they produce protocols (study plans)
and necessary forms for recording data from the trials. Then, somehow, they do the trials,
analyze the results, write up the results, and hand the write-ups in for a grade.
Design in the paradigm of experimentation is the portion of a plan that serves to
specify the variable to be manipulated (experimental variable), the levels or states of the
variable to be studied (treatments), and the way in which the treatments will be applied
(protocol). In the context of trials, the design is that portion of the plan that specifies
the treatments to be studied, how persons will be assigned to treatment, the numbers
to be assigned (sample size), the proportions assigned to the different treatment groups
(assignment ratio), and the details of treatment.
Clearly, planning is an activity that starts before any work can be done and
proceeds over the life of the activity. In the context of trials, it starts with the first glimmer
of an idea for a trial and continues to completion of the trial. ‘‘Planning’’ is over the ‘‘life’’
of the trial.
Much of the time devoted to ‘‘planning’’ will be spent in deciding how the trial is
to be organized, directed, and monitored and in arriving at closure on contentious issues
relating to matters of policy and practice. The likelihood is that more time will be spent
on matters relating to organization and ‘‘policy’’ than on the actual ‘‘science’’ of the trial.
Groups can be expected to become more interested and assertive regarding matters
of policy and procedures as they ‘‘mature.’’ Topics not on the ‘‘radar screen’’ early in
planning will show up later. Sooner or later, one can expect groups to want policies
concerning rights to data, authorship, credits, presentations, and ancillary studies.
Planners need to have the mindset of marathon runners, always with still another
hill to climb. They have to maintain the flexibility and patience needed for repairing
plans that ‘‘come apart’’ or for revising plans that have been ‘‘set.’’ They need to recognize
the politics of decision making, and they need to be practiced in the art of compromise.
They need a sense of timing to be able to know when to ‘‘hold them’’ and when to ‘‘fold
them.’’ They need to be able to sense the tolerance of the group at any point in time for
addressing aspects of organization or operation. They need to know that even if the detail
is important, no good will be achieved if it is seen as a ‘‘detail’’ by the group.
xv
Explanatory Notes, Focus, and
Conventions
A clinical trial is an experiment done on human beings to determine the feasibility, safety,
or efficacy of a treatment.‘‘Clinical trial’’ as a publication type in PubMed is a Pre-planned
clinical study of the safety, efficacy, or optimum dosage schedule of one or more diagnostic,
therapeutic, or prophylactic drugs, devices, or techniques in humans selected according to
predetermined criteria of eligibility and observed for predefined evidence of favorable and
unfavorable effects.
In 2010 there were 36,650 full-length publications indexed in PubMed to ‘‘clinical
trial’’; 35,000 in English language journals. About half of the 35,000 (19,500) were also
indexed to the publication type ‘‘randomized controlled trial’’ (defined in PubMed as a
trial that involves at least one test treatment and one control treatment, concurrent enrollment
and follow-up of the test- and control-treated groups, and in which the treatments to be
administered are selected by a random process, such as the use of a random-numbers table).
About 20% (4000) of the randomized controlled trials were also indexed to the
publication type ‘‘multicenter study,’’ defined in PubMed as work consisting of a controlled
study executed by several collaborating institutions.
The language in this handbook is that of clinical trials. Hence, the designation
for a person enrolled in trials is patient. Treatment is the experimental variable. The
treatments may be test treatments or control treatments. The group of persons assigned to
receive a study treatment is referred to as a treatment group.
The methods and procedures of trials are the same across a broad spectrum of trials
largely without regard to size, length of treatment, or choice of treatments. The emphasis
herein is on comparative trials motivated by underlying states of clinical equipoise.33
Design and methods unique to developmental phase I and II trials are not covered.
Broadly, randomized trials are of two design types: parallel treatment designs
(designs in which treatment groups are comprised of different persons) or crossover
treatment designs (designs that provide for the administration of two or more study
treatments to the same person, one after another in a specified or random order, often
with a washout period between administrations). Much of what is covered herein applies
to either type of design, but with emphasis on parallel treatment designs.
Definitions in this handbook are adapted from Clinical Trials Dictionary:
Terminology and Usage Recommendations58 and a second edition by the same name
published by Wiley (2012). Etymologies are from Webster’s New Collegiate Dictionary.95,96
Terms defined in the handbook are listed under the heading ‘‘Definitions’’ in the
index.
xvii
xviii
E X P L A N AT O R Y N O T E S , F O C U S , A N D C O N V E N T I O N S
Sample materials represented in slides at the head of pages in the handbook are
from:
ADAPT
CAMP
CBET
CDP
GLT
NETT
SOCA
FGCRT
CRRT
HPCRT
MACRT
GCCRT
UGDP
Alzheimer’s Disease Anti-inflammatory Prevention Trial (primary
prevention trial)1
Childhood Asthma Management Program (treatment trial)11
Chemoprevention for Barrett’s Esophagus Trial (secondary prevention
trial)36
Coronary Drug Project (secondary prevention trial)18
Glaucoma Laser Trial (treatment trial)35
National Emphysema Treatment Trial (treatment trial)62
Studies of Ocular Complications of AIDS (umbrella structure for trials and
observational followup studies)80
Foscarnet-Ganciclovir CMV Retinitis Trial (treatment trial)85
Cytomegalovirus Retinitis Retreatment Trial (treatment trial)84
HPMPC Peripheral Cytomegalovirus Retinitis Trial (treatment trial)83
Monoclonal Antibody CMV Retinitis Trial (treatment trial)82
Ganciclovir Cidofovir CMV Retinitis Trial (treatment trial)81
University Group Diabetes Program (treatment trial)93
All the trials in the list above are multicenter and randomized, and they have
parallel treatment designs. All have person as the randomization unit except the GLT
with eye as the randomization unit. The list is a mix of investigator- and sponsor-initiated
trials. All are NIH-funded, some in conjunction with drug companies.
Trials are done all over the world, but counts of where they are done are hard to
come by. The closest that one can get to place of conduct with PubMed indexing is from
country of publication. (There are no codes to indicate where studies are done.) About
half (16,300) of the 35,000 2010 English language publications were published in U.S.
journals. Another third (9,700) were published in UK journals.
Location is important because trials are subject to different rules and regulations,
depending on place of conduct and funding source. Some regulations are distinctly United
States-centric for NIH-funded studies—for example, as with the mandate for valid
gender analysis88 and data sharing (http://grants.nih.gov/grants/guide/notice-files/NOT
-OD-03-032.html).
The structure for review and approval of trials differs by country. In the United
States, this responsibility is vested in IRBs of institutions housing investigators doing
trials. This means, for multicenter trials, that there can be as many IRBs as centers in the
trial. Presently, central review, e.g., as required with NCI-funded trials is in addition to
individual reviews. The structure in states of the European Union is centralized with the
Clinical Trials Directive (effective 4 April 2001). Part of its purpose was to harmonize
administrative procedures in conduct of clinical trials including a centralized review of
trials to streamline approval processes. A similar structure is needed in the United States
to streamline the IRB review process here.
Another area of difference is in licensure of drugs, biologics, and medical devices.
The United States has a centralized structure vested in the Food and Drug Administration.
Explanatory Notes, Focus, and Conventions
xix
The European Union has moved toward harmonizing differences in member states in
control and approval of medicinal products with the establishment of the European
Medicines Agency (formerly the European Agency for the Evaluation of Medicinal
Products).
The coverage of regulations, principally as detailed in Section VIII and XX, is
U.S.-centric. Covering the waterfront of regulations is beyond the scope of this effort.
The number of locales involved in trials can be seen from counts of registrations in
clinicaltrials.gov for intervention studies with at least one study site in the countries listed
(counts as of 20 December 2011):
United States
Canada
United Kingdom
Japan
Mexico
India
Singapore
48,871
8,002
5,473
1,910
1,431
1,641
761
Discussion of issues of organization, publication, treatment effects monitoring,
and policies (Sections XIV, XV, XVIII, and XIX) is predicated on the assumptions that:
1. Trials are under the stewardship of study investigators.
2. Trials have treatment effects monitoring committees/data and safety monitoring
committees that report directly to study leaders or simultaneously to sponsors and
study leaders.
3. Study investigators have unfettered rights to publication.
4. Centers in trials are free-standing and independent of study sponsors.
Abbreviations and Designations
A
AACTG
AD
ADAPT
ADE
ADR
adj
AE
AIDS
ant
Adult AIDS Clinical Trials Group
Alzheimer’s disease
Alzheimer’s Disease Anti-inflammatory Prevention Trial
adverse drug experience
adverse drug reaction
adjective
adverse event
acquired immune deficiency syndrome
antonym
B
b.i.d. twice a day
Bl, BL baseline
BMJ British Medical Journal
C
CAMP
CAST
CBET
CC
CCC
CDP
CL
CMV
CO
CONSORT
CRF
CRRT
CV
CV
Childhood Asthma Management Program
Cardiac Arrhythmia Suppression Trial
Chemoprevention for Barrett’s Esophagus Trial
coordinating center
clinical coordinating center
Coronary Drug Project
central laboratory
cytomegalovirus
chair’s office
Consolidated Standards of Reporting Trials
case report form
CMV Retinitis Retreatment Trial
cardiovascular
curriculum vitae
D
DCC
defn
defns
dL
DSMB
data coordinating center
definition
definitions
deciliter
data safety monitoring board
xxi
xxii
A B B R E V I AT I O N S A N D D E S I G N AT I O N S
E
E
E
EC
ECOG
ECG
expected
English
executive committee
Eastern Cooperative Oncology Group
electrocardiogram
F
F
FDA
FGCRT
fem
FEV
FTE
Fu, FU
FVC
French
Food and Drug Administration
Foscarnet–Ganciclovir CMV Retinitis Trial
feminine
forced expiratory volume
full-time equivalent
followup
forced vital capacity
G
GCCRT
Gk
GLT
g
GRASE
Ganciclovir–Cidofovir CMV Retinitis Trial
Greek
Glaucoma Laser Trial
gram
generally recognized as safe and effective
H
HCFA
HDFP
HIPAA
HIV
HPCRT
HPT
Health Care Financing Agency
Hypertension Detection and Followup Program
Health Insurance Portability and Accountability Act
human immunodeficiency virus
HPMPC Peripheral CMV Retinitis Trial
Hypertension Prevention Trial
ICMJE
ID
Id,
IDE
IND
INDA
IOP
IP
IRB
ITT
IU
International Committee of Medical Journal Editors
infectious dose
ID identification
Investigational Device Exemption
Investigational New Drug
Investigational New Drug Application
intraocular pressure
internet protocol
institutional review board
intention-to-treat
international unit
I
Abbreviations and Designations
J
JAMA Journal of the American Medical Association
L
L Latin
LVRS lung volume reduction surgery
M
MACRT
ME
MF
mg
ML
mmHg
MPS
MRFIT
Monoclonal Antibody CMV Retinitis Trial
Middle English
Middle French
milligram
Middle Latin
millimeters of mercury
Macular Photocoagulation Studies
Multiple Risk Factor Intervention Trial
N
n
NCI
NCR
NDA
NETT
NEI
NEJM
neut
NHLBI
NIH
NLM
NSAID
noun
National Cancer Institute
no carbon required
New Drug Application
National Emphysema Treatment Trial
National Eye Institute
New England Journal of Medicine
neuter
National Heart, Lung, and Blood Institute
National Institutes of Health
National Library of Medicine
non-steroidal anti-inflammatory drug
O
OE
OF
OHRP
OHG
OIt
OMB
ONF
ORI
observed
Old English
Old French
Office of Human Research Protections
Old High German
Old Italian
Office of Management and Budget
Old North French
Office of Research Integrity
O
P
PC personal computer
pdf probability distribution function
xxiii
xxiv
A B B R E V I AT I O N S A N D D E S I G N AT I O N S
PEFR
PI
pl
PO
POAG
pp
prn
prp
peak expiratory flow rate
principal investigator
plural
project office; project officer
primary open angle glaucoma
past participle
as needed
present participle
Q
QA quality assurance
QC quality control
R
RC
RFA
RFP
rt
reading center
request for application
request for proposal
related term
S
SAS
SC
sd, SD
SHEP
SOCA
SUSAR
syn
statistical analysis software
steering committee
standard deviation
Systolic Hypertension in the Elderly Program
Studies of Ocular Complications of AIDS
suspected unexpected serious adverse reaction
synonym
T
TCC
TEMC
t.i.d.
trt
treatment coordinating center
treatment effects monitoring committee
three times daily
treatment
U
UGDP
UK
URL
U.S.
USPHS
University Group Diabetes Program
United Kingdom
uniform resource locator
United States (of America)
United States Public Health Service
V
v verb
W
WHO World Health Organization
General
1 . Te r m i n o l o g y
3
1. Terminology
SLIDE
Terminology: Studies of Ocular Complications of AIDS
(SOCA)80
Default language
Patient for persons studied
Treatment (any treatment group including placebo treatment)
Outcome or outcome measure (as opposed to event, endpoint)
Variable (as opposed to parameter)
Center director (as opposed to principal investigator)
Study treatment (any of the assigned treatment regimens)
Test treatment (any of the assigned treatments, except control treatments)
Control treatment (placebo treatment)
Terms avoided
Treatment failure (presumptive)
Informed consent (wishful thinking in the absence of information to indicate that
consent is truly informed)
Endpoint (operational implications usually inconsistent with requirements for
continued followup)
Placebo (as an adjective, e.g., as in placebo patients, or as a synonym for no
treatment)
Subject (condescending)
Drop-in (at odds with analysis by original treatment assignment)
N A R R AT I V E
Good research requires precision of language. The practice of using different terms to
mean the same thing may be a valued practice for poets and writers and for radio and TV
announcers, but not for researchers. The use of different words to mean the same thing
in study protocols and publications is confusing.
Troublesome terms in trials include dropout, drop-in, endpoint, missed visit,
and treatment failure. Concepts not well understood and subject to misuse include the
notation of stratification versus subgroup analysis, subgroup analysis vs data dredging,
randomization, internal validity versus external validity, bias (e.g., selection bias vs.
treatment-related bias), and ‘‘statistical significance.’’
Some terms are best avoided in trials because of their multidisciplinary nature
and especially in multicenter trials. For example, investigator as a synonym for clinician
investigator (investigatorship is not limited to the clinical side of activities in trials)
4
I. GENERAL
and principal investigator (PI) in multicenter trials where there are as many ‘‘principal’’
investigators as there are centers.
QUESTIONS
• What practices do you intend to follow to standardize terminology?
• Do you have a list of terms to be avoided? If not, should you prepare such a list?
• Do you have operational definitions for enrolled (randomized), dropout, and missed
visits?
• Are you planning to produce a glossary of terms and definitions for inclusion in the
trial handbook? If yes, who will produce it and who will maintain it?
2. Definitions
5
2. Definitions
SLIDE
Definitions: Studies of Ocular Complications of AIDS (SOCA)
trials80
Dropout: Person missing three consecutive FU visits; person unable or unwilling to
continue under followup
Scheduled visit: Any visit required in the data collection schedule of the trial
Missed visit: A scheduled visit not made
Interim visit: Any followup visit after randomization over and above scheduled visits
Protocol deviation: Any departure from the treatment, examination, or data
collection protocol
Adverse drug reaction: A drug reaction that results in hospitalization, or
prolongation of hospitalization, or that has negative health implications for
a study patient
R E L AT E D E N T R Y
Terminology (page 3)
N A R R AT I V E
The expectation is that terminology will be problematic. Terms subject to misuse include:
Adverse event
Baseline
Baseline visit
Completed visit
Consent
Drop-in
Dropout
Eligible
Enrolled
Interim visit
Missed visit
Protocol deviation
Randomized
Randomizable
Reportable adverse event
Scheduled visit
Treated
Started on treatment
QUESTIONS
• Is there to be a glossary of definitions (recommended)? If so, who will have responsibility
for producing it; maintaining it?
• Are you keeping a list of terms to be defined as planning proceeds (recommended)?
• Have you looked at glossaries of definitions prepared and maintained by other groups
doing trials (recommended)?
3. Measurement Units
7
3. Measurement units
SLIDE
Measurement units: Childhood Asthma Management
Program (CAMP)11
Time: 12-hr clock, local time
Height: Centimeters
Weight: Kilograms
N A R R AT I V E
The choice of measurement units is more than just a ‘‘detail’’ in trials. One can expect
variation without standardization. Variation is likely with measures such as height and
weight (metric vs. imperial) and with various kinds of laboratory tests. Planners will have
to decide whether to live with the variation (and accommodate for it in the way data
collection forms are constructed) or to eliminate it by imposing unit standards and/or
by centralizing measurements wherever possible. Indeed, one of the reasons for central
laboratories in multicenter trials is for standardization of measurement. Standardization
is usually out of the question for determinations done at local hospital laboratories.
Even standardization of the unit of measurement for simple measures such as
height and weight can be complicated. If measures are to be made in centimeters and
kilograms, clinics may have to be supplied with equipment calibrated in metric units.
An appealing expedient is to allow measurement in the unit of choice of a clinic,
but also to require personnel to convert to the desired unit when completing study forms.
This approach is to be discouraged because data are not improved by ‘‘conversions.’’ It is
better, in such cases, to design forms to allow for unit variation in reporting and to make
the necessary conversion by computer when data are harvested for inclusion in the study
database.
The unit represented in presentations and publications should be as reported on
data forms. If conversions are made for standardization or to satisfy journal editors, the
publication should make note of the conversion.
4 . Tr i a l T y p e
9
4. Trial type
SLIDE
Trial type: Childhood Asthma Management Program
(CAMP)11
Multicenter
Randomized
Double masked
Placebo controlled
Parallel treatment structure
Treatment trial
N A R R AT I V E
Trial as a noun is from Anglo-French, trier, meaning to try. The term can mean58 : 1.
An experiment designed and carried out to provide information on the merits of one
treatment or procedure relative to another treatment or procedure; controlled trial. 2. Any
tentative or experimental procedure or treatment carried out, performed, or administered
to obtain data to arrive at some judgment or conclusion concerning the procedure or
treatment. 3. One of a number of replications of an experiment, process, or procedure
(e.g., Bernoulli trial). 4. The action or process of putting something to a test or proof. 5.
Something tried.
Typically, the modifier clinical is used in reference to trials done in clinical settings,
those involving people with a disease or an adverse health condition, and those involving
treatment of people for cure, amelioration, or prevention of disease or for betterment of
an adverse health condition.
Trials come in many forms. Hence, the term trial or clinical trial, in the absence of
other descriptors or modifiers, is not informative. Some of the dimensions of classification
listed below overlap. For example, randomized trials are, by definition, controlled. Hence,
controlled —e.g., as in randomized controlled trial —is redundant.
Also, any trial involving two or more study groups is comparative, but only
those involving simultaneous enrollment of persons to the different treatment groups are
comparative, concurrent. Trials involving use of historical controls for comparison are
comparative, nonconcurrent.
Center
Single center
Multicenter
Comparison
Comparative, concurrent
10
I. GENERAL
Comparative, nonconcurrent
Noncomparative
Treatment assignment
Randomized
Nonrandomized
Deterministic (e.g., as in play the winner schemes)
Best medical judgment
Control
Controlled (e.g., via use of a placebo or via use of a ‘‘standard’’ treatment)
Uncontrolled
Mode of treatment administration
Unmasked
Single-masked
Double-masked
Treatment structure
Parallel, uncrossed
Parallel, crossed
Crossover
Sample size
Fixed
Sequential
Phase
I
II
I/II
III
IV
Post marketing surveillance
Purpose
Safety
Efficacy
Focus
Treatment
Prevention
Primary
Secondary
4 . Tr i a l T y p e
Class
Pilot
Feasibility
Superiority
Equivalence
Demonstration
11
5. Design and Flow Schematics
13
5. Design and flow schematics
SLIDE
Design schematic: Foscarnet–Ganciclovir CMV Retinitis Trial
(FGCRT)86
Location and extent
of retinitis
Zone 1 or Zone
2, 3 (≥ 25%)
Zone 2, 3
(< 25%)
Ρανδοµιζε
1:1
Φοσ : Γχϖ
Treatment
Preference
N A R R AT I V E
Consider using graphic representations for depicting design and flow processes. In addition
to schematics of the design, as pictured above, schematics can be used to depict steps
and decision points in screening patients for enrollment, the ordering of procedures
performed in relation to a given examination, the steps in preparing and shipping blood
to a central laboratory, and the steps in receiving and processing data for inclusion in the
study database.
Avoid unnecessary clutter and words for crispness and simplicity.
6. Design and Operating Principles
15
6. Design and operating principles
SLIDE
Studies of Ocular Complications of AIDS (SOCA) trials80
Common study protocol; all clinics expected to participate
Randomization as line of demarcation between the baseline and followup periods
Persons counted as enrolled when randomized
Analysis by treatment assignment
Contiguous time windows for followup visits
Followup regardless of course of treatment
R E L AT E D E N T R Y
Counting and analysis rules (page 17)
Typical design and operating principles
• Common study protocol (a specification in multicenter trials in which all clinics
are expected to follow the same protocol; important in that the protocol has to
be written with a common understanding; requirement precludes substudies as a
means of accommodation, i.e., studies in which only certain clinics participate)
• Persons counted as enrolled when randomized
• Person counted as randomized when treatment assignment is revealed to clinic
personnel
• Time of randomization used to mark end of the baseline period of data collection
and the start of the followup period of data collection
• Contiguous time windows for followup visits (operationally means a visit may not
be done before the designated window opens and is counted as missed if not done
within the designated time window)
• Followup regardless of course of treatment (operational impact is to require clinics
to continue to follow persons even if they are no longer receiving the assigned
treatment)
• Followup regardless of intercurrent events (operational implication is to require
clinics to continue to follow persons once enrolled regardless of intercurrent events)
• Analysis by treatment assignment
7. Counting and Analysis Rules
17
7. Counting and analysis rules
R E L AT E D E N T R Y
Design and operating principles (page 15)
N A R R AT I V E
Counting rules
1. Person counted as randomized the moment treatment assignment made known to
clinic personnel
2. All persons randomized counted to the treatment group to which assigned regardless
of course of treatment
3. All events occurring from the moment of randomization forward in time counted
4. Events counted to the assigned treatment group regardless of treatment being
administered at the time of the event and regardless of degree of treatment
compliance at the time of the event
Analysis rules
1. Primary analysis by treatment assignment
2. Analyses for outcome subset (e.g., deaths due to cardiovascular causes) preceded by
analyses of the entire outcome set (e.g., deaths, regardless of cause)
3. Analyses for composite outcome preceded by analyses for the component parts of
the composite outcome
4. Subgroup analyses limited to variables observed at or prior to randomization
The rules outlined above cannot be satisfied if:
1. Followup and data collection terminates when a person experiences a nonfatal
‘‘endpoint’’ (see page 39 for usage note)
2. Persons are dropped or withdrawn from the trial when they are no longer able or
willing to take or receive the assigned treatment
3. There are not continuing efforts to collect minimal information on dropouts
Questions relevant to formulating rules
• When is a person considered enrolled?
• What is the event or act defining enrollment?
• Is the baseline period of observation closed when the person is randomized?
(Reminder: A ‘‘yes’’ means that any observation made after randomization, even
moments after randomization, is not used as baseline data.)
• Is followup dependent on treatment or compliance? (Reminder: A ‘‘yes’’ implies a
likely violation of one or more of the rules listed above.)
18
I. GENERAL
• Will clinics be allowed to drop persons from followup when they have an ‘‘endpoint’’
or when treatment ‘‘fails’’? (Reminder: A ‘‘yes’’ implies a likely violation of one or
more of the rules listed above.)
• Will an effort be made over the course of trial to remain in touch with dropouts
and to provide minimal information on them including vital status?
8. Multi-Study Umbrella Name
19
8. Multi-study umbrella name
R E L AT E D E N T R Y
Study name (page 21)
DEFINITIONS
multi-study n - A study having two or more studies performed under the same
organizational structure; multi-trial when studies are trials. Usage note: Not to be
confused with a study having a series of substudies.
umbrella study name n - A study name encompassing a number of studies, e.g., Studies
of Ocular Complications of AIDS.80
N A R R AT I V E
Umbrella names are akin to family names, and study names are akin to given names, e.g.,
Studies of Ocular Complications of AIDS as the family name and Foscarnet–Ganciclovir
CMV Retinitis Trial a given name to yield ‘‘Studies of Ocular Complications of AIDS:
Foscarnet–Ganciclovir CMV Retinitis Trial.’’
A fair number of multi-trials emerge from the structures created at the outset
for doing a single trial, e.g., as with the Macular Photocoagulation Study (MPS). The
MPS came into being as a result of investigator initiative to evaluate laser-induced
photocoagulation of neovascularization associated with age-related macular degeneration.
Ultimately, the Macular Photocoagulation Research Group carried out several trials under
the MPS structure.48 – 50 One surmises, with the perspective of hindsight, that investigators
would have preferred to have had an umbrella name for the collection of trials performed.
As it was, they had to use the name used for the first trial also as the umbrella name;
sometimes confusing.
Often the name of a group comes to serve the function of an umbrella name, e.g.,
as with the Eastern Cooperative Oncology Group (ECOG). Originally the name referred
to a group of collaborating oncologists from the eastern region of the United States, but
now it refers to a network of researchers from public and private institutions from across
the country and beyond.
Originally the Adult AIDS Clinical Trials Group (AACTG) was the surname for
a group doing AIDS trials in adult populations, but now it serves as the name for a much
broader set of activities.
Names, once established, are difficult to change—a fact to be kept in mind when
establishing a name.
Reminders and recommendations
•
•
•
•
Choose in favor of brevity, crispness, and succinctness.
Avoid restrictive terms likely to render a name obsolete later on.
Choose a neutral, nonpromotional, name.
Consider in conjunction with likely names of particular studies; avoid redundancies
or contradictory terms when used in conjunction with study names.
20
I. GENERAL
• Keep in mind that the name chosen will be used in publication titles.
• Keep other likely uses in mind, as in funding applications, presentations, and other
writings.
• Keep contractions of name and acrostics or acronyms in mind when choosing.
• Avoid choosing to create a desired or ‘‘cute’’ acronym.
• Avoid names producing undesirable shortened name from letters of the name (a
meaningless sequence of letters in one language can have a specific meaning in
another).
9. Study Name
21
9. Study name
R E L AT E D E N T R Y
Multi-study umbrella name (page 21)
N A R R AT I V E
A study name should be informative, succinct, accurate, and telegraphic. The preferred
base term in the name is trial, because it is the most accurate descriptor of the study.
Other base terms like study (e.g., Coronary Artery Surgery Study20 ), project (e.g., Coronary
Drug Project 18 ), or program (e.g., University Group Diabetes Program93 ) are used, but they
are less informative than trial.
The name should include appropriate modifiers, such as randomized, controlled,
and masked or blind to characterize the nature of the trial. The name may also include
terms to characterize the phase of the trial (phase I, II, III, or IV) and, perhaps, terms
intended to convey information about the treatment structure (e.g., parallel, crossover,
or factorial). The name should contain terms intended to indicate the type of treatments
being tested (e.g., drugs, vaccines, diets, etc.) and the condition or disease under study
(e.g., hypertension, diabetes, prostate cancer). Also the name may contain demographic
terms to indicate the population enrolled (e.g., women, elderly, African-Americans).
The name should remain accurate in the presence of changes to the study design
during conduct. Everyday life is rich in names that have been sapped of their original
meaning; Big Ten, Motel 6, Dime Savings, and Dollar Car Rental to name a few. The
need for accuracy in names of trials argues for staying clear of descriptors related to
selection criteria because they may change over the course of enrollment.
One has to be careful in the use of descriptors of the treatment being tested. The
term drug in Coronary Drug Project was well chosen because all the treatments tested were
drugs (if one is willing to accept placebo—the control treatment—as a ‘‘drug’’). One
should steer clear of such descriptors if there is likelihood of adding treatments during the
trial that are not members of the class reflected in the name.
Names indicative of site (e.g., Oslo Diet and Exercise Study) are useful only so long
as the trial remains confined to the site. The term National or International to indicate
spread is questionable. Both terms are subject to being rendered inaccurate with expansion
of ‘‘National’’ to ‘‘International’’ or contraction from ‘‘International’’ to ‘‘National’’ with
the loss of sites during the trial.
Redundant terms, such as National and Cooperative in National Cooperative
Gallstone Study44 or University and Group in University Group Diabetes Program,93 are
best avoided. Repeating a term, e.g., as with Study in African American Study of Kidney
Disease and Hypertension Pilot Study,101 should be avoided if the reference is to a single
study.
Most study names are shortened for everyday use. Hence, the National Cooperative
Gallstone Study is also the NCGS, the Coronary Drug Project is also the CDP, and the
University Group Diabetes Program is also the UGDP.
Sometimes groups choose study names to generate pronounceable words from
letters of the names (acronyms). However, that practice is questionable, to the extent that
22
I. GENERAL
it leads to contrived study names. The practice should be to select an appropriate name
and then the shortened name, not the reverse.
Reminders and recommendations
•
•
•
•
•
Choose in favor of brevity; the fewer the characters, the better.
Choose being mindful of the use of the name in publications and study documents.
Choose in favor of a neutral, nonpromotional name.
Consider in conjunction with use in mastheads of study publications.
Keep likely uses in mind, as in funding applications, publications, presentations,
and other study documents.
• Keep likely contractions of name and acronyms in mind when choosing.
• Avoid choosing to create a desired or ‘‘cute’’ acronym.
• Avoid unnecessary words.
Characteristics of a good name
• Succinct
• Neutral one not favoring a particular treatment over another
• Robust; does not become obsolete or inaccurate with changes to the trial, e.g., as in
use of National when the study is expanded to include sites in other countries
• Indicates nature of treatment and population being studied
• Includes the term trial and other currency terms like randomized
• Does not contain unprintable graphic characters
• Does not contain abbreviations
Numbering
• Generally unnecessary
• Avoid if trial is a descendent of one done by another group
• Questionable if follow-on trial involves a distinctly different or expanded study
population in which treatment regimens or treatment groups are different
• Numbering (e.g., the XYZ Trial II) acceptable when the trial is largely a repeat of
the previous namesake or where the treatments are the same but the population
is more restrictive (e.g., as in PARIS II43 ); otherwise use other means to show
connection, e.g., as the Coronary Drug Project Aspirin Study17
• Things to remember about numbering:
❑ Numbering helps remind readers of other related publications.
❑ The connection may not be advantageous if the precursor study was a ‘‘bust.’’
❑ The connection can serve to erode trust in the precursor study if the one being
named turns out to be a ‘‘bust.’’
❑ Numbering usually indicates previous success; Rocky II came about because of
the success of Rocky; in regard to ships there was a Queen Elizabeth 2 (QE2),
but no Titanic 2.
9. Study Name
23
Shortened names
• Useful
• Avoid creating study names to produce pronounceable acronyms.
• Focus on name first, then on producing a shortened name; avoid the reverse of
starting with an acronym and then fashioning a name to match the acronym.
• Stress test before adopting (i.e., by use in different types of settings and by screening
for different meanings in other settings or languages).
Design Specifications
10. Objective
27
10. Objective
SLIDE
Objective: Coronary Drug Project (CDP)18
To evaluate the efficacy of different lipid-influencing drugs in prolonging life of
men with a history of MI
R E L AT E D E N T R Y
Specific aims (page 29)
N A R R AT I V E
The objective, in the case of a trial, is the reason for undertaking it. Typically, the reason
is to assess the efficacy, or the safety and efficacy, of a named treatment or set or class of
treatments.
The objective is limited to issues of safety or to determination of dosage in phase I
and II trials. It relates to issues of feasibility in pilot or feasibility trials, as well as ‘‘proof’’
or ‘‘demonstration’’ in the case of demonstration trials.
The objective should be written with an appreciation of the limitations that
investigators are likely to face regarding their ability to recruit, treat, and follow persons
in the trial.
Objectives change over the course of time. The evolution is toward greater
specificity as planning proceeds to implementation. Usually, objectives are stated in more
general (and sometimes grandiose) fashion in funding initiatives than as written when the
trial is implemented.
The objective should reflect the realities and limitations of the trial. Therefore, it
must be revised and refined to reflect the facts and limitations of the trial, as they are
imposed or become known. In this sense, ‘‘planning’’ continues over the course of the
trial. Changes to the protocol when the trial is underway may require changes in the
statement of objective.
Normally, there will be only one objective. However, there are occasions when it is
necessary or expedient to list several. In such cases, they should be arranged in descending
order of importance relative to the primary objective.
The Coronary Drug Project18 was a grant-funded, investigator-initiated trial. Its
primary objective was as stated in the slide above. Secondary objectives were:
1. To characterize the natural history and clinical course of coronary heart disease
2. To develop methods and procedures suited to the design and conduct of long-term,
large, multicenter clinical trials
QUESTIONS
• Is the objective realistic, given the scope of the trial and resources available?
• Is the objective succinctly stated?
28
I I . D E S I G N S P E C I F I C AT I O N S
• Is it ‘‘stand alone,’’ i.e., understandable and meaningful by itself, without other
supporting statements or documents?
• Does it name the treatment or class of treatments to be tested?
• Does the statement indicate the outcome or measure used to assess the treatments?
• Does the statement indicate specify the population to be treated?
• If there are multiple objectives:
❑ Is the primary objective (first in the list) the fundamental reason for undertaking the
trial?
❑ Are they arranged in descending order of importance relative to the primary
objective?
❑ Are the objectives compatible?
❑ Are they relevant and realistic?
11. Specific Aims
29
11. Specific aims
SLIDE
Specific aims: Studies of Ocular Complications of
AIDS—1988 grant application
• Develop and maintain core structure for support of multicenter studies
• Design and conduct multicenter randomized trials of treatments for AIDS-induced
ocular complications
• Design and conduct multicenter epidemiological studies of persons with AIDSinduced ocular complications
R E L AT E D E N T R Y
Objective (page 27)
N A R R AT I V E
Typically, at least in funding initiatives, one lists specific aims to be accomplished in
addressing the stated objectives. Indeed, a good check before submission is to make certain
that the aims are relevant to the objectives and that methods and procedures for achieving
the aims are spelled out.
QUESTIONS
•
•
•
•
•
Do the aims relate to the stated objectives?
Are they realistic?
Are they consistent with available resources and scope of activities planned?
Are they succinctly stated?
Are they several in number? If yes, can the number be reduced by combining,
rewording, or recasting?
• Are the methods and procedures for achieving the specific aims spelled out?
12. Experimental Variable
31
12. Experimental variable
R E L AT E D E N T R Y
Study treatments (page 75)
DEFINITIONS
experimental variable n - A variable that denotes the levels of a factor or treatment
applied in an experiment. The value will be binary where the factor or treatment is used
or not used; the value 1 indicates presence or use of the factor or treatment, and the value
0 denotes absence of the factor or treatment; treatment variable in trials.
treatment variable n - [trials] independent variable; experimental variable; treatment
assignment
N A R R AT I V E
The experimental variable in randomized trials is treatment assignment. The variable
denotes those aspects of treatment that are unique to the assignment and that are
administered as indicated in the treatment protocol.
1 3 . Tr e a t m e n t U n i t
33
13. Treatment unit
R E L AT E D E N T R I E S
Randomization unit (page 155), Sample size: Calculation (page 259)
DEFINITIONS
paired treatment design n - A parallel treatment design in which treatment units are
paired and assigned to treatment as members of a block. The pairing may be a part of the
design, as in some sequential designs, or may be imposed simply as a means of variance
control. The pairing may be arbitrary (e.g., patients paired on the basis of their arrival at
a clinic) or natural (e.g., the use of twins or paired body parts, such as hands or eyes; see
Glaucoma Laser Trial,35 for example, based on eyes).
treatment unit n - [trials] The unit to which treatment is applied; usually person or part
of a person; sometimes a group of persons, e.g., as represented in a household, census
tract, village, or community.
N A R R AT I V E
The options for treatment units are:
Aggregate of persons (e.g., census tract, town/village, school, household, siblings, or
twins)
Person
Person part (e.g., eye, tooth, hand, or foot)
C O N D I T I O N S FAV O R I N G A G G R E G AT E O F P E R S O N S A S T H E
T R E AT M E N T U N I T
• The effect of treatment extends beyond individual persons (e.g., in a diet trial
requiring a change in cooking practices in a household to achieve goals of treatment).
• Costs of administering treatment on per person basis are prohibitive or impractical.
• Outcome measure is one involving aggregates of persons (e.g., change in infection
rate by community).
• Treatment is administered at aggregate level.
C O N D I T I O N S FAV O R I N G P E R S O N A S T H E T R E AT M E N T U N I T
•
•
•
•
•
•
•
•
Organic disease as focus of treatment
Treatment trials
Secondary prevention trials
Drug trials
Surgery trials
Treatments carrying risks to persons receiving them
Clinical event as the primary outcome measure
Treatments that cannot be safely administered in the aggregate
34
I I . D E S I G N S P E C I F I C AT I O N S
C O N D I T I O N S FAV O R I N G P E R S O N PA R T A S T H E T R E AT M E N T
UNIT
•
•
•
•
•
Body part amenable to treatment
Disease or health condition isolated to individual body part
Study treatments with little or no ‘‘carryover’’ to matching body parts
Study treatments devoid of systemic effects
Outcome measures based on the state of or condition of body part
COMMENT
An aggregate treatment unit is required in trials involving mass treatment (e.g., in trials
where communities are exposed to different kinds of health messages intended to affect
changes in behaviors at the community level). Aggregate units are preferred over persons
as the treatment unit when it is impractical or costly to deliver treatment at the level
of person (e.g., as with fluoridation of water supplies or in use of enriched flour as a
treatment in impoverished settings).
The majority of trials published have person as the treatment unit. Of the 291
full-length publications indexed to the publication type ‘‘randomized controlled trial’’
in PubMed published in the BMJ, JAMA, Lancet, and NEJM in 2006, all but 15 had
person as the assignment unit.52 From a statistical perspective, per person designs are
more efficient than designs with aggregate assignment.
The virtue of designs involving part of a person lies in efficiency. The number of
persons required for study will be less than for designs with person as the treatment unit
if treatment effects do not carryover to other matching body parts. The limitation is that
most drugs or topical treatments have systemic effects that have the potential of carryover.
14. Primary Outcome
35
14. Primary outcome
SLIDE
Primary outcome measure: Studies of Ocular Complications
of AIDS (SOCA) trials
FGCRT85 Composite (death, progression of retinitis, and visual loss)
CRRT84 Composite (death, progression of retinitis, and visual loss)
MACRT82 Progression of retinitis
HPCRT83 Progression of retinitis
GCCRT81 Composite (visual acuity and field loss)
R E L AT E D E N T R Y
Outcome measures (page 39)
DEFINITIONS
design variable n - The variable used for determining or justifying sample size in a trial.
Usage note: Not to be used interchangeably with primary outcome, endpoint, or primary
endpoint. Generally, the design variable denotes an important measure, often the primary
outcome measure, but not always.
primary outcome n - 1. [trials] The event or condition a trial is designed to treat,
ameliorate, delay, or prevent. 2. The outcome of interest as specified in the primary
objective. 3. The foremost measure of success or failure of a treatment in a trial. 4. The
actual occurrence of a primary event in a study participant. 5. Primary endpoint (not
recommended; for reasons see usage note for endpoint; page 39). Usage note: Not to
be used interchangeably with design variable. The modifier, primary, should be used
sparingly, since use depends on perspective. Most trials involve observations of more than
one outcome, each with a different implication for well-being or life.
primary outcome measure n - 1. That measure in a trial that is of importance in its
design (e.g., the one used for the sample size calculation) or in primary analyses; may be a
continuous measure or an event depending on the trial. syn: primary outcome variable 2.
design variable
primary outcome variable n - [trials] The outcome variable regarded as key in the design
or analysis of a trial. Generally, the variable used for sample size calculations or the one
considered to be of primary importance in analyses performed. rt: design variable
N A R R AT I V E
Usually the primary outcome measure is named or telegraphed in the statement of the
objective, e.g., as in the example on page 27.
The variable used may be dictated by the sponsor. For example, a drug company
is likely to require that the primary outcome measure be the one it has targeted as relevant
to licensure of a drug. However, even if planners have the freedom to choose the variable,
they will be constrained by reality.
36
I I . D E S I G N S P E C I F I C AT I O N S
There is a kind of ‘‘bait and switch’’ process that goes on during selection of a
primary outcome. Initially, planners will be desirous of doing an unassailably ‘‘definitive’’
trial. Accordingly, their first thought will be to have a clinical event as the primary outcome
measure. However, their resolve is likely to weaken as they learn of the implications of
the choice. ‘‘Softer’’ outcomes of less clinical relevance will be seen as more appealing
when measured against required sample size and length of trial requirements. The ‘‘work
around’’ strategies, when confronted with the harsh realities of size or time, can be any of
the following:
•
•
•
•
•
•
•
•
•
Abandon plans for the trial.
Work to increase funding in order to meet original sample size requirements.
Plan to treat and follow people for a longer period of time.
Change the specifications for sample size calculation to yield a smaller sample size.
Limit enrollment to persons at high risk of the outcome (risk concentration).
Switch to less clinically relevant outcomes.
Switch from a ‘‘hard’’ outcome to a ‘‘soft’’ outcome.
Use a surrogate outcome as the primary outcome measure.
Use a composite of several different outcomes (e.g., death or any of several different
morbid events).
Death or a major morbid event has obvious clinical relevance, but is a reasonable
choice as the primary outcome only when the death rate or morbid event rate is expected
to be high enough to provide a reasonable chance of detecting a treatment difference if
one exists for a feasible sample size. The lower the rate, the larger and longer the trial.
The temptation invariably is to gravitate to a variable that enables one to do the
trial in the shortest possible time with the fewest patients possible, especially to one that
can be argued to be a surrogate for a clinically relevant outcome.5,70,100 To be useful as
a primary outcome measure, the outcome should be predictive of the outcome for which
it substitutes. Correlation with the outcome of interest is a necessary but not sufficient
condition. The correlation must be the result of the surrogate being in the causal chain
leading to the clinical event. The clinical relevance of a surrogate outcome measure, such
as a laboratory test, is difficult to gauge without the causality link.
The use of a composite measure is appealing primarily as a route to reducing
sample size requirements. The downside is that treatment differences are difficult to
interpret. If there is a treatment difference, one does not know if it is due to one of the
measures or a combination of measures. Likewise, in the absence of a difference, one
does not know if it is due to a combination of positive and negative effects that, when
combined, serve to produce a nil result.
The temptation to change screening and eligibility criteria to move the trial in the
direction of a risk concentration design can be great when the anticipated event rates are
‘‘low.’’ However, it is a move to be taken with caution and is a move that has obvious
cost implications with regard to the efforts devoted to screening (see Eligibility criteria
(page 243) and ref. 54).
14. Primary Outcome
37
QUESTIONS
• Is the variable chosen of obvious clinical relevance? If no, what is the rationale for
choice?
• If the outcome is a surrogate, what is it a surrogate for? If it is a surrogate, does it
meet the tests to justify use as a surrogate? (see Boissel et al.,5 Prentice,70 and Wittes
and Lakatos100 ) If no, choose a different outcome.
• Is the variable bias robust (i.e., objectively measured and reported with little or no risk
of bias)? If no, how are you dealing with the lack of robustness in planning and design?
• Is the variable a composite of several variables? If yes, will the component parts be
reported and analyzed separately (see Counting and analysis rules; page 17)
15. Outcome Measures
39
15. Outcome measures
SLIDE
Outcome measures: Coronary Drug Project (CDP)18
Primary
Death
Secondary
CV deaths
Coronary deaths
Myocardial infarction
Stroke
Acute coronary insufficiency
Transient ischemic attacks
Peripheral arterial occlusion
Peripheral arterial embolism
Pulmonary embolism
Arterial aneurysm
Tertiary
Cardiomegaly
Congestive heart failure
Intermittent claudication
Thrombophlebitis
R E L AT E D E N T R Y
Primary outcome (page 35)
DEFINITIONS
endpoint n - 1. An outcome measure recorded as an event (e.g., myocardial infarction or
death) that results in termination of treatment and followup. 2. Any outcome measure
recorded as an event regardless of whether it results in an alteration of treatment or
followup. 3. Any outcome measure recorded as an event. Usage note: Best avoided
because of misuse and potential for confusion. Most ‘‘endpoints’’ are not ‘‘ends’’ in regard
to treatment or followup. Often protocols are written calling for followup and continued
treatment in the presence of intercurrent events unless treatment is contraindicated. As a
rule, there are no endpoints in this operational sense of usage, except death. Use of the
term can cause personnel at clinics to stop treatment and followup on the occurrence of
an ‘‘endpoint’’ if they regard the term as having operational meaning.
40
I I . D E S I G N S P E C I F I C AT I O N S
outcome n - [trials] 1. An event or ()measure observed for a particular person or treatment
unit in a trial during or following treatment that is used to assess the safety or efficacy of
a study treatment. 2. Primary or secondary outcome measure, especially one measured or
recorded as an event; outcome variable. syn: endpoint (not recommended) Usage note:
Preferred to endpoint; for reasons see endpoint.
outcome event n - [trials] 1. An outcome measure that is binary, e.g., death or a morbid
event. 2. The event of primary interest in a trial with events as outcome measures; usually
the event used for sample size calculations or the one receiving the most attention in data
analyses.
outcome measure n - 1. [trials] An observation variable recorded for a treatment unit at
one or more time points after enrollment for the purpose of assessing the effect of a study
treatment. 2. A measurement or observation used to measure the effect of an experimental
variable in an experiment. syn: outcome variable
outcome variable n - [trials] An observation variable recorded for persons (observation
units) at one or more time points after enrollment for the purpose of assessing effects of
the study treatments. syn: outcome measure
N A R R AT I V E
Most trials involve observation of different outcome measures and continued observation
regardless of course of treatment or adherence to treatment.
Arrange measures in descending order of clinical relevance. The list is important
in planning for data collection.
QUESTIONS
• Does the list include all likely events even if unlikely to be treatment related?
• Does the list include general indicators of morbidity even if rare and unrelated to
treatment?
• Does the list include hospitalizations regardless of reason?
• Does the list include outcomes considered to be indicators of ill-effects such as
adverse drug reactions?
• Does the list include measures of quality of life?
• Is the list arranged in descending order of importance?
• Does the list include death (even if unlikely)?
• Are there suitable definitions for the outcomes listed?
• Do the means exist to diagnose outcome events represented in the list?
16. Design Synopsis
41
16. Design synopsis
SLIDE
Alzheimer’s Disease Anti-inflammatory Prevention Trial
(ADAPT) Design Synopsis1
Objectives
• Primary objective
❑ To evaluate the efficacy of naproxen sodium (Aleve) as compared
to placebo, and of celecoxib (Celebrex) as compared to placebo, for
prevention of Alzheimer’s disease (AD)
• Secondary objectives
❑ To determine whether the study treatments can attenuate cognitive decline
associated with aging
❑ To compare the safety of the study treatments with placebo and with each
other regarding mortality and the occurrence of side effects
Design
•
•
•
•
•
•
•
•
•
•
Multicenter
Randomized
Masked
Placebo-controlled
Parallel treatments
Fixed sample size design (Sample size goal: 2625)
Fixed assignment ratio (1:1:1.5; Celecoxib:Naproxen:Placebo)
Followup independent of treatment compliance
Followup to common closing date
Planned period of followup: 7 yr
Treatments
• Celecoxib, 200 mg b.i.d.
• Naproxen sodium, 220 mg b.i.d.
• Placebo (double dummy design)
Sample size
Type: Calculated
Design variable: AD incidence
Calculated sample size: 2625 (Celecoxib:Naproxen:Placebo = 748, 748, 1129);
accounting for losses due to death; losses to followup assumed to be 5%/yr
42
I I . D E S I G N S P E C I F I C AT I O N S
Assumptions
= 30% reduction in AD incidence
α = 0.05 (2-tailed)
β = 0.20
Power = 1 − β = 0.80
Treatment duration: 5–7 yr
Achieved sample size: 2,528
Achieved treatment duration: 0–3.75 yr
Stratification
• Clinic
• Age (three age groups)
Masking
• Double-masked: Treatment assignment masked to participants and clinic
personnel, including clinicians, neuropsychologists, and psychometricians
• Masked assessment of outcome assessments
• Unmasked treatment effects monitoring
Inclusion criteria
• Age 70 years or older at time of eligibility evaluation visit
• Family history of one or more first-degree relatives with Alzheimer-like
dementia
• Collateral respondent available to provide information on cognitive status of
study participant and to assist with monitoring of use of study medications if
necessary
• Sufficient fluency in written and spoken English to participate in study visits
and neuropsychological testing
• Willingness to limit use of the following for the duration of treatment:
–
–
–
–
vitamin E at doses > 600 IU/day
non-aspirin NSAIDs or aspirin at doses > 81 mg/day
histamine H2 receptor antagonists
Ginkgo biloba extracts
• Intention and ability to participate in regular study visits
• Consent
Exclusion criteria
• History of peptic ulcer complicated by perforation, hemorrhage, or obstruction
• History of peptic ulcer with symptoms within 4 weeks of enrollment
16. Design Synopsis
43
• Hypertension, anemia, liver disease, or kidney disease (per guidelines in
ADAPT Handbook)
• History of hypersensitivity or anaphylactoid response to sulfonamide antibiotics
(e.g., Bactrim, Septra, Gantrisin, Gantanol, Urobak), or to aspirin or other
NSAIDs (e.g., ibuprofen, diclofenac, celecoxib, naproxen)
• Concurrent use of warfarin, ticlopidine, or any other type of anti-coagulant
• Concurrent use of systemic corticosteroids
• Use of ≥ 4 doses/wk of any of the following in the 14 days prior to enrollment:
❑ histamine H2 receptor antagonists
❑ non-aspirin NSAIDs or aspirin use > 81 mg/day
• Plasma creatinine ≥ 1.5 mg/dL
• Enrollment in other trials or studies likely to interfere with ADAPT procedures
or treatments
• Cognitive impairment or dementia according to criteria specified in ADAPT
Neuropsychology Manual
• Alcohol dependence or abuse
• Any condition that, in the opinion of the study physician, makes it medically
inappropriate or risky for participant to enroll in ADAPT
Criteria for study treatment termination
• Participant develops complications of an ulcer, such as gastrointestinal bleeding,
perforation, or obstruction
• Any condition that, in the opinion of the study physician, makes it medically
inappropriate or risky for the participant to continue on study treatment
Criteria for study treatment interruption
• If the participant develops any signs or symptoms suggestive of an ulcer or
kidney disease; participant withdrawn from study treatment pending evaluation
by study physician and primary care physician; participant put back on study
treatment at the discretion of the study physician
• If the participant develops an elevated blood pressure, creatinine, or potassium
or a decreased hematocrit, participant referred for evaluation and treatment;
study physician determines whether it is necessary to interrupt study treatment
• If participant requires corticosteroids, or warfarin, ticlopidine or any type of
anti-coagulant, study treatment interrupted for duration of usage
• If the participant taking ≥ 4 doses per week of any of the following, study
treatment interrupted:
❑ vitamin E (at doses > 600 IU/day)
❑ non-aspirin NSAIDs or aspirin > 81 mg/day
• Participant enrolls in trial that is likely to interfere with ADAPT procedures or
affect treatment outcomes
44
I I . D E S I G N S P E C I F I C AT I O N S
Data collection schedule
• Eligibility evaluation visit
• Enrollment visit
• In-person followup visits at 1 month and 6 months after enrollment and every
6 months thereafter
• Cognitive assessment visits every 12 months after enrollment
• Telephone contacts at 3 months after enrollment and every 6 months thereafter
• Participant initiated contacts, as needed
• Dementia evaluation visits, as needed
Outcomes
•
•
•
•
Incidence of Alzheimer’s disease
Change in cognitive measures
Mortality
Adverse events
N A R R AT I V E
Design synopses are tabular outlines of the design and operating features of a trial, as
represented at a point in time. To be useful, they have to be updated to reflect changes as
the trial proceeds.
Funding
1 7 . Ty p e o f F u n d i n g I n i t i a t i v e
47
17. Type of funding initiative
SLIDE
Funding initiative: Clinical centers, National Emphysema
Treatment Trial (NETT)62
Type of initiative: Request for proposal
RFP no: RFP-NIH-NHLBI-HR-97-01
Title: Clinical centers for lung volume reduction surgery for
emphysema: A multicenter assessment and prospective
patient registry
Related title: Clinical coordinating center for lung volume reduction
surgery for emphysema; RFP-NIH-NHLBI-HR-97-01
Issuer: National Heart, Lung, and Blood Institute
Date of issue: 3 June 1996
Letter of intent: 3 July 1996
Due date and time: 5 August 1996; 4:30 pm
No of awards to be made: Multiple
Small business set aside: None
Start date: 20 December 1996
End date: 19 December 2003
R E L AT E D E N T R I E S
Funding: Terminology (page 51), Funding: Type (page 59), Funding: Initiative (page 61)
N A R R AT I V E
Trials can be thought of as investigator-initiated or sponsor-initiated and as being grant
or contracted funded.
Investigator-initiated
Grant funded (R01)
Grant funded (U10; cooperative agreement)
Contract funded
Sponsor-initiated
Grant funded (U10; cooperative agreement)
Contract funded
The usual route to investigator-initiated trials is via unsolicited proposals to wouldbe sponsors. The sponsors may be drug companies or vendors of proprietary products,
private foundations, or governmental agencies.
The route to sponsor-initiated trials is by solicitations from sponsors. The NIH
solicits applications via release of requests for applications (RFAs) or requests for proposals
(RFPs); see page 56 for definitions. As a rule, RFAs are less instructive as to the nature of
trials to be undertaken than RFPs. Applications received in response to RFAs are typically
grant funded. Applications received in response to RFPs are usually contract funded.
48
III. FUNDING
The type of initiative and nature of funding influences planning. Generally, the
number of prerogatives open to investigators diminish as one moves from investigatorinitiated trials to sponsor-initiated trials. Usually, the amount of control exercised by
sponsors is less with investigator-initiated, grant-funded trials. It is likely to be greatest
with sponsor-initiated RFPs and contract forms of funding, and intermediate for trials
initiated via requests for RFAs and funded via cooperative agreements involving grants
funding.
18. Funding: Specifications
49
18. Funding: Specifications
SLIDE
National Emphysema Treatment Trial (NETT) RFP63
Design
Multicenter, randomized trial
10–15 clinics
Sample size
Trial: 2,580
Registry: 13,000
Treatments
Lung volume reduction (two types)
Medical treatment
Followup: Common closing date
Outcome: Performance on 6-min walk test
Organization
10–15 clinical centers and coordinating center
Steering committee
Executive committee
Treatment effects monitoring committee
Performance
Stage 1: 20 Dec 1996–19 Sep 1997 (final protocol)
Stage 2: 20 Sep 1997–19 Dec 2002 (enrollment and followup)
Stage 3: 20 Dec 2002–19 Dec 2003 (analysis)
N A R R AT I V E
The basic elements of design are set during the funding process, as represented in RFAs or
RFPs in sponsor-initiated trials and in funding applications in investigator-initiated trials.
Planning, of necessity, starts from the ‘‘givens’’ as represented in funding applications or
agreements. Hence, it is a good idea to enumerate them as a prelude to planning. The list
should be compiled from the application as funded or from the RFAs or RFPs giving rise
to the trial. It should include elements listed below:
• Disease or condition to be treated
• General eligibility criteria
• Treatments or class of treatments to be investigated
50
III. FUNDING
•
•
•
•
•
•
•
•
•
•
Sample size
Period of recruitment
Number of clinics
Coordinating center and location
Method of treatment
Length of treatment
Length of followup
Expected rate of enrollment
Anticipated timetable of the trial
Period of funding and level of funding
1 9 . F u n d i n g : Te r m i n o l o g y
51
19. Funding: Terminology
R E L AT E D E N T R I E S
Funding: Type (page 59), Funding: Initiative (page 61), Funding: Period (page 63),
Funding: Budget (page 65), Funding: Mode (page 67)
DEFINITIONS
award statement n - A document confirming the fact of funding, amount, and period
covered.
best and final offer n - The final offer of a respondent in a competitive bidding process.
In relation to request for proposals, usually requested of respondents with proposals in
the competitive range.
business office n - 1. The place or office within an institution or business considered
to be the seat or headquarters of the institution or business. 2. The place or office of an
institution or business firm where financial records are processed and kept. 3. The office in
an investigator’s institution having legal responsibility for receipt of research funds from
a sponsor and overseeing expenditure of such funds.
centralized funding n - A method of funding centers in a multicenter structure in which
funds are awarded to a center for distribution to other centers in the structure. ant:
distributed funding rt: consortium funding agreement, consortium funding award
competitive bid n - A bid for funding considered reasonable and worthy of consideration
by the funding agency.
competitive bidding n - 1. Bidding done in the open, e.g., as at an auction. 2. The
original offer through the best and final offer made by a respondent to a request for
proposal; absent discussion or knowledge of the offers of other competitors. Usage note:
In defn 1 a bidder has the opportunity to rebid and to continue to do so until there is a
winning bid. In defn 2, the winning bid is selected from among those received, usually
with viable bidders having the opportunity to submit one or more revised bids prior to
selection of the winning bid.
competitive funding n - Funding obtained from an agency by submission of funding
proposals subjected to some form of peer review to select those suitable for funding.
competitive initiative n - 1. An initiative fit for competition. 2. An initiative in
competition with others for funding. 3. An investigator-initiated proposal submitted to an
agency for funding. 4. A request for proposal involving open competition. rt: competitive
proposal
competitive proposal n - 1. A funding proposal judged to be in the competitive range.
2. A funding proposal submitted to a funding agency for funding. 3. A proposal accepted
for review by a funding agency. ant: noncompetitive proposal rt: competitive initiative
competitive range n - The limits within which proposals are considered suitable for
funding; such limits as specified in a request for proposal or request for application or as
defined by proposals received and considered suitable for funding. Usage note: Being in
the competitive range does not ensure funding. However, being outside the range usually
precludes funding.
52
III. FUNDING
competitive renewal n - A renewal involving competition, e.g., as in that required to
renew funding for a grant-supported research project in its last year of approved funding,
or with a request for proposal being recompeted. rt: noncompetitive renewal Usage note:
Competitive renewal refers to a process involving the review and approval of funding
akin to that for initial funding. If the competition for renewal is successful, the project is
approved for funding for the period designated in the funding award or a lesser period,
usually a period of years. Renewals within the approved period will be noncompetitive.
See noncompetitive renewal and renewal for additional comments.
consortium funding n - A type of funding in which monies received by a designated
center are disbursed to other centers in a multicenter study according to terms set forth
in a consortium funding agreement and involving contracts (typically the case) or grants
with those other centers. rt: indirect distribution of funds
consortium funding agreement n - A funding agreement between the sponsor and a
center in a multicenter study in which funds are received by that center for disbursal to
one or more other centers in a study, typically via contractual agreements.
consortium funding award n - 1. A grant or contract awarded to a center in a multicenter
study that involves a consortium funding agreement. The center receiving the award
assumes responsibility for distribution of funds to all other participating centers in the
study. 2. Such an award except that it is for support of only certain centers in the study;
remaining centers funded other ways.
contract office n - 1. The office in the sponsoring agency whose staff are responsible
for negotiating, awarding, and funding contracts. 2. That office in a lead center, serving
as a surrogate for the sponsoring agency, under the consortium mode of funding and
involving use of contracts for dispersal of funds to the other centers. 3. business office
Usage note: Care should be taken to distinguish between usage in the sense of defn
2 versus defn 1. Use in the sense of defn 3 not recommended in that those offices
typically have responsibilities for grants as well as contracts. rt: grants management
office
contract officer n - 1. The individual in the sponsoring agency responsible for negotiating,
awarding, and funding contracts for specified projects. 2. Such a person in a lead center
under the consortium mode of funding and involving the use of contracts for dispersal of
funds to other centers. rt: grants management officer Usage note: Care should be taken
to distinguish between usage in the sense of defn 2 versus defn 1.
contract proposal n - A funding proposal that, if awarded, involves funding via a contract.
rt: grant proposal
cooperative agreement n - 1. An agreement between an institute of the National
Institutes of Health and a set of investigators that provides a structure for sponsorinvestigator cooperation in the design and execution of a research project funded by
grants. 2. Any written agreement between a sponsor and investigator(s) that provides a
defined role for both parties in the design and conduct of a specified research project. 3.
Cooperative Research and Development Agreement rt: contract, grant
core funding n - 1. Funding essential to maintenance of the infrastructure of a multi-study
network. 2. The funding needed to support key personnel of a center.
direct distribution of funds n - Distribution of funds to centers in a study directly from
the sponsor via direct funding awards. ant: indirect distribution of funds
1 9 . F u n d i n g : Te r m i n o l o g y
53
direct funding award n - A funding award (grant or contract) to a center directly from
the sponsor. ant: indirect funding award
distributed funding n - A method of funding centers in multicenter structures in which
funds are awarded to individual centers directly from the funding agency. ant: centralized
funding
distribution of funds n - The act or process of distributing funds, directly or indirectly,
to the various sites within a study. rt: direct distribution of funds, indirect distribution of
funds
extramural funding n - 1. Funding to institutions or agencies outside one’s own
institution or agency. 2. Funding provided by an agency or organization to some unit or
organization external to it; in the case of NIH, monies provided to awardees in relation
to its extramural research program. ant: intramural funding
funding agency n - An agency that provides fiscal support for a specified purpose or
activity. syn: sponsoring agency
funding agreement n - An agreement between the payer and payee concerning the nature
and extent of funding in return for a specified product or completion of some task.
funding application n - Funding proposal, especially one prepared in relation to a grant
application. syn: funding request rt: contract proposal
funding award n - A grant or contract awarded to an institution for a designated project.
funding office n - The office responsible for fiscal negotiations and disbursement of funds
in relation to a funding proposal. rt: grants management office, contract office
funding officer n - The head of a funding office. rt: grants management officer, contract
officer
funding period n - 1. The period of time covered in the budget of a funding application. 2.
The period of funding specified in an award statement. 3. The period of time represented
in an existing award; the period of time within which monies may be expended. 4. The
period of time over which funding is required to carry a project from beginning to end.
Usage note: Subject to confusion because times represented may differ. For example, the
period in defn 1 may be 5 years and 3 years in defn 2 for the same project. The period in
defn 3 is for a current award - usually a year or lesser period, even though the award (defn
2) is for a longer period. Similarly, the period represented in defn 4 is likely to be longer
than any of the periods represented in the other definitions. That will be the case with
NIH grant funded projects covering periods in excess of 5 years. The maximum period
of funding (defns 1 or 2) for NIH grants is 5 years. Funding will have to be renewed
one or more times over the life of the project to cover the time period represented by
defn 4.
funding proposal n - A proposal from an applicant, offerer, or proposer for funding a
specified activity. syn: funding application, funding request rt: contract proposal, grant
proposal
funding request n - A request for funding in relation to some project or activity; funding
proposal.
grant n - [general] Something given or granted; the act of granting; grant-in-aid; grant
application. [research] 1. An award of monies from a federal agency to a state or local
governmental unit, or to a private or public agency, institution, or foundation, to support
54
III. FUNDING
specified research as described in a grant application. 2. An award of monies made
in response to a research grant application. 3. Materials or goods provided in lieu of
money for the conduct of specified research, e.g., drugs supplied by a drug company
for use in a trial. 4. research grant application rt: contract, cooperative agreement Usage
note: The term carries the connotation of gift or giving and, hence, is best reserved
for awards providing a wide degree of control of the research by the recipient of the
award. A grant, as opposed to a cooperative agreement or contract, is generally made
with little involvement in the work by the sponsor. Medical research is funded by grants
and contracts. Hence, the two terms should not be used interchangeably. They have
different operational implications, especially in relation to review and administration in
the NIH setting. An NIH grant is a gift made to an investigator’s institution to allow
that investigator to perform research specified by the investigator. An NIH contract is a
legal agreement between the NIH and the investigator’s institution to perform designated
services or work under the general direction of the NIH. Normally, the grant mode of
support is reserved for investigator-initiated proposals and for sponsor-initiated proposals
as outlined in requests for applications (RFAs). The contract mode of funding is usually
reserved for activities coming about via requests for proposals (RFPs). Normally, the
mode of funding, once established, remains unchanged over the course of an activity, with
notable exceptions. Institutes of the NIH do convert traditional R01 grants to cooperative
agreements in some multicenter trial settings (e.g., as happened in the Glaucoma Laser
Trial35 ). Similarly, they can change from grant to contract or contract to grant support
during the life of an activity. For example, a switch from grant to contract took place
during the Diabetic Retinopathy Study26 in relation to funding for the coordinating
center for that study. In addition, the initiator role can change for activities that proceed
from a feasibility phase to a full-scale phase. A case in point is the Systolic Hypertension
in the Elderly Program (SHEP).77 The initial feasibility trial grew out of investigator
initiative and was funded via grants. The full-scale phase was initiated via an RFP from
the NIH and was funded via contracts. Usually the NIH will use the same type of funding
vehicle for all sites in a multicenter study, but there are exceptions here as well. For
example, some institutes have used grants to fund clinics in such settings and contracts
for core units, such as coordinating centers.
grant application n - 1. An application submitted to a federal governmental agency for a
grant-in-aid. 2. research grant application 3. grant proposal rt: contract proposal
grants management office n - 1. The office in the sponsoring agency responsible for
awarding, funding, and administrating grants. 2. That office in a lead center, serving as a
surrogate for the sponsoring agency, under the consortium mode of funding and involving
use of grants for dispersal of funds to the other centers. 3. business office rt: contract office
Usage note: Care should be taken to distinguish between usage in the sense of defn 2 as
opposed to that in the sense of defn 1. Use in the sense of defn 3 is not recommended in
that such offices typically have responsibilities for administering contracts as well as grants.
grants management officer n - 1. The individual in the sponsoring agency responsible for
awarding and funding grants for specified projects. 2. Such a person in a lead center under
the consortium mode of funding and involving the use of grants for dispersal of funds
to the other centers. rt: contract officer Usage note: Care should be taken to distinguish
between usage in the sense of defn 2 as opposed to that in the sense of defn 1.
incremental funding n - Funding provided at specified times (e.g., once a year) or after
completion of specified tasks over the course of a project.
1 9 . F u n d i n g : Te r m i n o l o g y
55
indirect distribution of funds n - Any system of funding in which funds flowing to a
site from a sponsor are via a party other than the sponsor, as in consortium funding. ant:
direct distribution of funds
indirect funding award n - A funding award made to a site by another site with funds
from a sponsor, as in a consortium funding award. ant: direct funding award
intramural funding n - 1. Monies provided or awarded from within one’s own institution
or agency for work to be done within or under the direct control of one’s own institution.
2. Funding provided by an agency or organization to some unit or subdivision of that
agency or organization in that agency or organization; in the case of NIH, monies provided
to units within the NIH for conducting its intramural research program. ant: extramural
funding
investigator-initiated research proposal n - 1. A research proposal conceived, prepared,
and submitted to a prospective sponsor absent a formal solicitation by the sponsor. 2. An
unsolicited grant proposal submitted to the NIH, such as an R01 grant application. ant:
sponsor-initiated research proposal rt: grant proposal Usage note: The initiating force
behind a proposal is not always clear, especially in the case of large-scale multicenter
trials, even for those funded by grants not solicited by requests for applications (RFAs).
Typically, investigators will not undertake the task of preparing fully developed proposals
for such trials, in itself arduous and expensive, without some indication from the sponsor
that it will be accepted for review and that the proposed work is consistent with the
general charge or scope of interest of the sponsor.
noncompetitive proposal n - 1. A funding proposal judged to be outside the competitive
range. 2. A proposal not fit for competition. 3. A funding proposal rejected by a funding
agency on scientific or other grounds. ant: competitive proposal
noncompetitive renewal n - A renewal within a defined period of approved funding,
e.g., a renewal for year 3 of a scheduled 5 years of support. rt: competitive renewal Usage
note: Noncompetitive renewal refers to the approval of funds and budgets for a designated
period of time within an approved period of funding. Noncompetitive renewals are routine
in comparison to competitive renewals. Typically, in multi-year research projects, funding
is in 1-year intervals. Hence, a 5-year project requires four noncompetitive renewals.
recompete, recompeted, recompeting, recompetes v - [research funding] 1. To engage
in a competitive funding process by submission of a heretofore unsuccessful request. 2.
competitive renewal 3. To invite submission of funding proposals by reissue of a request
for proposal (RFP) or request for application (RFA). 4. To seek to renew the funding of
an existing activity by issue of an RFP or RFA to provide funding for an additional period
of time.
recompetition n - 1. The act or process of competing again for funding, e.g., as in
resubmission of a funding proposal for competitive funding, or in a competitive renewal.
2. The act or process of requiring someone to compete again for funding, e.g., as with the
reissue of a request for proposal to renew or extend funding for an activity.
renewal n - [broadly] 1. To make like new. 2. To restore or to refresh. 3. To provide
or obtain an extension. [research] 4. A funding proposal that is renewed; noncompetitive
renewal; competitive renewal. 5. The providing of approval to continue a project for
a designated time increment, e.g., such an approval as given by an institutional review
board (usually in one year increments), on receipt, review, and approval of an application
56
III. FUNDING
to renew. 6. The granting of funds under an approved funding agreement or award for
a designated time increment (usually one year), on receipt of a proposed budget and
on evidence of satisfactory progress as contained in a progress report. 7. A request for
permission to continue for a designated time increment by submission of the necessary
documents for such approval.
request for application (RFA) n - A document prepared and distributed to solicit
applications pertaining to work detailed in the request; especially such a document
prepared and distributed by an agency of the federal government and in which said work
is to be supported by grants. rt: request for proposal Usage note: From the NIH perspective,
both RFAs and RFPs are used as vehicles for identifying and selecting investigators and
centers in multicenter trials. As a general rule (though there are exceptions), investigators
have more control over the activity proposed under the NIH RFA mode of initiation and
grant support than under the RFP mode of initiation and support.
request for proposal (RFP) n - A document prepared and distributed to solicit proposals
for execution of a specified task, especially such a document prepared and distributed by
an agency of the federal government, such as the NIH, and in which said work is to be
supported by contracts. rt: request for application Usage note: Not to be confused with
request for application.
research contract proposal n - 1. A contract proposal for carrying out a designated
research activity. 2. A funding proposal prepared in response to a request for proposal. rt:
research grant proposal
research grant n - A grant awarded to support a designated research activity or project.
Usage note: See grant for usage note.
research grant application n - 1. An application for a research grant submitted to an
agency or institution having a specified research plan, budget, and principal investigator.
2. Such an application submitted to the NIH. 3. Any application for a research grant
regardless of funding source, i.e., applications submitted to any federal, state, or local
governmental unit, to a private or public foundation, or to some business firm.
research grant proposal n - 1. A grant proposal for carrying out research; grant
application. 2. A funding proposal prepared in response to a request for application. rt:
research contract proposal
sponsor n - 1. A person or agency responsible for funding a designated function or activity;
sponsoring agency. 2. A person or agency that plans and carries out a specified project or
activity. 3. The agency or person named in an Investigational New Drug Application or
New Drug Application; usually a drug company or person at such a company, but not
always (as with an INDA submitted by a representative of a research group proposing to
carry out a phase III or phase IV drug trial not sponsored by a drug company). 5. A firm
or business establishment marketing a product or service.
sponsor-initiated research proposal n - A research proposal prepared in response to a
request by a sponsoring agency, as in relation to a request for proposal (RFP) or request
for application (RFA). ant: investigator-initiated research proposal rt: contract proposal
Usage note: See note for investigator-initiated research proposal for comments.
sponsoring agency n - The agency, institution, organization, or foundation that provides
financial support, and often also administrative and scientific support, for a given project
or activity. syn: funding agency
1 9 . F u n d i n g : Te r m i n o l o g y
57
subcontract n - 1. A contract with a prime contractor. 2. Such a contract consummated
with a party not funded via a contract, e.g., in the case of contracts with clinics in a
multicenter trial initiated by and consummated with a coordinating center, funded via a
grant (not recommended usage). Usage note: The term subcontract should be reserved
for usages in the sense of defn 1. The appropriate term for usages in the sense of defn 2
is contract, since the party initiating and consummating the contract is not itself funded
via a contract. Nevertheless, business offices in academic institutions may refer to any
contract initiated and consummated by them as subcontracts, regardless of whether their
funding is via contracts or grants.
subcontractor n - One who agrees to provide specified goods or services to a contractor
for specified payments or considerations. rt: contractor Usage note: See subcontract,
contract, and grant.
submission n - 1. An act of submitting something for consideration, review, or decision
(e.g., the act of sending a manuscript to a journal for publication or the act of sending
a research proposal to an agency for funding), or for compliance with a regulation or
procedure. 2. Something submitted.
2 0 . F u n d i n g : Ty p e
59
20. Funding: Type
R E L AT E D E N T R I E S
Funding: Terminology (page 51), Funding: Type (page 59), Funding: Initiative (page
61), Funding: Period (page 63), Funding: Budget (page 65), Funding: Mode (page 67)
N A R R AT I V E
The mode of funding is a function of initiative (see page 61). Usually it is via contract
for sponsor-initiated trials and via grant for investigator-initiated trials or for trials done
under cooperative agreements.
Grant funding from the NIH is usually in the form of R01 or U10 awards.
Single-center trials are usually funded via traditional R01 awards. Large multicenter trials
are likely to be funded via U10 awards, whether strictly investigator-initiated, or arising
as a result of Request for Applications (RFAs) from the NIH.
Contracts may be for fixed price or for cost reimbursement. Contracts covering
long-term multicenter trials are likely to be of the cost reimbursement type. Trials initiated
by the NIH via Requests for Proposals (RFPs) are contract-funded, usually via the cost
reimbursement type.
Both modes of funding may be represented in a trial. One way the mix comes
about in contract-funded trials is by supplemental funding via grant mechanisms. Grant
funding may be solicited by investigators over the course of the trial to fund ancillary
studies or investigations considered worthwhile, but not covered under the workscope of
the contract.
Another way for a mix to occur in multicenter trials is because of preference of
the sponsor to use contracts to fund certain centers in the trial and grants for the other
centers. For example, institutes of the NIH have, on occasion, funded clinics by grant and
coordinating centers by contract. The downside of such mixing is in the message implied
by the difference.
21. Funding: Initiative
61
21. Funding: Initiative
R E L AT E D E N T R I E S
Funding: Terminology (page 51), Funding: Type (page 59), Funding: Period (page 63),
Funding: Budget (page 65), Funding: Mode (page 67)
N A R R AT I V E
The initiative for a trial may arise from investigators, from the sponsoring agency, or
from a partnership of investigators and sponsor. Broadly, at least in regard to NIH
funding, there is a correlation between initiative and mode of funding. Trials arising from
investigator initiative are grant-funded. Trials initiated via RFPs are funded by contracts.
Trials initiated via RFAs from the NIH are grant-funded.
Research grant
•
•
•
•
Fixed funding ceiling
Award may not exceed 5 years without competitive renewal with NIH funding
Designed to produce or promote research in some area
Investigator-controlled
Research contract
•
•
•
•
Usually cost reimbursement
Funded in yearly increments
Designed for delivery of a product
Sponsor-controlled
Methods of initiation
Investigator
• Unsolicited grant application (R01)
• Unsolicited contract proposal (rare)
Sponsor
• Request for grant application (RFA)
• Request for contract proposal (RFP)
Characteristics of investigator-initiated funding
• Investigators specified in the funding application or selected by investigators after
receipt of funding
• Research plan developed by investigators
• Investigators organize and operate the trial
• Usually communications with sponsor during preparation of applications
62
III. FUNDING
Characteristics of sponsor-initiated funding
• Investigative group chosen by sponsor; unknown to individual applicants at time of
application
• Basic research plan developed by sponsor
• Sponsor usually has major role in organization and operation of trial
• No or limited communication with sponsor during preparation of response to RFA
or RFP
Questions concerning RFAs and RFPs: Investigator perspective
•
•
•
•
•
•
•
•
Is the request genuine?
Is the proposed trial worthwhile and ethical?
Is the trial doable?
Are the goals worthwhile and can they be achieved?
Is the timetable realistic?
Are the suggested staffing and budgeting guidelines realistic?
Is the project office experienced in clinical trials?
Does the RFA or RFP indicate the amount of money available for the trial?
Funding principles: Investigator perspective
• Request what is needed.
• Request adequate support for start up and close down.
• Make certain there is balance in the allocation of funds for data generation vs. data
intake and analysis.
• Monitor expenditures and project future costs.
22. Funding: Period
63
22. Funding: Period
R E L AT E D E N T R I E S
Funding: Terminology (page 51), Funding: Type (page 59), Funding: Initiative (page 61),
Funding: Budget (page 65), Funding: Mode (page 67)
DEFINITION
funding period n - 1. The period of time covered in the budget of a funding application. 2.
The period of funding specified in an award statement. 3. The period of time represented
in an existing award; the period of time within which monies may be expended. 4. The
period of time over which funding is required to carry a project from beginning to end.
Usage note: Subject to confusion because times represented may differ. For example, the
period in defn 1 may be 5 years and 3 years in defn 2 for the same project. The period in
defn 3 is for a current award—usually a year or lesser period, even though the award (defn
2) is for a longer period. Similarly, the period represented in defn 4 is likely to be longer
than any of the periods represented in the other definitions. That will be the case with
NIH grant funded projects covering periods in excess of 5 years. The maximum period of
funding (defns 1 or 2) for NIH grants is 5 years. Funding will have to be renewed one or
more times over the life of the project to cover the time period represented by defn 4.
N A R R AT I V E
Ideally, the funding period is tailored to correspond to the interval of time represented
in the timetable for the trial as designed. However, in reality, it is just as likely that
the timetable is fashioned to fit the limits of funding. Some fitting and trimming of the
timetable may be necessary but should be resisted when it leads to unrealistically ambitious
timetables (see study timetable, page 239).
The period of funding may be specified by the sponsor in the case of sponsorinitiated trials. The period of funding is set by investigators in the case of investigatorinitiated trials.
23. Funding: Budget
65
23. Funding: Budget
R E L AT E D E N T R I E S
Funding: Terminology (page 51), Funding: Type (page 59), Funding: Initiative (page
61), Funding: Period (page 63), Funding: Mode (page 67)
N A R R AT I V E
Typical budget categories
Personnel
Salary
Fringe benefits
Consultants (persons external to the applicants institution; usually paid on a per day
or meeting basis)
Dedicated equipment
Equipment needed at clinics for data collection (e.g., spirometers in asthma trial,
fundus cameras in eye trial, ECGs in heart trial)
Computing hardware, printers, and related peripherals for distributed data systems;
such equipment needed for data processing and analysis at the study data
center
Maintenance contracts
Software packages and licenses
Office Supplies
Desks, chairs, and filing cabinets
Consumable supplies (paper, pencils, pens, notebooks, etc.)
Computer supplies
Postage (U.S., FedEx, UPS, etc.)
Telephone (voice, fax)
Photocopying
Books, journals
Publication charges (page charges, reprints)
Travel
Site visits
Training meetings
Study committees meetings (steering committees, executive committees, writing
committees)
Research group meetings
TEMC meetings
Scientific meetings
66
III. FUNDING
Patient-related costs (limited to tests and procedures required because of the research
protocol; usually costs for tests and procedures considered to be part of routine
care are passed to third-party payers or directly to patients)
Other
Study drugs and medications
Central pharmacy (packaging and distribution of drug)
Space rental
Alterations/renovations (generally not covered)
Indirect costs
Suggested budget summaries and analyses
• Dollar cost by year; all centers combined and center type
• Full-time equivalents (FTEs) by year; total and by level of seniority, function or
activity (across all centers and by center type in multicenter trials)
• Fraction of total direct costs devoted to personnel; all centers combined and by type
of center
• Percentage distribution of funds across categories
• Percentage of total direct cost devoted to data processing and analysis
Observations
• Budgets in which 90% or more of the money is for personnel are likely to be
deficient in other categories (especially those needed to support the activities of
personnel in regard to supplies, hardware, software, etc.).
• The budgets in which less than 10% of the funds are for data processing and analysis
are likely to be inadequate in meeting the needs of the trial.
• The fraction of total direct funds for coordinating center function in multicenter
trials can be expected to run anywhere from 10% to 25% of the total budget,
depending on duties, number of centers in the trial, and overall responsibilities for
direction and coordination.
• One-third of the budget of coordinating centers is likely to go for supplies,
computing hardware and software, and travel.
• Budgets in multicenter trials, absent funds for travel, are, by definition, inadequate.
Travel will be needed for site visiting, for training, for meetings of study committees,
and for meetings of the investigator research group.
24. Funding: Mode
67
24. Funding: Mode
SLIDE
Funding mode: Studies of Ocular Complications of AIDS
(SOCA)80
Clinics: Contracts from Coordinating Center, annual renewal; salary support for
clinic coordinators (based on patient load) and for small fraction of time
for study ophthalmologists and infectious disease persons; head payments for
persons enrolled and followed
Coordinating Center: NEI grant; fixed-cost; 1-year budget, renewable over period
of award—5 years
Fundus Photography Reading Center: Same as for Coordinating Center
Office of Chair: Same as for Coordinating Center
Specimen Repository Bank: Contract with Coordinating Center; 1-year period,
renewal; fixed cost plus fee-for-service mode of payment
R E L AT E D E N T R I E S
Funding: Terminology (page 51), Funding: Type (page 59), Funding: Initiative (page 61),
Funding: Period (page 63), Funding: Budget (page 65)
DEFINITIONS
fee-for-service n - 1. A fee paid to a purveyor for services rendered. 2. fee-for-service
agreement
fixed-cost adj - Of or relating to a monetary cost fixed by agreement; unlike costreimbursement and fee-for-service.
head fee n - A fee based on person count, e.g., a fee in the amount of $2500 paid per
person enrolled and followed for 8 weeks.
incremental funding n - Funding provided at specified times (e.g., once a year) or after
completion of specified tasks over the course of a project.
N A R R AT I V E
The mode of payment for clinics may be by fixed budget, on a head basis, or a mix of the
two modes of payment. The downside of fixed budgets lies in the difficulties involved in
adjustments to match effort.
Head payments have the advantage of flexibility. Money to clinics flows to where
the action is. The downsides are in the administrative burden involved with the mode
of payment and in the potential such forms of payments carry for clinics to enroll
questionable people or even to fabricate data simply to maintain money flow.
The sponsor, with the head mode of payment, has no control over how monies
are used when they arrive at the clinic. While they are able to ensure that monies in fixed
68
III. FUNDING
budgets are spent on personnel essential to the trial, they are in decidedly weaker positions
to do so with head modes of payment.
Clinics can be expected to have difficulty staffing for the trial with the head mode
of payment. Clinics have to, in effect, earn their money. It will be difficult to hire on
the expectation of income, especially in academic institutions. Institutions are unlikely to
‘‘front’’ investigators money so they can hire in anticipation of recruitment.
A mixed model involving both modes of payment is perhaps best. In that mode
some monies are provided in fixed budgets. The rest flows to clinics based on recruitment
and followup.
Treatment
Groups/Treatment
Administration
25. Study Groups
71
25. Study groups
SLIDE
Study groups: Glaucoma Laser Trial (GLT)35
Assignment unit:
Treatment groups:
Test-treated group:
Control-treated group:
Eye
2
Eyes assigned to receive laser treatment
Eyes assigned to receive standard topical medications
R E L AT E D E N T R Y
Study treatments (page 75)
DEFINITIONS
control-assigned group n - 1. The group assigned to the control treatment. 2. The group
that receives a control treatment. rt: control-treated group, test-assigned group Usage
note: Use in the sense of defn 2 not recommended because those receiving a control
treatment may not have been control-assigned.
control-treated group n - 1. The group of persons or treatment units assigned to receive
a control treatment. 2. The group of persons or treatment units receiving a control
treatment, whether or not originally assigned to that treatment. rt: test-treated group,
control-assigned group Usage note: Not to be confused with control-assigned group. Use
control-assigned group for uses in the sense of defn 1.
study group n - 1. Any defined group of observation units on whom specified data are
collected. 2. The entire group of observation units included in a study. 3. treatment group
4. The group of investigators carrying out a study. 5. investigative group Usage note:
Subject to confusion. Note that defns 1, 2, and 3 refer to the focus of study, whereas defns
4 and 5 refer to those doing the study. Avoid confusion by reserving the term for uses in
the sense of defns 1, 2, and 3; use some other term, such as research group or investigative
group for uses in the sense of defns 4 and 5. Use treatment group rather than study group
for uses in the sense of defn 3.
test-assigned group n - The group assigned to receive a test treatment. rt: control-assigned
group, test-treated group
test-treated group n - 1. The group of persons or treatment units assigned to a particular
test treatment; test-assigned group. 2. The group of persons or treatment units receiving
a particular test treatment, whether or not originally assigned to that treatment. rt:
control-treated group Usage note: Not recommended in the sense of defn 2; obscures the
difference between an assigned and administered treatment.
treatment group n - The group of persons or treatment units assigned to receive a
specified treatment in a trial.
26. Comparison Group
73
26. Comparison group
SLIDE
Comparison group: University Group Diabetes Program
(UGDP)93
For tolbutamide assigned group Group assigned to receive matching tolbutamide
placebo
For phenformin assigned group Group assigned to receive matching phenformin
placebo
For insulin assigned group Group assigned to receive fixed insulin dose (10, 12,
14, or 16 units, depending on body surface)
R E L AT E D E N T R I E S
Study groups (page 71), Control/comparison treatment (page 79)
DEFINITIONS
comparison group n - A group of observational or experimental units, designated in the
study design or arbitrarily chosen, that is used as a basis for comparisons with other groups
in the study; typically the control-assigned group in a controlled trial. rt: reference group
comparison treatment n - The treatment against which others are evaluated or measured;
typically the control treatment in controlled trials. rt: standard treatment Usage note:
Usually synonymous with control treatment in randomized trials, except where all study
treatments are test treatments. If one of the test treatments is used as the base for
comparison, use comparison treatment to avoid connotations associated with control
treatment.
reference group n - 1. A group arbitrarily designated or otherwise recognized as the
one to which others are to be compared, e.g., the group aged 45–54 for comparison of
treatment differences among subgroups aged 55–64 and ≤65. 2. comparison group
standard treatment n - A treatment widely practiced and routinely applied against a
specified disease or health condition; standard care. Usage note: Often used in a loose
inferential sense with the inference based on limited observations or suppositions regarding
typical practice procedures. On occasion, the designation may be the result of a decree by
some agency, body, or society. Do not use in settings where the normal practice is to not
treat. Do not use in relation to placebo treatments. There are differences in connotation
between not treating at all and administering a placebo treatment.
N A R R AT I V E
The comparison group in a randomized controlled trial, by definition, is concurrent. That
is, the observation units comprising the comparison group are randomized, treated, and
followed over the same time frame as those comprising the other study groups. External
comparison groups, such as represented by historical controls or ‘‘population controls,’’
may be considered in addition to, but not instead of, a concurrent control.
74
I V. T R E A T M E N T G R O U P S / T R E A T M E N T A D M I N I S T R A T I O N
Persons assigned to the comparison group should be observed with the same
intensity and frequency as members of the other treatment groups. This feature is implicit
in double-masked trials.
The requirement may be difficult, if not impossible, to achieve in trials involving
different modes of treatment (e.g., medical vs. surgical treatment). Designs allowing
for or requiring differential visit or contact rates by treatment group carry risks of
treatment-related biases because, generally, the more one looks, the more one finds.
The treatment administered to the comparison group is dictated, in large measure,
by prevailing norms and standards of care extant during the trial and region of conduct.
The expectation is that all persons, regardless of assignment, will receive the treatment and
care deemed necessary to satisfy prevailing norms and standards. The comparison group
may or may not be given additional treatment. In cases where the comparison group does
not receive treatment, the group is usually referred to as an ‘‘observation only’’ control.
When the comparison group receives treatment by virtue of assignment, the group is
referred to as a treated-comparison group. The treatment administered may be active or
inactive. Treatments in the latter class include placebo and sham treatments.
27. Study Treatments
75
27. Study treatments
SLIDE
Study treatments: University Group Diabetes Program
(UGDP)93
Plbo
PlboT
PlboP
Tolb
Phen
IStd
IVar
Placebo
Tolbutamide
Phenformin
Insulin standard
Insulin variable
Tablet; dosage schedule same as for Tolb
capsule; dosage schedule same as for Phen
1.5 g (daily); 3 tablets
100 mg (daily); 2 capsules; 1/ day 1st 7 days
10, 12, 14, or 16 units, depending on body surface
Amount required to maintain ‘‘normal’’ glucose levels
R E L AT E D E N T R I E S
Comparison group (page 73), Test treatments (page 77), Control/comparison treatment
(page 79), Placebo treatment (page 87), Sham treatment (page 91)
DEFINITIONS
clinical equipoise n - [due to Benjamin Freedman33 ] In the context of clinical trials, a
collective state of doubt or indecision as to choice or course of treatment due to absence of
agreement among medical experts as to what that choice or course should be.33,78 Usage
note: The randomized clinical trial arises from a climate of clinical equipoise. Its ethical
base rests on the presence of a collective state of doubt regarding the course of treatment,
sufficiently balanced to justify randomization. In reality, a true state of equipoise is fleeting
and fragile. Hence, a sustained state of equipoise over the course of a trial is, to a degree,
a theoretical abstraction. Collective doubt waxes and wanes with the flow of data and
expert opinion. The purpose of treatment effects monitoring is to determine whether data
accumulating within a trial are sufficient to dissipate the state of doubt.
study treatment n - 1. A treatment that is the focus of study, especially in an experimental
setting; test treatment. 2. Any treatment, including a control treatment, applied in a trial
as part of a study protocol; treatment arm.
QUESTIONS
• Is there a state of equipoise underlying the choices? A ‘‘no’’ is usually sufficient to make
randomization ethically untenable or require a change in the choice of treatments.
• Are investigators free of proprietary interests, i.e., stand neither to gain nor to lose
financially regardless of the nature or direction of the results? A ‘‘no’’ implies the need
to ‘‘houseclean’’ and/or disclosure of such interests to institutional review boards and
to patients prior to enrollment.
• Are investigators neutral regarding the merits of the study treatments, i.e., have not
taken a stand extolling or condemning the wisdom of administering a particular test
treatment? A ‘‘no’’ has the same implications as for the question above.
• Is the sample size and length of treatment and followup sufficient to meet the objectives
of the trial? A ‘‘no’’ raises ethical questions regarding the usefulness of the trial.
76
I V. T R E A T M E N T G R O U P S / T R E A T M E N T A D M I N I S T R A T I O N
• Is there a likely favorable benefit to risk ratio for patients to be enrolled regardless of
their assignment? A ‘‘no’’ is reason for pause.
• Are institutional review boards likely to approve the study protocol? A ‘‘no’’ requires a
reexamination of the choice of treatments and protocol for administration.
• Are investigators willing to randomize a patient to any of the study treatments? A ‘‘no’’
requires a revision of the study treatments or revision of eligibility criteria.
• Is it likely that patients will consent to enrollment given the choice of study treatments?
A ‘‘no’’ should cause a review of the choices and of the feasibility of doing the trial.
• Can the treatments be administered in a proper and competent fashion? A ‘‘no’’
requires a revision of the list of treatments and/or of selection of more appropriate
sites.
• Are clinics adequately staffed and equipped for proper and safe administration of
treatments? A ‘‘no’’ requires a revision of the list of treatments, additional or different
staff, additional equipment or facilities, or a more suitable slate of clinics.
• Is it appropriate and safe to administer any of the treatments to any person consenting
to be randomized? A ‘‘no’’ requires a revision of the eligibility and exclusion criteria.
• Is there reason to suspect the existence of a qualitative treatment interaction by gender
or some other demographic or entry characteristic? If ‘‘yes,’’ the list of exclusions
should be revised to exclude persons likely to be harmed by a study treatment, or the
randomization design must be changed to exclude questionable treatments for those
entering via a particular strata.
• Is there reason to suspect the existence of a quantitative treatment interaction by
gender or some other demographic or entry characteristic? If ‘‘yes,’’ the variable
should be used as a stratification variable.
• Does the trial meet the ‘‘Mother’’ test, i.e., would you be willing to randomize your
mother to treatment if she was eligible and willing to be enrolled?
2 8 . Te s t T r e a t m e n t s
77
28. Test treatments
SLIDE
Test treatments: University Group Diabetes Program
(UGDP)93
Tolb
Phen
IVar
Tolbutamide
Phenformin
Insulin variable
1.5 g (daily)
100 mg (daily)
Amount required to maintain ‘‘normal’’ glucose levels
R E L AT E D E N T R I E S
Comparison group (page 73), Study treatments (page 75), Control/comparison treatment
(page 79), Placebo treatment (page 87), Sham treatment (page 91)
DEFINITION
test treatment n - 1. Any of the study treatments in a trial, except those designated as
control treatments. 2. The treatment or one of the treatments (except control treatments)
evaluated in a trial. 3. treatment variable rt: control treatment, experimental treatment,
study treatment, treatment arm, treatment variable Usage note: Typically, in medical
settings the term refers to a drug, device, or procedure administered or performed for its
presumed therapeutic or diagnostic value. However, the term can also be used in broader
settings. It may refer to nontherapeutic schemes or regimens applied to well people in
nonmedical settings, e.g., in a prevention trial involving counseling schemes intended to
produce lifestyle changes.
