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 Copyright 2013 by John Wiley & Sons, Inc. All rights reserved Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com. 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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 80 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 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 82 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 84 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. 88 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 90 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 162 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. 164 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 : 170 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. 172 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 174 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. 200 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) 202 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 204 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 210 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. 212 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 214 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 216 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 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 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 x x x x x x x x x x x x x x x 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 282 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 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 284 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. 286 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 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 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 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. 290 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 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 294 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 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. 296 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 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). 298 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 300 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 302 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 304 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 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. 306 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 • 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 308 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 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 312 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 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. 314 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 504 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 514 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 516 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 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 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 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 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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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