N A R R AT I V E
One should not randomize persons to inferior treatments or deny them a superior
treatment. One does not test treatments to ‘‘prove’’ harm or to show that they are useless.
Selections have to be defended on ethical ground.33 Considerations in making the choice
include the following:
C O N S I D E R AT I O N S I N C H O I C E O F T E S T T R E AT M E N T S
•
•
•
•
•
•
•
•
•
•
Prior evidence of safety
Practicability of the treatment
Availability of the treatment
Amount of interest in the treatment
Length of treatment and followup
Representative nature of the treatment if a member of a family of treatments
Method of administration
Degree to which administration approximates a real-world use
Level of masking desired
Treatment adherence measures to be used
78
I V. T R E A T M E N T G R O U P S / T R E A T M E N T A D M I N I S T R A T I O N
The limits of randomization are defined by questions such as listed below. A ‘‘no’’
to any of the questions should raise concerns. The test treatments, in the case of treatment
and prevention trials, should be chosen so that there is a legitimate hope that the treatment
will be shown to be superior to an existing treatment. The expectation, in the case of
equivalence trials, is that the test treatment will be shown to be equivalent to the control
or comparison treatment or to be otherwise better in some practical sense, e.g., easier to
use, fewer side effects, or cheaper.
QUESTIONS
• Is it possible to answer ‘‘yes’’ to the questions listed for Study treatments (page 75)?
• Do the test treatments hold promise of benefit to patients? (A ‘‘no’’ implies the absence
of a positive benefit to risk ratio for patients.)
• Are there sufficient preliminary data for the test treatments to warrant use in human
beings? (A ‘‘no’’ raises questions as to whether the trial is premature.)
• In the case of drug treatments, are the profiles for carcinogenicity, teratogenicity, and
toxicity known with reasonable certainty and are they compatible with risk/benefit
calculus for use in human beings?
• Are the treatments safe?
• Is the method of administration reasonable and consistent with existing norms and
standards of care? (A ‘‘no’’ raises questions as to whether one is justified in using the
treatment.)
• Is the dose reasonable and consistent with existing norms and standards of care?
• Is there reason to believe that the test treatments would be made part of the
armamentarium for care in the locale where tested if shown to be safe and effective?
(A ‘‘no’’ raises the question as to whether the locale is correct or that the population
is being ‘‘used.’’)
• Can the treatment be delivered on a wider scale if shown to be effective? (A ‘‘no’’
raises questions as to the practicality of the treatments.)
• If a test treatment is shown to be effective, will persons in the trial have access to it when
the trial ends? (This question is of relevance in drug trials done under investigational
new drug applications and in particular situations involving life-threatening conditions
or conditions requiring continued treatment. A ‘‘no’’ raises the possibility that a drug
could be found to be useful but would not be available to persons receiving it or for
those not assigned to that treatment until it is approved for marketing after the trial
finishes.)
29. Control/Comparison Treatment
79
29. Control/comparison treatment
SLIDE
Comparison treatment: University Group Diabetes Program
(UGDP)93
Plbo
IStd
Placebo
Insulin standard
Dosage schedules same as for Tolb or for Phen
10, 12, 14, 16 units, depending on body surface
R E L AT E D E N T R I E S
Comparison group (page 73), Study treatments (page 75), Test treatments (page 77),
Control/comparison treatment (page 79), Placebo treatment (page 87), Sham treatment
(page 91)
DEFINITIONS
active control treatment n - A negative or positive control treatment that is capable of
producing a treatment effect in excess of that produced with an inactive control treatment.
ant: inactive control treatment rt: negative control treatment, positive control treatment
alternative control treatment n - A non-nil control treatment administered to persons
assigned to the control group; often used as an aid in recruitment (e.g., in vaccine trials)
to provide some form of treatment to all persons enrolled; purposely chosen to have
negligible effects in regard to outcomes of interest.
alternative treatment n - 1. Treatment available to persons declining or withdrawing
from enrollment in a research project; one of a series of disclosures (§46.116 (4))66
considered essential to informed consent. 2. The treatment represented by an alternative
control treatment.
best medical judgment control treatment n - Control treatment determined by best
medical judgment; treatment taking account of the needs and conditions of a person.
comparison treatment n - The treatment against which others are evaluated or measured;
typically the control treatment in controlled trials. rt: standard treatment Usage note:
Usually synonymous with control treatment in randomized trials, except where all study
treatments are test treatments. If one of the test treatments is used as the base for
comparison, use comparison treatment to avoid connotations associated with control
treatment.
control treatment n - A treatment, active or inactive, that serves as a basis for comparison in
a clinical trial. rt: inactive control treatment, active control treatment, study treatment, test
treatment Usage note: Active treatments include standard care or use of a study treatment
intended to produce a positive or negative treatment effect; inactive treatments include
placebo treatment, sham treatment, nil treatment, nontreatment, and null treatment.
inactive control treatment n - A control treatment, such as a placebo or sham treatment
or nontreatment, not capable of producing an effect, except, perhaps, a placebo effect.
ant: active control treatment rt: negative control treatment
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negative control treatment n - 1. A control treatment that produces a negative treatment
effect. 2. An active control treatment that has an effect opposite to the one produced
by the test treatment, e.g., a hypertension trial having a control treatment providing for
diets high in sodium. 3. A control treatment that has an effect that is opposite to the
one produced by a positive control treatment. ant: positive control treatment rt: inactive
control treatment
nil treatment n - No administered treatment; observation only; nil treatment control.
syn: null treatment
nil treatment control n - 1. null treatment control 2. trace treatment control
null treatment n - 1. Absence of treatment of any form, including that represented by
placebos or shams. 2. nontreatment syn: nil treatment
placebo effect n - 1. The effect produced by a placebo; assessed or measured against the
effect expected or observed in the absence of any treatment. 2. The effect produced by an
inactive control treatment. 3. The effect produced by a control treatment considered to
be nil. 4. An effect attributable to a placebo. rt: sham effect Usage note: Limit usage to
settings involving the actual use of a placebo. Avoid in the sense of defns 2 and 3 when
the control treatment does not involve a placebo.
positive control treatment n - 1. A control treatment that produces a positive treatment
effect. 2. An active control treatment that has a positive treatment effect, e.g., a control
treatment involving use of suboptimal doses of the test treatment as in the use of a
fixed-dose of insulin in the University Group Diabetes Program93 as a positive control for
the test treatment involving varying doses of insulin, as required to reduce blood glucose
levels to a specified limit. 2. Any form of treatment administered in the context of a
clinical trial that has the potential of producing a positive treatment effect. 3. A control
treatment that has an effect that is opposite to the one produced by a negative control
treatment. ant: negative control treatment rt: active control treatment
standard treatment n - A treatment widely practiced and routinely applied for a specified
disease or health condition; standard care. Usage note: Often used in a loose inferential
sense based on limited observations or suppositions regarding typical practice procedures.
On occasion, the designation may be the result of a decree by some agency, body, or
society. Do not use in settings where the normal practice is to not treat. Do not use in
relation to placebo treatments. There are differences in connotation between not treating
at all and administering a placebo treatment.
trace control treatment n - A control treatment in which treatment is comprised of
administrating a trace amount of a test treatment; usually the amount administrated is
chosen to be of little or no pharmacological value.
trace treatment n - A treatment comprised solely of a trace amount of a test substance.
N A R R AT I V E
Types of control treatments
None
Nil
Trace
Alternative
29. Control/Comparison Treatment
81
Placebo
Sham
Minimal standard
Best medical judgment
Negative
Positive
Active
Positive
Trace
Alternative
Minimal Standard
Negative
Inactive
Nil
Placebo
Sham
The essence of the randomized trial lies in the control or comparison treatment.
That treatment provides the foundation for measuring the effect produced by the test
treatments. The choice of controls is of fundamental importance in the design of
randomized trials.
The control treatment has to meet minimum standards for care. If the standard
is that a condition must be treated to prevent or ameliorate the condition, the treatment
represented by the control treatment cannot be less than that of the standard. Part of the
difficulty faced in design lies in deciding when such a standard exists. It can be taken as
a ‘‘given’’ when treatment guidelines issue from consensus conferences, medical societies,
governmental agencies, or the World Health Agency.
Difficulty occurs when a standard is assumed to exist in the absence of published
guidelines. Often, in such instances, ‘‘standards’’ are more reflections of prevailing practice
norms than of reason or consensus among experts. Trialists, in such cases, need to decide
if the ‘‘standards’’ is convincing enough to warrant use as the control treatment in the
trial. If they decide it is not and opt, instead, for an inactive control treatment, then they
run the risk of being seen as violating an implied care standard. However, even if they opt
for an active treatment, they may still be subject to such criticisms if the control treatment
is seen as having been inadequately or ineptly applied. They are also at risk of ‘‘monday
morning quarterbacking’’ if they are seen as having made the ‘‘wrong’’ choice among the
several that were possible when they publish. For example, the criticism could be used
to dismiss a positive result by arguing that it is due to the ‘‘bad effect’’ of the control
treatment rather than the ‘‘good effect’’ of the test treatment.
Even when standards exist, it does not follow that they should be reflected in
the control treatment, or, said another way, it is not a foregone conclusion that inactive
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I V. T R E A T M E N T G R O U P S / T R E A T M E N T A D M I N I S T R A T I O N
forms of treatment should be ruled out. The basis for many of the everyday practices in
medicine is lacking. Practices arise because of their intuitive appeal. We use daily doses
of a drug to control a risk factor for disease in the hope, though unproven, that doing so
will also reduce the risk of subsequent disease or morbidity. A case in point is the drugs
to ‘‘normalize’’ blood sugar levels in type II diabetics.
Even if a standard exists, the trialist still has to decide if it applies when the site or
sites of conduct are remote from where the trial is designed and approved. Standards vary
from locale to locale even within the same country. They can be widely disparate from
country to country.
Trialists have to decide whether the choice of control treatment is ethical in the
setting of use. There are few global standards of care. Hence, the standard that exists in
the country of design and funding may not be applicable in the country of conduct. If the
control treatment proposed is at odds with the standard of care in the country of design,
is it ethical to use such a control in the country of conduct?
The control treatment has to be active and positive when there is evidence to
indicate that such treatment is beneficial in the setting of use. Negative forms of treatment
are limited to instances where such treatments are known to be safe and not ill-advised.
The treatment administered to persons assigned to receive the control treatment
may be specified in the study protocol or may be left to the discretion of study physicians,
as with a best medical judgment control treatment. The usual course is to specify
the particulars of the control treatment in the study protocol. Best medical judgment
control treatment comes into use when there is no prevailing consensus as to course of
treatment. However, the variation in treatment allowed by relying on judgments can be
troublesome when the results are reported, especially if they favor the test treatment.
One might argue in such cases that the result was due more to ‘‘bad’’ judgment in
treating persons assigned to the control treatment than to the superiority of the test
treatment.
Alternative treatment controls arise in settings where it is desirable or necessary
to offer some form of treatment to everyone to facilitate recruitment or to satisfy ethical
requirements for care. Use is limited to settings where one can reasonably argue (often
difficult) that the alternative is nil in regard to influence on the outcomes of interest.
Trace treatment controls arise in trials of vitamins and food supplements, usually
as an expedient to facilitate recruitment by being able to offer all persons some level of
the vitamins or supplement. The downside lies in the fact that even minute quantities
can have effects on the outcome measures of interest and because of the subterfuge
implied.
Some of the considerations leading to the different types of controls are outlined
below.
No control treatment
• Trials where all study treatments are a variation of a single test treatment, e.g., in a
phase II drug trial involving administration of different doses of the test treatment
to choose an ‘‘optimum’’ dose for a phase III trial
29. Control/Comparison Treatment
83
• Trials of treatments where ethics makes it difficult or untenable to use an inactive
control treatment, even if justifiable from the perspective of clinical equipoise, e.g.,
trials involving terminal diseases
• Head-to-head comparison of competing products, e.g., in equivalence trials
Nil control treatment
•
•
•
•
Benign conditions
Conditions lacking an indication for treatment
Conditions where there is uncertainty as to whether treatment provides benefit
Conditions amenable to use of a placebo or sham treatment, but where such use is
impractical, considered to be ethically untenable, or politically unwise
• Conditions where masked treatment involving use of placebo or sham treatments is
considered unnecessary because of bias-robust design
Trace control treatment
• Conditions where masking is considered proper and necessary to increase biasrobustness, but where use of a true placebo is impractical or unwise
• Conditions where care standards dictate that all persons receive some minimal level
of the test treatment
• Conditions where recruitment is likely to be made easier with a design in which all
persons receive at least some of the test substance
Alternative treatment
• Conditions where recruitment is likely to be made easier by virtue of having a
treated control, but where there is no suitable control treatment
• Conditions where it is desirable for ethical or practical reasons that all persons
receive some treatment, but where there is no suitable control treatment
Placebo treatment
• Conditions suitable for nil treatment and where the bias-robustness achieved by
masking via use of a placebo is deemed appropriate and necessary
• Conditions involving outcome measures highly susceptible to reporting or observer
bias
• Conditions where compliance to procedures in the study protocol or visit schedule
is likely to be influenced by treatment assignment when known
• Conditions where treatments have yet to be shown to be effective via randomized
trials
• Conditions where the evidence supporting the merit of treatment is lacking or weak
• Conditions where there is legitimate uncertainty as to the benefit of treatment
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I V. T R E A T M E N T G R O U P S / T R E A T M E N T A D M I N I S T R A T I O N
Sham treatment
• Largely the same as for placebo
• Conditions where there is a need to standardize a procedure to reduce likely sources
of variation
• Conditions where there is likely to be a sizable ‘‘placebo effect’’ in the way conditions
are observed or reported
Minimal standard treatment
• Conditions where treatment is indicated and where standards or guidelines are
promulgated
• Conditions lacking published guidelines but with widely accepted practice and
treatment procedures
• Published, local, national, or international standards for care
• Widely accepted de facto standards indicating need for treatment
Best medical judgment treatment
• Conditions where treatment is indicated and needs of patients are best served by
individualized approaches to treatment
• Life-threatening or life-limiting diseases where there is no single accepted standard
• Conditions where there is a desire to mimic real-world practice in the way
control-assigned patients are managed
Positive control treatment
• Same as for trace, alternative, minimal standard treatment
Negative control treatment
•
•
•
•
Benign conditions
Nonmedical conditions
Conditions where it is feasible to have positive control as well
Conditions where there are no known negative consequences from application
Indicators choice of control may be unsound
•
•
•
•
Where seen as violating a care standard
Where seen as involving undisclosed forms of deception
Use of procedures carrying more than minimal risk
Use of placebo or sham treatment carrying more than minimal risk or seen as
causing undue inconvenience or nuisance to persons receiving them
• Use of nil, placebo, or sham controls when treatment is indicated
• Placebo or sham treatments that require study personnel to ‘‘lie’’ to maintain a mask
29. Control/Comparison Treatment
85
• Use of a control treatment at odds with standards of care or practice within a clinic
• Use of a control treatment that is at odds with regulations or practice guidelines
Questions concerning choice of control
• Is the choice consistent with norms and standards of care?
• Are there risks associated with administration of the control treatment? If so, are
they minimized and reasonable?
• Is there a sound rationale underlying the choice?
• Will the nature and purpose of the control treatment be made explicit in consent
documents and consent processes?
• Will the consent form outline the treatment options available to persons declining
enrollment?
30. Placebo Treatment
87
30. Placebo treatment
SLIDE
Placebo treatment: University Group Diabetes Program
(UGDP)93
Tolbutamide placebo
Tablet (matching tablets containing tolbutamide)
1 tablet b.i.d.
Phenformin placebo
Capsule (matching capsules containing phenformin)
1 capsule per day during 1st week of treatment; thereafter 1 capsule b.i.d.
R E L AT E D E N T R I E S
Comparison group (page 73), Study treatments (page 75), Test treatments (page 77),
Sham treatment (page 91)
DEFINITIONS
placebo adj - 1. Of or relating to the use or administration of a placebo. 2. Of or relating
to something considered to be useless or ineffective. Usage note: Limit use to the sense
of defn 1. Avoid nonsensical uses such as ‘‘placebo patient’’ or ‘‘placebo group’’; use
placebo-assigned or placebo-treated instead.
placebo n - [ME, fr L, I shall please, fr placēre to please; the first word of the first
antiphon of the service for the dead, I shall please the Lord in the land of the living, fr
Roman Catholic vespers] 1. A pharmacologically inactive substance given as a substitute
for an active substance, especially when the person taking or receiving it is not informed
as to whether active or inactive. 2. placebo treatment (defn 1) 3. A sugar-coated pill
made of lactose or some other pharmacologically inert substance. 4. Any medication
considered to be useless, especially one administered in pill form. 5. nil treatment 6. An
ineffective treatment. rt: double placebo, homeopathic dose, multiple placebo, placebo
treatment, sham, sham procedure Usage note: Subject to varying use. Avoid in the sense
of defns 4, 5, and 6. Not to be confused with sham. The use of a placebo should
not be construed to imply the absence of treatment. Virtually all clinical trials involve
care. Investigators conducting them are obligated to meet standards of care, regardless
of treatment assignment and whether masked or not. As a result, a control treatment
involving use of a placebo is best thought of as a care regimen with placebo substituting
for one element of the care regimen. Labels such as ‘‘placebo patient’’ or ‘‘placebo group’’
create the impression that patients assigned to receive placebos are left untreated. The
labels (in addition to being wrong in the literal sense of usage) are misleading when
placebo treatment is in addition to other treatments (e.g., as in the University Group
Diabetes Program93 where all patients received dietary counseling).
placebo control n - 1. placebo-control treatment 2. A treatment involving the use of a
placebo. Usage note: See placebo treatment.
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I V. T R E A T M E N T G R O U P S / T R E A T M E N T A D M I N I S T R A T I O N
placebo effect n - 1. The effect produced by a placebo; assessed or measured against
the effect expected or observed in the absence of any treatment. 2. The effect produced
by an inactive control treatment, especially one involving use of a placebo. 3. The effect
produced by a control treatment considered to be nil or ineffective. 4. An effect attributed
to a placebo; an effect attributable to a placebo. rt: sham effect Usage note: Limit usage
to settings involving the actual use of a placebo. Avoid in the sense of defns 2 and 3 when
the control treatment does not involve use of a placebo.
placebo group n - 1. placebo-assigned group 2. placebo-treated group 3. A group not
receiving any treatment. Usage note: Avoid for the reasons stated in the usage note for
placebo patient.
placebo lead-in period n - [trials] A lead-in period in which persons receive a placebo
treatment (as in the Coronary Drug Project18 ) for a time prior to treatment assignment;
typically done to help identify compliant persons. See Brittain and Wittes [1990]7 for
discussion of the usefulness of such strategies. syn: placebo run-in period rt: lead-in period,
shakedown period
placebo patient n - 1. placebo-assigned patient 2. placebo-treated patient 3. A study
patient who does not receive any treatment. Usage note: Literally, a sugar-coated patient
(à la defn 3 for placebo). Use placebo-assigned patient or placebo-treated patient for uses
in the sense of defns 1 and 2, respectively; avoid in the sense of defn 3.
placebo period n - [trials] A period of time in which a person (treatment unit), to be
enrolled or already enrolled, receives a placebo (usually administered either in singleor double-masked fashion); when such a period precedes treatment assignment, usually
referred to as placebo lead-in period or as placebo run-in period; used to aid in the selection
of compliant persons or to facilitate the assessment of eligibility. Periods occurring after
enrollment may arise in relation to washouts or cessations of assigned treatment in relation
to episodes of intercurrent illnesses. rt: lead-in period, shakedown period
placebo reactor n - 1. A person who reports side effects normally associated with the test
treatment while receiving a placebo. 2. A person who reacts to a placebo as indicated by
symptoms or complaints similar to those experienced with the test treatment(s).
placebo treatment n - 1. A treatment involving the use of a placebo. 2. placebo-control
treatment (defn 1) 3. An ineffective or useless treatment used as a control treatment (not
recommended usage). syn: mock treatment rt: adjunctive treatment, control treatment,
sham treatment Usage note: Subject to misuse in the sense of defn 3. Not to be confused
with nontreatment as in trials with nil treatment controls. Also not to be confused with
sham treatment. Use of the adjective modifier placebo should be reserved for settings in
which a placebo is actually used, as in the sense of defns 1 or 2 for placebo.
placebo treatment effect n - 1. The effect produced, or capable of being produced, by
a placebo treatment (defn 1). 2. The effect produced, or capable of being produced, by
an inactive control treatment; placebo treatment (defn 3). Usage note: Subject to misuse
when used in the sense of defn 2. Use of the adjective modifier placebo should be reserved
for settings in which a placebo is actually used, as in the sense of defns 1 or 2 for placebo.
placebo washout n - Administration of a placebo for a defined period of time following
administration of a test treatment to allow time for re-establishment of a proper baseline.
Common in crossover trials following each treatment and prior to administration of the
next one; usually administered in single-masked or double-masked fashion. rt: washout
period
30. Placebo Treatment
89
placebo-assigned adj - 1. Of, related to, or being assigned to receive a placebo treatment.
2. Of, related to, or being assigned to receive an inactive treatment. rt: placebo-treated
Usage note: Use only in the sense of defn 1; avoid as an adjective modifier in the sense
of defn 2 except when a placebo (defns 1 or 2) is used. See placebo treatment for added
comments.
placebo-assigned group n - 1. The group of persons or treatment units assigned to a
placebo-control treatment (defn 1). 2. The group of persons or treatment units assigned to
an inactive control treatment. rt: placebo-assigned patient, placebo-treated group Usage
note: Use only in the sense of defn 1; avoid in the sense of defn 2 when a placebo (defns
1 or 2) is not used. See placebo treatment for added comments.
placebo-assigned patient n - 1. A patient assigned to receive a placebo treatment. 2. A
patient assigned to receive an inactive control treatment. rt: placebo-assigned group,
placebo-treated patient Usage note: Use only in the sense of defn 1; avoid in the sense of
defn 2 when a placebo (defns 1 or 2) is not used. See placebo treatment for added comments.
placebo-control treatment n - 1. An inactive control treatment involving administration
of a placebo in single-masked or double-masked fashion. 2. Any inactive control treatment,
including those not involving administration of a placebo. rt: study treatment Usage note:
Use in the sense of defn 1. Avoid in the sense of defn 2 when a placebo is not used. See
placebo treatment for added comments.
placebo-controlled trial n - 1. A trial in which the control treatment involves the
administration of a placebo. 2. A trial involving an inactive control treatment. Usage note:
Avoid in the sense of defn 2 except when a placebo (defns 1 or 2) is used. See placebo
treatment for added comments.
placebo-treated adj - 1. placebo-assigned (defn 1) 2. Of, related to, or being treated with a
placebo. 3. Of, related to, or being treated with an inactive treatment. rt: placebo-assigned
Usage note: Use only in the sense of defn 2; avoid as an adjective modifier in the sense of
defn 3 except when a placebo (defns 1 or 2) is used. Use placebo-assigned instead of placebotreated when used in the sense of defn 1. See placebo treatment for added comments.
placebo-treated group n - 1. The group of persons or treatment units receiving or
that have received a placebo (defns 1 or 2). 2. The group of persons or treatment units
that receive an inactive control treatment. 3. The group of persons or treatment units
assigned to a placebo-control treatment; placebo-assigned group. 4. The group of persons
or treatment units assigned to receive an inactive control treatment. rt: placebo-treated
patient, placebo-assigned group Usage note: Subject to misuse. Use only in the sense
of defn 1. Often used in the sense of defn 3 as a synonym for placebo-assigned group
(defn 1); avoid by using placebo-assigned group (since there may not be a one-to-one
correspondence between being placebo-assigned and being placebo-treated). Avoid in the
sense of defn 4; use placebo-assigned group if the inactive treatment involves use of a
placebo (defns 1 or 2). Avoid in the sense of defn 2 when a placebo (defns 1 or 2) is not
used. See placebo treatment for added comments.
placebo-treated patient n - 1. A patient receiving a placebo (defns 1 or 2). 2. A
patient receiving an inactive control treatment. 3. A patient assigned to a placebo-control
treatment; placebo-assigned patient. 4. A patient assigned to an inactive control treatment.
rt: placebo-treated group, placebo-assigned patient Usage note: Subject to misuse. Use
only in the sense of defn 1. Often used in the sense of defn 3 as a synonym for
placebo-assigned patient (defn 1); avoid by using placebo-assigned patient (since usually
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I V. T R E A T M E N T G R O U P S / T R E A T M E N T A D M I N I S T R A T I O N
there is not a one-to-one correspondence between being placebo-assigned and being
placebo-treated). Avoid in the sense of defn 2 when a placebo (defns 1 or 2) is not used.
Avoid in the sense of defn 4; use placebo-assigned patient when a placebo (defns 1 or 2)
is used. See placebo treatment for added comments.
N A R R AT I V E
Placebo treatment, narrowly used, refers to a pharmacologically inert substance fashioned
to resemble a test substance that is administered to keep those being treated, and usually
personnel administering the treatment as well, from knowing whether a placebo or test
substance is being administered. Trialists do well to limit use of the term to instances
involving the purposeful administration of an inert substance. The substance may be
injected, applied as a salve or ointment, swallowed as a tablet or capsule, or inserted.
The purpose of placebo treatment is to provide a basis for assessing treatment effect
by removal of effects due to ‘‘suggestion.’’ If administration of a pill reduces complaints
due to symptoms, then the reduction of such complaints with a test treatment has to
be larger than that observed with placebos to consider the test treatment superior. The
greater the likelihood of ‘‘placebo effects,’’ the greater the need for placebo.
Generally, the more objective the outcome measure, the less prone to observer or
reporting bias and the less the need for placebos. The need is greatest with outcomes based
on reports of well-being from the patients or reports of relief of symptoms.
Placebos are designed and used to deceive in a benign sense. To deceive, the
placebo treatment has to resemble the test treatment in all manner of detail—easier said
than done. Ideally, placebo pills should be designed to be indistinguishable from test pills
in shape, color, size, texture, and taste. However, even if one is able to match shape, color,
size, and texture, it may not to be possible to match taste. (See pages 111 through 123 for
more detail.)
Obviously, there are limits to the extent to which deception can be practiced.
Broadly, in the setting of clinical trials, such deception is acceptable only if the fact of
such deception is revealed when soliciting a person’s consent and then only in so far as
the practice can be defended as carrying no more than minimal risk to persons studied.
As a rule, one steers clear of placebo treatments in the absence of ‘‘yes’’ answers to
the questions below.
1. Is the use of placebo treatment defensible in the context of clinical equipoise?
2. Is the use of a placebo consistent with existing norms and standards of care?
3. Is the risk of harm in administrating the placebo nil?
4. Is the risk of harm due to masking (implied with use of a placebo) nil?
5. Are persons to be informed of the use of placebos, the reasons for use, and of safeguards
practiced to preserve persons from harm associated with such use?
6. Is the placebo and related masking necessary to provide reliable and reproducible
results? (likely not if the questions below can be answered yes)
(a) Is the outcome measure bias-robust?
(b) Are patients likely to behave the same regardless of treatment?
(c) Are study personnel likely to treat, observe, and follow patients in the same manner
regardless of treatment?
31. Sham Treatment
91
31. Sham treatment
R E L AT E D E N T R I E S
Study treatments (page 75), Test treatments (page 77), Control/comparison treatment
(page 79), Placebo treatment (page 87)
DEFINITIONS
mock treatment n - 1. sham treatment 2. placebo treatment
sham n - [perhaps fr E dial sham shame, alter of E shame] A trick that deludes; something
false presented to be genuine; a spurious imitation. rt: placebo Usage note: Technically,
both a placebo and sham represent ‘‘tricks’’ that delude and, hence, have a common basis.
However, for trials, placebo is usually reserved for something taken by the person being
studied, e.g., a pill, whereas sham refers to something applied or done to a person by
someone else, as in a sham surgical procedure.
sham effect n - The effect produced by a sham procedure. rt: placebo effect
sham procedure n - [trials] A bogus procedure designed to resemble a legitimate one and
performed for the purpose of masking the person on whom the procedure is performed,
persons administering the procedure, persons observing the person or all three types of
persons as to treatment. rt: placebo Usage note: See sham.
sham treatment n - 1. A bogus treatment that resembles a bona fide one; typically
administered in trials to mask the person receiving a study treatment, those administering
the study treatments, or those observing the person as to treatment; sham procedure.
2. placebo treatment (not a recommended synonym; see sham for reason) syn: mock
treatment
N A R R AT I V E
The adage that ‘‘thou shalt not deceive’’ is applicable in all aspects of life and obviously,
therefore, to clinical research in general and to clinical trials in particular. Largely, the only
deceptions permissible on ethical grounds are those reasonably free of risk and of undue
inconvenience to persons on whom practiced, and then only where persons are informed
that deceptions may be practiced, why they are practiced, and the limits of the deception.
The general mind set of investigators and of IRBs should be to reject deceptions
that have the potential of danger, as well as those likely to be misunderstood (in spite
of best efforts to inform prior to a person’s enrollment), or to be seen as unethical. One
should be wary of all invasive sham procedures to the extent they carry risks to the persons
on whom practiced without offsetting benefits. The benefit is to the research, not to
the persons studied. Even mock treatments involving no risk are questionable when they
involve considerable inconvenience and nuisance to the persons on whom practiced.
Technically, there is little separating placebo and sham treatments. Both forms
of treatment arise because of desire for unbiased assessments of treatment effects.
The difference is in what is required of study personnel to administer the treatment.
Participation is passive in use of masked placebos and typified by situations where neither
the patient nor physician knows whether the treatment being administered is the placebo
92
I V. T R E A T M E N T G R O U P S / T R E A T M E N T A D M I N I S T R A T I O N
or test treatment. Sham treatments are administered by study personnel and usually by
people who know that they are administering a sham.
In general, IRBs are loathe to approve studies involving sham treatments and
rarely in the absence of consents where persons know that shams are administered. The
reluctance comes from concerns regarding the effect of such forms of deception on the
patient–doctor relationship.
In general, the tendency should be to steer clear of sham procedures when
questions, such as below, cannot be answered ‘‘yes.’’
1.
2.
3.
4.
Is a sham-treated control defensible in the context of clinical equipoise?
Is the risk of harm associated with administration of the sham treatment nil?
Is the nuisance and inconvenience associated with administration nil?
Are persons to be informed of the use of a sham, the reasons for use, and of safeguards
to preserve persons from associated harm?
5. Is the sham procedure necessary to provide reliable and reproducible results? (likely
not if questions below answered yes)
(a) Is the outcome measure bias-robust?
(b) Are patients likely to behave the same regardless of treatment?
(c) Are study personnel likely to treat, observe, and follow patients in the same manner
regardless of treatment?
3 2 . Tr e a t m e n t M o d a l i t y
93
32. Treatment modality
R E L AT E D E N T R I E S
Study treatments (page 75), Test treatments (page 77)
DEFINITION
treatment modality n - The method or agent used to treat, ameliorate, or prevent
disease or to improve health; in regard to a test treatment in a trial, the general class of
method or agent by which effect is to be achieved, e.g., via surgery, medical treatment,
radiation, electrotherapy, drug, biologic, device, diet modification, dietary supplement,
counseling, etc.
N A R R AT I V E
The focus of designers should be on characterizing the treatments procedures.
Classifications along the lines as suggested in the definition above should be left to
others, preferably after the trial is finished. Treatment groups can be added or dropped
during the trial. Labels that make sense early in the trial may not make sense later on if
the design is modified to include a new treatment involving a new modality of treatment.
Labeling based on the principal modality represented in a given treatment group
(usually the test-treated group) should be avoided where the following apply
• Treatment in that group involves two or more modes of treatment.
• Study treatments represented in the different test-treated groups in the trial involve
different modes of treatment.
• Test- and control-assigned groups involve different modes of treatment.
The label ‘‘drug trial’’ is best reserved for trials (e.g., such as in the Coronary
Drug Project18 ) where all persons are treated via use of drug or matching placebo.
Most unmasked trials are multi-mode and therefore not amenable to labeling by a single
designated mode. For example, it is misleading to characterize the National Emphysema
Treatment Trial63 as a surgery trial because the control-assigned group is assigned to
receive medical treatment.
3 3 . Tr e a t m e n t S c h e d u l e
95
33. Treatment schedule
SLIDE
Treatment schedule: Coronary Drug Project (CDP)18
One capsule t.i.d. during first 4 weeks following randomization
Two capsules t.i.d. during the next 4 weeks of treatment
Three capsules t.i.d. after the 8th week of treatment
Medication to be taken following the morning, midday, and evening meals unless
contraindicated
Concentrations per capsule
.
ESG1 :
ESG2 :
CPIB :
DT-4 :
NICA :
PLBO :
Estrogen (Premarin)
Estrogen (Premarin)
Clofibrate (CPIB)
Dextrothyroxine (Choloxin)
Nicotinic acid
Lactose placebo
0.28 mg
0.56 mg
0.20 g
0.67 mg
0.33 g
0.33 g
R E L AT E D E N T R Y
Treatment compliance measures (page 97)
DEFINITION
treatment schedule n - The schedule according to which treatment is administered in a
trial. rt: dosage, dose schedule
N A R R AT I V E
A key consideration in any trial is the timing of the initial application of treatment—the
only application in some trials. An issue to be addressed in planning has to do with when
administration of treatment is to occur following randomization. Ideally, it should be
immediate or timed to occur within hours or days following randomization. Clearly, the
greater the time lag, the greater the chance of never applying the treatment.
The time lag should be nil in trials involving use of drugs to be taken by patients,
or where treatments are administered on-site by clinic personnel. It may not be nil
when treatments are administered to a group of persons in group settings (e.g., as in the
Hypertension Prevention Trial (HPT)38 ) or where special facilities and staff are required.
The goal, in such cases, should be to minimize the lag.
In surgical trials, lag can be minimized by scheduling required facilities and staff
prior to randomization. Scheduling in anticipation of assignment works well when the
same facilities and staff are required regardless of assignment (e.g., in eye trials involving
different forms of photocoagulation). It is problematic in trials if it is necessary to cancel
scheduling depending on assignment (e.g., as in a trial where only half of the patients
receive surgery).
96
I V. T R E A T M E N T G R O U P S / T R E A T M E N T A D M I N I S T R A T I O N
Questions relevant to most drug trials include those relating to:
•
•
•
•
•
•
Period of treatment?
Time of first dose?
Size of first dose?
Step-up dosage schedule?
Maintenance dose?
Phase-down dosing?
3 4 . Tr e a t m e n t C o m p l i a n c e M e a s u r e s
97
34. Treatment compliance measures
SLIDE
Treatment compliance measures: Coronary Drug Project
(CDP)18
Direct measures
Pill counts (based on unused portions returned in conjunction with followup
visits)
Laboratory tests for blood or urine level of study drug
Indirect measures
Change in lipid levels
R E L AT E D E N T R Y
Treatment schedule (page 95)
DEFINITIONS
lead-in period n - [trials] 1. A period of time prior to enrollment and within the baseline
period during which study candidates are placed on a treatment similar to one of those
to be evaluated in the trial to assess their tolerance to or acceptance of a treatment, or
to provide information on treatment compliance. The treatment administered may be
similar to the control treatment, as in the Coronary Drug Project,18 or may be a test
treatment [CAST Investigators, 1989].10 Typically, candidates judged to have had adverse
reactions to the treatment or to have unsatisfactorily adhered to the prescribed treatment
are not enrolled. See Brittain and Wittes [1990]7 for a discussion of usefulness of the
procedure. 2. baseline period syn: run-in period rt: placebo lead-in period
pill count n - 1. The number of pills dispensed to a person. 2. The number of pills
remaining in a person’s supply on return to a clinic. 3. The number of pills presumed to
have been taken, e.g., as indicated by the record from an electronic pill dispenser or by
subtracting the count of pills remaining from the number dispensed.
run-in period n - 1. lead-in period 2. enrollment period Usage note: Subject to confusion
because of different meanings, depending on whether used in the sense of defn 1 or 2.
Avoid by using lead-in period or enrollment period, depending on sense of usage.
shakedown period n - 1. A period of time in the course of a study when data forms
and procedures are tested prior to the official start of the study. 2. A period of time after
the start of the study when procedures are still being tested and subject to change. 3.
The initial workup and evaluation of a person for enrollment into a study; especially
one involving administration of treatment, as in a lead-in period, for the purpose of
assessing acceptance and compliance. 4. The period defined by initiation of treatment
after enrollment. rt: lead-in period
tracer substance n - 1. A substance, such as an element, used to trace the course
of a chemical or biological process. 2. A substance which, when introduced into a
98
I V. T R E A T M E N T G R O U P S / T R E A T M E N T A D M I N I S T R A T I O N
biological organism, can be detected and used to draw inferences regarding some action
or underlying process (e.g., about the ingestion or metabolism of a drug by presence of
the tracer substance in urine or blood). rt: biological marker, biological tracer substance
treatment compliance n - 1. Compliance to treatment requirements or procedures. 2. The
degree to which a person or the person’s treater follows the assigned treatment regimen.
syn: treatment adherence ant: treatment noncompliance rt: data collection compliance,
followup compliance, protocol compliance
treatment compliance measure n - Any of various measures of treatment compliance
including those based on medication diaries, pill counts, laboratory tests for tracer
substances of drugs themselves, physician or patient estimates of compliance, prescription
logs, and medication histories. rt: data collection compliance measure, followup
compliance measure, protocol compliance measure
N A R R AT I V E
Compliance measures are important. Obviously, one should not assume that assignment
is equivalent to exposure without descriptive measures of compliance.
‘‘High-tech’’ devices, such as represented by electronic pill dispensers, are appealing
because of the data provided, but there are downsides. The devices can be expensive, may
be ‘‘bulky’’ and not particularly ‘‘patient friendly,’’ and require specialized proprietary
software to harvest data from the devices.
Tracer substances can be used to measure compliance but with limitations. They
have to do with:
• Utility (useful only for indicating recent exposure to assigned treatment)
• Cost
• The need to reformulate a drug to include the tracer substance (addition may effect
bioavailability or interfere with drug)
• The negative physiological effect of blood or urine testing in relation to drug use
Blood or urine tests for metabolism by-products of study drugs can be used as
indicators of compliance. Use of such measures avoids the problems of reformulation with
use of tracer substances, but limitations listed above for tracer substances apply. Others
include:
• General lack of precision (most substances in blood or urine derive from various
sources and hence few tests can be used as positive or negative indicators)
• Need for as many tests as there are test treatments
• Lack of test for certain drugs and for placebos
In many senses, the simplest measures such as pill counts and qualitative assessments
of compliance made by clinic personnel may be best. For sure they are inexpensive.
However, the reality is that compliance measures, regardless of how measured, are
of limited utility. Measures of compliance, at best, are useful only when trying to account
for a lack of treatment difference or in buttressing conclusions regarding treatment effects.
Aids to compliance
• Exclusion of uncooperative or unreliable patients from enrollment
3 4 . Tr e a t m e n t C o m p l i a n c e M e a s u r e s
•
•
•
•
•
•
•
99
Shakedown period involving a lead-in period to exclude noncompliant persons
Emphasis on treatment compliance during consent process
Staff training to ensure familiarity with the treatment protocol
Staff commitment to maintaining treatment compliance
Use of compliance aids and measures
Ongoing checks for treatment protocol departures
Periodic reports on treatment compliance
Indicators of treatment compliance
• Observed administration
• Schedule of dispensing (e.g., as provided by recordings from electronic pill
dispensers)
• Patient reports (e.g., as represented by diary cards completed by patient)
• Counts of unused pills
• Qualitative estimate of consumption made by study personnel
• Tracer substance
• Blood or urine test for drug product
• Treatment effect on secondary outcome(s)
• Compliance scores (e.g., as used in the UGDP94 )
35. Protocol Overrides
101
35. Protocol overrides
R E L AT E D E N T R Y
Protocol bailouts (page 103)
DEFINITIONS
protocol deviation n - A departure from procedures as set forth in the study protocol. rt:
protocol override Usage note: Technically, any protocol deviation is a protocol violation,
but most deviations are of no or minor consequence to the trial or to persons studied.
For example, a clinic failing to supply a missing visit form to document the fact that a
visit was missed is technically in violation of the protocol. A few can be serious, sufficient
to place a person under study at risk of harm, e.g., administration of an overdose of the
study treatment.
protocol override n - A decision, after due consideration and review, to proceed with
some act or procedure contrary to requirements of the study protocol, e.g., as with a
decision to proceed with enrollment of a person not meeting eligibility requirements for
enrollment; especially one authorized by the study sponsor or study leader.
protocol violation n - 1. A protocol departure considered to be serious, e.g., administration
of the wrong treatment or enrollment of an ineligible person. 2. Any protocol departure
whether or not considered to be serious.
N A R R AT I V E
Most protocol overrides occur in relation to enrollment. Typically, protocols list conditions
that a person must have in order to be eligible for enrollment and a list of excluding
conditions. The temptation to deviate from the listings increases as the trial proceeds,
when investigators realize the enrollment goal is illusive.
The usual situation regarding overrides is where a study subject screens eligible
for enrollment save for absence of minor requirements for eligibility or save for presence
of minor excluding conditions. But, since the person is willing to be randomized, the
screening investigator contacts the study sponsor or study leader to request permission to
enroll anyway. If the sponsor or study leader approves, the person is enrolled. There can
be several such overrides over the course of enrollment.
The policy in trials should be proscribe overrides. If investigators believe that
eligibility conditions should be liberalized or that there should be fewer exclusions, they
should modify the protocol and forego enrollment under revised guidelines until the
revisions have been approved by IRBs.
Comments and reminders
• All eligibility overrides should be regarded as protocol violations and should be
reported to IRBs as such.
102
I V. T R E A T M E N T G R O U P S / T R E A T M E N T A D M I N I S T R A T I O N
• Eligibility overrides should be detailed in study publications.
• Requests for overrides should prompt investigators to revise eligibility and exclusions,
to submit such revisions to IRBs, and to refrain from enrollment under the revised
criteria until the amended protocol has been approved by IRBs.
36. Protocol Bailouts
103
36. Protocol bailouts
SLIDE
Treatment protocol bailouts: Childhood Asthma Management
Program (CAMP)11
Inadequate asthma control on full dose of the assigned medication:
Use beclomethasone in addition to assigned treatment (four 42 µg puffs
twice daily); if still not adequately controlled, discontinue assigned treatment and
treat according to best medical judgment.
R E L AT E D E N T R I E S
Treatment schedule (page 95), Treatment compliance measures (page 97), Protocol
overrides (page 101)
DEFINITIONS
crossover treatment n - The treatment given after a treatment switch or treatment
crossover.
protocol bailout n - Provisions allowing for judgment in execution of a study protocol,
e.g., provisions allowing a study investigator to unmask a treatment assignment when
doing so is deemed necessary for the well-being of the person being studied. rt: protocol
compliance, protocol deviation, protocol override, protocol violation Usage note: Not to
be confused with protocol deviation or protocol violation. Bailout provisions are part of
the protocol. Deviations and violations are departures from the protocol.
treatment cessation n - 1. Cessation of treatment of a patient, especially due to lack of
benefit or intolerable or undesirable side effects associated with treatment. 2. Cessation
of a designated treatment regimen in a trial because of lack of benefit, especially such
cessation arising from treatment effects monitoring. 3. treatment termination rt: treatment
suspension
treatment change n - 1. Any change in the treatment of a person mandated by or
consistent with the treatment protocol. 2. Any such change, whether or not mandated by
or consistent with the treatment protocol. rt: treatment switch
treatment crossover n - 1. A change in treatment that is part of the study protocol, as in
a crossover trial. 2. The use of a study treatment other than the one assigned to a person
in a trial having a parallel treatment design. Usage note: Distinguish usage in the sense
of defn 1 from that of defn 2. The two usages carry different implications. In defn 1 the
change is a part of the study protocol. It is not in defn 2.
treatment protocol suspension n - Suspension of the treatment protocol or elements of it;
such suspension based on a recommendation of a treatment effects monitoring committee
to stop a treatment. rt: treatment cessation, treatment suspension, treatment termination
Usage note: Usage generally implies that other elements of the protocol remain in force,
e.g., those having to do with followup and data collection. Hence, patients may continue
to be seen according to the data collection protocol of the trial and to be treated according
to best medical judgment.
104
I V. T R E A T M E N T G R O U P S / T R E A T M E N T A D M I N I S T R A T I O N
treatment suspension n - 1. The temporary cessation of treatment of a patient because
of intercurrent illness or other conditions or events making treatment ill-advised. 2.
treatment protocol suspension rt: treatment cessation, treatment termination
treatment switch n - 1. A change of treatment modality or regimen for a person during
the course of treatment, especially such a change indicated by protocol or best medical
judgment. 2. The administration of a treatment other than the one assigned, especially
such an administration as a result of an error or mixup. rt: crossover treatment, treatment
change
treatment termination n - 1. The termination of treatment of a person because
of intercurrent illness or other conditions or events making treatment ill-advised or
impossible. 2. The termination of a designated treatment regimen in a trial because of
lack of efficacy or because of the possibility of harmful effects. rt: treatment cessation,
treatment suspension
N A R R AT I V E
All protocols in trials are written allowing room for clinical judgment in execution of
the protocols. The duty to persons studied is of higher order than duty to protocol.
In the context of trials, this means that investigators are obliged to choose in favor of
study subjects when duty to them and study protocols are in conflict. In other words,
investigators can follow a treatment protocol only so long as doing so is compatible with
the duty to provide for proper care and treatment of persons studied. Investigators are
obliged to depart from the treatment protocol when following it is not in the best interests
of persons being studied.
Protocols for trials involving repeated application of the assigned treatment (e.g.,
in most drug trials) should be written allowing for reduction or cessation of treatment
based on clinical judgment. Provisions for reduced dosing or temporary cessation of an
assigned treatment are useful in dealing with complaints regarding side effects.
Planners have to decide whether to encourage people to restart treatment if
side effects disappear. Usually, dosing reductions and cessation of treatments is done
without knowledge of the treatments being reduced or stopped in masked trials. Hence,
algorithms for restarts or dose reinstatement have to be written without regard to treatment
assignment.
An issue arising in some trials is whether to allow treaters to administer another
study treatment when the assigned treatment fails to produce the desired effect. Switching,
for the most part, is limited to unmasked trials involving active study treatments. Generally,
switching does not make sense in placebo-controlled trials.
Often ‘‘crossover’’ and ‘‘switch’’ are used interchangeably, but the terms have
different meanings depending on treatment design. ‘‘Crossovers’’ are an expected part of
trials employing crossover treatment designs, whereas they are an ad hoc part of trials
with parallel treatment designs. For that reason it is best to reserve ‘‘crossover’’ to switches
required as part of the treatment design and ‘‘switch’’ for treatment changes in parallel
treatment designs.
Masking
37. Mask/Masking: Definitions
107
37. Mask/masking: Definitions
R E L AT E D E N T R Y
Critical event path analysis (page 241)
DEFINITIONS
blind, blinded adj - [trials] mask, masked; being unaware or not informed of treatment
assignment; being unaware or not informed of course of treatment. Usage note: The term
‘‘blind,’’ as an adjective descriptor in relation to treatment administration, is more widely
used in trials than its counterpart descriptor of ‘‘mask’’ or ‘‘masked.’’ The shortcoming of
‘‘blind’’ as a descriptor in relation to treatment administration has to do with unfortunate
connotations (e.g., as in ‘‘blind stupidity’’) and the fact that the characterization can
be confusing to study subjects (e.g., in vision trials where loss of vision or blindness
is an outcome measure). For these reasons, primary definitions herein involving the
characterization are with mask or masked as the base term.
concealment n - The process and structure in randomized trials for preventing disclosure
of treatment assignments to patients and clinic personnel until patients have been
judged eligible for enrollment, have consented, and have indicated willingness to accept
whatever treatments are assigned. Usage note: Not to be confused with masked treatment
assignment.
double mask, double masked n - 1. An arrangement in which two kinds of persons or
groups of persons are masked. 2. A mask of treatment assignment imposed on persons
receiving treatment and on those administering treatment in a trial. rt: single mask, triple
mask
mask, masked adj - Of, relating to, or being a procedure in which persons (e.g., patients,
treaters, or readers in a trial) are not informed of certain items of information, e.g., the
treatment represented by a treatment assignment in a clinical trial. Usage note: Preferred
to blind for reasons indicated in the usage note for that term.
mask n - [research] A condition imposed on an individual (or group of individuals) for
the purpose of keeping that individual (or group of individuals) from knowing or learning
of some condition, fact, or observation, such as treatment assignment, as in single-masked
or double-masked trials.
mask, masked, masking, masks v - To conceal by withholding, hiding, or obscuring
some condition, fact, or observation.
masked data analysis n - [trials] 1. Data analysis performed analysts masked to treatment
assignment. 2. Data analyses presented with treatment groups masked.
masked data collection n - Data collection performed with the imposition of a mask
in relation to some condition, fact, or observation, e.g., disease status in a case–control
study or treatment assignment in a clinical trial. rt: masked data collector
masked randomization n - 1. Randomization in which treatment assignments remain
masked until issued; concealment. 2. Single or double randomization. ant: unmasked
randomization Usage note: Masked randomization is a property of any assignment
scheme in which assignments are not known or revealed to anyone until a patient has been
108
V. M A S K I N G
judged eligible for enrollment and has consented to enrollment, e.g., as with assignments
generated on demand by computer. The actual treatment to be administered will be
revealed to clinic personnel and patients when assignments are issued in unmasked trials
and only to patients or clinic personnel in single-masked trials. The treatment is not
revealed to either clinic personnel or patients in double-masked trials.
masked reading n - A reading performed under masked conditions; masking may relate to
treatment assignment, disease state or condition of the patient, or information concerning
previous readings.
masked treater n - 1. A treater masked to treatment assignment. 2. A treater masked to
some condition or fact regarding a study subject.
masked treatment n - A treatment that is administered in masked fashion; single-masked
treatment; double-masked treatment.
masked treatment administration n - Treatment that is administered in single- or
double-masked fashion.
masked treatment assignment n - 1. Treatment assignment in which assignments remain
masked until issue, especially any such scheme in regard to the person to be assigned
to treatment and to those requesting the assignment; concealment. 2. Single- or doublemasked treatment assignment. Usage note: Subject to confusion. Limit use to sense of
defn 2. Use concealment for uses in the sense of defn 1.
masked treatment effects monitoring n - Treatment effects monitoring in which results
are masked to treatment assignment.
masked treatment effects monitoring committee n - A treatment effects monitoring
committee masked to treatment assignment, e.g., as achieved by presenting the committee
with a treatment effects monitoring report with treatment groups denoted by codes.
masked trial n - Single- or double-masked trial.
masking level n - The degree to which treatment assignment and treatment administration
is masked in a trial:
full: Masking in which neither study subjects nor study personnel know the treatments
being administered and such that all treatments are similarly masked to each other,
e.g., as in the Coronary Drug Project with all five test treatments masked against a
single placebo.18
partial: Masking that is not full; single masking; masking imposed only on a designated
group of persons: e.g., patients, treaters, data collectors, readers, monitors, or
analysts; double dummy masking; masking in which only some of the treatments
are masked, e.g., as in the University Group Diabetes Program with the insulin
treatments not masked and the two oral antidiabetic agents masked using a double
dummy design.93
none: No masking of treatment administration. Usage note: Double masking, unless
otherwise specified, is presumed to extend to all clinic personnel involved in
treatment and data collection. In unmasked trials, the masking level is none for
study subjects and treaters, but may be partial or full for other clinic personnel,
e.g., as with data collectors masked to treatment assignment.
single masked, single mask n - [trials] 1. A condition in which those being treated are
masked to treatment, but those applying the treatment are not. 2. A condition in which
37. Mask/Masking: Definitions
109
either those being treated or those applying the treatment (but not both) are masked to
treatment.
triple-mask, triple-masked adj - [trials] Of, relating to, or being a procedure in which
neither the experimenters, the people being experimented upon, nor those responsible for
treatment effects monitoring know the identity the treatments.
unmask, unmasked adj - 1. Of, related to, or concerned with not being masked. 2. Of,
related to, or concerned with no longer being masked. 3. Of, related to, or concerned
with removal of a mask.
unmask, unmasked, unmasking, unmasks v - 1. To reveal the treatment assignment of
a person to that person or to some other person (e.g., a person’s study physician). 2. To
reveal the treatment assignment of a group of persons to a person or group of persons (e.g.,
members of a treatment effects monitoring committee when unmasking a monitoring
report). ant: mask
38. Masking Principles
111
38. Masking principles
R E L AT E D E N T R I E S
Drug masking procedure (page 115), Drug packaging and labeling (page 117), Masking
safeguards (page 123)
N A R R AT I V E
The maxims regarding masking are:
• Masked treatment administration is preferred to unmasked treatment.
• Masked data collection is preferred to unmasked data collection.
• Masked readings and assessments are preferred to unmasked readings and
assessments.
Given those maxims, the general approach in planning a trial is to strive for double-masked
treatment administration, if feasible and practical. If not, then to try for single-masked
treatment administration; if that is not possible, then default to unmasked treatment
administration.
The ability to double-mask depends on the treatments. Generally, such masking
is out of the question in trials involving treatments delivered or administrated by different
types of persons (e.g., surgeons vs internists) and is out of the question or impractical
in trials where the route of delivery is different (e.g., in a trial involving comparison of
radiation vs. drug therapy).
As a matter of principle, investigators and IRBs should be disposed to reject
procedures imposed to improve the science of trials when doing so has the potential of
being at the expense of persons studied. As a result, planners should be disposed to look
askance at modes of masked treatment administration in which the likely effect is to:
• Compromise or reduce the ability of investigators to care for persons studied in a
competent manner
• Increase risks for persons studied
• Result in unreasonable levels of inconvenience or nuisance to persons studied
Masked administration of treatment should not be imposed in the absence of good
faith efforts to ensure that persons enrolled understand that treatments will be masked
and the reasons for masking. In general, masking should not be imposed if imposition or
maintenance of the mask requires subterfuge or lying to patients. Additionally, it is best
avoided where:
• The probability of error in administration is nontrivial because of masking.
• Administration of masked treatments involves nontrivial risk.
• Administration of masked treatments involves nontrivial nuisance or inconvenience
to persons being treated.
• Multiple forms of placebos or shams are needed to mask.
• Competency required to care for persons is reduced because of the masking.
112
V. M A S K I N G
• Procedures for unmasking in case of emergencies are lacking.
• Masking is transparent and charade-like.
• Masking requires contrived modes of administration or dosage or treatment
schedules having little or real-world relevance.
39. Masking, Censoring, and Shielding Specifications
113
39. Masking, censoring, and shielding specifications
SLIDE
Masking and censoring specifications: Coronary Drug
Project (CDP)18
Double-masked administration of treatment
Treatment assignments to remain masked to patient and clinic personnel, except in
cases of emergency
Cholesterol levels measured at central laboratory; results not fed back to clinic
R E L AT E D E N T R I E S
Masking principles (page 111), Drug masking procedure (page 115), Drug packaging and
labeling (page 117), Masking safeguards (page 123)
DEFINITIONS
censor, censored, censoring, censors v - To delete, suppress, or eliminate. rt: informative
censoring, uninformative censoring, mask Usage note: In the context of trials and other
types of followup studies, censoring occurs when the observation of interest cannot be
made or is not counted in an analysis because of some intervening condition or event.
Most of the censoring arises from the fact that enrollment continues over a period of time
and therefore persons at any point in time during the trial are seen for differing periods
of time, depending on when enrolled. For example, suppose observation up to 30 Jan
1996 for an interim analysis, one person enrolled on 30 Nov 1995 (P1 ), and one person
enrolled on 30 Dec 1995 (P2 ). P1 contributes 61 person-days of observation and P2
contributes 30 person-days of observation. Observation of P2 beyond day 30 is censored
because of when enrollment occurred. A second form of censoring occurs because of
missed visits or dropouts. For example, suppose it is not possible to observe P1 beyond day
45 because the person refused further observation. Observation is censored at day 45 for
variables requiring person contact for observation. Another form arises from eliminating
observations made after occurrence of some event or condition. For example, suppose
an analysis involving the comparison of treatment groups for an event while on assigned
treatment, e.g., the first occurrence of systolic blood pressure being above a specified level.
Suppose that P2 was taken off the assigned treatment on day 15 and that the event of
interest occurred on day 20. Observation, for purposes of the analysis, would be censored
at day 15; and the event, though observed, would not be counted because of the censoring
imposed. Censoring not related to or presumed not to be related to the variable of interest
is referred to as uninformative censoring (e.g., the censoring in the first example because
of when persons are enrolled). Censoring related to or likely to be related to the measure
or event of interest is referred to as informative censoring (e.g., censoring due to refusal to
continue under followup in the second example if missed visits are treatment-related or
in the blood pressure example).
informative censoring v - Censoring related to the variable of interest, e.g., in trials
censoring due to missed visits, where missed visits are related to treatment.27 ant:
uninformative censoring
114
V. M A S K I N G
mask, masked, masking, masks v - To conceal by withholding, hiding, or obscuring
some condition, fact, or observation.
shield, shielded, shielding, shields v - [trials] The act or process of keeping designated
types or classes of information (e.g., interim treatment results) from specified groups or
classes of persons (e.g., clinic personnel) during conduct of a trial.
uninformative censoring v - [trials] Censoring not related to treatment. ant: informative
censoring
N A R R AT I V E
Generally, treatment assignment is concealed to all concerned until released (see
Randomization procedures, page 157) and assignments will remain masked after release
to patients and clinic personnel in double-masked trials.
The trialist may opt to censor information considered likely to introduce treatmentrelated feedback bias, e.g., information for laboratory tests likely to be differential by
treatment group (provided the information is not essential in the care or treatment of
persons in the trial).
Shielding may be imposed to keep investigators from seeing interim results to
reduce the risk of treatment-related bias in the treatment and observation processes in
trials.
Study documents, principally the study protocol and study handbook, should
indicate the extent of masking to be employed, the information to be censored, and
whether investigators are to be shielded from interim results.
40. Drug Masking Procedure
115
40. Drug masking procedure
R E L AT E D E N T R I E S
Masking principles (page 111), Masking, censoring, and shielding specifications (page
113), Drug packaging and labeling (page 117), Masking safeguards (page 123)
DEFINITIONS
double placebo n - A placebo having two different shapes or forms, e.g., a tablet and a
capsule, as needed in a double placebo treatment design; also double dummy placebo. rt:
single placebo, multiple placebo
multiple placebo n - [trials] A placebo that has two or more forms or shapes, e.g., as
required for masking in a trial involving two or more test treatments having different
forms or routes of administration. rt: single placebo, double placebo
single placebo n - A placebo having a single shape or form, e.g., as needed in a trial
having a single placebo treatment design. rt: double placebo, multiple placebo
N A R R AT I V E
If masking is done via use of placebos, the placebos have to match the test treatments to
be useful. Generally, only drug manufacturers will have placebos matching their products.
If a manufacturer is not willing to supply a matching placebo for their product, the only
viable alternative will be overencapsulation or reformulation to allow repackaging, e.g.,
by pulverizing pills to produce a powder form for dispensing in capsules. The downside
is that the reformulation may affect the bioavailability of the product.
Generally, more than one placebo will be required in trials involving use of two or
more test treatments where one or more of the following apply:
• Administration is via different routes (e.g., via mouth for one test treatment and via
injection for another)
• Desire to use placebos provided by the manufacturers of the different test drugs
• Use of two or more medications on the same patient, each administered according
to its own schedule
If labeled drug is shipped to study clinics, indicate:
•
•
•
•
•
Recipient (usually the local pharmacy)
Person or group responsible for dispensing drug
Method of masking
Method of dispensing
Keeper of treatment codes
If dispensed in syringes, indicate where syringes are filled and method of masking
content.
41. Drug Packaging and Labeling
117
41. Drug packaging and labeling
SLIDE
Drug packaging and labeling: Coronary Drug Project (CDP)18
Number of drug regimens: 6 (1 placebo; 5 test treatments)
Route of administration: Oral (capsule; opaque gelatin shell; size #1)
ESG1:
ESG2:
CPIB:
DT-4:
NICA:
PLBO:
Estrogen (Premarin)
Estrogen (Premarin)
Clofibrate (CPIB)
Dextrothyroxine (Choloxin)
Nicotinic acid
Lactose placebo
Concentration/Capsule
0.28 mg
0.56 mg
0.20 g
0.67 mg
0.33 g
0.33 g
Formulary: USPHS pharmacy at Perry Point, Maryland
Drug distribution to study clinics: From Perry Point pharmacy
Dispensing: In bottles of 100 capsules from study clinics or local hospital pharmacy
Means of identification for purposes of assignment: Bottle number (1–30)
R E L AT E D E N T R I E S
Masking principles (page 111), Masking, censoring, and shielding specifications (page
113), Drug masking procedure (page 115), Masking safeguards (page 123)
DEFINITIONS
batch number n - A number displayed on a product, on its container, or on the label
serving to identify the production run from which it came; also lot number.
blister pack n - A card or strip of bubble-like blisters containing unit doses of a medication;
blisters backed by a foil-like paper designed to break when pressed; used in trials to aid
persons in following a time schedule for treatment (by arranging blisters to correspond
to times or days on which medications are to be taken) or to facilitate the assessment of
treatment adherence; may be on strips contained in a dispenser designed to electronically
record times when the strip is pulled from the container.
bin number drug system n - A system in double-masked randomized trials in which
treatment assignment is indicated by bin number (see Coronary Drug Project for example
involving 30 bins18 ); typically a system in which more than one person receives medication
from the same bin; system easier to implement and manage than med Id number system
and typically more medication conserving; downside relates to potential for collateral
unmasking if a bin number is unmasked.
lot number n - The number used to identify units of a lot; also batch number.
med Id number drug system n - A drug dispensing system in which assigned treatment
is indicated by a unique number, e.g., a system in which patient Id number corresponds
to med Id; dispensing system more difficult and expensive to implement and manage
118
V. M A S K I N G
and less medication conserving than the bin number dispensing system but immune to
collateral unmasking because of unique numbering scheme, e.g., as discussed in relation
to ADAPT.51
N A R R AT I V E
The devil is in the details when it comes to packaging and labeling drugs for masked
administration. One obvious clue in the masking is lot and run numbers. Study drugs
and matching placebos will have different lot and run numbers, whether packaged by
the same or different pharmacies. The best that can be done is to imbed the numbers in
sequences of numbers to make identification by those numbers difficult.
The package label will also display the product expiration date. Operationally, this
means that all product, including placebo, must have the same expiration date.
Interstate shipment of drugs requires labeling as to content. One approach to
complying with the regulation in placebo-controlled trials is to label the contents as being
either the test drug or lactose (matching placebo).
For drugs dispensed to study subjects in pill form, the simplest, and usually least
expensive, method of dispensing is in bottles. Investigators have to decide whether to
dispense with childproof caps; prudent for drugs going into homes with small children
but not necessarily for studies in the elderly with arthritic, hands.
An alternative to bottles is blister packs. This form of packaging can be useful
when patients are required to take two kinds of pills or where the number of pills to be
taken differ, depending on time of day or day of week. Disadvantages are those related to
the cost and reduced utility. Blister cards are not as easy to pack for transport or store as
bottles and may be more difficult to use, especially if the pills are small and the blisters are
hard to break.
Medication has to be labeled for randomization. Basically, there are two options:
bin numbering or med numbering.
With med numbering, each patient receives uniquely labeled medication. The
usual approach with such numbering is to supply clinics with medication labeled with
patient Id numbers or with numbers linked to patient Id numbers.
The virtues of unique labeling lies in its robustness in regard to preservation
of masking. Breaking the code for a particular patient affects only that assignment,
revealing nothing about any other assignment. The disadvantages are in the costs and
added logistical complexities in unique labeling. Product for a person has to be supplied
assuming perfect compliance over the period of treatment. Drug not used, for whatever
the reason, is wasted. The amount wasted can be large if compliance is low or if a person
drops out early in the course of treatment.
Med numbering is reasonable in short-term trials when all drug needed for a person
can be supplied on enrollment. It is problematic where patients have to be resupplied
with drug over the course of the trial.
The alternative to unique labeling is bin numbering. In its simplest form, in a
trial involving just one test drug and a matching placebo, there would be two bins, Bin
1 and Bin 2, of drug at a clinic: one containing the test drug and the other containing
the placebo. Persons, on enrollment, would be randomized to receive drug from Bin 1 or
Bin 2.
41. Drug Packaging and Labeling
119
The shortcoming with such a simple system is in its lack of robustness in regard to
treatment masking. Any unmasking, purposeful or accidental at a clinic, would unmask
all patients in that clinic. The obvious fix is to increase the number of bins. For example,
instead of two bins one could have 8 bins, with four bins containing drug A and the
other 4 containing drug B. The robustness of the system to unmasking increases with the
number of bins, but so does cost.
The bin system was used in the Coronary Drug Project.18,60 It involved 30 bins
per clinic, with each bin containing bottles of placebos or one of five different test
medications. Unmasking a particular bin at a clinic had the effect of unmasking all other
patients receiving medication from that bin. The amount of unmasking caused by such
unmasking was a function of the number enrolled at a clinic, e.g., 4 to 6 patients at a
clinic with an enrollment of around 150.
The obvious advantage of the bin system is in reduced wastage of drug and in
simplifying resupply. Clinics are supplied on a per bin basis rather than on a per patient
basis. Bins in short supply can be supplied accordingly. Similarly, clinics in multicenter
trials running low on medication in a particular bin before resupply can be temporarily
supplied from another clinic (assuming a common bin system). That possibility does not
exist with the unique labeling scheme.
Also of concern in masked drug trials is the ability to unmask in case of emergency.
The two most common modes of providing such capability are by access to a 24-hour
1-800 number or by use of ‘‘scratch-off’’ or ‘‘open in case of emergency’’ labels. Usually,
drugs are shipped to clinics with that label attached with instructions that it be removed
before dispensing. The tear-off labels are retained at clinics to be opened in case of
emergency.
42. Drug Supply
121
42. Drug supply
R E L AT E D E N T R I E S
Drug masking procedure (page 115), Drug packaging and labeling (page 117)
N A R R AT I V E
The options for drug supply from manufacturer to study clinics are:
1. Received packaged and labeled at study clinics from manufacturer
2. Bulk shipped to study clinics; packaged and labeled at clinic pharmacies for dispensing
3. Bulk shipped to a central pharmacy for packaging and labeling; shipped to study clinics
for dispensing from the central pharmacy
The method of supply depends on various factors including:
•
•
•
•
•
•
Number of study clinics
Location of study clinics (same country; different countries)
Enrollment period
Treatment period
Availability and uniformity of drug
Method of labeling for dispensing (med Id numbering or bin numbering; Drug
packaging and labeling; page 117)
The simplest approach to supply is to acquire the entire supply of product needed
before the start of enrollment. However, that approach is viable only if:
•
•
•
•
Drug can be formulated, packaged, and stored until needed
Number of persons to be enrolled is known at the outset
Number of clinics is known at the outset
Expiration date beyond period of use
The approach is not viable when:
• Clinics are likely to be added over the course of the trial
• Number of persons to be enrolled likely to change during the trial
• The amount of product required to supply a clinic at the outset is large making
storage difficult or problematic
• Treatment extends over a period of years
• Supply needs cannot be reliably predicted at the outset
Marketed drug can be purchased from manufacturers or wholesalers. The advantage
of purchase is that it eliminates the need to negotiate with manufacturers for gratis supply.
The disadvantage is that the cost can be significant, making it more difficult to fund the
trial.
The option for purchase does not exist for products under investigational new
drug applications. Such products have to be supplied gratis by the manufacturer because
they cannot be purchased.
122
V. M A S K I N G
One approach to supply is on a per-person basis when a person is randomized.
The amount needed is the amount required if the person takes the full dosage over the
course of the trial, plus an extra amount to cover loss and wastage.
Suppose a trial in which a person is to take a pill a day over a one-year period,
that the person will be seen at monthly intervals over the course of treatment, and that
the person will be given a new supply of medicine at each visit. In that case, one would
need 12 bottles of medication, each containing a sufficient number of pills to keep the
person in medicine even if a week or two late for an appointment, say 45 pills per bottle,
plus two or three bottles for reserve if a patient loses or misplaces bottles. The amount of
product not used when the year is out will depend on compliance of the patient to the
treatment schedule and losses.
The up-front per patient method of supply is not recommended where:
•
•
•
•
•
•
Drug is in scarce supply.
Drug is expensive.
Extended there is an extended period of treatment.
Dropout rate is nontrivial.
Patient compliance is likely to be low or nil in some cases.
Study physicians are likely to stop treatment.
An alternative to up-front supply is to resupply on a per-person basis as needed
over the course of the trial. The resupply can be done via local pharmacies by bulk
supplied to study clinics. Or it can be done from a central pharmacy by orders from study
clinics. Of the two approaches, the latter is preferable because:
• It is easier to manage and perform quality control.
• It limits access to treatment assignment schedule to a single pharmacy; treatment
assignment schedule known to local pharmacies when drug is labeled and dispensed
from local pharmacies.
• It is less prone to randomization breaches or inadvertent unmasking.
Systems of resupply are necessary when the up-front method of supply is impractical
or when the period of treatment is long.
The method of resupply is influenced by how assignments are issued. It has to be
done on a per-person basis when assignment is linked to patient Id number. It can be
done by bin with bin systems of dispensing drug.
43. Masking Safeguards
123
43. Masking safeguards
SLIDE
Masking safeguards: Chemoprevention for Barrett’s
Esophagus Trial (CBET)36
•
•
•
•
•
Unique labeling; assignments linked to Id number of patient
Drug and placebo bottled and packaged at a central pharmacy
Drugs dispensed from central pharmacy to clinics on per-patient basis
Drugs shipped with patient Id number, name code, and clinic Id on label
Unmasking at clinic proscribed except in special cases relating to emergencies
R E L AT E D E N T R I E S
Masking principles (page 111), Masking, censoring, and shielding specifications (page
113), Drug masking procedure (page 115), Drug packaging and labeling (page 117)
N A R R AT I V E
Mask preserving safeguards and practices for double-masked trials include the following:
• Good packaging and labeling procedures that are mask preserving (see Drug masking
procedures, page 115; and Drug packaging and labeling, page 117).
• Limit unmasking to emergencies or to where knowledge of treatment is essential for
well-being of person.
• Limit access to treatment codes in clinics (e.g., by placement of such codes with a
person in the clinic or with a central authority reachable day or night via an 800
number).
• Establish processes for unmasking aimed at preservation of mask, e.g., as by calling
a central number in which person strives to ensure that the request for unmasking
is appropriate before unmasking.
• Establish treatment procedures that are mask preserving, e.g., write the treatment
protocol to permit study physicians to cease using an assigned medication without
being informed as to whether the treatment is the test or control medication.
44. Unmasking Treatment Assignment
125
44. Unmasking treatment assignment
R E L AT E D E N T R I E S
Masking principles (page 111), Masking, censoring, and shielding specifications (page
113), Drug masking procedure (page 115), Drug packaging and labeling (page 117),
Masking safeguards (page 123)
N A R R AT I V E
Even with mask preserving safeguards (see page 123), one can expect to encounter
circumstances where it is necessary or prudent to unmask assignments for study subjects.
Instances are where:
• It is necessary to decide whether to proceed with a treatment (e.g., in an emergency
room) that is contraindicated in the presence of a particular study treatment.
• Patient demands to know assignment.
• Patient’s physician needs to know.
• IRB asks for assignment, e.g., in regard to a reported adverse event.
• Study staff responding to a call from a person reporting that someone other than
the patient has taken study drug.
Most unmasking occurs as a matter of course at the end of treatment when a trial
is stopped or finished.
Planners need to be mindful of processes and procedures for unmasking when the
trial is planned. The method of closeout (see Closeout design, page 225) in double-masked
drug trials has implications for packing of drug. The bin system of labeling (see Drug
packaging and labeling, page 117) is not recommended for systems of closeout based on
common period of followup. Patients and treaters in such designs are unmasked on a
per-patient basis as patients reach a defined point in followup. To allow that to happen
without unmasking treaters or patients still under followup, one needs a unique labeling
scheme. The bin system of labeling should be used only where en masse unmasking is
planned, e.g., as is usually the case in designs involving common closing date designs.
Conditions for unmasking
• When treatment assignment is needed to make an informed decision as to course of
treatment
• When patient or IRB demands to know
• Accidental overdose by a patient or use of patient’s study drug by a child or someone
else in patient’s family
• When a treatment is stopped because of lack of benefit or because of the potential
of harm
• When a treatment is considered superior to other study treatments and eligible
patients are to be offered that treatment
• When the trial comes to a natural end with a common closing date design
• When the trial is aborted or stopped
45. Results Blackouts
127
45. Results blackouts
R E L AT E D E N T R I E S
Masking, censoring, and shielding specifications (page 113), Unmasking treatment
assignment (page 125), Publication policy (page 429), Presentation policy (page 439):
Policy on access to study data and results (page 449)
DEFINITIONS
blackout n - In the jargon of trials, broadly, a proscription on the flow of information
concerning a trial until lifted by study leaders; may apply to persons inside and outside
the trial or only to persons outside the trial; results blackout. rt: shielding, results blackout
results blackout n - [trials] 1. A state of conduct in which investigators are shielded
from interim results, e.g., as required in imposed states of equipoise. 2. Any of various
constructs imposed to keep treatment results from being revealed or made known to the
public until presented or published by study investigators.
shield, shielded, shielding, shields v - [trials] The act or process of keeping designated
types or classes of information (e.g., interim treatment results) from specified groups or
classes of persons (e.g., clinic personnel) during conduct of a trial.
N A R R AT I V E
Blackouts are imposed to keep specified types of information from designated groups of
people. By definition, any blackout internal to the trial extends to the public at large.
Blackouts relating to the fact that a trial is being done and to details of its design
should not be imposed. (See Publicity policy, page 445; and Policy on access to study
documents, page 447.) That information should be freely available to anyone who wants
it. Openness in research on human beings is essential for public trust.
The usual practice in trials is to shield investigators from interim results when
possible. (The feasibility of such shielding is limited to situations where clinical
investigators do not have access to study data—the usual case in multicenter trials
with data residing in coordinating centers.) The practice exists because of concern
regarding the risks of treatment-related feedback biases if study investigators know the
trend of results.
Generally, regardless of whether or not investigators are shielded from interim
results, interim results are blacked out beyond the trial. (See Policy on access to study data
and results, page 449).
Recommendations concerning results shielding and blackouts
• Proscribe access to interim results outside the study (see Publication policy, page
429)
• Establish policy on whether investigators will be shielded from interim results;
default to shielding unless there are compelling reasons to the contrary
• Outline conditions and circumstances for lifting the investigator shield; outline
early in the course of the trial; submit to study officers for review and approval
128
V. M A S K I N G
• Specify groups or persons within the investigatorship who will see interim results
• Outline how investigators will be informed of results when the shield is lifted
Recommendations
•
•
•
•
Done at a face-to-face investigator meeting
Analyses performed by coordinating center
Presentation done by people from the coordinating center
Moratorium on public comment until results are presented or published
Usual conditions for lifting investigator shield
• When considering a recommendation for a results based protocol change as provided
by the treatment effects monitoring committee
• When the trial is finished or stopped
Usual conditions for unmasking treatment effects monitoring committee (if masked)
• When masking is transparent
• When there is a trend suggestive of need for action
• When members believe they cannot meet their responsibilities to patients and
investigators if masked
Bias and Variance
Control
46. Bias Control Procedures
131
46. Bias control procedures
SLIDE
Bias control: Glaucoma Laser Trial (GLT)35
Randomization
Assignments not revealed to clinic personnel until consent signed and necessary
baseline data obtained
Person counted as enrolled when assignment revealed to clinic personnel
Masking by separation (treatment and followup performed by different personnel)
Tonometer operator masked to IOP level during measurement
Training and certification of treating and following ophthalmologist, clinic
coordinator, and persons measuring IOP
Octopus automated perimetry
Ongoing data editing
Site visiting
R E L AT E D E N T R Y
Separations (page 141)
DEFINITIONS
bias n - [fr OF bias, oblique, fr OProv, perhaps from Gk, epikarsios, oblique] 1. An
inclination of temperament, state of mind, or action based on perception, opinion,
or impression that serves to reduce rational thought or action or making impartial
judgments; a specified instance of such an inclination; prejudice. 2. A tendency toward
certain measurements or outcomes over others as a result of a conscious or subconscious
mind set, temperament, or the like; a specific expression of such a tendency. 3. Deviation of
the expected value of an estimate of a statistic from its true value. Usage note: Distinguish
between uses in which bias (defn 1 or 2) is being proposed in a speculative sense as
opposed to an actual instance of bias. Usages in the latter sense should be supported
with evidence or arguments to substantiate the claim. Usages in the former sense should
be preceded or followed by appropriate modifiers, explanatory clauses, or statements to
make it clear that the user is speculating rather than stating a fact. Similarly, since most
undifferentiated uses (in the sense of defns 1 or 2) are in the speculative rather than fact
sense, prudent readers will treat all uses of the term as being in the sense of speculation,
except where accompanied by data, evidence, or arguments to establish bias as a fact.
frozen state of equipoise n - [trials] An imposed state intended to keep study investigators
from knowing the nature or trend of interim results; achieved by proscription of interim
analyses or by constructs to shield study investigators from results of interim analyses, e.g.,
as in apartheid treatment effects monitoring. rt: clinical equipoise, equipoise Usage note:
Not to be confused with masked treatment administration. The state is imposed to reduce
the risk of treatment-related feedback bias. Concerns regarding that bias are greatest in
unmasked trials, but are present in masked trials to the extent that masking is never perfect.
132
V I . B I A S A N D VA R I A N C E C O N T R O L
treatment-related bias n - 1. Bias related to treatment. 2. Bias related to treatment
assignment. rt: treatment-related feedback bias
treatment-related feedback bias n - [trials] 1. Bias in an observation, measurement,
reporting, analysis, or administration process or procedure due to knowledge of interim
treatment results on the part of the one observing, measuring, reporting, analyzing,
or administering. 2. Differential behavior of persons enrolled into a trial due to their
having knowledge of interim treatment results, e.g., a differential loss to followup due
to differences in the willingness of persons to continue because of knowledge of interim
treatment results. Usage note: Use with caution as a claim or assertion. The existence of
a feedback bias is difficult to establish. It does not operate in the absence of knowledge
of interim results and is unlikely to operate in the presence of nil interim treatment
results. Knowledge of an interim treatment result is not sufficient for the bias to operate.
One must also be able to argue plausibly that this knowledge can produce the bias. It
is difficult to do so in masked trials, and especially in double-masked trials. Even if a
treater has access to interim results, that information, to translate into a treatment-related
bias, must be related to individual patients and must influence how individual persons
are treated or observed in the trial. It is not possible to relate results to individual patients
if the treater is effectively masked to treatment assignment. Further, even if a treater or
data collector is not masked, it is difficult to argue plausibly that a treatment difference
is due to a treatment-related bias if the process or procedure in question is robust to the
bias. For example, there is not much of an opportunity for the bias to operate if the
measurement in question is not prone to errors of interpretation or reporting (e.g., as
with most event-type outcomes, such as death or events indicative of gross morbidity).
Nor is there much room for the bias to operate if a process or procedure is well-defined
(e.g., as in a treatment protocol with explicit rules for when and how treatments are to be
altered in the presence of specified conditions). Generally, the more objective the process
or procedure, the more difficult it is to plausibly argue that knowledge of interim results
can produce a treatment-related feedback bias.
treatment-related selection bias n - Broadly, bias related to treatment assignment
introduced during the selection and enrollment of persons or treatment units into a trial.
Often, selection bias due to knowing treatment assignments in advance of use and using
that information in the selection process. The risk of the bias is greatest in unmasked trials
involving systematic assignment schemes (e.g., one in which assignments are based on
order or day of arrival of persons at a clinic). It is nil in trials involving simple (unrestricted
randomization) but can arise in relation to blocked randomization if the blocking scheme
is known or deduced. For example, one would be able to correctly predict one-half of the
assignments before issue in an unmasked trial of two study treatments arranged in blocks
of size two, if the blocking is known or deduced. The chance of the bias operating, even if
the blocking scheme is simple, is minimal in double-masked trials (because correct guesses
are not likely to translate into a treatment-related selection bias when the treatments are
masked).
N A R R AT I V E
The usual methods of bias control are via any or all of the following:
• Randomization
• Masking (patients; physicians; data collectors; readings; data analysts)
46. Bias Control Procedures
•
•
•
•
•
•
133
Separations (see page 141)
Frozen state of equipoise
Training
Certification
Standardization (treatment procedures; data collection procedures; definitions)
Surveillance
47. Stratification
135
47. Stratification
SLIDE
Stratification: Coronary Drug Project (CDP)18
Stratification variables
Clinic (55)
MI risk category (2 levels)
Assignment strata: 55 × 2 = 110
R E L AT E D E N T R Y
Variance control procedures (page 139)
DEFINITIONS
stratification n - 1. Broadly, the act or process of stratifying. 2. An active ongoing process
of stratifying, as in placing patients into strata as they arrive at a clinic as a prelude to
enrollment and randomization to treatment in a trial. 3. The act or process of classifying
treatment units or observations into strata for a subgroup analysis; post-stratification. rt:
classification, quotification Usage note: Stratification is done as a means of controlling
sources of variation related to or assumed to be related to outcomes. Stratification and
blocking in the treatment assignment process serve different purposes. Blocking is imposed
as a means of ensuring that the assignment ratio in fixed treatment assignment schemes
will be satisfied; stratification is done to ensure the comparability of the treatment groups
with regard to the variable(s) used in stratification. There is confusion regarding the
meaning and impact of stratification in the design and operation of trials. Often the act
of stratification is seen as needed to perform treatment comparisons within the strata
represented in the stratification. Although that may be desirable, such comparisons are
not necessary. Valid comparisons of the treatment groups can be made without regard to
stratification. Confusion also arises from use of the term stratification in two distinctly
different contexts, as suggested in defn 2 and 3 above. Use post-stratification for uses
in the sense of defn 3, especially when in settings, such as trials, where both forms of
stratification are used.
stratification variable n - 1. A variable used to classify treatment units into strata in
relation to treatment assignment. 2. A variable used to classify observation units into strata
in relation to data analysis.
stratify, stratified, stratifying, stratifies v - 1. Broadly, to divide or arrange into classes
or groups. 2. To so divide or arrange in an active, ongoing way as a prelude to some
act or process, e.g., as in arranging or classifying patients into strata for randomization.
3. To so divide or arrange an assembled group of observation units or treatment units
and associated data preparatory to a subgroup analysis; post-stratify. Usage note: Not to
be confused with matching. Stratifying is a classification process. Matching is a pairing
process.
136
V I . B I A S A N D VA R I A N C E C O N T R O L
N A R R AT I V E
Conditions favoring stratification
• Expected quantitative interaction (expected qualitative interaction should lead
designers to exclude persons expected to not benefit from treatment)
• Different menu of treatment options or regimens depending on the state of a
stratification variable
• Control of variable known to be predictive of outcome
• Logistic practicality
• Designed subgroup comparisons
Considerations in choice of stratification variables
• Relationship to outcome of interest (limit choice to variables known or believed to
influence outcome)
• Number of variables (limit to small number)
• Gain in precision (gain diminishes with size of trial; small for trials involving >50
patients per treatment group)
• Logistics (stratification complicates the randomization process; variables that cannot
be directly observed, e.g., the result of a diagnostic test or reading, may cause delays
in assignment)
Stratification variable
Acceptable
• Demographic characteristics, e.g., gender, race/ethnicity, age at entry
• Baseline characteristic
• Disease history or state on entry
• Prior treatment on entry
• Location; clinic
Unacceptable
• Variables observed after randomization
Observations and facts regarding stratification
• The larger the number of assignment strata, the greater the chance of a sizable
departure from the expected assignment ratio (Note: One can guard against such
departures by using blocks of small size, but small size may allow study personnel to
predict assignments.)
• Having a great number of strata can be the operational equivalent of no stratification
in balance provided.
• Stratification does not eliminate need for adjustment for differences in the baseline
composition of the study groups.
• Stratification is for variance control; it does not obligate one to make treatment
comparisons by strata or to report results by strata.
47. Stratification
137
• Stratification implies a floating enrollment economy, i.e., it does not imply the need
to enroll designated numbers by strata and should not be confused with enrollment
quotas.
Stratification vs. post-stratification
Difference
• Stratification is an active process carried out as a prelude to treatment
assignment; post-stratification is a process performed at analysis time.
Similarity
• Both are done for variance control in regard to the variable(s) used for
classification.
Notes and observations
• Use stratification to refer to the active process and post-stratification to refer to
the passive process.
• Subgroup analyses using characteristics observed at or prior to randomization
are forms of post-stratification.
• Post-stratification is a poor person’s approach to other more sophisticated forms
of adjustment for baseline differences in the composition of the treatment
groups.
• There are profound operational differences between stratification as a
prerequisite to randomization and post-stratification.
4 8 . Va r i a n c e C o n t ro l P ro c e d u re s
139
48. Variance control procedures
SLIDE
Variance control procedures: Childhood Asthma
Management Program (CAMP)11
Masked treatment administration
Training and certification of key clinic personnel
Expert spirograph reader
Site visiting
Semiannual face-to-face meetings of investigators
Monthly performance reports distributed to clinics
Maintained protocol and study handbook
R E L AT E D E N T R Y
Stratification (page 135)
DEFINITION
variance n - [MF variaunce, fr MF, fr L varianita, fr variant-, varians, prp of variare to
vary] 1. A parameter equal to the second moment of its underlying variable (or associated
distribution function) about its mean. 2. The mean of the square of differences about the
mean of a frequency distribution; a similar quantity using n − 1 rather than n as a divisor.
3. The square of the standard deviation. rt: standard deviation
N A R R AT I V E
If the first concern of the trialist is to protect against treatment-related bias (see page
131), the second is with variance reduction and control. Variation is noise. The larger
it is, the harder it is to distinguish signal from noise. In the case of trials, the signal is
that associated with treatment assignment. Noise comes from variations among persons
studied, in how they are treated, in how and when they are observed, in how observations
are made, reported, and analyzed, and in a host of other activities over the life of a
trial.
Control and reduction strategies
Design
• Crossover designs
• Matching or pairing of assignment units
• Randomized comparison group
Patient selection
• Selectivity
• Exclusion
140
V I . B I A S A N D VA R I A N C E C O N T R O L
Execution
• Stratification
• Blocking
• Standardization
Analysis
• Use of baseline covariates for adjustment
• Multiple regression analyses
• Subgroup analyses
• Trimming and Winsorization
Reduction strategies
•
•
•
•
•
Increased sample size
Replication of a measurement
Ongoing surveillance and quality control
Ongoing data editing
Standardization
Other aids
•
•
•
•
•
•
•
Written protocol
Handbooks and manuals of operation
Outlier detection and trimming procedures
Standardized equipment
Central readings and determinations
Training and certification
Site visits
49. Separations
141
49. Separations
SLIDE
Separations: Glaucoma Laser Trial (GLT)35
Treating and following ophthalmologist
Coordinating center and clinics
Sponsor and investigators
Treatment effects monitoring committee and investigators
R E L AT E D E N T R Y
Bias control procedures (page 131)
N A R R AT I V E
One approach to bias control is by imposing separations as listed below. Separations are
imposed to eliminate or reduce the risk of treatment-related biases that may arise from
one’s role, position, duty, or responsibility in conduct of a trial.
The patient–physician separation is implicit to the design of trials.
The separation of treater and data collector is desirable in unmasked trials, but
unnecessary in masked trials (assuming masking to be effective).
The separation of clinical centers and coordinating center is desirable because of the
need for arms length relationship of the two kinds of centers. The same is true for sponsor
and clinical centers, sponsor and coordinating center, and sponsor and investigators.
Desirable separations
1.
2.
3.
4.
5.
6.
Patient and physician
Treater and evaluator (unmasked trials)
Treater and data collector (unmasked trials)
Clinical center and data coordinating center
Sponsor and clinical center
Sponsor and data coordinating center (especially if sponsor has proprietary interest in
products being tested)
7. Sponsor and investigators of trial (especially if sponsor has proprietary interest in
products being tested)
Treatment Assignment/
Randomization
50. Assignment Methods: Fixed vs. Adaptive
145
50. Assignment methods: Fixed vs. adaptive
R E L AT E D E N T R I E S
Treatment assignment: Random vs. nonrandom (page 147), Randomization: Complete
vs. restricted (page 151), Randomization unit (page 155), Randomization: Procedures
(page 157)
DEFINITIONS
adaptive treatment assignment n - Any method of treatment assignment in
which the treatment assignment ratio changes as a function of previous assignments,
baseline data, or observed outcomes [Simon, 1977].79 Types include baseline adaptive
treatment assignment, biased coin treatment assignment, minimization, minimum
likelihood treatment assignment, number adaptive treatment assignment, play-the-winner
treatment assignment, outcome adaptive treatment assignment, and urn model treatment
assignment. syn: dynamic treatment assignment ant: fixed treatment assignment
baseline adaptive treatment assignment n - A method of treatment assignment in
which treatment assignment probabilities change over the course of the trial as a function
of observed differences among the treatment groups for a designated baseline variable (or
variables) so as to achieve comparable treatment groups with regard to the distribution of
that variable or variables. rt: adaptive treatment assignment
biased coin treatment assignment n - An adaptive method of treatment assignment
for trials in which treatment assignment probabilities are modified as a function of the
observed difference in the number of patients already assigned to the various study
treatment groups represented.
fixed treatment assignment n - [trials] Any method of treatment assignment in which
the treatment assignment ratio remains fixed over the course of the trial. ant: adaptive
treatment assignment
minimization n - [trials] A method of adaptive treatment assignment [introduced
by Taves, 197487 ; see also pages 84–87 of Pocock, 198369 ] in which assignments are
generated to minimize some difference function, based on counts of previous assignments
among the various treatment assignment strata. Randomization is not normally used
with minimization, except for making assignments when the difference function is zero.
However, the method can be modified to include randomization with probabilistic
assignments according to a set treatment assignment ratio when the difference is not zero
as well to render the process nondeterministic, thereby reducing the chances of study
personnel predicting future assignments. rt: minimum likelihood treatment assignment
minimum likelihood treatment assignment n - A form of baseline adaptive treatment
assignment in which each assignment is made in such a way as to minimize the imbalance
(measured against a desired degree of balance) among the treatment groups with regard
to the distribution of a specified set of baseline characteristics [Aickin, 1982].2 rt:
minimization
number adaptive treatment assignment n - Adaptive treatment assignment using the
difference in the number assigned to the various treatment groups as the basis for adapting.
See adaptive treatment assignment for other types.
146
V I I . T R E AT M E N T A S S I G N M E N T / R A N D O M I Z AT I O N
outcome adaptive treatment assignment n - Adaptive treatment assignment based on
observed outcomes, with or without randomization.
play-the-winner treatment assignment n - A form of outcome adaptive treatment
assignment involving two study treatments (as a test and control treatment or as two test
treatments) and a binary outcome for determining the success or failure of the assigned
treatments. In the approach, treatment assignments are functions of observed outcomes.
A success observed for the last treatment unit enrolled, causes the next treatment unit to
be assigned to the treatment assigned to the last treatment unit. A failure causes the next
treatment unit to be assigned to the other treatment. The approach is used to maximize the
number of treatment units assigned to the better of the two treatments as determined by
observed successes. The approach is limited to conditions where success or failure can be
determined shortly after the initiation of treatment. Based on work of Robbins [195671 ,
195272 ] and extended by Zelen [1969]104 with the introduction of a probabilistic element
for assignments.
treatment assignment ratio n - 1. The ratio of the number of treatment units (usually
persons) in one treatment group relative to another, e.g., a ratio of 1:2 for a particular
test-treated group relative to the control-treated group. 2. The ratio of one group relative
to all others, e.g., a ratio of 1:1:1:1:1:2.5 for a trial with five test treatments and a
control-assigned group that is 2.5 times larger than any of the test-assigned groups.
urn model n - A model involving the concept of an urn containing a specified number of
sampling units (balls of different colors); e.g., a model used to illustrate the properties of
some random sampling or assignment scheme [e.g., as discussed by Friedman, 1949].34
urn model randomization n - Randomization based on an urn model, as proposed by
Wei [1977]98 and Wei and Lachin [1988]97 ; involves the concept of an urn model in
which the probability of assigning a person to a given treatment is made to diminish or
increase, depending on the direction of the imbalance observed in the assignment ratio for
all previous assignments. A member of the family of biased coin randomization schemes.
urn model treatment assignment n - Treatment assignment based on urn model
randomization.
N A R R AT I V E
Broadly, the methods of treatment assignment fall into two general classes: adaptive or
fixed. Of the two, fixed treatment assignment is the more commonly used. It should
be regarded as the method of choice and should be used unless designers can make
compelling arguments for adaptive.
5 1 . Tr e a t m e n t A s s i g n m e n t : R a n d o m v s . N o n r a n d o m
147
51. Treatment assignment: Random vs. nonrandom
R E L AT E D E N T R I E S
Assignment methods: Fixed vs. adaptive (page 145), Randomization: Complete vs.
restricted (page 151)
DEFINITIONS
concealed treatment assignment n - Any scheme in which treatment assignments remain
concealed until issue, especially any such scheme in regard to the person to be assigned
to treatment and to those requesting or administering the assignment. syn: masked
randomization ant: open treatment assignment rt: masked randomization
haphazard adj - Occurring without any apparent order or pattern. Usage note: Use
when characterizing a process that is unordered but not meeting the scientific definition
of random. Do not equate haphazard with random in scientific discourse. Distinct from
random, in that there is no mathematical basis for characterizing a haphazard process.
haphazardization n - 1. An act of assigning or ordering that is the result of a haphazard
process. 2. An order or sequence that is the result of a process considered to be akin
to randomization but lacking a scientific base. rt: randomization Usage note: Not to be
confused or used interchangeably with randomization.
open treatment assignment n - 1. Treatment assignment resulting from an open schedule,
e.g., as from a schedule posted in the clinic. 2. uncontrolled treatment assignment
pseudorandom adj - Being or involving entities that are generated, selected, or
ordered by a deterministic process that can be shown to generate orders that satisfy
traditional statistical tests for randomness. rt: quasirandom, random Usage note: Most
random number generators are, in fact, pseudorandom number generators, though usually
referred to as random number generators. Typically they are built using deterministic
computational procedures that rely on a user supplied seed to start the generation process;
use of the same seed will generate the same sequence of numbers.
quasirandom adj - 1. Appearing to be or resembling something random; random-like.
2. Of, relating to, or concerned with a process considered to approximate a formal
randomization process. 3. Being or involving entities, such as numbers, that are selected
or ordered by some rule or procedure (e.g., one based on the order in which people arrive
at a clinic) that generates sequences that can be viewed as being like those produced with
a random process but where the rule or procedure is not amenable to testing or, if tested,
can be shown to yield results that do not satisfy traditional statistical tests for randomness.
rt: pseudorandom, random Usage note: Not to be confused with pseudorandom. See
notes for random and pseudorandom.
random adj - [ME impetuosity, fr MF randon, fr OF, fr randir, to run, of Gmc origin,
akin to OHG rinnan to run] [general] 1. Having or appearing to have no specific pattern
or objective. 2. Of or designating a process in which the occurrence of previous events
is of no value in predicting future events. 3. haphazard [scientific] 4. Of or relating to
a sequence, observation, assignment, arrangement, etc., that is the result of a chance
process with known or knowable probabilities. 5. Of or relating to a process that has the
properties of one that is random. 6. pseudorandom 7. Of or relating to a single value,
observation, assignment, or arrangement that is the result of randomization. syn: casual,
148
V I I . T R E AT M E N T A S S I G N M E N T / R A N D O M I Z AT I O N
chance, haphazard Usage note: Subject to misuse. Avoid in the absence of a probability
base (e.g., as in random blood sugar); use haphazard or some other term implying less
rigor than random. Misuse in the context of trials arises most commonly in relation
to characterizations of treatment assignment schemes as random that are systematic or
haphazard. In scientific discourse, reserve the descriptor for uses in the sense of defns 4–7.
randomization n - 1. An act of assigning or ordering that is the result of a random
process such as that represented by a sequence of numbers in a table of random
numbers or a sequence of numbers produced by a random number generator, e.g., the
assignment of a patient to treatment using a random process. 2. The process of deriving
an order or sequence of items, specimens, records, or the like using a random process.
rt: haphazardization, quasirandomization Usage note: Do not use as a characterization
except in settings where there is an explicit or implied mathematical basis for supporting
the usage. Use other terms implying less rigor than implied by randomization, such
as haphazardization, quasirandomization, or chance, when that basis is not present or
evident.
N A R R AT I V E
The validity of a trial depends on having treatment groups that are free of selection
bias. A necessary requirement is a method of assignment of persons to treatment so
that assignments are independent of their preferences and of the persons responsible for
treating, observing, and following them. Operationally, the requirement can be considered
met if assignments:
1. Are independent of desires of assignees and those responsible for treating, observing,
and following them
2. Cannot be predicted in advance of issue
3. Remain concealed prior to issue
Only assignments that are products of unrestricted (complete) randomization and
concealed until issue satisfy the three requirements.
All open treatment assignment schemes have to be regarded as failing to meet the
second and third requirements. The same can be said of quasirandomization schemes
using birth date, social security number, or like numbers, as well as all alternation methods
of assignment.
Technically, all deterministic methods of assignment have to be regarded as having
the potential of failing the second requirement. They fail the requirement when the
method of determination is known to the assignee or clinic personnel and the information
used to make the determination is available to the assignee or clinic personnel. However,
in reality the failure may be more theoretical than real, especially with methods of
determination involving complicated algorithms, e.g., as with minimization.
Most adaptive schemes of assignment have to be regarded as failing to meet the
second requirement and, therefore, also at risk of failing to meet the third requirement.
However, the extent of failure, as with minimization, will depend on the extent to
which persons know the details of the adaptive procedure, the complexity involved in
determining the next assignment, and whether the treatments are masked.
The third requirement is at risk in self-administered assignment schemes where
it is possible to ‘‘peek’’ before issue, e.g., as with self-administered envelope schemes
5 1 . Tr e a t m e n t A s s i g n m e n t : R a n d o m v s . N o n r a n d o m
149
of assignment. The risk exists in any scheme where it is possible to obtain assignments
without having to account for them or where assignments can be obtained without
documentation of issue.
The preferred method of assignment is via randomization. Positive features of
randomization include:
• Protecting against selection bias in the assignment process
• Providing predictable sampling variation for differences in the baseline composition
of the treatment groups, as well as for subgroups of the treatment groups formed
using variables that are independent of treatment assignment (e.g., sex, ethnic group,
and all baseline observations)
• Providing the same expected degree of baseline comparability for unobserved
variables as for observed variables
Things to remember in regard to randomization are:
• Haphazardization is not the same as randomization.
• Randomization does not ensure comparable study groups.
• Differences in the baseline composition of the study groups does not, per se, provide
prima facie evidence of a breakdown in the randomization process.
• It is not possible to test for ‘‘randomness’’ (extreme distributions can occur by
chance).
• A study that does not involve random treatment assignments is not, by definition,
invalid.
52. Randomization: Complete vs. Restricted
151
52. Randomization: Complete vs. restricted
R E L AT E D E N T R I E S
Assignment methods: Fixed vs. adaptive (page 145), Treatment assignment: Random
vs. nonrandom (page 147), Randomization unit (page 155), Randomization: Procedures
(page 157)
DEFINITIONS
block n - [general] 1. A group, quantity, section, or segment that is considered as a
unit for some purpose, procedure, process, or action. [trials] 2. A group of treatment
assignments that satisfy a specified assignment ratio. 3. The experimental unit(s) receiving
the treatments represented in a block; typically a person in the case of crossover designs
and as many persons as there are treatment assignments represented in a block in parallel
treatment designs. syn: treatment assignment block rt: blocked treatment assignment,
blocked randomization Usage note: The minimum block size for parallel treatment
designs will be the sum of the numbers represented in an assignment ratio (e.g., 2 for
a design involving two study treatments and a uniform treatment assignment ratio; e.g.,
15 for a design involving six study treatments and an assignment ratio of 1:1:1:1:1:2.5).
The usual strategy in parallel treatment designs is to have a mix of blocks of different
sizes filled over the course of enrollment, themselves randomly ordered, with all blocks
being some multiple of the minimum block size. The purpose of blocking is to ensure
balance in the mix of treatment assignments over the course of enrollment. Blocking
helps eliminate the risk of differential baseline differences in the make-up of the treatment
groups. Time-related shifts in the nature of persons enrolled over the course of a trial
can confound treatment comparisons if the mix changes over time and is different by
treatment group. Blocking is not to be confused with stratification (see usage note for that
term; page 135).
block size n - 1. The number of experimental units comprising a block. 2. treatment
assignment block size
blocked randomization n - 1. Blocked treatment assignments in which the assignments
are the result of some randomization process. 2. Randomization constrained by blocking.
rt: restricted treatment assignment
complete randomization n - Randomization not constrained by restrictions, such as
those imposed by blocking. syn: simple randomization, unrestricted randomization
permuted block n - A block of treatment assignments representing one of the possible
permutations of the assignments. The number of different arrangements of blocks of n
assignments involving t different treatments and r1 assignments to trt1 , r2 assignments to
trt2 , . . ., rt−1 assignments to trtt−1 , and rt assignments to trtt is n!/(r1 !r2 ! . . . rt−1 !rt !),
e.g., 4!/(2!2!) = 6 for a trial involving two study treatments arranged in blocks of size 4
(i.e., ABAB, ABBA, AABB, BABA, BAAB, and BBAA).
restricted randomization n - Randomization involving restrictions, such as in blocked
randomization; not complete randomization. ant: complete randomization, unrestricted
randomization
treatment assignment ratio n - 1. The ratio of the number of treatment units (usually
persons) in one treatment group relative to another, e.g., a ratio of 1:2 for a particular
152
V I I . T R E AT M E N T A S S I G N M E N T / R A N D O M I Z AT I O N
test-treated group relative to the control-treated group. 2. The ratio of one group
relative to all others, e.g., a ratio of 1:1:1:1:1:2.5 for a trial with five test treatments
and a control-assigned group that is 2.5 times larger than any of the test-assigned
groups.
treatment assignment stratum n - A stratum, designated prior to the start of enrollment
and defined by a geographic variable, such as clinic site, or by one or more baseline
characteristic(s) of persons to be enrolled (e.g., age upon entry and gender), within which
treatment assignments are in the same proportionate mix as in all other strata. Such
variables are said to be controlled in the assignment process because their distribution is,
within the limits of the stratification, the same for all treatment groups represented.
N A R R AT I V E
The desired mix of treatment assignments is specified by designers. In the case of fixed
ratio designs, it is specified by the treatment assignment ratio. For example, in a trial
involving two study treatments, A and B, a design specification of 1:1 means that designers
want as many people assigned to A as to B. It is up to the designers to decide how close
they want to be to the specified mix when recruitment is finished. They can trust to luck
or they can restrict the randomization to limit potential departures.
The downside in trusting to luck (i.e., building a randomization scheme based on
complete randomization) is in the risk of departure from the desired mix. In the example
above and for a trial involving a sample size of 100, one can expect, on average, to have
50 persons assigned to A and 50 persons assigned to B. However, the assurance is small
consolation because the trialist is interested in but one replication—the one represented
by the planned trial. Wide departures from the specified assignment ratio, even though
consistent with chance, can be bothersome. The best break, from the perspective of
statistical precision, is with an even split across treatment groups. The chance of a 60:40
or 40:60 split or one more extreme with an underlying 50:50 probability mix with 100
assignments is 0.06. The chance of an 8 and 2 or 2 and 8 split or one more extreme with
10 assignments with an underlying 50:50 probability mix is 0.11.
The fix is to restrict the randomization to ensure the desired mix. If the only
requirement is to be near the desired mix when the trial is finished, then one might
arrange the assignments in a single block of size 100. The restriction would not come into
play until the number of assignments reached 50 for one of the two treatment groups.
The downside is the leeway for variation over the course of recruitment.
One of the reasons for more frequent blocking is in the protection provided against
time-related changes over the course of the trial. Blocking in smaller intervals reduces the
risk of time-related confounding. Tighter blocking has the effect of ensuring a mix always
near that desired. As a result, one has reasonable assurance that changes in procedure or
protocol can be made over the course of the trial without concern of confounding.
The smallest block is 2 in the example above. Hence, for the example, designers
have the option of blocking as frequently as after every two assignments. The blocking
ensures a continuing mix at or very near the desired 1:1 mix. The disadvantage is in
the risk such blocking entails in regard to the second requirement for valid assignment
procedures (see page 148). The smaller the block size, the greater the likelihood of being
able to predict future assignments. Indeed, in the example, it is possible in unmasked trials
52. Randomization: Complete vs. Restricted
153
to predict half the assignments if the blocking scheme is known. The ability to predict is
reduced by use of blocks of varying size, arranged in random order.
Blocking, even with small block, does not ensure the desired mix if enrollment
stops independent of the blocking. The maximum possible departure will be a function
of the number of blocks filled at any point in time. The possibility of departures increases
as a function of the number of assignment strata represented in the design. The greater
the number, the greater the potential for departures from the desired mix.
The finished sample size, for example, in the CDP was 1,101, 1,119, 1,103,
1,110, 1,119, 2,789 with an assignment ratio of 1:1:1:1:1:2.5.18 Blocks were of size 15.
Stratification was on clinic (53) and risk group (2) to produce 106 assignment strata.
53. Randomization Unit
155
53. Randomization unit
R E L AT E D E N T R I E S
Assignment methods: Fixed vs. adaptive (page 145), Treatment assignment: Random
vs. nonrandom (page 147), Randomization: Complete vs. restricted (page 151),
Randomization: Procedures (page 157)
DEFINITIONS
cluster randomization n - [trials] Randomization in which the unit of assignment and
treatment is a group of persons as defined by a geographical region, village, township,
census tract, household, or the like. ant: individual randomization
group randomization n - [trials] Randomization of a group of persons as a unit; cluster
randomization. ant: individual randomization
individual randomization n - [trials] Randomization in which the unit is a person or
part of a person. ant: group randomization
randomization unit n -[trials] The unit to which treatment, as dictated by randomization,
is to be applied; treatment assignment unit. The unit is usually a person (or a part of a
person, e.g., an eye) but may be an aggregate of persons, such as those occupying the same
household or housed in the same hospital ward.
N A R R AT I V E
The randomization unit is the unit to which treatment is applied. It is usually a person, but
can be a subpart of a person (e.g., eye or ear) or an aggregate of persons. The conditions
favoring the different options are as outlined below.
Conditions favoring person as the randomization unit
• When treatment must be on a per-person basis
• Treatment trials, most secondary prevention trials, and primary prevention trials
where treatment is on a per person basis
• Virtually all drug and device trials
• Trials involving the diagnosis and treatment of disease
Conditions consistent with a person subpart as the randomization unit
• Local treatment or topical treatments of a body part having few or no systemic
effects
• Paired body part (e.g., as with eyes, ears, arms, legs, hands, and feet)
Conditions favoring groups of persons as the randomization unit
• When treatments must be applied en masse (e.g., as in fluoridation of water supplies)
• When the effects of treatment extend beyond the person of interest (e.g., in diet
trial requiring change in cooking practices in a household to achieve goals of
treatment)
156
V I I . T R E AT M E N T A S S I G N M E N T / R A N D O M I Z AT I O N
• When costs of administering treatment on per-person basis are prohibitive or where
doing so is impractical because of locale of study
• When the outcome measure is one involving an aggregate of persons (e.g., change
in infection rate by household or community)
• Trials where success is measured by mass immunity; certain kinds of vaccination
trials
• Primary prevention trials involving mass treatment
54. Randomization: Procedures
157
54. Randomization: Procedures
R E L AT E D E N T R I E S
Stratification (page 135), Assignment methods: Fixed vs adaptive (page 145), Treatment
assignment: Random vs nonrandom (page 147), Randomization: Complete vs restricted
(page 151), Randomization unit (page 155)
N A R R AT I V E
Good practice procedures are those where:
• All necessary tests and procedures for determining eligibility are performed and
recorded on study forms prior to release of assignments.
• There is confirmation that persons satisfy eligibility requirements and are free of
excluding conditions (as determined from data recorded on study forms).
• There is signed, dated consent.
The hallmarks of well constructed and managed systems of randomization include:
• Reproducible randomization schedule
• Written description of procedure for generating the schedule and for administration
of the schedule (detail sufficient to allow independent party to reproduce the
assignment schedule)
• Release of assignments prevented until essential conditions for enrollment satisfied
• Assignments remain concealed to all concerned until issue (and after issue in the
case of masked treatment administration)
• Future assignments not predictable from past assignments
• Indelible audit trail for assignments
• Ability to detect departures from established procedures
IRBs and Consents
55. IRBS
161
55. IRBs
R E L AT E D E N T R Y
IRBs: Models and procedures (page 163)
DEFINITIONS
expedited review n - 1. An IRB review performed in prompt order and more expeditiously
than ordinary. 2. A review performed by the chair of an institutional review board or by
a member (or members) of an IRB, as designated by the chair; as distinct from a review
performed by the full board. Provisions for expedited reviews are limited by regulation
to proposals involving no more than minimal risk and to minor changes to approved
projects.66
institutional review board (IRB) n - A body, set forth in regulations emanating from
the United States Public Health Service concerning research involving human beings,47,66
appointed by authorities within a research institution and constituted to review and
approve studies to be carried out on human beings by investigators from that institution.
The review focuses on the ethics and legitimacy of the proposed research from the
perspective of risk–benefit to those studied and on the adequacy of safeguards for
persons put at risk by the research. The risk may be a direct consequence of procedures
performed or may be an indirect consequence of being studied (e.g., invasion of privacy or
breaches of confidentiality). The review deals with, but is not restricted to, the nature and
adequacy of the consent process and related consent statement when there is contact with
individuals, and in all cases, whether or not there is contact, to a review of the adequacy of
procedures to preserve privacy and confidentiality. Technically, the regulations apply only
to projects funded by the federal government, but most institutions require IRB review and
approval of all research involving human beings, regardless of funding source. The name,
institutional review board, arises from the regulations. The name is unfortunate in that it
is not suggestive of the functions performed. syn: ethics committee, ethics review board,
Helsinki committee, human experimentation committee, human volunteers committee
involve, involved, involving, involves v - In regard to IRB regulations, to engage in
research involving human beings. Usage note: Involve, as in research involving human
subjects in the Code of Federal Regulations for IRBs,66 has broad meaning and is not
to be interpreted as being restricted to uses where someone is actually enrolled into a
study or is otherwise contacted or seen by an investigator in relation to a research project.
Research, in IRB regulations, is considered to involve human beings and, hence, subject
to IRB review and approval prior to initiation, even where there is no contact with persons
(e.g., as in a case–control study based on chart reviews). The involvement in such cases is
indirect and arises because an investigator is using something related to a person, such as
the person’s medical record.
minimal risk n - In the setting of research involving human beings, a risk that is considered
to be not more than that of routine daily life, defined in the Code of Federal Regulations
for protection of human subjects as meaning that the probability and magnitude of harm or
discomfort anticipated in the research are not greater in and of themselves than those ordinarily
encountered in daily life or during the performance of routine physical or psychological
examinations or tests (§46.102(i))66 . rt: more than minimal risk
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VIII. IRBS AND CONSENTS
more than minimal risk n - A risk of harm, injury, or insult considered to be in excess
of a minimum; in the setting of research involving human beings the minimum is that of
routine daily life. Research considered to not involve more than minimal risk is eligible
for expedited review. rt: minimal risk
research n - In IRB regulations defined as: . . . systematic investigation, including research
development, testing and evaluation, designed to develop or contribute to generalizable
knowledge. Activities which meet this definition constitute research for purposes of this policy,
whether or not they are conducted or supported under a program which is considered research
for other purposes. For example, some demonstration and service programs may include research
activities.66
56. IRBS: Models and Procedures
163
56. IRBs: Models and procedures
SLIDE
IRB model and procedures: Studies of Ocular Complications
of AIDS (SOCA) trials80
Parent center: Coordinating Center
Parent IRB: IRB of Coordinating Center
Prototype consent forms and related informational documents prepared by
Coordinating Center
Protocol and prototype consent forms submitted to parent IRB; distributed to clinics
with instructions to submit to local IRBs after approval by parent IRB
Copy of approval letter from local IRB required at Coordinating Center before
clearing clinic for enrollment; randomizations not issued absent copy of approval
notice from local IRB
Randomizations not released if approval of clinic has expired (copy of renewal notice
required in Coordinating Center to resume randomization)
Numbered memos from Coordinating Center used to transmit approved protocol
and prototype consent forms and to instruct clinic on local IRB submission
process; similar notification process used for protocol amendments
Notice of adverse events communicated to clinics by the Coordinating Center via
numbered memos; memos instruct clinics to send notice to local IRBs
R E L AT E D E N T R I E S
IRBs (page 161), Consent: Process (page 185), Critical event path analysis (page 241)
DEFINITIONS
central IRB n - An IRB having review authority over a multicenter study, especially one
where approval by such a board is sufficient to allow investigators at study centers to
proceed without additional review or approval. rt: commercial IRB, institutional review
board, local IRB, parent IRB board
commercial IRB n - A board performing functions similar to an institutional review
board on a fee-for-service basis for investigators directed to submit to it by IRB officials of
their respective institutions or for investigators not affiliated with institutions having IRBs;
frequently used by investigators in industry-sponsored multicenter trials not at institutions
having IRBs. (see http://www.circare.org/info/commercialirb.htm for list) rt: central IRB,
independent IRB Usage note: Technically not an institutional review board as defined
in the code of federal regulations underlying IRBs.66 The name, as used therein, pertains
to a board created to review research arising from investigators at the institution housing
the IRB. As a rule, investigators submitting to commercial IRBs are doing so because they
are not associated with institutions having IRBs. Usually, investigators of major academic
institutions are required to submit to their own respective IRBs.
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VIII. IRBS AND CONSENTS
independent institutional review board n - 1. A board performing functions similar to
an institutional review board but not housed in institutions from which applications are
received; typically from investigators at institutions not having an IRB. 2. commercial
institutional review board
institutional review board (IRB) n - A body, set forth in regulations emanating from
the United States Public Health Service concerning research involving human beings,47,66
appointed by authorities within a research institution and constituted to review and
approve studies to be carried out on human beings by investigators from that institution.
The review focuses on the ethics and legitimacy of the proposed research from the
perspective of risk–benefit to those studied and on the adequacy of safeguards for
persons put at risk by the research. The risk may be a direct consequence of procedures
performed or may be an indirect consequence of being studied (e.g., invasion of privacy
or breaches of confidentiality). The review deals with, but is not restricted to, the nature
and adequacy of the consent process and related consent statement when there is contact
with individuals; in all cases, whether or not there is contact, the review focuses on
the adequacy of procedures to preserve privacy and confidentiality. Technically, the
regulations apply only to projects funded by the federal government, but most institutions
require IRB review and approval of all research involving human beings, regardless of
funding source. The name institutional review board arises from the regulations. The
name is unfortunate in that it is not suggestive of the functions performed. syn: ethics
committee, ethics review board, Helsinki committee, human experimentation committee,
human volunteers committee
lead center n - 1. A center in a multicenter study that takes the lead in testing or
performing certain procedures or which is otherwise designated to assume a leadership
position in a study. 2. The center responsible for disbursing funds to other centers in a
study funded via a consortium funding agreement. rt: parent center
local IRB n - 1. The institutional review board of one’s own institution. 2. The IRB
serving a particular center in a multicenter study. rt: central IRB, parent IRB
parent center n - 1. A study center that gives rise to or nurtures other centers. 2. A study
center that has administrative or operational primacy over other centers. 3. A study center
having an affiliate, associate, field, or satellite center.
parent IRB n - 1. The IRB of the institution housing the principal investigator of a
multicenter research project involving human beings. 2. The IRB of the parent center in
a multicenter trial. 3. The IRB of the coordinating center in a multicenter trial. rt: central
IRB, local IRB
N A R R AT I V E
Operationally, IRBs in the United States are created equal. They operate as autonomous
units. They are not given to reciprocity arrangements. There is no master IRB. The action
of one IRB is not binding on any other IRB. This means, in the case of multicenter trials,
that it is possible for a proposal for a trial to sail through one IRB and be rejected by
another.
The requirements of review apply to all research involving human beings. Research
is considered to ‘‘involve’’ human beings as subjects even if it is done without any
contact with them. It is considered to ‘‘involve’’ human beings if the research merely
involves use of data or materials belonging to persons. Therefore, in the context of trials,
56. IRBS: Models and Procedures
165
planners should assume need for IRB approval for all centers in the trial, not just clinical
centers.
IRB approval stands in the critical path to initiation of any research involving
human beings (see Start-up critical event path analysis, page 241). The time required from
initial IRB submission to definitive action will depend on the schedule of the IRB, on the
nature and complexity of the research, and on the amount of risk to subjects represented
in the research. The review process can stretch over months.
The submission will be as required by local IRBs. It is likely to include any or all
of the following for trials:
• Funding proposal (for initial approvals)
• Study protocol
• Investigational new drug (IND) application (in the case of drug trials involving
unapproved drugs)
• Investigator’s brochure (in the case of drug trials)
• Consent documents and forms
• Study forms; drafts or finished forms, depending on the IRB
IRBs will likely require disclosures from investigators relating to conflicts of
interests and whether they have any proprietary interests in products being tested.
Planners need to specify the minimum requirements for allowing clinics to proceed
with patient contact. Theoretically, a clinic can start initiating such contacts once it has
IRB approval to do so. The difficultly with such a laissez faire approach is obvious in
multicenter trials. It can allow clinics to start before other critical elements needed for
starting are in place.
The minimum recommended requirements before allowing any patient contact
are:
• Training and certification of clinic personnel
• Clinic certification
• IRB approval of the parent center, necessary resource center to service the trial, and
at least one clinic
• Necessary approvals and authorizations from sponsors and regulatory agencies
• Necessary drugs and supplies
• Approved protocol and consent forms
• Necessary data collection forms
Dos and don’ts regarding IRB processes
• Do assume the need for review and approval unless specifically told otherwise by
one’s IRB; operationally this means, in the case of multicenter trials, that every
center, including resource centers, should assume the need for review and approval.
• Do assume approvals to be time limited (by regulation, approvals granted by IRBs
may not be for more than a year; they may be for less time at the discretion of an
IRB).
• Do assume the need for revision of consents whenever the protocol is modified.
166
VIII. IRBS AND CONSENTS
• Do assume the need for approval of changes to the study protocol if likely to
adversely affect the risk–benefit ratio for study subjects.
• Do assume the need to report all serious adverse events (see Adverse events, page 471;
Adverse event reporting procedures, page 475).
• Do not initiate patient contact absent IRB approval.
• Do not proceed with a protocol change adversely affecting the risk–benefit ratio to
patients, absent IRB approval.
• Do not use invalid consent forms (many IRBs require use of forms bearing a stamp
affixed by the IRB that indicates approval and date approval expires).
• Do not assume that IRBs will not request changes to consent statements after
approval (typically, consent statements are reviewed in relation to each renewal of
an approval; the review may lead to requests for changes).
Recommended IRB practices for multicenter trials
•
•
•
•
•
•
•
•
•
Designate a center to serve as the lead center in regard to submissions and approval.
Regard the IRB of the lead center as the parent IRB.
Prepare prototype consent form; submit to parent IRB for approval.
Request that clinics prepare consent documents using approved prototype consent;
allow modifications to conform with local requirements, but require that information
imparted not be less than represented in the prototype.
Require that the lead center distribute documents to be used in local submissions,
to include:
❑ Current, dated version of study protocol (typically the one submitted to the
parent IRB or an updated version resulting from that review)
❑ Current, dated version of the approved prototype consent
❑ Current, dated version of the investigator’s brochure (in the case of drug trials
done under INDs)
❑ Other information needed for submissions, including, but not limited to,
information concerning funding sources, details regarding procedures for
reporting adverse events, and provisions for treatment effects monitoring
Require centers to supply copy of local IRB approval to lead center and copy of
approved consent form.
Perform review of consent form for adequacy of content.
Institute fail safe systems to prevent clinics from initiating contact until approval
has been obtained and clinic has been cleared to start by lead center
Institute procedures to avoid lapses of approvals by lead center keeping track of
expiration dates of individual approvals
Note The United States stands apart from many other parts of the world in its
review structure. The autonomous nature of IRBs in the United States has made it
difficult to centralize reviews. The absence of such a review and approval structure is
unfortunate. The current structure is cumbersome and inefficient. The European Union,
with its Clinical Trial Directive (2001), avoids the duplication by having created a
centralized structure for its member states. It remains to be seen whether similar structures
56. IRBS: Models and Procedures
167
will emerge in the United States to streamline review and approvals for multicenter
trials.
IRBs are under no obligation to act. Hence, reviews can drag on for months. In
Europe there is a 60-day limit for reviews. The reviewing authority is obliged to act within
that time period. If there are questions, the clock stops while waiting for answers to the
questions.
57. Consent
169
57. Consent
R E L AT E D E N T R I E S
Consent: Checklist (page 177), Consent: Disclaimers and notifications (page 181),
Consent: Principles and purpose (page 183), Consent: Process (page 185), Consent:
Types (page 189), Consent: Questions and answers (page 191)
DEFINITIONS
assent n - 1. The act of assenting; a permission granted. 2. An expression of acquiesce in
relation to something proposed after explanation of that proposed and consequences. rt:
consent, assent form, assent statement, oral assent, signed assent, preassignment consent,
post-assignment consent, signed consent, oral consent Usage note: Generally in research
settings, assent, in addition to consent, is required whenever consent is given by someone
else on behalf of the person being studied and where the person has sufficient mental
capacity to understand the nature and extent of what is being proposed. The age at which
assent is required may vary, but is usually 5, or thereabouts, for most institutional review
boards. For persons unable to read, the assent may be oral after the person has been
presented with an explanation of what is involved. For persons able to read (e.g., children
aged 7 or 8 to the age of majority), the process may require the use of a written assent
form and a signed assent before proceeding. The process, while used primarily in relation
to children, extends as well to adults with limited but sufficient mental capacities to allow
them to assent.
assent form n - A written document presented to a child above the age of assent or to
an adult with diminished mental capacity asked to enroll in a research project and having
the intended purpose of providing a description (in language consistent with the age or
mental capacity of the person) of the proposed research, of the nature of the commitment
required, of the procedures to be performed and reasons for them, of the purpose of
the research and why the person is being approached for study, of the potential risks
and benefits associated with study, and of the right of the person to refuse to enroll and
to withdraw anytime without prejudice in regard to the nature or amount of care or
treatment available to the person at the research site.
assent statement n - 1. assent form 2. signed assent form 3. A signed document, devoid
of details regarding the nature and extent of the undertaking, indicating assent and that
information regarding the undertaking was imparted orally. rt: assent form, consent
statement
consent n - 1. Voluntary agreement or acquiescence by a person, or by that person’s
guardian or representative on their behalf, to undertake, submit to, or comply with an
act or procedure that is to be done by another person, party, or agency. 2. consent
process rt: active consent, assent, deconsent, deferred consent, consent statement, implied
consent, informed consent, passive consent, preassignment consent, post-assignment
consent, oral consent, reconsent, signed consent Usage note: Not to be confused with
assent.
consent, documentation of n - The method and manner of documentation of consent;
that method and manner as specified in code underlying IRBs under the purview of
OHRP is as follows66 :
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VIII. IRBS AND CONSENTS
§46.117; ¶ (a): Except as provided in ¶ (c) of this section, informed consent shall be documented
by the use of a written consent form approved by the IRB and signed by the subject or the
subject’s legally authorized representative. A copy shall be given to the person signing the
form.
§46.117; ¶ (b): Except as provided in ¶ (c) of this section, the consent form may be either of
the following:
1. A written consent document that embodies the elements of informed consent required
by §46.116. This form may be read to the subject or the subject’s legally authorized
representative, but in any event, the investigator shall give either the subject or the
representative adequate opportunity to read it before it is signed
2. A short form written consent document stating that the elements of informed consent
required by §46.116 have been presented orally to the subject or the subject’s legally
authorized representative. When this method is used, there shall be a witness to the oral
presentation. Also, the IRB shall approve a written summary of what is to be said to the
subject or the representative. Only the short form itself is to be signed by the subject or
the representative. However, the witness shall sign both the short form and a copy of the
summary, and the person actually obtaining consent shall sign a copy of the summary.
A copy of the summary shall be given to the subject or the representative, in addition to
a copy of the short form.
§46.117; ¶ (c): An IRB may waive the requirement for the investigator to obtain a signed
consent form for some or all subjects if it finds either:
1. That the only record linking the subject and the research would be the consent document
and the principal risk would be potential harm resulting from a breach of confidentiality.
Each subject will be asked whether the subject wants documentation linking the subject
with the research, and the subject’s wishes will govern
2. That the research presents no more than minimal risk of harm to subjects and involves
no procedures for which written consent is normally required outside of the research
context
In cases in which the documentation requirement is waived, the IRB may require the
investigator to provide subjects with a written statement regarding the research.
consent, elements of n - The items of information to be imparted to a study subject prior
to asking for consent; those items as specified for research under the purview of OHRP
are66 :
§46.116; ¶ (a): Except as provided in ¶ (c) or (d) of this section, in seeking informed consent
the following information shall be provided to each subject:
1. a statement that the study involves research, an explanation of the purposes of the
research and the expected duration of the subject’s participation, a description of the
procedures to be followed, and identification of any procedures which are experimental
2. a description of any reasonably foreseeable risks or discomforts to the subject
3. a description of any benefits to the subject or to others which may reasonably be expected
from the research
4. a disclosure of appropriate alternative procedures or courses of treatment, if any, that
might be advantageous to the subject
5. a statement describing the extent, if any, to which confidentiality of records identifying
the subject will be maintained
57. Consent
171
6. for research involving more than minimal risk, an explanation as to whether any
compensation and an explanation as to whether any medical treatments are available
if injury occurs and, if so, what they consist of, or where further information may be
obtained
7. an explanation of who to contact for answers to pertinent questions about the research
and research subjects’ rights, and whom to contact in the event of a research-related
injury to the subject
8. a statement that participation is voluntary, refusal to participate will involve no penalty
or loss of benefits to which the subject is otherwise entitled, and the subject may
discontinue participation at any time without penalty or loss of benefits to which the
subject is otherwise entitled.
§46.116; ¶ (b): When appropriate, one or more of the following elements of information shall
also be provided to each subject:
1. a statement that the particular treatment or procedure may involve risks to the subject
(or to the embryo or fetus, if the subject is or may become pregnant) which are currently
unforeseeable
2. anticipated circumstances under which the subject’s participation may be terminated by
the investigator without regard to the subject’s consent
3. any additional costs to the subject that may result from participation in the research
4. the consequences of a subject’s decision to withdraw from the research and procedures
for orderly termination of participation by the subject
5. a statement that significant new findings developed during the course of the research
which may relate to the subject’s willingness to continue participation will be provided
to the subject
6. the approximate number of subjects involved in the study
§46.116; ¶ (c): An IRB may approve a consent procedure which does not include,
or which alters, some or all of the elements of informed consent set forth above, or
waive the requirement to obtain informed consent provided the IRB finds and documents
that:
1. the research or demonstration project is to be conducted by or subject to the approval
of state or local government officials and is designed to study, evaluate, or otherwise
examine: (i) public benefit or service program; (ii) procedures for obtaining benefits or
services under those programs; (iii) possible changes in or alternatives to those programs
or procedures; or (iv) possible changes in methods or levels of payment for benefits or
services under those programs
2. the research could not practicably be carried out without the waiver or alteration
§46.116; ¶ (d): An IRB may approve a consent procedure which does not include, or which
alters, some or all of the elements of informed consent set forth in this section, or waive the
requirements to obtain informed consent provided the IRB finds and documents that:
1. the research involves no more than minimal risk to the subjects
2. the waiver or alteration will not adversely affect the rights and welfare of the subjects
3. the research could not practicably be carried out without the waiver or alteration
4. whenever appropriate, the subjects will be provided with additional pertinent
information after participation.
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VIII. IRBS AND CONSENTS
§46.116; ¶ (e): The informed consent requirements in this policy are not intended to preempt
any applicable Federal, State, or local laws which require additional information to be disclosed
in order for informed consent to be legally effective.
§46.116; ¶ (f): Nothing in this policy is intended to limit the authority of a physician to provide
emergency medical care, to the extent the physician is permitted to do so under applicable
Federal, State, or local law.
consent form n - 1. A form used for obtaining consent, especially one reviewed and
approved by an institutional review board (or body with similar function), that has a place
for the consenting person (or that person’s parent or guardian) to sign acknowledging
consent; consists of a written statement read or presented to the person (or person’s
parent or guardian) that indicates the reason for the request, the nature and extent of the
commitment implied by consent, the methods and procedures to which the person will
be exposed, and the likely risks and benefits accruing to the person. 2. consent statement
rt: approved consent form, consent statement, consent process, disclosure statement,
informed consent, preassignment consent, post-assignment consent, signed consent, oral
consent
consent, requirement of n - The requirement of consent; in the case of regulations
underlying research under the purview of OHRP: (§46.116)66 Except as provided elsewhere
in this policy, no investigator may involve a human being as a subject in research covered
by this policy unless the investigator has obtained the legally effective informed consent of the
subject or the subject’s legally authorized representative. An investigator shall seek such consent
only under circumstances that provide the prospective subject or the representative sufficient
opportunity to consider whether or not to participate and that minimize the possibility of
coercion or undue influence. The information that is given to the subject or the representative
shall be in language understandable to the subject or the representative. No informed consent,
whether oral or written, may include any exculpatory language through which the subject or
the representative is made to waive or appear to waive any of the subject’s legal rights, or releases
or appears to release the investigator, the sponsor, the institution or its agents from liability for
negligence.
consent statement n - 1. A consent form with a signature block for the person consenting
to document the fact of consent. 2. signed consent rt: consent form, disclosure and
consent form, consent process, disclosure statement, informed consent, preassignment
consent, post-assignment consent, signed consent, oral consent
deconsent n - 1. An active communication process taking place on completion or cessation
of a person’s role in a research project intended to impart information deemed necessary
and appropriate for an informed separation. In the case of treatment trials, the information
imparted relates to treatment received (including identity of assigned treatment in the
case of a trial involving masked treatment), findings from the trial and relevance for
the departing person, and observations and recommendations regarding the person’s
subsequent care and treatment. 2. A process taking place on separation of a person from a
study aimed at assessing the adequacy of consent by the amount of information recalled
when consented. 3. A process taking place on completion of a single- or double-masked
trial, usually in relation to a closeout followup visit, in which the departing person is asked
to state a guess as to treatment assignment or treatment received. ant: consent
deferred consent n - [trials] Consent delayed or postponed beyond the point of
treatment assignment or start of treatment because of unconsciousness or other conditions
57. Consent
173
precluding consent before enrollment and treatment assignment; the actual consent
deferred or delayed until the person (or that person’s guardian) is in a position to give
or withhold consent [e.g., as reported by the Brain Resuscitation Clinical Trial II Study
Group, 1991].6 See Levine [1991]46 and Fost and Robertson [1980]32 for discussion of
conditions of use. rt: implied consent, post-assignment consent, passive consent Usage
note: Deferred consent involves contradictory notions. Consent implies a process designed
to allow a person the opportunity to make an informed decision as to whether to submit
to some planned activity before it is undertaken. There is no permission to be granted for
things already done.
informed consent n - A decision by a person (or that person’s parent, spouse, guardian, or
representative) to submit to some procedure or to be enrolled into some research project,
after being informed of its purpose, procedures, possible risks and benefits, and of the
consequences of refusing to consent, if any. For trials, generally a consent obtained after
being informed of the purpose of the trial, why the person is eligible for enrollment, the
test and control treatments being evaluated, associated potential risks and benefits, the
method of treatment assignment, the level of treatment masking, and the options for
treatment and care if consent is not given. rt: deconsent, deferred consent, documented
consent, oral consent, post-assignment consent, reconsent, reasonable person consent
model, signed consent, written consent Usage note: Often, the modifier informed is more
an expression of hope than of fact and, hence, best dropped. Its use is best reserved for
settings in which there are steps built into the consent process to ensure an informed
decision based on evidence of comprehension of what is involved, or for settings in which
the decision can be demonstrated to have been informed.
oral consent n - 1. Consent obtained on the basis of an oral exchange between the
requestor and consenting party; especially one not written. 2. Consent based on a written
statement read to the consenting party, as in a telephone interview or in the case of a direct
contact with a person unable to read. 3. Documented consent based on an oral exchange
between the requestor and the consenting party. rt: documented consent, signed consent,
written consent
reconsent n - 1. Affirmation of willingness to continue in a study after enrollment; such
an affirmation by a person enrolled in a trial after being told of a protocol change. 2.
The solicitation of a reaffirmation of willingness to continue in a study after revelation
of information considered important, e.g., such a solicitation of a person enrolled in a
trial after being informed that one of the study treatments has been terminated because of
ill-effects. 3. An updated signed consent obtained after revealing information considered
important in allowing one to make an informed judgment as to continuation, e.g., such
a consent obtained after a results-related change in the treatment protocol. rt: consent,
informed consent
signed consent n - [research] A consent form bearing the signature or mark of the
consenting party. rt: documented consent, disclosure statement
GENERAL ELEMENTS OF CONSENTS
(ADAPTED FROM MEINERT AND TONASCIA60 )
• A statement that the study involves research, an explanation of the research and the
expected duration of the subject’s participation, a description of the procedures to
be followed, and identification of any procedures that are experimental
• A description of any reasonably foreseeable risks or discomforts to the subject
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VIII. IRBS AND CONSENTS
• A description of any benefits to the subject or to others that may reasonably be
expected from the research
• A disclosure of appropriate alternative procedures or courses of treatment, if any,
that might be advantageous to the subject
• A statement concerning the extent, if any, to which confidentiality of records
identifying the subject will be maintained
• For research involving more than minimal risk, an explanation as to whether any
compensation or medical treatments are available if injury occurs and, if so, what
they consist of, or where further information may be obtained
• An explanation of whom to contact for answers to pertinent questions about research
and research subjects’ rights, and whom to contact in the event of research-related
injury to the subject
• A statement that participation is voluntary, refusal to participate will involve no
penalty or loss of benefits to which the subject is otherwise entitled, and the subject
may discontinue participation at any time without penalty or loss of benefits to
which the subject is otherwise entitled
• When appropriate, one or more of the following elements of information shall also
be provided to each subject:
❑ A statement that the particular treatment or procedure may involve risks to the
subject (or to the embryo or fetus, if the subject is or may become pregnant) that
are currently unforeseeable
❑ Anticipated circumstances under which the subject’s participation may be
terminated by the investigator without regard to the subject’s consent
❑ Any additional costs to the subject that may result from participation in the
research
❑ The consequences of a subject’s decision to withdraw from the research and
procedures for orderly termination of participation by the subject
❑ A statement that significant new findings developed during the course of the
research that may relate to the subject’s willingness to continue participation will
be provided to the subject
❑ The approximate number of subjects involved in the study
S U G G E S T E D I T E M S O F I N F O R M AT I O N T O B E I M PA R T E D I N
C O N S E N T S F O R C L I N I C A L T R I A L S (ADAPTED FROM MEINERT
AND TONASCIA60 )
General descriptive and design information
• Description of the disease or condition being studied and how the person qualifies
for the study
• Type of persons being studied and the number to be enrolled
• Anticipated length of followup
• Description of data collection schedule procedures
57. Consent
175
T R E AT M E N T I N F O R M AT I O N
•
•
•
•
•
•
•
List of the treatments to be studied and rationale for choice
Treatment alternatives available outside the study
Nature of the control treatment
Method of treatment administration
Method of assigning persons to treatment
Level of treatment masking
Nature of information regarding treatment results that will be made available to
persons during and at the conclusion of the trial
Risk–benefit information
• Description of the risks and benefits that may accrue to a person from participation
in the trial
• Enumeration of the potential risks and benefits associated with the study treatments,
as well as enumeration of common side effects
• Description of any special procedures that will be performed, including enumeration
of the risks and benefits associated with those procedures, and the time points at
which they are to be performed
Patient responsibilities and safeguards
• Outline of responsibilities of patients enrolled in the trial, including discussion of
the importance of continued followup
• Outline of what is expected of patients in following the examination schedule and
in carrying out special procedures between visits
• Outline of safeguards to prevent continued exposure of a patient to a harmful study
treatment or denial of a beneficial one
• Outline of safeguards for protecting a patient’s right to privacy and confidentiality
of information
• Indication of a patient’s right to withdraw from the trial at any time after enrollment
without penalty or loss of benefits to which the person is otherwise entitled
• Statement of the policy of the investigator’s institution on compensation for, or
treatment of, study-related injuries
• Statement of the patient’s right to have questions answered regarding the trial and
indication of items of information that will not be disclosed (e.g., the treatment
assignment in a double-masked trial)
• Statement of the length of time personal identifiers will be retained after the close
of the trial, where such information will be retained, and the reasons for keeping
it (e.g., for use in contacting or recalling the patient after the close of the trial).
Statement should also indicate ways in which the information may be used (e.g.,
to access the National Death Index or other information sources for determining
mortality status after the close of the trial)
• Details as to the extent and nature of data sharing during and after the trial
58. Consent: Checklist
177
58. Consent: Checklist
R E L AT E D E N T R I E S
Consent (page 169), Consent: Disclaimers and notifications (page 181), Consent:
Principles and purpose (page 183), Consent: Process (page 185), Consent: Types (page
189), Consent: Questions and answers (page 191)
N A R R AT I V E
Designers should specify content to be included in consent statements. Statements should
be written to include items of information considered necessary for informed consents.
Content should be checked against checklists before submission to IRBs. Essential
elements of consents are set down in regulations for IRBs (see Consent: Process, page
185). Elements relevant to trials are as listed below.
General
•
•
•
•
Purpose of trial
Eligibility requirements
Condition or illness targeted for treatment
Sources of funding and reasons for funding
Organization and operation
•
•
•
•
Center where person will be studied
Other participating centers
Location and responsibility of data center
Leadership structure and decision-making process
Design choices and rationale
•
•
•
•
•
•
•
•
•
Proposed sample size and rationale
List of test treatments to be studied and reasons for study
List of control treatments to be used and reasons for choice
Treatment design and reason (e.g., parallel; crossover)
Route or mode of treatment administration and reason
Treatment masking procedure (e.g., use of placebo or sham procedure) and reasons
Other masking and reasons
Primary and secondary outcomes measures and reasons for choice
Length of followup and reason
Methods and rationale
• Procedures to be performed and rationale
• Inconvenience, discomfort, and risks associated with procedures
• Data collection procedures and schedule
178
VIII. IRBS AND CONSENTS
•
•
•
•
•
•
•
•
•
•
Contact schedule and rationale
Clinic visit schedule and rationale
Method of treatment assignment and rationale
Method of treatment administration and rationale
Methods of masking (treatment, data collection, data analysis)
Methods followup and rationale
Method of locating dropouts and persons lost to followup
Methods of ensuring and protecting confidentiality
Method of communication with parents and surrogates when children are enrolled
Method of protecting patient from prolonged exposure to useless or harmful
treatment
• Method of providing patient access to beneficial treatment
• Method of ongoing monitoring for treatment effects
• Anticipated method of close-out
Risk–benefit
• List of invasive procedures to be used, rationale, frequency of use, and associated
risks and discomfort
• Risks associated with procedures and treatments
• Expected side effects
• List of possible adverse events or consequences of treatment and chances of
occurrence
• Benefits of treatments
• Short- and long-term benefits of participation
Patient rights
•
•
•
•
•
•
Right to confidentiality
Right to care regardless of decision regarding participation
Right to withdraw without prejudice
Right to refuse to answer questions
Right to benefit from new information emerging during the trial
Parent and guardian rights in the case of children
Investigator rights and expectations
• Right to terminate participation
• Right to follow participant unobtrusively after data collection ends or after dropping
out
• Expectation of cooperation and compliance
Disclaimers and conditions
• Limits on protection of confidentiality
58. Consent: Checklist
179
• Limits on injury protection
• Right of FDA to inspect records
Other
•
•
•
•
•
•
•
•
•
•
Extent to which treatment and care procedures differ from standard care procedures
Limits on access to treatment information during participation
Limits on access to personal study data during trial
Amount of information on study results available to investigators during and at
conclusion of trial
Method of communicating results of trial to participants and study physicians
Method of communicating and implementing treatment recommendations
emanating from trial
Costs to patient for care and procedures
Presumed value of research
Intentions regarding publication
Extent of public access to results and database on completion of trial
59. Consent: Disclaimers and Notifications
181
59. Consent: Disclaimers and notifications
R E L AT E D E N T R I E S
Consent (page 169), Consent: Checklist (page 177), Consent: Principles and purpose
(page 183), Consent: Process (page 185), Consent: Types (page 189), Consent: Questions
and answers (page 191)
DEFINITION
Certificate of Confidentiality n - A certificate, issued by the U.S. Secretary of the
Department of Health and Human Services (or designees of the Secretary) having the
intended purpose of protecting study records and forms from subpoena in criminal, civil,
administrative, or legislative hearings at the federal, state, or local level. The protection
provided is void to the extent waived in writing by a study subject. The protection does
not preclude access to study records by the Food and Drug Administration in relation to
audits or reviews performed by that agency. The protection provided is not time limited.
It remains up to and beyond the time of death of individual research subjects. Certificates
are granted only on request and then only when the applicant makes a case as to need
(usually stated in terms of the likely negative impact on the degree of cooperation absent
the protection provided with a certificate). Typically, issue is limited to research involving
the collection of data on persons which, if revealed, could be embarrassing or in some
way injurious to such persons. Use generally limited to studies involving study of aberrant
or illegal behaviors or involving the collection of intimate information having to do with
highly personal and private lifestyles.
N A R R AT I V E
Common disclaimers and notices in consents
•
•
•
•
•
•
•
•
Limits on protection of confidentiality
Protection of confidentiality as provided by certificates of confidentiality
Duty to report suspicion of physical abuse
Right of FDA to review patient records in IND drug trials
Mode of addressing questions
Redress of complaint
Limitations on compensation for study-induced injury
Limits on say as to how banked specimens may be used
Sample language
Limitations on ability to protect confidentiality. Every effort will be made within the
limits of the law to preserve the confidentiality of your records and data collected
in this study.
Protection of confidentiality as provided by certificates of confidentiality. A certificate of
confidentiality has been issued to us by the National Institutes of Health. This
means that researchers in this study cannot be forced to reveal your identity to
anyone who is not directly involved in this research project, including for any
Federal, State, or local civil, criminal, administrative, or legislative proceeding.
182
VIII. IRBS AND CONSENTS
Duty to report suspicion of physical abuse. None of the information obtained during
these interviews will be shared with any agency or person without your written
permission. The only exception is if we find you or your child may be in danger
of physical harm. We are required by law to report such findings to appropriate
authorities.
Right of FDA to record review in IND drug trials. Officials of the Food and Drug
Administration (FDA) may look at the relevant part of your medical record as part
of their job in reviewing trials involving drugs or devices.
Mode of addressing questions. If you want to talk to someone about questions or concerns
you have regarding the study you should contact the study investigator, (name;
phone no), or contact the name of the IRB at address; telephone: number.
Redress of complaint. If you want to talk to someone regarding the study because you
think you have not been treated fairly or because you think you have been injured
you should contact the name of the IRB at address; telephone: number. Either
the investigator or the people in the Committee office or IRB office will answer
your questions and/or help you find medical care for an injury you feel you have
suffered.
Limitations on protection from injury. Neither this institution nor the Federal
Government have systems for compensation of study-related injuries if you
suffer injury not the fault of study investigators. Efforts will be made to help you
find medical care for your injuries or bad effects.
Banked specimens and uses. Cells from the blood you donate may be stored, grown, and
studied in laboratories.
60. Consent: Principles and Purpose
183
60. Consent: Principles and purpose
R E L AT E D E N T R I E S
Consent (page 169), Consent: Checklist (page 177), Consent: Disclaimers and
notifications (page 181), Consent: Process (page 185), Consent: Types (page 189),
Consent: Questions and answers (page 191)
N A R R AT I V E
Consent processes consistent with obtaining and maintaining informed consents are
paramount to research on human beings. The privilege of researching upon human beings
exists only in openness and societies trusting enough to grant the privilege. Secrecy is a
death knell for the privilege.
It is a violation of basic ethical principles of medical research to undertake the
study of a person without their voluntary, uncoerced, consent, or to continue against a
person’s will. The supposition in studies involving contact with study subjects is that the
principles are violated in the absence of an active, documented process for soliciting and
ensuring informed consents and for maintaining them once obtained.
A researcher may not continue the study of a person if that person, regardless of
reason, no longer wishes to be studied. Persons must be assured on entry of the inviolate
right to withdraw from being studied. Persons may not be coerced or unduly coaxed to
continue if they wish to withdraw. Withdrawal has to be without consequence in regard
to continuing care in the institution where studied.
The goal in design is to devise methods, procedures, and consent documents
consistent with obtaining and maintaining quality consents. Consents, to be informed,
must be based on information that a reasonable person would deem necessary for making
an informed judgment. The information conveyed is not sufficient if details are left out
that would likely cause a reasonable person to wonder why the information was not
imparted, or, if divulged, would be likely to cause such a person to decline enrollment.
There are also practical reasons for consents. The most obvious and tangible one
is from the bonding implicit in good consent processes. An elemental fact of life is that
people are more willing to cooperate if they are treated with respect and dignity.
Involvement as a subject in a trial requires the subject’s active participation. There
is nothing to be gained by enrolling a person, even if the consent is informed, if the person
has little interest in the trial or commitment to continue once enrolled. A passive interest
will translate into poor compliance and, at best, a spotty followup record.
Consents, if properly done and documented, can also help reduce the likelihood of
subsequent complaint or cry of ‘‘foul.’’ They may not, however, be seen as legal documents
serving to abridge or abrogate a person’s right to complaint or subsequent legal action.
61. Consent: Process
185
61. Consent: Process
SLIDE
Consent: Process—National Emphysema Treatment Trial
(NETT)62
Type: Staged
Form: Written, signed, and dated in hand of patient, signing witnessed and dated by
witness
Reading level: 9th to 10th grade
Stage 1: Consent for screening and registry; to take place at initial visit to NETT
clinic
Stage 2: Consent for pulmonary rehabilitation; to take place after patient has
completed NETT diagnostic procedures and rehabilitation assessment and has
been judged eligible to continue for possible enrollment into NETT
Stage 3: Consent for randomization; to take place after patient has completed 6 to
10-week rehabilitation procedure
Consent related to surgery obtained when patient scheduled for surgery
R E L AT E D E N T R I E S
Consent (page 169), Consent: Checklist (page 177), Consent: Disclaimers and
notifications (page 181), Consent: Principles and purpose (page 183), Consent: Types
(page 189), Consent: Questions and answers (page 191)
DEFINITION
consent process n - The methods and procedures used in obtaining consent in relation
to enrollment into a study or other forms of research; including description of the setting
in which consent is requested, type of information to be presented prior to requesting
consent, name of person or persons responsible for obtaining and documenting consent,
and description of the nature and extent of opportunity offered for dialogue and query
prior to requesting consent. In trials and other forms of research involving direct contact
with study subjects, the process and related materials used for obtaining consent must be
reviewed and approved by the appropriate institutional review board (or similar board
or committee). The nature and complexity of the process proposed and related materials
will depend on the type and setting of the research proposed. The process may be carried
out in a single session (e.g., in a simple, short-term, largely risk-free trial) or may extend
over two or more sessions, conditions and circumstances permitting. Generally, all other
things being equal, a process involving two or more sessions, separated in time by one or
more days, is preferable to a single session—especially in trials where persons enrolled are
expected to undergo complicated or risky procedures or are to be exposed to potentially
risky treatments, or where data collection and followup are to continue over an extended
period of time. rt: consent, informed consent
186
VIII. IRBS AND CONSENTS
N A R R AT I V E
Hallmarks of good processes
• Person talked to as a fellow human being, not as an ‘‘object’’ of research
• Person given ample time to consider consent; preferably days when possible
• Person encouraged to discuss pros and cons of enrollment with family members,
friends, or advisors
• Person encouraged to decline enrollment or to wait on enrolling if in doubt
• Person given ample opportunity to ask questions regarding the study; staff
conscientious in answering questions
• Consent dialog conducted in quiet, relaxed, private settings conducive to thoughtful
interaction and unhurried, uncoerced decisions
• Person given consent statement and related documents for review prior to being
asked for consent, ideally to take home for study
• Person queried or tested prior to enrollment in effort to be satisfied that the consent
is informed; knowledge assessment tests if a formal process is desired or required
• Affirmation of consent on the day of randomization when consent obtained prior
to that day
• Checks to make certain consent is signed and dated prior to randomization
• Copy of signed consent given to person on enrollment
• Periodic review of consent statements, documents, and processes by study leadership
for revision, updating, and maintenance; reviews yearly; more often when indicated
Hallmarks of good consent statements and related consent materials
•
•
•
•
Presentation of detail and facts essential for making informed decisions
Correctness and accuracy of materials presented
Dispassion in regard to the way materials are written and presented
Reading level suitable to the population being studied; as assessed by reading score
computed using resident word processing software
• Legibility; font 11 point or larger; ‘‘clean’’ format and layout
• Consistency of facts and language across forms and documents
• Uniformity of materials across sites (in multicenter trials), as achieved by use of
prototype documents and by central review of locally approved documents to ensure
consistency of content, readability, and legibility
Do’s and don’ts of soliciting consents
•
•
•
•
•
Do be honest and direct.
Do proceed in stages when possible.
Do provide time for person to make informed decision.
Do whenever possible, allow at least 24 hours for person to decide on enrollment.
Do provide person with written description of the trial and requirements for
participation prior to requesting consent.
61. Consent: Process
187
• Do provide a copy of the consent statement for review prior to requesting enrollment.
• Do solicit consents in private setting conducive to cordial exchange and questioning
of study investigator regarding the trial.
• Do be certain the information imparted is accurate and correct.
• Do provide for witnesses of consent.
• Do provide participant with signed statement.
•
•
•
•
•
Do not
Do not
Do not
Do not
Do not
hard sell.
make promises that cannot be met.
misinform or distort.
be evasive.
ignore real or implied questions or concerns.
6 2 . C o n s e n t : Ty p e s
189
62. Consent: Types
R E L AT E D E N T R I E S
Consent (page 169), Consent: Checklist (page 177), Consent: Disclaimers and
notifications (page 181), Consent: Principles and purpose (page 183), Consent: Process
(page 185), Consent: Questions and answers (page 191)
DEFINITIONS
active consent n - A consent process producing documented consent. ant: implied consent
deferred consent n - [trials] Consent delayed or postponed beyond the point of
treatment assignment or start of treatment because of unconsciousness or other conditions
precluding consent before enrollment and treatment assignment; the actual consent
deferred or delayed until the person (or that person’s guardian) is in a position to give
or withhold consent [e.g., as reported by the Brain Resuscitation Clinical Trial II Study
Group, 1991].6 See Levine [1991]46 and Fost and Robertson [1980]32 for discussion of
conditions of use. rt: implied consent, post-assignment consent, passive consent Usage
note: Deferred consent involves contradictory notions. Consent implies a process designed
to allow a person the opportunity to make an informed decision as to whether to submit
to some planned activity before it is undertaken. There is no permission to be granted for
things already done.
documented consent n - 1. Documented evidence of consent by the presence of a signed
and dated consent form; signed consent. 2. Witnessed consent; as in the case of an oral
consent, by presence of a document detailing the nature of the information imparted, the
date consent was obtained, and bearing the signature of the person requesting the consent
and that of a witness. rt: signed consent, witnessed consent
implied consent n - Consent implied by absence of objection or by willingness to
proceed without formal consent; distinguished from active consent by the absence of a
documented consent. syn: passive consent ant: active consent rt: deferred consent Usage
note: Limited to minimal risk research where it can be reasonably assumed that persons
approached for study know they are free to terminate participation without prejudice or
fear of consequence; typically limited to telephone interviews, mail surveys, door-to-door
surveys, and street or mall interviews.
passive consent n - Consent that is inferred or implied from or by the absence of objection
or resistance; distinguished from active consent by the absence of a documented consent.
syn: implied consent ant: active consent rt: deferred consent Usage note: Use implied
consent.
witnessed consent n - 1. Consent given by a study subject in the presence of a third
party. 2. The act of obtaining a signed consent in the presence of a witness, especially one
in which the witness affixes his/her signature to the consent form below the signature of
the study subject. rt: documented consent
190
VIII. IRBS AND CONSENTS
N A R R AT I V E
Trials, because of the application of treatment, can be assumed to require active, written,
signed consents. For the most part, trials are not amenable to implied forms of consent.
Deferred consents are limited to settings in which consents cannot be obtained
before the fact of assignment. Use is limited primarily to emergency situations in which
treatment must be started promptly or where patient is unconscious or incoherent.
63. Consent: Questions and Answers
191
63. Consent: Questions and answers
R E L AT E D E N T R I E S
Consent (page 169), Consent: Checklist (page 177), Consent: Disclaimers and
notifications (page 181), Consent: Principles and purpose (page 183), Consent: Process
(page 185), Consent: Types (page 189)
QUESTIONS AND ANSWERS
What if a person is randomized and the consent form has not been signed?
Answer: The lapse of protocol is serious. The presumption, while sometimes wrong, is
that there was no consent in the absence of documented evidence of consent. Data for
the person should be expunged from the study dataset.
The fact of the breach should be reported to the IRB of record. The action of the
IRB will depend on the seriousness of the breach. It will not likely be understanding of
any instance in which persons are enrolled absent consent and is likely, in such cases,
to require a halt of enrollment pending a review of procedures for consent. If the breach
was of a procedural nature where consent was obtained but the form was not signed,
the action is likely to be less severe.
The investigator should write a memo to the patient’s file noting the breach, the
reason or likely reason for the breach, when and how it was noted, when it was reported
to the IRB, and the action taken. The processes for consent and documentation of the
fact of consent should be reviewed and tightened to prevent future occurrences.
You are well into the trial when you discover the consent form contains information
that is wrong. What should you do?
Answer: The course of action depends on when the deficiency is noted. Consents for
persons enrolled and still under followup should be updated and the fact of the updating
should be documented. Persons still to be enrolled should be consented based on
correct information as contained in a revised, IRB approved, consent form.
Persons, when consented, were told they would be treated and followed for one year
and then separated from the trial. Later on, investigators decide to treat and follow
everyone to a common closing date regardless of when they enrolled. What to do?
Answer: The change requires reconsent. The reconsent should detail the reason for the
change and what the change means to persons enrolled. Persons not willing to commit
to the new design but willing to remain in the trial under the old design should have that
option.
When should a person be informed of the treatment they received in masked trials?
Answer: The answer varies depending on the trial. The expectation, except where
persons are told otherwise on enrollment, is that persons will be unmasked when they
finish in the trial. The closeout design and procedures for unmasking should be reviewed
and approved by IRBs before implementation.
IRBs can be expected to be wary of proposals in which patients are not informed of
treatment assignment on completion of treatment and followup. Likewise, plans in which
persons are to be informed at some point after the close of the trial are suspect in the
absence of means for maintaining contact after close of the trial.
The treatment should be unmasked on separation if the information is of value to
the subject or to persons advising the subject on care subsequent to the trial.
A person withdraws from a double-masked trial and asks to be informed of the
treatment to which assigned. What do you do?
Answer: There should be efforts to turn the request aside. Part of the reason for doing
so is that unmasking during the trial increases the chance of treatment-related feed back
192
VIII. IRBS AND CONSENTS
bias. The risk of such bias can be reduced by masking schemes in which it is possible
to unmask an assignment without any peripheral unmasking. That is possible with med
Id labeling but not with bin Id labeling (for definitions see Drug packaging and labeling,
Page 117).
The issue of unmasking should be covered during consent. If unmasking is not to be
done until the end of the trial, persons should be so informed when enrolled. They should
know that they may withdraw from the trial at any time but that they will not learn of the
treatments they were receiving until the end of the trial except in special circumstances
involving time critical treatment decisions.
What if that same person asks to have his/her data removed from the trial?
Answer: Again, under ideal circumstances that issue is covered in consent. Persons
enrolled should know that they can withdraw but that data collected on them will not be
expunged from the study database.
What is a deconsent and when is it indicated?
Answer: Deconsent is the opposite of consent. It takes place on separation from the
trial at its conclusion. In the case of treatment trials, the information imparted relates to
treatment received (including identity of assigned treatment in the case of a trial involving
masked treatment), findings from the trial and relevance for the person departing,
and observations and recommendations regarding the person’s subsequent care and
treatment.
What is a reconsent and when is it indicated?
Answer: Reconsent is a reaffirmation of the willingness of a person to continue in a study
under new or revised circumstances. The new or revised circumstance may be due to the
addition of procedures heretofore not in force, an extension of the period of treatment
or of followup, or the addition or deletion of a treatment in the randomization schedule.
Reconsents are necessary when changes in study procedures have the potential of
causing persons to withdraw from participation because of the change. Reconsents
should be documented in the same way consents are documented.
A treatment is stopped during the trial because it is seen as inferior to the control
treatment. Patients on the treatment are informed of the result and taken off
treatment. Is there a need to reconsent patients not effected by the change?
Answer: Yes. The information could cause persons not effected by the change to
withdraw when informed of the action.
Midway into your trial, another set of investigators, doing a similar trial, announce
that they are stopping the trial because the test treatment is superior to the control
treatment. The results in your trial do not provide evidence of superiority. What is
your duty to patients in your trial?
Answer: They should be informed of the result, that the trial they are in will continue,
and why continuation is indicated.
A serious side effect, not anticipated when the trial was designed, is reported
outside the trial. The side effect has not been noted to-date in patients in your trial
and is not mentioned as a possibility in the existing consent form. Should the form
be revised to include mention of the side effect? Should persons already enrolled
be informed of the possibility of the side effect?
Answer: Yes to both questions.
A person agrees to be randomized. The randomization is issued and the person
declines treatment. What do you do?
Answer: There is nothing to be done. Persons have the right to decline treatment, and
that right remains regardless of having consented to randomization. The randomization is
counted to the treatment group indicated by the assignment, and the person is counted
as enrolled.
63. Consent: Questions and Answers
193
A person believes that she has not been adequately informed as to risks or
requirements of the study. What to do?
Answer: Try to address the concerns in a polite and forthright manner. Remind the
person of her rights and options, including those to withdraw and to take her complaint
to others, including the investigator’s IRB.
What if the complaint relates to injury caused by study?
Answer: The consent form should include a statement on what persons can expect and
not expect in relation to redress of study-related injuries. The ‘‘boiler plate’’ on injury, as
contained in consents for studies reviewed by the IRB for the Johns Hopkins Hospital
and Medical School, is:
If you want to talk to anyone about this research study because you think you have not
been treated fairly, or you have been hurt by joining the study, or you have questions
about the study, you should call the principal investigator, (name), at (phone no), or call
the Office of the Joint Committee on Clinical Investigation at 410 955–3008 or call the
Francis Scott Key Medical Center Institutional Review Board for Human Research at
550–1853. Either the investigator or the people in the Committee office or IRB office will
answer your questions and/or help you find medical care for an injury you feel you have
suffered. The Johns Hopkins University, The Johns Hopkins Hospital, The Francis Scott
Key Medical Center (other), and the Federal Government do not have any program to
provide compensation to you if you experience injury or other bad effects which are not
the fault of the investigator
Investigators are required to clear amendments to protocols through IRBs before
they are implemented. There are dozens of changes to forms and procedures over
the course of trials. Which among those rise to the level of amendments in the eyes
of IRBs?
Answer: Changes having potential of adversely affecting the benefit/risk ratio for persons
studied, changes likely to reduce the willingness of persons to enroll or remain under
study, and introduction of questions considered to be sensitive in nature.
Which changes require changes to consent documents and procedures?
Answer: Changes having potential of adversely effecting the benefit/risk ratio of being
studied as well as any changes likely to reduce a person’s willingness to enroll or remain
under study.
If changes are to be reviewed and approved by one’s IRB before implementation,
what does one do when the need for change is time critical and where it is unwise
to wait for IRB approval before proceeding?
Answer: In matters of urgency, investigators are expected to act without the time delays
in waiting for IRB approvals. In such cases, IRBs are informed after-the-fact and of the
reasons for the action.
Enrollment and
Followup
64. Notation
64. Notation
SLIDE
Visit and treatment group notation: Childhood Asthma
Management Program (CAMP)64
BL:
S:
Rz:
F:
Baseline
Screening
Randomization
Followup
BL visits: S1, S2, S3, S4, Rz
FU visits: F2, F4, F8, F12, F16, . . . (digits indicating month of followup)
Treatment groups
.
Bud:
Ned:
Plbo:
PBud:
PNed:
Budesonide
Nedocromil
Placebo
Budesonide placebo
Nedocromil placebo
SLIDE
Center and organization notation: Studies of Ocular
Complications of AIDS (SOCA) notation conventions80
Study centers
.
Cl:
CC:
OC:
RC:
PO:
Clinic (individual clinics identified by three letter mnemonic codes)
Coordinating Center
Office of Study Chair
Reading Center
Project Office
Organizational units
.
SC: Steering Committee
SO: Study Officers
PDMB: Policy and Data Monitoring Board
197
198
IX. ENROLLMENT AND FOLLOWUP
N A R R AT I V E
Establish nomenclature conventions in the design stage of the trial. Revise and update as
necessary. The list should be the starting point for a glossary of notations and abbreviations
for the eventual inclusion in the study handbook and other documents of the trial.
Recognize that there can be a Freddy Krueger quality to notation created. Once
established, notation is difficult to change or get rid of. The notation takes on a life of
its own. It will show up first in the protocol and from there be transported into study
handbooks, forms, and related study documents. Eventually it will be transported into
study publications. So be careful!
Choose mnemonic labels for treatment groups suggestive of the treatments
administered; preferred to labels such as Trt 1 and Trt 2.
Number visits relative to the point of randomization. Time slots for visits prior
to randomization may be numbered in ascending order to the randomization visit (e.g.,
BL-2, BL-1, and Rz for a schedule calling for two baseline visits prior to the randomization
visit). Followup visits should be numbered in ascending order starting with 1, e.g., FU 1,
FU 2, etc.
Numbering schemes based on completed followup visits should be avoided because
the numbering varies depending on whether visits are missed. Consider two people under
observation in a trial calling for followup visits at 6 months, 12 months, and 18 months
after randomization. Person 1 completes FU 1, 2, and 3 in the designated time windows
for the visits. Person 2 completes the first visit in the designated time interval for FU 1
but is not seen again until 18 months after enrollment, but, because the visit is the second
followup visit for the person, it is labeled as FU 2. Obviously, any analysis using followup
visit number as a surrogate for visit date is confounded by numbering schemes based on
competed visits.
Avoid subscript notation for visits, e.g., FU3 instead of FU 3. It is easier to write
the latter than the former.
Maintain consistency. For example, if followup is designated by FU, do not use
Fu. Likewise, if baseline is designated as BL do not use Bl. Avoid letters, such as lowercase
L and uppercase O because of potential of being read as numbers.
Other notation conventions useful in multicenter trials are as illustrated in the
second slide above for centers and leadership bodies represented in the trial.
QUESTIONS
• Have you reviewed publications of like trials for notation?
• What uses do you expect to make of the notation? Data forms? Protocol? Handbook?
Numbered memos? Manuscripts?
• Is the notation unique and internally consistent?
• Is the numbering system for visits sequential and related to times at which visits are to
be performed?
• Is the notation for treatment group mnemonic and unique?
65. Timing Conventions
199
65. Timing conventions
SLIDE
Timing conventions: Studies of Ocular Complications of AIDS
(SOCA) trials80
• Contiguous time windows (BL and FU visits)
• Data collection periods numbered sequentially
• Patient zero time: Point at which randomization revealed to clinic personnel;
also line of demarcation between BL and FU periods
• Clinic zero time: Time of initial IRB approval
• Trial zero time: Day of randomization of 1st patient enrolled
• Trial end time: Day of last completed followup visit
• Clock time: AM and PM 12-hour clock
• Date format: day, month (three letters) year; e.g., 3 Feb 2012
N A R R AT I V E
Trials are about time. Activities are ordered by clocks and dates. There are as many
clocks and dates in trials as persons enrolled. The treatment and followup clock starts on
enrollment, defined by some unequivocal landmark event—usually the point at which
the treatment assignment is revealed to clinic personnel. That time point marks the end
of the baseline period of observation and the start of the followup period. Time-to-event
analyses are timed from that zero time point.
The unit for timing visits should be specified in the design stage of the trial. The
unit is important in devising time windows for study visits (see Part 101: Time window
specifications). The unit should be invariant. This means that, if choosing between weeks
or months, the choice should be weeks. The trouble with months is that length varies,
depending on month. Hence, a followup visit schedule in which persons are seen every
three months can mean the visit schedule is every 12 weeks, every 13 weeks, or four times
a year on dates in months 3, 6, 9, and 12 after enrollment.
Establishing conventions for recording times and dates is important for
construction of data forms and for data collection, especially in multicenter studies
where conventions may differ.
One option for time of day measurements is the 24-hour clock, but 24-hour times
are confusing to lay people. For that reason it is best to stick to the AM–PM 12-hour
clocks except in special settings.
The convention for recording dates in the United States is month, day, year in
numeric form, e.g., 6/8/2011 for June 8th, 2011. However, that format is subject to error
and misinterpretation. The problem is that the same numbers can stand for different
dates, depending on where used. In various parts of the world, 6/8/2011 stands for the
6th day of August 2011. The confusion can be eliminated by writing the date as 8 Jun
2011.
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IX. ENROLLMENT AND FOLLOWUP
Time windows are used to indicate the allowable intervals within which
observations or procedures are to be performed. Windows should be contiguous.
Noncontiguous windows lead to ‘‘dark periods’’ in data collection schedules where
persons are not eligible for any data collection. Contiguous time windows avoid that
problem.
QUESTIONS
• Is there agreement on the zero point defining enrollment of a person?
• Is there an expected end date for the trial? Is the date consistent with funding?
• Are investigators committed to counting observations on a person not made within
the permissible windows as missed?
• Are investigators committed to having the baseline period close with randomization?
• At what point is a clinic regarded as ‘‘enrollment ready’’? Point at which IRB approval
is granted? Point at which clinic is certified as enrollment ready by the CC?
• Does the trial involve clinics from other countries with different time or date
conventions?
66. Required Approvals, Permissions, Accesses, and Supplies
201
66. Required approvals, permissions, accesses, and
supplies
SLIDE
Required Approvals: Monoclonal Antibody CMV Retinitis Trial
(MACRT)82
Investigator approval
PDMB approval
NEI approval
FDA approval (expressed by absence of objection within 30-day time window)
Sign-off on protocol by Protein Design Labs (manufacturer of monoclonal antibody
to be tested)
IRB approval (first by parent IRB, then by local IRBs)
R E L AT E D E N T R Y
Critical event path analysis (page 241)
N A R R AT I V E
Specify required permissions, approvals, accesses, and supplies necessary during the design
stage of the trial. Essential or likely permissions, approvals, and accesses are listed below.
Permissions/accesses
• Cross referencing of IND held by proprietary sponsor (for drug trials done under
IND held by study investigators)
• Copyrighted materials to be used in the trial
• Contact of patients under physician care
• Mailing lists for use in patient recruitment
Approvals
• IRB approvals
• OMB clearance of study forms (required with certain forms of government funding)
• Sponsoring agency sign-off on study protocol (likely for proprietary sponsors and
for large-scale government funded trials)
• Approval of study protocol by extant advisory committee (often assumed by the
TEMC in multicenter trials lacking an advisory committee)
• FDA in regard to trials done under INDs (typically, approval is communicated by
lack of objection within 30 days of submission of an application for an IND)
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IX. ENROLLMENT AND FOLLOWUP
Supplies/equipment
•
•
•
•
Drug
Testing reagents
Forms
Equipment specified in study protocol
67. Start-Up Design
203
67. Start-up design
SLIDE
Start-up design: Chemoprevention for Barrett’s Esophagus
Trial (CBET)36
Training meeting
Prototype consent form submitted to parent IRB
Finished protocol and prototype consent form distributed from CC to clinics for
submission to local IRBs
Certification of clinic
Certification of personnel
Certification of clinics for enrollment
Distributed data system shipped to clinics after enrollment of second patient
R E L AT E D E N T R I E S
Required approvals, permissions, accesses, and supplies (page 201), Recruitment design
(page 209), Closeout design (page 225), Critical event path analysis (page 241)
DEFINITIONS
clinic start-up design n - Start-up design for recruitment and certification of clinics, for
training and certification of clinic personnel, and for clearance of clinics to start patient
recruitment. ant: clinic closeout design rt: patient recruitment start-up design
feasibility study n - A study designed and performed for the purpose of determining
whether it is possible to perform a full-scale study or a specified set of tasks or functions in
relation to such a full-scale study, e.g., a study aimed at testing the ability of investigators
to recruit specified numbers of patients in a designated time period. rt: demonstration
study, pilot study
lead clinic n -[multicenter trials] 1 - A clinic responsible for testing proposed patient
examination and data collection procedures prior to their use in other clinics. 2. The first
clinic funded, especially when that clinic is responsible for developing and testing data
collection procedures to be used in the study.
lead-in period n -[trials] 1 - A period of time prior to enrollment and within the baseline
period during which study candidates are placed on a treatment similar to one of those
to be evaluated in the trial to assess their tolerance to or acceptance of a treatment, or
to provide information on treatment compliance. The treatment administered may be
similar to the control treatment, as in the Coronary Drug Project,18 or may be a test
treatment [CAST Investigators, 1989].10 Typically, candidates judged to have had adverse
reactions to the treatment or to have unsatisfactorily adhered to the prescribed treatment
are not enrolled. See Brittain and Wittes [1990]7 for a discussion of usefulness of the
procedure. 2. baseline period syn: run-in period rt: placebo lead-in period
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IX. ENROLLMENT AND FOLLOWUP
pilot study n - A small preliminary study performed as a possible prelude to a full-scale
study and intended to provide training and experience in carrying out such a study if
undertaken. rt: demonstration study, feasibility study, pilot test
run-in period n - 1. lead-in period 2. enrollment period Usage note: Subject to confusion
because of different meaning, depending on whether used in the sense of defn 1 or 2.
Avoid by using lead-in period or enrollment period, depending on sense of usage.
shakedown period n - 1. A period of time in the course of a study when data forms
and procedures are tested prior to the official start of the study. 2. A period of time after
the start of the study when procedures are still being tested and subject to change. 3.
The initial workup and evaluation of a person for enrollment into a study; especially
one involving administration of treatment, as in a lead-in period, for the purpose of
assessing acceptance and compliance. 4. The period defined by initiation of treatment
after enrollment. rt: lead-in period
start-up patients n - The collective set of patients designated as constituting a start-up
set for some purpose or function. rt: test patients, vanguard patients Usage note: Avoid,
except when there is some operational meaning or importance given to the designation, as
in relation to the way such patients are treated or handled relative to trial-proper patients.
See also notes for test patients and vanguard patients.
test patients n - [trials] 1. The collective set of patients on whom something is being
tested. 2. start-up patients; vanguard patients Usage note: In the setting of trials, use
should be limited to instances in which there is a need to differentiate between trial-proper
patients and test patients, e.g., because results from test patients are not to be combined
with results from trial-proper patients.
trial-proper adj - Of, relating to, or concerned with that portion of the trial concerned
with trial-proper patients; typically that set designated at the outset to comprise the
treatment groups for use in assessing treatment effects in primary data analyses; may be
exclusive of start-up patients or vanguard patients.
trial-proper patient(s) n - A patient(s) enrolled in the trial proper.
vanguard patients n - [trials] The set of patients designated on whom the various
procedures of the different visits called for in the treatment and data collection schedule
of the trial are tested in advance of trial-proper patients. rt: start-up patients, test patients
Usage note: Limit use to settings where specific patients are designated as being in a
vanguard set (e.g., the set represented by the first two patients enrolled at each clinic in a
multicenter trial) and where information from that set is intended for use in modifying or
adjusting methods or procedures.
QUESTIONS AND ANSWERS CONCERNING START-UP
Should forms be tested before use?
Answer: Of course!
Should procedures be pilot tested?
Answer: A good idea if possible.
Should the trial be preceded by feasibility studies?
Answer: A trial is a trial and a feasibility study is a feasibility study. If feasibility is the
issue, then by all means; otherwise go for the real thing.
67. Start-Up Design
205
Should test patients be enrolled prior to the start of full blown enrollment?
Answer: Perhaps, but not without IRB approval and then only if patients know they are
being enrolled to test procedures.
If test patients are enrolled, should data on them be combined with study proper
patients?
Answer: No. Data for them are best kept separate. The purpose of including test patients
is to test forms and procedures. The data generated are not likely to be comparable to
trial-proper data.
Should there be a shakedown period?
Answer: An alright idea when feasible.
Should there be a lead-in or run-in period?
Answer: Generally not recommended. Gain in precision is likely to be minimal. See
Brittain and Wittes [1990].7
Should a clinic in a multicenter trial be designated as the lead clinic?
Answer: Reasonable if there is a clinic willing to serve that function and is qualified
to serve that function. Most useful when the clinic is located in close proximity to the
coordinating center.
Should each clinic be required to enroll a specified number of test patients before
being cleared for general enrollment?
Answer: Perhaps, if clinics are inexperienced and the protocol is complicated.
Should all clinics in a multicenter trial be brought online at the same time?
Answer: No. Holding clinics at the starting gate until all are ready to start slows
enrollment.
Should the full complement of clinics be available when enrollment starts?
Answer: No for the reason above. In any case, one can think the complement is full only
to discover later that additional clinics are needed to meet the enrollment goal.
Should there be a certification procedure for clearing clinics to start enrollment?
Answer: Yes.
Should clinic personnel be trained and certified prior to start-up?
Answer: Yes.
68. Start-Up Checklist
207
68. Start-up checklist
R E L AT E D E N T R I E S
Start-up design (page 203), Critical event path analysis (page 241)
N A R R AT I V E
It is up to the designers to list the conditions that must be satisfied in order to allow the
trial to start. The conditions should be expressed in the form of checklists as illustrated
below and should be maintained by an officer of the trial with the authority to maintain
a trial or clinic in a hold condition until all checks have been met.
Sample checklist for the XYZ drug trial
Trial
()
()
()
()
()
()
()
IRB approval of parent IRB
Date:
Investigator sign-off on study protocol
Date:
Sponsor sign-off on protocol
Date:
IND in place
Tested data collection forms
Investigator sign-off on data collection forms
Date:
Sufficient supply of drug packaged and labeled as required for the trial
Clinic
()
()
()
()
()
()
IRB approval of local IRB
Clinic certified
Staff trained and certified
Form 1572 on file at the FDA for clinic investigators
Clinic supplied with data collection forms
Clinic supplied with drug
Date:
Date:
69. Recruitment Design
209
69. Recruitment design
SLIDE
Recruitment design: Childhood Asthma Management
Program (CAMP)11
Prerequisites to initiation of recruitment
•
•
•
•
•
DSMB approved protocol
NHLBI approved protocol
IRB approved protocol
Approved data collection forms
Coordinating Center ready
Clinics
• Clinics cleared for enrollment by CC
• Common start date (all clinics to start recruitment between 1 Nov 93 and 31
Dec 93)
• Common shutdown date (clinic asked to stop recruitment of new patients 1
July 1995; last patient screened 5 Sept 1995)
• Common enrollment goal of 120 per clinic (clinics allowed to enroll beyond
the 120 goal subject to overall enrollment limit of 960 or thereabouts)
R E L AT E D E N T R I E S
Enrollment goals (page 211), Enrollment quotas (page 213)
N A R R AT I V E
Issues to be addressed by planners when considering enrollment design include the
following:
• Minimum requirements necessary for clearing the trial for enrollment
• Minimum requirements necessary to clear a clinic for enrollment
• Whether to test procedures and forms prior to official start of enrollment; if so:
❑ Nature and extent of testing; patients procedures only, forms only, or both
❑ Whether to test on actual patients
❑ If plan calls for enrollment of test or vanguard patients, whether data for patients
will be included in the finished dataset of the trial
• Sample size requirement
• Time limit for completion of enrollment
Additional issues relevant to trials having multiple clinics:
• Whether to regard a particular clinic as the lead clinic for initiating enrollment
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IX. ENROLLMENT AND FOLLOWUP
• Whether to allow individual clinics to start independent of other clinics (preferred
to the option where clinics are not allowed to start until all clinics are ready to start;
common start models are likely to increase time to the stated recruitment goal and
to frustrate personnel at clinics ready to go)
• Whether to operate with a single enrollment goal or individual per clinic goals (see
Enrollment goals; page 211)
• Whether to continue enrollment to a common closing date (recommended; preferred
to option where clinics stop enrollment per clinic goals; see Enrollment goals;
page 211)
• Whether to require clinics to achieve a minimum rate of enrollment in order to
remain active in enrollment
• Whether to impose an upper limit on the number of patients a clinic may enroll
70. Enrollment Goals
211
70. Enrollment goals
SLIDE
Recruitment goals: Childhood Asthma Management Program
(CAMP)11
Subjects will be 1056 children with asthma between the ages of 5 and 9 years. Each
clinical center expected to recruit 132 patients into the study over an 18 month
period. The composition of study subjects selected for the study should reflect the
diversity of groups affected by this disease.64
R E L AT E D E N T R Y
Enrollment quotas (page 213)
N A R R AT I V E
The enrollment goal, in terms of the number to be enrolled and the time allotted for
enrollment, should be specified when the trial is designed. The number derives from
sample size calculations or from pragmatic considerations. The time is an estimate.
The actual number enrolled and the time taken for enrollment may be quite
different from what was specified when the trial was planned. Often the result is to fall
short of the number required and/or to exceed the time set for enrollment. The reason is
that eligible persons are almost always harder to find and enroll than anticipated in the
design stage of the trial.
Comparison of the expected and observed enrollment over the course of enrollment
provides a crude measure of performance—crude because the expected rate is based on
the assumption that the rate is uniform over time. The reality is that it rarely is. Normally,
enrollment starts slow (except perhaps where there is a backlog of patients waiting to be
enrolled—rare) and increases to some steady state as the trial progresses.
The overall enrollment rate in multicenter trials, when divided by the number of
recruiting clinics, gives the average clinic enrollment rate. The actual rates across clinics
will vary. The rate for top enrolling clinics may be twice that for low enrolling clinics and
still be within the ‘‘normal range’’ of expectation.
An issue for designers in multicenter trials is whether to impose an upper limit on
the number of persons that may be enrolled from any given clinic. They will be inclined
to do so if there are concerns that the quality of data or compliance to protocol will be
reduced as a result of unreasonable work load due to high numbers of enrollees. They may
do so as well in cases where payment is on a per-head basis in order to ensure a reasonable
distributions of monies across clinics.
One of the reasons for an upper limit on clinic enrollment is to ensure balance in
the numbers enrolled across clinics. Typically, the desire for balance derives from concerns
that marked imbalances in the numbers enrolled by clinic will, somehow, reflect badly on
the trial or ‘‘skew’’ results. However, the concern is more theoretical than real, especially
in designs involving randomization by clinic.
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IX. ENROLLMENT AND FOLLOWUP
The disadvantage of imposing an upper limit is that the limit, to the extent the
limit is encountered, will reduce enrollment efficiency. The impact will be modest if the
limit is high and rarely encountered. It will be marked if encountered by the majority of
clinics. The time required to achieve the overall enrollment goal will increase if fewer and
fewer clinics are enrolling as the limit is encountered. For example, setting the limit to the
average (required sample size divided by number of clinics) can be expected to extend the
time required to achieve the overall goal, sometimes by a goodly amount when clinics are
widely disparate in rate of enrollment. Usually, the best strategy is to allow all clinics to
enroll until the overall goal is achieved.
71. Enrollment Quotas
213
71. Enrollment quotas
SLIDE
Enrollment quota: Childhood Asthma Management Program
(CAMP)11
Each clinical center shall recruit males and females and must specifically include
at least 44 children from minority groups, such as Blacks, Hispanics, and Native
Americans.64
R E L AT E D E N T R Y
Enrollment goals (page 211)
DEFINITIONS
overrepresent, overrepresented, overrepresenting, overrepresents v - To represent in
larger or higher amount or degree than desired or required. ant: underrepresent
quota n - 1. A proportional part or share. 2. The number or amount representing or
constituting a proportional share or limit, as in a recruitment quota.
quota requirement n - [trials] A requirement imposed to ensure a specified mix in the
study population with regard to one or more demographic characteristics, disease states, or
other variables observed at or prior to enrollment; stated in numbers required, proportions
required, or as minimums required; e.g., in regard to gender, 50 males and 50 females,
50% female, or at least 50% female. rt: recruitment quota, sample size requirement Usage
note: See quotification.
quotification n - The act or process of imposing a quota requirement on the mix
of persons enrolled in a trial. rt: quota requirement, stratification Usage note: Not
to be confused with stratification. The purpose of stratification is to ensure that the
different treatment groups have the same proportionate mix of people with regard to the
stratification variable(s). The purpose of quotification is to ensure that a study population
has a specified mix with regard to the variables used for quotification.
recruitment quota n - 1. The number of individuals of a specified type to be recruited;
patient recruitment quota. 2. The proportionate share of a whole to be represented by a
designated type or class of persons. rt: quota requirement Usage note: Not to be confused
with recruitment goal. Recruitment goal relates to the overall number to be enrolled in
a recruitment effort; recruitment quota relates to the mix of people to be enrolled, as
specified in absolute or relative terms. The imposition of quotas in trials should be done
with caution since they make achieving a stated recruitment goal more difficult in that
they limit the type of people who can be considered for enrollment after individual quotas
have been met. For example, a trial having a recruitment goal of 100 and a quota of 50
males and 50 females means that only males or females can be considered for enrollment
once the quota is met for the other gender group, thereby prolonging the time required to
achieve the stated recruitment goal of 100. Quotas should not be imposed except where
there is a need or desire to carry out subgroup analyses within subgroups defined by the
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IX. ENROLLMENT AND FOLLOWUP
quota and where there is a need or desire to perform comparisons within those subgroups
at a specified level of precision.
representativeness n - The state or nature of being representative. In the context of trials,
the extent or degree to which persons studied can be considered to be representative
of a larger general population. ‘‘Representativeness’’ is an elusive state, absent means
for achieving it. Such means do not exist for trials since only persons willing to be
enrolled can be studied. Hence, the state is largely a matter of conjecture. Measurements
are, of necessity, limited to observations involving comparisons of distributions of key
demographic and disease characteristics of the study population with corresponding
distributions for persons screened for enrollment or with those of the general population.
underrepresent, underrepresented, underrepresenting, underrepresents v - To
represent in lower or lesser amount or degree than desired or required. ant: overrepresent
rt: understudy Usage note: Use with caution; value-laden and vacuous when used as
a claim or assertion in the absence of definition or supporting data, e.g., women have
been underrepresented in heart trials. (Underrepresented in what sense? Is it in terms of
the proportionate mix of men and women studied compared to some desired mix as
represented in a population at large, and, if so, what is that population? Or is it in terms of
the impact of heart disease on women relative to men, and if so then in what sense? Is it in
relation to the number of deaths due to heart disease in women relative to men, in terms of
years of life lost due to heart disease for women versus men, or in terms of some morbidity
measure, such as the incidence of myocardial infarctions in women versus men?) The
notion of representation has a host of possible meanings. Hence, it is incumbent on the
user to define sense of use. See note for understudy for added comments.
understudy, understudied, understudying, understudies v - To study less than desired
or required. ant: overstudy rt: underrepresent Usage note: Use with caution; value-laden
and vacuous when used as a claim or assertion in the absence of definition or supporting
data. The notion of understudying is predicated on the supposition that there is a
‘‘proper’’ amount of studying but that is an elusive concept. If used, accompany with
supporting definition or data to indicate sense of usage. See note for underrepresent for
added comments.
N A R R AT I V E
Enrollment quotas are imposed to ensure a specified mix of persons in regard to a disease
state, health condition, or entry baseline characteristic, such as gender, race/ethnic origin,
or age. Quota requirements should not be imposed in the absence of sound scientific
rationale and where there is need to estimate treatment effect by quota subgroup.
They should be viewed with wariness in all cases. The most obvious reason is
because of reduced enrollment efficiency.
Consider a trial with an enrollment goal of 100, a screening flow rate of 20 people
per week, and a 10:1 screening to eligible yield rate. Under those conditions the average
time required to enroll 100 people would be 50 weeks.
Now suppose the imposition of a mix requirement of 50 males and 50 females. If
the male-to-female flow rate is 50:50 and the screening to eligible yield rate is the same for
males and females, then the impact of the mix requirement on time to enroll 100 people,
evenly split between males and females, will be nil. The impact on time comes as gender
flow rates depart from unity and screening yields differ by gender.
71. Enrollment Quotas
215
Suppose a 75:25 male-to-female flow and an eligibility screening rate of 10:1 for
males and females. The clinic, on average, will be screening 15 males and 5 females per
week with a yield of 1.50 males and 0.50 females per week. The clinic will achieve its
quota of males in 33 weeks and the female quota in 100 weeks. If the clinic opts to keep
enrolling males until the quota for females is met, the finished sample size would be 200
(150 males and 50 females).
The time required for meeting quota requirements is a function of eligibility
screening rates. If the eligibility screening yield for females is half that for males, 20:1
versus 10:1 for males, it will take 200 weeks to enroll 50 females compared to 33 weeks
for males.
Mix requirements are superfluous for the validity of randomized trials. Treatment
comparisons are valid so long as the mix is the same across treatment groups. Validity
does not depend on having a specified mix.
The imposition of mix requirements because of concern that the effect of treatment
may be different by subgroup is generally ill-advised. The likelihood of finding subgroup
differences, even when there are reasons to expect they exist, is small given the usual size
limitations of trials. It is smaller still when quotas are imposed simply because of the mere
possibility of differences.
Designers should be parsimonious when it comes to imposing mix requirements.
Principles of parsimony, when explaining results, require that one gives the greatest weight
to those explanations requiring the fewest assumptions. In the case of explaining treatment
effects, that means analysts should not attempt to explain results requiring assumptions of
heterogeneity of treatment effect, if results are consistent with homogeneity of treatment
effect. By extension, the principle suggests that designers should avoid committing to the
added cost or increased time for enrollment by imposing mix requirements in the absence
of evidence suggestive of heterogeneity of treatment effect in the subgroups represented
by the quotification variable.
The truth is that most effects, at least within the limits of detection possible in
trials, are consistent with homogeneity of effect. Indeed, most subgroups identified in
trials, whether they be in relation to quota subgroups or in relation to post-hoc subgroup
analyses, are not reproducible and therefore have to be regarded with skepticism.9,102
Demographic-based mix requirements should not be imposed in treatment
trials involving life-threatening or life-limiting diseases, or in settings where the mix
requirements are administered in such a way as to require clinics to reject persons for
enrollment based on mix requirements.
Also, they should not be imposed with the expectations that flows to clinics can be
regulated to meet mix requirement. That may be possible in risk concentration primary
prevention trials and perhaps in trials done in primary care facilities, but not in trials done
in tertiary care facilities. The flow to such facilities is not under the control of the facility.
It is solely a function of feeds from outlying primary and secondary care facilities.
The preferred strategy is to avoid mix requirements in favor of unrestricted flows
and mixes. Assessments of treatment effects can be done via subgroup analyses based on
whatever numbers are enrolled in the various subgroups of interest.
Gender-based mix requirements have come into being because of the perception
that women and their diseases and conditions have been understudied relative to those of
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IX. ENROLLMENT AND FOLLOWUP
men in trials. As a result, gender mix requirements as well as minority mix requirements
are imposed more for political than for scientific reasons. Designers have little choice but
to implement mix requirements when mandated by sponsors. Recent examples of such
imposition are below:
Childhood Asthma Management Program (CAMP): Subjects will be 1056 children
with asthma between the ages of 5 and 9 years. Each clinical center would be expected
to recruit 132 patients into the study over an 18 month period. The composition of
study subjects selected for the study should reflect the diversity of groups affected by
this disease. Each clinical center shall recruit males and females, and must specifically
include at least 44 children from minority groups, such as Blacks, Hispanics, and
Native Americans.64
National Emphysema Treatment Trial (NETT): The offerors for clinical centers will
describe, in detail, the gender and racial/ethnic characteristics of the patient population
that is available for study. This information will be used to make the final decision of
the Clinical Centers which will be made with the objective of obtaining a study-wide
patient mix which includes 6 percent minorities and 30 percent women.63
The goal of designers, when mix requirements are imposed, is to minimize effect
on recruitment by implementing the requirement in the least restrictive and disruptive
fashion while still complying with the spirit of the requirement. For example, in the case
of CAMP, that meant lifting the clinic mix requirement (132 persons per clinic) in favor
of an overall gender and ethnic origin mix requirement.
A question encountered with an imposed mix requirement is whether the
requirement is to be regarded as an absolute with enrollment stopping in the group
where the quota is met or as a minimum with enrollment continuing across all subgroups
until the minimum is reached in a designated subgroup. The downside in stops by
subgroup is the procedural and ethical issues involved in turning away persons simply
because they do not meet mix requirements. Differential stops can create ethical problems
when patients in need of treatment are turned away. The preferred strategy in such cases
is to regard the requirement for the least common subgroup requirement as a minimum
and to continue to enroll all comers until the minimum is met.
7 2 . F o l l o w u p : Te r m i n o l o g y
217
72. Followup: Terminology
R E L AT E D E N T R I E S
Notation (page 197), Followup: Method (page 221), Followup: Length (page 223),
Closeout design (page 225)
DEFINITIONS
active followup n - 1. Followup done by direct contact of a person or the person’s
representative; may be by mail, by telephone, or face-to-face by home visits or clinic visits.
2. The state of not being lost to followup. rt: passive followup
close of followup n - 1. The point at which followup ceases for a person. 2. The point
at which followup ceases with the chosen method of closeout; common closing date or
anniversary closing date. 3. The point at which all followup ceases; close of trial.
concurrent followup n - Followup that takes place over the same time period for the
different study groups represented in a study design; generally prospective and performed
in real time.
followup (Fu, FU) n - [also follow-up] 1. The act of or an instance of following up. 2.
Something done in or as followup, e.g., reexamination of a person as part of scheduled
followup. 3. Maintenance of contact with a person or observation unit for care or
administration of treatment.
followup cohort n - 1. A group of people (or larger observation units) followed over time.
2. A group of people enrolled in a study and followed over time.
followup compliance n - The nature, extent, or degree of compliance to prescribed
followup procedures. rt: data collection compliance, protocol compliance, treatment
compliance
followup data n - Data collected on an observation unit or a set of observation units after
enrollment of that unit or units in a study.
followup observation n - 1. An observation made at a designated point in the course
of followup. 2. A series of observations made at various time points over the course of
followup. 3. An item of data collected on a person (or larger observation unit) after
enrollment in a study.
followup period n - 1. A period of time from enrollment of an observation unit (usually
a person) in a study to termination of followup of that unit. 2. A period of time in the
course of a study defined by the start of followup of the first observation unit and by the
end of followup of the last unit enrolled; followup stage.
followup stage n - [trials] A stage of trial with followup as the sole objective; typically
starting with the completion of treatment administration and ending with the start of
the termination stage. The stage does not exist in trials in which treatment and followup
proceed concurrently, as in treatment and followup stage.
followup study n - 1. A study in which data collection for those enrolled proceeds forward
in time, either from a point in the past to a more recent point in the past, from a point in
the past to the present or one in the future, or from the present to a point in the future.
2. concurrent followup study syn: cohort study, longitudinal study, prospective study ant:
218
IX. ENROLLMENT AND FOLLOWUP
cross-sectional study Usage note: All trials, by definition, involve followup and in this
general sense are, therefore, members of this class of studies. However, the term is best
reserved for the subset excluding trials to avoid confusion.
followup study design n - The portion of a study design that details methods and
procedures to be used for following those enrolled in the study and for data collection
during followup.
followup visit n - [trials] Any study clinic visit by a person after treatment assignment,
especially a required followup visit.
interim followup n - 1. Followup that is in addition to that required or specified in the
study protocol; e.g., added followup taking place between scheduled followup visits. 2.
unscheduled followup
loss to followup n - Any loss of followup data on a person (or other observation unit)
after enrollment into a study; loss may occur because a person cannot be located for
required data collection or because the person is unwilling or unable to submit to required
data collection procedures. rt: lost to followup Usage note: The majority of losses to
followup in trials occur because of dropout since most data in trials are generated via
direct interview and examination of those enrolled. However, some forms of followup
may continue even after a person drops out, e.g., as with followup for mortality via death
indexes.
losses to followup n - The sum total of lost information because of loss to followup.
Usage note: See loss to followup for comment.
lost to followup adj - 1. Characterized by unknown whereabouts in a followup study. 2.
An observation unit in a followup study that cannot be followed for some outcome or
observation of interest. rt: losses to followup Usage note: The characterization in trials is
usually applied to a person who is unwilling or unable to return to the clinic for followup
examinations. The characterization is subject to misuse, especially when used without
regard to nature or extent of information lost. In good usage, the observation or set of
observations lost is specified. Specification is important when followup is possible by
other means, e.g., by telephone instead of by scheduled clinic visits. It is bad practice to
use lost to followup interchangeably with dropout. A person, no longer willing or able to
return for clinic visits, is lost to followup for observations made during such visits, but not
necessarily for observations that can be made in other ways, e.g., by telephone interview.
Even individuals who refuse any contact with study personnel may not be lost to followup
for certain events, such as death.
nonconcurrent followup study n - 1. A followup study having two or more study groups
and nonconcurrent followup of at least one of those groups in relation to another. 2.
nonconcurrent cohort study 3. nonconcurrent prospective study ant: concurrent followup
study
passive followup n - Followup absent direct contact of the person of interest or that
person’s representatives, e.g., as with mortality surveillance achieved by querying the
National Death Index. rt: active followup
post-treatment followup n -[trials] 1. Any followup after completion of administration
of the assigned treatment. 2. Any followup occurring after the first application of the
assigned treatment. 3. post-trial followup Usage note: Best limited to use in the sense of
defn 1. Subject to confusion if used in the sense of defn 2 before treatment is completed.
7 2 . F o l l o w u p : Te r m i n o l o g y
219
post-trial followup n - Any form of followup taking place after completion of the closeout
stage of a trial or cessation of the trial.
post-trial followup stage n - [trials] A stage of trial occurring after the termination stage
and intended to provide followup data on some outcome measure.
prospective followup n - Followup that proceeds forward in time. syn: cohort study,
concurrent followup study, longitudinal study ant: retrospective followup
regular followup visit n - Any of a series of visits to be made during followup;
also required followup visit. syn: scheduled followup visit ant: interim followup visit,
unscheduled followup visit Usage note: Regular in this context refers to visits intended
to take place at specified times over the course of followup as required for data collection
and for carrying out procedures and assessments specified in the study protocol.
required followup visit n - Any followup visit required as part of the study protocol and
that is to be done at a specified time after enrollment; in the case of trials, such visits
include treatment application and adjustment followup visits, regular followup visits,
closeout followup visits, post-closeout followup visits, and post-trial followup visits. ant:
nonrequired followup visit rt: regular followup visit
retrospective followup n - 1. Followup proceeding backward in time from some
designated time point. 2. Followup proceeding forward in time from some designated
starting point in the past to a more recent time in the past or to the present. ant:
prospective followup Usage note: Not a recommended term because of the different
meanings of the two definitions and because of the contradictory nature of retrospective
and followup: The latter term implies something moving forward in time, whereas the
former term implies something moving backward in time.
scheduled followup n - Followup that is planned or specified in the study protocol;
required followup; not interim followup. syn: required followup ant: unscheduled followup
unscheduled followup n - Followup that is not part of that required; not scheduled
followup; interim followup. ant: scheduled followup
73. Followup: Method
221
73. Followup: Method
R E L AT E D E N T R I E S
Followup: Terminology (page 217), Followup: Length (page 223), Missed visit (page
229), Dropout (page 231), Loss to followup (page 235)
DEFINITIONS
active followup n - 1. Followup done by direct contact of a person or the person’s
representative; may be by mail, by telephone, or face-to-face by home visits or clinic visits.
2. The state of not being lost to followup. rt: passive followup
direct followup n - Followup achieved by direct contact with the person of interest or
the person’s parent, spouse, family member, or guardian via clinic or home visits or by
telephone or letter. ant: indirect followup
indirect followup n - 1. Followup absent direct contact with the person of interest. 2.
Followup absent direct contact with the person of interest or members of the person’s
family or guardian, e.g., as with mortality surveillance achieved by querying the National
Death Index or by use of agencies specialized in tracing and locating persons. syn: passive
followup ant: direct followup
passive followup n - Followup absent direct contact of the person of interest or that
person’s representatives, e.g., as with mortality surveillance achieved by querying the
National Death Index or by use of agencies specialized in tracing and locating persons. rt:
active followup
N A R R AT I V E
Followup is a process involving the collection and recording of data on study subjects
at periodic intervals after enrollment. For the most part, it is achieved in trials via
visits of study subjects to study clinics. As a result, followup tends to be seen simply
as a function of whether a person is seen in a study clinic within the specified time
window (see Time window specifications, page 299). A person, who does not have a visit
within the time window, is regarded as ‘‘lost to followup’’ (see Loss to followup, page
235).
In reality, however, followup is rarely an all-or-none process. Even if a person
shows up for scheduled visits, it may not be possible to perform the necessary tests and
procedures needed for complete followup. By the same token, missing a clinic visit does
not mean that the constellation of variables associated with the visit are ‘‘lost to followup.’’
They need not be if alternative means of followup are available and used to provide needed
data.
Designers should list key followup variables, whether they may be followed via
alternative means, and what those alternative means are to be. The information may be
displayed in table format as illustrated below.
222
IX. ENROLLMENT AND FOLLOWUP
Primary means of FU
Alternative means of FU
Mortality
Hospitalizations
Adverse events
Etc.
The table should indicate the primary mode of collection, whether an alternative
mode is permissible, and what the mode or modes are to be. The modes may be as follows:
Direct
Face-to-face
Scheduled clinic visit
Home visit
Visit elsewhere
Telephone
Mail
Etc.
Indirect
Third person or party
Newspaper obituary
National Death Index
Etc.
74. Followup: Length
223
74. Followup: Length
R E L AT E D E N T R I E S
Followup: Terminology (page 217), Followup: Method (page 221)
DEFINITION
followup period n - 1. A period of time from enrollment of an observation unit (usually
a person) in a study to termination of followup of that unit. 2. A period of time in the
course of a study defined by the start of followup of the first observation unit and by the
end of followup of the last unit enrolled; followup stage.
QUESTIONS AND ANSWERS
How long should persons be followed?
Answer: As long as study treatments are administered and usually for a period of time
after cessation of treatment sufficient to track post-treatment effects.
How does length of followup play into sample size design?
Answer: See Sample size: Design (page 253). In general, the longer the period of
followup the easier to find treatment differences if they exist.
Should the period of followup be the same as the period of treatment?
Answer: It may be in drug treatment trials, but will, of necessity, extend beyond the
period of treatment in trials involving a single application of treatment or a short course
of treatment.
Should followup stop when a person is no longer receiving the assigned treatment?
Answer: No. Followup during the trial should proceed independently of persons
compliance to treatment.
When do efforts at followup terminate?
Answer: When the trial enters the closeout stage of activities (see Closeout design, page
225) or when a treatment is stopped because of convincing interim results.
Should length of followup be the same for every person?
Answer: It will be with an anniversary closing date but not in closeout designs where all
persons are followed to a common closing date regardless of when they were enrolled
(see Closeout design, page 225).
75. Closeout Design
225
75. Closeout design
SLIDE
Closeout design: Childhood Asthma Management Program
(CAMP)11
Time period for closeout: 1 March 1999–31 October 1999
Number of closeout visits: 2; initial transition visit and final transition visit
Time interval for completion of initial transition visits: 1 March 1999–30 June 1999
Time requirements for completion of final transition visits: Within 60 days of initial
transition visit and on or before 31 October 1999
R E L AT E D E N T R Y
Start-up design (page 203)
DEFINITIONS
anniversary closing date n - [trials] A closing date determined by when persons enroll
such that all persons have the same period of followup on exit, e.g., closeout after 26
weeks of followup; aka common period of followup.
closeout design n - Design relating to closeout; in regard to patient closeout, design
for separating persons from a trial, e.g., as accomplished with a common closing date or
anniversary closing date.
closeout followup visit n - A followup visit performed in relation to closeout; patient
closeout followup visit. rt: closeout examination
closeout stage n - [trials] A stage of trial in which persons enrolled are separated from the
trial in preparation for the termination stage; typically starts with the first such separation
and ends with the last; patient closeout stage of trial.
common closing date n - [trials] 1. A calendar date for the close of followup that is the
same for all persons enrolled; common date patient closeout. 2. A date common to all
sites in a multicenter trial for ceasing or closing some function or activity, e.g., the use of
the same date for cessation of enrollment regardless of when a clinic entered a trial.
N A R R AT I V E
The length of followup is the same for every person enrolled with anniversary closing
date designs. It is a function of when the person was enrolled when closeout occurs on
the same date for all persons regardless of when enrolled. Obviously, the person units
of followup time differs with the two methods. The common closing date design in the
example below produces 25 units of followup time compared to 6 units of followup time
with the anniversary closing date design.
226
IX. ENROLLMENT AND FOLLOWUP
Common closing date
.
Followup time units
6.5
6.0
5.5
4.0
2.0
1.0
Total person units of followup time: 25.0
Common period of followup
.
Followup time units
1.0
1.0
1.0
1.0
1.0
1.0
Total person units of followup time: 6.0
Features
• Methods similar when recruitment takes place over short time period
• Common closing date:
❑ Maximizes followup information
❑ Easier to implement because closeout activity is concentrated in time
❑ Avoids patient and staff attrition sometimes associated with staged shut-down
• Common period of followup generally preferred when patients are to be treated for
a specified period of time
Closeout process
• General
❑ Decide on method of closeout
❑ Design and test closeout data collection forms
❑ Formulate treatment recommendations for patients
• Patient
❑ Prepare patient for closeout
❑ Provide advance notice
❑ Make provisions for subsequent care
❑ Prepare summary medical record, as needed
❑ Inform patient of study results (usually precluded with anniversary closeout
designs)
❑ Recommend future course of treatment
❑ Outline future followup plans, if any
❑ Update locator information for future followup
75. Closeout Design
227
• Referring physician
❑ Discuss treatment recommendations and care requirements with referring
physician
❑ Arrange for transfer
• Housekeeping and administrative
❑ Collect and dispose of unused drugs in drug trial
❑ Provide lead time for staff to find alternative employment
❑ Document patient closeout process, including list of materials and information
given to patient
❑ Cancel INDA, if applicable
• Data storage and deposition
❑ Finalize dataset
❑ Carry out final data checks before clinics cease to function
❑ Outline and implement study archive procedures
❑ Ensure proper retention and storage of medical records
Considerations for premature closeout
•
•
•
•
•
•
•
Method of patient recall
Type of treatment recommendation
Impact on other study patients
Method of disseminating study information prior to publication
Method of documenting that a change has been made
Method of informing patients of design changes
Circumstances under which a new consent is required
76. Missed Visit
229
76. Missed visit
SLIDE
Missed visit followup: Childhood Asthma Management
Program (CAMP)11
Completely missed: Person not seen for a scheduled followup visit in the period
allowable for that visit
Partially missed: Person seen for a scheduled followup visit in the permissible
period of time for that visit but refuses or the clinic is otherwise unable to
complete all aspects of the visit
R E L AT E D E N T R I E S
Dropout (page 231), Loss to followup (page 235), Time window specifications (page 299)
DEFINITION
missed study visit n - 1. A required visit that has been missed. 2. A scheduled study visit
not made within the permissible time window.
N A R R AT I V E
Designers need to provide crisp, unambiguous, operational definitions of missed study
visits or contacts. Invariably, the determination of whether a visit or contact is to be
counted rests on whether it occurred within a specified time window. Visits or contacts
required within a specified time window that are not made in the window are counted
as missed. Persons responsible for monitoring performance will not be able to calculate
missed visit rates without such definitions.
Good procedures require clinics to acknowledge the fact of a missed visit or contact
by filing a ‘‘missed visit form.’’ Absent such formal notification, the trialist has no way of
distinguishing between visits and contacts missed and visits and contacts done but where
forms have not been keyed.
77. Dropout
231
77. Dropout
SLIDE
Dropout: Studies of Ocular Complications of AIDS (SOCA)80
A person announcing intent to separate from a SOCA study because of
dissatisfaction; characterized as dropout at close of window for first followup
visit following announcement
A person having moved from the clinic area and, as a result, is unable to return
to a SOCA clinic for regular followup visits; characterized as dropout after
having missed two consecutive followup visits
A person missing two consecutive followup visits, regardless of reason
R E L AT E D E N T R I E S
Missed visit (page 229), Loss to followup (page 235), Time window specifications (page
299)
DEFINITIONS
dropout n - 1. [general] One who terminates involvement in an activity by declaration
or action or as deduced from an unbroken sequence of failed contacts or absences from
scheduled activities; especially one who terminates because of waning interest or for
physical, practical, or philosophical reasons. 2. A person who withdraws from a trial or
followup study by an announced unwillingness to continue to submit to the required
procedures for treatment, evaluation, or data collection or as deduced in retrospect from
an unbroken series of absences from scheduled contacts for such treatment, evaluation, or
data collection. 3. A person who misses a scheduled visit or who is not contacted within the
indicated time window for a scheduled contact. [trials] 4. One who refuses or stops taking
the assigned treatment. 5. One who stops taking the assigned treatment and whose reason
for doing so is judged not to be related to the assigned treatment. Usage note: Subject to
varying usage. Use should be limited to that implied by defns 1 and 2. Most trials require
continued data collection regardless of course of treatment. Hence, a ‘‘dropout’’ in the
sense of defns 4 and 5 will continue to be an active participant in regard to scheduled
data collection. Avoid uses in the sense of defn 5 because of difficulty in making reliable
judgments regarding the reason a person stops taking the assigned treatment. The stated
reason may not be the real reason; and seemingly vague reasons, which on the surface do
not appear to be related to treatment, may, in fact, be treatment-related. Defn 2 includes
persons who actively refuse, and those who passively refuse, and those who are simply
unable to continue in a trial or followup study for physical or practical reasons, e.g.,
because of having moved to a location where it is no longer possible or convenient to
return for scheduled visits. Dropout is not a permanent state. Most long-term trials will
have provisions for reinstating persons classified as dropouts if and when they return to
a study clinic for required data collection. Avoid in the sense of defn 3 in relation to a
single visit or contact in the absence of other reasons for regarding a person as a dropout.
232
IX. ENROLLMENT AND FOLLOWUP
Use other language, such as missed visit or missed procedure, to avoid the connotation
of dropout in the broad sense of usage. The term should not be confused with lost to
followup, noncompliant, withdrawal, or endpoint. A dropout (defn 2) need not be lost to
followup if the outcome of interest can be ascertained without having to see or contact the
person (as in some forms of followup for survival) but will be lost to followup for measures
made by examination of the person. Similarly, the act of dropping out need not affect
treatment compliance to the assigned treatment. A person will become noncompliant
on dropping out in trials where dropping out results in discontinuation of an active
treatment process (e.g., as in the case of a drug trial where access to study drugs is via
visits to the study clinic). There will not be any effect on treatment compliance in trials
where the assigned treatment is administered only once on enrollment if that treatment is
not available outside the trial, e.g., as in a surgery trial involving a special operation and
where there is no established standard treatment, such as in the Program on the Surgical
Control of the Hyperlipidemias [Buchwald et al., 1990].8 Similarly, the term should not
be confused with or used as a synonym for withdrawal (defn 2) since the meaning of that
term is different from that for dropout.
dropout compensation n - 1. A method of determining sample size in which the
planned sample size is made including a jack-up factor for loss of precision due to
dropout. 2. dropout replacement Usage note: With defn 1, enrollment continues to the
calculated sample size without regard to actual losses due to dropouts; whereas with defn
2, enrollment is conditioned on dropouts by enrolling to a specified sample size based on
complete followup.
dropout replacement n - A system of recruitment requiring the enrollment of an
additional person for each person not able or willing to submit to the required data
collection procedures or for whom it is not possible to continue the assigned treatment
regimen. rt: dropout compensation Usage note: The term has unfortunate connotations
because it suggests that dropouts can be replaced. The replacement is only in the sense
of some overall finished sample size. The effect of dropout, if dropping out is related to
treatment assignment, cannot be eliminated by replacement. The replacement practice
arises primarily in small-scale, short-term trials where there is some perceived need to have
a specified number of evaluable persons and where ‘‘replacements’’ are easy to recruit. The
approach is impractical in long-term trials where people are treated and followed for long
periods of time after enrollment. The practice usually means that the primary analysis will
be restricted to the subset of persons followed for a specified time and who were treated
with the assigned treatment.
withdrawal n - 1. The act of withdrawing. 2. The removal of a person or observation
unit from a lifetable analysis for a designated event at the cessation of followup or at the
occurrence of the event of interest; removal due to cessation of followup may occur as
a consequence of when the person or unit was enrolled (e.g., calculation of a three-year
event rate of necessity is based on data provided by those who were enrolled at least
three years prior to the date of the analysis) or because the person or unit dropped out.
[trials] 3. dropout (not a recommended synonym) 4. One who has been removed from
treatment (not recommended usage). 5. One who is not receiving or taking the assigned
treatment (not recommended usage). rt: censor Usage note: Usage should be limited to
those implied in defns 1 and 2. The term should not be used as a synonym for dropout or
77. Dropout
233
loss to followup for reasons discussed in usage notes for those terms. The term, when used
in the context of treatment, has different meanings and should be avoided or accompanied
with detail indicating nature of use. Use in the sense of defn 5 is as an indicator of action
taken by study personnel to forego or halt use of the assigned treatment, usually because
of lack of benefit or bad effects (e.g., as used in the Consolidated Standards of Reporting
Trials (CONSORT)4 ). Use in the sense of defn 4 is broader as an indicator of those
persons no longer taking or receiving the assigned treatment, whether due to choice or
direction of study personnel. In either use, it is important to recognize that withdrawal
from treatment, for whatever the reason, does not remove the effect of treatment. One
can be withdrawn from treatment but not from its effects.
N A R R AT I V E
A dropout, in the context of trials, is a person who is rendered or becomes unable or
willing to continue under scheduled followup. The state may come as a result of a person
moving, making it impractical or impossible to return for followup visits. Or the state
may come about because the person does not wish to continue in the trial.
Obviously the state is not permanent. Persons unwilling to continue under
followup can change their minds. Similarly, persons who drop out because of moves can,
later on, move back and be reinstated to followup.
There is no term more subject to misuse and confusion than dropout in trials.
A great deal of the confusion arises because of the tendency to view the processes of
treatment and followup as one in the same. Hence, when a study physician decides that
it is no longer prudent to continue using the assigned treatment, the person is seen as
a ‘‘dropout’’ and is no longer followed. Similarly, when a person announces he/she no
longer wishes to be treated with the assigned treatment, that announcement is taken as
reason to terminate followup as well.
An important operational issue is when to count a person as a dropout. The
definition has operational importance in calculating dropout rates during the trial and
because the definition serves to define the point from which other activities are timed,
e.g., contacting dropouts at yearly intervals after dropout to determine whether still alive,
and for collecting information on health and well-being. Persons rarely declare intent
to drop out. Typically, the state has to be inferred after a series of consecutive missed
visits.
Routinely, persons who drop out are assumed to be noncompliant to treatment.
That is usually the case in drug trials where access to drugs depends on being seen at a
study clinic. However, the effects of treatment do not cease to exist with the cessation of
treatment.
Obviously, exposure to treatment does not have to be continuous to justify
followup to assess the effect of treatment. Effects can come about long after cessation.
Hence, followup is not merely a function of whether or not treatment continues to be
applied. Exposure is continuous in drug trials involving the daily administration of a
drug, but takes place with a single application with surgical treatments, with most types
of vaccines, and with drug treatments requiring but a single or a few applications.
234
IX. ENROLLMENT AND FOLLOWUP
QUESTIONS
•
•
•
•
What is your operational definition of dropout?
Can dropouts be reinstated in the trial?
Are dropouts to be followed for mortality and gross morbidity?
Are there to be procedures for maintaining contacts with dropouts to provide
information on survival and to encourage reinstatement?
• Are there plans to pay transport costs to study clinics for patients who move from a
clinic area?
78. Loss to Followup
235
78. Loss to followup
SLIDE
Loss to followup reduction procedures: Ganciclovir Cidofovir
CMV Retinitis Trial (GCCRT)81
•
•
•
•
•
•
•
Informed consents
Arrangements for transport of patients to clinic when necessary
Arrangements for child care in relation to clinic visits when necessary
Telephone and mail reminders of appointments for clinic visits
Reinstatement of dropouts if a person returns for followup visit
Systematic efforts to locate persons lost to followup
100% followup for mortality
R E L AT E D E N T R I E S
Missed visit (page 229), Dropout (page 231)
DEFINITIONS
loss to followup n - Any loss of followup data on a person (or other observation unit)
after enrollment into a study; loss may occur because a person cannot be located for
required data collection or because the person is unwilling or unable to submit to required
data collection procedures. rt: lost to followup Usage note: The majority of losses to
followup in trials occur because of dropout since most data in trials are generated via
direct interview and examination of those enrolled. However, some forms of followup
may continue even after a person drops out, e.g., as with followup for mortality via death
indexes.
lost to followup adj - 1. Characterized by unknown whereabouts in a followup study.
2. An observation unit in a followup study that cannot be followed for some outcome or
observation of interest. rt: losses to followup Usage note: The characterization in trials is
usually applied to a person who is unwilling or unable to return to the clinic for followup
examinations. The characterization is subject to misuse, especially when used without
regard to nature or extent of information lost. In good usage, the observation or set of
observations lost is specified. Specification is important when followup is possible by
other means, e.g., by telephone instead of by scheduled clinic visits. It is bad practice to
use lost to followup interchangeably with dropout. A person, no longer willing or able to
return for clinic visits, is lost to followup for observations made during such visits, but not
necessarily for observations that can be made in other ways, e.g., by telephone interview.
Even individuals who refuse any contact with study personnel may not be lost to followup
for certain events, such as death.
Followup aids
• Dedicated pleasant staff
• Patient friendly data collection schedules
236
IX. ENROLLMENT AND FOLLOWUP
• Clinic hours geared to patient needs
• Pleasant clinical setting, located in a safe area
• Dedicated equipment to avoid waiting or to have to go to other departments for
testing
• Payment of fees for clinic visits
• Payment of transportation and other related costs
• Attending to medical needs of patient
• Periodic phone and mail contacts with patient
Methods of minimizing losses to followup
• Use of followup aids outlined above
• Maintenance of up-to-date locator information
• Special provisions, such as: clinic transfers (in multicenter trials), reduced clinic visit
schedule, home visits, transport to and from clinic
Mortality followup principles
• Provide for reports of deaths as they occur
• Follow all patients for mortality regardless of outcome of interest
• Set up mechanisms aimed at avoiding losses to followup for mortality, such as
regular contact with dropouts
Mortality followup procedures
• Make concerted effort to maintain contact with all patients during the trial
• Primary responsibility for maintaining contact and for re-establishing contact, when
lost, to reside with clinic staff
• Contacts for a patient should be via study clinics
• Extraordinary search procedures should not be implemented until routine searches
have been performed
• Respect and honor patient’s right to privacy in searches
Resources for determining mortality status
•
•
•
•
National Death Index
Social Security Administration Death Index
Credit agencies
Special search agencies
Key data for mortality followup
• Full name including given and assumed surname for women
• Sex
• Date of birth
78. Loss to Followup
•
•
•
•
•
•
•
Place of birth
Social security number
Place of residence and telephone number
Name, address, and telephone number of present employer
Name, address, and telephone number of close relative or friend
Driver’s license number
Other Id numbers
237
79. Study Timetable
239
79. Study timetable
SLIDE
Timetable: National Emphysema Treatment Trial (NETT) as
outlined in RFP62
Stage Months
1
2
3
9
63
12
Calendar time
Activity
20 Dec 1996–19 Sept 1997 Protocol development
20 Sept 1997–19 Dec 2003 Recruitment, treatment, and followup
20 Dec 2003–19 Dec 2004 Data analysis
R E L AT E D E N T R I E S
Start-up design (page 203), Critical event path analysis (page 241)
N A R R AT I V E
The timetables for trials are driven by funding. They are written by investigators, sponsors,
or investigators and sponsors together.
Investigators and sponsors, alike, are given to producing unrealistically optimistic
timetables. Even experienced investigators have a tendency to underestimate the amount
of time required to get started and time required for recruitment—a fact evident in the
axiom ‘‘The way to cure a disease is to start a trial.’’
The time from the start of funding to start of enrollment is likely to be a half year
or longer. IRB approvals may take months. But IRBs cannot reviews until investigators
have ‘‘finalized’ the protocol and production of data collection forms cannot commence
until the protocol has been ‘‘finalized.’’
Ideally, funding is fashioned to meet the time requirements of the trial. That
requires investigators asking for funding to be realistic about time schedules, even if that
reduces the chance of being funded. There is no point in getting funded if the project
cannot be done in the time allotted for funding.
Unrealistic timetables should be revised. Left unrevised, they are likely only to
embarrass and to turn into clubs to bludgeon investigators with when they fall short of
the stated goals or when they have to go back to sponsors for additional funding.
Investigators have a responsibility to bring timetables and funding into line or to
‘‘stand down’’ if funding is inadequate. In cases where they are handed an unworkable
timetable, they need to either revise the design to bring it in line with funding, seek
additional funding, or stand down.
80. Critical Event Path Analysis
241
80. Critical event path analysis
SLIDE
Critical path to start up: Chemoprevention for Barrett’s
Esophagus Trial (CBET)36 (as of June 1999)
Drug packaging
IRB submission ready protocol
Sign-off on protocol by funding agency
Drug supplied to central pharmacy
Submission of protocol to parent IRB
Approval by parent IRB
Distribution of protocol and prototype consent form to clinics
Submission of protocol and consent form to local IRBs
Local IRB approval
Finished data collection forms
Enrollment of first patient
Shipment of distributed data system (per clinic, after enrollment of two patients)
R E L AT E D E N T R Y
Start-up design (page 203)
DEFINITION
Gantt chart n - [After Henry Laurence Gantt, 1861–1919, American engineer] A type
of graphic display for showing time requirements for different components of a project
as used in planning, coordinating, and monitoring progress in implementation and
completion of the project.
Time
Develop protocol
Develop data forms
Test data forms
Revise data forms
Enroll study patients
N A R R AT I V E
The countdown to the finish of a trials starts when funding is awarded. The systems of
importance in trials are those having to do with:
• Recruitment pipeline
• Randomization
242
•
•
•
•
•
•
•
•
•
•
IX. ENROLLMENT AND FOLLOWUP
Treatment
Followup
Data collection
Data entry and processing
Database maintenance
Data analysis for performance monitoring and treatment effects monitoring
Closeout
Deconsent
Final analysis
Paper writing
Designers do well to specify the conditions required to clear the trial to proceed to
recruitment and from there to randomization, treatment, followup, and subsequent steps.
They should specify the critical events required for:
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Protocol completion and sign-off
IRB approval
Compilation of consent documents
Approvals: Sponsor, FDA, other approvals
Filing of IND and cross referencing; FDA acceptance of IND
Drug supply, packaging, distribution
Personnel training
Clinic and personnel certification
Randomization design and procedures
Testing and distribution of baseline and followup data collection forms
Data entry design and system
Database design and system
Protocol and forms for closeout
Authorship policy
Organizational structure
The start of recruitment creates, in effect, a forced march dictated by the baseline
and followup data collection schedule. Ideally, recruitment is not started until the data
collection forms and procedures for receiving data are in place. In reality, the ideal is rarely
met. There is always a rush to get started and, therefore, always a tendency for designers to
push the envelope by starting before systems have been adequately developed and tested.
The hope, often unrealistic, is that the systems needed to support randomization, data
collection, and entry will come on-line as needed. Investigators are well-advised to resist
the temptation. They should recognize that they are playing a form of Russian roulette
when they proceed to start before being certain they have the supply lines needed to
sustain the activity. Hasty starts can lead to embarrassing and troubling delays later on,
and invariably produce a crisis atmosphere at mission central as people play ‘‘catch up.’’
Indeed, a desirable side benefit of distributed data entry systems in multicenter trials has
to do with the fact that activities cannot start until the system is distributed.
81. Eligibility Criteria
243
81. Eligibility criteria
SLIDE
Eligibility criteria: Childhood Asthma Management Program
(CAMP)11
• Age 5 to 12 at time of screening
• Chronic asthma as evidenced by one or more of the following for at least 6
months during the past year
❑ Asthma symptoms at least 2 times per week
❑ 2 or more usages per week of an inhaled bronchodilator
❑ Daily asthma medication
• Current asthma symptoms either by diary symptom code of 1 or greater or
AM or PM PEFR less than 80% of personal best post-bronchodilator value by
diary, on 8 or more days during the prn screening period
• Methacholine sensitivity: Estimated PC20 FEV1 less than or equal 12.5 mg/mL
• Consent of guardian and assent of child
• Ability to comply with requirements of trial for 5–6 1/2 years
R E L AT E D E N T R I E S
Primary outcome (page 35), Exclusions from enrollment (page 245), Eligibility and
exclusions by reason (page 249)
N A R R AT I V E
A person must be suitable for study to be considered eligible for study. Suitability is
expressed in the form of requirements relating to:
•
•
•
•
•
•
•
•
Medical history
Family history
Diagnosis
Physiological or biological characteristics
Demographic characteristics
Feasibility of study
Domicile
Informed consent
It is up to planners to specify eligibility requirements. The requirements should be
limited to those essential to justify randomization, treatment, and followup.
Consent is essential. Designers should ensure that consents are informed, obtained,
and documented prior to randomization.
Requirements, other than those for consent and for assessing the willingness
and suitability of persons for study, should be limited to those needed to qualify a
person for treatment, by history, diagnosis, or condition. Requirements imposed simply
to homogenize the study population (e.g., demographic requirements) or to reduce the
244
IX. ENROLLMENT AND FOLLOWUP
variation in who is studied are usually best avoided. They serve only to make recruitment
more difficult. They should not be used unless cogent arguments can be made relating to
the risks of treatment in persons not possessed of the specified eligibility characteristics.
It is up to designers to establish processes and procedures for ensuring that persons
enrolled meet eligibility requirements. Operationally, this means that they should opt
for systems of assignment where assignments are not released until eligibility has been
established, the fact of eligibility has been documented, and data establishing eligibility
have been recorded on study forms and, ideally, entered into the study database.
Designers have to specify criteria that have to be met for persons to qualify for
enrollment. In treatment trials they will have to decide whether to accept the presenting
diagnosis in the case of referrals. The decision will depend on the reliability of such
diagnoses and on the amount of time, inconvenience, and risk entailed for patients if
subjected to study imposed diagnostic tests and procedures.
The likelihood is that not all persons enrolled will meet all eligibility requirements.
Hence, designers will have to specify how ineligibles are to be handled when enrolled. The
action taken will depend on the basis for ineligibility. If ineligibility is largely technical
(e.g., as in the UGDP in regard to the definition of adult-onset diabetes93 ), ineligibles may
continue on their assigned treatments. Treatment will have to be stopped if treatment is
contraindicated.
Normally, one does not randomize until diagnosis is established, but there are
instances where treatment has to be implemented on the presumption of eligibility, e.g.,
in emergency rooms with persons appearing to have myocardial infarctions. It may be
necessary, in such cases, to randomize and initiate the assigned treatment and then to stop
or alter the treatment if subsequent tests do not establish the diagnosis.
Generally, designers are well-advised to forego use of centralized adjudicated
reading processes for determining eligibility. The difficulty with adjudication for eligibility
is the time it takes to come to a decision. One can expect, with any complicated diagnostic
process, to have disagreements. The fact that a diagnosis made at a clinic does not jibe
with an adjudicated decision does not mean the decision at the clinic level is wrong.
Another reason to avoid adjudication is the effect that delays in coming to a
decision have on other requirements for enrollment. For example, it is common to require
baseline data to be collected within a specified time interval prior to randomization.
Delays in decisions can mean that certain tests and procedures will have to be repeated to
qualify the person for enrollment.
82. Exclusions from Enrollment
245
82. Exclusions from enrollment
SLIDE
Coronary Drug Project (CDP) exclusions from enrollment18
Contraindications for study treatments
New York Heart Association class III or IV
Age >70 on entry
Female
R E L AT E D E N T R I E S
Eligibility criteria (page 243), Eligibility and exclusions by reason (page 249)
N A R R AT I V E
General reasons for excluding persons from enrollment are:
•
•
•
•
•
•
•
•
•
•
•
•
Diagnosis/medical condition
State of health
Treatment not advised or contraindicated
Unfavorable benefit to risk ratio
Risk to fetus; risk to future pregnancies
Medical history; previous treatment history
Incompatibility; including those arising from persons being enrolled in other studies
or trials involving procedures or protocols incompatible with those in the proposed
trial
Consent considerations
Medical–legal considerations; regulatory considerations
Precision; variance reduction
Cost
Practical/logistical considerations
One may not randomize persons to treatment when:
•
•
•
•
•
•
•
•
Treatment is not indicated
The person is not likely to benefit from treatment
The treatment is substandard
The likelihood of risk is not minimized
The likelihood of risk exceeds the likelihood of benefit
The person does not have the disease or condition of interest
The person has a history incompatible with treatment
Requirements for consent cannot be met
Trialists are obliged to exclude, if the potential for harm to the subject is greater
than the potential for benefit. They are obliged to exclude pregnant women when
study treatments carry potential risks to fetuses except where treatment is necessary for the
246
IX. ENROLLMENT AND FOLLOWUP
well-being of the woman. They are disposed to excluding women of childbearing potential
when there is potential for risk to pregnancies and where the benefits of treatment are
likely to be modest, or where treatment is not essential for the well-being of the woman.
Exclusions due to perceived unfavorable benefit/risk ratio are matters of judgment
and, therefore, cannot be sharply defined; usually, conveyed on enrollment study forms
by some general catch-all category, such as ‘‘Patient unsuitable for study,’’ with reasons
supplied by the person making the judgment. Reasons include:
• Preexisting conditions likely to interfere with treatment
• Lifestyle or practices likely to make treatment and followup difficult (e.g., drug use;
heavy drinking)
• Deteriorating health
• Unsuitable support structure (e.g., elderly person living by self)
• Inadequate powers of mentation or judgment; insufficient for informed consent
The need for informed consent obligates the trialist to exclude persons where
consents are not given and where there are reasons to doubt the adequacy of consents. In
general, the obligation means that persons having inadequate powers to consent may not
be enrolled except under special circumstances. Similarly, the trialist is obliged to exclude
if consents are seen as coerced.
There are practical reasons to strive for minimal exclusions. Clearly, the more
exclusions, the harder it is to recruit. Exclusions that cannot be justified should be
eliminated.
Exclusions in treatment trials should be limited to those relating to suitability for
study in regard to consent, likely compliance to study treatment and procedures, diagnosis
and disease state, and treatment. Largely, in treatment trials, it is best to design to allow
the disease or condition to drive the mix of who is enrolled. Exclusions based on gender
should be avoided when the disease or condition is common to both gender groups
and where the study treatments can be safely applied to either gender group. Largely,
differences in prevalence or incidence of disease in the two gender groups is not a basis for
exclusion, except, perhaps, where the difference is profound (e.g., as with the exclusion of
males in breast cancer treatment trials because of the low prevalence of male breast cancer).
Exclusions based on gender are open to challenge on ethical grounds in trials
where they deprive persons access to treatment. However, the challenge is not limited to
just treatment trials. It extends to prevention trials. The exclusion of women from several
high-profile heart disease prevention trials54 has been used to argue that the exclusion
represented a form of distributive injustice because it has meant that results are more
likely to benefit men than women.
Similar arguments have been made in challenging exclusions based on ethnic
origin. Ethnic origin-based exclusions should be avoided except in those few instances
where the disease or condition is largely unique to a particular ethnic group.
Designers make a mistake by imposing demographic based exclusions because
of the small number likely to be represented in the subgroup excluded (e.g., as in the
Physicians’ Health Study54,68 in regard to the exclusion of women; see discussion on
recruitment quotas, page 213). Some information on treatment effect in women, even if
based on small numbers, is better than none at all.
82. Exclusions from Enrollment
247
Exclusions based on age are common. Reasons for lower age limits are to restrict
enrollment to persons above the age of majority, to avoid issues of consent in minors, and
to protect children from the risks and nuisances of being studied.
Designers should shy away from exclusion of children in treatment trials of serious
conditions where the condition occurs in children, even if at a much lower frequency than
in adults. Exclusions should not be practiced simply as a matter of convenience to avoid
having to clear IRBs for enrollment of children.
Lower limit exclusions
• Exclude children: Because of risk of treatments; because treatments have not been
tested in children; because treatments not regarded as safe for children; because
sponsor requires the exclusion; because of unwillingness of investigators to expose
children to treatment; to limit trial to adults
• Exclude young adults: Because of difficulties in recruitment; because of concerns
regarding followup because of mobility (moves from home to college, jobs, etc.);
because of difficulties in maintaining treatment
• Exclude below a specified age: Because of low prevalence of disease or condition;
because disease or condition likely to be of different origin or nature below the age
limit
Upper limit exclusions
• Exclude elderly: Because of limited remaining life; because of likely difficulties in
maintaining treatment or followup (e.g., because of not being able to transport self
to study clinic or because of being home bound because of infirmities); because
of likely transition to nursing home or other institutionalized forms of care over
the course of the trial; because of concern of the person being able to follow study
procedures or treatment regimens
• Exclude above a specified age range: Because of the low prevalence or incidence of
the disease above that age; because disease is likely to be different above the age limit
Upper age limits, imposed to exclude persons because of expected years of
remaining life, are generally ill-advised. For example, the conditional life expectancy of a
U.S. white female at age 65 in 1990 was 19.1 years and 15.2 years for her white male
counterpart. In general, even persons in their 80’s have a fair number of years of life
remaining given the condition that they have reached 80. Hence, limits, if imposed at
all, should be set as high as possible and should be considered only in trials involving
long-term treatment where years of treatment may be required to reap the benefits of
treatment. Largely, they are not recommended in trials involving treatment of acute
conditions where benefits of treatment are likely to be immediate.
The desire for distributive justice can be at odds with the desire for efficiency.
The mix of the study population enrolled has implications for the precision of the trial.
Sample size calculations are based on assumptions regarding the underlying variation of
the outcome measure in the different subgroups represented in the trial. The larger the
variation, the larger the sample size required to detect a given size difference overall. As
248
IX. ENROLLMENT AND FOLLOWUP
a result, the trialist is driven to focus on strategies aimed at controlling and reducing
variation. That drive, in the case of recruitment, translates into urges for selectivity in
regard to who is studied.
Likewise, precision, in the case of prevention trials designed to detect reductions in
mortality or morbidity, is a function of the degree to which such event rates are influenced
by demographic or baseline characteristics of persons enrolled. All other things being
equal, the trialist focuses on the portion of the population at highest risk for the event
because, within limits, the higher the event rate, the smaller the sample size required to
detect a given difference. Hence, there is less to be gained by enrolling persons having low
probabilities of events if persons with higher probabilities of such events can be found.
These realizations lead trialists to concentrate on ‘‘high-risk’’ persons (risk concentration
design) and exclusion of ‘‘low-risk’’ persons. The push toward risk concentration is most
evident in primary prevention trials such as MRFIT.54,61
83. Eligibility and Exclusions by Reason
249
83. Eligibility and exclusions by reason
SLIDE
Eligibility and exclusions: Childhood Asthma Management
Program (CAMP)11
Eligibility
Age 5–12 on entry
Chronic asthma
Current asthma symptoms
Methacholine sensitivity
Consent
Exclusions
Presence of confounding or complicating problems (active pulmonary disease;
pulmonary function test indicative of ventilatory defect other than asthma;
evidence of irreversible lung disease)
Evidence of severe asthma (≥2 hospitalizations for asthma in past 12 months; need
for continuous use of glucocorticoids, oral or inhaled; intubation for asthma
at any time in past)
Inability to perform acceptable FVC maneuvers sufficient to produce reproducible
FEVs
Unstable or noncompliant family
R E L AT E D E N T R I E S
Eligibility criteria (page 243), Exclusions from enrollment (page 245)
N A R R AT I V E
It is good practice to list the eligibility and exclusion requirements for enrollment and
reasons for them. Entries for which reasons are nonexistent or unclear should be eliminated
from the protocol.
Designers should be wary of demographic-based exclusions, especially those based
on gender or ethnic origin. They should have compelling bases or should be eliminated.
Designers should avoid exclusion of women, simply because they are of ‘‘childbearing
potential.’’
Designers should be wary also of exclusions for convenience or expediency; likewise
with exclusions rationalized as variance reducing. Exclusions for variance reduction should
be avoided unless designers are able to support such exclusions with data showing the
variability likely to be added if the exclusions are not imposed.
The use of age limits for exclusions should be justified or should be eliminated.
250
IX. ENROLLMENT AND FOLLOWUP
Checklist for reasons for eligibility requirements
•
•
•
•
•
Consent (e.g., requirement that person is competent to give consent)
Proximity/suitability
Medical history consistent with disease or condition of interest
Diagnosis/diagnostic tests
Physiological (e.g., body weight within a specified range; blood pressure above a
certain cutpoint)
• Laboratory (e.g., fasting blood sugar above a specified cutpoint)
• Other (specify)
• Uncertain
Checklist for reasons for exclusions
•
•
•
•
•
•
•
•
Treatment contraindication (e.g., allergy to one of the study treatments)
Treatment ill-advised
Treatment risk
Demographic (age; gender; ethnic origin; other)
Variance control
Precision/sample size
Other (specify)
Uncertain
Sample Size
84. Sample Size: Design
253
84. Sample size: Design
SLIDE
Sample size: Design—Coronary Drug Project (CDP)18
α = 0.01 (type I error, 1-sided)
β = 0.05 (type II error)
Pc = 0.30 (5-yr death rate for placebo treated group)
Pt = 0.225 (5-yr death rate for test treated group)
D0 = 0.30 (5-yr loss rate per treatment group)
Computed sample size
CPIB
DT-4
ESG1
ESG2
NICA
PLBO
1117
1117
1117
1117
1117
2793
Total
8378
R E L AT E D E N T R I E S
Sample size: Specifications (page 257), Sample size: Calculation (page 259)
DEFINITIONS
closed sequential design n - [trials] A sequential design with a closed region defined by
diverging boundary lines (upper and lower) positioned about the x-axis and extending to
the right from the y-axis to points of intersection with lines extending from the x-axis;
region defined by the y-axis and specified boundary lines referred to as region of indecision;
closed in order to impose an upper limit on the number of observations needed for a
decision. An observed treatment difference that lies above the upper or below the lower
boundary line favors an alternative treatment hypothesis in which the test treatment is
considered to be superior or inferior (depending on the boundary crossed) to the control
treatment. An observed difference lying to the right of boundary lines rising from the
x-axis corresponds to a result considered to favor the null hypothesis. Boundary lines
extending from the x-axis do not exist for open sequential designs.
0
Closed sequential design
254
X. SAMPLE SIZE
fixed sample size design n - [trials] 1. A design in which the number of observation
units to be enrolled is fixed as determined by a sample size calculation prior to the start
of enrollment or as fixed by other considerations (e.g., cost or availability of patients). 2.
Any nonsequential sample size design, even if the sample size is not fixed or determined
before the start of the trial. ant: sequential sample size design
group sequential design n - [trials] A sequential design (open or closed) in which treatment
comparisons are made only at designated time points or intervals (e.g., every 6 months),
after enrollment of specified numbers of patients (e.g., after every 50 randomizations), or
after occurrence of specified numbers of events (e.g., after every 10 deaths) and the results
of which are used to decide whether or not to continue the trial.
open sequential design n - [trials] A sequential design with an open region of indecision;
design does not provide for an upper limit on the number of patients that may be enrolled
because region of decision is not delimited; differs from closed sequential design in that
the region of indecision is circumscribed for closed designs. An observed difference that
lies outside the region of indecision favors an alternative treatment hypothesis in which
the test treatment is superior or inferior (depending on boundary crossed) to the control
or comparison treatment.
0
Open sequential design
sequential design n - [trials] Any design with open or closed boundary limits where
enrollment continues until the observed treatment difference for the outcome of interest
is found to lie beyond a boundary limit. In the context of hypothesis testing involving
a test and control treatment, differences within the boundary limits or that crosses the
boundary closing the region support the null treatment hypothesis. Differences beyond
the upper or lower boundary limit favor the alternative treatment hypothesis that the test
treatment is superior to the control treatment or that the control treatment is superior to
the test treatment, depending on the boundary crossed. rt: closed sequential design, open
sequential design, group sequential
sequential sample size design n - [trials] 1. The sample size design underlying a sequential
design; a design in which sample size is a function of results observed as in an open or
closed sequential design. 2. Any scheme in which sample size changes as a function of
observations or considerations made during the course of enrollment. ant: fixed sample
size design Usage note: Best reserved for use in the sense of defn 1. Not recommended in
the sense of defn 2 in relation to fixed sample size designs, whether or not the changes are
independent of observed treatment differences.
N A R R AT I V E
It is up to designers to specify the sample size design (see page 145 for assignment design).
They have to choose between fixed or sequential. Designers usually default to the fixed
sample size designs when any of the following apply:
84. Sample Size: Design
255
•
•
•
•
Treatment of a person extends over a period of time.
Followup for outcomes of interests extend over a period of time.
Enrollment, treatment, and followup run on different time schedules.
Period of followup varies depending on when a person is enrolled; the case with
common closing date designs (see Closeout design; page 225).
• The measure of success or failure of a treatment, as applied to a person, cannot be
made by focusing on a single outcome or measure.
• Success is defined by the absence of failure, and failure can occur at any time over
an extended period of time.
Basically, sequential designs are feasible only in limited circumstances where it is
reasonable to assess outcome shortly after enrollment. They are not feasible in the setting
of most clinical trials because of the nature of the outcome measure and need to disconnect
recruitment, treatment, and followup.
85. Sample Size: Specifications
257
85. Sample size: Specifications
SLIDE
Sample size calculation: Coronary Drug Project (CDP)18
α = 0.01 (type I error, 1-sided)
β = 0.05 (type II error)
Pc = 0.30 (5-yr death rate for PLBO-treated group)
Pt = 0.225 (5-yr death rate for test-treated group)
D0 = 0.30 (5-yr loss rate per treatment group)
Computed sample size:
.
CPIB
DT-4
ESG1
ESG2
NICA
PLBO
1117
1117
1117
1117
1117
2793
Total
8378
R E L AT E D E N T R I E S
Sample size: Design (page 253), Sample size: Calculation (page 259)
DEFINITIONS
detectable difference n - [trials] A hypothesized difference in treatment effect considered
to be important and worthy of detection; such a difference specified for purposes of a
sample size calculation. rt: clinically meaningful difference, treatment difference
jack-up factor n - A multiplier used to inflate the calculated sample size to compensate
for loss of precision due to noncompliance or loss to followup, e.g., a multiplier of 1.30
used to inflate the calculated sample size by 30% to compensate for loss of precision due
to reduced treatment compliance and dropout.
power n - 1. The probability of rejecting the null hypothesis when it is false; one minus
the type II error. 2. exponent rt: conditional power, expected power, observed power
treatment lag n - The time required for a treatment to exert its full effect.
type I error n - [statistics] The probability of rejecting the null hypothesis when it is true,
usually denoted by the Greek symbol α. rt: significance level
type II error n - [statistics] The probability of accepting the null hypothesis when it is
false, usually denoted by the Greek symbol β. rt: power
N A R R AT I V E
The first thing designers have to do in preparing for a sample size calculation is to choose a
design variable (see page 35 for definition). Next, they have to decide whether the sample
258
X. SAMPLE SIZE
size is for confidence estimation (i.e., one intended to yield a confidence interval of a
specified size for treatment effect) or hypothesis testing (i.e., one intended for testing the
null hypothesis of no treatment effect, against a specified alternative). The usual approach
is to proceed under a hypothesis testing framework.
For trials involving r test-assigned treatments and one control-assigned group,
designers will have to decide whether to take account of the fact that the trial is capable
of providing r test-assigned vs control-assigned comparisons. Taking account of the fact
that multiple comparisons are possible, as done by Dunnett,28 requires more persons in
the control-assigned group than for the test-assigned groups. The number is increased by
square root of r (e.g., if r is 4, the number of persons assigned to the control treatment
would be twice the number assigned to any of the four test-assigned groups).
Designers must specify the assignment ratio. Typically, it is uniform across
treatment assignment groups, but need not be as seen above or where designers, for
whatever the reasons, want more persons in one study group than in another.
They will also have to decide if the calculation is to be jacked up to take account
of treatment lag, losses to followup, or loss of precision due to reduced compliance.
The length of treatment or followup to be represented in the calculation must also
be specified.
Specifications
α = Type I error; typically set at 0.05; one- or two-tailed
β = Type II error protection desired; typically set to 0.80 or higher
Continuous variable as outcome measure
µc = Mean of outcome measure for control-assigned group
µt = Mean of outcome measure for test-assigned group
σ2 = Variance of outcome measure
= Detectable difference: µt − µc or (µt − µc )/σ
H0 : µt = µc (superiority trial)
H0 : |µt = µc | < (equivalence trial)
Binary event as outcome measure
Pc = Event rate in control-assigned group
Pt = Event rate in test-assigned group
= Detectable difference: Pt − Pc or (Pt − Pc )/Pc
H0 : Pt = Pc (superiority trial)
H0 : |Pt = Pc | < (equivalence trial)
Calculation formula (see Sample size: Calculation, page 259)
86. Sample Size: Calculation
259
86. Sample size: Calculation
R E L AT E D E N T R I E S
Enrollment goals (page 211), Sample size: Design (page 253), Sample size: Specifications
(page 257)
N A R R AT I V E
Usually, the enrollment goal (page 211) is established by sample size calculations. There
is a certain arbitrariness to such calculations because they depend on specifications (page
257) and assumptions underlying the calculations. A change in any of the specifications
or underlying assumptions changes the sample size requirement.
Indeed, there is the ‘‘opportunity’’ to repeat the calculations, using different
specifications and assumptions, until coming to the ‘‘right’’ result—usually the one
consistent with available resources. The better approach in those cases is to fix the goal
by pragmatic considerations and perform calculations simply to determine likely power
given the sample size.
Clearly, one way to ‘‘reduce’’ the sample size requirement is by hypothesizing a
larger treatment effect. A trial with a hypothesized 50% reduction in an event rate for the
test-assigned group requires fewer patients than one with a hypothesized 25% reduction.
There is no doubt that large differences are of clinical importance. The question for
designers is whether it is reasonable to expect them to exist. Large differences are indicative
of ‘‘miracle’’ treatments, and there are few of those around.
The observed power may turn out to be more or less (usually less) than the power
underlying the calculation. There is a ‘‘healthy person’’ effect in trials. The ‘‘effect’’ is due
to selection of the more robust and exclusion of the ‘‘lame’’ and the ‘‘halt.’’ For example,
5-year mortality in the control-assigned group was hypothesized to be 25/100 in the
Coronary Drug Project. The observed 5-year mortality was 21/100.16
Assumptions can be checked using observed data in the trial. Observed estimates
for losses to followup and loss of precision due to noncompliance and the underlying event
rate can be compared to those used in the sample size calculation. Large differences may
lead to mid-course corrections. The correction may be to extend the period of recruitment
to allow for an increased sample size or the period of treatment and followup to allow for
more events.
Sample size methods for event type outcomes
Exact method: Pc and Pt between 0 and 1
Normal approximation: Pc and Pt between 0.20 and 0.80; Nc Pc , Nc Qc , Nt Pt , and
Nt Qt all ≥ 15
Arcsin approximation: Pc and Pt between 0.05 and 0.95; Nc Pc , Nc Qc , Nt Pt , and Nt Qt
all ≥ 15
Poisson approximation: Pc and Pt < 0.05 or > 0.95 and Nc Pc and Nt Pt ≥ 10
260
X. SAMPLE SIZE
Power formulas
β = Type II error
Power = 1 − β = 1 − (A)
(A) = Proportion of area of N (0, 1) curve to left of point A on the abscissa
Normal
A = {Zα/2 [P. Q. (1/Nc + 1/Nt )]1/2 − |Pc − Pt |}/(Pc Qc /Nc + Pt Qt /Nt )1/2
Arcsin
A = Zα/2 − 2| sin−1 (Pc )1/2 − sin−1 (Pt )1/2 |/(1/Nc + 1/Nt )1/2
Poisson
A = Zα/2 − |Pc − Pt |/(Pc /Nc + Pt /Nt )1/2
See reference 52, Chapter 16 or reference 60, Chapter 9 for definitions of notation.
87. Fixed vs. Sequential Sample Size Designs
261
87. Fixed vs. sequential sample size designs
R E L AT E D E N T R I E S
Sample size: Design (page 253), Fixed vs. adaptive designs (page 263)
DEFINITIONS
fixed sample size design n - [trials] 1. A design in which the number of observation
units to be enrolled is fixed as determined by a sample size calculation prior to the start
of enrollment or as fixed by other considerations (e.g., cost or availability of patients). 2.
Any nonsequential sample size design, even if the sample size is not fixed or determined
before the start of the trial. ant: sequential sample size design
sequential sample size design n - [trials] 1. The sample size design underlying a sequential
design; a design in which sample size is a function of results observed as in an open or
closed sequential design. 2. Any scheme in which sample size changes as a function of
observations or considerations made during the course of enrollment. ant: fixed sample
size design Usage note: Best reserved for use in the sense of defn 1. Not recommended in
the sense of defn 2 in relation to fixed sample size designs, whether or not the changes are
independent of observed treatment differences.
N A R R AT I V E
The appeal of sequential sample size designs is that, on average, they allow researchers to
answer questions with smaller sample sizes than with fixed sample sizes. However, that
said, the reality is that most trials have fixed sample size designs. The reason is because
sequential sample size designs are limited to settings where outcomes can be categorized as
successes or failures and where that categorization can be made shortly after enrollment.
The categorization is crucial because enrollment of the next person or group of persons
depends on the outcome observed in the last person or group of persons enrolled.
The usual case in trials is for enrollment and treatment to proceed independently.
That disconnect is implicit to fixed sample size designs. Sequential sample size designs are
not feasible if any of the following apply:
• Not practical to orchestrate enrollment following observed outcomes (sequential
designs are limited to settings where there is a ready stable of people suitable for
enrollment in short order following the observed outcome in the last person or group
of persons enrolled).
• The outcome of interest can occur any time after enrollment, i.e., the time between
initiation of treatment and outcome is variable—the situation in most clinical trials.
• Period of treatment extends over time (often the case, especially in drug trials).
• Not possible to classify treatment as success or failure (usually the case; often the only
thing one can say is whether an outcome event has occurred, the absence of an outcome
event does not mean success; only the absence of an outcome).
88. Fixed vs. Adaptive Designs
263
88. Fixed vs. adaptive designs
R E L AT E D E N T R I E S
Fixed vs. adaptive designs (page 145), Sample size: Design (page 253), Fixed vs. sequential
sample size designs (page 261)
DEFINITIONS
adaptive study design n - [trials] A study design constructed to accommodate change,
e.g., a trial in which treatment assignment ratios change as a function of observed outcomes
or as a function of baseline characteristics of people enrolled [Chow and Chang, 2008].12
ant: fixed study design Usage note: Not to be confused with changes in trials with fixed
study designs during conduct.
adaptive treatment assignment n - Any method of treatment assignment in which
the treatment assignment ratio changes as a function of previous assignments,
baseline data, or observed outcomes [Simon, 1977].79 Types include baseline adaptive
treatment assignment, biased coin treatment assignment, minimization, minimum
likelihood treatment assignment, number adaptive treatment assignment, play-the-winner
treatment assignment, outcome adaptive treatment assignment, and urn model treatment
assignment. syn: dynamic treatment assignment ant: fixed treatment assignment
fixed study design n - [trials] A study design executed with the intent of holding design
elements fixed during execution; e.g., a trial with a fixed sample size design and fixed
treatment assignment ratio. ant: adaptive study design Usage note: The descriptor ‘‘fixed’’
is an indication of intent to hold design elements fixed. Looking back when the trial is
finished may reveal various changes in the sample size goal and addition or deletion of
treatment groups.
N A R R AT I V E
Chow and Chang,12 in a review article covering adaptive designs, characterize adaption
as prospective, concurrent (ad hoc), and retrospective. Prospective adaption in Chow and
Chang’s characterizations are those representative of adaptive treatment assignment. (They
also characterize changes made during trials because of treatment effects monitoring as
prospective, e.g., as in an early stop of treatment because of ill-effects, but most references to
adaptive design are in regard to changes in treatment assignment ratios based on observed
data.) Concurrent adaption is in relation to changes made during the trial because of
extrinsic conditions encountered during the trial. This category includes changes to the
enrollment criteria, changes in treatment dosing schedules or changes to data collection,
changes in sample size requirements, and any other change requiring amendment of the
protocol. Retrospective adaption relates to things done at analysis time, e.g., as in focusing
analysis on an outcome different from the one specified in the original design.
Virtually all designs are adaptive by these characterizations, but only a small
fraction are prospectively adaptive. The reasons are akin to those outlined for Fixed vs.
264
X. SAMPLE SIZE
sequential sample size designs (page 261). Adaption focused on treatment assignment
ratios complicates the treatment assignment process and, in drug trials, also complicates
supplying clinics with study drug because predicting need is made difficult by the fact
that need is dictated by changing assignment ratios.
89. Designed Subgroup Comparisons
265
89. Designed subgroup comparisons
R E L AT E D E N T R I E S
Enrollment quotas (page 213), Subgroup analysis (page 423)
DEFINITIONS
data dredging v - Ad hoc data analyses aimed at finding statistically significant differences
among subgroups represented in a trial aimed at explaining a treatment difference,
especially such analyses leading to presentations or publications heralding differences
found as being important and meaningful. Usage note: Often used in a pejorative
sense, especially in reference to analyses in which it appears that only large differences
are presented and where the number of comparisons made is not specified. Not to be
confused with subgroup analysis or exploratory data analysis.
designed subgroup comparison n - [trials] 1. A subgroup comparison specified in the
study protocol, especially one based on a sample size calculation when the trial was
designed. 2. A treatment comparison in a subgroup enrolled to a quota. ant: ad hoc
subgroup comparison
exploratory data analysis n - Data analysis performed for the purpose of finding
relationships of importance, subgroups of people, or data subsets that may explain
observed results; usually performed without benefit of prior hypotheses. Usage note: Not
to be confused with data dredging.
subgroup n - 1. A subordinate group whose members share some distinguishing trait
or feature. 2. A subset of a study population distinguished by a characteristic or set of
characteristics; in the case of trials, such a subset as distinguished by one or more baseline
characteristics.
subgroup analysis n - 1. Data analysis focused on a selected subgroup (defn 2). 2.
Analysis aimed at characterizing observed differences among subgroups, especially, in the
case of trials in comparison of treatment differences in subgroups of patients defined
by baseline characteristics. 3. A form of exploratory data analysis aimed at identifying a
subgroup of persons that account for an observed difference, e.g., such an analysis in a
trial to determine whether or not an observed treatment difference can be accounted for
by some subgroup, especially such analyses using baseline characteristics. Usage note: Not
to be confused with ‘‘data dredging.’’ Analyses involving subgroups formed using entry
demographic and other baseline characteristics are an essential part of the analysis processes
for trials. The analyses are done to determine whether or not it is reasonable to regard
an observed treatment effect as being homogeneous (i.e., independent of entry and other
important baseline characteristics). The analyses have bearing on conclusions reached
from trials. Evidence of qualitative or quantitative treatment by baseline characteristic
interaction obligates the trialist to temper or qualify conclusions accordingly. A treatment
effect cannot be assumed to be homogeneous across subgroups absent analyses aimed at
addressing the question. Subgroup analyses become forms of data dredging if results of
such analyses are used to identify ‘‘significant’’ differences and presentation to suggest that
the differences are the result of clinical insight regarding an underlying disease process.
266
X. SAMPLE SIZE
subgroup comparison n - [trials] A comparison of treatment groups within a specified
subgroup of people to assess treatment effect; subgroup typically defined by disease state
or history on entry or by entry baseline or demographic characteristics.
subgrouping v - 1. The process of separating observation units into subgroups on the
basis of specified characteristics (e.g., sex and age on entry) or designated cutpoints for
variables used for making the separations. 2. The process of identifying subgroups through
subgroup analyses.
subgrouping cutpoint n - The value of a subgrouping variable used to separate persons
into subgroups; e.g., formation of subgroups of patients less than 35 years of age, 35
through 54 years of age, and 55 years of age or older requires use of cutpoints at 35 and
55 years of age.
subgrouping variable n - A variable, such as age, used to classify observation units or
treatment units into subgroups; a baseline characteristic for most subgroup analyses in
trials.
N A R R AT I V E
Most subgroup differences reported from trials are the result of ad hoc subgroup
analyses.102 Occasionally, when the treatment difference is large and where there is a
convincing rationale as to why the difference may be real, the subgroup is the focus of
a follow-on trial, e.g., as in PARIS II,43 as spawned from PARIS.67 The fact that most
treatment subgroup differences do not reproduce when subjected to follow-on trials serves
as a sobering reminder for trialists proclaiming subgroup treatment effects.
The trialist-analyst can be expected to carry out dozens of subgroup analyses in
monitoring and analyzing results of a trial. Indeed, one can argue that the trialist-analyst
has a duty to perform such analyses to the extent needed to determine whether the results
are consistent with the treatment effect being homogeneous. Clearly, the trialist-analyst
should not conclude that an effect is homogenous, if subgroup analyses indicate otherwise.
The trialist, at design time, has to decide whether to enroll to meet sample size
requirements for designated subgroups or to rely on a floating subgroup enrollment
economy. The difference is that with the added sample size requirements, the comparison
can be done with the precision planned (assuming enrollment to the specified numbers),
whereas with a floating economy, precision will be a function of actual sample sizes
achieved in subgroups.
Designers, for reasons outlined in regard to enrollment quotas (page 213), are
advised to rely on floating enrollment economies except, perhaps, in those few cases where
there is strong a priori evidence for subgroup differences and where that effect is likely to
be reasonably large and clinically important. Failing that, they should be content with the
precision in subgroup analyses deriving from floating enrollment economies.
The absence of designed subgroup comparison does not preclude performing
them. All the absence means is that the precision of the comparison is not controlled in
the enrollment design.
Use of a variable in the design for stratification does not obligate the trialist to
analyze and present by the subgroups defined by the stratification variable. Nor does stratification imply an enrollment quota for the subgroups defined by the stratification variable.
Data Collection and
Processing
90. Contact Schedule
269
90. Contact schedule
SLIDE
Contact schedule: Monoclonal Antibody CMV Retinitis Trial
(MACRT)82
Baseline:
Followup:
As often as necessary to establish eligibility and to collect required
baseline data in specified time window
Monthly during first year of followup; every 3 months thereafter
R E L AT E D E N T R I E S
Examinations/visits (page 271), Examination/clinic visit schedule (page 275)
DEFINITIONS
patient contact schedule n - [trials] 1. The schedule on which a patient is to be contacted
by or to be in contact with study personnel for the purpose of enrollment, treatment, or
followup; all scheduled contacts, including clinic visits, home visits, telephone contacts,
and mail contacts. 2. The actual contact schedule of a patient.
patient mail contact n - [trials] A clinic initiated patient contact via mail.
patient telephone contact n - [trials] A clinic initiated patient contact via telephone.
N A R R AT I V E
List all scheduled contacts, starting with clinic visits but including all required for conduct
of the trial. For each contact indicate the following:
• Purposes of contact (e.g., baseline evaluation, eligibility assessment, treatment
administration, followup data collection, compliance assessment, etc.)
• Place of contact (e.g., clinic, home, elsewhere)
• Idealized time of contact and allowable time window for contact to be counted in
the allowable time window
• Initiator of contact (e.g., patient, clinic coordinator, etc.)
• Mode of contact (face-to-face, telephone, mail)
91. Examinations/Visits
271
91. Examinations/visits
R E L AT E D E N T R I E S
Examination/clinic visit schedule (page 275), Data collection: Schedules and procedures
(page 281)
DEFINITIONS
baseline (Bl, BL) n - 1. An observation, set of observations, measurement, or series of
measurements made or recorded on a person just prior to or in conjunction with treatment
assignment that serves as a basis for gauging change in relation to treatment assignment.
2. An observation, series of observations, measurement, or series of measurements made
or recorded at some point after enrollment in relation to some act or event that serves
as a basis for gauging change (e.g., a blood pressure measurement made in relation to
an increase in dosage of an anti-hypertensive drug to measure the effect of the increase).
Usage note: Subject to varying uses. Typically, in trials, unless otherwise indicated, the
term should be reserved for characterizations that are consistent with defn 1. Baseline
observations in most trials arise from a series of baseline examinations, separated in time
by days or weeks. Hence, the time of observation for one baseline variable, relative to
another, may be different.
baseline examination n - 1. A patient examination carried out during the baseline period
of observation for the purpose of collecting baseline data. 2. Such an examination that is
used to assess a patient’s eligibility for enrollment into a trial or followup study.
baseline period n - [general] A period of time that is used to perform procedures needed
to assess the suitability and eligibility of a study candidate for enrollment into a study, to
collect required baseline data, and to carry out consent processes. [trials] 1. For a study
subject, the period defined by the first data collection visit and ending with assignment
to treatment. 2. Such a period ending shortly after assignment to treatment. 3. A period
of time during the course of treatment or followup of a person, marked by some event,
process, or procedure, in which new measurements or observations are made to serve as a
base for gauging subsequent change. 4. enrollment period Usage note: Avoid in the sense
of defn 2 or 4 without defining qualifications. Provide qualifying detail for uses in the
sense of defn 3. Traditionally, the point defining the end of the baseline period in trials
is assignment to or initiation of treatment. The tendency to ‘‘stretch’’ the baseline period,
as in defn 2, arises from a desire to reduce missing baseline data. Clearly, the utility of a
measure as a baseline measure is diminished if there are possibilities of the observation
being influenced by treatment. Hence, the practice is not recommended, even if the time
interval following treatment assignment or initiation of treatment is small and even if the
likelihood of treatment having had an effect on the variable(s) being observed within that
interval is small.
closeout examination n - An examination performed on separation of a person from a
study.
closeout followup visit n - A followup visit performed in relation to closeout; patient
closeout followup visit. rt: closeout examination
272
X I . D ATA C O L L E C T I O N A N D P R O C E S S I N G
followup (Fu, FU) n - [also follow-up] 1. The act of or an instance of following up. 2.
Something done in or as followup, e.g., reexamination of a person as part of scheduled
followup. 3. Maintenance of contact with a person or observation unit for care or
administration of treatment.
followup visit n - [trials] Any study clinic visit by a person after treatment assignment,
especially a required followup visit.
home visit n - A patient contact that takes place in the patient’s home.
interim followup visit n - [trials] Any followup visit that takes place after enrollment
that is not part of the required sequence of followup visits and that is initiated because
of some problem or concern; ordinarily not counted as a required followup visit unless it
takes place within the specified time period for a required visit and required procedures
for that visit are carried out as part of the interim visit; nonrequired followup visit. ant:
required followup visit
nonrequired followup visit n - [trials] A followup visit (after the treatment assignment
visit) that is not part of the required sequence of followup visits, e.g., one initiated by a
study patient because of some medical problem. syn: interim followup visit, unscheduled
followup visit
post-closeout followup visit n - [trials] 1. Any followup visit that takes place after the
closeout followup visit. 2. Any followup visit that takes place after completion of the
closeout stage of a trial. 3. post-trial followup visit
regular followup visit n - Any of a series of visits to be made during followup;
also required followup visit. syn: scheduled followup visit ant: interim followup visit,
unscheduled followup visit Usage note: Regular in this context refers to visits intended
to take place at specified times over the course of followup as required for data collection
and for carrying out procedures and assessments specified in the study protocol.
required followup visit n - Any followup visit required as part of the study protocol and
that is to be done at a specified time after enrollment; in the case of trials, such visits
include treatment application and adjustment followup visits, regular followup visits,
closeout followup visits, post-closeout followup visits, and post-trial followup visits. ant:
nonrequired followup visit rt: regular followup visit
scheduled study visit n - A study visit that is part of the visit schedule of a study.
study examination n - Any examination of a person performed in relation to a study
protocol; includes examinations performed for evaluation or assessment, administering
treatment or care, data collection, and followup. rt: study visit
study visit n - Any visit by a study candidate or study participant to a study site for the
purpose of assessment, treatment, care, or data collection in relation to a study protocol.
rt: study examination
treatment application and adjustment followup visit n - A followup visit made to
enable study personnel to apply or adjust treatment, depending on the needs of the person
being treated and the study protocol.
treatment assignment visit n - A visit of a patient to a study clinic at which the treatment
assignment is issued or announced.
unscheduled followup visit n - interim followup visit, also nonrequired followup visit
ant: scheduled followup visit
91. Examinations/Visits
273
N A R R AT I V E
Designers should list the different classes of examinations/visits required and purposes to
be served.
Classes of examinations/visits
•
•
•
•
•
•
Baseline
Treatment assignment/initiation
Treatment application and adjustment
Followup
Closeout
Post closeout
Purpose of examinations/visits
• Baseline examinations
❑ Determine eligibility
❑ Exclude unsuitable patients
❑ Provide information to patients for obtaining informed consent
❑ Establish baseline for evaluation of subsequent changes
❑ Provide descriptive data on entry characteristics of the study population
• Treatment assignment/initiation
❑ Final check of eligibility
❑ Consent
❑ Randomization
❑ Initiation of treatment
• Treatment application and adjustment examinations
❑ Initiate treatment
❑ Adjust and ‘‘touch up’’ treatment
❑ Record details of treatment and related events
❑ Observe events in the treatment period
❑ Provide initial followup data
• Scheduled followup examinations
❑ Provide essential care to patients
❑ Evaluate course of treatment for modification of treatment if necessary
❑ Provide uniform basis for observing and recording clinical events
❑ Provide data to assess differences in treatment procedures
❑ Provide data for evaluating changes over time
❑ Maintain patient contact
• Unscheduled interim followup examinations
❑ Provide essential care to patients
❑ Provide data on circumstances surrounding need for interim exam
❑ Assess treatment side effects
274
X I . D ATA C O L L E C T I O N A N D P R O C E S S I N G
• Closeout examinations
❑ Provide data surrounding termination of treatment
❑ Provide documentation of exit procedures and information supplied to patient
on exit
❑ Check for occurrence of untoward events during termination of treatment
• Post closeout examinations
❑ Provide data on events following closeout and cessation of treatment
❑ Maintain contact with patient for subsequent followup
92. Examination/Clinic Visit Schedule
275
92. Examination/clinic visit schedule
SLIDE
Clinic visit schedule: Glaucoma Laser Trial (GLT)35
Visit
Baseline 1
Baseline 2
Treatment 1
Post-treatment 1
Treatment 2
Post-Treatment 2
Followup 1
Followup 2
Followup 3
Followup 4
Time from randomization
−3 wk
−2 wk
0
1 wk
4 wk
5 wk
3 mo
6 mo
9 mo
12 mo
etc.
R E L AT E D E N T R I E S
Contact schedule (page 269), Examinations/visits (page 271), Data collection: Schedules
and procedures (page 281)
DEFINITIONS
baseline period n - [general] A period of time that is used to perform procedures needed
to assess the suitability and eligibility of a study candidate for enrollment into a study, to
collect required baseline data, and to carry out consent processes. [trials] 1. For a study
subject, the period defined by the first data collection visit and ending with assignment
to treatment. 2. Such a period ending shortly after assignment to treatment. 3. A period
of time during the course of treatment or followup of a person, marked by some event,
process, or procedure, in which new measurements or observations are made to serve as a
base for gauging subsequent change. 4. enrollment period Usage note: Avoid in the sense
of defn 2 or 4 without defining qualifications. Provide qualifying detail for uses in the
sense of defn 3. Traditionally, the point defining the end of the baseline period in trials
is assignment to or initiation of treatment. The tendency to ‘‘stretch’’ the baseline period,
as in defn 2, arises from a desire to reduce missing baseline data. Clearly, the utility of a
measure as a baseline measure is diminished if there are possibilities of the observation
being influenced by treatment. Hence, the practice is not recommended, even if the time
interval following treatment assignment or initiation of treatment is small and even if the
likelihood of treatment having had an effect on the variable(s) being observed within that
interval is small.
closeout period n - [trials] The period of time for closeout of a person or treatment unit.
rt: baseline period, treatment period, followup period, treatment and followup period
followup period n - 1. A period of time from enrollment of an observation unit (usually
a person) in a study to termination of followup of that unit. 2. A period of time in the
276
X I . D ATA C O L L E C T I O N A N D P R O C E S S I N G
course of a study defined by the start of followup of the first observation unit and by the
end of followup of the last unit enrolled; followup stage.
treatment period n - 1. The period of time over which treatment is administered to
persons or treatment units in a study. 2. The period of time in a study in which treatment
is actually administered to a person or treatment unit.
N A R R AT I V E
The clinic visit/examination schedule can be divided as follows:
•
•
•
•
Baseline period
Treatment period
Followup period
Closeout period
The end of the baseline period, usually marked by issue of the treatment assignment, also
marks the start of the treatment and followup periods. The treatment period ends with
the last application of treatment. The followup period ends with the last contact for data
collection. In many cases the end for the two periods is the same—for example, as in the
case in most trials involving long-term treatment for chronic conditions. The two periods
are different in trials where treatment is applied over a short period of time and where
followup extends over a longer period of time.
The factors influencing schedule for the different periods are as outlined below.
Baseline period
• Time and number of visits needed for diagnosis and for determining eligibility
• Number of procedures performed for establishing diagnosis and eligibility and for
baseline data collection
• Number of visits required to provide necessary baseline data
• Time needed to solicit consent and for person to consider whether to enroll
• Time needed to issue treatment assignment and to inform person of assignment
Treatment period
• Time period of treatment
• Place of treatment—outpatient or inpatient
• Need for documentation of the fact of treatment administration (e.g., is there need
for observed administration of treatment at the study clinic?)
• Need for treatment adjustments (e.g., dosage change depending on observed effect)
• Likelihood of treatment-related side effects
• Need for treatment ‘‘touch-up’’ or reapplication of treatment
• Need for assessing compliance to treatment
Followup period
• Underlying rate of events requiring diagnosis and observation by clinic personnel
92. Examination/Clinic Visit Schedule
277
• Likely rate of change for measures used to assess outcome
• Number of different procedures that can be reasonably performed at any given visit
• Maximal allowable separation between visits consistent with care requirements and
for ensuring continuing followup
Closeout period
• Time required to safely withdraw treatment
• Time needed to collect desired data on persons prior to separation from the trial
• Time needed for deconsent and for orderly transfer of care (when indicated)
Ideally, the examination schedule should be the same for all study subjects.
Schedules that depend on treatment assignment are more complicated to maintain and
increase the probability of mix-ups and of bias in data collection.
A serious drawback of differential treatment schedules depending on assignment
is the chance of them producing artifactual differences in the effects observed. The adage
that ‘‘the more you look, the more you find’’ applies to observations in trials. One can
expect, within limits, that clinic personnel will report more side effects and morbid events
for persons seen more frequently than for those seen less frequently (see, for example,
morbidity results reported from the Hypertension Detection and Followup Program
(HDFP), where persons assigned to Stepped Care were seen more frequently than persons
assigned to Usual Care37 ).
The same schedule is implicit in trials involving masked treatment administration,
but need not be when treatments are not masked. It may be possible in unmasked trials
to have the same schedule if the mode of treatment is the same across study treatments,
but usually is not possible when the modes are different. For example, one can expect to
have to deal with different schedules in trials involving a medical and surgical modality
(e.g., as in NETT62 ).
The ‘‘workarounds’’ when dealing with different schedules are few. Designers
can strive to minimize the possibility of artifactual differences by censoring observation
during analyses, e.g., by restricting considerations to visits common to all study groups.
Censoring may reduce the artifactual difference but is unlikely to eliminate it because
observations made at visits are not independent of previous observations. If there is a
Hawthorne effect∗ from the attention implied by the extra visits, it is likely to be present
throughout the data.
∗ An
effect on the person under study by being the focus of study; halo effect. The name arises from the site of the
study at which the phenomenon was observed—a Western Electric plant located in Hawthorne, Illinois.74
93. Data Collection
279
93. Data collection
R E L AT E D E N T R I E S
Data collection: Schedules and procedures (page 281), Form design: Principles and
procedures (page 295)
N A R R AT I V E
The admonishment ‘‘never collect more than 10 times the amount of data needed’’
is a tongue-in-cheek comment on the natural inclination of trialists. In regard to data
collection, they have mentalities akin to squirrels gathering nuts for winter. The nuts are
plentiful and winter is coming. Bury enough so that those not found will not be missed.
The mentality is fueled by ‘‘starry eye’’ effects when a trial is on the drawing board.
The effect leads to the ‘‘Christmas Tree’’ approach to data collection.
Christmas comes but once a year. We just cut this wonderful tree, so let’s adorn
it—with my ornaments, his ornaments, her ornaments, everyone’s ornaments! Keep
going until the branches droop like those on Charlie Brown’s tree.
Most every member of a research group has ‘‘pet’’ interests and trials present the
perfect opportunity to pursue those interests. It would be a shame, even some kind of
research crime, to miss the opportunities.
Just as in remodeling one’s house, it is the ‘‘mightaswells’’ in data collection that
cost.
The propensity for violation of the ‘‘10 times’’ rule is fueled, in part, by the
misperception that data collection is easy and inexpensive. The clinician assumes that the
majority of costs are in recruiting, treating, and retaining persons in the trial. They are
largely oblivious to the costs and energies associated with data collection and processing.
There is a cost and energy expenditure for every piece of data collected. The larger
the data system, the more complex it is to manage. The expenditures are for:
•
•
•
•
Obtaining or generating the information
Recording the information on study forms
Keying the information
Processing the information for conversion to computer readable format and for
storage and retrieval in the study database
• Editing the information
• Quality control of the information
Designers need defenses against the ‘‘mightaswells’’ when it comes to data
collection. The best defense is a system of categorizing data proposed for collection against
a list of essential activities and functions as listed below and ‘‘nixing’’ data that do not
relate to those activities or functions.
Activity
• Workup; diagnosis
• Physical exam
280
•
•
•
•
•
•
X I . D ATA C O L L E C T I O N A N D P R O C E S S I N G
History (medical, family)
Measurement (height, weight, etc.)
Specimen collection/laboratory test
x-ray, ECG, fundus photography
Biopsy
Consent
Purpose
•
•
•
•
•
•
•
•
•
•
•
•
•
Eligibility assessment
Baseline determination
Disease characterization
Population characterization
Stratification
Randomization
Treatment administration/modification
Compliance assessment
Recording/documenting events (morbidity, mortality)
Recording/documenting adverse events
Change assessment
Followup
Identification (patient, visit, time of visit, etc.)
The listing of activities should be fleshed out to include the time points and visits
at which they are to be performed. A useful discipline, consistent with lean design, is to
require justification of each item listed in relation to a particular activity or function in
the trial. Items not meeting the justification test should be eliminated.
The goal should be to standardize data collection across time. To do that, the
arrangement and wording of items should be standardized across forms. Usually that is
best accomplished by creating modules of items (e.g., a module for measure of blood
pressure, another for blood chemistries, etc.) and then using the modules across data
collection visits.
The developmental process should include ‘‘cross checks’’ to reduce the risk of
‘‘goofs.’’ Generally, measurements and recordings made during the baseline period of data
collection are repeated at various points during followup. It is good practice to carry out
checks aimed at making certain that items appearing on baseline forms are represented on
followup forms and vice versa.
Another kind of check relates to baseline data. In general, a variable used for
selection (e.g., blood pressure to select people having values above a certain level) cannot
also be used to provide a baseline for measuring subsequent change. The measurement
must be repeated at a visit subsequent to the one generating the data for selection to
provide a reading free of shrinkage due to ‘‘regression to the mean.’’
94. Data Collection: Schedules and Procedures
281
94. Data collection: Schedules and procedures
SLIDE
Data collection schedule: Ganciclovir Cidofovir CMV Retinitis
Trial (GCCRT)81 (thru first year of followup)
Visit
Time (wk)
Bl F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12
0 4 8 12 16 20 24 28 32 36 40 44 48
Physical exam
Medical history
Quality of Life
x
x
x
Eye exam
Fundus photos
Visual acuity
Visual fields
Treatment
Adverse events
Blood for CMV load
Blood for HIV load
CMV cultures
Hematology
Lymphocyte analysis
x
x
x
x
x
x
x
x
x
x
x
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R E L AT E D E N T R I E S
Contact schedule (page 269), Examinations/visits (page 271), Examination/clinic visit
schedule (page 275)
N A R R AT I V E
Designers do well to fashion data charts such as depicted above when developing the data
collection design for a trial. The process of form development should start from such
charts.
The data collection schedule is a function of the contact schedule. Most contacts
will result in some data collection, even if only to record the fact of contact.
Factors influencing data collection schedules
.
Prior to enrollment
•
•
•
•
•
•
Time required to assess eligibility
Stability of baseline data
Urgency of treatment
Importance of shakedown period
Time required for consent process
Convenience and practicability
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After enrollment
•
•
•
•
•
Need for treatment application and adjustment
Care requirements
Expected event rate
Maintenance of compliance and interest of persons enrolled
Convenience and practicability
Purposes and requirements of data collection
.
Prior to enrollment
•
•
•
•
•
•
•
Documentation of eligibility
Stratification variables
Population characteristics
Disease characteristics
Risk factors
Baseline for assessing subsequent changes
Locator and tracing information
After enrollment
•
•
•
•
•
•
Particulars of treatment
Treatment changes
Treatment adherence
Time and nature of events
Change from baseline for change measures
Update locator and tracing information
Features of robust data collection schedules
.
•
•
•
•
•
•
•
•
•
•
Defined entry point for enrollment
Specified examination schedule
Ideal and permissible times for examinations
Contiguous time windows
Operational definitions for missed visit, dropout, lost-to-followup
Forms tested before use
Phased start up
Personnel training, certification, and recertification
Continuous data flow
Ongoing data entry, editing, and analysis
95. Data Flow
283
95. Data flow
R E L AT E D E N T R I E S
Data processing procedures (page 285), Form design: Principles and procedures (page
295)
DEFINITIONS
bolus data flow n - Data flow from generation sites to a processing site in batches, e.g.,
such flow for the case report form of data flow. rt: continuous data flow
case report form (CRF) n - A collection of individual data forms related to a person
enrolled into a study, especially when arranged in order of use and completed in totality
before submission to the center or sponsor responsible for receiving and processing such
forms.
continuous data flow n - Data flow from generation sites to a processing site as data are
keyed; such flow by data form as keyed or within short order after keying. rt: bolus data
flow
data flow n - The way in which data flows from generation sites to the processing site;
broadly, in the context of trials continuous or bolus data flow.
real-time data entry n - Data entry as data are generated or collected, e.g., data entry as
done via laptops while persons are seen in a study.
N A R R AT I V E
The options of the trialist regarding data harvests from data generation sites are:
1. Wait to harvest until the trial is finished.
2. Harvest data in batches over the course of the trial, e.g., as with bolus data flows.
3. Harvest data continuously as they are generated over the course of the trial.
The first option is not a viable option, except in the simplest of trials where the
entire trial is done in a matter of days—rarely the case. In all other cases, the choice is
between options 2 and 3; of those, the third option is preferable to the second option.
Why? Because the absence of flows or gaps in flows creates ‘‘blind spots’’ in the
processing and analysis site. The closer the flow is to real-time, the better the ‘‘vision’’ in
monitoring performance in the data collection processes and in monitoring the trial for
treatment effects.
The prerequisites for timely continuous data flows are:
1. Arrangements in which data are keyed where generated
2. Arrangements in which data are keyed as generated or within a short period of time
(hours or days) after generation
3. Arrangements in which data flow to the processing and analysis site on keying or
within a short period of time (hours or days) after generation
4. Data collection forms that are closed on the day when opened
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X I . D ATA C O L L E C T I O N A N D P R O C E S S I N G
Data flow is automatically lagged when data forms are designed to capture data
from different clinic visits or from procedures performed at different locations during the
same visit.
The conditions above are listed as prerequisites because, even if satisfied, there is
no assurance of timely flow if data generation sites are not disciplined in data entry. One
of the advantages of real-time data entry is that data have to be keyed as collected. Short
of that, the trialist has to monitor and urge data generation sites to enter data in a timely
fashion.
96. Data Processing Procedures
285
96. Data processing procedures
SLIDE
Data processing procedures: Studies of Ocular
Complications of AIDS (SOCA)80
•
•
•
•
•
•
Paper forms
Visit driven
Near real-time continuous flow to processing site
Initially centralized data entry then distributed
100% double, dependent, data entry
All information on forms keyed; keyed as recorded; keyed from forms (no
intermediate coding or transcription)
• SAS database
R E L AT E D E N T R I E S
Form design: Principles and procedures (page 295), Data entry design (page 301),
Performance monitoring (page 399)
DEFINITIONS
data editing v - 1. The process of reviewing data for the purpose of detecting deficiencies
or errors in the way they are collected or recorded. 2. The actual process of detecting
deficient or erroneous values on completed data forms. rt: data query
data element n - A unit of data recorded for a specified data item or data field.
data field n - A space on a data form or in an electronic record designated to contain
alphabetic and/or numeric characters of information recorded in response to a specified
data item on a data form.
data file n - A collection of data records as contained on paper forms or in electronic
records arrayed or organized in some fashion.
data form n - 1. A collection of data items as contained in a data record. 2. A form
containing data. 3. A form, paper or electronic, for data collection. rt: case report form
data freeze n - Data held in a fixed state, especially such a state imposed on a database in
order to complete some task requiring a stable, nonchanging database (e.g., as required
for preparation of a treatment effects monitoring report). rt: data snapshot
data generation n - 1. data collection 2. The generation of data from specimens,
documents, or materials collected by others, e.g., data generated from blood samples
received at a laboratory or from fundus photographs received at a reading center.
data generation site n - 1. A site that generates data from existing records, e.g., a reading
center. 2. data collection site Usage note: See note for data collection site.
data keying n - A process involving use of a keyboard and key strokes to represent
observed data; data entry.
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data management n - A constellation of activities, typically performed by a data center,
data coordinating center, or coordinating center, related to receiving, editing, updating,
storing, and retrieving data for some specified task or function.
data purge n - The removal of specified data elements from a dataset because of known
or suspected deficiencies; e.g., removal of data known to have been fabricated.
data query n - A query regarding a data element or item. rt: data editing, edit query
data record n - A collection of data items as contained in a paper or electronic form
treated as a unit for some defined purpose or function.
data snapshot n - A freeze of an active database or file; generally not preceded by any
special effort to ensure clean data. rt: data freeze
data system n - A collection of interrelated procedures and routines (performed by
hand or computer) that are used in the creation and maintenance of a database or some
data-related function, such as data analysis. rt: centralized data system, distributed data
system
data transcription n - 1. Transcription of data onto a data collection form. 2. Transcription
of data already recorded on a data collection form to some other form, document, or list;
not to be confused with data coding or data editing.
data transformation n - 1. A one-to-one mapping of data from one measurement scale to
another; typically performed to simplify calculations for data analysis or to provide data
having distributional or other properties better suited than the original to some form of
display or statistical analysis. 2. Any form of data reduction or simplification, regardless of
whether or not a one-to-one mapping, e.g., the distillation of multiple outcome measures
into a single composite outcome. 3. data coding rt: inverse sine transformation, log
transformation, square root transformation, standard score, T -score, Z -transformation,
Z -score
N A R R AT I V E
Designers should strive for data flows that are continuous and timely, usually best
accomplished by practices discussed in Form design: Principles and procedures (page 295)
and by use of real-time, or near real-time data entry.
Designers should specify the edits and checks to be performed on data for quality
control. Reasonable checks and edits include those relating to:
•
•
•
•
•
•
•
•
•
•
Record linkage
Unanswered items
Impossible or improbable answers
Inconsistent information (within and across forms)
Abnormal and outlier values
Suspicious changes from one exam to the next
Inadmissible codes
Data collection by uncertified persons
Improper treatment or protocol violations
Unsigned or improperly signed and dated forms
97. Laboratory Tests
287
97. Laboratory tests
R E L AT E D E N T R Y
Readings (page 289)
DEFINITIONS
central laboratory (CL) n - 1. A study center in the structure of a multicenter study
responsible for performing specified tests on specimens collected on persons enrolled or
considered for enrollment into the study; as distinct from local laboratory. 2. A facility
within an institution, such as a hospital, responsible for performing a variety of tests or
analyses, as ordered by and received from staff of the various departments or units of the
institution. rt: local laboratory
laboratory n - 1. A facility equipped for study primarily by experimentation or for
testing and analysis in some area of study or activity. 2. A place providing opportunity for
experimentation, observation, or practice in a field of study or learning. 3. A place equipped
to perform tests and analyses of bodily fluids and specimens. rt: central laboratory, local
laboratory
local laboratory n - 1. A laboratory that serves a center in a multicenter study. 2. A
laboratory located within the same geographic region as its users, e.g., one located in the
same city or institution as its users. 3. A laboratory set up and operated for the benefit
of a specific person or set of persons in relation to some research activity or specialized
function; especially one under the control of and located within one’s own administrative
unit and the services of which are available only to specified persons housed within that
administrative unit. rt: central laboratory
N A R R AT I V E
Virtually every trial involves laboratory tests. The tests are performed on urine, blood, or
other bodily fluids or tissues collected at specified times over the course of study. The
extent and nature of testing is up to designers. Issues in the timing of determinations,
where they are done, and how they are to be done come down to questions, such as below.
When are local determinations preferable to central determinations?
Answer: When results are needed for the care and management of a patient and where
time is of the essence. Also when emphasis is on real-world conditions and practices in
the way a study is done.
When are central determinations preferable to local determinations in multicenter
studies?
Answer: When the cost of standardization and quality control of individual laboratories
is difficult or impossible or where the cost of such effort is likely to be greater than the
costs of standardization of a central laboratory. There may be no choice but to use a
central laboratory for highly technical or specialized procedures that are done only in
specialized laboratories.
What are the factors that influence the choice?
Answer: Whether the determination can be made from shipped material (many
determinations can be done only on fresh specimens; tests may degrade when done
288
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on shipped specimens), the cost and difficulty in shipping, the turnaround time for
central determinations vs. local determinations, and the importance of standardization
and quality control.
Who pays for laboratory tests?
Answer: The study if the tests are done primarily or solely for research purposes. The
patient or third-party payers if the tests are needed for ordinary care and treatment.
What is the frequency of determinations?
Answer: See Data collection schedule, page 281.
Should tests be replicated?
Answer: The answer depends on the test and its inter-aliquot variation. There is little
value in replication when replicate variation is small.
Should results be fed back to study clinics?
Answer: Yes when the results are needed for care or treatment. Generally no when
the tests are done only for research purposes. No when the tests relate to a treatment
variable and where treatments are administered in masked fashion (e.g., as in the CDP
with regard to tests done to measure the effect of treatment on cholesterol values18 ).
Is one better off storing specimens for analysis at the ‘‘end’’ of the trial then doing
them ‘‘real-time’’?
Answer: Generally no, especially when results of tests are likely to be of importance in
monitoring for treatment effects. In trials, one never knows when the ‘‘end’’ comes. In
any case, waiting to the ‘‘end’’ usually serves only to increase the chance that specimens
will remain unanalyzed because of waning interests. A reason for waiting is to be able
to analyze all specimens in a short period of time and hence reduce the influence of
time-related variation in determinations; a plausible rationale only if it is reasonable to
expect large secular trends in determinations.
What about banking specimens for analyses later on?
Answer: Many specimens are banked but few are ever analyzed. Investigators have a
pack rat mentality that leads to ‘‘banking.’’ There is appeal in having specimens stored
to enable investigators to carry out special analyses ‘‘later on.’’ The costs in banking are
not trivial, to say nothing about energy and time needed to set up and maintain banking
procedures. Banking should not be entered into lightly!
98. Readings
289
98. Readings
R E L AT E D E N T R Y
Laboratory tests (page 287)
DEFINITION
reading center (RC) n - 1. A center responsible for interpreting and codifying information
from a specified set of materials, records, or documents (e.g., ECGs, fundus photographs,
x-rays, biopsy or autopsy specimens, death certificates). 2. Such a center in a multicenter
study.
N A R R AT I V E
The typical trial is likely to involve the collection of tissues, tracings, or recordings that
have to be ‘‘read.’’ Designers will have to deal with a series of issues having to do with
how, where, and when readings are done. Their decisions will depend on the purpose
of the readings and on how they are to be used for assessment or treatment effects. The
issues come down to a series of questions, such as represented below.
Should the readings be done by hand or should they be automated?
Answer: Designers, on first blush, are likely to gravitate to automated readings when
the option exists. Automated readings are likely to be seen as being more reliable
and reproducible than ‘‘eyeball’’ readings. They can be, but increased reliability and
reproducibility should not be taken for granted absent studies showing that. Complicated
reading processes are likely to involve judgments, even if readings are ‘‘automated.’’
Automated readings, no matter how appealing, should not be used as replacements
for manual readings if eyeball readings are the standard and the readings are used for
determination of eligibility or for treatment or care of patients in a trial.
Why not have both manual and automated readings when possible?
Answer: There are no free lunches. Automation is never hands-free and involves costs
for software, for managing the process, and for receiving and coordinating data flows.
An argument often made for doing both is because of the ‘‘opportunity’’ provided
to obtain comparative information regarding the two methods. An OK argument, but at
what cost to the trial? And, more importantly, what is the relevance of the information
relative to objectives of the trial? Usually not much.
When are central readings indicated?
Answer:
❑ When readings are likely to vary from clinic to clinic or person to person
❑ When there is no established practice or convention for reading at local sites
❑ When qualified readers are in short supply at local sites
❑ When the cost of training and of quality surveillance at the local level is prohibitive
❑ When treatments are not masked but where masked readings are desired
❑ Where results of readings are not to be fed back to study clinics
When the option exists, should one choose in favor of central readings?
Answer: Not necessarily. They may not be advisable when they are needed for diagnosis,
care, or treatment of patients because of the time lag involved in central readings, or
where the usual practice is to rely on local readings.
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If done centrally, should readings be fed back to clinics?
Answer: The answer depends on the purpose of the reading and utility of the information
in caring for or treating persons in the trial. They need not be if the information has no
obvious value in diagnosis, care, or treatment.
Should one have both local and central readings?
Answer: Perhaps. The two readings may be necessary where central readings are
desired, but where local readings are needed by clinic personnel in the care or treatment
of study subjects.
Should reading centers be involved in the patient care loop?
Answer: Generally no. Involvement in that loop requires reliable near real-time feedback.
Such turnaround is difficult to achieve and maintain with central readings. If readings are
required for care or treatment, they should be done locally.
Should readers be masked?
Answer: The answer depends on who does the reading, whether readers can be masked,
and whether they should be masked. Obviously, masking is not advisable if readers need
to know treatment assignment to properly read or interpret a record.
Obviously also, masked readings are not possible in unmasked trials when readings
are done by treating physicians. Readers will be masked when treatments are masked
(to the limit of treatment masking), even if the readers are treating physicians.
Masking can be achieved, even if the treatments are not masked, if information
on treatment is withheld from readers. Masking may be difficult to achieve with local
readings. Masking is assured with central readings, assuming information on treatment
assignment is withheld from the central readers.
How many readers should there be in a trial?
Answer: At least two. Reliance on a single reader, even if desirable from the perspective
of variance control, is not practical in any trial running over months or years, with
vacations, illnesses, and leaves or departures during the trial.
How many readings should the trialist have per record?
Answer: Usually just one. One reading per record is sufficient to provide a valid
comparison of treatments so long as readings are unbiased relative to treatment
assignment. Multiple readings per record may provide a modest increase in the precision
of the comparison, but the gain is not usually worth the added costs and logistics of
extra readings.
Designers have to decide how information from multiple readings will be used. The
usual approach is ‘‘averaging’’ when readings produce numerical values amenable to
averaging.
Other means of combining are necessary when the readings are qualitative. One
approach is to use the readings to produce a ‘‘worst’’ or ‘‘best’’ case reading based on
the combined readings.
Should readings be adjudicated?
Answer: Generally no. Most adjudication processes are difficult to implement and to
maintain, and the adjudication process can be expected to delay the flow of information
from readings to the study database. Adjudication should not be used in time critical
situations.
If adjudicated readings are required, how are they to be obtained?
Answer: One way is to convene a panel of persons to read and then to adjudicate
differences. Another way is to have records read independently by two or more readers
and then have differences adjudicated by a third ‘‘master’’ adjudicator.
Adjudication processes are best when the persons involved in adjudication are equal
in standing and competence. Adjudicated readings may be little more than the readings
98. Readings
291
of a single reader if the adjudication process is dominated by that person because of
standing or credentials.
Should records be read stand alone?
Answer: Generally yes for reasons of practicality. It is more difficult and costly to
implement and manage systems where records from two or more visits are read together
than when read stand alone. The reason for reading records together is to read for
changes over time. However, similar kinds of assessments can be made numerically
from individual readings.
If records are read together for change, should the dates of the records be masked?
Answer: The answer depends on the extent to which readers are likely to be biased
by knowing the time ordering of the recordings. Ideally, results of readings for pairings
should be complementary. That is, if the change reported when comparing record 2 to
record 1 is positive, then the change should be negative when the reading is based on
a comparison of record 1 with record 2. Masking with regard to time is achieved by
systems in which records can be presented in such a way so as to keep readers from
knowing or seeing the dates of recording.
The approach, when time masking is imposed, is to present pairs of records for
readings where the record for comparison is the more recent recording in some pairing
and the older record in other pairings. If a reader is to read under both kinds of pairing,
as is often the case if part of the purpose is to determine the amount of time-related
bias present in the reading process, then they have to be presented with both pairings,
generally in separate reading sessions.
Should records be stored and then read en masse at the end of the trial?
Answer: Generally not a good idea, especially if readings are important in monitoring for
treatment effects.
Reasons for waiting are to be able to read all records together and to reduce the
variability of readings due to secular trends by making the readings over a short period
of time. The difficulty with waiting to the ‘‘end’’ is that the end can come any time and
when it does priorities, of necessity, have to go to closing the trial and readying results
for publication not to readings.
Should records be reread at the end of the trial?
Answer: There is nothing to preclude such a possibility but such readings should be
unnecessary if readings were done in some ongoing fashion over the course of the trial.
Should readings be done in an ongoing fashion over the course of the trial?
Answer: Yes, especially where readings provide information for use in treatment effects
monitoring. The advantage to near real-time readings is that information is available as
the trial proceeds. An intangible advantage to near real-time readings relates to quality
surveillance. Quality deficiencies noted by real-time readings can be fed back with the
expectation of improvements. Deficiencies noted if records are read at the end of study
are not useful in quality control. Bad procedures or techniques detected then will not be
correctable.
When possible, is it best to read all records for a patient at the same time?
Answer: Usually no, especially in long-term trials for reasons alluded to in answers to
questions above.
When should results of readings be keyed and processed?
Answer: As soon after reading as possible. Results are not results until they are keyed
and available for analysis.
99. Tissue Repositories
293
99. Tissue repositories
SLIDE
Specimen repository: Studies of Ocular Complications of
AIDS (SOCA)80
Location: ThermoFisher Scientific, Rockville, MD
Specimens stored: Leukocytes and plasma
Frequency of collection: Baseline and followup visits
Shipment: Batched; three collections per shipment; shipped on dry ice
Mode of shipment: Fed Ex Next Day
Labeling
Dry Ice label (label UN1845)
‘‘Air eligible’’ sticker
Biological substance: Category B (label UN3373)
‘‘Keep frozen’’ label
‘‘Double upward arrows’’ label
R E L AT E D E N T R I E S
Laboratory tests (page 287), Readings (page 289)
DEFINITIONS
public repository n - A repository open to use by the public or to members of a defined
class (e.g., students and faculty of a university in regard to use of its library). In regard to
such a repository for datasets: One in which access to datasets is provided to the public
or to members of a defined class without regard to privilege, position, rank, or motive of
the requesting party. syn: public archive Usage note: In regard to datasets, a repository
is not public if the datasets it holds remain under the control of the investigators or
research organization responsible for collection of the data or if those investigators or that
organization retain the right to decide whether a request for use is granted.
repository n - 1. A place, room, or container where something is deposited or stored
for safekeeping and for subsequent inspection or use; archive. 2. public repository syn:
archive rt: bank Usage note: Usage should be reserved for settings in which the facility
is established largely for collection and storage of specimens or documents, with only
limited and sporadic withdrawals, as in a serum repository created primarily as a resource
for pursuing questions that may arise later. If the primary function is to serve as a depot
until documents or specimens are needed, use bank. Use archive if the facility is concerned
with the storage and retrieval of paper or electronic records or documents.
N A R R AT I V E
Increasingly, trials have protocols with provisions for banking of blood products or biopsy
materials for storage and for future use, specified or unspecified. Banking may be part of
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the protocol of a trial as planned or an add-on after the trial has started. Obviously, the
issues and logistics of banking are easier to deal with if envisioned from the outset than if
added mid-course. This means that designers should be proactive when planning to try to
make informed decisions as to whether or not to bank.
Issues in banking include:
• What is to be banked?
• When and how are specimens to be collected?
• On whom are specimens to be collected? Everybody consenting or only a selected
subset of consenting persons?
• How are specimens to be prepared for transport to the bank?
• How are specimens to be stored?
• Where are specimens to be banked? At the site of collection or at a commercial
repository remote from sites of collection?
• How are specimens to be labeled? By name? By Id number?
• Who will pay the costs of banking and for retrieving specimens from the bank?
• Who has access to the bank? Only investigators from the trial or others not associated
with the trial?
• Who controls access to the bank and uses of the specimens?
• How long will specimens be stored?
IRB and consent issues in the collection and use of specimens:
• Provisions for IRB approval of the banking process and of proposed uses of banked
specimens
• Option for study participants to decline contributing specimens for banking
(generally required by IRBs)
• Statement of consequences to persons, if any, declining banking
• Consent form that indicates:
❑ Reason for banking
❑ Uses of banked material
❑ Whether persons will learn of results from analyses of specimens
❑ Whether investigators intend to use stored materials for development of
commercial products
❑ Whether a person has the option of withdrawing specimens once banked
❑ Whether a person has the option of having data generated from specimens
withdrawn from the study database
❑ How long specimens will be stored
❑ Confidentiality of information generated
100. Form Design: Principles and Procedures
295
100. Form design: principles and procedures
SLIDE
Form design principles: Chemoprevention for Barrett’s
Esophagus Trial (CBET)36
Paper
Self-contained (sufficient instructional material to allow completion without
reference to other materials)
Visit driven; designed to be open and closed on day of use
Explicit skip logic
Portrait page orientation
Print on demand at clinic from print masters
Keyed at site of completion
Data entry from form
R E L AT E D E N T R I E S
Examinations/visits (page 271), Examination/clinic visit schedule (page 275), Data
collection (page 279), Data collection: Schedules and procedures (page 281)
DEFINITION
form n - 1. A paper document consisting of a collection of data items and data fields
in which the data items serve to characterize the types of information required and the
fields represent spaces to be used for recording the requested information. 2. Any such
arrangement, including those represented electronically on video screens. rt: data form,
data record, record, questionnaire
N A R R AT I V E
Ideally, one does not start recruitment for a trial until the entire form set needed for the
trial is in hand. The reason for wanting this idyllic state is that forms are linked and
that deficiencies or flaws in one form will affect others. Hence, the last form developed
can result in changes and revisions to others already in ‘‘final’’ form. The process is
iterative—not only in regard to a single form but in regard to the entire set.
The harsh reality, however, is that the world is rarely so idyllic. It is rare for trialists
to hold the ‘‘kick off’’ of recruitment until all systems are ‘‘Go’’. The likelihood is that
recruitment will be started before the entire form set is finished. Forms, in all likelihood,
will be developed in order of use. The start to recruitment will come when the baseline
set of forms are finished and when it is reasonable to hope that designers will be able to
stay ahead of demand as people move through the trial. Once enrollment starts, form
designers are on a ‘‘forced march,’’ driven by the forthcoming schedule of followup visits.
Flaws found in previous forms as a result of development of forms needed ‘‘downstream’’
will have to be ‘‘fixed’’ under live conditions.
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The finished form set, for the typical trial, can be huge. The finished set in the HPT
consisted of 58 forms—28 for data entry and 30 for administration and management of
the trial. The GLT had a set of 51 forms (34 data entry forms and 17 that were used for
administration and management of the trial).
Designers need to be straight on big dial design issues before getting to the nitty
gritty of form construction. They need to know how data will be collected.
The approach to form construction is different when completed from medical
records as opposed to when completed during patient visits. In the latter case, designers
need to be clear on who is to fill out the forms. The format and wording, of necessity, is
different when they are filled out by study patients vs. study personnel.
Designers must also decide on the format of items. They need to decide when the
information is to be collected in ‘‘interview format’’ vs. ‘‘history/summary format.’’
Designers have to decide if forms are to be constructed to be ‘‘self-contained’’
(constructed to include necessary definitions and instructions for completion on the form),
whether to be completed stand alone (i.e., independent of other forms), and whether to
be capable of being opened and closed on the day of use.
Recommended design philosophies and principles
• Real-time data collection (i.e., design forms to be completed when patient is seen)
• Stand-alone (forms designed to include instructions and definitions necessary for
completing the form)
• Unlinked (i.e., forms may be completed without regard to other forms)
• Separate forms for procedures or activities that are separated in time or that are
performed at sites that are geographically or administratively distinct from the
primary data collection site
• Forms capable of being completed in a single setting and closed on the same day as
when opened
• Explicit item logic to preclude use of blanks to indicate negative responses and to
allow for checks on whether skips and ‘‘Go to items’’ are properly executed
• Common page orientation across forms (portrait orientation preferred)
• Common form format and lay out
• Common identifying information (e.g., all data collection forms designed to require
patient Id number and name code, check digit, and visit number; located in the
same position on all forms)
Suggestions
• Name and number forms.
• Number each item.
• Date and number each version of a form (including the original); display date and
number in a standard location across forms (e.g., in headers or footers) on each page
of forms.
• Standardize the location of patient name (or name code) and Id number across
forms.
100. Form Design: Principles and Procedures
297
• Provide space for recording patient Id number and visit number on each page of a
form (standardize location across pages and forms).
• Use page numbering schemes to indicate page number and total number of pages
(e.g.,page 3 of 10).
• Include items to record date form is completed and name of individual completing
form.
• Allow adequate right, left, top, and bottom margins for binding and photocopying.
• Box instructions and definitions or set off in some other way (e.g., by use of a special
font).
• Precode where possible.
Considerations
•
•
•
•
•
•
Paper size and weight
Page orientation (portrait vs. landscape)
Photocopy masters vs. printed supply
NCR (no carbon required) paper vs. photocopying for copies of completed forms
Full page vs. multiple column layout
Color coding of forms (not recommended as sole means of identification)
Item construction principles
•
•
•
•
•
•
Avoid use of blanks or skips as responses.
Use checklists in place of unformatted responses when feasible.
Use ‘‘stop’’ items as reminders of enrollment exclusions.
Distinguish between ‘‘no,’’ ‘‘don’t know,’’ and ‘‘unknown’’ item as responses.
Use conventional units of measure.
Distinguish between response lists that are to be read as written (for interview
forms of data collection) from those to be used as checklists for recording responses
volunteered by patients in the history/summary form of data collection.
Lay-out
•
•
•
•
•
•
Arrange items in order of use.
Collect related items into sections and label with appropriate headings.
Number items.
Use vertical (rather than horizontal) format for checklists.
Right or left align check spaces.
Maintain uniformity in the order of check responses (e.g., always ‘‘yes’’ followed by
‘‘no’’).
• Use symbols, arrows, etc., to guide respondent around conditional items.
• Allow adequate space for completion of individual items (≥ 1/4 inch between
lines).
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X I . D ATA C O L L E C T I O N A N D P R O C E S S I N G
Housekeeping responsibilities
•
•
•
•
•
•
•
•
Clearance of data forms for trials by study sponsor
Supply clinics with forms and other essential documents
Equipment acquisition and distribution
Documenting changes to forms, handbooks, and manuals of operations
Filing and storage of completed forms
Disposal of completed forms
Microfilming and archiving
Inventorying, data entry, and editing
101. Time Window Specifications
299
101. Time window specifications
SLIDE
Time window specifications: Childhood Asthma Management
Program (CAMP)11
Baseline
Period: 4 to 12 weeks
Visits: 5 (S1, S2, S3, S4, Rz)
Maximum allowable time separation between S1 and Rz: 12 weeks
Minimum time separation between S1 and Rz: 4 weeks
Followup
Period: Minimum of 5 years
Zero point: Day of randomization
Visits: 2, 4, 8, and 12 months following randomization; thereafter every 4 months
(f2, f4, f8, f12, f16, f20, etc.)
Time window construction: Contiguous, centered on ideal date for designated
followup visit (calculation based on day of randomization); symmetrical on
ideal date
Minimal allowable separation between adjoining completed visits: 60 days
R E L AT E D E N T R I E S
Missed visit (page 229), Examination/clinic visit schedule (page 275), Data collection:
Schedules and procedures (page 281)
DEFINITIONS
ideal time window n - A time interval in a permissible time window within which an
activity or procedure is ideally performed, e.g., a 14-day interval centered at the ideal visit
time within a permissible time window of 56 days similarly centered. rt: permissible time
window
permissible time window n - The allowable time interval for performing a specified
activity or procedure; usually centered at the ideal visit time and usually contiguous to
adjacent time windows for visits. rt: ideal time window
time window n - The time interval for performing a specified activity or procedure. In
trials and followup studies, usually the window for performing a specified examination or
data collection, such as for a baseline or followup visit. rt: contiguous time windows, ideal
time window, permissible time window, time interval, time measure
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X I . D ATA C O L L E C T I O N A N D P R O C E S S I N G
N A R R AT I V E
The schedules for data collection are idealized. The actual schedules will vary around the
idealized schedule. An issue for designers is setting allowable limits for visits and data
collection. That limits are necessary is obvious. Personnel at clinics will need rules for
deciding when it is permissible to see a patient in relation to a specified study visit. People
responsible for performance monitoring or for analysis of study data will need rules for
counting visits as completed or missed by time.
The approach to dealing with the variation is to construct time windows about
idealized time points for visits. The normal method of construction is to center the
window on the idealized time of the visit and to make it of such width so as to be
contiguous to adjoining windows. If followup visits are to be at 4-week intervals following
randomization, then the allowable intervals are 4 weeks, centered at 4 weeks, 8 weeks, etc.
The window for the first visit opens at the start of week 3 and closes at the end of week 6.
The window for the second followup visit opens at the start of week 7 and closes at the
end of week 10, etc.
The advantage of contiguous time windows is that there are no ‘‘dark periods’’ in
the data collection schedule.
A difficulty with contiguous time windows is that there is no minimum for
separation of visits. Technically, with contiguous windows, it is possible to perform
followup visits for two time periods on adjoining days. The solution, if such possibilities
are to be precluded, is to impose minimum requirements for time separation of visits. The
minimum has the effect of causing a window to remain closed until a specified time has
passed following completion of the visit in the preceding time interval.
102. Data Entry Design
301
102. Data entry design
SLIDE
Data entry design: Chemoprevention for Barrett’s Esophagus
Trial (CBET)36
Paper forms
Distributed data system
Forms keyed at site of completion
Inventory based on keyed forms
Keying direct from data collection forms
Double, dependent, data entry
R E L AT E D E N T R I E S
Data processing procedures (page 285), Form design: Principles and procedures (page
295)
DEFINITIONS
centralized data entry n - A form of data entry in which data, generated and recorded
at different sites, are sent to a central facility for conversion to machine-readable form by
coding and keying for storage in a database. ant: distributed data entry rt: centralized data
analysis
data entry n - 1. The process of entering data, raw or edited, into a data system for
storage and subsequent use; typically done by keying responses to queries appearing on
a computer screen or by transcribing information contained on a paper data form to
produce a database; data keying. 2. The process of completing a data form. rt: centralized
data entry, distributed data entry, double data entry
dependent double data entry n - Double data entry with both entries performed by the
same person in a single session. rt: independent double data entry, quasi-independent
double data entry
direct data entry n - 1. on-line data entry 2. Data entry done from paper forms completed
during the data collection process without any intermediate coding or transcription. 3.
Data entry done at the generation site. ant: indirect data entry
distributed data entry n -[multicenter study] Data entry performed at the site of collection
or generation. ant: centralized data entry
double data entry n - A method of data entry in which data are keyed twice by the
same person (dependent double data entry) or different persons (independent double data
entry).
electronic data form n - A collection of data items arrayed on computer screens and
completed via those screens. rt: paper data form
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X I . D ATA C O L L E C T I O N A N D P R O C E S S I N G
independent double data entry n - Data entry in which data are keyed by two different
people working independently of one another; as distinct from dependent double data
entry. rt: quasi-independent double data entry
indirect data entry n - 1. Data entry performed using code sheets or other documents
produced from original study forms and documents. 2. Data entry not performed at the
data generation site. ant: direct data entry
keyless data acquisition n - Any method of converting data to computer readable form
without keying, e.g., as accomplished by optical scanning to convert entries on a data
form to digital form for storage and processing; aka keyless data entry but technically a
misnomer because the process does not involve keying data.
on-line data entry n - Data entry performed as data are generated by use of computerdriven video screens and displayed prompts.
paper data form n - A collection of data items arrayed on paper. rt: electronic data form
paperless data entry n - 1. on-line data entry 2. direct data entry
PC-based data entry n - 1. Data keying and storage using a desktop personal computer;
storage may be temporary until transmission and harvest at a central storage or processing
point. 2. Such data entry, storage, and transmission using a laptop computer. rt: web-based
data entry Usage note: The term, PC (personal computer), came into our lexicon with
the introduction of IBM desktop personal computers and was used to refer to IBM or
IBM-like desktop computers. However, increasingly, the term has come to refer to any
desktop computer designed for use by persons, one at a time, regardless of manufacturer.
quasi-independent double data entry n - Double data entry with both entries performed
by the same person but at different times, e.g., keyed on one day and rekeyed on another
day. rt: dependent double data entry, independent double data entry
web-based data entry n - Data entry done via the internet and web servers for data
storage. rt: PC-based data entry
N A R R AT I V E
Designers have a series of decisions to make regarding data entry. The first is whether to
design for keyless data acquisition. Keyless data acquisition requires data forms in which
recorded information is converted to computer readable format by some mechanical or
electronic process (e.g., as with mark-sense forms or with use of pattern recognition
software).
The likelihood of being able to develop all forms in a trial to be keyless is slim to
none. It may be possible for a few forms but rarely for the entire set. The keyless form
of data acquisition may be viable in relation to forms completed by study subjects and
may be required with certain proprietary forms that have to be returned to the vendor for
scoring.
Questions for designers for forms to be keyed include the following:
Should keying be centralized or distributed?
Should forms be paper or electronic?
When should the keying be done?
102. Data Entry Design
303
Who should do the keying?
How should keyings be checked?
Centralized data entry is where paper forms are forwarded to a site remote from
the point of generation for keying and processing, usually the coordinating center in
multicenter trials. The forms are keyed at the site of generation with distributed data
entry. The keyed data are then transmitted to a central site, usually the coordinating
center in multicenter trials, for assimilation into a database for processing and analysis.
As a rule, the effort and dollar outlay for distributed data systems is greater than
for centralized data entry, especially if distribution requires purchase of hardware and
software for the distributed system. In addition, distributed data systems are also more
costly to maintain than centralized systems.
But the disadvantages have to be balanced against advantages. The primary
advantages are in having data entry done at the site of generation by people most familiar
with data collection and in the prospect of more rapid flow of data from generation to
harvest for analysis than typically possible with centralized data entry.
The overhead with distributed systems has to do with the costs of equipment
and software needed for distribution. The costs and effort will increase with the number
of sites that have to be equipped and maintained for distribution. Generally, designers
should tilt in favor of centralized systems in trials covering short time spans, trials on
‘‘fast-track forced marches,’’ and trials involving a large number of data generation sites
with low data yield per site, as well as in settings where clinics are not likely to have the
equipment needed for distribution.
Distributed data systems should not be considered if there is not sufficient lead
time to develop and install the system prior to the start of patient enrollment. Personnel
responsible for creating the system cannot develop the system until the protocol has been
finalized and data collection procedures and requirements have been set. The process of
development should proceed lock-step with the forms.
Designers should steer away from distribution if the lock-step nature of
development is not assured. Failing that, designers may succeed only in coming up
with an expensive way of ‘‘stockpiling’’ forms while they languish in wait of distribution
of the system.
Designers are advised as well to steer clear of starting centralized with the intent of
converting to distributed when time permits. If there is a plan to distribute, it should be
implemented up front. Efforts to convert later are more costly than if the piper is paid at
the outset.
The question of who keys is largely answered by the decision whether to distribute
or centralize. The expectation is, with a distributed system, the keying will be done by
clinic personnel and that the keying will be done in a timely fashion following completion
of data forms. The purpose of distribution is for timely entry and flow to the data
processing site. That advantage is lost the further data entry is from real-time.
The option as to whether to use paper or electronic data forms for data collection
exists only if the data entry is distributed. There are urges to go paperless—because of the
‘‘nuisance’’ of paper and because of desires to be ‘‘green.’’ The urges in the case of trials
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should be kept in check. Even if the forms are electronic, there will be need for paper.
Paper forms are, for certain, more robust and user friendly than electronic forms.
Direct data flow
• Avoids need for entry by direct link to generation instrument and flow to data
processing site
• Opportunities limited in trials; may be possible with laboratory determinations
done in central laboratory and for digital data generated from scans or tracings
Keyless data acquisition
• Opportunities limited in trials
• Typically possible only with a few forms
• May be more cost efficient to key even if form is designed to be keyless if volume of
data generated via this mode is low or if error rate via keyless acquisition is nontrivial
Electronic data forms
• Advantages
❑ Eliminates lag time between generation and entry
❑ May eliminate need for filing space (not if facsimile of form is printed and filed
as hard copy; often necessary and usually prudent)
❑ Helps to promote good form design by logic needed for screen design and ‘‘skips’’
• Disadvantages
❑ Front loaded effort needed to develop and distribute the forms
❑ PC/laptop ‘‘dependent’’; potential of not being able to complete a form because
of malfunction or ‘‘crashes’’
❑ Expense of equipment and effort for maintenance and updates
Paper data forms
• Advantages
❑ User-friendly
❑ Form ready for use without ‘‘booting’’ a system
❑ Not dependent on being next to a computer for completion
• Disadvantages
❑ Filing space required for paper forms
❑ Need for keying after competition
❑ Potential for lag from completion to keying
Centralized data entry
• Pros
❑ Relative ease of implementation and management
❑ Relative ease in dealing with changes in data collection forms
102. Data Entry Design
305
Allows start of data collection absent a functioning system for entry
❑ Less cost than distributed system
❑ Flexibility in when forms are keyed
• Cons
❑ ‘‘Old fashioned’’
❑ Data entry in hands of people not knowledgeable as to how data are collected
❑ Data entry may be far removed in time from collection, thus reducing value of
data editing as a means of quality control and assurance
❑ Potential for backlog of unentered forms
• Recommended uses: In trials where volume of data generated is low; in multicenter
trials involving a large number of data generation sites and low data volume per
site; in short-term, data simple trials; in multinational trials where standardization
of hardware and software is problematic
❑
Distributed data entry
• Pros
❑ Forces a disciplined approach to form development
❑ Data entry done by personnel familiar with data collection procedures and
requirements
❑ Near real-time data entry allowing for better quality surveillance
• Cons
❑ ‘‘Forced’’ march (data collection may not start until system is distributed)
❑ Cost of hardware and software needed for distribution and for updating over the
life of the trial
❑ Effort involved in distributing, installing, maintaining, and updating data entry
software system
❑ Time and effort required to make changes to the data system during the trial
• Recommended uses: In long-term trials involving large data volumes; in multicenter
trials where volume per site is high
R E C O M M E N D E D D ATA E N T R Y P O L I C I E S A N D P R O C E D U R E S
• In the case of paper forms, design for entry directly from forms without intermediate
transcription.
• Design for double entry of key data items.
• Design to allow forms to be checked for deficiencies on completion before patient
exits the clinic.
• Design with the goal of minimizing the number of transcriptions required for data
on their way to data entry.
• Design to avoid need for calculations by persons completing forms or keying
them (design data collection forms to include items of information needed for
calculations; let computers make the calculations).
• Design to allow data to take the shortest and most direct route to the entry site.
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• Design the entry system to require data to be keyed as recorded on forms (i.e., no
editing during data entry).
• Design to allow for conversion of data to computer readable form as soon after
entry as feasible.
• Design to allow for all items to be keyed when a form is keyed, including comments
and information in ‘‘Other specify’’ spaces.
103. Data Sharing: Internal
307
103. Data sharing: internal
SLIDE
ADAPT internal data sharing policy1
• Results blackout lifted by presentation of treatment results by coordinating
center at face-to-face meeting of investigators after early stop because of lack of
efficacy
• Dataset (without deidentification) and corresponding data dictionary supplied
to investigators after publication of findings leading to stop
• Coordinating center IRB informed of distribution
• Receiving investigators required to:
❑ Acknowledge receipt
❑ Agree to not identify persons
❑ Agree to limit uses to those consistent with ADAPT policy on data uses
❑ Agree to not copy data for distribution to others outside the investigator
group
R E L AT E D E N T R I E S
Data sharing: External (page 311), Policy on access to study data and results (page 449)
DEFINITIONS
data dictionary n - A print or electronic database detailing the location, content, and
meaning of variables in an electronic dataset by linking locations to items on data
collection forms.
deidentified data n - Data stripped of personal identifiers; data contained in a limited
dataset.25 Deidentification, as spelled out in HIPAA.24
deidentify, deidentification, deidentified, deidentifies v - [study subjects] To remove
personal identifiers from a record or dataset so as to preclude linkage to a person.
external data sharing n - Data sharing outside the group responsible for collection and
generation of the data. ant: internal data sharing
identified data n−1. Data identified to persons by name, Id number, or other personal
identifiers. (Note: Data are considered to be identifiable even if the dataset does not
contain name, address, and other personal identifiers if data can be linked to a person by
means of relating Id number to name.) 2. Data not deidentified. Usage note: Subject to
confusion because use can be simply to indicate data are not deidentified in the HIPAA24
sense of deidentification. ant: deidentified data
internal data sharing n - Sharing of data within the investigator group responsible for
having generated them. ant: external data sharing
linkable data n - Data capable of being linked to persons by name. Usage note: The need
to link to persons by name is essential for record auditing and for ensuring the safety and
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well-being of persons studied in trials. Usually the ability to link to persons by name is limited to where persons are seen. The ability of coordinating centers in multicenter trials to
link by name may not exist. It does not exist when names and other personal identifiers are
not harvested into data files maintained at the coordinating center. Most coordinating centers do not harvest such data or, if harvested, those data are isolated from the study database.
results blackout n - [trials] 1. A state of conduct in which investigators are shielded from
interim treatment results. 2. Any of various constructs imposed to keep treatment results
from being revealed or made known to the public until presented or published by study
investigators.
primacy , right of n - [study investigators] Right to be the first to present or publish one’s
own data, to do so as seen fit and in the absence of external restraint or control, and to be
able to do so before being required or made to provide data to the study sponsor or to
agencies, persons, or parties external to the study for publication.
N A R R AT I V E
An issue in trials has to do with when and how study data are made available to study
investigators. Typically, study data reside in a data center/coordinating center with access
restricted to persons in the center. As a rule, the only results people in the study outside
the data center/coordinating center see during the trial are summaries of baseline data
and data on performance. Investigators doing approved ancillary studies may be supplied
with baseline data exclusive of treatment assignment. Baseline and followup data for the
control-assigned group may be supplied in relation to observational studies focused on
the control-assigned group, e.g., as in the Coronary Drug Project.18,75
As a rule, trials are conducted under the blackout mode of operation—a mode
where treatment results are not seen by clinic personal during the trial. The purpose is
to reduce the risk of treatment-related feedback biases by keeping clinic personnel in the
dark regarding the nature or trend of interim treatment results (see Results blackout, page
127, for rationale). Under that mode, the only people who have access to treatment results
are people in the data center and members of the treatment effects monitoring committee.
Assuming a policy to provide investigators with copies of the finished dataset
when the trial is finished, the issue then for the data center/coordinating center is when
to do that. Obviously, if the trial operates under a blackout, the distribution cannot be
consummated until after the blackout is lifted. Operationally, in trials where the policy
is to publish the primary results regardless of nature or direction, the distribution should
not be done until after the primary results are published and should not be done until
the dataset is complete and finished (i.e., all study forms having been keyed and harvested
and data have been fully edited and cleaned).
A central issue in internal sharing is whether the data center/coordinating
center supplies identified data, i.e., data identified to the same degree as in the data
center/coordinating center, i.e., without deidentification. Assuming that consents contain
statements indicating investigators will have access to study data, there is no reason for
HIPAA-type deidentification.
Investigators receiving datasets should:
• Acknowledge receipt of the dataset
• Agree to not identify persons by name or by other means
103. Data Sharing: Internal
309
• Agree to limit uses to those allowed by study policy
• Agree to not supply the dataset to persons outside the investigator group without
the express approval of study leaders
• Vet users of the dataset
The issue of whether the data center/coordinating center needs approval from its
IRB to make the distribution is moot if the original approvals cover access. It does not if the
consents indicate that investigators have access to study data. The data center/coordinating
center, in that case, need merely inform its IRB of the distribution.
104. Data Sharing: External
311
104. Data sharing: external
SLIDE
ADAPT external data sharing policy1
• Availability of data announced on public portion of ADAPT website
(www.jhucct.com/adapt/documents.htm)
• Statement of availability of data included in ADAPT publications subsequent
to the web posting
• Study officers to review requests for data or analyses and determine disposition
of request
• Study chair to communicate decision to requestor; datasets, if supplied, not
deidentified but recipient, as conditions for receipt, must:
❑ Present evidence of IRB approval to receive data
❑ Agree to refrain from attempting to identify persons by name or place of
study
❑ Limit use to that outlined in the request
❑ Provide ADAPT investigators with opportunity to review use prior to
publication
• Study officers to determine if recipient to pay charges for preparation of dataset
or requested analyses
R E L AT E D E N T R I E S
Data sharing: Internal (page 307), Policy on access to study data and results (page 449)
DEFINITIONS
data dictionary n - A print or electronic database detailing the location, content, and
meaning of variables in an electronic dataset by linking locations to items on data
collection forms.
data sharing n - 1. An arrangement in which two or more parties agree to share data for
some common end. 2. An arrangement in which data generated from a research project
are made available to others outside the research group under specified conditions, e.g., as
specified in data use agreements.
data use agreement n - An agreement between the supplier and recipient of a dataset that
specifies limits and conditions of use; typically such agreements restrict recipients from
supplying the dataset to others not covered in the agreement and, in regard to deidentified
personal health information, assurance that recipient will not reidentify persons. rt: limited
dataset
deidentified data n - Data stripped of personal identifiers; data contained in a limited
dataset.25 Deidentification, as spelled out in HIPAA,24 involves deleting for persons
studied, their relatives, household members, and employers:
Names
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Any geocodes that identify an individual household such as street address or Post
Office Box Number
Telephone numbers
Fax numbers
Electronic mail addresses
Social Security Numbers
Medical record numbers
Health plan beneficiary identifiers
Account numbers
Certificate/license numbers
Vehicle identifiers and serial numbers, including license plate numbers
Medical device identifiers and serial numbers
Web universal resource locators (URL)
Internet Protocol (IP) address numbers
Biometric identifiers, including finger and voice prints
Full face photographic images
Datasets must also be devoid of:
Geographic subdivision designations smaller than a state (i.e., county, city, town,
precinct) five- or nine-digit ZIP codes (first three digits allowable in most cases)
All elements of dates (except year) directly related to an individual, including dates
of birth or death, dates of health care services or health care claims (deidentified
datasets cannot contain birth dates; file may contain the individual’s age expressed
in years, months, days, or hours, as appropriate, except for individuals aged 90 or
above; such persons to be identified simply as being 90 or above)
Any other unique identifying number, characteristic, or code that could be used to
identify the individual (supplier of data may affix codes to allow user to associate
data with persons, provided codes cannot be used to reidentify persons)
external data sharing n - Data sharing outside the group responsible for collection and
generation of the data. ant: internal data sharing
identified data n - 1. Data identified to persons by name, Id number, or other identifiers.
(Note: Data are considered to be identifiable even if a dataset does not contain name,
address, and other personal identifiers if data can be linked to persons by means of relating
Id number or other identifiers to name.) 2. Data not deidentified. Usage note: Subject to
confusion because one use of the term is simply to indicate data are not deidentified.
internal data sharing n - Sharing of data within the investigator group responsible for
having generated them. ant: external data sharing
limited use dataset n - A dataset provided with use limitations; in regard to datasets
containing personal health information: deidentified data subject to limitations of use as
specified in data use agreements.
mandated data sharing n - Data sharing external to the investigator group mandated by
the sponsoring agency as a condition of funding. rt: data sharing
public use dataset n - 1. A dataset residing in a public repository. 2. A dataset residing at
a Federal, State, County, or City agency that is available for use by the general public.
104. Data Sharing: External
313
N A R R AT I V E
Data sharing is not new. It has gone on for millennia the old-fashioned way—by request.
What is new is mandated data sharing. Mandated data sharing has come about because of
meta-analysts wanting access to data from like trials in the hope of drawing conclusions
about the merits of treatments.
Investigators requesting funding from the NIH in amounts in excess of $500,000
per year (direct costs) since 1 October 2003 are expected to include plans for data
sharing in their applications or explanations as to why data sharing is not possible.
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html)
The NIH policy on data sharing (NIH Data Sharing Policy and Implementation
Guidance; 5 March 2003): provides wide latitude on how data can be shared
The method for sharing that an investigator selects is likely to depend on several factors, including
the sensitivity of the data, the size and complexity of the dataset, and the volume of requests
anticipated. Investigators sharing under their own auspices may simply mail a CD with the data to
the requestor, or post the data on their institutional or personal Website. Although not a condition
for data access, some investigators sharing under their own auspices may form collaborations with
other investigators seeking their data in order to pursue research of mutual interest. Others may
simply share the data by transferring them to a data archive facility to distribute more widely to
interested users, to maintain associated documentation, and to meet reporting requirements. Data
archives can be particularly attractive for investigators concerned about a large volume of requests,
vetting frivolous or inappropriate requests, or providing technical assistance for users seeking help
with analyses.
The basic issues that have to be addressed, assuming an investigatorship committed
to external data sharing, are when to allow such data sharing and how to affect such
sharing.
Typically, the issue of sharing outside the investigatorship does not arise until
the trial is finished. That means that external data sharing usually does not happen until
after data collection is finished, after data have been harvested, and after data editing and
cleaning, and usually not until investigators have written up and published the primary
results.
In regard to how, the first issue is whether to externally data share at all. Obviously,
if undertaken, the sharing should not preempt investigator rights of primacy. Also, the
sharing should not be done if the efforts and costs involved are not covered by existing
funding or if the effort involving in data sharing syphon away effort and money needed
for more essential functions.
Assuming an investigatorship committed to external data sharing, then the options
are for investigators to:
1. Assume responsibility for receiving and disposing of requests for data or analyses.
2. Prepare a deidentified dataset for repose with a custodian responsible for processing
requests for data.
If investigators commit to either option the expectation is that they will make
the fact of willingness to data share known in study publications and announced on
non-password protected study websites.
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X I . D ATA C O L L E C T I O N A N D P R O C E S S I N G
A key issue in external data sharing is whether to turn data over to a custodian to
receive and dispose of data requests. The effort in preparing deidentified datasets can be
sizable (as discussed in postings on trialsmeinertsway.com).
The primary advantage of option 1 is that it does not involve creation and deposit
of a deidentified dataset. Under option 1, investigators vet requests and, hence, can refuse
requests inconsistent with the dictates of the trial or with consents of study participants.
Another advantage is that investigators know who uses their data and how they are used.
They will not know that with data deposited with a custodian unless the custodian informs
them of uses.
A disadvantage of option 1 is that investigators have to deal with and dispose of
requests. They are free of that responsibility with option 2.
The vetting process, whether done by investigators themselves or by a custodian,
should include the following:
• Approvals of the coordinating center’s IRB to share data external to the
investigatorship
• Evidence that requestors have approvals of their IRBs to receive data
• Signed statements from requestors agreeing to not identify persons by name or place
of study and to not supply datasets to others not covered in user agreements
Study Centers
105. Center Types
317
105. Center types
SLIDE
Center types: SOCA Ganciclovir Cidofovir CMV Retinitis Trial
(GCCRT)81 (as of June 1999)
Clinics
Resource centers
Coordinating Center
Fundus Photography Reading Center
Project Office
Office of Chair
Support centers
20
4
3
R E L AT E D E N T R Y
Centers (page 323)
DEFINITIONS
center n − 1. study center (defn 4) 2. A place, such as a study clinic, where study
candidates and study enrollees are seen for evaluation and treatment in a trial; study
center (defn 1). Usage note: In multicenter trials, often used in the sense of defn 2 to the
exclusion of associated resource centers. Avoid such usage because of lack of precision and
insensitivities to those in the resource centers of such trials. Reserve the term center for
uses in the collective sense of that term; use study clinic or some other appropriate term,
such as field site or data collection site, in references to the subset of centers responsible
for data collection.
clinic n - [F clinique,¯ fr Gk klinike, medical practice and pertaining to sick bed, fr fem
of klinikos of a bed, fr kline¯ bed fr klinein] 1. A place where medical care is provided
to ambulatory nonresident patients. 2. The instruction of medical students through
observation of and participation in the examination and care of patients. 3. An assembly
of students for such instruction. 4. A place of instruction for medical students. 5. study
clinic
data collection site n - 1. A site responsible for data collection, e.g., a clinic in a clinical
trial; a site that receives forms in a followup study done by mail. 2. data generation site
(defn 1) Usage note: Distinguish between data collection and data generation sites. A data
collection site is, by definition, a data generation site, but a data generation site need not
be a data collection site, e.g., a reading center responsible for reading fundus photographs
taken at a data collection site.
data generation site n - 1. A site that generates data from existing records, e.g., a reading
center. 2. data collection site Usage note: See note for data collection site.
parent center n - 1. A study center that gives rise to or nurtures other centers. 2. A study
center that has administrative or operational primacy over other centers. 3. A study center
having an affiliate, associate, field, or satellite center.
318
XII. STUDY CENTERS
resource center n - Any center providing support and expertise in a differentiated
structure; in multicenter trials usually any of the following: data center, data coordinating
center, treatment coordinating center, coordinating center, central laboratory, reading
center, quality control center, project office, and procurement and distribution center.
satellite center n - A center, subordinate to a parent center, organized to perform a
designated set of functions at the behest of or as an agent of that parent center; affiliate
center, associate center.
study center n - [trials] 1. data collection site; study clinic 2. Data collection or data
generation site. 3. The center (defn 3 or 4) from which activities are directed; coordinating
center; project office. 4. An operational unit in the structure of a study, especially a
multicenter structure, separate and distinct from other operational units in the structure,
responsible for performing specified functions in one or more stages of the study; e.g.,
a clinical center or resource center. Usage note: Avoid usage in the sense of defn 1 in
multicenter trials for reasons stated in the usage note for center. Use an appropriately
modified term when the reference is to a specific subset of centers. For example, use study
clinic when referring to the subset of centers responsible for enrolling and treating study
patients.
N A R R AT I V E
A multicenter trial is characterized by its centers. It is obvious, therefore, if for no reason
other than for characterization of the trial and for proper attribution and crediting (page
435), that planners and organizers have to agree on when a site assumes the status of
center in a trial and when a site, having that status, is no longer counted as a center in the
trial. The counting is not as easy as it might seem because it depends on the definition of
center. The definition recommended is that represented by defn 4 for study center.
Centers
affiliate center
analysis center
associate center
biostatistical center
central laboratory (CL)
chair’s office (CO)
clinical center
clinical coordinating center (CCC)
coordinating center (CC)
data center
data coordinating center (DCC)
daughter center
distribution center
field center
field site
key center
105. Center Types
lead center
parent center
primary care center
procurement and distribution center
procurement center
project office (PO)
quality control center
reading center (RC)
referral medical care center
resource center
satellite center
secondary care center
sibling center
sister center
statistical center
study center
study center director
support center
tertiary care center
treatment coordinating center (TCC)
Centers by type of function
Data collection
affiliate clinic
associate clinic
clinical center
daughter clinic
field clinic
lead clinic
parent clinic
satellite clinic
sibling clinic
sister clinic
study clinic
Data generation
central laboratory (CL)
local laboratory
reading center (RC)
319
320
XII. STUDY CENTERS
Data processing and analysis
analysis center
biostatistical center
coordinating center (CC)
data center
data coordinating center (DCC)
statistical center
Leadership/direction
chair’s office (CO)
clinical coordinating center (CCC)
coordinating center (CC)
data coordinating center (DCC)
lead center
project office (PO)
treatment coordinating center (TCC)
Monitoring/surveillance
chair’s office (CO)
clinical coordinating center (CCC)
coordinating center (CC)
data coordinating center (DCC)
project office (PO)
treatment coordinating center (TCC)
quality control center
Other
archive
bank
distribution center
procurement and distribution center
procurement center
repository
Names indicative of standing or order
affiliate center
associate center
daughter center
key center
lead center
105. Center Types
parent center
primary care center
referral medical care center
satellite center
secondary care center
sibling center
sister center
support center
tertiary care center
321
106. Centers
323
106. Centers
SLIDE
Centers: Childhood Asthma Management Program (CAMP)11
Study clinics
Albuquerque
Baltimore
Boston
Denver
San Diego
Seattle
St Louis
Toronto
Bennie McWilliams
N. Franklin Adkinson
Scott Weiss
Stanley Szefler
Robert Zeiger
Gail Shapiro
Robert Strunk
Henry Levison
University of New Mexico
Johns Hopkins University
Brigham & Women’s Hospital
National Jewish Center
University of Califòrnia, San Diego
ASTHMA, Inc
Washington University
Hospital for Sick Children
Coordinating Center
Baltimore
James Tonascia
Johns Hopkins University
Chairman’s Office
Denver
Reuben Cherniack
National Jewish Center
Project Office
Bethesda
NHLBI
Virginia Taggart
R E L AT E D E N T R Y
Center types (page 317)
N A R R AT I V E
The organizing unit of multicenter trials is center. More often than not, the key governing
body of the trial—steering committee—is composed along center lines (e.g., by according
one or two votes per center, usually vested in the director or the director and deputy
director). Hence, the definition used to define ‘‘center’’ is of fundamental importance in
organizing.
Basically a center is a stand-alone, autonomous unit in the structure of a trial.
To be stand-alone, the unit must be staffed and equipped to enable it to perform the
functions assumed or assigned to it. Units reliant on other entities to perform essential
functions by subcontracting or other means are not stand-alone in the sense herein.
To be autonomous, the unit must be housed in an administrative entity that is
separate and distinct from all other administrative entities in the trial. It must have a
budget that is separate and distinct from all other units in the trial and must control its
budget. Its director must be independent of all other center directors. A unit housed in
departments housing another unit does not meet the test for autonomy if the director of
the two units is the same or if the director of one unit reports to the director of the other
unit. Nor does it meet the test if some other director has sign-off authority on budget and
spending.
The tests as to whether a unit performs an essential function is whether, in the
absence or cessation of the function, the trial would be adversely affected. A unit performs
324
XII. STUDY CENTERS
an essential function if absence or deletion of the unit would slow progress in the trial
in pursuit of goals relevant to objectives of the trial, reduce the amount of information
generated bearing on objectives, reduce the ability to receive, process, analyze, or report
results from the trial, or reduce or jeopardize the integrity or credibility of the trial.
Units not meeting the test for center should not be counted as centers in the
organization and operation of the trial.
It is common, in the course of trials, for clinics to establish satellites to facilitate
recruitment or for other reasons. A satellite clinic is a clinic created by a parent clinic and
subservient to it. Its head, if different from the head of the parent, reports to the head
of the parent clinic and its budget is subsumed within the budget of the parent clinic.
Satellites are represented through the parent clinic. Satellites that evolve to satisfy tests for
stand-alone, autonomous centers should graduate to center status.
Being clear on what defines centers has organizational and operational importance
in the operation of the trial and in listings of credits in publications (see Credits, page 435).
107. Center Requirements
325
107. Center requirements
SLIDE
Center requirements for clinics in National Emphysema
Treatment Trial (NETT)62
Randomize and follow a minimum of 75 patients and follow for up to 5 years
Board certified adult pulmonary specialist
Board certified thoracic surgeon with experience in LVRS; must have performed
at least 50 bilateral type LVR surgeries or at least 30 of each of two types of
LVR surgeries
Clinical investigators must have followed at least 10% of patients for a minimum
of 12 months; at least 30% for a minimum of 6 months; at least 40% for a
minimum of 3 months; average mortality experience not to be greater than
9%; average length of hospitalization not to be in excess of 18 days
R E L AT E D E N T R I E S
Investigator requirements (page 331), Clinic staffing requirements (page 333)
DEFINITION
center n − 1. study center 2. A place, such as a study clinic, where study candidates and
study enrollees are seen for evaluation and treatment in a trial; study center (defn 1). Usage
note: In multicenter trials, often used in the sense of defn 2 to the exclusion of associated
resource centers. Avoid such usage because of lack of precision and insensitivities to those
in the resource centers of such trials. Reserve the term ‘‘center’’ for uses in the collective
sense of that term; use study clinic or some other appropriate term, such as field site or
data collection site, in references to the subset of centers responsible for data collection.
N A R R AT I V E
Planners need to specify qualifications for centers, e.g., as specified above for study clinics
in NETT, as contained in the RFP issued by the NHLBI.
The corresponding requirements for the coordinating center were as follows:
• Ensuring that the clinical centers adhere to patient entry and randomization criteria
• Monitoring
• Ensuring that clinical centers follow the pulmonary rehabilitation, surgical, and
medical protocols
• Assuring that the patient data are submitted on time and correctly
• Maintaining quality control of the study data; including site visiting
It is good practice to list essential requirements for clinics. The list serves to remind
study clinics of requirements and is useful if and when additional clinics are selected
during the course of the trial.
326
XII. STUDY CENTERS
General requirements for clinics, coordinating centers, reading centers, and central
laboratories are listed below.
Study clinic
•
•
•
•
•
•
•
•
•
•
•
Evidence of access to study population
Evidence of ability to recruit and retain study patients
Prior experience in trials
Access to staff and expertise needed for proper care of patients and conduct of
required study procedures
Ownership or access to equipment necessary for doing the trial
Access to facilities and expertise needed to perform study procedures
Adequate space
Suitable location
Hours of operation appropriate to needs of study patients
Facilities adequate to meet the needs of the trial; operating rooms; research
pharmacy; etc.
Other requirements depending on trials
❑ Research pharmacy
❑ Clinical research unit
❑ Local IRB
❑ Local laboratory facilities
Coordinating center
•
•
•
•
•
•
•
•
•
•
•
Prior experience in coordinating trials
Evidence of staff capable of collaboration
Evidence of ability to receive and process data in a timely and efficient manner
Professional staff
Staff having expertise in data management, analysis, and statistics
Housed in an institution providing a suitable environment for recruiting, training,
and retaining programmers, data processors, and analysts
Housed and headed independent of other centers in the trial
Adequate space (preferably contiguous space adequate for housing staff of center)
Hours of operation appropriate for servicing needs of study (e.g., as in issuing
treatment assignments to clinics spanning several time zones)
Ownership or access to computing facilities necessary for database maintenance and
processing
Other requirements depending on trials
❑ Ability to contract (e.g., with clinics in order to fund them)
❑ IRB willing to serve as parent IRB (in multicenter trials)
❑ Access to senior statistical expertise
107. Center Requirements
327
Reading center
•
•
•
•
•
•
•
•
Prior reading experience
Evidence of expertise in area of reading
Staff experienced in reading in a timely and efficient manner
Housed in an institution providing a suitable environment for recruiting, training,
and retaining readers
Housed and headed independent of other centers in the trial
Adequate space (preferably contiguous space adequate for housing staff of center)
Hours of operation appropriate for servicing needs of study (especially in the case
of real-time readings on demand from clinics)
Ownership or access to equipment necessary for readings
Central laboratory
•
•
•
•
•
•
•
•
Prior experience with required laboratory test
Necessary laboratory expertise
Staff experienced in real-time processing of laboratory specimens
Housed in an institution providing a suitable environment for recruiting, training,
and retaining necessary staff
Housed and headed independent of other centers in the trial
Adequate space
Hours of operation appropriate for servicing needs of study
Ownership or access to equipment necessary for readings
Investigators/Study Staff
108. Investigator Requirements
331
108. Investigator requirements
SLIDE
Investigator requirements: National Emphysema Treatment
Trial (NETT)62
Board certified adult pulmonary specialist
Board certified thoracic surgeon with experience in LVRS; must have performed at
least 50 bilateral-type LVR surgeries or at least 30 of each of two types of LVR
surgeries
Director of coordinating center with demonstrated leadership experience in large
data management systems and in protocol development for large multicenter
studies
R E L AT E D E N T R I E S
Center requirements (page 325), Clinic staffing requirements (page 333)
DEFINITIONS
center director n - 1. One who heads a center. 2. study center director
co- prefix - [ME, fr L, fr com-; akin to OE ge-, perfective and collective prefix, Gk koinos
common] 1. In or of the same degree; with, together, joint, or jointly, as in covariance. 2.
One that is associated in action with another, co-investigator; one with such an association
but having a lesser share of responsibility or authority such as a deputy or alternate.
Usage note: Avoid when contradictory or incompatible with the term to which affixed,
e.g., co-principal investigators or co-primary investigators. Principal and primary connote
being first; it is not possible for two persons or things to both be first.
co-investigator n - Broadly, one who works with another in an investigation. In research,
usually a peer but administratively subordinate to the principal investigator. rt: deputy
director
deputy director n - A person second-in-command to the director and empowered to act
in the absence of the director. rt: director
investigator n - 1. Broadly, one who investigates. In the case of research, generally one
who has a key role in conducting the research or some aspect of the research. 2. study
investigator 3. clinical investigator Usage note: Use appropriate modifiers when referring
to a particular subset of investigators, e.g., clinical investigator when referring to the subset
of people responsible for administration of treatment in a clinical trial. Avoid as a generic
designation when used to the exclusion of others having investigator status, as in use as a
synonym for clinical investigator in settings also involving nonclinical investigators. See
principal investigator and center for added comments.
principal investigator (PI) n - 1. The person having responsibility for conduct of the
research proposed in an NIH grant application; such a person in any funding application
submitted to the NIH, whether for grant or contract funding; such a person named on
any funding proposal, regardless of funding source. 2. The person in charge of a research
project; the lead scientist on a research project; chief investigator. 3. The person having
332
X I I I . I N V E S T I G AT O R S / S T U D Y S TA F F
fiscal control of NIH grant funds provided to an institution for conduct of a particular
research project; such a person regardless of NIH funding mechanism; such a person
named on any funding proposal, regardless of funding source. 4. The head of a center in a
multicenter study. 5. The chair of a multicenter study. 6. The head of a clinical center in
a multicenter trial. 7. One among two or more designated as principal investigator under
NIH guidelines for multiple principal investigators. Usage note: ‘‘Principal’’ means first,
highest, or foremost in rank, importance, or degree; chief. Hence, uses where reference
is to multiple persons, e.g., as in ‘‘the principal investigators in the XYZ trial,’’ represent
oxymorons of sorts. Confusion arises when the term is used to refer to multiple individuals
because of the implication that an activity can be headed or directed by multiple chiefs.
Avoid uses in the sense of defn 6 because of subtle connotations that persons heading
resource centers are not as ‘‘principal’’ as their clinical counterparts.
study center director n - 1. The scientific head of a study center. 2. The administrative
and scientific head of such a center. 3. The administrative head of such a center.
N A R R AT I V E
Broadly, investigator, as used here, is one who has responsibility for directing or carrying
out an investigation. In the case of trials involving investigational new drugs, the term
includes any physician who assumes full responsibility for the treatment and evaluation of
patients on research protocols, as well as the integrity of the research data (Investigators
Handbook of the FDA; Part D: The organization of a clinical trial; FDA Form 1572:
Statement of investigator). In the context of multicenter trials, the term includes directors
and deputy directors of centers (clinical as well as resource centers) and include persons
broadly referred to as co-investigators.
The usual requirements are:
•
•
•
•
•
•
IRB training
Prior experience in trials
Training in a specified area
Evidence of competency in the area of specialization
Absence of disqualifying conflicts of interest
Absence of history of debarment
109. Clinic Staf f ing Requirements
333
109. Clinic staffing requirements
SLIDE
Clinic staffing requirements: Studies of Ocular Complications
of AIDS (SOCA) trials80
Board certified ophthalmologist
Board certified infectious disease physician
Clinic coordinator
Fundus photographer
Person trained and certified for measurement of visual acuity
Pharmacist (for drug trials done under IND)
R E L AT E D E N T R I E S
Center requirements (page 325), Investigator requirements (page 331)
DEFINITIONS
clinic coordinator n - 1. study clinic coordinator 2. data coordinator
clinical research associate n - A person, in the employ of a drug firm, contract research
organization, or study center having responsibility for monitoring data collection in trials.
data coordinator n - 1. An individual in the data center, data coordinating center, or
coordinating center responsible for coordinating the receipt of data from study centers
and for communicating with study centers regarding data flow. 2. study clinic coordinator
study clinic coordinator n - 1. An individual in a study clinic responsible for coordinating
the data collection activities for that clinic and for expediting the flow of data and related
records from the clinic to the data center, data coordinating center, or coordinating
center. 2. An individual in the data center, data coordinating center, or coordinating
center responsible for coordinating the receipt of data from study clinics and for
communicating with clinics regarding data flow; data coordinator.
study physician n - 1. A physician associated with a study. 2. A physician in a study
clinic, responsible for the diagnosis, treatment, or evaluation of study candidates or study
patients according to plans and procedures set forth in the study protocol, study manual,
or study handbook. 3. treating physician
treating physician n - 1. A physician responsible for administering and managing
treatment. 2. A study physician responsible for administering study treatments and for
managing treatment of study patients.
N A R R AT I V E
The list of personnel should include personnel needed to screen, enroll, treat, and follow
study patients. A key person, in addition to study physician, is study clinic coordinator. A
good coordinator is invaluable. Typical duties include those having to do with scheduling
of patients for visits, directing the activities of visits, reviewing completed data forms, and
responding to edit quires from the data center.
110. Research Group/Investigators
335
110. Research group/investigators
SLIDE
Research group: Studies of Ocular Complications of AIDS
(SOCA)80
All SOCA study personnel; SOCA-supported or SOCA-certified personnel
associated with functioning SOCA clinics or resource centers as well as members
of any SOCA committee, except voting members of the SOCA treatment effects
monitoring committee
R E L AT E D E N T R I E S
Centers (page 323), Credits (page 435)
DEFINITION
research group n - The entire set of personnel involved in the conduct of a research
project; in multicenter trials includes center directors and support staff, representatives
from the sponsoring agency, and study committee members. syn: investigative team,
investigative group, study group (not a recommended syn, see usage note for study group)
N A R R AT I V E
An investigator, narrowly defined, is one who is able to make‘‘substantial contributions
to conception and design’’ or to ‘‘analysis and interpretation of data’’41 generated from
the research (see page 431; Authorship). Used narrowly, the label is reserved for a
select few—usually senior people and persons in key leadership positions. The rest are
‘‘staff.’’
A more egalitarian approach is advised in trials, especially in large-scale multicenter
trials with casts of 100s. People should be identified by position, function, or duty rather
than by a binary label of ‘‘investigator’’ or ‘‘staff.’’
Certainly, ‘‘conception and design’’ and ‘‘analysis and interpretation’’ are
important investigative activities, but so are the activities of ‘‘execution.’’ Indeed, there is
no ‘‘analysis and interpretation’’ without execution and of the various classes of activities
in trials, ‘‘execution’’ is the most energy and time consuming. Hence, definitions failing
to take account of ‘‘execution’’ are not consistent with the requirements of investigation.
To function effectively, the research group must meet, in the same way that it
would meet from time to time if housed under one roof. The group cannot deliberate,
act, or execute as a cohesive whole in the absence of active interchange. The frequency of
meetings will depend on the trial and stage, but should be at least once a year.
There are costs in convening the research group in multicenter trials. They can be
sizable when the group is large and widely dispersed. Even if planners anticipate the need
for periodic meetings of the group, they may be stymied in bringing such meetings about.
The meetings are likely to be seen as ‘‘unnecessary’’ by review groups and, hence, budgets
for meetings trimmed or deleted in the review process.
336
X I I I . I N V E S T I G AT O R S / S T U D Y S TA F F
Usually, the best strategies in the case of trimmings or deletions is persistence. The
resistance to meetings is likely to diminish as planning proceeds. Eventually, sponsors
come to recognize that planners cannot train and certify personnel for study procedures
without meetings.
A strategy sometimes practiced to blunt the ‘‘cost’’ argument is to ‘‘piggyback’’
meetings of the research group on other meetings. The idea is appealing but flawed.
Generally, people have enough trouble sitting still for one meeting extending over days,
let alone two different meetings.
The purpose of meetings of the research group include the following:
• Training and certification of study personnel
• Familiarization with study protocol and procedures; familiarization with data
collection forms
• Performance review
• Updating on protocol changes
• Deliberation on issues of procedure or protocol
• Receive, review, and accept or reject recommendations from leadership committees
• Receive, review, and accept or reject recommendations from the treatment effects
monitoring committee for protocol changes based on interim treatment results
Recommendations
•
•
•
•
Define research group early in the course of planning; define to be broadly inclusive
List members of the research group in the study directory
Update the list periodically
Maintain listings so that a history of membership can be compiled (i.e., by listing
past and present members)
Committees
111. Key Committees
339
111. Key committees
SLIDE
Key committees: Studies of Ocular Complications of AIDS
(SOCA)80
Steering committee
Executive committee
Policy data monitoring board
R E L AT E D E N T R I E S
Standing and working committees (page 341), Executive committee (page 353), Steering
committee (page 359), Treatment effects monitoring committee (page 387)
DEFINITION
key committee n - A committee essential to the operation of a trial; generally any
of the following: steering committee, executive committee, advisory-review committee,
treatment effects monitoring committee, and advisory-review and treatment effects
monitoring committee.
112. Standing and Working Committees
341
112. Standing and working committees
SLIDE
Standing and working committees: Coronary Drug Project
(CDP)18
•
•
•
•
•
•
•
•
•
Steering Committee
Executive Committee
Data Monitoring Committee
Policy Board
Treatment Criteria Committee
Natural History Committee
Laboratory Committee
Mortality Classification Committee
Editorial Review Committee
R E L AT E D E N T R Y
Key committees (page 339)
DEFINITIONS
standing committee n - [trials] A committee in the organization structure of a trial
charged with performing specified duties and functions over the duration of the trial and
beyond.
working committee n - [trials] A committee in the organization structure of a trial
created to perform a specified task and that ceases to exist when the task is finished, e.g., a
committee created for writing a study publication.
N A R R AT I V E
Operators of trials should keep records of standing and working committees and their
memberships. The records should be maintained over the life of the trial for use in credit
listing in study publications.
113. Committee Rules and Procedures
343
113. Committee rules and procedures
SLIDE
Committee rules and procedures: Studies of Ocular
Complications of AIDS (SOCA) Steering Committee80
Rules:
Quorum:
Voting:
Proxies:
Absentee votes:
Robert’s
Majority of officers; majority of members
Simple majority of members present (two-thirds for specified issues)
Proscribed
Proscribed
R E L AT E D E N T R I E S
Key committees (page 339), Standing and working committees (page 341)
N A R R AT I V E
Virtually all clinical trials involve committees. Principally, committees for design, steering,
treatment effects monitoring, and for paper writing. A multicenter trial can have dozens
of committees.
The goal should be to create a lean, efficient, committee structure. The approach
should be to minimize the number of committees. To do that, groups have to avoid
creating new committees when ‘‘old’’ ones will do. They should avoid commissioning
committees as vehicles for quieting vocal minorities or creating impressions of progress.
They should avoid creating committees with overlapping functions or with duties and
responsibilities likely to conflict with other committees.
A good practice is to prepare and maintain specification sheets for each committee
created. The sheet should include:
•
•
•
•
•
•
•
•
•
•
Statement of charge
Members
Chair; vice-chair
Secretary; rapporteur
Period of function
Reporting procedure
Meeting procedures and rules
Quorum requirement
Voting rules and procedures
Number of votes required for decision or action
There is a tendency in inexperienced groups to downplay the need for formal rules of
conduct such as represented by the last several items in the list above. They are inclined
to believe that it will be possible to reach consensus on major issues and, hence, no need
for votes. However, almost always, sooner or later, consensus fails and votes are necessary.
Obviously, the time to be straight on who can vote is before it is time to vote.
344
X I V. C O M M I T T E E S
Indicators of faulty structures
• Structures leaving most of the research group disenfranchised
• Steering committee comprised exclusively or primarily of members of a single
medical speciality in trials involving different medical specialities for administering
the different study treatments
• Uncertainty as to the interrelationship of committees or lack of delineation or
separation of functions
Factors and considerations affecting organization
•
•
•
•
•
•
Mode of funding (grant vs. contract)
Expectations and requirements of sponsors
Size and diversity of the research group
Number and location of centers
Diversity of disciplines and pecking order of disciplines
Desired or required separations
Good organizing principles
•
•
•
•
•
•
Formulation of organizational structure early in the course of the trial
Delineation and separation of functions of key committees
Specification of the interrelation of committees
Specification of committee membership and tests or requirements for membership
Specification of quorum requirements and voting rules and procedures
Delineation of disclosure requirements for members of the research group for
protection against conflicts of interest
• Provisions for periodic review and revision of the organizational structure
• Written bylaws
Housekeeping tasks
•
•
•
•
•
Creation and maintenance of committee lists and rosters of membership
Replacement of departed members or nonfunctioning members
Minute taking
Establishing and maintaining repository for minutes
Dissolving defunct committees
Mistakes concerning committees
•
•
•
•
•
Creating absent a charge
Creation to allow for charge ‘‘creep’’
Creation not providing for a vice-chair or recording secretary
No rules of membership or for conduct of business
Failure to update and revise charge or membership
113. Committee Rules and Procedures
345
• Meetings without agendas
• Piggybacking (i.e., meet in conjunction with some other meeting)
• Memory-less meetings (no minutes)
Maintenance suggestions
• Appoint or elect with attendance clauses (i.e., miss three or more meetings and out)
• Assign responsibility for maintaining committee and credit roster to someone
• Review committee structure on annual basis
Voting
Secret ballot
Recommendation: Voting where anonymity is desirable, e.g., on contentious issues
related to matters of personal choice or philosophy
Open written ballot (written ballot, but vote and person revealed in counting)
Recommendation: On issues where voting should be without knowledge of other votes,
but where there is a need to know how persons voted, e.g., on issues where
positions or views need to be discussed in order to take proper action
Show of hands
Recommendation: Default mode
Voice (aye or nay)
Recommendation: On routine mechanical and procedural matters
Roll call
Recommendation: On issues of import and where position of persons should be revealed
‘‘Straw vote’’
Recommendation: Sometimes used in formulating issues and in gauging the sense of a
group; generally not helpful
Issues
Who is allowed to vote?
Are there conditions where proxy votes are allowed?
Are there conditions where absentee votes are allowed?
Mode of dealing with challenges to votes?
Issues requiring two-thirds majority vote?
‘‘Tests’’ of organization structure
When being organized
1. Who chooses the centers?
2. Who will have the last word on the treatment protocol?
3. Who will have the final say on the data collection protocol?
346
4.
5.
6.
7.
8.
9.
10.
11.
X I V. C O M M I T T E E S
Who will chair the SC?
How will the primary results paper be authored?
Who owns the data?
Who has access to study data?
How are members of the SC to be chosen?
Who will appoint the TEMC?
To whom will the TEMC report?
How will recommendations flow from the TEMC to study investigators?
After organized
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
How is replacement study chair to be selected?
Who is responsible for selecting a new CC director?
How will the primary results paper be authored?
Who speaks for the study?
Who ‘‘owns’’ the data?
Who has access to interim treatment results?
Does the sponsor have review authority over study publications?
Who has the ultimate responsibility for firing a center?
Who decides if a recommendation from the TEMC is to be implemented?
Who will be listed in the credits for the study?
114. Study Officers
347
114. Study officers
SLIDE
Officers: Studies of Ocular Complications of AIDS (SOCA;
as of 1990)80
Douglas Jabs, MD
Curtis Meinert, PhD
Matthew Davis, MD
Natalie Kurinij, PhD
James Tonascia, PhD
Chair of SOCA
Director, Coordinating Center
Director, Fundus Photography Reading Center
Project Officer, NEI
Deputy director, Coordinating Center
R E L AT E D E N T R Y
Executive committee (page 353)
DEFINITIONS
ex-officio adj - By virtue or because of an office or position. Usage note: Used to denote
members of a committee or board that serve because of the office or position held to
distinguish from elected or appointed members. Depending on circumstances, the rights
and privileges of ex-officio members may be the same as for other members or may be
restricted. Unless otherwise indicated, the rights and duties should be assumed to be the
same as for other members. Indicate if positions are without vote.
officers of the study n - The set of persons holding elected or designated offices in a study;
in multicenter trials generally the study chair and vice-chair and the heads or directors of
key centers, such as the data center, data coordinating center, or coordinating center, and
project office. rt: executive committee
study officers (SO) n - The officers of a study; typically in multicenter trials, the study
chair, study vice-chair, coordinating center director, coordinating center deputy director,
and project officer; one of the key committees in multicenter structures. rt: executive
committee
N A R R AT I V E
List officers of the study; listing should indicate whether positions are ex-officio or with
term. If with term, indicate length of term. If elected, indicate electing body and whether
person may stand for re-election.
115. Study Chair/Vice-Chair
349
115. Study chair/vice-chair
R E L AT E D E N T R Y
Study officers (page 347)
DEFINITIONS
appointed study chair n - A study chair appointed by the study sponsor or some other
body or person. rt: elected study chair, fiat study chair, rotating study chair, study chair
external, study chair internal
elected study chair n - A study chair selected by election with or without term; typically
in trials, election by the steering committee or research group. rt: appointed study chair,
fiat study chair, rotating study chair, study chair external, study chair internal
fiat study chair n - A person assuming the position of study chair by virtue of some
act or action, e.g., the act of submitting a proposal for a trial with the person assuming
the position named as the principal investigator in the funding application. rt: appointed
study chair, elected study chair, rotating study chair, study chair external, study chair
internal
rotating study chair n - An arrangement in which the position of study chair rotates on
some basis over the course of a trial, e.g., rotation in a multicenter trial with the head of
the study center hosting the annual meeting of the research group serving as study chair
for the year preceding or following the meeting. rt: study chair, study chair external, study
chair internal
study chair n - Chair of the investigative group; chair of the steering committee of an
investigative group. rt: study vice-chair
study chair external n - A study chair not associated with any of the study centers. ant:
study chair internal
study chair internal n - A study chair associated with a study center. ant: study chair
external
study vice-chair n - A person elected or designated to perform the functions of a
vice-chair, especially one who performs or is expected to perform the functions of the
chair in the absence or incapacitation of the study chair. syn: vice study chair rt: study
chair
Factors determining choice of chair
Mode of initiation (investigator initiated vs. sponsor initiated)
Source of funding
Desire of sponsor to control or assert ‘‘ownership’’
Independence and separation from sponsor
Chair designate in the funding proposal
Specified
Implicit (assumed to be PI in R01 application)
350
X I V. C O M M I T T E E S
Designated (person named, e.g., as in investigator-initiated applications for
multicenter trials; rare in RFA and RFP modes of initiation)
Unspecified (usually the case in RFAs)
Appointment considerations
How is a candidate identified?
Domain of choice (internal or external to the study group)?
How are candidates screened for eligibility in regard to conflicts of interest, integrity,
and research credentials?
Who makes the appointment: Investigators or sponsor?
Advise and consent role for nonappointing authority (investigators when sponsor
appoints and sponsor when investigators appoint)?
Election considerations
Process for identification of suitable candidates?
Domain of choices (Internal or external to study? Discipline? Degree?)
Type of election: By vote or acclimation?
When is an election held?
Who may vote? Absentee or proxy votes?
Open or closed vote?
Term? Term limit?
Rotation of chair duties
Persons eligible for rotation?
Period of service?
Order of rotation? (Lots, position, location)
Desired characteristics of a chair
Integrity
Experience
Standing
Patience
Resilience
Independence
Objectivity
Observations regarding study chair
One of the most important positions in the study
A weak chair makes for a bad study
115. Study Chair/Vice-Chair
351
Generally, the rotating chair model leads to weak and inconsistent leadership
A chair that does not respect or appreciate what a coordinating center does is ‘‘trouble’’
A good chair knows how to run a meeting
Observations regarding methods of selection
General
Entering a study where the chair is unknown is the academic equivalent of joining
a chair-less department
Investigator-initiated proposals for multicenter trials are likely to be seen as ‘‘weak’’
during review when chair-less, even if details included to indicate how a chair
would be selected
Vagueness of detail as to chair in RFPs should be read assuming the sponsor will
have the final say in selecting or designating the chair
Appointed
Investigators will find it hard to appoint when they are choosing among their own
Appointment necessary when person is to be external to the trial
Advantage to appointed external chair is independence (i.e., not associated with
any center in the trial); disadvantage can be in detachment
Sponsors intending to select the chair should make that intention known when
soliciting applications from investigators; if the selection has been made when
the RFP is released, the RFP should name the person
Appointment should be with the advice and consent of the sponsor when made by
investigators and with the advice and consent of the investigators when made
by the sponsor
Election
If by election, avoid until the research group has formed and ‘‘matured’’
Usually requires some pro tem appointment until elections can be held
Ideally, pro tem chair should be a person not interested in being elected chair
Likely to produce weak leadership structure, especially if election for short term
and in the absence of provision for re-election
Directive sponsor unlikely to be pleased with election as method of selection
Term can be a useful expedient for ‘‘escape’’ from inept chair
Use election rather than arbitrary rotation
If uncertain as to leadership qualities of elected persons, elect for limited terms
Nomination and election processes can be contentious and may result in ‘‘bruised’’
feelings
Election can produce appearance of ‘‘democracy’’, but only if the processes are
open and votes are open to all members of the research group
Election by a select few is likely to be seen as a travesty by the research group
membership
352
X I V. C O M M I T T E E S
Election by the steering committee is likely to be seen as creating a ‘‘have’’ and
‘‘have not’’ investigatorship
Rotation
Change can be refreshing, but most transitions are messy and ‘‘memory’’ is usually
lost (loss can be serious when study is short or period of rotation is short)
Usually, rotating chairs make for uncertain and weak leadership structures
Sometimes useful as an expedient to deal with inept de jure chair
Generally best avoided, except perhaps when planned and timed to correspond to
stage of trial (e.g., in transition from design and implementation to execution)
Study vice-chair
Qualifications : Same as for study chair
Selection : Usually by designation in conjunction with the chair and steering committee
or executive committee
116. Executive Committee
353
116. Executive committee
SLIDE
Executive committee: National Emphysema Treatment Trial
(NETT)62
Alfred Fishman, MD (Chair)
Steven Piantadosi, MD,
PhD (Vice-chair)
Reuben Cherniack, MD
Larry Kaiser, MD
Fernando Martinez, MD
Keith Naunheim, MD
Andrew Ries, MD
Frank Sciurba, MD
David Sugarbaker, MD
Gail Weinmann, MD
School of Medicine, University of Pennsylvania
School of Public Health, Johns Hopkins University
National Jewish Medical and Research Center
School of Medicine, University of Pennsylvania
School of Medicine, University of Michigan
School of Medicine, St Louis University
School of Medicine, University of California at
San Diego
School of Medicine, University of Pittsburgh
Brigham and Women’s Hospital, Harvard
National Heart, Lung, and Blood Institute
R E L AT E D E N T R I E S
Study officers (page 347), Executive committee members (page 357)
DEFINITIONS
executive committee (EC) n -[multicenter trials] A committee within the organizational
structure of some studies, especially multicenter studies, responsible for direction of
the day-to-day affairs of the study. One of the key committees in the organizational
structure of multicenter trials. Usually consists of the officers of the study and others
selected from the steering committee; typically headed by the chair or vice-chair of the
steering committee and reporting to that committee. rt: steering committee Usage note:
Sometimes used interchangeably with steering committee (not recommended). The term,
executive committee, should be reserved for settings in which it is part of or subservient
to a larger committee or body. In settings where there is only one leadership committee,
use steering committee. Synonymous with officers of the study when members of the
committee limited to study officers.
multi-study structure n - An umbrella organizational structure created and maintained
to initiate and carry out a series of related studies involving the same or different study
populations. Usage note: Use multi-trial if all studies are trials.
N A R R AT I V E
The executive committee, as implied by the name, is a committee responsible for the
day-to-day decisions needed for planning, operation, and direction of the trial. The goal
should be to create it as a small compact body. Modest size is a desirable feature because
of the function of the committee and the need for frequent meetings. That frequency may
be as often as weekly when the trial is being planned or at critical states in its conduct. It
can be expected to meet regularly over the course of the trial; at least 4 to 6 times a year.
354
X I V. C O M M I T T E E S
The meeting mode may be face-to-face or by conference telephone—usually the latter for
multicenter trials.
All things considered, usually the best mode of creation is to limit membership to
officers of the trial. They are the executives of the trial and, hence, are the persons with
the responsibility and duty for performing those functions.
Bodies created as miniature steering committees tend to operate and function
more like steering committees than as executive committees. Its members tend to be more
interested in ‘‘steering’’ than in dealing with the nitty gritty of day-to-day issues. The end
result is a weak executive arm of the trial, creation of an ‘‘officers committee’’ to meet the
executive function of the trial, or the creation of a shadow de facto structure for dealing
with day-to-day operational issues.
Planners can expect difficulties when creating an executive committee after the
steering committee has been formed and functioning. The creation of a smaller more
compact body, even if ostensibly only to deal with executive functions and to report to
the steering committee, is likely to be seen as a dilution of the function and authority of
the steering committee. The likely end result will be dissention in the ranks.
The need for day-to-day decisions in the conduct of a trial exists whether or not
there is a committee created to address them. The lack of structure for dealing with them
is likely to result in a poorly run trial or lead to a person or center obliged to assume the
function. The absence of structure exposes that person or center to risks of censure if seen
as having acted inappropriately.
Conditions indicative of need for an executive committee
•
•
•
•
•
Multicenter trials having six or more centers
Multi-national trials
Large or diverse investigatorship
Multi-study and multi-trial structures
Multicenter trials with steering committees too large to assume executive functions
Usual duties and responsibilities
• Day-to-day decisions for directing the activities of planning and conducting the
trial
• Preparation of agendas for meetings of the research group and steering committee
and other study related meetings; conduct of such meetings
• Make recommendations to the steering committee and research group for protocol
changes
• Monitor performance; take necessary corrective actions or recommend corrective
actions to the steering committee
• Direct and coordinate funding renewals
• Perform other duties as assigned by the research group or steering committee
116. Executive Committee
355
Recommendations
• Assume the need for an EC if any of the conditions listed above apply
• Create early, ideally as the first body; if not as the first body, then when the steering
committee is formed
• Create with six or fewer members
• Create to include study officers; ideally with membership limited to officers
117. Executive Committee Members
357
117. Executive committee members
R E L AT E D E N T R Y
Executive committee (page 353)
N A R R AT I V E
Create and maintain a list of members of the executive committee. If persons are elected,
indicate term and mode of election. Indicate whether person or position listed is with or
without vote. Indicate chair, vice-chair, and rapporteur. List support staff and function
and person or center responsible for meeting arrangements. Maintain list of past members
and term of membership.
118. Steering Committee
359
118. Steering committee
R E L AT E D E N T R I E S
Steering committee members (page 361), Steering committee: Questions, answers, and
observations (page 363), Steering committee representation models (page 367)
DEFINITION
steering committee (SC) n - A committee of an organization responsible for directing or
guiding the activities of that organization. In multicenter trials, the committee responsible
for conduct of the trial and to which other study committees report. Usually headed by
the study chair and consisting of persons designated or elected to represent study centers,
disciplines, or activities. One of the key committees in multicenter structures. rt: executive
committee Usage note: Sometimes used interchangeably with executive committee; not
recommended.
Conditions indicative of need for a steering committee
•
•
•
•
•
Multicenter trial
Multidisciplinary clinical investigatorship
Large diverse investigatorship
Multi-study and multi-trial structures
Trials involving complex treatment or data collection protocols
Usual duties and responsibilities
•
•
•
•
•
•
•
•
•
Protocol development, implementation, and maintenance
Good and welfare considerations of persons studied
Commissioning of subcommittees, working groups, and writing committees
Performance monitoring and related corrective and disciplinary actions
Research agenda
Review and input for meeting agendas
Policy setting in regard to authorship for study publications and presentations
Reviewing authority for ancillary studies
Deliberating body for proposed protocol changes
Recommendations
• Create following formation of executive committee or in conjunction with executive
committee
• Create to include study officers and directors of key centers
• See Steering committee representation model, page 367, for other recommendations
SC recommended specifications
Membership: ≤ 20 including study officers (ideally ≤ 15)
Representation construct: See Steering committee representation model, page 367
360
X I V. C O M M I T T E E S
Meeting mode: Face-to-face or conference phone; at least one face-to-face meeting per
year; face-to-face for important deliberations
Meeting frequency: At least twice per year, face-to-face at least once a year
Minimum meeting frequency: Once per year, face-to-face
Quorum: At least two officers (chair or vice-chair and at least one other officer) and
≥50% of members
Voting: Show of hands, roll call, or secret ballot as determined when question is voted;
no proxies; no absentee votes
119. Steering Committee Members
361
119. Steering committee members
SLIDE
Steering committee: Coronary Drug Project (CDP)18 (as of
November 1972)
Jeremiah Stamler, MD (chair)
Kenneth Berge, MD (vice-chair)
William Bernstein, MD
Henry Blackburn, MD
Gerald R Cooper, MD
Jerome Cornfield
Nicholas J Galluzzi, MD
Max Halperin, PhD
Christian R Klimt, MD, DrPH
Charles A Laubach, Jr, MD
Bernard I Lewis, MD
Jessie Marmorston, MD
William B Parsons, Jr, MD
William J Zukel, MD
NIH Medical Liaison Officer
Northwestern University
Mayo Clinic
Mount Sinai Hospital, Miami Beach
University of Minnesota
Center for Disease Control, Atlanta
George Washington University
USPHS Hospital, Staten Island
National Heart and Lung Institute
University of Maryland
Geisinger Medical Foundation, Danville
Palo Alto Medical Clinic & Research Foundation
University of Southern California
Jackson Clinic and Foundation, Madison
National Heart and Lung Institute
National Heart and Lung Institute
R E L AT E D E N T R I E S
Steering committee (page 359), Steering committee: Questions, answers, and observations
(page 363), Steering committee representation models (page 367)
N A R R AT I V E
Create and maintain a list of members of the steering committee. If persons are elected
indicate term and mode of election. Indicate whether person or position listed is with or
without vote. Indicate chair, vice-chair, and rapporteur. List support staff and function
and person or center responsible for arrangements. Maintain list of past members and
term of membership. Indicate mode of composition (see page 367).
For steering committee formation indicate:
•
•
•
•
Mode of representation (see page 367)
Membership by discipline
Restrictions on membership
Membership to include persons external to the investigatorship? If so, persons or
positions to be represented?
• Chair person
• Ex-officio positions
• Size
For operating steering committees indicate the following:
• Members by study position and by center
• Membership; voting, nonvoting, and total
• Membership count by relationship to study (internal, external)
362
•
•
•
•
X I V. C O M M I T T E E S
Staff and function
Person or group responsible for arrangements and scheduling of meetings
Chair and vice-chair
Rapporteur
120. Steering Committee
363
120. Steering committee: questions, answers, and
observations
R E L AT E D E N T R I E S
Steering committee (page 359), Steering committee members (page 361), Steering
committee representation models (page 367)
QUESTIONS AND ANSWERS
When to create?
Answer: The committee may exist prior to the initiation of funding in the case of
investigator-initiated trials. Indeed, in those settings it is common for such bodies to
be formed and convened to come to agreement on the broad outline of the trial to
be proposed. The committee, in such cases, serves the function of planning and is
named in the funding initiative. It will exist in principle only prior to funding in the case of
sponsor-initiated trials.
The SC should be the first committee created and convened if the intent is for it to
serve as the premier leadership body of the trial. Indeed, a way to gauge the likely role
of the SC in directing the trial is by noting when and how the body was created. As a
rule, the later in the course of development, the lesser the role and the more likely that
the seat of power in the trial resides elsewhere.
There are risks in moving to create the committee before the research group has
‘‘gelled.’’ The risk is greatest in large-scale, sponsor-initiated trials because of the ‘‘cold’’
start implied with that mode of funding. It will take time for the collection of persons
brought together to develop a sense of group.
Generally, once the SC is created, it starts taking on a life of its own. That means, in
effect, that it will be difficult to correct mistakes in formulation or composition once the
body is formed.
A prudent course in sponsor-initiated trials is to create an interim planning committee
as a precursor to a SC. The function of the committee is assumed by the SC when
created. Its membership is subsumed in the SC.
Creating authority?
Answer: The investigators in the case of an investigator-initiated trial and the
investigators with the advice of the sponsoring agency in the case of trials created
by requests for applications (RFAs) or by requests for proposals (RFPs) (see Funding:
Terminology, page 51)
If the investigators are the creating authority, who among them is responsible for
creating the committee?
Answer: Usually, the officers of the study.
Charge, duties, and responsibilities?
Answer: Typically, the SC is the steward of the trial. Its charge is to create, implement,
and maintain a study protocol pursuant to the objectives of the trial (see Objective,
page 27), consistent with duties and responsibilities for ensuring proper care and
well-being of persons studied and for protecting them from harm. As a rule, it has
sign-off authority for the study protocol and study procedures. It receives and acts upon
recommendations for change in treatment protocols as received from the treatment
effects monitoring committee, sponsor, or IRBs.
Membership?
Answer: The answer depends on the mode of representation (see Steering committee
representation model, page 367) and on whether the SC includes elected members.
364
X I V. C O M M I T T E E S
Members external to the investigatorship, e.g., as drawn from patient or other
advocacy groups?
Answer: The answer depends on the general charge and function of the SC and general
disposition of the research group. External members should not be seated with votes
if members of the research group object to vesting votes in persons having no line
responsibilities for conduct of the trial and not accountable to any IRB.
Treatment effects monitoring committee members represented on the SC?
Answer: Generally ‘‘no’’ for voting members of the treatment effects monitoring
committee but sometimes ‘‘yes’’ for nonvoting members, for example, as with the
director of the coordinating center when the coordinating center is responsible for
producing reports for the treatment effects monitoring committee.
Size?
Answer: Not too big and not too small. Generally, the larger the committee, the more
unwieldy it becomes and the greater the difficulty and cost in meeting. The trick is
to arrive at a mode of construction consistent with a lean membership. However, a
lean membership at the outset does not mean leanness throughout if the mode of
construction is built along center lines. An expansion in centers in the trial will lead to an
expansion of membership.
Operationally, the number is ‘‘too many’’ if microphones are needed for meetings
of the SC, if name plates are needed to identify members, or if members cannot be
seated around a table and be in eye contact with every other member. It is ‘‘too few’’
if the membership does not include the various disciplines and skills needed for design
or operation of the trial or if absence of a member deprives the committee of a required
expertise.
Quorum requirement?
Answer: To be set by the SC; usually a simple majority and designated officers; see
Committee rules and procedures (page 343).
Voting?
Answer: To be determined by the SC; on major issues such as whether to stop a
treatment or to implement a major protocol change, two-thirds majority; no proxies; see
Committee rules and procedures (page 343).
Rules?
Answer: To be determined by the SC; usually ‘‘Robert’s Rules’’; see Committee rules
and procedures (page 343).
Relationship to the sponsor?
Answer: See When to create? and Creating authority? The SC should be created to
be independent of the sponsoring agency. Input from the sponsoring agency should be
provided by a representative of the sponsoring agency on the SC, if such a position
is desired by the sponsor. Reports to the sponsoring agency should be via that
representative, by the study chair, or via another officer of the SC.
Relationships to other committees?
Answer: Normally, all study committees (except the treatment effects monitoring
committee) are subservient to or accountable to the SC, including the executive
committee, subcommittees of the steering committee, and all working or writing
committees commissioned by the SC.
Relationships to the research group?
Answer: The SC is accountable to the research group (see Research group/Investigators,
page 335). The power of the SC to direct and govern depends on a research group
willing to be directed and governed by it. Technically, the SC recommends to the
research group, and the research group acts. It acts either by accepting or rejecting SC
recommendations.
120. Steering Committee
365
Primary meeting mode?
Answer: Face-to-face.
Frequency of meetings?
Answer: At least two face-to-face meetings per year; more often during planning.
Access to meetings?
Answer: Usually closed; may be open to members of the research group but not to
persons outside the research group.
Access to records of meetings, such as minutes?
Answer: Usually limited to members of the research group and the sponsoring agency.
Housekeeping and maintenance procedures?
Answer: See Committee rules and procedures (page 343).
Membership renewal and removal of deadwood?
Answer: See Committee rules and procedures (page 343).
Observations
•
•
•
•
Usually, the larger the committee, the greater the need for an executive committee.
Planning and complicated deliberations are best done via face-to-face meetings.
Poor attendance is usually symptomatic of other problems.
‘‘Reorganization’’ to streamline and downsize the SC can have negative political
consequence if seen by the SC membership as an erosion of power or influence.
121. Steering Committee Representation Models
367
121. Steering committee representation models
SLIDE
Steering committee representation: Studies of Ocular
Complications of AIDS (SOCA)80
Voting members: 15
Officers: 5 (ex-officio, voting)
Elected: 12 (4-year term, eligible for re-election, voting)
Ophthalmologists: 3
Infectious disease physicians: 3
Clinic coordinators: 3
Photographers: 3
R E L AT E D E N T R I E S
Steering committee (page 359), Steering committee members (page 361), Steering
committee: Questions, answers, and observations (page 363)
DEFINITIONS
advocacy representation construct n -[multicenter studies] A representation construct
based on advocacy, e.g., one where membership on the steering committee includes
persons external to the study chosen to advocate a position or to represent an
interest. rt: aristocracy representation construct, center representation construct, discipline
representation construct, PI representation construct
aristocracy representation construct n - [multicenter studies] A representation construct
limited to founding members, e.g., one where membership on the steering committee
is limited to persons responsible for getting the study funded. rt: center representation
construct, discipline representation construct, PI representation construct
center representation construct n -[multicenter studies] A representation construct based
on center, e.g., one where membership on the steering committee is by center or one
where voting is by center. rt: advocacy representation construct, aristocracy representation
construct, discipline representation construct, PI representation construct
discipline representation construct n -[multicenter studies] A representation construct
based on discipline, e.g., one where membership on the steering committee is apportioned
by discipline or one where voting is by discipline. rt: advocacy representation construct,
aristocracy representation construct, center representation construct, PI representation
construct
PI representation construct n -[multicenter studies] A representation construct based on
PI-ship, especially one where membership on the steering committee is limited to PIs or
one where voting is by PI (see page 331 for definition of PI). rt: advocacy representation
construct, aristocracy representation construct, center representation construct, discipline
representation construct
368
X I V. C O M M I T T E E S
representation construct n -[multicenter studies] Any of various constructs used for representation on the key governing bodies of a multicenter study or study network; includes
advocacy representation construct, aristocracy representation construct, center representation construct, discipline representation construct, and PI representation construct.
PI-based SC
Construct: Only persons recognized or designated as PIs seated
Strengths
Intuitively appealing; easy to rationalize and to implement
Avoids anxiety of sharing power with persons not having PI responsibilities
Shortcomings
Elitist, especially when PI is used as synonym for physician investigators or for
clinic directors
Creates governance structure top heavy in clinical expertise; impoverished in other
areas of expertise
Emphasis on PIship disenfranchises or all others in the research group
Leads to unmanageable size when number of PIs is large
Recommendation
Generally best avoided because of shortcomings
Do not use where number of centers is large, where only physician-investigators
are considered to be PIs, or where trial involves competing medical specialities
Center-based SC
Construct: One or two members per center
Strengths
Largely the same as PI-based representation
Common and appealing mode of formation, especially when the number of centers
is small
Shortcomings
Similar to those for PI-based to the extent that PI is synonymous with clinic or
center director
Ill-suited for trials involving competing medical specialities (e.g., surgeons and
medical people in a trial of surgery vs. medical treatment), especially when
clinics are selected to be headed by a given speciality
Leads to unmanageable size with large numbers of centers
Likely to lead to proxy voting or to challenges to votes when a center is not
represented
Recommendation
Avoid with large number of centers and where trial involves competing specialities
Use cautiously and only when members and voting rules are spelled out in advance
Do not use if sponsor is unwilling to cover travel cost for nonvoting members of
the SC
121. Steering Committee Representation Models
369
Function and discipline-based SC
Construct: Formulated to include persons from the trial with the disciplines and
functions needed for conduct of the trial
Strengths
Provides a discipline and function balanced body; in that regard, better than PIor center-based construct
Can make for better deliberative and decision making processes because of
collective understanding and knowledge
Egalitarian; may produce more active and involved research group
Avoids implied elitism of PI-based and center-based constructs
Shortcomings
Not usually ‘‘appealing’’ to PIs or center directors because of implied power
sharing
Requires compromises with regard to positions and disciplines to be represented
Requires system for nomination of representatives of positions and disciplines
Observations
Difficult to move to this form of representation once SC is organized under
PI-based or center-based construct
Shortcomings of PI-based or center-based constructs will not be obvious at outset;
senior investigators may be loath to embrace construct when organization is
formed
Recommendation
Preferred when number of centers is large and in discipline- or function-complex
trials
Implement at outset for reasons noted above
Election-based SC
Construct: Committee created and maintained by elections for designated terms;
usually with restriction on number or types of persons or positions to be
represented
Strengths
Democratic
Shortcomings
Not conventional
Can be divisive if persons are competing for nominations or seats
Not likely to provide strong leadership
Recommendation
Generally best avoided as sole mode of formulation; may be useful in combination
with other modes of representation
370
X I V. C O M M I T T E E S
Interest-based SC
Construct: Members selected to represent interests of investigators, patients, sponsor,
community, etc.
Strengths
Has political appeal, especially when seats are provided for activists, community
representatives, etc.
Useful in defending against criticism from the outside community
Shortcomings
Difficult to identify interests to be represented
Can lead to continuing expansion of membership as new interests are identified
Individuals chosen to represent a given interest are not likely to be seen as
representative unless they themselves are elected by their constituencies
Produces a leadership group with members external to the trial; may create
problems because those dictating protocol are free of responsibilities for
carrying it out
Recommendations
Avoid as sole basis for representation; may be used in conjunction with other
modes of representation but sparingly
Aristocracy-based SC
Construct: Membership limited to persons responsible for initiation, or to persons
associated with initial set of centers
Strengths
Can provide strong and consistent leadership
Has long-term ‘‘memory’’
Shortcomings
Tends to be seen as ‘‘Ole boys’’ club
May be seen as elitist
Can lose touch with rank and file members
Has many of the shortcomings of PI-based or center-based mode of representation
Recommendations
Avoid as sole mode of formation
May be used in conjunction with elected members (e.g., as in CDP)
Mixed-mode SC constructs
Construct: Use of two or more modes for creation or maintenance
Common mixes
Grandfathers plus elected (e.g., as a means of providing wider representation when
a trial is expanded)
Center-based or PI-based representation plus appointed or elected members (e.g.,
as fixes to a restive research group when the trial matures)
Treatment Effects
Monitoring
1 2 2 . Tr e a t m e n t E f f e c t s M o n i t o r i n g
373
122. Treatment effects monitoring
R E L AT E D E N T R I E S
Treatment effects monitoring: Purpose (page 375), Treatment effects monitoring:
Approach (page 377), Treatment effects monitoring committee (page 387), Treatment
effects monitoring: Questions and answers (page 383)
DEFINITIONS
harm n - 1. Physical or mental damage or injury from something done or applied. 2.
Hurtful mischief; hurt or injury from something wrong or evil. 3. Something deleterious.
Usage note: Harm in the sense of defn 1 is from something done that causes damage
or injury. In defn 2 it is from something mischievous, wrong, or evil. In defn 3 harm is
from something that is deleterious. The Hippocratic Oath admonishes against all three
forms of harm in the passage I will follow that system of regimen which, according to my
ability and judgment, I consider for the benefit of my patients, and abstain from whatever is
deleterious and mischievous. I will give no deadly medicine to anyone if asked, nor suggest any
such counsel.42,65,73,99 The most direct form of harm in the context of trials arises from
use of a harmful treatment. More subtle and indirect forms of harm arise from use of
ineffective treatments when more effective treatments exist, or by failure to use a superior
treatment. Continued enrollment, assignment to treatment, and treatment according to
the assignment can be considered to fall into the forms of harm denoted by defns 2 and 3.
Note that by those definitions, harm arises even if the treatment in question is not itself
harmful, e.g., as with placebo forms of treatments, if, by their use, persons are denied
treatment with effective treatments.
interim data analysis n -[trials] 1. Data analysis carried out during a trial for the purpose
of treatment effects monitoring. 2. Any data analysis done before data collection is
completed, for whatever reason, but usually concerned with assessments of treatment
effects.
interim look n - [trials] 1. A look at the treatment results of a trial while underway,
especially when performed for the purpose of determining whether the trial should be
stopped or modified. 2. Any summary of interim results made during the course of a trial
having the potential of being used to stop or modify the trial. 3. interim result
interim result n - A result seen or obtained during the course of a study.
treatment effects monitoring n - 1. In trials, the act of or an instance of reviewing
accumulated outcome data by treatment group to determine if the trial should continue
unaltered. 2. The act or an instance of watching for treatment effects in an individual
patient. syn: data monitoring, safety monitoring, data and safety monitoring
treatment effects monitoring v - Monitoring done to assess the effects of treatments
used in a trial as measured by designated treatment comparisons and for the purpose of
deciding whether the trial should continue unaltered. Typically, a process starting early in
the course of the trial and continuing to its planned end or until a decision is made to stop
it as a result of the monitoring. The monitoring may be done in masked or unmasked
fashion and may be done by a single individual or a formally constituted treatment effects
monitoring committee. In multicenter trials, usually performed by such a committee
using treatment effects monitoring reports prepared by the data center, data coordinating
374
X V. T R E A T M E N T E F F E C T S M O N I T O R I N G
center, or coordinating center. syn: data monitoring, safety monitoring, data and safety
monitoring
N A R R AT I V E
Designers should assume the need for treatment effects monitoring and proceed
accordingly. Monitoring is required for protection of persons from harm in most
randomized trials. It is required in any trial where the treatments being studied have
potential for harm and where that potential can be reduced or eliminated by monitoring
and action when indicated. The harm can be from the ill-effects of treatment or from the
failure to provide a better treatment.
Monitoring, to be effective, must be timely and complete. The requirement of
timeliness is defeated by lagged data flows. The longer the interval between generation
and processing for inclusion in the monitoring database, the less timely the monitoring
and the less its value in preserving persons from harm. To meet timeliness requirements,
designers need to establish data flow consistent with data collection principles outlined
on page 281.
The requirement of completeness is defeated by archiving for processing or analysis
at a later date. It is degraded by systems of linked readings or analysis where a record or
specimen for a patient is held until it can be read, analyzed, or processed in conjunction
with a subsequent record or specimen for that patient. It is defeated when all readings or
analyses are postponed to the end of the trial.
The obvious difficulty with linked readings and with waiting to the end of the trial
to read or process in regard to monitoring is that information generated is not available
for monitoring over the course of the trial.
1 2 3 . Tr e a t m e n t E f f e c t s M o n i t o r i n g : P u r p o s e
375
123. Treatment effects monitoring: Purpose
R E L AT E D E N T R I E S
Treatment effects monitoring (page 373), Treatment effects monitoring: Approach
(page 377), Treatment effects monitoring committee (page 387), Treatment effects
monitoring: Questions and answers (page 383)
DEFINITIONS
efficacy monitoring v -[trials] 1. Monitoring for efficacy, as performed at periodic time
points over the course of a trial, to determine whether the trial should be stopped or
modified because of efficacy; as distinct from safety monitoring. 2. treatment effects
monitoring rt: safety monitoring, treatment effects monitoring, interim look, interim
result Usage note: Often used in contradistinction to safety monitoring in settings where
the user wishes to distinguish between interim looks performed for efficacy monitoring
versus those made for safety monitoring; e.g., in settings where looks for safety monitoring
are not counted as looks for purposes of adjusting p-values for multiple looks. The
distinction is predicated on the assumption that safety and efficacy are independent
dimensions of treatment—usually not the case.
safety monitoring v -[trials] 1. Monitoring performed at points over the course of a
trial to determine whether the trial should be stopped or modified because of safety
considerations; as distinct from efficacy monitoring. 2. treatment effects monitoring rt:
data and safety monitoring, efficacy monitoring, treatment effects monitoring, interim
look, interim result Usage note: See usage note for efficacy monitoring.
N A R R AT I V E
Treatment effects has different purposes depending on the trial and circumstance of
monitoring. It is up to designers to specify the plan for monitoring and the ends it is
intended to serve.
It is necessary for protection of patients from the potential of harm due to use of
study treatments (see page 373). It is a required part of any trial where that potential exists
and where the potential can be reduced by timely monitoring.
The potential for harm, depending on the condition being treated, can be from
continued use of an unsafe treatment or from continued use of an ineffective treatment
when an effective one exists. The routes to harm are different. In one case, the harm is
the direct result of a treatment applied. In the other case the harm is due to denial of
access to a better treatment. The difference leads some groups to differentiate between
monitoring required to protect against the two forms of harm (safety monitoring versus
efficacy monitoring) and to a different frequency of looks for the two forms of monitoring.
The usual practice in such cases is to provide for a higher frequency of looks for safety
monitoring than for efficacy monitoring. The limitation on looks for efficacy monitoring,
when imposed, usually arises in relation to conservation of p-values and to reduce the
likelihood of an early stop for reasons of efficacy.
It is up to designers to decide if the distinction is to be made. It is not a
recommended distinction in trials involving morbidity or serious morbid events as
376
X V. T R E A T M E N T E F F E C T S M O N I T O R I N G
outcome measures or in other settings where the line of demarcation between safety and
efficacy is blurred.
Designers, in fashioning the monitoring plans, should be mindful of the intrinsic
value of monitoring. Monitoring requires discipline in regard to the collection and harvest
of data for creating and maintaining up-to-date databases for use in monitoring and the
creation of programs and procedures for producing reports for evaluation of treatment
effects. The practices in producing the databases and in carrying out analyses needed to
produce reports are the same as those needed for producing the final database and analyses
for inclusion in manuscripts summarizing results of the trial when it is finished.
1 2 4 . Tr e a t m e n t E f f e c t s M o n i t o r i n g : A p p r o a c h
377
124. Treatment effects monitoring: Approach
SLIDE
Treatment effects monitoring approach: Studies of Ocular
Complications of AIDS (SOCA)80
Voting members of monitoring committee appointed by SOCA investigators
with advice and consent of NEI sponsor
SOCA study officers seated as nonvoting members
Committee not masked to treatment assignment
No preordained stopping rules
p-values not adjusted for multiple looks
Semiannual face-to-face meetings; more if necessary; meetings by conference
phone in case of emergencies
R E L AT E D E N T R I E S
Treatment effects monitoring (page 373), Treatment effects monitoring: Purpose
(page 375), Treatment effects monitoring committee (page 387), Treatment effects
monitoring: Questions and answers (page 383)
N A R R AT I V E
If treatment effects monitoring is required, than the questions that have to be answered
have to do with:
• Who will do the monitoring?
• When will the monitoring be done?
• How will the monitoring be done?
The ‘‘Who’’ options are:
•
•
•
•
Person (e.g., study statistician, principal investigator)
Investigators (e.g., steering committee or executive committee)
Independent committee
Sponsor
Monitoring, to be of value in protecting study subjects from the potential of
harm, while at the same time protecting against hasty action, must be both competent
and objective. The two qualities, while elusive, are more likely to be found together
when the ‘‘who’’ is a specially constituted committee independent of investigators and
sponsor. The single person model is likely to be lacking of competency in that it is
unlikely, no matter how skilled or accomplished a person may be, that a single person
can be possessed of the skills and expertise needed for competent monitoring. Monitoring
entrusted to sponsors or investigators is open to challenge on the grounds of objectivity
in that sponsors and investigators can be seen as having vested interest in the outcome of
the trial.
378
X V. T R E A T M E N T E F F E C T S M O N I T O R I N G
The ‘‘When’’ options are:
• As needed
• After specified numbers of events
• At certain landmarks in the trial (e.g., at the half way point of enrollment, after the
last person enrolled, etc.)
• At specified time intervals (e.g., every 6 months)
The ‘‘as needed’’ option is not viable because of the vagueness of the requirement.
Determined by whom? How determined?
The most common approach and also most practical approach is that represented
by the last option. It is easier to prepare for and schedule meetings when the schedule is
tied to calendar dates than to events or conditions driven by the trial.
The ‘‘How’’ options relate to questions such as:
•
•
•
•
Should monitors be masked?
Reports, who prepares them?
Should monitoring be driven by stopping rules?
What authority should monitors have in regard to stopping the trial?
Questions and answers having to do with ‘‘how’’ may be found starting on pages
383 and 391.
1 2 5 . Tr e a t m e n t E f f e c t s M o n i t o r i n g : M a s k i n g
379
125. Treatment effects monitoring: Masking
R E L AT E D E N T R I E S
Treatment effects monitoring (page 373), Treatment effects monitoring: Purpose
(page 375), Treatment effects monitoring: Approaches (page 377), Treatment effects
monitoring: Questions and answers (page 383)
DEFINITIONS
masked treatment effects monitoring n - Treatment effects monitoring in which results
are masked to treatment assignment.
masked treatment effects monitoring report n - A report in which treatment group is
coded to obscure identity, e.g., a report in a trial involving a single test and a single control
treatment in which results are identified to ‘‘Trt A’’ and ‘‘Trt B’’ without any indication
of whether A is the test or control treatment.
N A R R AT I V E
The issue of whether treatment effects monitoring is to be done in masked fashion is a
question that should be answered by study investigators. Often, the question is left up
to the monitoring body when it organizes, but doing that can lead to tensions if the
monitoring body chooses to operate in ways contrary to the wishes or needs of the study
investigators.
That investigators should have a say in how monitoring is done is obvious from
the fact that the monitoring body serves as their surrogate when the trial is ongoing
in protecting persons studied from harm. Investigators have to be satisfied that the
monitoring body is competent to perform those duties. One of the issues of competency
has to do with whether masking reduces competency in monitoring.
If the option is to mask, then the first question for designers is how to mask?
Masking is achieved by producing treatment effects monitoring reports with result
group coded (see definition above). The people producing the report will have to decide
whether the same code designation is used throughout a report and across reports. The
obvious downside in changing the designation within or across reports is that it makes
comparison across tables with different code designations impossible.
People producing the report will also have to decide on the extent of the masking.
If all tables summarizing results in a report are coded, the masking may be transparent to
the extent that some differences are unique to treatment and hence breaking the code.
The other issue that has to be addressed if masked treatment effects reports are
produced is when the mask is lifted. The options are:
1. Revealed
2. Individual
3. Group
Option 1 is where reports are masked, but monitors are informed of the coding
when the report is reviewed. This form of masking is practiced simply to protect results
from being revealed outside the monitoring group if the report is seen by others.
380
X V. T R E A T M E N T E F F E C T S M O N I T O R I N G
Option 2 is where individual monitors have the option of unmasking themselves
whenever they choose and of doing so independent of all other monitors. Typically, this
option is accomplished by providing monitors with envelopes indicating the coding and
where individual monitors are free to open the envelope whenever they choose; usually by
announcement to other members of the monitoring body.
Option 3 is where the mask stays in place for all members of the monitoring body
until the monitoring body votes to unmask. Usually, motions and votes to lift the mask
start to come when treatment differences emerge. With the masking in place, monitors
do not know if the difference they are seeing is beneficial or harmful because they do not
know the sign of the treatment difference with masking.
Masking complicates production of monitoring reports and increases the chance
of errors in production because of the coding. It also reduces the utility and readability of
monitoring reports. Its primary value is in perceived objectivity in the monitoring process,
but that benefit has to be balanced against the reduced competency in monitoring because
of the masking. If masking is done, there should be compelling reasons to mask and
should never be done without knowledge of IRBs or of persons enrolled into the trial.
126. Stopping Rules and Guidelines
381
126. Stopping rules and guidelines
R E L AT E D E N T R I E S
Treatment effects monitoring (page 373), Treatment effects monitoring: Purpose
(page 375), Treatment effects monitoring: Approaches (page 377), Treatment effects
monitoring committee: Questions and answers (page 391), Treatment effects monitoring
committee (page 387), Treatment effects monitoring: Questions and answers (page 383),
Performance monitoring (page 399)
DEFINITIONS
stopping boundary n -[trials] 1. The set of boundary values formed by lines, as determined
for sequential designs, which, if crossed, cause investigators to stop the trial. 2. The set of
boundary values formed by a line or pair of lines for a fixed sample size design, usually
specified before or shortly after the start of enrollment, which, if crossed, indicate the
existence of a treatment difference that satisfies certain statistical properties (e.g., has a
p-value of less than a specified size).
stopping guideline n - 1. A guide for determining when to stop or alter a trial. 2. A
guide as to size or type of treatment differences that may cause treatment effects monitors
to recommend stopping or altering a trial. rt: stopping rule Usage note: Not to be used
interchangeably with stopping rule. Use stopping guideline if used simply as a guide as to
when a stop or alteration may be indicated.
stopping rule n - 1. A rule for determining when to stop or alter a trial. 2. A rule
for determining when to terminate or alter the treatment protocol of a trial based on
the observed treatment difference for an outcome of interest; usually some function of a
p-value produced by a designated test statistic evaluated at predetermined points in the
course of the trial. The rule is an implicit part of the design in the case of sequential trials,
it is established at or near the outset of the trial in the case of fixed sample size designs.
A difference exceeding the set limit leads to termination of the trial or one of the study
treatments, depending on the nature and direction of the observed treatment difference.
rt: early stopping, stopping guideline Usage note: Not to be used interchangeably
with stopping guideline. Reserve for uses where a stop or alteration proceeds when the
conditions of the rule are met. Use stopping guideline if the rule is not binding.
N A R R AT I V E
In regard to treatment effects monitoring, designers have to decide whether monitoring is
to be done under hard and fast stopping rules, under stopping guidelines, or no rules or
guidelines at all.
To fashion stopping rules or stopping guidelines for treatment effects monitoring,
designers must, first, identify the outcome (or outcomes) that will be used for stopping.
The usual approach is to focus on the outcome used for sample size calculation.
The next step is to specify the comparison or comparisons to be made in applying
the rule. If the application is based on hypothesis testing under a frequentist construct,
designers have to indicate the value of the test statistic that has to be achieved for action,
generally measured by an appropriately small p-value. They must also decide whether to
have ‘‘spending rules’’ for p-values based on the number of looks made.
382
X V. T R E A T M E N T E F F E C T S M O N I T O R I N G
The advantage in having a stopping rule set before the trial starts is that there
can be no question as to objectivity of the decision process. Use eliminates prospects of
‘‘shopping’’ for outcomes and differences that are significant and then stopping.
For certain, the FDA prefers stopping rules. The concern, in the absence of
stopping rules set before enrollment starts, is that sponsors will ‘‘switch’’ the outcome if
the results are not encouraging for the one specified when the trial was designed or that
they will ‘‘data dredge’’ to find a significant difference and then present those results as a
basis for a claim.
Stopping rules are better suited for gauging beneficial effects than for nil or
negative effects. Trials are done to find beneficial effects. They are not done to show that
treatments are ineffective or harmful. Hence, trialists do not normally continue a trial as
long in the face of a negative trend as in the face of a positive one.
Another reason to be wary of stopping rules for ill-effects is that it is more difficult
to anticipate ways in which a treatment may fail than for how it might succeed. Basically,
there are fewer routes to success than to failure. But even if one comes up with all the ways
of interest, it is obvious that the differences will be far short of ‘‘significant’’ for reasons
already stated.
Consider the National Cooperative Gallstone Trial.44,76 Chenodeoxycholic acid
was known to be nephrotoxic in primates when the trial started. Hence, liver function
was closely monitored. Although the cases of chronic hepatitis were few, they were in
patients receiving chenodeoxycholic acid. The treatment effects monitoring committee
was concerned enough to have considered stopping the trial even though the difference
was far from being statistically significant.
By and large, trialists tend to steer clear of stopping rules for phase III and IV
treatment trials because of the limitations outlined above. They have to decide in such
cases whether to provide monitors with guidelines as to when they might consider stopping
or to proceed without any guidelines at all. If they opt for guidelines, the guidelines will be
evaluated in the exact same fashion as stopping rules, the difference being that monitors
may recommend continuing even if the guideline conditions are reached or may stop prior
to encountering the guideline conditions. The distinction, while perhaps meaningful to
monitors, may be lost on most others. As a rule, guidelines come to be seen as ‘‘rules’’
once in place.
In some sense, perhaps, the best approach is to create a sound monitoring
committee and let it operate with a minimum of rules or guidelines. If it is more
comfortable monitoring with guidelines, let it so proceed; but, if its members prefer
otherwise, let it be as well. It is not evident that the quality of the monitoring is enhanced
by rules or that patients are better served with them in place.
1 2 7 . Tr e a t m e n t E f f e c t s M o n i t o r i n g : Q u e s t i o n s a n d A n s w e r s
383
127. Treatment effects monitoring: Questions and
answers
R E L AT E D E N T R I E S
Treatment effects monitoring (page 373), Treatment effects monitoring: Purpose
(page 375), Treatment effects monitoring: Approach (page 377), Treatment effects
monitoring committee: Questions and answers (page 391), Treatment effects monitoring
committee (page 387)
DEFINITIONS
alpha spending function n - A function serving to apportion the amount of type I
error spent per look when engaged in testing involving multiple looks at accumulating
data, e.g., as in treatment effects monitoring, so as to preserve an overall type I error
level; achieved by testing early on at high levels of error protection and later on with
lower levels of error protection such that the total error is at the level specified at the
outset.23
Bayesian adj - Being or relating to a school of thought in which a prior probability
distribution is assigned to parameters (hypotheses) fashioned from observed data by
application of Bayes’ theorem. The resulting posterior probabilities are viewed as measures
of existing evidence and prior opinion, a result of logical reasoning, or subjective degree
of belief. rt: frequentist, likelihoodist
frequentist adj - Being of or relating to a school of thought in which statistical inferences
about data depend on the probability distribution for parameter values based on the
notion of a study being repeated many times under the same conditions.
likelihoodist adj - Being or relating to a school of thought for analysis and interpretation of
data based on the likelihood principle—a principle that asserts that all of the information
for assessing one hypothesis versus an alternative hypothesis, given a set of data and
an assumed model, is contained in the likelihood function of the hypotheses for the
data.30 In the case of trials, the principle implies that the interpretation of a given set of
data, in regard to the amount of support provided for one hypothesis versus another, is
independent of the reason for the analysis, i.e., is not influenced by the number of interim
looks performed or by whether or not the trial was subject to a stopping rule [Dupont,
198329 ; Cornfield, 1966.15 ] rt: frequentist, Bayesian
QUESTIONS AND ANSWERS
Does the trial require monitoring?
Answer: Assume that it does unless convincing arguments can be made that it does
not. To be convincing that it does not, designers must be able to argue that the risks
associated with being treated with study treatments are minimal and that risks are not
materially altered by monitoring. Arguments based on cost, difficulties in monitoring, or
the ‘‘risks’’ of early stops because of monitoring are not valid. A decision not to monitor,
and rationale for not doing so, should be reported to IRBs of record and should be
implemented if required by IRBs.56
384
X V. T R E A T M E N T E F F E C T S M O N I T O R I N G
Should there be a stopping rule?
Answer: The answer depends on who you ask. Persons with a frequentist philosophy
will tilt in favor of stopping rules. Persons with a likelihood or Bayesian philosophy will
shun stopping rules.
Stopping rules tend to be favored by the FDA and, hence, by proprietary sponsors
engaged in trials going before the FDA. They are favored because of the aura of objectivity
implied by stopping rules fashioned before data are collected. They are preferred as
well by some trialists simply as a means of keeping monitoring groups from having itchy
‘‘trigger fingers.’’ The concern is that, absent such rules, the monitoring body may be
disposed to act before they should.
The trouble with reliance on stopping rules is that the rules are rarely richly enough
defined or fashioned to deal with all the conditions that could lead to stops. Once
fashioned, they can become blocks to stopping even if such action seems prudent.
Rules based on p-values have the added drawback of reducing the entire process
of monitoring to one driven by p-values. The reality is that the decision-making
process, as a rule, is much more complicated than implied by p-value-driven stopping
rules.
What is the difference between stopping guideline and stopping rule?
Answer: A stopping rule is for determining when to stop. If the conditions of the
rule are satisfied, the trial is stopped. A stopping guideline is used as a gauge for
stopping. It does not require a stop when the conditions indicated in the guideline are
satisfied.
Is statistical significance a necessary condition for stopping?
Answer: No. It is usually for stops because of the superiority of a test treatment but not
for a stop due to inferiority or safety of the test treatment.
Should p-values be adjusted for multiple looks?
Answer: The answer depends on philosophy. Groups adherent to a frequentist view of
analysis and reliant on p-value-based stopping rules are likely to take account of looks
in the p-values used for stopping. Groups adherent to a likelihood or Bayesian view of
analysis are largely indifferent to the issue of adjustment.
Should there be restrictions on the number of looks that can be made?
Answer: Generally not advisable.
When should looks be made?
Answer: In trials involving avoidable risks, as often as deemed appropriate by the
monitoring body. The usual ‘‘look’’ frequency is dictated by the calendar (e.g., every 6
months), but sometimes at certain points in the course of the trial (e.g., at the halfway
point to enrollment, on completion of enrollment, etc.), or at intervals determined by
counts of events (e.g., after 20 events, again after 40 events, etc.).
What constitutes a look?
Answer: In the case of fixed sample size designs, whenever the body or group
constituted to perform treatment effects monitoring convenes and reviews treatment
effects data.
Should monitoring reports be prepared by masked data analysts?
Answer: Ill-advised, even if the monitoring committee is masked. One of the side
products of monitoring is in its utility in helping to find errors and discrepancy in
data as they are being accumulated and analyzed. The ability to find such errors and
discrepancies and to resolve them is reduced when analysts are denied access to the
most important variable in the trial—treatment assignment.
In any case, masking data analysis is logistically difficult and unlikely to be effective.
Treatment effects have telltale patterns. Often the patterns are sufficient to inform
analysts as to treatment group.
1 2 7 . Tr e a t m e n t E f f e c t s M o n i t o r i n g : Q u e s t i o n s a n d A n s w e r s
385
Should monitors be masked?
Answer: Not advised, especially in trials where stops are possible because of harmful
effects (see refs 55 and 57).
If monitors are masked, when should the mask be lifted?
Answer: The usual approach is to leave the answer to the monitors. A common approach
is for monitors to continue masked until a difference is observed and where a majority
of the members believe they need to be unmasked in order to know the direction of the
difference and to better direct analyses to explore the difference.
Who gets to see treatment effects monitoring reports?
Answer: Usually only those responsible for preparing them and members (voting and
nonvoting) of the monitoring body.
Who prepares treatment effects monitoring reports?
Answer: Personnel in the data center or coordinating center.
Should IRB receive monitoring reports?
Answer: No. IRBs have neither the time nor the expertise for the nitty gritty of treatment
effects monitoring. The prospect of maintaining a blackout on interim results is diminished
by such distributions.
What should be stated about monitoring in consent forms?
Answer: Enough to satisfy a person that they will be protected from harm. The consent
form should indicate who will be responsible for monitoring and how recommendations
for treatment changes will be implemented and communicated to them.
Is a recommendation for a stop issuing from the monitoring group binding on study
investigators?
Answer: No. The buck stops with investigators. Investigators bear the ultimate
responsibility for those they study. Hence, recommendations for stops are not binding,
but it is rare for such recommendations to be rejected by study investigators.
How is a decision to stop implemented?
Answer: The usual process, where monitoring is done by a committee independent of
study investigators, is one in which the chair or some other member of the committee
presents the recommendation and basis for the recommendation to study leaders. The
study leaders, in turn, convene study investigators to present the recommendation
and data supporting the recommendation. The investigators deliberate and ultimately
vote to accept or reject the recommendation. If they vote to accept, they proceed to
implementation of the change by contacting patients and taking the actions indicated.
1 2 8 . Tr e a t m e n t E f f e c t s M o n i t o r i n g C o m m i t t e e
387
128. Treatment effects monitoring committee
R E L AT E D E N T R I E S
Treatment effects monitoring (page 373), Treatment effects monitoring: Purpose (page
375), Treatment effects monitoring: Approach (page 377), Treatment effects monitoring
committee: Questions and answers (page 391), Treatment effects monitoring: Questions
and answers (page 383)
N A R R AT I V E
Issues
When to create the committee?
Who nominates members of the committee?
What are the eligibility requirements for members?
Who appoints the members?
Who chairs the committee? Who serves as vice-chair of the committee?
What is the advise and consent role for the sponsor if investigators appoint the
committee and what is that role for investigators if the sponsor appoints the
committee?
What is the size of the committee?
Are study investigators represented in the committee? If yes, who, and do they sit with
vote or without vote?
Are meetings of the committee open or closed?
Are voting members to be paid?
Who covers costs of meetings?
Usual modes of creation for TEMCs
Recruitment and appointment of members by study leaders absent advise and consent
role for sponsor (common in small-scale trials and grant-funded trials where
sponsor remains at arms length; use only if sponsor specifically declines advise and
consent role)
Recruitment and appointment of members by study investigators with advise and
consent of sponsor (likely in grant-funded, cooperative agreements)
Recruitment and appointment of members by sponsor with advice and consent of
investigators (likely in sponsor-initiated trials with contract funding)
Recruitment and appointment of members by sponsor; no advise and consent role for
investigators (may be the case in high-profile government-initiated and contractfunded trials; not recommended unless investigators specifically decline advise and
consent role)
TEMC membership issues
Total number of members (voting and nonvoting)
388
X V. T R E A T M E N T E F F E C T S M O N I T O R I N G
Mix of members by discipline and speciality; medical disciplines and number from
each; number and type of statisticians
Number and type of study officers represented
Skills and functions represented from the trial (treater; data analyst; reader)
Other members (nonhealth professional; activist; patient)
TEMC procedural questions
Stopping rules? (Often desired; tend to be simplistic and encumbering; not
recommended in trials where stop may be required for safety or efficacy; not
recommended in treatment trials)
Stopping guidelines?
Constraint on number of looks that may be performed? (not recommended in trials
where stop may be required because of safety)
Adjustment of p-values for multiple looks? (optional)
Masked monitoring? (Preferred by some; seen as reducing bias and making monitoring
more objective; not recommended because of effect of masking on competency of
the TEMC)55
Membership to include at least one study treater? (Convention is to exclude because
of concern regarding treatment-related feedback bias and potential conflicts of
conscience when treater is privy to interim results; downside is in what is lost in
collective understanding of results. Recommendation: Err on side of competency
and include)
Seating of advocates? (Sometimes done, usually for political reasons; generally best
avoided; the purpose of treatment effects monitoring is to review, analyze, and
interpret data, monitoring is not about advocacy)
Executive sessions? (Sometimes used when membership includes nonvoting study
personnel; done to allow voting members to deliberate and vote in the absence
of nonvoting study members; not recommended; include all members whether
voting or nonvoting)
TEMC recommendations
When to establish: On initiation of funding or soon thereafter; IRBs unlikely to approve
trial in the absence of detail regarding the general structure for monitoring56
Membership: 10–12 members; 5–7 voting members plus study officers (nonvoting)
Appointing authority: Sponsor with advise and consent of SC or SC with advise and
consent of sponsor
Reporting: Direct to SC, simultaneous to SC and sponsor, or to sponsor with assurance
of timely transmission to SC
Meeting frequency: Twice yearly, more often if necessary; not less than once a year
Meeting mode: Face-to-face or conference phone
Meeting access: Closed (access limited to members and associated support staff)
1 2 8 . Tr e a t m e n t E f f e c t s M o n i t o r i n g C o m m i t t e e
389
Closed executive session limited to voting members: Not recommended; deliberations
and votes should be taken in presence of nonvoting members
Quorum: Chair or vice-chair of TEMC, majority of voting members and majority of
officers
Voting: Roll call; in presence of nonvoting members; no proxies; no absentee votes
1 2 9 . Tr e a t m e n t E f f e c t s M o n i t o r i n g C o m m i t t e e
391
129. Treatment effects monitoring committee:
Questions and answers
R E L AT E D E N T R I E S
Treatment effects monitoring (page 373), Treatment effects monitoring: Purpose (page
375), Treatment effects monitoring: Approach (page 377), Treatment effects monitoring
committee (page 387)
QUESTIONS AND ANSWERS
Who decides on membership?
Answer: Ideally, investigators, or investigators and sponsors together. Membership
determined by sponsors without any input or right of objection from investigators is
ill-advised though sometimes practiced. Investigators have to have faith and trust in the
committee. It serves no good to have a committee with members not acceptable to
investigators.
Who appoints the committee?
Answer: Usually the investigators by an officer of the study or an official of the sponsoring
agency. It is likely to be the investigators in investigator-initiated, NIH-grant-supported
trials, and the sponsor in the case of NIH, RFP-initiated trials.
To whom should the committee report?
Answer: Ideally, directly to study investigators since their duty is to them. Investigators,
when monitoring is done by an independent committee, place trust in the committee in
meeting their commitment in preserving the persons they study from harm. The link to
them should be inviolate. Arrangements in which the reporting is to the sponsor carry
potential for breaking the link. Such arrangements should not be used except where
there is a written commitment of sponsors that recommendations for change, passed to
it, will be passed to study leaders within two working days of receipt by the sponsor.
How big should the committee be?
Answer: Not too big and not too small. The usual size is 10 or fewer members (voting
and nonvoting).
Who is eligible for membership?
Answer: The answer depends on the organizing philosophy of the committee. Most
committees, even if created to be independent of study investigators, will be comprised
of two kinds of members: Members with vote and members without vote.
A monitoring committee cannot function without input and support from the study
and its investigators. Hence, most committees will include representatives from the
coordinating center as nonvoting members. They may be also comprised to include
other study leaders as nonvoting members.
Philosophies vary as to whether membership should include at least one person
with treatment and data collection responsibilities in the trial. The argument for inclusion
of at least one such person is that first-hand experience in the trial is necessary for
competent monitoring. The argument against has to do with concerns regarding the
possibility of feedback bias because of the person’s involvement in treatment and being
privy to interim results.55
Who votes?
Answer: Usually, in the case of independent monitoring committees, only those
members not associated with the trial. Members associated with the trial sit, but
without vote.
392
X V. T R E A T M E N T E F F E C T S M O N I T O R I N G
Should the committee be masked?
Answer: Not recommended. Masking reduces competency and, therefore, is open to
question. The primary purpose of monitoring is to preserve persons from the potential of
harm. That is made more difficult when monitors are masked and therefore uncertain as
to whether a treatment difference is due to the superiority or inferiority of a treatment.
Should deliberations and votes be in sessions closed to nonvoting members of the
committee?
Answer: Not recommended. Ideally, the only distinguishing characteristic of members
when committees are comprised of voting and nonvoting members should be in who
votes, not in rights of attendance.
When should the committee be formed?
Answer: Early in the course of the trial. Usually at or around the start of enrollment.
How often should it meet?
Answer: As often as necessary, but always at least once a year, face-to-face; actual
frequency dictated by underlying event rates and the likelihood of major changes in the
nature or direction of results from meeting to meeting.
Where should it meet?
Answer: In a place convenient to the membership, often an airport hotel for committees
comprised of members scattered about the country. Fancy resort or vacation settings
are not recommended in that ‘‘opulence’’ can be seen as corrupting by the public.
Does the committee have the power to stop the trial?
Answer: No. They have the power to recommend stopping but the investigators have
the ultimate say and responsibility as to stop or continue.
What happens to recommendations from the committee?
Answer: They are passed directly or indirectly to study investigators.
If voting members are to be independent of trial, what is the definition of
independence?
Answer: It means that voting members do not derive support from the trial and that
they or people under their direction or control do not depend on funding from it. If they
are from an institution housing a study center, it means that they are administratively
independent of the center.
What constitutes conflicts of interest in the membership?
Answer: See Policy on conflicts of interest (page 463).
What is the ‘‘fix’’ for conflicts of interest in the membership?
Answer: Exclusion from membership.
What do IRBs want to know about the committee?
Answer: The answer depends on the IRB. Some may be passive in regard to monitoring,
while others may be assertive and demanding. Part of the duty of IRBs is to ensure
adequate monitoring in the case of trials. To meet that responsibility, they can be
expected to want to be satisfied that treatment effects monitoring will be done, that it will
be timely, and that it will be competently and objectively done. They can be expected
to want to know who will do the monitoring, the frequency of monitoring, and how
recommendations for change, if any arising from monitoring, will reach investigators,
them, and patients.
Quality Control and
Assurance
130. Quality Control and Assurance Procedures
395
130. Quality control and assurance procedures
SLIDE
Quality assurance procedures: Studies of Ocular
Complications of AIDS (SOCA)80
Performance monitoring
Treatment effects monitoring
Clinic certification
Staff training and certification
Site visiting
Record audits
Dependent double data entry
Ongoing data editing and querying
Periodic sweeps to determine vital status on all persons enrolled
R E L AT E D E N T R I E S
Data processing procedures (page 285), Data entry design (page 301), Performance
monitoring (page 399), Training procedures (page 401), Assurances and certifications
(page 403), Site visiting procedures (page 405), Audit procedures (page 409)
DEFINITIONS
quality assurance (QA) n - 1. [broadly] Any method, procedure, process, or practice
aimed at achieving, ensuring, or improving the quality or reliability of something; the
aggregate of such methods, procedures, processes, or practices. 2. [data collection] Any
method, procedure, process, or approach for collecting, processing, or analyzing data
aimed at maintaining or improving their reliability or validity; includes any of the
following: pilot testing, pretesting, repeat reading, replicate measurement, data editing,
double data entry, performance monitoring, aspects of data analysis for treatment effects
monitoring, site visiting (defn 1), and record auditing; the aggregate of such methods,
procedures, processes, or approaches. 3. A procedure or practice intended to reduce or
eliminate the chance of error; the aggregate of such procedures or practices. rt: quality
control Usage note: The terms quality assurance and quality control have similar meanings
and are used interchangeably. Use quality control in contexts where the reference is to a
process or procedure having a statistical component. Use quality assurance in regard to
the aggregate of procedures used to ensure quality.
quality control (QC) n - 1. An aggregate of sampling and testing procedures based on
statistical theory and analysis designed to ensure quality in relation to a finished product.
2. A procedure or practice aimed at reduction or elimination of defective parts or errors;
in relation to collection, transcription, or entry of data, a procedure or practice intended
to eliminate or reduce the chance of error; the aggregate of such procedures or practices.
rt: quality assurance Usage note: See quality assurance.
396
XVI. QUALITY CONTROL AND ASSURANCE
N A R R AT I V E
Planning for QA and QC is likely to receive short shrift when the trial is designed. One
reason is because of preoccupation with more pressing matters. Another is because of the
tendency for planners to assume that the ‘‘statisticians’’ will attend to QA and QC once
the trial is underway.
The approach, absent attention at the outset, tends to be ad hoc and ‘‘after the fact’’
crisis driven. The primary value of QA and QC practices is in prevention of problems,
not in recovery from them.
The choice of QA and QC procedures and practices should be from a ‘‘topdown perspective.’’ Procedures and practices of higher importance in producing quality
data should have priority over those of lesser importance. The perspective means that
‘‘standard practices,’’ such as repeat laboratory determinations or adjudicated readings as
QA procedures, should be avoided when only of marginal value in regard to enhancing
validity of treatment comparisons.
Replication is useful in reducing variance, but the reduction is superfluous if the
precision provided with a single determination is already more than sufficient (often the
case). Usually, the same can be said in regard to adjudicated readings. Valid comparisons
of treatment groups can be made using a single reading if readings are not treatmentrelated biased. The procedures for adjudication are almost always logistically complicated
(especially when readers are geographically separated and where they have to meet or be
linked in some other way to arrive at an adjudicated reading) and, almost always, result in
delays in the processes of enrollment, treatment, or data processing.
The use of adjudicated readings to determine eligibility will complicate the
randomization processes and delay the assignment process. If adjudication is used at all,
it is best to keep it out of time critical and decision pathways in regard to enrollment,
treatment, or care of patients.
Adjudicated readings have their greatest value in ‘‘natural history’’-type studies
where there is need for rigor in description. The need for such absolute accuracy is less in
randomized trials where the search is for relative truths.
Designers need to apportion QA and QC efforts based on cost and contribution
of such efforts to the overall quality of results from the trial. The difficulty in doing that
is that budgets are rarely so specific. Typically the costs for QA and QC are subsumed
under the general budgets of the various centers represented in a trial. Nonetheless, there
is merit in identifying costs for QA and QC. There should be some balance between
overall funding and the portion of the budget devoted to QA and QC. What that fraction
should be will vary by trial, but there is reason for concern if the budget is less than 10%
of total direct costs.
Top-down planning should start by listing events or practices to be protected
against. The list should be headed by events or practices having the greatest negative
impact on the trial. Entries heading the list are those causing the trial to be aborted, to
have to ‘‘redesign’’ it, to have to retract conclusions or analyses, or to have the effect of
discrediting investigators or the trial. Obvious entries on the list are:
• Enrollment of ineligible persons
• Enrollment without consent or properly documented consents
130. Quality Control and Assurance Procedures
397
•
•
•
•
•
•
•
•
•
‘‘Busted’’ randomization scheme due to ‘‘peeking’’ or ‘‘breaking the code’’
Ad hoc changes to the study design
‘‘Fudged’’ or ‘‘cooked’’ data
Discrediting conflicts of interests in the investigatorship
Data fraud
Scientific misconduct
Errant analysis procedures
Counting mistakes in regard to who is randomized or in reported events
Inability to account for all persons randomized; absence of mortality followup on
person randomized
• Absence of documentation on deaths or other serious morbid events
Quality control planning aids
• Outline desired quality control procedures for each element of the data generation
and analysis process
• Evaluate importance of each procedure to overall objectives of the trial
• Choose the procedures to be implemented using a ‘‘top-down’’ approach
Examples of QA or QC procedures
•
•
•
•
•
•
•
Edit of data for missing, inconsistent, or outlier values
Independent reprogramming of analysis procedures
Double data entry
Duplicate lab determinations
Repeat readings
Separation of the treatment and data collection functions in unmasked trials
Special committee to code cause of death
Quality control/assurance credos
•
•
•
•
•
•
To err is human
Data that are collected without ongoing quality checks are best left uncollected
The only way to have any assurance regarding data quality is to check, check, check
Perfection is impossible
Quality control is everyone’s responsibility
Trust but verify
Requirements for QA and QC
•
•
•
•
Quality conscious staff
Timely data flow from clinic to processing site
Expeditious data processing
Organizational structure for implementing correction procedures based on QA and
QC findings
398
XVI. QUALITY CONTROL AND ASSURANCE
General edit rules
•
•
•
•
Computer checks are preferable to hand checks
Edit queries should be directed to the persons responsible for data collection
Changes made to data files as a result of edit queries should be documented
Entries in electronic files with outstanding unresolved edit queries should be flagged
Quality control schemes
Fixed time
• Repeat measurement by the same or different person during an examination
• Aliquot determinations (in the same or different runs)
• Replicate readings by the same individual within a short period of time or by
two persons at the same time
Over time
• Periodic submission of masked laboratory samples containing a known or fixed
concentration of a substance
• Resubmission of previously read records to the same individual or reading
center for rereading
QA and QC menu of procedures
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Replication
Adjudication
Auditing
Site visiting
Near-real-time data entry
Ongoing data editing
Training/retraining of study personnel
Certification/recertification of study personnel
Written performance standards and guidelines
Double data entry
Conflict of interest disclosure
Regular meetings of the research group
Study handbook and procedures manuals
Numbered policy and procedure memos
Standardized equipment and procedures
Tested data forms
Regular face-to-face meetings of clinic coordinators
On-site data entry
Pitfalls
• Reliance on editing system for detecting forged data
• Reliance on ranking as a means of identifying poor performing clinics
• Overemphasis on one aspect of quality control while overlooking other, more
important aspects
131. Performance Monitoring
399
131. Performance monitoring
R E L AT E D E N T R Y
Quality control and assurance procedures (page 395)
DEFINITIONS
administrative review n-[trials] 1. An ad hoc interim review of performance of some
activity to determine whether it is practical to continue a trial unaltered; especially a
review considering costs. 2. performance review (defn 1) 3. performance monitoring
Usage note: Note that defn 1 has a different operational meaning than defn 3; defn 1
refers to an ad hoc evaluation, whereas defn 3 refers to an ongoing process; not to be
used interchangeably. Not to be confused with reviews involving evaluations of treatment
results as in safety review, efficacy review, or in treatment effects monitoring. Do not
use in contexts where the review includes a review of treatment results. Use is ordinarily
limited to review of performance where there is a desire or need to distinguish such a
review from one involving an interim look, as in relation to treatment effects monitoring.
performance monitoring n - The act of or an instance of reviewing performance of an
ongoing activity to determine if corrective action is necessary. syn: data monitoring, safety
monitoring, data and safety monitoring rt: administrative review, efficacy monitoring,
multiple looks, safety monitoring, treatment effects monitoring
performance monitoring v - 1. Monitoring of performance of some activity (or set
of activities) at points over the course of the activity to determine whether the activity
should continue unaltered; in the context of trials, such monitoring as summarized in a
performance monitoring report; such monitoring as part of ongoing quality assurance; in
the context of multicenter trials, monitoring relating to the performance of the various
centers in the trials. 2. performance review (defn 1) rt: administrative review, treatment
effects monitoring Usage note: Not to be confused with forms of monitoring involving
evaluations of treatment results as in treatment effects monitoring, safety monitoring, or
efficacy monitoring. Defns 1 and 2 have different operational meanings and should not
be used interchangeably. Use performance monitoring when the interim review is part
of a planned ongoing process; use performance review when it is not. See also note for
administrative review.
performance monitoring committee n - 1. A committee charged with performance
monitoring. 2. A committee that reviews performance monitoring reports and takes
or recommends appropriate corrective actions when indicated to deal with identified
performance problems. rt: treatment effects and performance monitoring committee
performance monitoring report n - A report summarizing performance of a center or
centers and used for performance monitoring. In the case of multicenter trials, typically
prepared by the data coordinating center and reviewed by the full research group, steering
committee, or some other body or committee having responsibility for performance
monitoring. rt: treatment effects monitoring report
performance review n -[trials] 1. An ad hoc interim review of performance of activities
or functions to determine whether the trial should be stopped or allowed to continue
unaltered; e.g., one done to determine whether the rate of enrollment is adequate to justify
continuation of the trial. 2. performance monitoring (defn 1) 3. administrative review
(defn 1) Usage note: Not to be confused with reviews involving treatment results. Note
400
XVI. QUALITY CONTROL AND ASSURANCE
also that defns 1 and 3 have different operational meanings than defn 2. Use performance
monitoring when the interim review is part of a planned ongoing process.
N A R R AT I V E
Performance monitoring is an essential part of quality assurance in trials. It must be based
on up-to-date data to be useful. It is of little value when data are so lagged as to be
akin to the light of a distant star reaching earth. The monitoring should be designed to
provide timely information in regard to recruitment, compliance to protocol, compliance
to treatment, completeness of followup, and data processing.
Designers have to decide whether to have set monitoring rules and guidelines akin
to those in treatment effects monitoring to guide decisions related to performance (see
Stopping rules and guidelines, page 381). For example, should they have a rule that tells
them what do if recruitment lags far below what is needed? Likewise, should they have
statistical tests for measuring performance of clinics and rules as to how to deal with
clinics when performance falls below specified limits?
Rules are nice but, as with stopping rules for treatment effects monitoring, rarely
are they adequate alone for decision making.
Sample performance data (presented as counts or rates at a specified point in time and
over time; by clinic and over all clinics)
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Number of patients enrolled and recruitment rate
Number of ineligible patients enrolled
Number of patients enrolled with missing baseline data
Number of dropouts
Number of treatment departures by treatment group
Number of persons lost to followup by treatment group
Number of missed examinations
Number and percent of forms received free of error
Treatment adherence patterns
List of major protocol violations (e.g., unauthorized unmasking, improper lab tests,
improper treatment)
Analysis of laboratory data for secular trend
Inter-aliquot variability
Count of abnormal and outlier values
Data error rates by clinic
Number of time delinquent forms
Issues for designers
• What is to be covered in performance monitoring?
• Who produces the reports? (Recommendation: Data coordinating center)
• Who sees the reports? (Recommendation: All standing to benefit from the
information; investigators, TEMC, and sponsors)
• Who is responsible for taking action? (Recommendation: Steering committee)
• How is action taken? (Recommendation: Via the steering committee)
1 3 2 . Tr a i n i n g P r o c e d u r e s
401
132. Training procedures
R E L AT E D E N T R Y
Assurances and certifications (page 403)
N A R R AT I V E
List particulars regarding training of study personnel. Indicate the nature of the training,
the persons to whom applied, and the time or times when applied over the course of the
trial. Much of the training will be directed at standardization of procedures in order to
reduce observer or recording variations.
Usually, the need for training arises as a prelude to initiation of recruitment and
remains over the life of the trial. There will be need for ‘‘retraining’’ and ‘‘refresher’’
sessions in long-term trials because of fading memories and changes in study personnel.
In addition to training provided for performing specific functions in the trial,
all members of the research group should receive general training. It is good practice to
require all members of the research group to sit through at least one session devoted to a
general review of the trial, its design, and operating features (best accomplished by using
design slides as represented in Appendix 2). It is wise to make certain that all members of
the research group have a basic working knowledge of the trial, as evidenced by scores on
tests given at the end of such a session. Others topics to be covered in training of study
personnel include:
• Review of general procedures for data collection and related study forms
• Review of general design and operating features of the trial, including principles of
data collection, followup, and analysis
• Review of general policies, as represented in Section XIX
• Discussion of duties and responsibilities to patients in protection of their rights and
in preserving them from harm
• Discussion of requirements for integrity and consequences of fraud to guilty parties
and to the trial in general
• Regulatory requirements for reporting adverse events
• Requirements for maintaining IRB approvals and responsibilities to IRBs
133. Assurances and Certif ications
403
133. Assurances and certifications
SLIDE
Certifications: National Emphysema Treatment Trial (NETT)62
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Principal pulmonary physician
Pulmonary physician
Principal thoracic surgeon
Thoracic surgeon
Principal clinic coordinator
Clinic coordinator
Anesthesiologist
Consenter
Data system operator
Oxygen titration and 6 minute walk tester
Pulmonary function coordinator
Quality of life assessor
Radiologist
Rehabilitation coordinator
Rehabilitation medical director
R E L AT E D E N T R Y
Training procedures (page 401)
DEFINITIONS
blacklist n - 1. A listing of persons or agencies singled out for punishment or
disapproval because of some wrongful or wayward act. 2. A list of investigators
restricted in or disqualified from receiving investigational drugs, biologics, or devices
because of failure to comply with FDA regulatory requirements, or for having
submitted fraudulent data or information to a sponsor in regard to some study
under the purview of the FDA; such a list published on the FDA website
(http://www.fda.gov/ICECI/EnforcementActions/FDADebarmentList/default.htm). 3.
A list of persons debarred or otherwise restricted in regard to receiving federal monies for
research or in conducting or participating in such research because of fraud; such a list as
published in the NIH Guide to Grants and Contracts.
certification n - 1. The act or process of certifying. 2. The state of being certified. In
the case of trials, a process for clearing a center or personnel for participation. In regard
to a center, a process intended to ensure that it has the requisite facilities, equipment,
staffing, approvals, and that it meets specified standards; may involve onsite inspections.
In regard to personnel, typically a process involving study specific training and evidence of
proficiency in regard to performing key procedures and activities related to data collection.
debarment n - The state of being debarred from doing or having something, e.g., an
investigator debarred for a specified period of time from applying for or receiving federal
404
XVI. QUALITY CONTROL AND ASSURANCE
monies for research as a result of an agreement with or actions taken by the Office of
Research Integrity in relation to acts of alleged fraud.
N A R R AT I V E
Institutions receiving Federal monies have to meet a number of requirements to be eligible
to receive such monies. Principal among them are requirements relating to research on
human beings. A key requirement in this regard is the requirement for IRB review and
approval before any research involving human beings is undertaken. Monies may not be
expended prior to approval and money stops flowing if the institution’s IRB is decertified.
Funding agreements may include provisions for exclusion of persons debarred
or blacklisted by the FDA. If the funding agreement does not contain such provisions,
designers are well-advised to impose their own requirements for such exclusion.
Designers are also well-advised to institute a formal process for assuring that study
investigators have detailed understanding of the study protocol before starting the trial.
The assurance should be documented.
It is good practice, as well, to make certain that all investigators are exposed to
study orchestrated sessions devoted to the norms and standards for research integrity.
The sessions should include review of case histories of fraud, the consequences of fraud
to the person or persons guilty of fraud, the impact of fraud on the trial, and the duties
and responsibilities of study personnel for ensuring integrity and for reporting suspected
fraud to the appropriate person or body. The assurance may be achieved by requiring
all study personnel to attend at least one session devoted to integrity and by receipt of
signed statements attesting to an understanding of duties and responsibilities for ensuring
integrity.
Designers may also specify procedures for certifying clinics for participation. Those
procedures may include requiring clinic directors to certify to their facilities, staffing, and
equipment. The data needed for certification may be collected on a study form developed
for clinic certification.
In addition, designers may institute formal processes for certifying study personnel
for specified activities in the trial. The process may include training as well as demonstration
of proficiency in performing specified procedures. It is up to designers to list personnel
requiring certification, what the certifications are to be, how certification is obtained, and
whether, when once obtained, it needs to be maintained by periodic recertification.
134. Site Visiting Procedures
405
134. Site visiting procedures
SLIDE
Site visiting procedures: Studies of Ocular Complications of
AIDS (SOCA)80
Frequency: On or shortly after funding of a clinic and every year to 18 months
thereafter; Fundus Photography Reading Center and Coordinating Center as
needed
Team: 2–4 people depending on time and purpose; at least two from coordinating
center; usually only persons internal to SOCA; teams visiting clinics may include
at least one person from another SOCA clinic; teams for cause visits to include
at least one study officer
Length of visit: Usually one day; 4–6 hours
Activities (clinic visits): Review of approvals and certifications including
correspondence and approvals from local IRB; review of study documents
(for completeness, accuracy, and currentness); review of enrollment and consent
process; review of study procedures including demonstration of procedures;
check of equipment; review of previous site visit report; forms audit; check of
consent documents and check for properly dated and signed consent for each
patient enrolled
Reporting: Report of visit, complete with list of action items, produced by
Coordinating Center and forwarded to center director; copies of reports supplied
to Steering Committee for review
Actions: Probation or separation of center in the case of inadequate or inappropriate
performance; actions responsibility of study officers and Steering Committee
R E L AT E D E N T R I E S
Quality control and assurance procedures (page 395), Performance monitoring (page
399), Audit procedures (page 409)
DEFINITIONS
circuit rider n - In the setting of multicenter trials, typically a person from the sponsoring
agency, or coordinating center responsible for visiting participating clinical centers on a
regular basis to monitor, audit, and trouble-shoot. rt: clinical research associate, study
clinic monitor
site visit n - A visit to a proposed or functioning study site by personnel not associated with
the site or its parent institution, mandated by a study section, review group, sponsoring
agency, or study leaders and carried out for the purpose of assessing performance potential
or actual performance in order to arrive at a recommendation for funding or continued
funding of the site.
study clinic monitor n - 1. An individual, in the treatment coordinating center, data
center, data coordinating center, coordinating center, or sponsoring agency, responsible
406
XVI. QUALITY CONTROL AND ASSURANCE
for monitoring data collection and data flow procedures at associated clinics. 2. A person
located within a clinic and responsible for monitoring data collection and data flow
procedures for that clinic; field monitor. rt: circuit rider, study clinic coordinator
N A R R AT I V E
Clinic site visits are conducted for various reasons. They can be a part of the training and
certification process. In such cases, visits have to be made before clinics are cleared to start
enrollment. There are reasons to recommend the practice, but it will be difficult to sustain
in multicenter trials with backlogs of clinics awaiting visits. An alternative is to remove
the visits from the critical path of training and certification, but to require a round of
visits within the first several months following the initiation of recruitment at clinics.
Designers have to decide whether to conduct visits on a regular basis over the
course of the trial and, if so, the frequency of visits. An option is for rounds of visits every
year in the first 2 or 3 years of operation and then a larger interval as the trial proceeds.
Designers should anticipate the need ‘‘for cause’’ visits. They should specify causes
leading to the need for visit, the composition of ‘‘for cause’’ visiting teams, and the
process for dealing with ‘‘for cause’’ site visit reports. Typically, ‘‘for cause’’ clinic visits
are made because of poor performance in regard to recruitment, in regard to the quality
or completeness of data provided, in regard to protocol adherence, or in regard to fraud
or suspicion of fraud.
Visits may be made in relation to separating a clinic from the trial or in relation
to the closeout process of the trial. The final round of visits done in relation to closeout
should address issues of final data edits, storage of study records, disposition of unused
drugs, and separation of study subjects from the trial.
The number and mix of visitors will depend on purpose and timing of the visit.
The team will include one or more persons from the data center. Others represented will
depend on the time and purpose of the visit. Teams for visits done early in the course are
best comprised of a mix of people including leaders of the trial and persons experienced
in the recruitment and treatment of persons being enrolled into the trial.
Clinic visiting teams may be comprised to include at least one person from another
clinic, e.g., a treating physician or the clinic coordinator. The advantages are in terms of
exchange of ideas and ‘‘cross pollination’’. The downside is in the logistics of arrangement
and cost.
A sometimes practice in large-scale multicenter trials is to regionalize the clinic
visiting process, e.g., as in the CDP,18 to distribute the travel burden across a wider cadre
of people.
Responsibilities for arranging for clinic visits typical falls to the coordinating
center. Costs for the visits are either covered directly by the funding agency or covered
from budgets awarded to the coordinating center.
Visits to the coordinating center will be arranged by the sponsor or office of the
study chair. Visits to other resource centers will be arranged by the coordinating center
or office of the study chair. Usually, teams visiting resource centers will be comprised of
a mix of people from within and outside the trial. People from outside the trial will be
people experienced in activities performed by the resource center being visited.
134. Site Visiting Procedures
407
Planners need to make certain that there is a system for reviewing and acting on
site visit reports, especially ‘‘for cause’’ visits. The usual approach is to provide reports
to the SC and for that body to review the reports and for advise as to actions required.
Usually the SC has responsibility for dealing with reports containing recommendations
for termination of a clinic for cause.
Note: The clinic site visiting process may be in addition to or instead of the process
performed by a circuit rider in industry-sponsored trials.
135. Audit Procedures
409
135. Audit procedures
SLIDE
Audit procedures: Childhood Asthma Management Program
(CAMP)11
In relation to site visits
Form sets for selected patients reviewed in total; forms compared to keyed
dataset
Consent forms checked for signature and dating (100% audit)
Monthly at Coordinating Center
24–30 forms re-keyed at CC to check for discrepancies in keying as done at
clinics
R E L AT E D E N T R I E S
Quality control and assurance procedures (page 395), Site visiting procedures (page 405)
DEFINITIONS
audit n - 1. A systematic examination or review of an organization, activity, or procedure.
2. A careful step-by-step review of some method or process. 3. record audit rt: desk audit,
off-site audit, on-site audit, record audit Usage note: Subject to varying usage; accompany
with sufficient detail to make sense of usage clear. Take care to distinguish usages having
legal implications from those devoid of such meanings, such as audits done primarily as a
part of quality assurance processes.
audit, audited, auditing, audits v - To examine, verify, or correct. Usage note: Not to
be used interchangeably with monitor v. As a rule, audit v, implies a more detached and
passive process than is the case with monitor v.
audit trail n - The sequence of transactions linking two events or actions. In data
processing, the sequence of transactions linking data in a finished dataset to those
recorded in source documents.
monitor, monitored, monitoring, monitors v - 1. To watch, observe, check, regulate, or
control for some purpose or end. 2. An ongoing evaluation of some process or procedure
for determining when and if changes in that process or procedure are required (as in
treatment effects monitoring or performance monitoring). 3. record auditing Usage note:
In the trial setting, use should be limited to settings denoting an ongoing process.
record audit n - 1. A comparison of data recorded in one document with those recorded
in another document to determine accuracy or reliability; in the context of trials, often
the comparison of data in study records with those in medical charts. 2. A comparison
of information keyed with that recorded on a study form for the purpose of determining
the accuracy or reliability of the keying process. 3. An audit of records by the FDA in
relation to an INDA or NDA. 4. A search for evidence that a person purported to have
been enrolled in a study actually exists. rt: audit, desk audit, off-site record audit, on-site
record audit, record monitor Usage note: Subject to varying uses and interpretations. Use
410
XVI. QUALITY CONTROL AND ASSURANCE
with sufficient detail to make sense of usage clear. Details should include information
concerning the purpose or intent of the audit and its nature, extent, and method. Usages
involving the notion of comparison, as in the sense of defns 1, 2, and 3, should include
details regarding the nature of the records being compared. Clearly, the number of
discrepancies noted will be larger when the comparison involves records having different
formats or functions (e.g., study forms versus medical charts) than when records have
similar formats or functions (e.g., paper form vs. its electronic counterpart as created by
data entry). Most audits are ad hoc and, hence, are of little value as tools for estimating
error or discrepancy rates. Rates require denominators defined by sampling frames or
audits of all records. The absence of denominator data makes it impossible to calculate
discrepancy or ‘‘error’’ rates. In addition, even with denominator data, resulting rates
must be interpreted with caution, especially if viewed as ‘‘error’’ rates. Most rates are
better thought of as discrepancy rates. They should not be regarded as error rates, except
where one of the sources of information in the comparison is known to be correct or
is regarded as being correct. Use descriptors or modifiers (such as random record audit
or 100% record audit) to characterize the method used for selecting records for audit or
the extent of the audit. Use ‘‘on-site’’ when the audit is performed at the site where the
records were generated (e.g., an audit of clinic records as performed by a circuit rider
or record monitor). Use ‘‘off-site’’ when the audit is performed remote from the site of
generation (as in the case of an audit of clinic records on file at the coordinating center).
N A R R AT I V E
Designers should specify audit requirements in regard to quality assurance procedures to
be practiced in the trial. They should list documents, processes, and procedures to be
audited, when audits are to be performed, where and how they are to be performed, and
plans for use of information from audits in maintaining and improving data quality.
Records and documents typically subjected to a 100% audit include the following:
• IRB records: Dates of approvals, dates of submissions and approvals of amendments,
renewals
• Consent forms: IRB approval, revisions, proper current version
• Reports of adverse events to IRBs and FDA
• IND and amendments to IND
• FDA Form 1572 for listed investigators
• Signatures and dates on consent forms for persons enrolled
• Randomization: Dates of release, use of assignments, etc.
• Reports of deaths
• Reports of serious adverse events
Documents and records checked on a sampling basis:
• Laboratory reports: Test results as reported from laboratory compared to recordings
on study forms
• Verification of diagnoses from medical records
• Reports of hospitalization and morbid events
Auditing, in regard to data collection, involves comparison of information recorded
on data collection forms with source documents, usually, in the case of clinical trials,
135. Audit Procedures
411
medical records. Auditing is limited to cases where information recorded is abstracted
from source documents. There is nothing to compare when study forms serve as source
documents, for example, as they do in trials not involving patient populations and as they
do for most of the information recorded on study forms, even when patients are involved.
The primary value of auditing in regard to data collection lies in the discipline
implied by an ongoing checking process. The fact that one’s activities and recordings are
subject to checks by audits serves as a reminder of the need for care in the collection and
recording processes.
Auditing is used in cases of suspected fraud and can, on occasion, be useful in
discovering fraud. It can have value as a quality assurance procedure when done on a
sampling basis in an ongoing fashion over the course of the trial and when used as a basis
for taking corrective measures and for providing feedback to investigators in regard to
performance.
The 100% audit, while seen by some as the ‘‘ultimate’’ check (e.g., as in
the NSABP13 following revelations of fraud), is overrated. They are costly and timeconsuming. Often there is more to be gained in increased quality via other less costly
procedures.
Data Analysis
136. Analysis Datasets
415
136. Analysis datasets
R E L AT E D E N T R I E S
Final analysis (page 421), Closeout design (page 225), Data processing procedure (page
285), Data sharing: Internal (page 307), Data sharing: External (page 311)
DEFINITIONS
analysis dataset n - The dataset used for an analysis, e.g., a dataset prepared for use in
writing a results paper; typically involving a data freeze and assembly of data from various
databases comprising the study database. rt: dataset
data freeze n - Data held in a fixed state, especially such a state imposed on a database in
order to complete some task requiring a stable, nonchanging database (e.g., as required
for preparation of a treatment effects monitoring report). rt: data snapshot
data harvest v - The act of receiving and assembling data from data collection and
generation sites, e.g., as accomplished by a data center in a multicenter trial by downloading
data residing at study clinics or by receipt of electronic files from study clinics.
dataset n - A collection of information organized and arrayed in some way for convenience
of access and use, especially one arrayed electronically for computer processing. Usage
note: Subject to varying uses, often used in references to electronic databases but may
refer to collections of information not amenable to electronic processing or manipulation.
In the setting of trials, used in references to collections of data on the study population.
rt: database
frozen data n - Data held in a fixed state by virtue of a data freeze.
frozen dataset n - A dataset created from a database of an ongoing study held fixed;
created by specifying a cutoff date for harvest of data into the dataset; created in relation
to data analyses.
N A R R AT I V E
Any analysis, except one done on the fly, is based on a frozen dataset. Freezes are necessary
to provide fixed datasets immune to changes by additions or changes.
Frozen analysis datasets are created over the life of the trial. They are needed
in relation to performance and treatment effects monitoring during the trial. They are
needed in relation to analyses of results for study publications during and after the trial.
Decisions in creating analysis datasets include:
• Setting a cutoff date beyond which changes or additions to the study database are
not accepted
• Determining whether the dataset includes data with outstanding edit queries
(typically the case for interim analyses but not for final analyses)
• Determining whether data harvests are to be done preparatory to creation of the
dataset (usually the case for datasets prepared for interim analyses)
• Deciding what is to be done about errors in the datasets discovered during or after
use (generally ignored if inconsequential; if serious enough to affect results, analyses
redone and revisions reported)
137. Analysis Questions Regarding Study Results Publications
417
137. Analysis questions regarding study results
publications
R E L AT E D E N T R I E S
Counting and analysis rules (page 17), Subgroup analysis (page 423), Publication policy
(page 429)
DEFINITIONS
ancillary publication n - 1. A publication containing ancillary results. 2. A publication
related to an ancillary aim of a research project; in the case of trials, usually publications
from ancillary studies. rt: primary publication, secondary publication
baseline results paper n - A type of paper devoted to description of the study population
on enrollment.
mainline paper n -[trials] A paper detailing the design, methods, or baseline results of a
trial or containing original results related to the primary objective of a trial and written
by study personnel commissioned by the investigative group or its representative. syn:
primary publication rt: secondary paper
primary publication n - 1. A publication containing original data; in trials, especially one
containing a primary result. 2. A publication from a research project considered essential
in relation to the primary purpose or objective of the project; in the case of trials, includes
publications of primary results and publications on the design, methods, and baseline
results of the trial.
results paper n - A paper devoted to presentation and analysis of primary, secondary, or
ancillary results from a study.
secondary paper n - [trials] A study paper dealing with a secondary objective of the study.
study result n - 1. A finding from a study. 2. A result stated in a study publication,
especially one stated in the abstract of a publication.
QUESTIONS AND ANSWERS
When should one publish results?
Answer: When the trial is finished or when there is a results-based protocol change. See
Publication policy (page 429).
Should one present results before publication?
Answer: : No. The only exception (rare) is when the information has life-saving potential.
See Publication policy (page 429).
Should one wait until data are final?
Answer: Often not practical, especially if the publication is to report an interim result
leading to cessation of a study treatment because of harm.
Should one follow the counting and analysis rules outlined on page 17?
Answer: Yes!
Should analyses be verified by another person before publication?
Answer: Yes. It is better to discover errors before publication than after publication.
418
X V I I . D A T A A N A LY S I S
Should there be a cutoff date for the analysis dataset?
Answer: Of course. One needs an unchanging dataset for analyses and for follow-on
analyses generated by queries after publication.
Should the cutoff date be reported in the publication?
Answer: Yes
Should the primary analysis be by intention to treat (ITT)?
Answer: Yes. Others may be done, but the one featured in the publication and the
analysis carrying the weight of the conclusions should be that analysis.
Should the analysis include subgroup analyses?
Answer: Yes, for reasons indicated elsewhere (Subgroup analysis, page 423). Whether
any subgroup analyses are presented in the finished manuscript depends on what is
found and journal space. Obviously, they will be presented for credible treatment-related
subgroup effects. They should be presented if the study involves designed subgroup
comparisons (page 265). Authors may elect to present results for selected demographic
characteristics, like age and gender, simply for descriptive purposes if space permits.
Should events be adjudicated?
Answer: The answer depends on who you ask. The reason for adjudication is to provide
classifications that are less ‘‘noisy’’ because of common evaluation procedures (see
Readings, page 289).
138. Frequentist vs. Bayesian Analysis
419
138. Frequentist vs. Bayesian analysis
DEFINITIONS
Bayes’ theorem n - A probability theorem, developed by Thomas Bayes,3 of the form
P(E|C) = P(C|E) × P(E)/
[P(C|E) × P(E) + P(C|E) × P(Ē)]
where P(E|C) is the posterior probability of the event E, given condition C, and is
expressed as the product of the prior probability for the event, P(E), and the posterior
probability of the condition given the event, P(C|E), divided by the sum of that product
and the one for the prior probability when the event is absent, P(Ē), and the posterior
probabilities for the condition when the event is absent, P(C|Ē).
Bayesian adj - Being or relating to a school of inference in which a prior probability
distribution is assigned to parameters (hypotheses) fashioned from observed data by
application of Bayes’ theorem. The resulting posterior probabilities can be viewed as
measures of existing evidence and prior opinion, a result of logical reasoning, or subjective
degree of belief. rt: frequentist, likelihoodist
Bayesian analysis n - Any method of or approach to data analysis in which prior
information or belief concerning some condition (expressed in the form of a prior
probability distribution) is used in conjunction with data obtained from a study or
experiment (expressed in the form of a likelihood function) to draw inferences concerning
that condition [Cornfield, 196914 ; 196615 ]. See frequentist analysis for alternative
approach.
frequentist adj - Being of or relating to a school of thought in which statistical inferences
about data depend on the probability distribution for parameter values based on the
notion of a study being repeated many times under the same conditions.
frequentist analysis n - A method of data analysis based on the notion that a study can
be repeated many times under the same conditions and that inferences should be based
on the hypothetical frequencies of repeated outcomes under a given hypothesis. Analyses
are expressed as verdicts regarding the acceptance or rejection of the null or alternative
hypothesis and p-value interpreted as an ‘‘observed’’ type I error rate or confidence
intervals. Usage note: Most analyses in clinical trials are of this form. Generally the
characterization ‘‘frequentist analysis’’ is used only in contradistinction to a method of
analysis not requiring a frequentist view, e.g., as in Bayesian analysis.
likelihood principle n - [statistics] A principle that asserts that all of the information for
assessing a hypothesis vs. an alternative hypothesis, given a set of data and an assumed
model, is contained in the likelihood function of the hypotheses for the given data.30 In
the case of trials, the principle implies that the interpretation of a given set of data, in
regard to the amount of support provided for one hypothesis vs. another, is independent
of the reason for the analysis, i.e., is not influenced by the number of interim looks
performed in the past or by whether the trial was subject to a stopping rule [Dupont,
198329 ; Cornfield, 196615 ].
likelihoodist n - One who subscribes to the likelihood school of thought for the analysis
and interpretation of data.
420
X V I I . D A T A A N A LY S I S
N A R R AT I V E
Inferences in medical research are predominately frequentist-based. Evidence of this is
seen in publications of trials. Searching abstracts of 2010 publications of multicenter
randomized clinical trials indexed as having NIH support in JAMA and NEJM (124
articles; 23 JAMA; 101 NEJM) for the terms ‘‘Bayes’’ and ‘‘CI’’ (for confidence interval)
yields two occurrences of ‘‘Bayes’’ and 200+ of ‘‘CI.’’
Design drives analysis. Trials with fixed sample size designs are usually analyzed
from a frequentist’s perspective. Trials with sequential sample size designs may be run and
analyzed from the frequentist or Bayesian perspective.
The primary virtue of Bayesian analysis and inference is that it allows for
incorporation of prior information in the inference process. A discourse on the use
of Bayesian inference can be found in Guidance for the Use of Bayesian Statistics in
Medical Device Clinical Trials (http://www.fda.gov/MedicalDevices/DeviceRegulationand
Guidance/GuidanceDocuments/ucm071072.htm). The difficulty with the Bayesian
approach is in deciding what constitutes prior information and where the information
comes from. Use of the method is more plausible when prior information is from trials
than when it is from other sources.
139. Final Analysis
421
139. Final analysis
R E L AT E D E N T R I E S
Analysis datasets (page 415), Analysis questions regarding study results publications (page
417), Publication (page 427), Publication policy (page 429)
DEFINITIONS
final adj - 1. Of or relating to end or conclusion. 2. Not amenable to change. 3. Of
or relating to a finished analysis or result. Usage note: Final is an elusive state. In trials,
things labeled as ‘‘final’’ have ways of changing. For this reason, study protocols are better
labeled by version number than as ‘‘final.’’ Data considered ‘‘final’’ are suddenly not final
because of errors or edits.
final data analysis n - 1. Data analysis carried out at the end or last stage of a study, e.g.,
analysis performed during the termination stage of a trial. 2. Data analysis performed in
relation to the final version of a manuscript or report.
final dataset n - The dataset compiled on completion of a study for use in final data
analysis and for archiving.
final treatment result n - [trials] 1. The result of treatment as seen at the end of treatment.
2. The treatment difference observed at close of trial.
N A R R AT I V E
The term final in regard to analyses is more an expression of hope than of fact. Final
analyses are only final until there are more analyses prompted by queries from reviewers,
editors, or colleagues.
There is no such thing as a final dataset. Datasets are subject to change long after
data collection is finished and as with analyses from ‘‘final’’ datasets.
QUESTIONS
Should one wait until data are final before undertaking analyses for a publication,
i.e., until all data have been keyed and harvested and outstanding edits have been
resolved?
Answer: A luxury rarely available because it takes a long time for data to be ‘‘final.’’
Waiting is not possible if the analysis is done in relation to a publication of results
detailing bases for mid-course protocol changes, e.g., as with an early stop because of
harm. Even if the analysis is to report results at the end of the trial, the dataset will likely
include data still under edit.
What does one do about errors in the final dataset?
Answer: There is no such thing as error free datasets. Errors can be discovered months
or years after data are ‘‘final.’’ The more a dataset is used the more errors found. If errors
affect analyses, the dataset should be updated and the analyses redone if the errors
impact analyses; if errors discovered after results have been published and the errors
affect published results, the errors should be made known to journal editors and authors
should proceed as directed by the editors.
What does one do about questionable data in the analysis dataset?
Answer: Unless there are valid reasons to reject data, data should stand as recorded.
Rejecting data because they are ‘‘questionable’’ is a slippery road. Data that are rejected
422
X V I I . D A T A A N A LY S I S
should be reported as rejected, and reasons for the rejection should be reported in
finished study publications.
What does one do about fraudulent data in a dataset?
Answer: Data established as having been falsified or fabricated should be purged. The
nature and extent of the purge should be reported in study publications.
What does one do about errors in the data analysis?
Answer: The answer depends on when they are discovered. Obviously, if identified
during analysis, the errors should be corrected. If they are discovered after a paper is
published and they change results, journal editors should be notified and the authors
should proceed as instructed.
What does one do about outcome events after the cutoff date for the dataset?
Answer: If the dataset has been created after the close of the trial, all outcome events
should be captured in the dataset. If the dataset has been created before all events have
been harvested or events are still being reported, the cutoff date for counting should be
stated in the publication along with rationale for the date chosen.
What does one do about events discovered after a paper has been published?
Answer: Make the discovery known to journal editors and proceed accordingly.
140. Subgroup Analysis
423
140. Subgroup analysis
R E L AT E D E N T R Y
Designed subgroup comparison (page 265)
DEFINITIONS
data dredging v - Ad hoc data analyses aimed at finding statistically significant differences
among subgroups represented in a trial aimed at explaining a treatment difference,
especially such analyses leading to a presentation or publication heralding differences
found as being important and meaningful. Usage note: Often used in a pejorative
sense, especially in reference to analyses in which it appears that only large differences
are presented and where the number of comparisons made is not specified. Not to be
confused with subgroup analysis or exploratory data analysis.
exploratory data analysis n - Data analysis performed for the purpose of finding
relationships of importance, subgroups of people, or data subsets that may explain
observed results; usually performed without benefit of prior hypotheses. Usage note: Not
to be confused with data dredging.
subgroup n - 1. A subordinate group whose members share some distinguishing trait
or feature. 2. A subset of a study population distinguished by a characteristic or set of
characteristics; in the case of trials, such a subset as distinguished by one or more baseline
characteristics.
subgroup analysis n - 1. Data analysis focused on a selected subgroup (defn 2). 2.
Analysis aimed at characterizing observed differences among subgroups, especially, in the
case of trials in comparison of treatment differences in subgroups of patients defined
by baseline characteristics. 3. A form of exploratory data analysis aimed at identifying a
subgroup of persons that account for an observed difference, e.g., such an analysis in a
trial to determine whether or not an observed treatment difference can be accounted for
by some subgroup, especially such analyses using baseline characteristics. Usage note: Not
to be confused with ‘‘data dredging.’’ Analyses involving subgroups formed using entry
demographic and other baseline characteristics are an essential part of the analysis processes
for trials. The analyses are done to determine whether or not it is reasonable to regard
an observed treatment effect as being homogeneous (i.e., independent of entry and other
important baseline characteristics). The analyses have bearing on conclusions reached
from trials. Evidence of qualitative or quantitative treatment by baseline characteristic
interaction obligates the trialist to temper or qualify conclusions accordingly. A treatment
effect cannot be assumed to be homogeneous across subgroups absent analyses aimed at
addressing the question. Subgroup analyses become forms of data dredging if results of
such analyses are used to identify ‘‘significant’’ differences and presentation to suggest
that the differences are the result of clinical insight regarding an underlying disease
process.
subgroup comparison n - [trials] A comparison of treatment groups within a specified
subgroup of people to assess treatment effect; subgroup typically defined by disease state
or history on entry or by entry baseline or demographic characteristics.
subgroup treatment difference n - [trials] A difference in treatment effect in one subgroup
of people versus another (e.g., males versus females), especially such a difference for some
424
X V I I . D A T A A N A LY S I S
baseline subgrouping variable; such a difference considered to be statistically significant; a
treatment by subgroup interaction. rt: treatment interaction
subgrouping cutpoint n - The value of a subgrouping variable used to separate persons
into subgroups; e.g., formation of subgroups of patients less than 35 years of age, 35
through 54 years of age, and 55 years of age or older requires use of cutpoints at 35 and
55 years of age.
subgrouping variable n - A variable, such as age, used to classify observation units or
treatment units into subgroups; a baseline characteristic for most subgroup analyses in
trials.
N A R R AT I V E
Subgroup analysis has a bad name because it is associated with data dredging, but
subgroup analysis is essential preparatory to publishing treatment results. Investigators
have a responsibility to know if a treatment effect is homogeneous across subgroups of
people studied before reporting results.
To be useful in exploring treatments effects, subgroup analyses must, of necessity,
be limited to variables independent of treatment assignment. This means that the choice
of subgrouping variables is limited to invariant demographic characteristics like gender
or to variables observed at or prior to randomization. Cut points to create subgroups
based on a continuous variable, e.g., as for age at entry, must be chosen independent of
treatment differences.
Publication/Presentation
141. Publication
427
141. Publication
R E L AT E D E N T R I E S
Publication policy (page 429), Authorship (page 431), Credits (page 435), Presentation
policy (page 439)
DEFINITIONS
ancillary publication n - 1. A publication containing ancillary results. 2. A publication
related to an ancillary aim of a research project; in the case of trials, usually publications
from ancillary studies. rt: primary publication, secondary publication
mainline paper n - [trials] A paper detailing the design, methods, or baseline results of a
trial or containing original results related to the primary objective of a trial and written
by study personnel commissioned by the investigative group or its representative. syn:
primary publication rt: secondary paper
natural history study n - A prospective followup study designed to yield information
on the natural course of a disease or health condition, especially one having minimal
exclusions; such a study within a clinical trial that focuses on the control-assigned group
when the control treatment is a placebo or standard medical care.
presentation n - 1. A work displayed (as in a poster session) or read at a professional
meeting. 2. The act of presenting; something presented. 3. Something disseminated for
the purpose of generally informing but not qualifying as a publication. rt: publication
Usage note: Presentation and publication have overlapping connotations to the extent
that both terms relate to displaying or presenting for the purpose of informing.
primary publication n - 1. A publication containing original data; in trials, especially one
containing a primary result. 2. A publication from a research project considered essential
in relation to the primary purpose or objective of the project; in the case of trials, includes
publications of primary results and publications on the design, methods, and baseline
results of the trial.
primary result n - [research] A result of direct relevance to the primary objective of a
study. In clinical trials, a result based on the primary outcome measure or on the design
variable of the trial. rt: secondary result, ancillary result
publication n - 1. The act or process of publishing. 2. A published work. 3. A manuscript
appearing in an indexed journal (print or electronic). 4. A print document or its electronic
equivalent appearing in a book, proceedings of a meeting, or other similar compendium,
as normally found in a library or residing in an electronic database open to public
use. rt: presentation Usage note: Publication has connotations overlapping those of
presentation. Publication, in the research setting, is best reserved for use in relation to
defns 3 and 4.
secondary publication n - [research] 1. A publication containing original secondary
results. 2. A publication considered essential in relation to a secondary purpose or
objective of a research project; in the case of trials, usually publications devoted to results
for a secondary outcome measure or publications providing added information bearing
on a primary result. rt: primary publication, ancillary publication
428
X V I I I . P U B L I C AT I O N / P R E S E N TAT I O N
Types of papers
•
•
•
•
•
•
•
•
Primary results
Secondary results
Design and methods
Baseline results
Descriptive and natural history
Ancillary studies
Methodological
Review and summary
142. Publication Policy
429
142. Publication policy
SLIDE
Publication policy: Results of Studies of Ocular
Complications of AIDS (SOCA) trials80
Publish regardless of outcome, direction, or nature of results
Publish in peer-reviewed, NLM indexed, journal
Publish as soon after trial is stopped or completed as possible; preferably within
6-months
Content and conclusions exclusive prerogative of investigators
Sponsors provided opportunity to comment on manuscripts prior to submission;
comments considered; those deemed reasonable acted upon; no sign-off
authority by proprietary sponsors
R E L AT E D E N T R I E S
Publication (page 427), Authorship (page 431), Credits (page 435), Presentation policy
(page 439)
N A R R AT I V E
Being able to research upon human beings is a form of public trust. The trust is predicated
on the expectation that results of the research will be published for the good of all when
finished. One can argue that that trust is violated when investigators fail to publish.
Recommended policy in regard to treatment results
1.
2.
3.
4.
Publish first, present later (i.e., no presentation of results prior to publication)
Publish regardless of nature or direction of results
Publish in peer-reviewed, PubMed-indexed journals
No publication of interim results except in relation to protocol changes
Of the recommendations, the first is foremost but the ‘‘no presentation prior to
publication’’ clause is difficult to sell to with most investigators because it is contrary to
the norms of scientific discourse. Therefore, even if investigators accept the ‘‘publish first,
present later’’ policy, the tendency will be for investigators to ‘‘waffle’’ when it comes time
to publish.
An argument voiced for presentation is the need to provide timely communication.
However, that argument, to have any appeal, has to be limited to results involving treatment
of life-limiting or debilitating diseases and where the information from the trial is of
immediate importance in dealing with the disease or debilitation. Most results of trials are
not of that nature. In the few instances where they are, it is better to use more efficient
and effective means of communication, such as clinical alerts or Dear Dr letters, than
presentations at scientific meetings.
An argument made to support presentation prior to publication is that presentation
will facilitate publication. However, that argument lacks force. There is no evidence to
430
X V I I I . P U B L I C AT I O N / P R E S E N TAT I O N
suggest that presentation speeds publication. In fact, there are reasons to suspect the
opposite. Presentation and publication represent different modes of communication.
Therefore, only a fraction of the time and energy spent in preparing a presentation
transfers to preparing a publication. Indeed, one can argue that presentation may slow
publication. One can expect a temporary lag in energy after presentation if for no reason
other than to rebuild steam for a writing effort.
A largely self-serving argument made for favoring presentation prior to publication
is that it represents the only opportunity for investigators to present. Waiting until results
are published is seen as tantamount to precluding presentation. However, if the results
are important there will be ample opportunity to present following publication.
There are practical reasons for the last recommendation. There is nothing to be
gained by way of useful information from interim results unless in relation to early stops
or other results-based protocol changes. The proof of trials is in finished results. It is not
from ‘‘preliminary results.’’
The publication policy should be written to allow other kinds of study publications,
as listed for Publication (page 427). There is no reason to wait until the end of the trial
or until a treatment is stopped, in fact there are good reasons to the contrary, to produce
other kinds of publications as early as possible in the course of the trial including papers
on design, methods, and baseline results.
An issue is whether to publish in monograph or stand-alone manuscript form. The
monograph form involving a collection of related manuscripts from the trial is not viable
for publication of primary results because of the time required to produce an orchestrated
series of interconnected manuscripts.
Monographs, if produced at all, are best done near the end of the active life of a
trial after the primary results have been published (e.g., as with the supplement edited
by GJ Criner consisting of 30+ papers having to do with the National Emphysema
Treatment Trial appearing as a supplement to Proc Am Thorac Soc 19 ). If considered
at all, monographs should be produced as supplements to PubMed-indexed journals.
Monographs not indexed in PubMed are largely lost to the world’s readership.
Investigators should establish policy regarding the nature and extent of review and
approval rights granted to sponsors in regard to publications of results. The policy should
be written to guard investigators’ right of primacy. That right requires that those who do
the trial be the first to analyze, interpret, and conclude and also be able to present and
publish before being required to provide data to the sponsor or others for analysis. The
investigators’ right of primacy is vitiated if publications are subject to approval of sponsors
as conditions for submission to journals for publication.
Typically, policy is written to allow sponsors a time-limited right of review
of results manuscripts with indication that such reviews will be considered (but not
necessarily accepted) in finished manuscripts. The policy should apply alike to private and
public sponsors and should apply whether or not sponsors have proprietary interests in
the treatments tested.
143. Authorship
431
143. Authorship
SLIDE
Authorship: Childhood Asthma Management Program
(CAMP)11
Primary results paper:
Other primary papers:
Secondary papers:
Ancillary papers:
Modified corporate
Modified corporate
Modified conventional
Conventional
R E L AT E D E N T R I E S
Publication (page 427), Publication policy (page 429), Credits (page 435)
DEFINITIONS
author n - [ME auctour, fr ONF, fr L auctor promoter, originator, author, fr auctus, pp
of augēre to increase] 1. The writer or one of the writers of a document. 2. The source or
originator of a notion or concept. rt: authorship attribution Usage note: See Vancouver
Convention.
author citation n - 1. The listing of authors in the masthead or title page of a document,
manuscript, or work; conventional author citation, corporate author citation. 2. The
citing of authors in relation to a document, manuscript, or work of the authors, e.g., in a
reference citation.
authorship n - 1. The source of a work, such as a manuscript. 2. The state or act of
creating or writing, especially in relation to something written. Usage note: See Vancouver
Convention and authorship attribution.
authorship attribution n - The persons, group, or agency to which a work is attributed.
See conventional authorship and corporate authorship. Usage note: The requirements for
attribution under the Vancouver Convention of uniform requirements for manuscripts
submitted to biomedical journals are that it should be based only on substantial contributions
to (a) conception and design, or analysis and interpretation of data; and to (b) drafting the
article or revising it critically for important intellectual content; and on (c) final approval of
the version to be published. Conditions (a), (b), and (c) must all be met.41
conventional author n - A person responsible for writing some document, such as a
manuscript, and who is identified as an author in the masthead or title of a work. ant:
corporate author
conventional author citation n - 1. A form of author citation in which only individuals
are named in the masthead or title of a work. 2. Such a citation in a bibliography or
reference list. ant: corporate author citation rt: modified conventional author citation
conventional authorship n - A form of authorship involving only individuals as named
authors. ant: corporate authorship rt: modified conventional authorship
corporate author n - A corporate entity, such as an agency, institution, or collaborative
group, designated as author of some work; usually in the absence of named authors in the
masthead of papers. ant: conventional author rt: corporate author citation
432
X V I I I . P U B L I C AT I O N / P R E S E N TAT I O N
corporate author citation n - 1. A form of citation in which only a corporate entity
is named as author in the masthead or title of a work. 2. Such a citation in a
bibliography or reference list. ant: conventional author citation rt: modified corporate
author citation
corporate authorship n - A form of attribution in which authorship is attributed to a
corporate entity. ant: conventional authorship rt: modified corporate authorship
modified conventional author citation n - 1. A form of conventional author citation in
which, in addition to individuals, a corporate entity or entities under which the work was
done is named in the masthead or title of a work (e.g., Nancy Jones and Harry Brown
for the XYZ Research Group). 2. Such a citation in a bibliography or reference list. ant:
modified corporate author citation rt: conventional author citation
modified conventional authorship n - A form of authorship involving named authors
and a corporate entity in the masthead listing of authors; see modified conventional author
citation for example. rt: modified corporate authorship
modified corporate author citation n - 1. A form of corporate author citation in which
the names of the persons responsible for writing the work appear in a footnote to the
title page or in the credits or acknowledgments section of the work. 2. A citation in a
bibliography or reference list in which individual names appear in relation to a corporate
work. ant: modified conventional author citation rt: corporate author citation
modified corporate authorship n - A form of authorship in which the masthead
attribution is to a corporate entity (e.g., the XYZ Research Group), but where authors are
listed elsewhere in the work (in the credits or acknowledgments section or in a footnote
to the title page). rt: modified conventional authorship
Vancouver Convention n - The set of rules and specifications relating to authorship
attribution and manuscripts submitted for publication to biomedical journals; named for
the site of the first meeting of journal editors; held in Vancouver, British Columbia in
1978.41
Masthead formats
conventional: Masthead attribution to named persons
Results from the XYZ Trial
Ann L Jones, Fred A Brown, Ian F Smith, and Carol W Jackson
modified conventional: Masthead attribution to named persons and a for or of tag
line for the research group
Results from the XYZ Trial
Ann L Jones, Fred A Brown, Ian F Smith, Carol W Jackson
for the XYZ Research Group
or
Results from the XYZ Trial
Ann L Jones, Fred A Brown, Ian F Smith and Carol W Jackson
of the XYZ Research Group
143. Authorship
433
corporate: Masthead attribution to corporate entity; authors not listed
Results from the XYZ Trial
The XYZ Trial Research Group
modified corporate: Masthead attribution to corporate entity; authors listed in
footnote to the masthead page or in credit listings
Results from the XYZ Trial
The XYZ Trial Research Group
Footnote: Authors: Ann L Jones, Fred A Brown, Ian F Smith, and Carol W Jackson for
the XYZ Trial Research Group
Credit listing: Writing committee: Ann L Jones (chair), Fred A Brown, Carol W Jackson,
and Ian F Smith
Conventional authorship
Advantages
• Identifies authors
• Preferred by most journal editors
• Recognized by promotions committees
• Compatible with National Library of Medicine indexing procedures
Disadvantages
• Difficult to devise equitable system for authorship in studies with large numbers
of investigators
• Naming authors may lead to bickering and dissent
• May discourage young investigators from participation if system of naming
authors seen as precluding them from authorship
Recommended usage
• Single-center trials with small numbers of investigators
• Ancillary studies
• Special investigations or studies prompted by the trial but not directly related
to it
Corporate authorship
Advantages
• Avoids association of study with specific individuals
• Avoids bickering over authorship rights and ordering
• Enables all personnel with documented role to cite in curriculum vitae
Disadvantages
• Does not directly identify responsible authors
• Makes retrieval or identification by author via PubMed difficult
• May discourage individual initiative
• Unfair to key people
434
X V I I I . P U B L I C AT I O N / P R E S E N TAT I O N
Recommended usage
• Multicenter trials, especially for primary results and mainline papers
• Single-center trials with 10 or more investigators
• Papers reflecting a corporate activity or point of view
Considerations in choosing a format
• Size of the investigatorship and number of centers represented
• Discipline diversity of investigatorship
• Number and types of papers to be written
• Skills and expertise types needed for writing efforts
• Need or desire to have publications identified with research group vs individual
authors
• Egalitarianism vs PIship
• Authorship needs of study personnel
• Conventions and preference of journals
Recommendations
• Formulate authorship policy with input from entire research group
• Establish policy early in course of trial
• Provide ample opportunity for review and modification before adoption
• Review and modify policy as trial proceeds
• Avoid needlessly rigid or inflexible authorship rules
• Develop plan that stimulates individual initiative
• Avoid use of authorship as a vehicle for rewards or credits
• Persons listed as authors should have a role in writing and should be able to
testify to the content and veracity of a paper
• Persons instrumental in the design, execution, or analysis of the study, not listed
as authors of paper, should be acknowledged or listed in credit rosters of papers
Considerations in selection of authors
• Compatibility
• Experience (at least one member should be an experienced writer)
• Subject matter expertise (majority of members should have subject matter
expertise)
• Statistical and analytic expertise (at least one member should be expert in data
analysis and statistics)
Considerations in creation of writing committees
• Number of active committees in existence (too many will create log jam if all
committees depend on the coordinating center for analytic and statistical help)
• Number of members on a committee (best to limit to six or fewer members)
• Mix of members (formulate to have subject matter and analysis expertise)
• Choice of chairperson (choose a person committed to write)
• Appointing authority (typically the steering committee or study officers)
144. Credits
435
144. Credits
SLIDE
Credits policy: Studies of Ocular Complications of AIDS
(SOCA)80
Full format (primary publications; corporate masthead authorship
attribution)
Funding sources: Footnote to title page
Key committees: Steering committee, executive committee (officers), and treatment
effects monitoring committee; members as of publication, plus past members
in special cases (e.g., paper on methods and procedures)
Other committees and working groups: As indicated depending on nature of paper
Centers: Clinics and resource centers; support centers pertinent to publication
Research group: List by center, by position or function within center, exclusive of
past personnel except in special cases
Acknowledgments: As indicated per paper
Abbreviated format (secondary publications; modified corporate or modified
conventional form of authorship attribution)
Funding sources: Footnote to title page
Key committees: Steering committee, executive committee (Officers), and
treatment effects monitoring committee; members as of publication; exclusive
of other committees except as relevant to paper
Centers: Name and location of clinics and resource centers pertinent to publication
Research group: Not listed, or listed alphabetically without regard to center
affiliation
Acknowledgments: As indicated
R E L AT E D E N T R Y
Authorship (page 431)
DEFINITIONS
acknowledgment n - 1. An expression of appreciation or thanks for something done
or contributed or for a kindness given. 2. A written expression of such appreciation or
thanks, e.g., as appearing in a published manuscript. rt: credit
credit n - [MF, fr OIt credito, fr L creditum something entrusted to another, loan, fr neut
of creditus; pp of credere to believe, entrust] 1. Recognition by name of some person,
group, or agency for having performed specific functions or duties in relation to some
activity, project, or production. 2. Such a recognition appearing in print in a published
manuscript or at the start or end of a film. rt: acknowledgment
436
X V I I I . P U B L I C AT I O N / P R E S E N TAT I O N
Credit formats (names and titles made up)
Nonspecific: Undifferentiated listing of personnel arranged in alphabetic order (not
recommended)
Ann J Brown, MD
Frank M Curran, MD
Kate S Duran, RN
Raymond V Ellison, PhD
Beth L Grant
Milton J Handly, BS
etc.
Discipline/activity specific
Physicians
Ann J Brown, MD
Frank M Curran, MD
William J Dutton, MD
Nurses
Kate S Duran, RN
Estelle N Lawson, LPN
Carol J Morrison, RN
Data processors
Raymond V Ellison, PhD
Nancy L Harrison, MSc
etc.
Position-specific
Center directors
Ann J Brown, MD
Frank M Curran, MD
William J Dutton, MD
Raymond V Ellison, PhD
etc.
Clinic coordinators
Kate S Duran, RN
Emily N Eaton, BS
Marie K Fisher
etc.
144. Credits
437
Center/committee-specific (recommended for multicentertrials)
Clinics
University of California, Davis
Ann J Brown, MD (Director)
Van H Ho, MD (Deputy director)
Amy B Butler, BS (ECG technician)
Kate S Duran, RN (Clinic coordinator)
Joe T Mews, BS (Lab technician)
etc.
Coordinating Center: University of Minnesota, Mpls
Raymond V Ellision, PhD (Director)
Mary W Baker, MD (Deputy director)
S Kern Forster, PhD (Sr statistician)
Elaine B Garrison, MSc (Coordinator)
Edward N Hartman, MSc (Programmer)
Grace R Zelier, BA (Secretary)
etc. for other resource centers
Steering Committee
Ann J Brown, MD (Chair)
Raymond V Ellision, PhD (Vice-chair)
Frank M Curran, MD
Kate S Duran, RN
William J Dutton, MD (nonvoting)
etc.
etc. other committees
Likely uses
• For inclusion in study publications
• Document detailing composition of the study group and its committees
• Documentation of participation in event of query (e.g., from FDA or person’s
promotion committee)
• For compiling and updating study address directories
• For inclusion in requests for renewal of funding
• For inclusion as front or back matter in study handbooks or other documents
issuing from the study
438
X V I I I . P U B L I C AT I O N / P R E S E N TAT I O N
Considerations and questions
• Who crafts philosophy reflected in listing? Recommendation: Study officers,
executive committee, or steering committees
• What are the limits of listing? Recommendation: Study investigators as represented
by centers of record and associated personnel, study officers, committees and
memberships, funding sponsors, contributors of drugs or other materials needed for
conduct of trial
• Will the list be maintained over the course of the trial? Recommendation: Yes
• Who will be the keeper (custodian) of the list? Recommendation: Office of study
chair or coordinating center
• How will listing be checked for accuracy? For completeness? Recommendations:
Require custodian to circulate at periodic intervals to solicit updates from individual
centers; require a ‘‘sign-off’’ process of center directors prior to use of list in
manuscripts being readied for submission for publication; supplement process with
central review to ensure uniformity of listing and fairness of listings
• Degrees of persons listed? Recommendation: Limit to advanced degrees of relevance;
expect task of listing degrees to be difficult and tedious and likely to be error-prone
unless concerted effort made for accuracy; expect list to need periodic updating
• Time coverage of listing: Snapshot or cumulative? Recommendation: Maintain
to be cumulative (i.e., to include dates and times of comings and goings in
regard to centers, investigators, and committee members); reduce to snapshot when
appropriate, e.g., for inclusion in funding renewal; use cumulative list in primary
publications
• Format of listing: abridged or unabridged? Recommendation: Maintain as
unabridged; trim as needed
• List submitted with study publications? Recommendation: Use in relation to
all publications; submit unabridged listing in relation to primary and mainline
publications; produce shortened abridged listing for secondary and ancillary
publications
145. Presentation Policy
439
145. Presentation policy
SLIDE
Presentation policy: Studies of Ocular Complications of AIDS
(SOCA) trials80
Presentation of published results: Unrestricted; prior notification of study officers
desirable; approval not required
Presentation of facts of study and details regarding design and methods: Unrestricted
if information presented limited to that considered to be in public domain; prior
notification of study officers desirable; approval not required
Presentation of results of a trial: Precluded prior to publication, except in special
circumstances
Presentation of results of secondary outcome data: Precluded until completion or
closure of trial and publication of primary results; review and approval by study
officers required prior to presentation
Presentation of results of ancillary studies: Review and approval required prior to
presentation
R E L AT E D E N T R I E S
Publication policy (page 429), Authorship (page 431), Credits (page 435)
DEFINITION
presentation n - 1. A work displayed (as in a poster session) or read at a professional
meeting. 2. The act of presenting; something presented. 3. Something disseminated for
the purpose of generally informing but not qualifying as a publication. rt: publication
Usage note: Presentation and publication have overlapping connotations to the extent
that both terms relate to displaying or presenting for the purpose of informing.
N A R R AT I V E
Reasons for proscribing presentation of treatment results prior to publication are because
(see also Publication policy, page 429):
• May make publication difficult (most journals want new results; results that have
been presented may be seen as ‘‘old’’)
• May reduce drive for publication
• Analyses likely to be ‘‘preliminary’’
• No good way of answering criticism arising from presentation
• Negative imprinting if results are controversial
The so-called Ingelfinger Rule of the New England Journal of Medicine, as originally
written, required that ‘‘Papers are submitted to the Journal with the understanding that
they are, or their essential substance, have been neither published nor submitted elsewhere
440
X V I I I . P U B L I C AT I O N / P R E S E N TAT I O N
(including news media and controlled-circulation publications)’’. 39 The policy, because of
criticisms, has been softened to a degree, but remains a policy hostile to prior presentation.
A reason for favoring prior presentation lies in the belief that they facilitate
paper-writing. Hence, it is argued that prior presentation of results will produce a better
manuscript, make it easier to write one, and will, in fact, speed production of it. While
it is possible that presentation will lead to a better manuscript, the other two reasons are
open to question, as discussed elsewhere (page 429).
Presentations, by their very nature, are telegraphic summaries of findings. The
analyses are likely to be ‘‘preliminary’’ and so also the conclusions. In any case, once the
slides disappear from the screen, there will be nothing for people to turn to in answering
questions generated by the presentation. They will have to wait for the publication.
Similarly, investigators will be hard put to answer criticism of the trial generated
by the presentation. Investigators will have to remain largely silent until a manuscript is
published. That interim period will be frustrating if the presentation produces a fire storm
of criticism, e.g., as in the case in the UGDP.60 If the attacks are fierce and concerted, the
battle may be lost before publication.
Investigators, invariably, are tempted to want to have their cake and eat it too by
orchestrating publication to coincide with presentation; not recommended for the basic
reason that the time schedules for presentations and publications are independent of each
other. Programs for meetings are set months in advance of the meeting date. Journal
review and acceptance processes run on their own time schedules. Gambling that the two
schedules will coincide is foolish.
Recommended policy
• Establish policy on presentation in conjunction with publication policy.
• Establish limits on what may be presented (usually limited to information on design
and methods, performance and process information and baseline results; usually
written to preclude presentation of followup results).
• Write policy to be consistent with policy on publication (e.g., if policy is ‘‘publish
first, present later’’ in regard to treatment results, then such results must be regarded
as ‘‘off-limits’’ for presentations prior to publication).
• Establish internal procedures for review of invitations to present and for abstracts
submitted for presentation at scientific meetings (typically, review in multicenter
trials done by study officers); if policy on abstracts is laissez faire (i.e., one where
abstracts may be submitted prior to review), establish policy requiring submitter to
withdraw abstract if not approved in review.
Policies
146. Policies
443
146. Policies
SLIDE
Policies: Studies of Ocular Complications of AIDS (SOCA)
trials80
•
•
•
•
•
•
•
Common protocol
In regard to primary results: Publish first, present later
Corporate authorship for primary results publications
Primary analysis by treatment assignment
Review and approval (by study officers) of presentations relating to results
Steering committee approval of ancillary studies
Study protocols, handbooks, and data collection forms available to public on
request
• Independent treatment effects monitoring committee
N A R R AT I V E
Policies likely to be needed include:
•
•
•
•
•
•
•
•
•
•
•
•
•
Publication policy (page 429)
Presentation policy (page 439)
Authorship policy (page 431)
Credits policy (page 435)
Policy on production of manuscripts (page 429)
Policy on study publicity (page 445)
Policy on ancillary studies (page 459)
Policy on substudies (page 467)
Policy on access to study documents such as protocols, handbooks, and study forms
(page 447)
Policy on access to study data (page 449)
Policy on advertising (page 453)
Policy on patient-related payments (page 461)
Policy on payment of study-related travel for patients (page 457)
147. Publicity Policy
445
147. Publicity policy
R E L AT E D E N T R I E S
Publication policy (page 429), Presentation policy (page 439): Policy on access to study
data and results (page 449)
N A R R AT I V E
Trials are likely to generate queries from the public, especially, high-profile trials. Waiting
until there are queries before devising a plan to deal with them is not wise. A plan should
be devised before there are queries when the trial is planned. The plan should indicate,
for all study personnel to know, where queries from outside the investigator group are to
be directed—typically to the head of the study or someone else designated by the head.
The policy should indicate the classes and types of information that can be supplied
in dealing with queries. A reasonable policy is to freely supply information on the purpose
and design of the trial by depositing key design documents, like the study protocol,
consent form, study forms, and design synopsis on a public website.
Information not normally supplied include minutes of study meetings, drafts of
study manuscripts, copies of performance or treatment effects monitoring reports, and
interim treatment results.
If inquiries from the press are expected with the kickoff off of the trial, because
of decisions to alter or stop the trial, or because of its normal end, it is wise to prepare
standby press releases. It is better to have them and not need them than to need them and
not have them.
Investigators and the sponsor should be informed of queries and kept up-to-date
with news stories regarding the trial.
148. Policy on Access to Study Documents
447
148. Policy on access to study documents
SLIDE
Policy on access to study documents: Studies of Ocular
Complications of AIDS (SOCA)80
Access restricted to study investigators during drafting and testing
Unrestricted access and use on distribution to SOCA center on approval for use
in SOCA
Documents not copyright-protected
SOCA approved documents placed on deposit at a public repository (National
Technical Information Service, Arlington, Virginia)
Study documents covered by policy
• Study protocols and consent forms
• Study Handbooks and Manuals
• Study forms
R E L AT E D E N T R Y
Key study documents (page 481)
N A R R AT I V E
One can expect requests for documents such as named on page 481 from persons or
groups not associated with the trial. The requests may come from other researchers,
citizen groups, members of the press, governmental agencies, lawyers, or other persons
or parties. It is useful, therefore, to establish policy on access and to create and maintain
lists of documents that are or will be made available to the public during the trial or on
completion.
The tendency should be to toward openness. The list of releasable facts should, at
a minimum, be those contained in consent forms as well as facts of funding and sponsors,
sample size, stage of the trial, estimated time to completion, participating centers, and
investigators of record.
Certain facts cannot be guarded, even if a group wishes to do so. Federal agencies,
such as the NIH, publish lists of funded projects complete with dollar amounts, and
investigators of record. In addition, information contained in the research proposal,
exclusive of line item budgetary information, of funded proposals can be obtained
under the Freedom of Information Act. Various IRBs publish lists of approved projects.
Obviously, therefore, the facts made available to the public via the study group should
not be fewer than those available via other routes.
The tendency toward openness should predispose groups to making documents
(such as listed on page 481), for interested persons or parties and making them available
forthrightly and expeditiously. Documents available for unfettered use may be placed in
a public archive or on an open study website.
448
XIX. POLICIES
A concern with unfettered access is with ‘‘piracy,’’ i.e., the use of study related
materials by another group without attribution or knowledge. If the concern is legitimate,
the likelihood of ‘‘piracy’’ can be reduced by copyright protections.
There are obvious limits to openness. One should not make documents or facts
available to the public having the potential of violating anonymity or confidentiality
protections accorded study subjects, compromising the integrity of the trial, or revealing
interim results of the trial. Facts and documents routinely protected from release to or
access by outside parties during the trial include:
•
•
•
•
•
•
Randomization codes and blocking procedures
Center specific performance characteristics or features
Minutes of study committees
Site visit reports
Treatment effects monitoring reports
Line item budget information
Policy, when formulated, should be promulgated within the research group. The
policy statement should list facts that may be freely divulged, documents that are releasable,
and contact person for receiving requests for information or documents.
Issues
•
•
•
•
•
•
•
Facts available to the public?
Documents to be placed in the public repository?
Documents to be placed on the internet for public access?
Documents available on request?
Point at which a document may be released?
Place of deposit or of access?
Documents to be copyright protected?
149. Policy on Access to Study Data and Results
449
149. Policy on access to study data and results
SLIDE
Policy on access to study data: Studies of Ocular
Complications of AIDS (SOCA) trials80
Access limited to study investigators during conduct of trial; use for presentation
at public meetings proscribed except as approved by Study Officers and NIH; no
public presentation of results of treatment until trial is completed or stopped
Performance data: Distributed to study personnel on regular basis; presented to
investigators at meetings of the research group
Baseline data: Distributed and presented at meetings of the research group
Treatment effects data: Access limited to members of the treatment effects
monitoring committee; blackout for study investigators (except for study
officers serving as nonvoting members of the treatment effects monitoring
committee)
Datasets used in producing publications containing results placed in public repository
(National Technical Information Service, Arlington, Virginia) on publication
R E L AT E D E N T R I E S
Data sharing: Internal (page 307), Data sharing: External (page 311), Policy on access to
study documents (page 447)
N A R R AT I V E
‘‘Access,’’ as used here, is passive or active. Passive access is that made possible by providing
persons or groups with data contained in reports or documents routinely distributed by
the coordinating center or some other body in the study. Active access is that made
possible by providing data specific to a request.
Policy regarding access will depend on whether it is internal or external to the
investigatorship of the trial.
Generally, only passive access is allowed during a trial and is limited to members
of the investigator group.
As a rule, there is no access to interim treatment results, except by those responsible
for performing interim analyses or reviewing such results (e.g., as represented by persons in
the coordinating center, study officers, and members of the treatment effects monitoring
committee). Usually, personnel responsible for enrolling, treating, and following patients
do not have access to interim results. (They have the means, in the case of unmasked
trials, to summarize their own results by treatment assignment, but are expected to refrain
from doing so.)
Largely, passive access will be in the form of summary reports prepared by the
coordinating center for presentation or distribution to members of the investigator group,
such as:
450
XIX. POLICIES
• Reports needed for monitoring performance; containing counts of persons enrolled,
missed visits, and other performance characteristics
• Characterization of demographic and disease state of persons on enrollment
• Characterization of treatment groups in regard to baseline characteristics
As a rule, there is no active access involving treatment assignment until a trial
is finished or stopped. That means that analyses of ancillary studies where treatment
assignment is a variable of interest cannot be undertaken until the trial is completed or
stopped.
Generally, policies are written to preclude external access during the trial, except
as required by the sponsor or as required to dispose of requests for information under the
Freedom of Information Act.
Usually, policy is written to give priority to requests for access from study
investigators over those from others. Requests from the inside will relate to paper writing
activities and to use of data in analyzing or writing up results of an ancillary study.
As a rule, requests external to the group for data to be used in meta-analyses or other
analyses involving comparison of treatment groups are denied or placed on hold until the
investigators have completed their analyses and related paper writing activities.
It is necessary to balance the needs of the research group against those of society.
That there is such a need is apparent from the fact that investigators are the recipients of
a form of public trust in being allowed to perform research on human beings. They have
a duty to maintain that trust by proper conduct and by reporting of trials and access to
results.
However, it is also clear that those who undertake trials must have primacy rights
if society is to retain a cadre of people willing to undertake them. It is necessary that
investigators have such rights, but also necessary to recognize that those rights are time
limited. Eventually, those rights become secondary to the broader rights of society. The
question is, When?
Operationally, the right can be considered to expire after some reasonable period
of time following the close of a trial, when funding ends, or when investigators cede the
right.
Requests for datasets containing treatment results should be denied during the
trial. Datasets provided to proprietary sponsors containing treatment results during the
trial should be provided with the stipulation that use is limited to those required to meet
regulatory requirements.
Some requests, once results are published, will be for additional analyses or for
datasets for performing analyses. Issues relevant to such requests have to do with:
•
•
•
•
•
•
Amount of time and resources necessary to address the request
Means of covering costs for the analysis or preparation of a dataset
Impact of addressing the request on study objectives
Importance of the analysis in relation to study objectives
Proposed use of such analyses
In the case of requests from outside party for dataset in order to perform their own
analyses; nature of restrictions on use and on dissemination of such analyses
149. Policy on Access to Study Data and Results
451
Issues in drafting policy
•
•
•
•
•
Operational definitions of ‘‘final dataset’’ and ‘‘end of trial ’’
Investigator rights of primacy
Limits to investigator rights of primacy
Limits on access to interim treatment results
Method of reviewing and servicing requests for access to study data
Recommended policy and practice
• Preserve patient confidentiality; do not release or deposit datasets where patients
can be identified.
• Limit access to treatment results prior to finish or stop of the trial to persons or
group responsible for treatment effects monitoring.
• Be kindly disposed to requests for data or analyses arising from inside or outside the
study group relevant to study objectives.
• Provide access to supplementary tables on publication of manuscriptss.
• Provide investigators with datasets before providing them to the public.
• Consider making datasets available to persons outside the research group after
primary results have been published.
150. Policy on Advertising for Patients
453
150. Policy on advertising for patients
SLIDE
Policy on advertising for patients: National Emphysema
Treatment Trial (NETT)62
In regard to information concerning the trial promulgated by clinics:
• Not to tout one treatment over the other
• Should indicate:
❑ Study is collaborative, multicenter
❑ Study sponsored by NHLBI and HCFA
❑ Trial being done because best approach to treatment is not known
❑ Trial ongoing and likely to take several years to complete
❑ Results not available until released by NHLBI
• Limited to efforts to enhance recruitment
• Recruitment material must be approved by local IRB
R E L AT E D E N T R Y
Policy on incentive payments (page 455)
N A R R AT I V E
Newspaper, radio, and TV ads have their places in recruiting study subjects. They are used
primarily in recruitment in primary or secondary prevention trials, e.g., by issuing calls
for persons having a certain history or constellation of risk factors, but otherwise healthy.
Advertising for patients already under care for the condition being treated in a trial is not
advised. That is likely to be seen as a way of bolstering the practice of study clinics.
Advertising should not be undertaken without IRB approval.
151. Policy on Incentive Payments
455
151. Policy on incentive payments
R E L AT E D E N T R Y
Policy on advertising for patients (page 453)
DEFINITIONS
finder’s fee n - 1. A monetary sum paid to a person or agency for finding a person, e.g.,
as in tracing persons lost to followup. 2. Such an amount paid to a person or agency
for referring a person for some purpose; in the context of research, typically referral for
screening to determine suitability for study. rt: incentive payment Usage note: Fees in
the context of defn 2, especially in relation to treatment trials, are frowned upon and,
certainly, should not be provided without IRB approval.
incentive n - 1. Anything monetary or material used to incite or induce to action or to
continue an activity or process. 2. Anything valued or cherished, promised or offered,
having or intended to have the effect of inciting or inducing one to act or maintain an
association or process. 3. Anything given as a reward for something done or completed.
Usage note: Incentives in regard to persons approached for study in a trial or being
studied in a trial are anything offered to incite, induce, or maintain an action or behavior.
Typically the offers are token in nature (e.g., a small dollar sum paid to persons on
completion of a followup study visit to encourage continued participation). Anything
having value to persons to whom promised or offered is something serving to ‘‘incite’’
or ‘‘induce.’’ Obviously, the extent to which something does that depends on the value
of the offer. Value is determined by culture and by the interests and ages of persons to
whom offered. A monetary sum viewed as a token amount in one culture or to one age
group may be seen as sizable in another culture or to another age group. For example, the
promise of a meal certificate at McDonald’s is seen differently by a child than by an adult.
Incentives include certificates given to study participants commemorating achievements
or milestones reached in the course of study and token gifts (e.g., t-shirts, cups, mugs,
tote bags, household trinkets, etc.) given to reinforce behaviors or for maintaining interest
and participation. IRBs expect to be informed of incentives before they are offered.
They will object to offers considered to be at odds with obtaining uncoerced consents
or with maintaining uncoerced participation. As a rule, the greater the risks in being
studied, the greater the wariness of IRBs in allowing the use of incentives. Generally, even
token monetary incentives for study participants are regarded as unnecessary or unwise
in settings, such as those of treatment trials, where participants are enrolled because of
a disease or health condition needing care or treatment. Usually, the care or treatment
offered is considered inducement enough for enrollment and continued participation. See
usage notes for finder’s fees for payments to people for referring people for enrollment
into a trial.
incentive payment n - 1. A sum of money offered as an incentive for a desired action
or on completion of some process or procedure. 2. A payment of a specified sum on
rendering a service or on completion of some process or procedure. 3. Goods or materials
given in return for a desired service or requested action. rt: finder’s fee, incentive Usage
note: Most payments are to study participants and are made in relation to completion of
specified tasks or procedures. However, the definition also includes payments to persons
for finding or referring patients for study. Such payments, when monetary, are usually
456
XIX. POLICIES
referred to as finder’s fees and are, as a rule, frowned upon. They should not be offered or
made without approval of governing IRBs. Even the less obnoxious form involving goods
or materials (e.g., as with presentation of a desired textbook to residents for referring
patients for screening for possible study) has the potential of being seen in the same light
and should not be offered or made without knowledge and approval of governing IRBs.
Pay to study participants
• Used primarily as an aid to recruitment of healthy adults, especially in studies where
they stand to gain little from being studied and where being studied represents a
sizeable time commitment.
• Pay should be reasonable but not exorbitant.
• Pay should not be so large as to be likely to cause a person to commit to an activity
or undertake risks that are unreasonable; pay should be scaled for setting of study
(i.e., an amount considered to be nominal in one culture may be large in another
culture).
• Generally, not advised for people in treatment or secondary prevention trials where
prospect of benefit from being studied is sufficient inducement for enrollment.
• Never to be used without IRB approval.
Monetary rewards and incentives for encouraging compliance
• Use generally limited to trials where there is a desire to reinforce certain behaviors
such as for completing a diary record of medication or following a particular dietary
regimen.
• Monetary rewards should be of token sums, if used at all.
• Rewards or incentives should never be so large to be likely to cause a person to
assume risks they would not otherwise assume.
• Should never be used without knowledge and approval of governing IRBs.
Rewards and incentives for recruiting
• Generally frowned upon in trials; especially in treatment trials; likely to be seen as
akin to ‘‘ambulance chasing’’ or ‘‘stealing’’ patients to bolster one’s own practice.
• Should never be used without express approval of governing IRBs.
152. Policy on Payment of Patient-Related Travel Expenses
457
152. Policy on payment of patient-related travel
expenses
SLIDE
Policy on payment of patient related travel expenses: Studies
of Ocular Complications of AIDS (SOCA)80
Funds provided to clinics to cover costs of local transport and parking as per
patient request (cab fares, bus and subway tokens, local train fares)
Arrangements for transport made by clinic when necessary
Arrangements for babysitting when necessary
N A R R AT I V E
The norm is to cover incidental expenses incurred by persons coming to clinics for study
visits, such as for parking, bus, or taxi fares. It is also reasonable to pay for lodging
and living expenses for persons traveling great distances to get to a study clinic or when
overnight stays are required because of the requirements of a study visit. It is also reasonable
to use the offer of paying airfare and related living expenses for a person as an inducement
to get the person back for a visit, especially one considered of particular importance to the
trial (e.g., as for a final study visit in relation to the close of a trial).
153. Ancillary Study Policy
459
153. Ancillary study policy
SLIDE
Ancillary study policy: Childhood Asthma Management
Program (CAMP)11
Ancillary study : A study done by CAMP investigators and involving patients
enrolled in CAMP or involving data collected or generated in CAMP
but not relevant to the objectives of CAMP; must be resource neutral
from the perspective of CAMP, must not interfere with CAMP procedures
or data collection requirements, and must not increase the likelihood of
noncompliance or dropout in CAMP
Policy
•
•
•
•
Proposals for ancillary studies subject to review by CAMP SC
Studies may not be undertaken in absence of SC approval
Analyses by treatment group proscribed until completion of CAMP
Manuscripts and presentations resulting from ancillary studies subject to
review of SC prior to submission for publication or presentation
R E L AT E D E N T R Y
Substudy policy (page 467)
DEFINITION
ancillary study n - 1. A supplementary study done in association with a parent study.
2. Such a study done by personnel associated with a parent study. rt: daughter study,
sister study, substudy Usage note: Subject to misuse when used interchangeably with
substudy. A substudy is part of the parent study, an ancillary study is not. Ancillary studies
are the result of the varying interests and pursuits of investigators in the parent study.
Most multicenter trials have procedures for reviewing and approving proposed ancillary
studies. Generally, investigators must satisfy the reviewing body of the parent study that
the proposed studies are impact neutral relative to the parent study. Studies seen as having
a likely adverse impact on the parent study are not usually approved. Proposals calling
for the collection of additional data or the conduct of additional procedures on persons
enrolled in the parent study are not approved when seen as interfering with data collection
procedures or requirements of the parent study, or when seen as increasing the risk of
dropout or missing data. Studies are expected to be resource neutral from the perspective
of the parent study. Studies calling for use of treatment-related data are assumed to be
impact-negative and are not approved, or are approved with the proviso that such data
are not to be released or used until the parent study has been completed.
Guidelines for ancillary studies
• System for review and approval of ancillary study is set by study leadership.
460
XIX. POLICIES
• Funding (if needed) should be independent of that for parent study.
• Data collection procedures should not interfere with recruitment, treatment, or data
collection in parent study.
• Proposals for ancillary studies should be subjected to internal review to ensure that
they will not interfere with the objectives of the parent study, will not cause patients
to decline enrollment, or will not cause patients to miss visits in the parent study.
• Arrangements for data analysis and access to data files of parent study should be
specified prior to start of ancillary study.
• Limitations on time of publication or amount of information that can be presented
or published should be agreed upon prior to approval.
154. Policy on Patient-Care-Related Payments
461
154. Policy on patient-care-related payments
SLIDE
Policy on patient-care-related payments: Studies of Ocular
Complications of AIDS trials (SOCA)80
Tests and procedures necessary for care, even if also part of the study protocol, billed
to third party or patient
Tests or procedures performed solely for purpose of study covered by study
Study drugs provided at no cost to patient or third-party payer in trials done
under IND. Cost billed to third parties in trials involving approved drugs;
compassionate use access of drug via drug company for patients not having
insurance
N A R R AT I V E
The general expectation is that patients and their insurers will be spared expenses for
tests and procedures not required in relation to their care. However, tests and procedures
considered necessary in caring for them usually billed to study patients or their insurers.
155. Policy on Conflicts of Interest
463
155. Policy on conflicts of interest
SLIDE
Policy on conflicts of interest: Studies of Ocular
Complications of AIDS (SOCA) trials80
Conflict of interest: Broadly defined; not limited simply to those related to money
or to relationships in which a person stands to gain financially; includes conflicts
due to philosophy or belief
Disclosures
Center directors
Study officers
Steering committee members
Treatment effects monitoring committee members
Frequency : At the outset of a new study; annual updates
DEFINITIONS
conflict of interest n - 1. Any financial holding, proprietorship, relationship, post, or
position that is perceived of or acknowledged as constituting a corrupting influence in the
way a person decides or acts. 2. A conflict due to competing needs, e.g., the conflict of
a physician engaged in caring for patients in a trial when deciding whether to choose in
favor of the patient or study protocol when in conflict; such a conflict arising from pursuit
of conflicting values, e.g., the value of unmasked treatment effects monitoring in regard
to competency requirements versus the value of masked treatment effects monitoring in
regard to objectivity requirements. 3. A moral dilemma arising from the need to engage
in some act or process that is at odds with one’s belief or conviction, e.g., the dilemma
of a physician engaged in recruiting patients into a randomized trial in the absence of
a state of equipoise; the dilemma of a person in a coordinating center in performing
treatment effects monitoring considered to violate competency requirements. Usage note:
Most often used in relation to financial, business, or proprietary interests, but can be used
more broadly as seen in definitions above. Avoid as an implied charge or in speculative
senses. Not to be used in an accusatory sense unless supported with factual information
detailing the nature of the interest or circumstance considered to constitute a conflict.
Avoid suppositions as to effect. The direction or nature of the effect of a conflict may be
opposite to the one suggested by the conflict in cases in which the individual is aware of
the conflict and ‘‘overcompensates’’ for it.
disclosure form n - A form used to solicit or record factual information regarding real or
potential conflicts of interest.
insider n - 1. A person having knowledge of or access to privileged or confidential
information. 2. A person seen, recognized, or accepted as a member of a group, especially
such a person with power or influence within that group. Usage note: In the context of
464
XIX. POLICIES
trials, persons in possession of interim treatment results are seen as being in possession of
insider information. See insider trading for additional comments.
insider information n - Information obtained by virtue of being an insider or from an
insider, especially information considered to be of value in anticipating a forthcoming
action or event.
insider trading v - The act of buying or selling stocks, bonds, or options by a person
having insider information. Usage note: In the context of trials, insider trading in regard
to publicly owned proprietary products tested in trials, is the buying or selling of stock
or stock options based on information not available to the general public. Broadly, any
person sitting on a treatment effects monitoring committee privy to interim treatment
results who buys or sells stock or stock options related to products being tested is engaged
in insider trading. So too is a person associated with that member who learns of interim
treatment results via that association and buys or sells stock or options related to the
product being tested; including members of that person’s family, colleagues, friends, or
associates. The same is true for passing acquaintances who, by virtue of idle conversation
with an insider, uses the information to buy or sell. The person providing the information
may or may not be seen as an accomplice depending on circumstance and relationship.
Conflicts of interest
Associational: Association or relationship with an agency, firm, or person standing
to gain or lose depending on results of a trial (includes board memberships,
consulting or retainer agreements, and being a recipient of funds from such an
agency, firm, or person for one’s self or staff)
Financial: Having a monetary interest in the goods or services of a proprietary firm
standing to gain or lose depending on results of the trial; includes ownership of
stock of such a firm (exclusive of ownership in mutual funds or blind trusts), stock
options, patent rights, and future rights or interest of financial value
Professional: Being involved in competing activities (e.g., recruiting for competing
trials, serving on the steering committee of competing trials, serving on the TEMC
of competing trials)
Philosophical: Taking positions counter to operating tenets of a trial or being
opposed to organizational or operational aspects of the trial; engaging in actions
incompatible with the organizational or operating tenets of the trial; being of a
mind that a treatment being tested has already been shown to be superior or
inferior to another study treatment; giving testimony or interviews hostile to tenets
of the trial; public positions espousing the virtue of one of the study treatments;
editorials or letters espousing positions at odds with clinical equipoise
Moral: A conflict arising because of competing duties or responsibilities (includes
conflict of a treater when the needs of a study patient conflicts with the requirements
of the protocol; uncertainty as to whether randomization should continue because
of interim results)
Reminders and recommendations
• The most common usage of the term is in relation to financial interests.
155. Policy on Conflicts of Interest
465
• The general public is likely to assume that judgments are colored by conflicts of
interest.
• Conflicts of interest are irrelevant to the results of a trial if the person possessed of
the conflicts is unable to influence results or decisions.
• In the broad sense of usage, it is impossible to create groups free of conflicts of
interest.
• It is good practice to discuss the nature of conflicts of interest and ways in which
they may erode credibility with the research group prior to the start of the trial and
from time to time over its course.
• It is wise to organize a round-table discussion for members of a research group to
enumerate their real or perceived conflicts of interest and to do so before the start
of the trial.
• It is wise to set up procedures for disclosure and review of conflicts of interest and
to establish processes for dealing with potentially discrediting conflicts.
• Groups involved in testing proprietary products of publicly held companies should
be advised of the meaning of insider trading and of consequences and punishments
of such trading.
• Conflict of interest disclosure forms should be required of center and deputy
center directors, senior study investigators, study officers, members of the steering
committee, and members of the treatment effects monitoring committee; disclosures
should be requested prior to the start of the trial and at annual intervals thereafter.
• Disclosures should be reviewed by the study officers or some other study body.
• Disclosures should be broad enough to include the spectrum of conflicts represented
by the different types listed above.
• Disclosure statements filed by investigators should be retained for inspection by
interested parties to well beyond the end of the trial.
156. Substudy Policy
467
156. Substudy policy
R E L AT E D E N T R Y
Ancillary study policy (page 459)
DEFINITIONS
main study n - The portion of a study addressing the primary objective of a study. rt:
parent study, secondary study
parent study n - 1. main study 2. A study having one or more ancillary or substudies.
substudy n - 1. A study nested within a parent study and considered to be part of it. 2.
A study done on selected participants of a parent study bearing on the goals or objectives
of the parent study. rt: add-on study, ancillary study, daughter study, sister study Usage
note: Subject to confusion if used interchangeably with ancillary study. A substudy is
part of the parent study, an ancillary is not. A substudy may not be impact neutral (see
ancillary study) and may require resources from the parent study for conduct.
N A R R AT I V E
A substudy, unlike an ancillary study, is part of the parent study. It is a ‘‘substudy’’
because it is limited to selected study centers or persons at study centers. The selection of
persons may be determined by their characteristics or conditions, by random or systematic
sampling, or by some other means (e.g., by studying all persons seen in a given time
period). The selection of performance sites, typically, is on the basis of interest or expertise
of persons at performance sites, or available resources and facilities at selected sites.
The impetus for substudies arises because of a need to address a legitimate question
in pursuing the objective of the parent study, but where it is considered expedient or
efficient to limit the activity to selected persons or sites. To justify limiting the study
to selected persons or selected performance sites it must be possible to show that the
precision obtained is adequate to meet the objectives of the study.
To show that it is efficient, it must be possible to show that the overall effort
and money needed is less by undertaking a substudy than it would be by studying all
persons. Often the savings in effort and money by limiting the study to selected persons
or sites is offset by increased efforts and cost to the coordinating center. Every substudy
has overhead in the coordinating center to the extent that it has to be managed much like
any other study. It requires forms, protocol, training, and the like.
Substudies should not be used as vehicles for appeasement or for allowing
influential investigators the opportunity to pursue pet topics. Nor should groups default
to them when they are divided as to whether a particular set of observations is necessary.
They should not be voted into existence at the same meeting at which they are proposed,
and they should not be voted upon until the coordinating center has carried out an
‘‘environmental impact’’ assessment.
One can expect pressures for substudies in trials involving disparate treatment
modalities managed by different speciality groups, e.g., as in the National Emphysema
Treatment Trial involving surgery for lung volume reduction versus medical treatment.
That trial had three substudies defined when the trial started enrollment.
Adverse Events
157. Adverse Events
471
157. Adverse events
SLIDE
Reportable events: Studies of Ocular Complications of AIDS
(SOCA) trials80
Overdoses
Administration of wrong treatment
Mistakes or misadventures in administration of assigned treatments, including
overdoses, failure to administer necessary concomitant treatments, failure to
stepup or stepdown dose when required by treatment protocol
Deaths or serious morbidity likely due to treatment or to study procedures
Treatment side effects (by grade: 1 Mild, 2 Moderate, 3 Severe, 4 Life-threatening;
by relationship to treatment: None, Unlikely, Possible, Probable, Definite,
Unknown)
R E L AT E D E N T R Y
Adverse event reporting procedures (page 475)
DEFINITIONS
adverse drug experience (ADE) n - As defined in the Code of Federal Regulations for
the Food and Drug Administration: Any adverse event associated with the use of a drug in
humans, whether or not considered drug related, including the following: An adverse event
occurring in the course of the use of a drug product in professional practice; an adverse event
occurring from drug overdose, whether accidental or intentional; an adverse event occurring
from drug abuse; an adverse event occurring from drug withdrawal; and any failure of expected
pharmacological action. (page 23)31 rt: safety report, serious adverse drug experience,
unexpected adverse drug experience
adverse drug reaction (ADR) n - A drug reaction that results in hospitalization or a
prolongation of hospitalization or that otherwise has negative health implications for the
patient having such a reaction. rt: toxic drug reaction, serious adverse drug experience
Usage note: See drug reaction.
adverse event (AE) n - 1. Any unfavorable sign, symptom, state, condition, or laboratory
finding in a study subject. 2. Any such sign, symptom, state, condition, or laboratory
finding, except one considered to be associated with a beneficial treatment effect. 3. An
event seen to threaten the integrity of a study. 4. reportable event rt: adverse reaction
Usage note: Not to be used interchangeably with adverse reaction. Best reserved for defns
1 and 2. See reportable event for additional comments.
adverse reaction n - Broadly, a reaction that has negative consequences or implications
for the one experiencing it and that is the result of some act, agent, or stimulus. In
the context of trials, such a reaction due to or that is attributed to a study treatment;
adverse drug reaction when the treatment involves a drug. Usage note: Not to be used
472
XX. ADVERSE EVENTS
interchangeably with adverse event. In the context of trials, adverse reactions represent
that subset of adverse events due or attributable to study treatments.
adverse side effect n - A side effect that has adverse health implications for the person
having such a side effect.
adverse treatment effect n - A treatment effect that has negative health implications; a
treatment effect contrary to the one intended or desired.
drug reaction n - A reaction caused by a drug, especially one that is undesirable or
annoying. Usage note: Use with caution as a claim or assertion. The mere occurrence of
some event or condition in a person taking a drug does not mean that it was the result
of the drug. Accompany all uses implying drug-related cause with supporting evidence
or argument as to the reasons for the presumption. Use cause-neutral language when
in doubt as to cause. Avoid as a label for a collection of events or conditions having a
variety of explanations and as a label spanning treatment groups receiving different drugs
or treatments. Use of the term in relation to events or conditions observed in people
not receiving a drug is misleading. It is illogical to view control treatments involving
nontreatment or placebos as producers of ‘‘drug reactions’’ in the usual physiological sense
of usage.
investigational new drug safety report n - A report to the Food and Drug Administration
of an adverse drug experience in relation to an investigational new drug that is both serious
and unexpected; written or telephoned. In relation to such reports, the regulations specify
for written reports: The sponsor shall notify FDA and all participating investigators in a
written IND safety report of any adverse experience associated with use of the drug that is both
serious and unexpected. Such notification shall be made as soon as possible and in no event
later than 10 working days after the sponsor’s initial receipt of the information. Each written
notification shall bear prominent identification of its contents, i.e., ‘‘IND Safety Report.’’
Each written notification to FDA shall be transmitted to the FDA division of the Center for
Drug Evaluation and Research or the Center for Biologics Evaluation and Research, which
has responsibility for review of the IND. In each written IND safety report, the sponsor shall
identify all safety reports previously filed with the IND concerning a similar adverse experience
and shall analyze the significance of the adverse experience in light of the previous, similar
reports. In regard to telephone reports, the regulations specify: The sponsor shall also notify
FDA by telephone of any unexpected fatal or life-threatening experience associated with use of
the drug in the clinical studies conducted under the IND no later than 3 working days after
receipt of the information.31 syn: safety report (defn 2) rt: serious adverse drug experience,
unexpected adverse drug experience
reportable event n - 1. adverse drug experience, serious adverse drug experience,
unexpected adverse drug experience 2. adverse event 3. Any event or experience relating to
a study subject and relevant to an oversight body, such as an IRB, in determining whether
an approval should be maintained; any such event or occurrence listed as needing to be
reported to an oversight body, such as an IRB, as a condition for approval or continuing
approval. 4. Any event, circumstance, or occurrence threatening the integrity of a study.
5. Any event or occurrence listed as reportable by an extant governing, funding, oversight,
or regulatory authority, such as the NIH, FDA, and ORI. Usage note: Problematic when
used in the absence of defining detail regarding what, when, how, and where to report.
The domain of reportable events is subject to change depending on perspective. Events
considered not reportable during conduct of a study may be seen as reportable when
157. Adverse Events
473
a study is audited or reviewed. It is up to study investigators to develop and maintain
essential reporting procedures in regard to the entire domain of events implied above. The
duty to report extends to the broad class of events covered by defn 5, including events
of fraud, though the guidelines for deciding when the suspicion of fraud is sufficient to
trigger a report to one’s institutional committee dealing with such matters, or to the ORI,
are largely lacking. All research involving human beings is under the purview of IRBs
or like-named bodies. Approvals from those bodies carry reporting obligations. In all
cases, investigators are obliged to report mistakes or misadventures occurring in relation
to the processes of enrolling, studying, treating, or following study subjects, and to do so
regardless of whether such occurrences were of consequence to persons studied. Generally,
approvals are predicated on the presumption that investigators will report deaths and
morbidities occurring in the study population, that they will do so in a timely fashion,
and that they will do so regardless of whether they are considered to be study-related. The
presumption, in the case of multicenter studies, should be that study population refers to
the entirety of persons in the trial as represented by all centers combined and, therefore,
that all investigators and associated IRBs are to receive reported events regardless of
where observed. The reporting requirements can lead to a flood of papers in large-scale
multicenter trials.59 IRBs may limit reporting to study-related deaths and morbid events
in long-term treatment trials where the population being treated has high underlying
mortality and morbidity rates. The reporting procedures imposed by the FDA relate to
adverse events (defn 1) arising in relation to drugs, biologics, and devices being tested in
relation to possible licensure. There are no corresponding procedures for trials of surgical
procedures, trials of established medical treatments, or trials of other treatments not under
the purview of the FDA. Hence, in those cases, investigators are largely left to establish
definitions and procedures for reporting and informing investigators and associated IRBs.
The likely minimum reporting requirements (in addition to those concerning mistakes
or misadventures as mentioned above) are morbid events or deaths induced or likely
caused by a study procedure (including those where it is reasonable to so assume because
of temporal relationship); any event occurring in conjunction with a study procedure,
administration of a study treatment, or in relation to a change in treatment; deaths or
major morbidities occurring in association with initiation or change of treatment; and
events or occurrences leading to contact of an IRB by a study subject or representative
and judged by that IRB to have legitimacy.
safety report n - 1. treatment effects monitoring report 2. A report to the Food and Drug
Administration of an adverse drug experience that is both serious and unexpected; written
or telephoned; investigational new drug safety report; also IND safety report.
serious adverse drug experience n - 1. An adverse drug experience that is serious. 2.
Adverse drug reaction that is serious. 3. In FDA parlance, as contained in the Code of
Federal Regulations for drugs for that agency31 : Any experience that suggests a significant
hazard, contraindication, side effect, or precaution. With respect to human clinical experience,
a serious adverse drug experience includes any experience that is fatal or life-threatening, is
permanently disabling, requires inpatient hospitalization, or is a congenital anomaly, cancer, or
overdose. With respect to results obtained from tests in laboratory animals, a serious adverse drug
experience includes any experience suggesting a significant risk for human subjects, including
any finding of mutagenicity, teratogenicity, or carcinogenicity. rt: unexpected adverse drug
experience, safety report
474
XX. ADVERSE EVENTS
unexpected adverse drug experience n - An adverse drug experience that is unexpected.
In the parlance of the FDA: Any adverse experience that is not identified in nature, severity,
or frequency in the current investigator brochure; or, if an investigator brochure is not required,
that is not identified in nature, severity, or frequency in the risk information described in the
general investigational plan or elsewhere in the current application, as amended.31 rt: serious
adverse drug experience, safety report
N A R R AT I V E
Adverse event, as seen in the definition above has varying meanings, depending on context
of usage. Most usages are in relation to events that are to be reported to IRBs or to the
FDA. Planners should take care to list events qualifying for reporting.
158. Adverse Event Reporting Procedures
475
158. Adverse event reporting procedures
SLIDE
Reporting procedure for adverse events: Studies of Ocular
Complications of AIDS (SOCA) trials80
• Report using designated SOCA form (for side effects indicate grade—Mild,
Moderate, Severe, or Life-threatening—and relationship to treatment
administered—None, Unlikely, Possible, Probable, Definite, Unknown)
• Forward completed form to Coordinating Center; within 3 working days from
occurrence for events to be reported to the FDA via safety reports
• Coordinating Center responsible for filing safety reports with FDA; to be filed
within 10 working days from date of receipt
• Coordinating Center responsible for forwarding reportable events to its IRB
and to directors of study centers for distribution to their respective IRBs
R E L AT E D E N T R Y
Adverse events (page 471)
DEFINITIONS
reportable event n - 1. adverse drug experience, serious adverse drug experience,
unexpected adverse drug experience 2. adverse event 3. Any event or experience relating to
a study subject and relevant to an oversight body, such as an IRB, in determining whether
an approval should be maintained; any such event or occurrence listed as needing to be
reported to an oversight body, such as an IRB, as a condition for approval or continuing
approval. 4. Any event, circumstance, or occurrence threatening the integrity of a study.
5. Any event or occurrence listed as reportable by an extant governing, funding, oversight,
or regulatory authority, such as the NIH, FDA, and ORI. Usage note: Problematic when
used in the absence of defining detail regarding what, when, how, and where to report.
The domain of reportable events is subject to change depending on perspective. Events
considered not reportable during conduct of a study may be seen as reportable when
a study is audited or reviewed. It is up to study investigators to develop and maintain
essential reporting procedures in regard to the entire domain of events implied above. The
duty to report extends to the broad class of events covered by defn 5, including events
of fraud, though the guidelines for deciding when the suspicion of fraud is sufficient
to trigger a report to one’s institutional committee dealing with such matters, or to the
ORI are largely lacking. All research involving human beings is under the purview of
IRBs or like named bodies. Approvals from those bodies carry reporting obligations.
In all cases, investigators are obliged to report mistakes or misadventures occurring in
relation to the processes of enrolling, studying, treating, or following study subjects,
and to do so regardless of whether such occurrences were of consequence to persons
studied. Generally, approvals are predicated on the presumption that investigators will
report deaths and morbidities occurring in the study population, that they will do so
in a timely fashion, and that they will do so regardless of whether they are considered
to be study-related. The presumption, in the case of multicenter studies, should be that
476
XX. ADVERSE EVENTS
study population refers to the entirety of persons in the trial as represented by all centers
combined and, therefore, that all investigators and associated IRBs are to receive reported
events regardless of where observed. The reporting requirements can lead to a flood of
papers in large-scale multicenter trials.59 IRBs may limit reporting to study-related deaths
and morbid events in long-term treatment trials where the population being treated
has high underlying mortality and morbidity rates. The reporting procedures imposed
by the FDA relate to adverse events (defn 1) arising in relation to drugs, biologics,
and devices being tested in relation to possible licensure. There are no corresponding
procedures for trials of surgical procedures, trials of established medical treatments, or
trials of other treatments not under the purview of the FDA. Hence, in those cases,
investigators are largely left to establish definitions and procedures for reporting and
informing investigators and associated IRBs. The likely minimum reporting requirements
(in addition to those concerning mistakes or misadventures as mentioned above) are
morbid events or deaths induced or likely caused by a study procedure (including
those where it is reasonable to so assume because of temporal relationship); any event
occurring in conjunction with a study procedure or with administration of a study
treatment, or in relation to a change in treatment; deaths or major morbidities occurring
in association with initiation or change of treatment; and events or occurrences leading
to contact of an IRB by a study subject or representative and judged by that IRB to have
legitimacy.
reported event n - 1. An event reported to a supervising, monitoring, or oversight agency,
authority, or body. 2. An adverse event reported to one’s IRB. rt: reportable event Usage
note: Ideally, investigators are found to have satisfied their reporting obligations if and
when their practices are reviewed. However, the reality is that reporting is the result of
judgments that can come into question when a study is subjected to searching scrutiny
following a high profile event, e.g., as in trials of fialuridine.40 See reportable event for
additional comments.
N A R R AT I V E
The definition of what is reportable is likely to vary from IRB to IRB, even among
IRBs of the same institution. Hence, investigators have to make certain they know the
operative definition for their institution and have a duty to comply with the requirements
of reporting under the definition.
Definitions, regardless of how written, leave room for judgment on the part of the
investigator as to whether events are reportable. A reasonable rule of thumb is to report if
in doubt.
IRBs want to know of any event that is iatrogenic. Operationally, events that
produce a yes to any of the questions below should be presumed to be reportable.
1. Is the event due to a mistake or misadventure?
2. Was the event preventable?
3. Is the event the result of performing a study procedure (answer ‘‘yes’’ when in doubt
or when it is reasonable to presume that the event may have been caused or induced
by a study procedure)?
4. Did the event occur in temporal proximity to application of the assigned treatment or
in relation to a study mandated change or modification of treatment?
158. Adverse Event Reporting Procedures
477
5. Is it likely that the risk of subsequent similar events could be reduced by informing
fellow investigators of the event and of the circumstances leading to it?
6. Is the event indicative of the need to revise the study protocol or study procedures?
Serious events that are the result of mistakes are reported to the Office of Human
Research Protections (OHRP). Those reports may lead to additional queries or orders to
the investigator.
Investigators working under INDs or IDEs are required to report serious adverse
drug experiences to the FDA. Reports are required within 10 working days of experiences
that are serious and unexpected. Designers have to establish procedures for reporting of
adverse events and for ensuring filing and distribution of safety reports. Typically, the
holder of the IND or an agent of the holder is responsible for the filing of safety reports
with the FDA. The sponsor or agent, in turn, is responsible for ensuring the timely
distribution of safety reports to investigators of record and, via them, to their respective
IRBs.
The usual approach in multicenter trials is for reports to funnel through the
coordinating center for filing with the FDA or for distribution to the sponsor for filing
(when the sponsor holds the IND). The coordinating center or sponsor is responsible for
distribution of safety reports to study investigators and the investigators are responsible
for distribution of the reports to their respective IRBs.
Miscellaneous
159. Key Study Documents
481
159. Key study documents
R E L AT E D E N T R Y
Policy on access to study documents (page 447)
N A R R AT I V E
Study documents likely needed for a trial include:
•
•
•
•
•
•
•
•
•
•
Study protocol
Study forms
Study handbook/manual of operations
Consent form
Patient information booklet
Credit roster
Design synopsis
Study CV
IRB approvals
Investigator and TEMC conflict of interest disclosures
Produce the list early in the course of development of the trial and update over
the course of the trial. Indicate the person or group responsible for development and
maintenance of listed documents and the custodian and official repository of maintained
documents.
160. Design Synopsis
483
160. Design synopsis
R E L AT E D E N T R I E S
Appendices 1, 2, and 3
N A R R AT I V E
The process and detail of design is facilitated by maintaining design synopses, e.g., as
represented in Appendix 1. The worksheet, as represented on pages in Appendix 3, is
useful in preparing synopses.
The synopsis, to be useful, has to be maintained over the life of the trial, typically
by people in the coordinating center in multicenter trials. Design synopses have a variety
of uses. They represent useful summaries for inclusion in study handbooks or manuals of
operations, in funding applications, in meeting books and treatment effects monitoring
reports, and in preparing study publications or presentations.
161. Slide Sets
485
161. Slide sets
R E L AT E D E N T R Y
Policy on access to study documents (page 447)
DESIGN SLIDES
Design slide sets, as represented in Appendix 2, are useful in training study personnel in
the start-up stage of trials and over the life of the trial. To be useful the sets have to be
maintained and updated over the course of the trial. Typically the task of creation and
maintenance is assumed by people in coordinating centers in multicenter trials.
Slide sets should be dated. The ‘‘as of date’’ should be displayed on individual
slides if slides from different sets are used in slide displays.
Design slide sets have a variety of purposes. Hard copy of the slides can be used as
front or back matter in study documents, such as study manuals, handbooks, and treatment
effects monitoring reports. They are useful for presentations to the investigatorship, for
preparing for presentations at scientific meetings, and in paper writing.
R E S U LT S S L I D E S
The primary purpose of results slides is in presentations to study investigators in trials
operated under a results blackout mode of operation when the trial is finished or in
relation to an early stop. Typically, the sets are prepared and maintained by people in the
coordinating center in multicenter trials. They are needed as well if results are presented
at scientific meetings.
162. Study CV
487
162. Study CV
R E L AT E D E N T R I E S
Study website (page 489), Study history log (page 491)
DEFINITION
study curriculum vitae n - A curriculum vitae similar to that for a person but with the
study being the subject of the vitae; giving particulars of the study including history,
purpose, design, funding, mode of initiation, centers and related personnel, presentations,
and publications, see http://jhuccs1.us/adapt/ for example.
N A R R AT I V E
An important document in virtually any trial, and especially in long-term multicenter
trials, is the study CV giving particulars regarding the trial. The document is useful in
funding proposals and as a reference source for manuscript production in the trial.
To be useful the document has to be maintained. Study leaders need to designate
the person or center responsible for maintenance of the document.
163. Study Website
489
163. Study website
R E L AT E D E N T R I E S
Study CV (page 487), Policy on access to study documents (page 447)
N A R R AT I V E
It is usually prudent to create a study website and to do so as early in the course of the
trial as possible. Websites are useful communications and document distribution tools.
They are especially useful in multicenter trials, but have utility even in single-center trials
to the extent that people in such trials are rarely within easy reach of one another.
Most, if not all, of the material on the website will be password protected and with
the means to control access and to terminate access for persons leaving or dismissed from
the study roll.
Designers of large-scale, high-profile trials are also well-advised to create a public
website for deposit of information regarding the trial including as many of the key study
documents that can be deposited without compromising the integrity of the trial. Key
documents (see Key study documents; page 481) should be placed on the website unless
cogent arguments can be made as to why placement is ill-advised.
164. Study History Log
491
164. Study history log
SLIDE
History: University Group Diabetes Program (UGDP)60
Year
Month
1959
1960
1961
1962
1966
1969
1970
1971
1971
1975
1975
1978
1980
1982
Jun
Sept
Feb
Sept
Feb
Oct
Nov
May
Aug
Feb
Aug
Jul
Apr
Nov
Event
First meeting of investigators
Start of NIH funding
Enrollment of first patient
Addition of phenformin treatment; five clinics added
Patient enrollment completed
Tolbutamide treatment stopped
Tolbutamide results published; Diabetes94
Investigators vote to stop phenformin
Preliminary report on phenformin published; JAMA92
Final report on phenformin published; Diabetes91
Termination of patient followup
Preliminary report on insulin findings published; JAMA90
NIH grant support expires
Final report on insulin results published; Diabetes89
R E L AT E D E N T R Y
Landmark events and dates (page 493)
N A R R AT I V E
It is difficult to think ‘‘history’’ in the here and now. It is useful, therefore, to maintain a
running log of events in the course of the trial. The log is useful in requests for renewal of
funding, in preparation of study publications, and answering queries concerning course
and conduct of the trial.
Histories
• Funding (funding sources; changes in funding sources; start and end dates for
funding by center; changes in the way centers are funded; renewal dates of
funding; etc.)
• Design (dates for addition or deletion of treatment; change in randomization
procedure, design, or assignment ratio; change in eligibility or exclusion criteria;
change in design variable; change in sample size requirement)
• Personnel (names and dates personnel join or depart a center, deaths in the
investigatorship, changes in directorship of a center)
• IRB (dates of approvals and renewals by center; dates of hold or shutdown
orders, etc.)
• Protocol (list of changes to eligibility requirement and dates implemented; list of
changes to treatment procedures and dates implemented; list of changes in patient
492
•
•
•
•
•
XXI. MISCELLANEOUS
procedures and dates implemented; list of procedures added or deleted and dates
effective; etc.)
Data collection (list of form changes, effective dates, and reasons; list of forms added
or deleted, effective dates, and reasons; version and print histories of forms, etc.)
Data processing (list of changes to data intake and processing procedures, effective
dates, and reasons; dates of data harvests; dates and nature of edits; dates of creation
for archival datasets)
Enrollment and followup (date first person enrolled; date last person enrolled;
numbers enrolled by date; numbers or percent completing designated followup
visits; date of closeout for first person separated in closeout; date of last closeout
visit, etc.)
Publication and presentation (list of published manuscripts and dates; list of
presentations made on behalf of trial, dates, and locations; etc.)
Landmark dates and events (page 493)
165. Landmark Events and Dates
493
165. Landmark events and dates
SLIDE
Landmark dates: SOCA FGCRT85
15
17
15
17
5
13
14
30
7
Aug
Mar
Jun
Nov
Jan
Mar
Dec
Aug
Oct
88
89
89
89
90
90
90
91
91
Funding initiated
RFP for clinic selection due
Clinic selection
1st meeting of SOCA Research Group (Baltimore)
1st start-up patient enrolled (Chicago)
1st trial proper patient enrolled
Reinduction dosage for foscarnet modified
Enrollment into stratum 1 closed
PDMB recommendation to suspend treatment protocol
R E L AT E D E N T R Y
Study history log (page 491)
N A R R AT I V E
Dates of important events in the design or conduct of a trial are difficult to construct in
retrospect. Hence, such lists, for maximal utility should be maintained real-time over the
course of the trial.
The events and corresponding dates recorded should be those considered to impact
the design or operation of the trial. Obviously, events and dates needed to properly report
and understand study results should be recorded. Also, to be included are events and dates
involving changes in the study protocol or operational procedures impacting on the way
data were recorded, collected, or analyzed. Events such as those listed below should be
considered for inclusion.
Candidate landmark events for recording and dating
•
•
•
•
•
•
•
•
•
•
•
•
Addition or deletion of a study treatment
Change of assignment ratios; change in randomization procedure
Change in the treatment protocol
Change of eligibility or exclusion criteria
Addition or deletion of clinics
Change of design variable
Change in the sample size requirement
Change in duration of treatment
Change in the duration of followup
Change of investigators at centers
Stopping a treatment because of lack of efficacy or possible harm
Hold or shutdown orders from IRBs
166. Registration
495
166. Registration
DEFINITION
registration n - The act or fact of a trial being registered on clinicaltrials.gov or similar
websites as required by the International Committee of Medical Journal Editors (ICMJE)
as a condition for considering papers from trials for publication.21,22
N A R R AT I V E
Registration of trials got a push in 2004 by the International Committee of Medical
Journal Editors (ICMJE) in a statement indicating that ICMJE member journals will
require, as a condition of consideration for publication, registration in a public trials registry.22
The requirement applied to trials starting enrollment after 1 July 2005. The requirement
for registration published in 2004 did not extend to phase I trials. That exclusion was
made more explicit in 2005 with a statement indicating that:
We have excluded trials from our registration requirement if their primary goal is to assess major
unknown toxicity or determine phamacokinetics (phase 1 trials).21
However, in 2007, the statement was revised to include the World Health
Organization (WHO) definition of clinical trial:
any research study that prospectively assigns human participants or groups of humans to one or
more health-related interventions to evaluate the effects on health outcomes.45
The upshot was to extend the requirement to ‘‘preliminary trials’’ including phase
I trials.
103
Investigators are responsible for registration and for keeping information in the
registry up-to-date. Hence, investigators are well-advised to designate someone in the trial
organization with responsibility for registration and updating the registration site. Good
practice is to print out the registration material annually for review by study leaders and
updating as necessary.
Appendices
APPENDIX 1
Design Summaries for Selected
Finished Trials
DESIGN SUMMARIES
CAMP (Childhood Asthma Management Program)
NETT (National Emphysema Treatment Trial)
FGCRT (Foscarnet–Ganciclovir CMV Retinitis Trial)
CRRT (CMV Retinitis Retreatment Trial)
MACRT (Monoclonal Antibody CMV Retinitis Trial)
HPCRT (HPMPC Peripheral CMV Retinitis Trial)
GCCRT (Ganciclovir–Cidofovir CMV Retinitis Trial)
HPT (Hypertension Prevention Trial)
GLT (Glaucoma Laser Trial)
500
505
507
509
511
512
513
514
515
499
500
A P P E N D I X 1 : D e s i g n S u m m a r i e s f o r S e l e c t e d F i n i s h e d Tr i a l s
CAMP (Childhood Asthma Management Program)11
Objective
The Childhood Asthma Management Program (CAMP) is a clinical trial carried out in
children with asthma. The trial is designed to determine the long-term effects of three
treatments (budesonide, nedocromil, or placebo) on pulmonary function as measured by
normalized FEV1 over a 5 to 6 1/2-year period.
Type of study
• Multicenter, masked, placebo-controlled, randomized
• Population: 960 (288 each in budesonide and nedocromil groups and 384 in
placebo group) children aged 5–12, of whom at least 1/3 are minority
Stratification
Clinic
Treatments [abbreviation]
• [Bud] Inhaled glucocorticoid (budesonide) + intermittent β2 -agonist (albuterol)
• [Ned] Inhaled nonsteroidal anti-inflammatory (nedocromil) + intermittent β2 agonist (albuterol)
• [Plbo] Intermittent β2 -agonist (albuterol) +
❑ [PBud]: budesonide placebo
❑ [PNed]: nedocromil placebo
Treatment administration
• Budesonide (Pulmicort), two 100 µg puffs b.i.d. + two 90 µg puffs albuterol
(Ventolin) prn
• Nedocromil (Tilade), four 2 mg puffs b.i.d. + two 90 µg puffs albuterol prn
• Two 100 µg puffs budesonide placebo b.i.d. + two 90 µg puffs albuterol prn, or
four 2 mg puffs nedocromil placebo b.i.d. + two 90 µg puffs albuterol prn
• Tapering of doses from 100% to 50% to 0% for patients who have sustained
minimal symptoms and satisfactory lung function
• Addition of beclomethasone (four 42 µg puffs b.i.d.) for patients whose asthma is
inadequately controlled while on full dose study medication and albuterol
Masking
• Masked with respect to active drug or placebo [masked Turbuhaler (budesonide or
matching placebo), masked metered dose inhaler (nedocromil or matching placebo)]
• Unmasked use of intermittent β2 -agonist (albuterol)
• Unmasked Data and Safety Monitoring Board
Inclusion criteria
• Age 5–12 years at time of screening
• Chronic asthma as evidenced by one or more of the following historical findings for
at least 6 months during the past year:
CAMP (Childhood Asthma Management Program)
501
Asthma symptoms at least 2 times per week
❑ 2 or more usages per week of an inhaled bronchodilator
❑ Daily asthma medication
Current asthma symptoms either by diary symptom code of 1 or greater or am or
pm PEFR less than 80% of personal best post-bronchodilator value by diary, on
eight or more days during the prn screening period
Methacholine sensitivity: Estimated PC20 FEV1 less than or equal 12.5 mg/mL
Consent of guardian and assent of child
Ability to comply with trial for 5–6 1/2 years
❑
•
•
•
•
Exclusion criteria
• Presence of one or more of the following confounding or complicating problems:
❑ Any other active pulmonary disease
❑ Any chronic condition presumed to interfere with the successful completion of
the project or confound its interpretation
❑ Pulmonary function testing findings suggesting a ventilatory defect other than
asthma, or evidence of existing irreversible lung damage
❑ Severe chronic sinusitis or nasal polyposis
❑ Introduction of or a change in allergen immunotherapy within the past month
❑ Use of more than four sprays of nasal steroids daily (only beclomethasone
allowed)
❑ Pregnancy
❑ Current use of metoclopramide, ranitidine, or cimetidine
❑ Treatment for gastroesophageal reflux
❑ Participation in another drug study
• Evidence of severe asthma as indicated by one or more of the following:
❑ Two or more hospitalizations for asthma in the past year
❑ Six or more steroid bursts in the past year
❑ Demonstrated need for continuous use of glucocorticoids, either oral or inhaled
❑ When off inhaled β2 -agonist for more than 4 hr and theophylline for more than
24 hr, FEV1 less than 65% predicted
❑ Intubation for asthma at any time in the past
❑ Need for nine or more puffs/day of albuterol for each of three consecutive days
(excluding preventive use prior to exercise), or nocturnal asthma awakenings
more than 1.5 times per week on average, or average diary card symptom code
greater than 2, or requirement for other medications to control asthma, during
prn screening period
• Inability to perform three acceptable FVC maneuvers of which at least two
reproducible FEV1 s are within 10% of the largest FEV1
• Inability to complete the methacholine challenge or methacholine PC20 FEV1
greater than 12.5 mg/mL
• Evidence that patient or family may be unreliable or noncompliant or may move
from the metropolitan area before trial completion
502
A P P E N D I X 1 : D e s i g n S u m m a r i e s f o r S e l e c t e d F i n i s h e d Tr i a l s
CAMP (Continued)
Recruitment
• To sample size goal
• 18 months
Duration of followup
• To common closing date 5 years after end of recruitment stage (5–6 1/2 yr)
Outcomes
Primary
• Lung function (FEV1 )
Secondary
•
•
•
•
•
•
•
•
Bronchial responsiveness to methacholine
Need for beclomethasone due to asthma symptoms
Termination of assigned treatment due to cessation of symptoms
Asthma morbidity
❑ Frequency and severity of asthma symptoms
❑ Frequency and magnitude of PEFR measurements less than 80% of personal best
❑ Prn use of supplemental inhaled albuterol
❑ Nocturnal awakenings, days of limited activity and absences from school
❑ Courses of steroids (days and dose)
Mortality, long-term safety, and side effects
Physical growth and development
❑ Somatic growth measures (linear growth, weight, body mass index, truncal
growth, sexual maturation)
❑ Steroid effects (bone density)
❑ Lung growth (spirometry)
Psychological growth and development
❑ Neurocognitive function (Wechsler Preschool and Primary Scale of Intelligence,
Wechsler Intelligence Scale for Children III, Woodcock–Johnson PsychoEducational Battery Tests, Wide Range of Assessment of Memory and Learning,
Gordon Diagnostic System)
❑ Individual and family functioning measures (Youth Self Report, Children’s
Depression Inventory, Revised Children’s Manifest Anxiety Scale, Social Anxiety
Scale for Children, Child Behavior Checklist, Family Environment Scale, Impact
on Family Scale, Medical Outcome Study Social Support Survey)
Use of health care resources
❑ Emergency room visits
❑ Hospitalizations
❑ Physician visits/contacts
CAMP (Childhood Asthma Management Program)
503
Treatment adjustment for inadequate control of asthma (addition of
beclomethasone)
•
•
•
•
•
Six or more prednisone courses in the previous 12 months
Thirty-one or more days of prednisone use in the previous 12 months
Two or more hospitalizations for asthma in the previous 12-month period
Excessive use of albuterol (more than 1.5 canisters/month prn use for 4 months)
Other asthma worsening judged to warrant addition of beclomethasone
Treatment adjustment because of adverse reaction to study drug, pregnancy,
need for assisted ventilation, or asthma worsening after addition of
beclomethasone
• Treatment at the discretion of the CAMP and/or private physician
Treatment tapering for well-being
• Adjustment of treatment downward to be considered after 7.5 months on protocol
and at 4-month intervals thereafter
• Treatment drug dose down 50% from full dose if all of the following conditions are
met:
❑ On full dosage at least 7.5 consecutive months;
❑ Pre-bronchodilator FEV1 at least 85% predicted and pre-bronchodilator
FEV1 /FVC ratio at least 85%; and
❑ Four puffs (two usages) or less per week of albuterol during each week in the
preceding 6 months, excluding preventive use before exercise; and
❑ One day or less per month of asthma symptoms curtailing daily activities
(symptom code at least 2) in the preceding 6 months.
• Treatment drug tapered to no use if all of the following conditions are met:
❑ On half dosage for at least 7.5 consecutive months;
❑ Pre-bronchodilator FEV1 at least 85% of predicted and pre-bronchodilator
FEV1 /FVC ratio at least 85%;
❑ Four puffs (2 usages) or less per month of albuterol during each month in the
preceding 6 months, excluding preventive use before exercise; and
❑ One day or less per month (and fewer than 5 days total) of asthma symptoms
curtailing daily activities (symptom code at least 2) in past 6 months.
• Resumption of full-dose trial medication if any of the following occurs:
❑ Pre-bronchodilator FEV1 less than 90% previous best or less than 85% of
predicted, or pre-bronchodilator FEV1 /FVC less than 85%; or
❑ 8 or more days during any 4-week period with asthma symptoms curtailing
daily activities (symptom code at least 2) or mean daily PEFR less than 80% of
personal best; or
❑ At least 32 puffs (16 usages) of albuterol during any 4-week period, excluding
preventive use before exercise; or
❑ Other anti-asthmatic medications required for control of asthma symptoms; or
❑ Judgment by physician that resumption of full-dose study drug is appropriate
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A P P E N D I X 1 : D e s i g n S u m m a r i e s f o r S e l e c t e d F i n i s h e d Tr i a l s
CAMP (Continued)
• If adjustment fails, the full-dose trial medication would be resumed for 7.5 months,
after which the adjustment criteria will be applied again.
Data collection schedule
• Baseline: 5 visits
❑ −7wk, −6 wk, −2 wk, −1 w, and 0 wk
• Followup:
❑ At 2 months and every 4 months from baseline for duration of trial
Treatment comparisons and detectable changes in FEV1
(FEV1 % = Detectable differences in FEV1 percent of predicted, assuming a two-sided
Type I error of 0.01, a power of 0.9, and an 11% within group SD for the FEV1 %
predicted)
• Bud vs. Ned (FEV1 % = 3.8%)
• If PBud vs. PNed (FEV1 % = 4.6%) combinable
❑ Bud vs. Plbo (FEV1 % = 3.5%)
❑ Ned vs. Plbo (FEV1 % = 3.5%)
• If PBud vs. PNed not combinable
❑ Bud vs. PBud (FEV1 % = 4.2%)
❑ Ned vs. PNed (FEV1 % = 4.2%)
Data analysis and monitoring
• Review of data by Data and Safety Monitoring Board (DSMB) at semiannual
meetings
• Early termination of the trial or protocol modifications made by the DSMB (no
formal stopping rules)
• Primary analyses by original treatment assignment
• All events or measurements made after randomization will be included in primary
analyses
N E T T ( N a t i o n a l E m p h y s e m a Tr e a t m e n t Tr i a l )
505
NETT (National Emphysema Treatment Trial)19
The NETT is a randomized clinical trial of medical therapy versus medical therapy plus
LVRS for emphysema. Only patients who are HCFA beneficiaries or whose insurance is
willing to cover the costs of participation in NETT may enroll in the trial.
The trial consists of a main protocol (performed by all participating centers and
involving all enrolled patients) and several substudies (performed by selected centers
and involving only patients enrolled at those centers). Patients with moderate to severe
emphysema, who have been nonsmokers for at least 6 months prior to randomization and
who are judged free of other disease, disability, or condition presumed likely to interfere
with data collection, therapy, or followup, will be enrolled.
Patients will be randomized to medical therapy alone or medical therapy plus
LVRS in a 1–1 ratio at all clinical centers, regardless of whether the clinical center offers
LVRS by VATS, MS, or both VATS and MS. The choice of type of surgery (VATS
or MS) will be selected at random at those centers that offer both types of surgery; the
allocation of VATS to MS will be 1–1 at those centers.
The recruitment goal for the trial is 4,700 patients, of whom 6% (282 patients)
are expected to be of minority (non Caucasian) background and 30% (1,410 patients)
are expected to be female. The study duration (based on a target accrual rate of 4.8
patients/month/clinic) is fixed at 4.5 years with a 0.5–year closeout period.
All patients will have the following outcomes assessed:
• Survival
• Maximum exercise capacity as measured by cycle ergometry performed on 30%
supplemental oxygen: Maximal exercise workload, EKG, symptom assessment of
perceived breathlessness and muscle fatigue, expired minute ventilation and carbon
dioxide elimination with or without maximal oxygen consumption
• Quality of life/respiratory symptoms as measured by four self-administered
questionnaires: Quality of Well-Being, MOS SF-36, UCSD Shortness of Breath
Questionnaire, St George’s Respiratory Questionnaire
• Spirometry
• Lung volumes as measured by body plethysmography
• Diffusing capacity
• Maximum inspiratory and expiratory mouth pressures
• Supplemental oxygen requirement, steady-state treadmill walking
• Functional capacity as measured by six-minute walk distance with symptom assessment of perceived breathlessness and muscle fatigue, expired minute ventilation,
and carbon dioxide elimination with or without maximal oxygen consumption
• Gas exchange as measured by arterial blood gas at rest
• Attention and psychomotor functioning as measured by the Trail Making Test
• Degree of hyperinflation as assessed by evaluation of chest x-rays and lung function
• Severity and distribution of emphysema as assessed by evaluation of HRCT scans
• Cardiac function as measured by echocardiogram
• Health care utilization and costs as obtained by interview and/or analyses of
databases maintained by the patients’ insurers
506
A P P E N D I X 1 : D e s i g n S u m m a r i e s f o r S e l e c t e d F i n i s h e d Tr i a l s
NETT (Continued)
The following outcome measures will be assessed in patients at selected clinics (substudies):
• Gas exchange as measured by arterial blood gas during maximal exercise
• Pulmonary mechanics and respiratory muscle function (lung elastic recoil pressure,
flow-volume relationship, and pulmonary resistance)
• Partial and maximal flow-volume curves
• Right heart function as measured by right heart catheterization
• Utility as measured by U-Titer computer-based interview
Samples of the tissue excised from the lungs of the patients randomized to LVRS
will be stored locally until sufficient numbers accumulate for transfer to a central bank.
Studies of these specimens could lead to information on the role of genetics in the
development of emphysema and could provide information on the role of airway disease
in the outcome of LVRS.
Ultimately, the NETT investigators also hope to establish a central repository for
the digitized CT and perfusion scans obtained on NETT patients. As an interim step,
NETT clinics have been instructed to store scans for NETT patients on dedicated media
within the clinic.
F G C R T ( F o s c a r n e t–G a n c i c l o v i r C M V R e t i n i t i s Tr i a l )
507
FGCRT (Foscarnet–Ganciclovir CMV Retinitis Trial)85,86
Status
• Completed (data collection closed as of 1 October 1992)
• 260 patients (including 20 startup patients) enrolled at 12 clinics (March 1990–
October 1991)
• Vital status continued to death of last patient (December 1996)
Obectives
• Determine the relative safety and efficacy of foscarnet compared with ganciclovir
for treating CMV retinitis in people with AIDS
• Compare the relative benefits of immediate treatment with foscarnet or ganciclovir
with deferral of treatment in zones 2 & 3 retinitis
Trial characteristics
• Phase III/IV
• Multicenter treatment trial
Treatment groups
• Ganciclovir (127 patients)
• Foscarnet (85 patients)
• Deferred (24 patients; restricted to patients with small peripheral lesions only)
Inclusion criteria
• Males and females with AIDS, age 13 or older
• Newly diagnosed CMV retinitis
Masking
• Treatment administration unmasked
• Fundus photography reading masked
Other features of trial
• IND held by SOCA
• Patient preference design for patients eligible for deferral
Results
• Equal efficacy of foscarnet and ganciclovir in treating CMV retinitis
• No difference between foscarnet and ganciclovir for preventing progression of
retinitis
• Excess mortality associated with ganciclovir compared to foscarnet
• p24 antigen levels associated with mortality, but not with treatment assignment
• Characterization of patients with newly diagnosed CMV retinitis
• Comparison of centralized fundus photography readings with clinician
interpretations
• Development of quality of life instrument
508
A P P E N D I X 1 : D e s i g n S u m m a r i e s f o r S e l e c t e d F i n i s h e d Tr i a l s
FGCRT (Continued)
• Positive CMV cultures at baseline associated with increased risk of retinitis
progression and mortality
• Foscarnet associated with adverse drug reactions; however, these reactions rarely had
long-term effects
• Retinal detachments associated with increasing lesion size over time
Support
• Funding: NIH
• Drug support for all patients provided by Astra, Syntex, and Burroughs–Wellcome
C R R T ( C M V R e t i n i t i s R e t r e a t m e n t Tr i a l )
509
CRRT (CMV Retinitis Retreatment Trial)84
Status
• Completed (data collection closed as of 31 July 1995)
• 279 patients enrolled at 12 clinics (December 1992–February 1995)
• Vital status continues to death of last patient
Objectives
• Compare the safety and efficacy of three aggressive therapeutic regimens in patients
with AIDS-related CMV retinitis previously treated with foscarnet or ganciclovir
whose retinitis progresses or recurs
• Compare the safety and efficacy of continuing to treat patients with the same
anti-CMV drug versus switching to the alternative drug
Trial characteristics
• Phase III/IV
• Multicenter treatment trial
Treatment groups
• Ganciclovir (94 patients)
• Foscarnet (89 patients)
• Combination ganciclovir and foscarnet (96 patients)
Inclusion criteria
• Males and females with AIDS, age 13 or older
• Relapsed CMV retinitis
Masking
• Treatment administration unmasked
• Fundus photography reading masked
Other features of trial
• Protocol suspended before planned sample size of 300 reached
• IND held by SOCA
Results
• Combination therapy most effective treatment in controlling CMV retinitis
• For monotherapy patients, switching to alternative drug was no more effective than
continuing the same drug
• Survival advantage associated with prior foscarnet use
Ongoing analysis
• Association between GCSF use and bacterial infections
• Quality of life comparisons among the three treatment groups
510
A P P E N D I X 1 : D e s i g n S u m m a r i e s f o r S e l e c t e d F i n i s h e d Tr i a l s
CRRT (Continued)
Support
• Funding: NIH
• Drug support for all patients provided by Amgen, Astra, Bristol–Myers Squibb,
Syntex, and Burroughs–Wellcome
M A C R T ( M o n o c l o n a l A n t i b o d y C M V R e t i n i t i s Tr i a l )
511
MACRT (Monoclonal Antibody CMV Retinitis Trial)82
Status
• Completed (data collection closed as of 15 November 1996)
• 209 patients enrolled at 15 clinics (September 1995 to November 1996)
• Followup for vital status continued to death of last patient
Objectives
• Evaluate safety and efficacy of human anti-CMV monoclonal antibody (MSL 109)
as an adjunct treatment for CMV retinitis in patients with AIDS
• Evaluate the CMV viral load in patients with CMV retinitis
Trial characteristics
• Phase II/III
• Multicenter treatment trial
Treatment groups
• MSL 109, concurrent with active primary treatment for CMV retinitis (104 patients)
• Matched placebo for MSL 109, concurrent with active primary treatment for CMV
retinitis (105 patients)
Inclusion criteria
• Males and females with AIDS, age 13 years or older
• Diagnosis of active CMV retinitis (new or relapsed)
Masking
• Treatment assignment masked
• Fundus photography reading masked
Other features of trial
• Protocol suspended before planned sample size of 325 reached
• IND held by Protein Design Labs
Results
• MSL 109 ineffective as adjunct treatment for CMV retinitis
• Excess mortality in patients receiving MSL 109 as compared to placebo group in
patients with relapsed CMV at baseline
Ongoing analysis
• CMV and HIV viral load
Support
• Funding: NIH and Protein Design Labs
• Drug support for all patients provided by Protein Design Labs
512
A P P E N D I X 1 : D e s i g n S u m m a r i e s f o r S e l e c t e d F i n i s h e d Tr i a l s
HPCRT (HPMPC Peripheral CMV Retinitis Trial)83
Status
• Completed (data collection closed as of 1 September 1996)
• 64 patients enrolled in 13 clinics (April 1994 to February 1996)
• Vital status continued to death of last patient
Objectives
• Evaluate safety and tolerance of intravenous HPMPC (cidofovir) in patients with
CMV retinitis
• Obtain data on the safety and efficacy of two different dose regimens of HPMPC
Trial characteristics
• Phase II/III
• Multicenter treatment trial
Treatment groups
• Deferral of treatment (26 patients)
• H-3: Induction with HPMPC at 5 mg/kg/wk and maintenance at 3 mg/kg/2 wk
(26 patients)
• H-5: Induction with HPMPC at 5 mg/kg/wk and maintenance at 5 mg/kg/2 wk
(12 patients)
Inclusion criteria
• Males and females with AIDS, age 13 and older
• Newly diagnosed patients with peripheral CMV retinitis involving less than 25%
of the retina
Masking
• Treatment assignment unmasked
• Fundus photography reading masked
Other features of trial
• Protocol suspended before planned sample size of 90 reached
• IND held by Gilead Sciences, Inc.
Results
• Cidofovir is effective in treatment of CMV retinitis at both 3 mg/kg and 5 mg/kg
maintenance doses
Ongoing analysis
• Long-term followup for patients tested with cidofovir
Support
• Funding: NIH and Gilead Sciences
• Drug support for all patients provided by Gilead Sciences
G C C R T ( G a n c i c l o v i r–C i d o f o v i r C M V R e t i n i t i s Tr i a l )
513
GCCRT (Ganciclovir–Cidofovir CMV Retinitis Trial)81
Objectives
• To compare the efficacy of two treatment regimens in preventing vision loss as
measured by visual acuity and visual field for patients with AIDS and CMV retinitis
• To compare a treatment regimen that incorporates highly active local therapy with
a treatment regimen that does not
Trial characteristics
• Phase IV
• Multicenter treatment trial
Treatment groups
• Ganciclovir intraocular device plus oral ganciclovir
• Intravenous cidofovir
Inclusion criteria
• Males and females with AIDS, age 13 years or older
• Diagnosis of active CMV retinitis (new or relapsed)
Masking
• Treatment administration unmasked
• Fundus photography reading masked
Other features of trial
• Surgical Quality Assurance Committee
• Visual Acuity Quality Assurance Committee
Support
• Funding: NIH
• Drug support for hardship patients provided by Chiron and Gilead
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A P P E N D I X 1 : D e s i g n S u m m a r i e s f o r S e l e c t e d F i n i s h e d Tr i a l s
HPT (Hypertension Prevention Trial)38
Type of trial
Prophylactic
Centers
Four clinics
Five resource centers
Sample size
841 (919 with test cohort)
Eligibility criteria
Normotensive men and women
Ages 25–49 at BL1
Length of treatment
3 years
Length of followup
3 years
Treatment groups
Four test treatments
One control treatment
Treatment
Counseling for diet change
Outcomes of interest
Change in DBP and SBP
Change in dietary and urinary Na and K
Change in body weight
Treatment assignment
Random, via onsite computers
Stratified by clinic (4), body weight
(2 strata), and cohort (4)
Level of treatment masking
None. However data collection performed
Data collection schedule
by persons not informed of treatment
Three BL visits FU visits, every 6 months
assignment
after randomization (at BL3)
G LT ( G l a u c o m a L a s e r Tr i a l )
515
GLT (Glaucoma Laser Trial)35
Support
• Grants from the National Eye Institute
Period of support
• 5 years (February 1, 1983 through January 31, 1988)
Patient selection criteria
•
•
•
•
Age ≥ 35 years
Diagnosis of primary open-angle glaucoma
IOP ≥ 22 mmHg in each eye
Glaucomatous field loss in at least one eye or marked disc changes in the presence
of extremely elevated IOP
Length of followup
• Minimum of 2 years
Outcome measures
Primary
• Prescription of more than one medication to control glaucoma in absence of visual
field loss
Secondary
•
•
•
•
•
•
•
Change in visual field loss
Change in IOP
Number of steps in care
Adverse reaction
Change in disc cupping
Need for non-protocol treatment
Change in visual acuity
Method of treatment assignment
• Random
Stratification variables
• Clinic, higher pressure eye
Level of treatment masking
• Masked measurement of IOP and masked evaluation of fields and disc cupping
Type of trial
• Therapeutic
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A P P E N D I X 1 : D e s i g n S u m m a r i e s f o r S e l e c t e d F i n i s h e d Tr i a l s
GLT (Continued)
Study treatments
Test treatment
• Argon Laser Trabeculoplasty with topical medication as necessary
Ctrl treatment
• Topical medication
APPENDIX 2
Sample Design Slide Sets
SAMPLE DESIGN SLIDE SETS
Monoclonal Antibody CMV Retinitis Trial (MACRT): Slide set
Childhood Asthma Management Program (CAMP): Slide set
Glaucoma Laser Trial (GLT): Slide set
518
522
532
517
518
APPENDIX 2: Sample Design Slide Sets
Monoclonal Antibody CMV Retinitis Trial (MACRT): Slide set
Objective of the MACRT
Assess the safety and efficacy of Human Anti-CMV Monoclonal Antibody, MSL 109
(MA+), treatment versus placebo (Plbo+) treatment as supplemental treatment
for CMV retinitis in patients with AIDS
Trial type
• Phase II/III
• Multicenter, masked, placebo-controlled, randomized
• Total N = 300, with a programmed look for continuation after enrollment of 76
patients
Stratification
• Clinic
• Stage of CMV retinitis: newly diagnosed vs. relapsed
Treatment Administration
Groups
• MA+: 60 mg MSL 109, IV every 2 weeks as supplemental treatment to active
primary treatment for CMV retinitis
• Plbo+: Matched placebo for MSL 109, IV every 2 weeks as supplemental treatment
to active primary treatment for CMV retinitis
Observation
• Each administration to be observed and documented by a health care professional
• Observation to continue for at least 30 minutes following administration
• First administration to be observed in the clinic
General
•
•
•
•
Administer supplemental treatment first if given with other IV therapy
First dose 20 min, thereafter bolus with syringe pump recommended
Peripheral or central venous line
Introduce into downstream port to prevent uptake of agent by plastic tubing
Treatment interruption
Grade 3 or grade 4 adverse event, judged to be due to the supplemental treatment
Note: Supplemental treatment should continue if primary therapy is interrupted or
terminated.
Masking
• Double-masked treatment for CMV retinitis
• Masked reading of fundus photographs
• Unmasked Policy and Data Monitoring Board
M o n o c l o n a l A n t i b o d y C M V R e t i n i t i s Tr i a l ( M A C R T ) : S l i d e S e t
519
Outcomes: Design variables
• CMV retinitis progression as determined by reading of fundus photographs
• Change in CMV virologic status
Outcomes: Other variables
Primary
• Mortality
• Visual acuity
Secondary
•
•
•
•
Adverse events
Clinician assessment of CMV retinitis progression
Visual fields
Morbidity
❑ Extra-ocular CMV
❑ Opportunistic infections
❑ Hospitalizations
❑ Sepsis
• Quality of Life
Inclusion criteria
•
•
•
•
•
Age 13 or older
AIDS according to current CDC definitions
Active CMV retinitis diagnosed by SOCA-certified ophthalmologist
At least one photographable lesion ≥ 750 µm in diameter
Receiving (for relapsed patients), or scheduled to receive (for newly diagnosed
patients), active primary treatment for CMV retinitis which is not contraindicated
for use with MSL 109
• Willingness and ability (with assistance of a caregiver if necessary) to comply with
treatment and followup procedures
• Signed consent
Exclusion criteria
• Karnofsky score 50 or less
• Treatment with intravenous immune globulin (IV IG), CMV immune globulin
(CMV IG), alpha-interferon (alpha-IFN), gamma-interferon (gamma-IFN), or
interleukin-2 (IL-2)
• Media opacity that precludes photography of the fundus in involved eyes
• Unwillingness to use appropriate contraceptive methods
Data collection schedule
• Baseline
• Followup: Every month for first 12 months; every 3 months thereafter to common
closeout date
520
APPENDIX 2: Sample Design Slide Sets
MACRT (Continued)
• CMV DNA Polymerase Chain Reactions (PCR) at baseline, 1 month, 3 months,
and 6 months
Procedures required at scheduled visits
−1 1 2 3 4 5 6 7 8 9 10 11 12 15
18
day mo mo mo mo mo mo mo mo mo mo mo mo mo mo . . .
BL F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12
...
History
Medical History
Concomitant
Treatment Hx
Treatment Log
Adverse Event
Log
Eligibility Review
Eye
Visual Acuity
Eye Exam
Fundus
Photograph
Visual Fields
Lab
Hematology &
Urine
Chemistry
Lymphocyte
Subset
Analysis
CMV DNA PCR
Pregnancy test
Other
Quality of Life
Interview
Physical Exam
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Sample size determination
Sample size = 150 per treatment group = 300
Assignment ratio = 1:1 for MA+ vs. Plbo+
Type I error = 0.05 (two-sided)
10% increase in sample size due to loss to followup, treatment lag effects, and
noncompliance
• 10% increase in sample size due to heterogeneity of effects in patients with newly
diagnosed CMV retinitis vs. relapsed CMV retinitis
• Recruitment rate = 20 patients/month [(14 newly diagnosed patients/month +
12.5 relapsed patients/month) × 0.75]
•
•
•
•
MACRT Design Schematic
521
• Recruitment period = 15 months
• Minimum followup = 12 months
• Estimated event rates (based on FGCRT)
❑ Median time-to-progression in Plbo+ assigned group in newly diagnosed patients
= 48 days
❑ Median time-to-progression in Plbo+ assigned group in relapsed patients = 35
days
• Estimated proportion of newly diagnosed patients = 50%
• Estimated (minimum clinically significant) increase in median time-to-progression
= 50%
• Estimated power = 0.91
• Method of calculation
❑ Logrank test
Data analysis
• Plbo+ vs. MA+
• Primary analysis by assigned treatment group
• All events after randomization counted by assigned treatment group
Safety monitoring plan
• Review of data by Policy and Data Monitoring Board (PDMB) at semiannual
meetings or more often if necessary
• Recommendations for protocol modifications or early termination of the trial will
be made by the PDMB
• Decision to proceed to full stage made jointly by SOCA and PDL
MACRT Design Schematic
Newly dx
CMVR
Relapse
CMVR
RZ
1:1
RZ
1:1
MA
Plbo
MA
Plbo
522
APPENDIX 2: Sample Design Slide Sets
Childhood Asthma Management Program (CAMP)11 : Slide set
Childhood Asthma Management Program (CAMP)
•
•
•
•
A multicenter trial of 960 children with asthma
Provides 5–6 1/2 years of asthma care for each patient
At least 1/3 minorities
A randomized controlled trial sponsored by the National Heart, Lung, and Blood
Institute, National Institutes of Health
Hypothesis
Long-term treatment of children with asthma with anti-inflammatory agents will prevent
detrimental effects of asthma on lung growth.
CAMP Slide Set
523
CAMP study sites
Seattle
*
Toronto Boston
*
*
Denver
*
Sen Diego
*
St. Louis
*
Baltimore
*
Albuquerque
*
CAMP Centers
Study clinics
Albuquerque
Baltimore
Boston
Denver
San Diego
Seattle
St Louis
Toronto
Bennie McWilliams
N. Franklin Adkinson
Scott Weiss
Stanley Szefler
Robert Zeiger
Gail Shapiro
Robert Strunk
Henry Levison
University of New Mexico
Johns Hopkins University
Brigham & Women’s Hospital
National Jewish Center
University of California, San Diego
ASTHMA, Inc.
Washington University
Hospital for Sick Children
Coordinating Center
Baltimore
James Tonascia
Johns Hopkins University
Chairman’s Office
Denver
Reuben Cherniack
National Jewish Center
Project Officer
Bethesda
Virginia Taggart
NHLBI
Primary objective
To determine the long term effects of inhaled anti-inflammatory therapy on pulmonary
function.
Forms of inhaled anti-inflammatory therapy to be used:
• Budesonide (steroid)
• Nedocromil (non-steroid)
Treatment arms
• Budesonide (bud)
• Nedocromil (ned)
• Placebo (bud or ned)
524
APPENDIX 2: Sample Design Slide Sets
Each active drug will be compared to its own placebo. All subjects will have prn
bronchodilator (albuterol) for rescue therapy.
Treatment groups
Rz
Bud
n=288
Ned
n=288
Plbo
n=384
PBud
n=192
PNed
n=192
Secondary objectives
• To determine if the three treatments differ with respect to:
❑ Bronchial responsiveness to methacholine
❑ Morbidity and mortality
❑ Remission of asthma
❑ Long-term safety and side effects
❑ Physical growth and development
❑ Use of health care resources
❑ Psychological growth and development
• To determine if the three treatments differ with respect to psychological growth
and development as indicated by measures of neurocognitive functioning and
psychological adjustment
• To determine if the response to treatment is related to environmental and
psychological factors and to atopic status
Purpose of growth and development measures
To examine:
• Effect of asthma
• Effect of asthma medications
CAMP Slide Set
525
CAMP (Continued)
Measures of growth and development
• Somatic growth
❑ height
❑ weight
• Lung growth
• Sexual development
Somatic growth—height
• Height growth rate velocity increases and peaks during adolescence
• Pubertal growth accounts for 20% to 25% of final adult height
• Height growth rate velocity is highly variable
Somatic growth—weight
• Weight growth rate velocity increases and peaks during the adolescent growth
spurt
• Pubertal weight gain accounts for about 50% of final adult body weight
• Onset and velocity is highly variable
Somatic growth—other considerations
• Lean body mass
❑ females—decreases from 80% to 75%
❑ males—increases from 80% to 90%
• Adipose tissue
❑ increases in females and decreases in males
• Pelvic remodelling in females
• Skeletal mass
❑ increased density and bone mineralization
Lung growth
• Follows a pattern similar to somatic growth
• Lung growth and growth velocity curves are similar to height measurements except
they are slightly delayed with regard to linear growth
Sexual development
• Male
❑ pubic hair
❑ testes and penile development
• Female
❑ pubic hair
❑ breast development
526
APPENDIX 2: Sample Design Slide Sets
Sexual development males—genital
• G1: Stage 1 (Prepubertal)
❑ testes: volume <1.5 cc
❑ phallus: childlike
• G2: Stage 2
❑ testes: 1.6–6 cc
❑ scrotum: reddened, thinner, larger
❑ phallus: no change
• G3—Stage 3
❑ testes: 6–12 cc
❑ scrotum: further enlargement
❑ phallus: increased length
• G4: Stage 4
❑ testes: 12–20 cc
❑ scrotum: further enlargement and darkening
❑ phallus: increased length and circumference
• G5: Stage 5
❑ testes: >20 cc
❑ scrotum and phallus—adult
Sexual development female—breasts
• B1: Stage 1
❑ breast—prepubertal; no glandular tissue
❑ areola and papilla—conforms to chest line
• B2: Stage 2
❑ breast—breast bud; small amount of glandular tissue
❑ areola and papilla—areola widens
• B3: Stage 3
❑ breast—larger and more elevated; extends beyond areolar perimeter
❑ areola and papilla—areola enlarges but still on contour with the breast
• B4: Stage 4
❑ breast—larger and more elevated
❑ areola and papilla—form a mound projecting from the breast contour
• B5: Stage 5
❑ breast—adult
❑ areola and papilla—areola and breast in same plane, with papilla projecting
above areola
Sexual development—pubic hair
• PH1: Stage 1
❑ no hair
• PH2: Stage 2
❑ small amount of long slightly pigmented downy hair
CAMP Slide Set
527
CAMP (Continued)
• PH3: Stage 3
❑ moderate amount of more curly, pigmented and coarse hair; more lateral
extension
• PH4: Stage 4
❑ resembles adult hair except does not extend to the medial surfaces of the thighs
• PH5: Stage 5
❑ adult pattern
Effect of asthma on growth
May cause delays in growth due to chronic illness or asthma medications, particularly
inhaled steroids.
Asthma medications
• Bronchodilators
❑ Beta-adrenergic agents
❑ Methylxanthines
❑ Anticholinergic agents
• Anti-inflammatory agents
❑ Cromolyn sodium
❑ Nedocromil
❑ Glucocorticoids
Systemic effects of glucocorticoids
•
•
•
•
•
•
Somatic growth
Lung growth
Maturation
Bone growth
HPA axis effects
Other effects
❑ Cushingoid facies—‘‘Moon’’ facies, ‘‘Buffalo hump’’
❑ Skin changes—thinning, striae, easy bruising, ulcers, acne
❑ Hypertension
❑ Altered fat distribution
Measurements obtained every 4 months
• Height, weight
• Spirometry (FEV1 , FVC) (methacholine challenge at 8 months)
Yearly measurements
• General physical exam
❑ height and weight
❑ sitting height
❑ waist and hip circumferences
528
APPENDIX 2: Sample Design Slide Sets
physical findings of systemic glucocorticoid effects: ‘‘Moon’’ facies, ‘‘Buffalo
hump,’’ thin arms, skin changes
• Sexual development
• Bone densitometry measurements
• Bronchial responsiveness
❑
Height measurements
• One of the most important parameters to measure
• Highly variable unless performed correctly
• Considerations to measurements
❑ equipment
❑ protocol
Height measurement—equipment
Reasons not to use height readings from scales:
•
•
•
•
Platform wobbles
Crosspiece never a true 90 degrees
No support for back, head, heels, or buttocks
Measurements often off by 3–4 cm
Height measurement—stadiometer
• Harpenden stadiometer
• Standardized height measurement protocol
Height measurement—protocol
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Shoes removed, thin socks or barefoot
Stand erect
Heels, buttocks, and shoulders against stadiometer
Ankles and feet touching
Knees straight and locked
Push on abdomen to minimize lordosis
Look straight ahead; do not raise chin; the middle of the ear and corner of the eye
in a straight line
When child is standing correctly, lower the platform to his/her head
The operator is at the child’s head level for measurements
Read the height
Three measurements are recorded
The measurements must be within 0.3 cm of each other
In younger children, a parent may hold the heels to keep the child from standing
on toes
If the child has ‘‘high hair,’’ the platform must be pushed down to flatten the hair
Height is measured in centimeters
This is done every 4 months
CAMP Slide Set
529
CAMP (Continued)
Weight measurement
• Equipment—standard medical scale (Detecto #337)
• Protocol
❑ child wears underwear and a gown (or a T-shirt and shorts)
❑ child stands in the center of the scale
❑ measurements are made yearly
• Weight is measured in kilograms
• This is done every 4 months
Other measurements
• Sitting height
❑ The child sits on a flat surface against the stadiometer. The sitting height (truncal
length) is measured from the top of the head to the top of the flat sitting surface
❑ Measurements are in centimeters
❑ Measurements are done yearly
• Waist and hip circumferences
❑ Measurements are in centimeters
❑ The largest hip and smallest waist measurements are recorded
❑ Measurements are done yearly
Bone densitometry measurements
• Lumbosacral spine bone density measurements are performed yearly
• Systems used
❑ Lunar DPX
❑ Hologic QDR 1000
❑ Hologic QDR 1000/W
❑ Hologic QDR 1500
❑ Hologic QDR 2000
• Bone density is measured as g/cm2
Psychosocial questionnaires
• Mood
❑ Revised Children’s Manifest Anxiety Scale
❑ Children’s Depression Inventory
• Social adjustment
❑ Social Anxiety Scale for Children
• Physical activity
❑ Child Behavior Checklist
• Behavior problems
❑ Child Behavior Checklist
❑ Youth Self Report (age 11 and older)
530
APPENDIX 2: Sample Design Slide Sets
• Family adjustment
❑ Family Environment Scale
❑ Impact on Family Scale
❑ Social Support Survey
Psychosocial tests
• Intellectual skills
❑ Wechsler Preschool and Primary Scale of Intelligence—Revised (age 5)
❑ Wechsler Intelligence Scale for Children—Third Edition
• Academic skills (reading, writing, math)
❑ Woodcock–Johnson Psychoeducational Battery
• Memory
❑ Wide Range Assessment of Memory and Learning
• Attention
❑ Gordon Diagnostic System
Psychosocial baseline measures associated with trial outcome
• Emotional and behavioral adjustments
• Family adjustment
Psychosocial areas affected by asthma medications
•
•
•
•
•
Attention
Memory
Mood
Academic achievement
Emotional and behavioral adjustments
Psychosocial areas affected by chronic asthma
•
•
•
•
•
•
Academic progress
Mood
Behavior problems
Physical activity
Social adjustment
Family adjustment
Psychosocial measurement areas
•
•
•
•
•
•
•
•
Academic progress
Attention
Memory
Mood
Behavior problems
Physical activity
Social adjustment
Family adjustment
CAMP Slide Set
531
CAMP (Continued)
Schedule of CAMP behavioral measures
Administration
Child
WISC-II or WPPSI-R
Woodcock Johnson
Achievement Battery
Wide Range
Assessment of
Memory &
Learning
Gordon Diagnostic
System
Children’s Manifest
Anxiety Scale
Children’s Depression
Inventory
Social Anxiety Scale for
Children
Youth Self-Report (11
and older)
Parent
Child Behavior Checklist
Family Environment
Scale
Impact on Family Scale
MOS Social Support
Survey
Amount of time
BL
Yr 1
Yr 2
Yr 3
Yr 4
Yr 5
20 min
X
X
X
30 min
X
X
X
20 min
X
X
30 min
X
X
10 min
X
X
X
X
X
X
10 min
X
X
X
X
X
X
5 min
X
X
X
X
X
X
15 min
X
X
X
X
X
X
30 min
X
X
X
X
X
X
25 min
12 min
X
X
X
X
X
X
X
X
X
X
X
X
5 min
X
X
X
X
X
X
X
X
532
APPENDIX 2: Sample Design Slide Sets
Glaucoma Laser Trial (GLT): Slide set
Objective
Compare initial treatment with ALT followed by topical medication if needed vs initial
treatment with topical medication for controlling IOP in eyes with newly diagnosed
POAG
Design
Test treatment
ALT followed by stepped topical medications as needed
Control treatment
Stepped topical medications
Treatment assignment
Random
Randomization unit
Eye
Outcome measures
•
•
•
•
•
•
Number of medications (outcome used to calculate sample size)
Change in visual field
Change in optic disc
Change in visual acuity
Need for nonprotocol treatment
Change in IOP
Criteria for changing medication
• Inadequate control of glaucoma; defined as
❑ IOP ≥ 22 mmHg on two consecutive occasions
❑ IOP < 20% below baseline level on two consecutive occasions
❑ Visual field deterioration
❑ Optic disc deterioration
• Adverse ocular or systemic reaction
GLT protocol
Laser
• Argon blue-green
Sessions
• 2 sessions spaced 4 weeks apart
• 180◦ of trabecular meshwork treated at each session
G l a u c o m a L a s e r Tr i a l ( G LT ) : S l i d e S e t
GLT (Continued)
Burns
• 48 per session (45–50 allowed)
• Placed to saddle pigmented and nonpigmented anterior trabecular meshwork
• 50-µm spot size
Power
• Power adjusted to achieve threshold of bubble formation
• 0.1-sec duration
Immediate post ALT therapy
• Dexamethasone 0.1% 4 times per day for 6 days
Medication stepping regimen
1.
2.
3.
4.
5.
6.
7.
Timolol
Dipivefrin
Low dose pilocarpine
High dose pilocarpine
Timolol with high dose pilocarpine
Dipivefrin with high dose pilocarpine
Best medical judgement
Centers
Clinical centers (8)
•
•
•
•
•
•
•
•
Emory Eye Center
Massachusetts Eye and Ear Infirmary
Medical College of Wisconsin
New York Eye and Ear Infirmary
Ohio State University
Sinai Hospital of Detroit
University of Illinois Eye and Ear Infirmary
Wills Eye Hospital
Resource centers (5)
•
•
•
•
•
Chairman’s Office (Sinai Hospital of Detroit)
Coordinating Center (Johns Hopkins University)
Disc Stereophotography Reading Center (Wills Eye Hospital)
Visual Field Reading Center (University of Illinois Eye and Ear Infirmary)
Project Office (National Eye Institute)
533
534
APPENDIX 2: Sample Design Slide Sets
GLT clinical centers
Albany
Detroit
Boston
Chicago
New York City
Philadelphia
Tucson
Committees
•
•
•
•
Steering Committee
Executive Committee
Design and Quality Assurance Committee
Treatment Effects Monitoring and Advisory Committee
Chronology
Date
1983
1984
1984
1985
1985
1985
1987
1987
1989
1991
1993
1994
Event
Feb 1
Feb 15
Oct
Feb
Apr
Jul
Apr 30
Jun 2
Nov 1
Dec
Aug
Aug
Funding awarded for 7 clinics, CC and reading centers
1st patient enrolled
Tucson clinic resigns
Funding for 5 additional clinics awarded
Albany clinic resigns
Los Angeles and New Orleans clinics resign
Recruitment ends with 271 patients
NEI approves funding for continuation of GLT through January 31, 1991
End of GLT treatment stage
Start of GLT Followup Study
End of GLT Followup Study data collection
End of funding for GLT Followup Study
535
G l a u c o m a L a s e r Tr i a l ( G LT ) : S l i d e S e t
GLT (Continued)
Clinic visit schedule
Visit
Time from randomization
−3 wk
−2 wk
0
1 wk
4 wk
5 wk
3 mo
6 mo
9 mo
12 mo
15 mo
18 mo
21 mo
24 mo
Baseline 1
Baseline 2
Treatment 1
Post-treatment 1
Treatment 2
Post-Treatment 2
Followup 1
Followup 2
Followup 3
Followup 4
Followup 5
Followup 6
Followup 7
Followup 8
etc.
Data collection schedule
Procedure
Time from randomization
−3 wk
−2 wk
1 wk
4 wk
5 wk
3 mo
6 mo
9 mo
12 mo
15 mo
18 mo
21 mo
24 mo
etc.
VA
IOP
VF
Slit lamp
Fundus photo
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization features
Stratification variables
• Clinic
• Eye with higher IOP at baseline visit 2 (if RE IOP = LE IOP, higher IOP eye is
selected randomly)
Block size
• Length 4, 6, or 8, selected randomly
536
APPENDIX 2: Sample Design Slide Sets
Data management features
•
•
•
•
•
Centralized
Paper-based
Double data entry (same sitting)
Separate inventory and data files
Edit checks for consistency, completeness, and accuracy
APPENDIX 3
Template Summary Worksheet 537
537
538
A P P E N D I X 3 : Te m p l a t e S u m m a r y W o r k s h e e t
Summary Worksheet
1. Umbrella name (see Multi-study umbrella name, page 19)
2. Name of trial (see Study name, page 21)
3. Type of trial (check all that apply; see Trial type, page 9)
Multicenter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Randomized . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Double-masked . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Placebo-controlled . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
)
)
)
)
Treatment structure
Parallel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ( )
Crossover . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ( )
Phase
Phase I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .(
Phase II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Phase I/II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Phase III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Phase IV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
)
)
)
)
)
Purpose
Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .(
Primary prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Secondary prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Equivalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Superiority . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Other (specify) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
4. Objective (≤ 15 words; see Objective, page 27)
5. Centers (give number of each; see Center types, page 317)
Clinics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Affiliate sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
)
)
)
)
)
)
Summary Worksheet
Satellite sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Other sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Resource centers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Coordinating centers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Reading centers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Central laboratories. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Project office . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Other resource centers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Total no. of centers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6. Treatment groups (give number; see Study treatments, page 75)
Test-treated groups (see Test treatments, page 77) . . . . . . . . . . . . . . . . . . . . .
Control-treated groups (see Control/comparison treatment, page 79) . . . .
Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7. Test treatment (see Test treatments, page 77)
Test trt 1
Name:
Abbreviated name/code name . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Schedule (e.g., daily, b.i.d., t.i.d., weekly, etc.):
Dose:
Duration of trt:
Test trt 2
Name:
Abbreviated name/code name . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Schedule (e.g., daily, b.i.d., t.i.d., weekly, etc.):
Dose:
Duration of trt:
Test trt 3
Name:
539
540
A P P E N D I X 3 : Te m p l a t e S u m m a r y W o r k s h e e t
Abbreviated name/code name . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Schedule (e.g., daily, b.i.d., t.i.d., weekly, etc.):
Dose:
Duration of trt:
Test trt 4
Name:
Abbreviated name/code name . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Schedule (e.g., daily, b.i.d., t.i.d., weekly, etc.):
Dose:
Duration of trt:
Test trt 5
Name:
Abbreviated name/code name . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Schedule (e.g., daily, b.i.d., t.i.d., weekly, etc.):
Dose:
Duration of trt:
8. Control treatments (see Control/comparison treatment, page 79)
Ctrl trt 1
Name:
Abbreviated name/code name . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Schedule (e.g., daily, b.i.d., t.i.d., weekly, etc.):
Dose:
Duration of trt:
Ctrl trt 2
Name:
Abbreviated name/code name . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Schedule (e.g., daily, b.i.d., t.i.d., weekly, etc.):
Dose:
Duration of trt:
541
Summary Worksheet
9. Treatment summary table
Test trts
Trt 1
Trt 2
Trt 3
Ctrl trts
Trt 4
Trt 5
Trt 1
Trt 2
Trt 3
Abbreviated name
Treatment mode (Check all that apply; see Treatment modality, page 93)
Drug
(
) (
) (
) (
) (
) (
) (
Biologic
(
) (
) (
) (
) (
) (
) (
Device
(
) (
) (
) (
) (
) (
) (
Vaccine
(
) (
) (
) (
) (
) (
) (
Vitamin
(
) (
) (
) (
) (
) (
) (
Diet supplement
(
) (
) (
) (
) (
) (
) (
Diet
(
) (
) (
) (
) (
) (
) (
Surgical
(
) (
) (
) (
) (
) (
) (
Medical
(
) (
) (
) (
) (
) (
) (
Radiation
(
) (
) (
) (
) (
) (
) (
Lifestyle change
(
) (
) (
) (
) (
) (
) (
Other
)
)
)
)
)
)
)
)
)
)
)
(
(
(
(
(
(
(
(
(
(
(
)
)
)
)
)
)
)
)
)
)
)
(
)
(
)
(
)
(
)
(
)
(
)
(
) (
)
(
)
(
)
(
)
(
)
(
)
(
)
(
) (
)
(
)
(
)
(
)
(
)
(
)
(
)
(
) (
)
Treatment unit (usually same as randomization unit; see Treatment unit, page 33)
Village/community (
) (
) (
) (
) (
) (
) (
) (
Household
(
) (
) (
) (
) (
) (
) (
) (
Person
(
) (
) (
) (
) (
) (
) (
) (
Body part
(
) (
) (
) (
) (
) (
) (
) (
Other
)
)
)
)
(
)
(
)
(
)
(
)
(
)
(
)
(
) (
)
(
)
(
)
(
)
(
)
(
)
(
)
(
) (
)
)
)
)
)
(
(
(
(
)
)
)
)
(
(
(
(
)
)
)
)
(
(
(
(
)
)
)
)
(
(
(
(
)
)
)
)
(
(
(
(
)
)
)
)
(
(
(
(
)
)
)
)
)
)
)
)
Route of administration
Not applicable
(
Mouth
(
Injection
(
IV
(
Other
Schedule
Dose
Duration of trt
10. Design variable (variable used for sample size or power calculation)
(
(
(
(
542
A P P E N D I X 3 : Te m p l a t e S u m m a r y W o r k s h e e t
11. Outcome measures
Primary (usually same as design variable, see Primary outcome, page 35)
Other (list in descending order of clinical importance; see Outcome measures, page
39)
1
2
3
4
5
6
7
8
9
10
11
12
12. Stratification
Number of variables. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Variable 1:
No. of states/levels . . . . . . . . . . . . .
Variable 2:
No. of states/levels . . . . . . . . . . . . .
Variable 3:
No. of states/levels . . . . . . . . . . . . .
Total number of allocation stratification (product of states/levels) . . . . . . . .
13. Randomization
Unit (e.g., community, village, household, person, part of person, such as eye, as
listed in item 9; see also Randomization/unit, page 155)
Design (e.g., permuted blocks)
Assignment ratio (e.g., 1:1:2; in order listed in item 9; control treatment last; see
Assignment methods: Fixed vs. adaptive, page 145) . . . . . . . . . . . . . . . . .
Assignments concealed prior to release?
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (yes) (no)
If yes, describe
Site of release and mode of generation (see Randomization: Procedure, page 157)
( ) Coordinating center
( ) Computer, as needed
Summary Worksheet
543
( ) Sealed list
( ) Open list
( ) Other
( ) Clinic
( ) Computer, as needed
( ) Numbered, sealed, envelopes
( ) Open list
( ) Other
Control (against release prior to completion of necessary data collection,
ascertainment of eligibility, consent, or where clinic or person is not ready
to start treatment)
None (check with open assignment schedules posted in clinic and with
sealed, numbered, envelopes obtained and opened without check
or control) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Local/internal (e.g., in clinic administered envelope system of assignment,
scheme in which a 2nd person checks to make certain necessary data
have been collected, consent obtained, and physician ready to start
treatment before envelope is opened) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Central/external (e.g., system as described for CDP with central release or
scheme where assignments are generated via on-site computer but only
after necessary data have been keyed and eligibility checked via
keyed data) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
14. Sample size
Test treatment groups
Trt 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Trt 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Trt 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Trt 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Trt 5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Control treatment groups
Trt 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Trt 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Total (all treatment groups) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Method of determination (see Sample size: Calculation, page 259)
Calculated . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Pragmatic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
)
)
)
544
A P P E N D I X 3 : Te m p l a t e S u m m a r y W o r k s h e e t
Specifications (give particulars, e.g., α, β, , and control rate for event type outcome)
15. Separations (check all that apply; see Separations, page 141)
Sponsor and investigators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Sponsor and coordinating center . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Clinic(s) and coordinating center . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Treaters and data collectors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Treaters and treatment effects monitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Other. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .(
)
)
)
)
)
)
Specify
16. Bias control procedures (check all that apply; see Bias control procedures, page 131)
Randomization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Masked treatment administration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .(
Masked data collection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Masked readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Masked data analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Masked treatment effects monitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Imposed frozen state of equipoise on clinic personnel (see page 131) . . . . . . . (
Other. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .(
)
)
)
)
)
)
)
)
Specify
17. Variance control procedures (check all that apply; see Variance control procedures,
page 139)
Randomization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Stratification of assignments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Replication of measurements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .(
Matching . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Adjustment of analyses for baseline differences . . . . . . . . . . . . . . . . . . . . . . . . . . (
Subgroup analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Other. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .(
Specify
)
)
)
)
)
)
)
Summary Worksheet
545
18. Treatment masking (see Mask/masking: Definitions, page 107)
Degree (check one)
None . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Partial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Full . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
)
)
)
Level (check one)
None . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Single . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Double . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Triple . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
)
)
)
)
Method (check all that apply)
Placebo treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Sham treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Separation of treater and data collectors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Other . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
)
)
)
)
19. Types of persons enrolled (check all that apply)
Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Adolescents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Toddlers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Babies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Pregnant women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Women of childbearing potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Prisoners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Other institutionalized persons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Students . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Mentally incompetent persons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Illiterate persons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Non-English speaking people . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Persons residing outside the United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
)
)
)
)
)
)
)
)
)
)
)
)
)
)
Specify
Healthy volunteers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Persons with a diagnosed condition or disease . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Specify disease or condition
)
)
546
A P P E N D I X 3 : Te m p l a t e S u m m a r y W o r k s h e e t
Persons at risk for a disease or adverse health condition . . . . . . . . . . . . . . . . . . . ( )
Specify risk factor
Other. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .( )
Specify
20. Study population: Inclusions/exclusions
Persons of either gender?
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (yes) (no)
If no, specify gender excluded . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Person of any race or of any ethnic origin?
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (yes) (no)
If no, specify exclusions
Person of any age?
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (yes) (no)
If no, specify age limits; upper and lower
21. Other exclusions
22. Enrollment design
Start-up method (e.g., individual by clinic or common start; see Start-up design,
page 203)
Quota requirements (see Enrollment quotas, page 213)
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (yes) (no)
If yes, specify nature of requirement and how applied, e.g., by clinic or overall)
Summary Worksheet
547
23. Consent procedure (check all that apply)
Consent form prepared from prototype distributed from coordinating
center or study chair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Consent statements reviewed for content, adequacy, and readability
prior to submission to local IRB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Consent statements approved by local IRBs reviewed for content,
adequacy, and readability prior to clearing clinics for enrollment . . . . . . . . . (
Multistage consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
At least 24 hr between request of consent and fact of consent. . . . . . . . . . . . . . . . .(
Review of consent at periodic intervals after consent with enrollee . . . . . . . . . . . . (
Other . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
)
)
)
)
)
)
)
Specify
24. Clinic visit schedule (see Notation, page 197; Timing conventions, page 199;
Contact schedule, page 269; Examination/clinic visit schedule, page 275)
Contact
Code
Example
Proposed
Screening
Sc 1, Sc 2
Baseline
Bl 1, Bl 2
Trt assign
Rz ( = Bl 3)
Trt adm
Rx 1, Rx 2
Followup
Fu 1, Fu 2
Number
Schedule
25. Types of scheduled data collection contacts (check all that apply)
Clinic visits only . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Home visits only . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .(
Both . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Telephone interview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Other (specify) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
)
)
)
)
)
548
A P P E N D I X 3 : Te m p l a t e S u m m a r y W o r k s h e e t
26. Scheduled contacts (including visits to clinic, home visits, and telephone contacts)
Min no.
Max no.
Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Baseline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Followup . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Closeout . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Total. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27. Length of followup (min equal to max for anniversary closeout design)
On treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Off treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28. Closeout design
Type (see Closeout design, page 225)
Common closing date . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ( )
Specify:
Anniversary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ( )
Specify:
29. Procedures (e.g., blood draw, needle biopsy, x-ray, fundus photography, etc.)
30. Key observation variables (list variables to be observed at one or more points during
data collection)
Summary Worksheet
549
31. Procedure and observation schedule (see Data Collection: Schedule and procedures,
page 281; indicate visits at which procedure or observations to be made in table
below)
Baseline visits
Followup visits
Visits
Procedures
Observation variables
32. Projected timetable (give approximate start and end calendar dates)
Start date
End date
Comment
Design stage
Protocol development
Enrollment stage
Trt and followup stage
Closeout stage
Post closeout
33. Committees
Key committees (see Key committees, page 339)
Other standing and working committees (see Standing and working committees,
page 341)
34. Funding
Source (names, e.g., NCI, Glaucoma Foundation)
550
A P P E N D I X 3 : Te m p l a t e S u m m a r y W o r k s h e e t
Initiative (see Funding: Initiative, page 61)
Investigator. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .(
Sponsor
RFA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
RFP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Other. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .(
)
)
)
)
Funding vehicle (see Funding: Type, page 59)
Grant (R01) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Grant (cooperative agreement) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Contract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Other (specify) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
)
)
)
)
Funding route for clinics (check one)
Direct from sponsor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Indirect
Via contract from coordinating center . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Via contract from office of study chair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Other (specify) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
)
)
)
)
Mode of payment to clinics (check one; see Funding: Mode, page 67)
Effort budget based on FTEs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .( )
Head payments per person enrolled or followed . . . . . . . . . . . . . . . . . . . . . . . . . ( )
Other (specify) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ( )
35. Principles and policies (check all that apply)
Once randomized, counted . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Analysis by original treatment assignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Publish primary results prior to presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Group authorship for mainline papers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .(
Deposit of finished dataset in public archive . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
Other (specify) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (
)
)
)
)
)
)
References
1 ADAPT Research Group: Alzheimer’s Disease Anti-inflammatory Prevention Trial: Design,
methods, and baseline results. Alzheimer’s & Dementia 2009; 5: 93–104.
2 Aickin M: A program for balancing the allocation of subjects to treatment in a clinical trial.
Computers and Biomedical Research 1982; 15: 519–524.
3 Bayes T: An essay towards solving a problem in the doctrine of chances. (Reproduced in Biometrika
45:296–315, 1958.) Philos Trans R Soc Lond 1763; 53: 370–418.
4 Begg C, Cho M, Eastwood S, Horton R, Moher D, Olkin I, Pitkin R, Rennie D, Schultz KF,
Simel D, Stroup DF: Improving the quality of reporting of randomized controlled trials: The
CONSORT statement. JAMA 1996; 276: 637–639.
5 Boissel J-P, Collet J-P, Moleur P, Haugh M: Surrogate endpoints: A basis for a rational approach.
Eur J Clin Pharmacol 1992; 43: 235–244.
6 Brain Resuscitation Clinical Trial II Study Group: A randomized clinical trial of calcium entry
blocker administration to comatose survivors of cardiac arrest: Design, methods and patient
characteristics. Control Clin Trials 1991; 12: 525–545.
7 Brittain E, Wittes J: The run-in period in clinical trials. Control Clin Trials 1990; 11: 327–338.
8 Buchwald H, Varco RL, Matts JP, Long JM, Fitch LL, Campbell GS, Pearce MB, Yellin AE,
Edmiston WA, Smink Jr RD, Sawin HS, Campos CT, Hansen BJ, Tuna N, Karnegis JN,
Sanmarco ME, Amplatz K, Castaneda-Zuniga WR, Hunter DW, Bissett JK, Weber FJ, Stevenson
JW, Leon AS, Chalmers TC, and the POSCH Group: Effect of partial ileal bypass surgery on
mortality and morbidity from coronary heart disease in patients with hypercholesterolemia: Report
of the Program on the Surgical Control of the Hyperlipidemias (POSCH). N Engl J Med 1990;
323: 946–955.
9 Canner PL: Monitoring clinical trial data for evidence of adverse or beneficial treatment effects.
INSERM 1977; 76: 131–149.
10 Cardiac Arrhythmia Suppression Trial (CAST) Investigators: Preliminary report: Effect of encainide
and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial
infarction. N Engl J Med 1989; 321: 406–412.
11 Childhood Asthma Management Program Research Group: The Childhood Asthma Management
Program (CAMP): Design, rationale, and methods. Control Clin Trials 1999; 20: 91–120.
12 Chow S-C, Chang M: Adaptive design methods in clinical trials—A review. Orphanet J Rare Dis
2008 3:11.
13 Christian MC, McCabe MS, Korn EL, Abrams JS, Kaplan RS, Friedman MA: The National
Cancer Institute audit of the National Surgical Adjuvant Breast and Bowel Project Protocol B-06.
N Eng J Med 1995; 333: 1469–1574.
14 Cornfield J: The Bayesian outlook and its application (including discussion by S Geisser, HO
Hartley, O Kempthrone, H Rubin). Biometrics 1969; 25: 617–657.
15 Cornfield J: Sequential trials, sequential analysis and the likelihood principle. Am Statistician 1966;
20: 18–23.
16 Coronary Drug Project Research Group: Influence of adherence to treatment and response of
cholesterol on mortality in the Coronary Drug Project. N Engl J Med 1980; 303: 1038–1041.
17 Coronary Drug Project Research Group: Aspirin in coronary heart disease. J Chron Dis 1976; 29:
625–642.
551
552
REFERENCES
18 Coronary Drug Project Research Group: The Coronary Drug Project: Design, methods, and
baseline results. Circulation 1973; 47(Suppl I):I-1–I-50.
19 Criner GJ Editor: National Emphysema Treatment Trial. (compendium of 34 parts ) Proc Am
Thorac Soc 2008; 5: 379–574.
20 Davis KB, Fisher L, Gillespie MJ, Pettinger M: A Test of the National Death Index Using the
Coronary Artery Surgery Study (CASS). Control Clin Trials 6: 179–191, 1985.
21 DeAngelis CD, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, Kotzin S, Laine C, Marusic
A, Overbeke AJPM, Schroeder TV, Sox HC, Van Der Weyden MB: Is this clinical trial fully
registered?—A statement from the International Committee of Medical Journal Editors. N Engl
Med 2005; 352: 2436–2438.
22 DeAngelis CD, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, Kotzin S, Laine C,
Marusic A, Overbeke AJPM, Schroeder TV, Sox HC, Van Der Weyden MB: Clinical Trial
Registration: A Statement From the International Committee of Medical Journal Editors. JAMA
2004; 292:1363–1364.
23 DeMets DL, Lan KKG: Interim analysis: The alpha spending function approach. Stat Med 1994;
13: 1341–1352.
24 Department of Health and Human Services: HIPAA Administrative Simplification: Standard
Unique Health Identifier for Health Care Providers (final rule). Federal Register 23 January 2004;
69: 3434–3469.
25 Department of Health and Human Services; Office for Civil Rights: Standards for privacy of
individually identifiable health information (Unofficial version) (45 CFR Parts 160 and 164):
Regulation text (28 Dec 2000: as amended: Part 160 (31 May 2002); Parts 160, 164 (14 Aug
2002); 31 pages; Oct 2002.
26 Diabetic Retinopathy Study Research Group: Diabetic Retinopathy Study: Report Number 6.
Design, methods, and baseline results. Invest Ophthalmol Vis Sci 1981; 21: 149–209.
27 Diggle P, Kenward MG: Informative drop-out in longitudinal data analysis. Appl Statist 1994; 43:
49–93.
28 Dunnett CW: A multiple comparison procedure for comparing several treatments with a control.
JASA 1955; 50: 1096–1121.
29 Dupont WD: Sequential stopping rules and sequentially adjusted p-values; Does one require the
other? Control Clin Trials 1983; 4: 3–10.
30 Edwards AWF: Likelihood: An account of the Statistical Likelihood Concept of Likelihood and its
Application to Scientific Inference. Cambridge University Press, Cambridge, 1972.
31 Food and Drug Administration: Code of Federal Regulations; 21, Parts 300–499, Revised as of
April 1, 1994. Office of the Federal Register, National Archives and Records Administration,
Washington, 1994.
32 Fost N, Robertson JA: Deferring consent with incompetent patients in an intensive care unit. IRB
1980; 2(7): 5–6.
33 Freedman B: Equipoise and the ethics of clinical research. N Engl J Med 1987; 317: 141–145.
34 Friedman B: A simple urn model. Commun Pure and Appl Math 1949; 2: 59–70.
35 Glaucoma Laser Trial Research Group: The Glaucoma Laser Trial (GLT): 3. Design and methods.
Control Clin Trials 1991; 12: 504–524.
36 Heath EI, Canto MI, Piantadosi S, Montgomery E, Weinstein WM, Herman JG, Dannenberg
AJ, Yang VW, Shar AO, Hawk E, Forastiere AA, On behalf of the Chemoprevention for
Barrett’s Esophagus Trial Research Group: Secondary Chemoprevention of Barrett’s Esophagus
with Celecoxib: Results of a Randomized Trial. J Natl Cancer Inst 2007; 99: 545–557.
37 Hypertension Detection and Follow-up Program Cooperative Group: Five-year findings of the
Hypertension Detection and Follow-up Program: I. Reduction in mortality of persons with high
blood pressure, including mild hypertension. JAMA 1979; 242: 2562–2571.
References
553
38 Hypertension Prevention Trial Research Group: The Hypertension Prevention Trial (HPT):
Design, Methods, and Baseline Results (C Meinert, J Tonascia, S Tonascia, editors). Control Clin
Trials 1989; 10(Suppl):1S–117S.
39 Ingelfinger FJ: Definition of ‘‘sole contribution’’. Engl J Med 1969; 281: 676–677.
40 Institute of Medicine Committee to Review the Fialuridine (FIAU/FIAC) Clinical Trials: Review
of the Fialuridine (FIAU) Clinical Trials. National Academy Press, Washington, 1995.
41 International Committee of Medical Journal Editors: Uniform requirements for manuscripts
submitted to biomedical journals. N Engl J Med 1997; 336: 309–315.
42 Katz J: Experimentation with Human Beings. Russell Sage Foundation, New York, 1972.
43 Klimt CR, Knatterud GL, Stamler J, Meier P: Persantine–aspirin reinfarction study. Part II.
Secondary coronary prevention with persantine and aspirin. J Am Coll Cardiol 1986; 7: 251–269.
44 Lachin JM, Marks JW, Schoenfield LJ, and The NCGS Protocol Committee ( Tyor MP, Bennett
PH, Grundy SM, Hardison WGM, Shaw LW, Thistle JL, Vlahcevic ZR, and The National
Cooperative Gallstone Study Group): Design and Methodological Considerations in the National
Cooperative Gallstone Study: A Multicenter Clinical Trial. Control Clin Trials 1981; 2: 177–230.
45 Laine C, Horton R, DeAngelis CD, Drazen JM, Frizelle FA, Godlee F, Haug C, Hébert PC,
Kotzin S, Marusic A, Sahmi P, Schroeder TV, Sox HC, Van Der Weyden MB, Verheugt FWA:
Clinical trial registration: Looking back and moving ahead. Ann Intern Med 2007; 147: 275–277.
46 Levine RJ: Deferred consent. Control Clin Trials 1991; 12: 546–550.
47 Levine RJ: Ethics and Regulation of Clinical Research, 2nd ed. Yale University Press, New Haven,
1988.
48 Macular Photocoagulation Study Group: Argon laser photocoagulation for ocular histoplasmosis:
Results of a randomized clinical trial. Arch Ophthalmol 1983; 101: 1347–1357.
49 Macular Photocoagulation Study Group: Argon laser photocoagulation for ideopathic
neovascularization. Results of a randomized clinical trial. Arch Ophthalmol 1983; 101: 1358–1361.
50 Macular Photocoagulation Study Group: Argon laser photocoagulation for senile macular
degeneration: Results of a randomized clinical trial. Arch Ophthalmol 1982; 100: 912–918.
51 Martin BK, Meinert CL, Breitner JCS for the ADAPT Research Group: Double placebo design in
a prevention trial for Alzheimer’s disease. Control Clin Trials 2002; 23: 93–99.
52 Meinert CL: Clinical Trials: Design, Conduct, and Analysis, 2nd ed. Oxford University Press, New
York, 2012.
53 Meinert CL: An Insider’s Guide to Clinical Trials (279 pages). Oxford University Press, New York,
2011.
54 Meinert CL: Redesign of trials under different enrollment mixes. Statist Med 1999; 18: 241–251.
55 Meinert CL: Masked monitoring in clinical trials—Blind stupidity? N Engl J Med 1998; 338:
1381–1382.
56 Meinert CL: IRBs and randomized clinical trials. IRB 1998; 20: 9–12.
57 Meinert CL: Clinical trials and treatment effects monitoring (with discussion). Control Clin Trials
1998; 19: 515–543.
58 Meinert CL: Clinical Trials Dictionary: Terminology and Usage Recommendations; The Johns
Hopkins Center for Clinical Trials, Baltimore, 1996.
59 Meinert CL: An open letter to the FDA regarding changes in reporting procedures for drugs and
biologics proposed in the wake of the FIAU tragedy. Control Clin Trials 1996; 17: 273–284.
60 Meinert CL, Tonascia S: Clinical Trials: Design, Conduct, and Analysis. Oxford University Press,
New York, 1986.
61 Multiple Risk Factor Intervention Trial Research Group: Multiple Risk Factor Intervention Trial.
Risk factor changes and mortality results. JAMA 1982; 248: 1465–1477.
62 National Emphysema Treatment Trial Research Group: Rationale and design of the National
Emphysema Treatment Trial (NETT): A prospective randomized trial of lung volume reduction
surgery. Chest 1999; 116: 1750–1761.
554
REFERENCES
63 National Heart, Lung, and Blood Institute: Clinical coordinating center for lung volume reduction
surgery for emphysema. RFP-NIH-NHLBI-HR-97-01, Bethesda, 1997.
64 National Heart, Lung, and Blood Institute: Clinical Coordinating Center for the Study of a Childhood
Management Program (CAMP). RFP-NIH-NHLBI-HR-90-12, Bethesda, 1990.
65 Nutton V: What’s in an oath? J Royal Coll of Phys of London 1995; 29: 518–524.
66 Office for Protection from Research Risks: Code of Federal Regulations, Title 45: Public Welfare, Part
46: Protection of Human Subjects. Department of Health and Human Services, National Institutes
of Health, Bethesda, Md, (revised) 18 June 1991.
67 Persantine–Aspirin Reinfarction Study Research Group: Persantine and aspirin in coronary heart
disease. Circulation 1980; 62: 449–461.
68 Physicians’ Health Study Research Group Steering Committee: Preliminary report: Findings from
the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1988; 318:
262–264.
69 Pocock SJ: Clinical Trials: A Practical Approach. John Wiley and Sons, Chichester, 1983.
70 Prentice RL: Surrogate endpoints in clinical trials: Definition and operational criteria. Statistics in
Medicine 1989; 8: 431–440.
71 Robbins H: A sequential decision problem with finite memory. Proc Natl Acad Sci 1956; 42:
920–923.
72 Robbins H: Some aspects of the sequential design of experiments. Bull Am Mathematics Soc 1952;
58: 527–535.
73 Robin ED, McCauley RF: Cultural lag and the Hippocratic Oath. Lacent 1995; 345: 1422–1424.
74 Roethlisberger FJ, Dickson WJ: Management and the Worker. John Wiley & Sons, New York,
1964.
75 Schlant RC, Forman S, Stamler J, Canner PL: The natural history of coronary heart disease:
Prognostic factors after recovery from myocardial infarction in 2789 men. The 5-year findings of
the coronary drug project. Circulation 1982; 66: 401–414.
76 Schoenfield LJ, Lachin JM, The Steering Committee ( Baum RA, Habig RL, Hanson RF, Hersh
T, Hightower NC Jr, Hoffmann AF, Lasser EC, Marks JW, Mekhjian H, Okun R, Schaefer RA,
Shaw L, Soloway RD, Thistle JL, Thomas FB, Tyor MP) and the National Cooperative Gallstone
Study Group: Chenodiol (chenodeoxycholic acid) for dissolution of gallstones: The National
Cooperative Gallstone Study. Ann Intern Med 1981; 95: 257–282.
77 SHEP Cooperative Research Group: Prevention of stroke by antihypertensive drug treatment in
older persons with isolated systolic hypertension: Final results of the Systolic Hypertension in the
Elderly Program (SHEP). JAMA 1991; 265: 3255–3294.
78 Shimm DS, Spece RG: Ethical issues and clinical trials. Drugs 1993; 46: 579–584.
79 Simon R: Adaptive treatment assignment method and clinical trials. Biometrics 1977; 33: 743–749.
80 Studies of the Ocular Complications of AIDS Research Group: SOCA General Handbook,
https://jhuccs1.us/soca/SOCAgenhandbook/socagenhndbk.pdf, accessed (6:38am Saturday) 10
December 2011.
81 Studies of the Ocular Complications of AIDS Research Group in collaboration with the AIDS
Clinical Trials Group: The ganciclovir implant plus oral ganciclovir versus parenteral cidofovir for
the treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome:
The Ganciclovir Cidofovir CMV Retinitis Trial. Am J Ophthalmol 2001; 131: 457–467.
82 Studies of the Ocular Complications of AIDS Research Group in collaboration with the AIDS
Clinical Trials Group: MSL-109 adjuvant therapy for cytomegalovirus retinitis in patients with
acquired immunodeficiency syndrome: The Monoclonal Antibody Cytomegalovirus Retinitis
Trial. Arch Ophthalmol 1997; 115: 1528–1536.
83 Studies of the Ocular Complications of AIDS Research Group in collaboration with the AIDS
Clinical Trials Group: Parenteral cidofovir for cytomegalovirus retinitis in patients with AIDS: The
HPMPC Peripheral Cytomegalovirus Retinitis Trial. A randomized, controlled trial. Ann Intern
Med 1997; 126: 264–274.
References
555
84 Studies of the Ocular Complications of AIDS Research Group in collaboration with the AIDS
Clinical Trials Group: Combination foscarnet and ganciclovir therapy vs. monotherapy for the
treatment of relapsed cytomegalovirus retinitis in patients with AIDS: The Cytomegalovirus
Retreatment Trial. Arch Ophthalmol 1996; 114: 23–33.
85 Studies of Ocular Complications of AIDS Research Group in collaboration with the AIDS
Clinical Trials Group (ACTG): Studies of ocular complications of AIDS foscarnet–ganciclovir
cytomegalovirus retinitis trial: 1. Rationale, design, and methods. Control Clin Trials 1992; 13:
22–39.
86 Studies of Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical
Trials Group: Mortality in patients with the acquired immunodeficiency syndrome treated with
either foscarnet or ganciclovir for cytomegalovirus retinitis. N Engl J Med 1992; 326: 213–220.
87 Taves DR: Minimization: A new method of assigning patients to treatment and control groups.
Clin Pharmacol Ther 1974; 15: 443–453.
88 United States Congress (103rd; 1st session): NIH Revitalization Act of 1993, 42 USC § 131 (1993);
Clinical Research Equity Regarding Women and Minorities; Part I: Women and Minorities as Subjects
in Clinical Research. 1993.
89 University Group Diabetes Program Research Group: Effects of hypoglycemic agents on vascular
complications in patients with adult-onset diabetes: VIII. Evaluation of insulin therapy: Final
report. Diabetes 1982; 31(Suppl 5): 1–81.
90 University Group Diabetes Program Research Group: Effects of hypoglycemic agents on vascular
complications in patients with adult-onset diabetes: VII. Mortality and selected nonfatal events
with insulin treatment. JAMA 1978; 240: 37–42.
91 University Group Diabetes Program Research Group: A Study of the effects of hypoglycemic
agents on vascular complications in patients with adult-onset diabetes:V. Evaluation of Phenformin
therapy. Diabetes 1975; 24(Suppl 1): 65–184.
92 University Group Diabetes Program Research Group: Effects of hypoglycemic agents on vascular
complications in patients with adult-onset diabetes: IV. A preliminary report on phenformin
results. JAMA 1971; 217: 777–784.
93 University Group Diabetes Program Research Group: A study of the effects of hypoglycemic agents
on vascular complications in patients with adult-onset diabetes: 1. Design, methods, and baseline
characteristics. Diabetes 1970; 19(Suppl 2): 747–783.
94 University Group Diabetes Program Research Group: A study of the effects of hypoglycemic agents
on vascular complications in patients with adult-onset diabetes: II. Mortality results. Diabetes
1970; 19(Suppl 2): 785–830.
95 Webster’s Eleventh New Collegiate Dictionary. Merriam-Webster Inc, Springfield, Mass, 2009.
96 Webster’s Ninth New Collegiate Dictionary. Merriam-Webster Inc, Springfield, Mass, 1991.
97 Wei LJ, Lachin JM: Properties of the urn randomization in clinical trials. Control Clin Trials 1988;
9: 345–364.
98 Wei LJ: A class of designs for sequential clinical trials. JASA 1977; 72: 382–386.
99 Winau R: The hippocratic oath and ethics in medicine. Forensic Sci Int 1994; 69: 285–289.
100 Wittes J, Lakatos E: Surrogate endpoints in clinical trials: Cardiovascular diseases. Statistics in
Medicine 1989; 8: 415–425.
101 Wright JT Jr, Kusek JW, Toto RD, Lee JY, Agodoa LY, Kirk KA, Randall OS, Glassock R for the
AASK Pilot Study Investigators: Design and Baseline Characteristics of Participants in the African
American Study of Kidney Disease and Hypertension (AASK) Pilot Study. Control Clin Trials
1996; 16: 3S–16S.
102 Yusuf S, Wittes J, Probstfield J, Tyroler HA: Analysis and interpretation of treatment effects in
subgroups of patients in randomized clinical trials. JAMA 266: 93–98, 1991.
103 Zarin DA, Ide NC, Tse T, Harlan WR, West JC, Lindberg DAB: Issues in the registration of
clinical trials. JAMA 2007; 297: 2112–2120.
104 Zelen M: Play the winner rule and the controlled clinical trial. JASA 1969; 64: 131–146.
Index
Abrams JS, 551
African American Study of Kidney Disease and
Hypertension, 555
Agodoa LY, 555
Aickin M, 145, 551
AIDS Clinical Trials Group, 554, 555
Alzheimer’s Disease Anti-inflammatory
Prevention Trial, 551, 553
Amplatz K, 551
analysis
analysis dataset, 415
Bayesian analysis, 419
exploratory data analysis, 265, 423
final data analysis, 421
frequentist, 383, 419
frequentist analysis, 419
interim data analysis, 373
likelihoodist, 419
masked data analysis, 107
subgroup analysis, 265, 423
assignment
adaptive treatment assignment, 145, 263
baseline adaptive treatment assignment, 145
biased coin treatment assignment, 145
fixed treatment assignment, 145
masked treatment assignment, 108, 147
minimum likelihood treatment assignment,
145
number adaptive treatment assignment, 145
open treatment assignment, 147
outcome adaptive treatment assignment,
146
play-the-winner treatment assignment, 146
treatment assignment ratio, 146, 151
treatment assignment stratum, 152
treatment assignment visit, 272
urn model treatment assignment, 146
author/authorship
author, 431
author citation, 431
authorship, 431
authorship attribution, 431
conventional author, 431
conventional author citation, 431
conventional authorship, 431
corporate author, 431
corporate author citation, 432
corporate authorship, 432
modified conventional author citation, 432
modified conventional authorship, 432
modified corporate author citation, 432
modified corporate authorship, 432
Vancouver Convention, 432
baseline
baseline, 271
baseline adaptive treatment assignment, 145
baseline examination, 271
baseline period, 271, 275
minimum likelihood treatment assignment,
145
Baum RA, 554
Bayes T, 419, 551
Bayes’ theorem, 419
Begg C, 551
bias
biased coin treatment assignment, 145
conflict of interest, 463
control, 132
definition, 131
selection, 149
treatment-related bias, 132
treatment-related feedback bias, 132
treatment-related selection bias, 132
Bissett JK, 551
block/blocking
block, 151
block size, 151
blocked randomization, 151
permuted block, 151
board
central institutional review board, 163
commercial institutional review board, 163
independent institutional review board, 164
local institutional review board, 164
parent institutional review board, 164
Boissel J-P, 551
Brain Resuscitation Clinical Trial II Study
Group, 172, 189, 551
Breitner JCS, 553
Brittain E, 88, 97, 203, 551
Buchwald H, 231, 232, 551
557
558
INDEX
Campbell GS, 551
Campos CT, 551
Canner PL, 551, 554
Canto MI, 552
Cardiac Arrhythmia Suppression Trial, 551
Cardiac Arrhythmia Suppression Trial
Investigators, 97, 203
Castaneda-Zuniga WR, 551
censor/censored
informative censoring, 113
uninformative censoring, 114
center
center director, 331
center representation construct, 367
central laboratory (CL), 287
definition, 317, 325
lead center, 164
parent center, 164, 317
reading center (RC), 289
resource center, 318
satellite center, 318
study center, 318
study center director, 332
Chalmers TC, 551
Chang M, 551
Chemoprevention for Barrett’s Esophagus Trial,
552
Childhood Asthma Management Program, 554
Childhood Asthma Management Program
Research Group, 551
Cho M, 551
Chow S-C, 551
Christian MC, 551
clinic
clinic coordinator, 333
definition, 317
lead clinic, 203
study clinic coordinator, 333
study clinic monitor, 405
closeout
anniversary closing date, 225
close of followup, 217
closeout design, 225
closeout examination, 271
closeout followup visit, 225, 271
closeout period, 275
closeout stage, 225
common closing date, 225
post-closeout followup visit, 272
Collet J-P, 551
committee
executive committee (EC), 353
key committee, 339
masked treatment effects monitoring
committee, 108
performance monitoring committee, 399
standing committee, 341
steering committee (SC), 359
working committee, 341
comparison
comparison group, 73
comparison treatment, 73, 79
designed subgroup comparison, 265
subgroup comparison, 266, 423
compliance
followup compliance, 217
treatment compliance, 98
treatment compliance measure, 98
consent
active consent, 189
consent form, 172
consent process, 185
consent statement, 172
consent, documentation of, 169
consent, elements of, 170
consent, requirement of, 172
deconsent, 172
deferred consent, 172, 189
documented consent, 189
implied consent, 189
informed consent, 173
oral consent, 173
passive consent, 189
reconsent, 173
signed consent, 173
witnessed consent, 189
Consolidated Standards of Reporting Trials
(CONSORT), 232
control
active control treatment, 79
alternative control treatment, 79
best medical judgment control treatment, 79
control treatment, 79
control-assigned group, 71
control-treated group, 71
inactive control treatment, 79
negative control treatment, 80
nil treatment control, 80
placebo control, 87
placebo-control treatment, 89
positive control treatment, 80
sham procedure, 91
trace control treatment, 80
controlled
placebo-controlled trial, 89
coordinating center
resource center, 318
Cornfield J, 419, 551
Coronary Drug Project, 56, 88, 97, 203, 551, 552
credit roster, 436
Index
Criner GJ, 552
crossover
crossover treatment, 103
treatment crossover, 103
Dannenberg AJ, 552
data
analysis dataset, 415
bolus data flow, 283
centralized data entry, 301
continuous data flow, 283
data collection site, 317
data coordinator, 333
data dictionary, 307, 311
data dredging, 265, 423
data editing, 285
data element, 285
data entry, 301
data field, 285
data file, 285
data flow, 283
data form, 285
data freeze, 285, 415
data generation, 285
data generation site, 285, 317
data keying, 285
data management, 286
data purge, 286
data query, 286
data record, 286
data sharing, 311
data snapshot, 286
data system, 286
data transcription, 286
data transformation, 286
data use agreement, 311
dataset, 415
deidentified data, 307
dependent double data entry, 301
direct data entry, 301
distributed data entry, 301
double data entry, 301
electronic data form, 301
exploratory data analysis, 265, 423
external data sharing, 307, 312
final data analysis, 421
final dataset, 421
followup data, 217
frozen data, 415
frozen dataset, 415
identified data, 307, 312
independent double data entry, 302
indirect data entry, 302
interim data analysis, 373
internal data sharing, 307, 312
559
keyless data recording, 302
limited use dataset, 312
linkable data, 307
mandated data sharing, 312
masked data analysis, 107
masked data collection, 107
on-line data entry, 302
paper data form, 302
paperless data entry, 302
PC-based data entry, 302
public use dataset, 312
quasi-independent double data entry, 302
real-time data entry, 283
web-based data entry, 302
data analysis
exploratory data analysis, 265, 423
final data analysis, 421
interim data analysis, 373
data collection
data collection site, 317
editing and processing, 305
masked, 111
masked data collection, 107
data editing
rules, 398
data entry
considerations, 305
Davis KB, 552
DeAngelis CD, 552, 553
Definitions
acknowledgment, 435
active consent, 189
active control treatment, 79
active followup, 217, 221
adaptive study design, 263
adaptive treatment assignment, 145, 263
administrative review, 399
adverse drug experience, 471
adverse drug reaction, 471
adverse event, 471
adverse reaction, 471
adverse side effect, 472
adverse treatment effect, 472
advocacy representation construct, 367
alpha spending function, 383
alternative control treatment, 79
alternative treatment, 79
analysis dataset, 415
ancillary publication, 417, 427
ancillary study, 459
anniversary closing date, 225
appointed study chair, 349
aristocracy representation construct, 367
assent, 169
assent form, 169
560
INDEX
Definitions (cont.)
assent statement, 169
audit, 409
audit trail, 409
author, 431
author citation, 431
authorship, 431
authorship attribution, 431
award statement, 51
baseline, 271
baseline adaptive treatment assignment, 145
baseline examination, 271
baseline period, 271, 275
baseline results paper, 417
batch number, 117
Bayes’ theorem, 419
Bayesian, 383, 419
Bayesian analysis, 419
best and final offer, 51
best medical judgment control treatment, 79
bias, 131
biased coin treatment assignment, 145
bin number drug system, 117
blacklist, 403
blackout, 127
blind, 107
blister pack, 117
block, 151
block size, 151
blocked randomization, 151
bolus data flow, 283
business office, 51
case report form, 283
censor, 113
center, 317, 325
center director, 331
center representation construct, 367
central IRB, 163
central laboratory, 287
centralized data entry, 301
centralized funding, 51
Certificate of Confidentiality, 181
certification, 403
circuit rider, 405
clinic, 317
clinic coordinator, 333
clinic start-up design, 203
clinical equipoise, 75
clinical research associate, 333
clinical trial, xvii
close of followup, 217
closed sequential design, 253
closeout design, 225
closeout examination, 271
closeout followup visit, 225, 271
closeout period, 275
closeout stage, 225
cluster randomization, 155
co-, 331
co-investigator, 331
commercial IRB, 163
common closing date, 225
comparison group, 73
comparison treatment, 73, 79
competitive bid, 51
competitive bidding, 51
competitive funding, 51
competitive initiative, 51
competitive proposal, 51
competitive range, 51
competitive renewal, 52
complete randomization, 151
concealed treatment assignment, 147
concealment, 107
concurrent followup, 217
conflict of interest, 463
consent, 169
consent form, 172
consent process, 185
consent statement, 172
consent, documentation of, 169
consent, elements of, 170
consent, requirement of, 172
consortium funding, 52
consortium funding agreement, 52
consortium funding award, 52
continuous data flow, 283
contract office, 52
contract officer, 52
contract proposal, 52
control treatment, 79
control-assigned group, 71
control-treated group, 71
conventional author, 431
conventional author citation, 431
conventional authorship, 431
cooperative agreement, 52
core funding, 52
corporate author, 431
corporate author citation, 432
corporate authorship, 432
credit, 435
crossover treatment, 103
data collection site, 317
data coordinator, 333
data dictionary, 307, 311
data dredging, 265, 423
data editing, 285
data element, 285
data entry, 301
Index
data field, 285
data file, 285
data flow, 283
data form, 285
data freeze, 285, 415
data generation, 285
data generation site, 285, 317
data harvest, 415
data keying, 285
data management, 286
data purge, 286
data query, 286
data record, 286
data sharing, 311
data snapshot, 286
data system, 286
data transcription, 286
data transformation, 286
data use agreement, 311
dataset, 415
debarment, 403
deconsent, 172
deferred consent, 172, 189
deidentified data, 307, 311
deidentify, 307
dependent double data entry, 301
deputy director, 331
design variable, 35
designed subgroup comparison, 265
detectable difference, 257
direct data entry, 301
direct distribution of funds, 52
direct followup, 221
direct funding award, 53
discipline representation construct, 367
disclosure form, 463
distributed data entry, 301
distributed funding, 53
distribution of funds, 53
documented consent, 189
double data entry, 301
double mask, 107
double placebo, 115
dropout, 231
dropout compensation, 232
dropout replacement, 232
drug reaction, 472
efficacy monitoring, 375
elected study chair, 349
electronic data form, 301
endpoint, 39
ex officio, 347
executive committee, 353
expedited review, 161
experimental variable, 31
exploratory data analysis, 265, 423
external data sharing, 307, 312
extramural funding, 53
feasibility study, 203
fee-for-service, 67
fiat study chair, 349
final, 421
final data analysis, 421
final dataset, 421
final treatment result, 421
finder’s fee, 455
fixed sample size design, 254, 261
fixed study design, 263
fixed treatment assignment, 145
fixed-cost, 67
followup, 217, 272
followup cohort, 217
followup compliance, 217
followup data, 217
followup observation, 217
followup period, 217, 223, 275
followup stage, 217
followup study, 217
followup study design, 218
followup visit, 218, 272
form, 295
frequentist, 383, 419
frequentist analysis, 419
frozen data, 415
frozen dataset, 415
frozen state of equipoise, 131
funding agency, 53
funding agreement, 53
funding application, 53
funding award, 53
funding office, 53
funding officer, 53
funding period, 53, 63
funding proposal, 53
funding request, 53
Gantt chart, 241
grant, 53
grant application, 54
grants management office, 54
grants management officer, 54
group randomization, 155
group sequential design, 254
haphazard, 147
haphazardization, 147
harm, 373
head fee, 67
home visit, 272
ideal time window, 299
identified data, 307, 312
implied consent, 189
561
562
INDEX
Definitions (cont.)
inactive control treatment, 79
incentive, 455
incentive payment, 455
incremental funding, 54, 67
independent double data entry, 302
independent institutional review board, 164
indirect data entry, 302
indirect distribution of funds, 55
indirect followup, 221
indirect funding award, 55
individual randomization, 155
informative censoring, 113
informed consent, 173
insider, 463
insider information, 464
insider trading, 464
institutional review board, 161, 164
interim data analysis, 373
interim followup, 218
interim followup visit, 272
interim look, 373
interim result, 373
internal data sharing, 307, 312
intramural funding, 55
investigational new drug safety report, 472
investigator, 331
investigator-initiated research proposal, 55
involve, 161
jack-up factor, 257
key committee, 339
keyless data acquisition, 302
laboratory, 287
lead center, 164
lead clinic, 203
lead-in period, 97, 203
likelihood principle, 419
likelihoodist, 383, 419
limited use dataset, 312
linkable data, 307
local IRB, 164
local laboratory, 287
loss to followup, 218, 235
losses to followup, 218
lost to followup, 218, 235
lot number, 117
main study, 467
mainline paper, 417, 427
mandated data sharing, 312
mask, 107, 114
masked data analysis, 107
masked data collection, 107
masked randomization, 107
masked reading, 108
masked treater, 108
masked treatment, 108
masked treatment administration, 108
masked treatment assignment, 108
masked treatment effects monitoring, 108,
379
masked treatment effects monitoring
committee, 108
masked treatment effects monitoring report,
379
masked trial, 108
masking level, 108
med Id number drug system, 117
minimal risk, 161
minimization, 145
minimum likelihood treatment assignment,
145
missed study visit, 229
mock treatment, 91
modified conventional author citation, 432
modified conventional authorship, 432
modified corporate author citation, 432
modified corporate authorship, 432
monitor, 409
more than minimal risk, 162
multi-study, 19
multi-study structure, 353
multicenter study, xvii
multiple placebo, 115
natural history study, 427
negative control treatment, 80
nil treatment, 80
nil treatment control, 80
noncompetitive proposal, 55
noncompetitive renewal, 55
nonconcurrent followup study, 218
nonrequired followup visit, 272
null treatment, 80
number adaptive treatment assignment, 145
officers of the study, 347
on-line data entry, 302
open sequential design, 254
open treatment assignment, 147
oral consent, 173
outcome, 40
outcome adaptive treatment assignment, 146
outcome event, 40
outcome measure, 40
outcome variable, 40
overrepresent, 213
paired treatment design, 33
paper data form, 302
paperless data entry, 302
parent center, 164, 317
parent IRB, 164
parent study, 467
Index
passive consent, 189
passive followup, 218, 221
patient contact schedule, 269
patient mail contact, 269
patient telephone contact, 269
PC-based data entry, 302
performance monitoring, 399
performance monitoring committee, 399
performance monitoring report, 399
performance review, 399
permissible time window, 299
permuted block, 151
PI representation construct, 367
pill count, 97
pilot study, 204
placebo, 87
placebo control, 87
placebo effect, 80, 88
placebo group, 88
placebo lead-in period, 88
placebo patient, 88
placebo period, 88
placebo reactor, 88
placebo treatment, 88
placebo treatment effect, 88
placebo washout, 88
placebo-assigned, 89
placebo-assigned group, 89
placebo-assigned patient, 89
placebo-control treatment, 89
placebo-controlled trial, 89
placebo-treated, 89
placebo-treated group, 89
placebo-treated patient, 89
play-the-winner treatment assignment, 146
positive control treatment, 80
post-closeout followup visit, 272
post-treatment followup, 218
post-trial followup, 219
post-trial followup stage, 219
power, 257
presentation, 427, 439
primacy, right of, 308
primary outcome, 35
primary outcome measure, 35
primary outcome variable, 35
primary publication, 417, 427
primary result, 427
principal investigator, 331
prospective followup, 219
protocol bailout, 103
protocol deviation, 101
protocol override, 101
protocol violation, 101
pseudorandom, 147
563
public repository, 293
public use dataset, 312
publication, 427
quality assurance, 395
quality control, 395
quasi-independent double data entry, 302
quasirandom, 147
quota, 213
quota requirement, 213
quotification, 213
random, 147
randomization, 148
randomization unit, 155
randomized controlled trial, xvii
reading center, 289
real-time data entry, 283
recompete, 55
recompetition, 55
reconsent, 173
record audit, 409
recruitment quota, 213
reference group, 73
registration, 495
regular followup visit, 219, 272
renewal, 55
reportable event, 472, 475
reported event, 476
repository, 293
representation construct, 368
representativeness, 214
request for application, 56
request for proposal, 56
required followup visit, 219, 272
research, 162
research contract proposal, 56
research grant, 56
research grant application, 56
research grant proposal, 56
research group, 335
resource center, 318
restricted randomization, 151
results blackout, 127, 308
results paper, 417
retrospective followup, 219
rotating study chair, 349
run-in period, 97, 204
safety monitoring, 375
safety report, 473
satellite center, 318
scheduled followup, 219
scheduled study visit, 272
secondary paper, 417
secondary publication, 427
sequential design, 254
sequential sample size design, 255, 261
564
INDEX
Definitions (cont.)
serious adverse drug experience, 473
shakedown period, 97, 204
sham, 91
sham effect, 91
sham procedure, 91
sham treatment, 91
shield, 114, 127
signed consent, 173
single masked, 108
single placebo, 115
site visit, 405
sponsor, 56
sponsor-initiated research proposal, 56
sponsoring agency, 56
standard treatment, 73, 80
standing committee, 341
start-up patients, 204
steering committee, 359
stopping boundary, 381
stopping guideline, 381
stopping rule, 381
stratification, 135
stratification variable, 135
stratify, 135
study center, 318
study center director, 332
study chair, 349
study chair external, 349
study chair internal, 349
study clinic coordinator, 333
study clinic monitor, 405
study curriculum vitae, 487
study examination, 272
study group, 71
study officers, 347
study physician, 333
study result, 417
study treatment, 75
study vice-chair, 349
study visit, 272
subcontract, 57
subcontractor, 57
subgroup, 265, 423
subgroup analysis, 265, 423
subgroup comparison, 266, 423
subgroup treatment difference, 423
subgrouping, 266
subgrouping cutpoint, 266, 424
subgrouping variable, 266, 424
submission, 57
substudy, 467
test patients, 204
test treatment, 77
test-assigned group, 71
test-treated group, 71
time window, 299
trace control treatment, 80
trace treatment, 80
tracer substance, 97
treating physician, 333
treatment application and adjustment
followup visit, 272
treatment assignment ratio, 146, 151
treatment assignment stratum, 152
treatment assignment visit, 272
treatment cessation, 103
treatment change, 103
treatment compliance, 98
treatment compliance measure, 98
treatment crossover, 103
treatment effects monitoring, 373
treatment group, 71
treatment lag, 257
treatment modality, 93
treatment period, 276
treatment protocol suspension, 103
treatment schedule, 95
treatment suspension, 104
treatment switch, 104
treatment termination, 104
treatment unit, 33
treatment variable, 31
treatment-related bias, 132
treatment-related feedback bias, 132
treatment-related selection bias, 132
trial, 9
trial-proper, 204
trial-proper patient(s), 204
triple-mask, 109
type I error, 257
type II error, 257
umbrella study name, 19
underrepresent, 214
understudy, 214
unexpected adverse drug experience, 474
uninformative censoring, 114
unmask, 109
unscheduled followup, 219
unscheduled followup visit, 272
urn model, 146
urn model randomization, 146
urn model treatment assignment, 146
Vancouver Convention, 432
vanguard patients, 204
variance, 139
web-based data entry, 302
withdrawal, 232
witnessed consent, 189
working committee, 341
Index
DeMets DL, 552
Department of Health and Human Services, 552
design
adaptive study design, 263
clinic start-up design, 203
closed sequential design, 253
closeout design, 225
design variable, 35
designed subgroup comparison, 265
fixed sample size design, 254, 261
fixed study design, 263
followup study design, 218
group sequential design, 254
open sequential design, 254
paired treatment design, 33
sequential design, 254
sequential sample size design, 255, 261
deviation/deviate
protocol deviation, 101
Diabetic Retinopathy Study, 53, 552
Dickson WJ, 554
Diggle P, 552
Drazen JM, 552, 553
drug
adverse drug experience, 471
adverse drug reaction (ADR), 471
bin number drug system, 117
blister pack, 117
drug reaction, 472
investigational new drug safety report, 472
med Id number drug system, 117
serious adverse drug experience, 473
unexpected adverse drug experience, 474
Dunnett CW, 552
Dupont WD, 419, 552
Eastwood S, 551
Edmiston WA, 551
Edwards AWF, 552
effect
masked treatment effects monitoring, 108
placebo effect, 80
sham effect, 91
treatment effects monitoring, 373
error
type I error, 257
type II error, 257
event
adverse event, 471
FDA related terms
adverse drug experience, 471
adverse drug reaction (ADR), 471
adverse side effect, 472
blacklist, 403
565
drug reaction, 472
investigational new drug safety report, 472
safety report, 473
serious adverse drug experience, 473
sponsor, 56
unexpected adverse drug experience, 474
Fisher L, 552
Fitch LL, 551
followup
active followup, 217, 221
close of followup, 217
closeout followup visit, 225, 271
concurrent followup, 217
direct followup, 221
followup, 217, 272
followup cohort, 217
followup compliance, 217
followup data, 217
followup observation, 217
followup period, 217, 223, 275
followup stage, 217
followup study, 217
followup study design, 218
followup visit, 218, 272
indirect followup, 221
interim followup, 218
interim followup visit, 272
loss to followup, 218, 235
losses to followup, 218
lost to followup, 218, 235
nonconcurrent followup study, 218
nonrequired followup visit, 272
passive followup, 218, 221
post-closeout followup visit, 272
post-treatment followup, 218
post-trial followup, 219
post-trial followup stage, 219
prospective followup, 219
regular followup visit, 219, 272
required followup visit, 219, 272
retrospective followup, 219
scheduled followup, 219
treatment application and adjustment
followup visit, 272
unscheduled followup, 219
unscheduled followup visit, 272
Food and Drug Administration (FDA), 409,
552
Forastiere AA, 552
Forman S, 554
Fost N, 172, 189, 552
Freedman B, 75, 552
Friedman B, 146, 552
Friedman MA, 551
Frizelle FA, 552, 553
566
INDEX
funding
award statement, 51
best and final offer, 51
centralized funding, 51
competitive bid, 51
competitive bidding, 51
competitive funding, 51
competitive initiative, 51
competitive proposal, 51
competitive range, 51
competitive renewal, 52
consortium funding, 52
consortium funding agreement, 52
consortium funding award, 52
contract office, 52
contract officer, 52
contract proposal, 52
cooperative agreement, 52
core funding, 52
direct distribution of funds, 52
direct funding award, 53
distributed funding, 53
distribution of funds, 53
extramural funding, 53
funding agency, 53
funding agreement, 53
funding application, 53
funding award, 53
funding office, 53
funding officer, 53
funding period, 53, 63
funding proposal, 53
funding request, 53
grant, 53
grant application, 54
grant vs contract, 61
incremental funding, 54, 67
indirect distribution of funds, 55
indirect funding award, 55
intramural funding, 55
investigator initiated, 61
investigator-initiated research proposal, 55
methods of initiation, 61
noncompetitive proposal, 55
noncompetitive renewal, 55
recompete, 55
recompetition, 55
renewal, 55
request for application, 56
request for proposal, 56
research contract proposal, 56
research grant, 56
research grant application, 56
research grant proposal, 56
sponsor-initiated research proposal, 56
subcontract, 57
subcontractor, 57
Gillespie MJ, 552
Glassock R, 555
Glaucoma Laser Trial, 33, 53, 552
Glaucoma Laser Trial Research Group, 33
Godlee F, 553
group
control-assigned group, 71
group randomization, 155
subgroup, 265, 423
subgroup analysis, 265, 423
subgroup comparison, 266, 423
subgroup treatment difference, 423
subgrouping cutpoint, 266, 424
subgrouping variable, 424
test-assigned group, 71
Habig RL, 554
Hansen BJ, 551
Hanson RF, 554
Harlan WR, 555
Haug C, 552, 553
Haugh M, 551
Hawk E, 552
Health Insurance Portability and Accountability
Act (HIPAA)
de-identified data, 307
Heath EI, 552
Hébert PC, 553
Herman JG, 552
Hersh T, 554
Hightower NC Jr, 554
Hippocratic Oath, 373
Hoey J, 552
Hoffmann AF, 554
Horton R, 551–553
Hunter DW, 551
Hypertension Detection and Follow-up Program,
552
Hypertension Prevention Trial, 553
Ide NC, 555
identification
deidentify, 307
linkable data, 307
Ingelfinger FJ, 553
Institute of Medicine, 553
institution
commercial institutional review board, 163
institutional review board (IRB), 161, 164
assent, 169
assent form, 169
assent statement, 169
Index
central institutional review board, 163
consent, 169
consent form, 172
consent process, 185
consent, requirement of, 172
documented consent, 189
expedited review, 161
finder’s fee, 455
incentive, 455
incentive payment, 455
independent institutional review board, 164
informed consent, 173
involve, 161
local institutional review board, 164
parent institutional review board, 164
renewal, 55
research, 162
International Committee of medical Journal
Editors, 553
Kaplan RS, 551
Karnegis JN, 551
Katz J, 553
Kenward MG, 552
Kirk KA, 555
Klimt CR, 553
Knatterud GL, 553
Korn EL, 551
Kotzin S, 552, 553
Kusek JW, 555
Lachin JM, 146, 553–555
Laine C, 552, 553
Lakatos E, 555
Lan KKG, 552
Lasser EC, 554
Lee JY, 555
Leon AS, 551
Levine RJ, 172, 189, 553
likelihood
likelihood principle, 419
Lindberg DAB, 555
Long JM, 551
Macular Photocoagulation Study Group, 553
Marks JW, 553, 554
Martin BK, 553
Marusic A, 552, 553
mask/masking
blinded, 107
double mask, double masked, 107
mask, 107
mask, masked, 107
mask, masked, masking, masks, 107, 114
masked data analysis, 107
567
masked data collection, 107
masked randomization, 107
masked reading, 108
masked treater, 108
masked treatment, 108
masked treatment administration, 108
masked treatment assignment, 108, 147
masked treatment effects monitoring, 108,
379
masked treatment effects monitoring
committee, 108
masked treatment effects monitoring report,
379
masked trial, 108
masking level, 108
principles, 111
shields, 114, 127
single masked, single mask, 108
treatment administration, 111
triple-mask, triple-masked, 109
unmask, unmasked, 109
unmask, unmasked, unmasking, unmasks, 109
Usage note, 107
Matts JP, 551
McCabe MS, 551
McCauley RF, 554
Meier P, 553
Meinert CL, 553
Mekhjian H, 554
model
urn model, 146
urn model randomization, 146
Moher D, 551
Moleur P, 551
monitor/monitoring
administrative review, 399
efficacy monitoring, 375
interim look, 373
masked treatment effects monitoring, 108,
379
masked treatment effects monitoring
committee, 108
masked treatment effects monitoring report,
379
monitor, monitored, monitoring, monitors,
409
performance monitoring, 399
performance monitoring committee, 399
performance monitoring report, 399
performance review, 399
safety monitoring, 375
study clinic monitor, 405
treatment effects monitoring, 373
Montgomery E, 552
Multiple Risk Factor Intervention Trial, 553
568
INDEX
National Cooperative Gallstone Study, 553,
554
National Emphysema Treatment Trial, 554
National Emphysema Treatment Trial Research
Group, 553
National Heart, Lung, and Blood Institute, 554
National Institutes of Health (NIH), 554, 555
number
batch number, 117
Nutton V, 554
Office for Protection from Research Risks
(OPRR), 554
office/officer
business office, 51
contract office, 52
contract officer, 52
funding office, 53
funding officer, 53
grants management office, 54
grants management officer, 54
officers of the study, 347
office/officer
study officers, 347
Okun R, 554
Olkin I, 551
organization
desired separations, 141
outcome
outcome, 40
outcome adaptive treatment assignment,
146
outcome event, 40
outcome measure, 40
outcome variable, 40
primary outcome, 35
primary outcome measure, 35
primary outcome variable, 35
Overbeke AJPM, 552
patient/person
trial-proper patient, 204
Pearce MB, 551
period
baseline period, 271, 275
Persantine-Aspirin Reinfarction Study, 554
Pettinger M, 552
Physicians’ Health Study, 554
Piantadosi S, 552
Pitkin R, 551
placebo
double placebo, 115
multiple placebo, 115
placebo, 87
placebo control, 87
placebo effect, 80, 88
placebo group, 88
placebo lead-in period, 88
placebo patient, 88
placebo period, 88
placebo reactor, 88
placebo treatment, 88
placebo treatment effect, 88
placebo washout, 88
placebo-assigned, 89
placebo-assigned group, 89
placebo-assigned patient, 89
placebo-control treatment, 89
placebo-controlled trial, 89
placebo-treated, 89
placebo-treated group, 89
placebo-treated patient, 89
single placebo, 115
Pocock SJ, 145, 554
post-stratification
vs stratification, 137
power
arcsin approximation, 260
definition, 257
normal approximation, 260
Poisson approximation, 260
Prentice RL, 554
probability
Bayes’ theorem, 419
likelihood principle, 419
Probstfield J, 555
Program on the Surgical Control of the
Hyperlipidemias, 232, 551
proposal
competitive proposal, 51
protocol
protocol bailout, 103
protocol deviation, 101
protocol override, 101
protocol violation, 101
treatment protocol suspension, 103
publication
ancillary publication, 417, 427
baseline results paper, 417
primary publication, 417, 427
publication, 427
results paper, 417
secondary publication, 427
quality control
aids, 397
credos, 397
pitfalls, 398
planning aids, 397
requirements, 397
Index
Randall OS, 555
random/randomized
pseudorandom, 147
quasirandom, 147
random, 147
randomization
blocked randomization, 151
cluster randomization, 155
complete randomization, 151
features, 149
group randomization, 155
haphazardization, 147
individual randomization, 155
masked randomization, 107
misconceptions, 149
randomization, 148
randomization unit, 155
restricted randomization, 151
urn model randomization, 146
record
record audit, 409
recruitment
recruitment quota, 213
Rennie D, 551
research
clinical research associate, 333
result
final treatment result, 421
interim result, 373
primary result, 427
results blackout, 127, 308
review
central institutional review board, 163
commercial institutional review board, 163
independent institutional review board, 164
local institutional review board, 164
parent institutional review board, 164
right
primacy, right of, 308
Robbins H, 146, 554
Robertson JA, 172, 189, 552
Robin ED, 554
Roethlisberger FJ, 554
Sahmi P, 553
sample size
fixed sample size design, 254, 261
jack-up factor, 257
sequential sample size design, 255, 261
Sanmarco ME, 551
Sawin HS, 551
Schaefer RA, 554
Schlant RC, 554
Schoenfield LJ, 553, 554
Schroeder TV, 552, 553
569
Schultz KF, 551
Shar AO, 552
Shaw L, 554
Shimm DS, 554
side effect
adverse drug experience, 471
adverse side effect, 472
safety report, 473
serious adverse drug experience, 473
unexpected adverse drug experience, 474
Simel D, 551
Simon R, 145, 263, 554
Smink Jr RD, 551
Soloway RD, 554
Sox HC, 552, 553
Spece RG, 554
Stamler J, 553, 554
start-up
clinic start-up design, 203
start-up patients, 204
test patients, 204
vanguard patients, 204
Stevenson JW, 551
stratification
considerations, 136
variable, 136
when to, 136
stratify/stratification
stratify, 135
Stroup DF, 551
Studies of Ocular Complications of AIDS, 554,
555
study
adaptive study design, 263
ancillary study, 459
feasibility study, 203
fixed study design, 263
followup study, 217
followup study design, 218
main study, 467
missed study visit, 229
multi-study structure, 353
natural history study, 427
nonconcurrent followup study, 218
officers of the study, 347
parent study, 467
pilot study, 204
study center director, 332
study chair, 349
study chair external, 349
study chair internal, 349
study result, 417
study vice-chair, 349
substudy, 467
570
INDEX
study index
Coronary Drug Project, 117
Glaucoma Laser Trial, 33
Program on the Surgical Control of the
Hyperlipidemias, 551
subgroup
designed subgroup comparison, 265
subgrouping, 266
subgrouping variable, 266
Systolic Hypertension in the Elderly Program, 53,
554
Taves DR, 145, 555
test
test-assigned group, 71
test-treated group, 71
theorem
Bayes’ theorem, 419
Thistle JL, 554
Thomas FB, 554
Tonascia S, 553
Toto RD, 555
treatment
active control treatment, 79
alternative control treatment, 79
alternative treatment, 79
best medical judgment control treatment, 79
comparison treatment, 73, 79
control treatment, 79
crossover treatment, 103
final treatment result, 421
inactive control treatment, 79
masked treatment, 108
masked treatment administration, 108
mock treatment, 91
negative control treatment, 80
nil treatment, 80
nil treatment control, 80
null treatment, 80
placebo treatment, 88
placebo-control treatment, 89
positive control treatment, 80
post-treatment followup, 218
sham treatment, 91
standard treatment, 73, 80
study treatment, 75
subgroup treatment difference, 423
test treatment, 77
test-treated group, 71
trace control treatment, 80
trace treatment, 80
treatment application and adjustment
followup visit, 272
treatment cessation, 103
treatment change, 103
treatment compliance, 98
treatment compliance measure, 98
treatment group, 71
treatment lag, 257
treatment modality, 93
treatment period, 276
treatment protocol suspension, 103
treatment schedule, 95
treatment suspension, 104
treatment switch, 104
treatment termination, 104
treatment unit, 33
treatment variable, 31
treatment-related bias, 132
treatment-related feedback bias, 132
treatment-related selection bias, 132
treatment assignment
adaptive treatment assignment, 145, 263
baseline adaptive treatment assignment, 145
biased coin treatment assignment, 145
bin number drug system, 117
cluster randomization, 155
fixed treatment assignment, 145
group randomization, 155
individual randomization, 155
masked treatment assignment, 108, 147
med Id number drug system, 117
minimum likelihood treatment assignment,
145
number adaptive treatment assignment, 145
open treatment assignment, 147
outcome adaptive treatment assignment, 146
play-the-winner treatment assignment, 146
randomization, see also, 148
treatment assignment ratio, 146, 151
treatment assignment stratum, 152
treatment assignment visit, 272
urn model treatment assignment, 146
treatment crossover
treatment crossover, 103
treatment design
paired treatment design, 33
treatment effect
masked treatment effects monitoring, 108,
379
masked treatment effects monitoring
committee, 108
masked treatment effects monitoring report,
379
placebo treatment effect, 88
treatment effects monitoring, 373
trial
masked trial, 108
placebo-controlled trial, 89
post-trial followup, 219
Index
post-trial followup stage, 219
trial-proper, 204
trial-proper patient, 204
Tse T, 555
Tuna N, 551
Tyor MP, 554
Tyroler HA, 555
United States Congress, 555
University Group Diabetes Program, 80, 87, 131,
491, 555
University Group Diabetes Program Research
Group, 555
usage note
adaptive study design, 263
administrative review, 399
adverse drug reaction (ADR), 471
adverse event, 471
adverse reaction, 471
ancillary study, 459
assent, 169
audit, 409
audit, audited, auditing, audits, 409
author, 431
authorship, 431
authorship attribution, 431
baseline, 271
baseline examination, 271
baseline period, 271, 275
bias, 131
blind, 107
block, 151
censor, censored, censoring, censors, 113
center, 317, 325
clinical equipoise, 75
co-, 331
commercial institutional review board,
163
comparison treatment, 73, 79
competitive bidding, 51
competitive range, 51
competitive renewal, 52
concealment, 107
conflict of interest, 463
consent, 169
contract office, 52
contract officer, 52
control treatment, 79
control-assigned group, 71
control-treated group, 71
data collection site, 317
data dredging, 265, 423
data generation site, 285, 317
dataset, 415
deferred consent, 172, 189
571
design variable, 35
dropout, 231
dropout compensation, 232
dropout replacement, 232
drug reaction, 472
efficacy monitoring, 375
endpoint, 39
ex-officio, 347
executive committee (EC), 353
exploratory data analysis, 265, 423
final, 421
finder’s fee, 455
fixed study design, 263
followup study, 217
frequentist analysis, 419
frozen state of equipoise, 131
funding period, 53, 63
grant, 53
grants management office, 54
grants management officer, 54
haphazard, 147
haphazardization, 147
harm, 373
identified data, 307, 312
implied consent, 189
incentive, 455
incentive payment, 455
informed consent, 173
insider, 463
insider trading, 464
investigator, 331
investigator-initiated research proposal, 55
involve, involved, involving, involves, 161
lead-in period, 97, 203
linkable data, 307
loss to followup, 218, 235
lost to followup, 218, 235
mask, 107
masked randomization, 107
masked treatment assignment, 108
masking level, 108
monitor, monitored, monitoring, monitors,
409
multi-study structure, 353
noncompetitive renewal, 55
outcome, 40
passive consent, 189
PC-based data entry, 302
performance monitoring, 399
performance review, 399
placebo, 87
placebo control, 87
placebo effect, 80, 88
placebo group, 88
placebo patient, 88
572
INDEX
usage note (cont.)
placebo treatment, 88
placebo treatment effect, 88
placebo-assigned, 89
placebo-assigned group, 89
placebo-assigned patient, 89
placebo-control treatment, 89
placebo-controlled trial, 89
placebo-treated, 89
placebo-treated group, 89
placebo-treated patient, 89
post-treatment followup, 218
presentation, 427, 439
primary outcome, 35
principal investigator (PI), 331
protocol bailout, 103
protocol deviation, 101
pseudorandom, 147
public repository, 293
publication, 427
quality assurance, 395
quality control, 395
quasirandom, 147
quota requirement, 213
quotification, 213
random, 147
randomization, 148
record audit, 409
recruitment quota, 213
registration, 495
regular followup visit, 219, 272
reportable event, 472, 475
reported event, 476
repository, 293
request for application (RFA), 56
request for proposal (RFP), 56
research grant, 56
retrospective followup, 219
run-in period, 97, 204
safety monitoring, 375
sequential sample size design, 255, 261
sham, 91
sham procedure, 91
sponsor-initiated research proposal, 56
standard treatment, 73, 80
start-up patients, 204
steering committee (SC), 359
stopping guideline, 381
stopping rule, 381
stratification, 135
stratify, 135
study center, 318
study group, 71
subcontract, 57
subcontractor, 57
subgroup analysis, 265, 423
substudy, 467
test patients, 204
test treatment, 77
test-treated group, 71
treatment crossover, 103
treatment effects monitoring, 373
treatment protocol suspension, 103
treatment-related feedback bias, 132
triple-mask, triple-masked, 109
underrepresent, underrepresented,
underrepresents, 214
understudy, understudied, understudying,
understudies, 214
vanguard patients, 204
withdrawal, 232
Van Der Weyden MB, 552, 553
Varco RL, 551
variable
design variable, 35
experimental variable, 31
outcome variable, 40
primary outcome variable, 35
stratification variable, 135
subgrouping variable, 266, 424
treatment variable, 31
variance
control, 139, 140
reduction, 140
reduction via analysis, 140
variance, 139
Verheugt FWA, 553
visit
closeout followup visit, 225, 271
followup visit, 218, 272
home visit, 272
interim followup visit, 272
missed study visit, 229
nonrequired followup visit, 272
post-closeout followup visit, 272
regular followup visit, 219, 272
required followup visit, 219, 272
scheduled study visit, 272
site visit, 405
study visit, 272
treatment application and adjustment
followup visit, 272
treatment assignment visit, 272
unscheduled followup visit, 272
Index
Weber FJ, 551
Wei LJ, 146, 555
Weinstein WM, 552
West JC, 555
Winau R, 555
Wittes J, 88, 97, 203, 551, 555
Wright JT Jr, 555
Yang VW, 552
Yellin AE, 551
Yusuf S, 555
Zarin DA, 555
Zelen M, 146, 555
573