PubH 7420
Clinical Trials
Instructor: Jim Neaton
612-626-9040
jim@ccbr.umn.edu
2221 University Ave SE, Room 200
Text:
Fundamentals of Clinical Trials
Friedman, Furberg, and DeMets
Evaluation: Homework: 3 exercises (15%)
Group debates (5%)
Protocol project (20%)
Mid Term (30%)
Final (30%)
Web Site: http://www.biostat.umn.edu/~ph7420
1
Books on Reserve
• Pocock: Clinical Trials. A Practical Approach.
• Meinert: Clinical Trials. Design, Conduct and
and Analysis
Reading Room – 4th floor Mayo
2
TAs for PubH 7420
ChiHyun Lee – leex5865@umn.edu
Donald Musgrove – musgr007@umn.edu
Debashree Ray – rayxx267@umn.edu
3
Group Work: Protocol and Debate Topics
• Eight multidisciplinary groups, 7-8 members.
• Four protocol topics, 2 groups assigned to
each.
• Eight debate topics; 2 groups will debate (each
group twice)
– 20 minute debate, 10 minutes per group (max of 7
slides per group)
– Each side of the debate should be presented by 1
person. Pro side goes first. All group members
are expected to participate (see calendar for
4
schedule).
Protocol Project
• Protocol
– 10 -12 pages.
– On the last page of the protocol indicate the
members of the team and the sections they
contributed to.
– Turn in by the last day of class.
• Presentation
– 20 minutes during the last 2 weeks of class,
followed by questions and discussion.
5
Outline of Protocol
1.
Background and rationale for study
2.
Study design

Objectives (primary, secondary, subgroup hypotheses)

Primary and secondary endpoints (efficacy and safety)

Inclusion and exclusion criteria

Treatments

Sample size
3.
Data collection plan and follow-up schedule
4.
Data analysis plan, including plan for interim
monitoring and guidelines for early termination
6
Advice for Groups
• Elect a chairperson and rapporteur.
• Divide up the work among all group members.
• Give each group member a list of names and email
addresses.
• Plan to meet 6-7 times during the semester.
• Plan to have 1 member present the debate slides
and 3 members present the protocol.
7
General Methods of Investigation
1. Chance observations
2. Case histories
– individual cases
– case series
3. Uncontrolled trials of an intervention
No planned
concurrent
comparison
group
4. Cross-sectional (naturalistic) studies
5. Case-control studies
6. Prospective follow-up studies
7. Randomized clinical trial
8
Did Investigator Assign Exposures?
Yes
No
Experimental study
Observational study
Random allocation?
Comparison group?
Yes
No
Yes
Analytical
study
Nonrandomised
controlled
trial
Randomised
controlled
trial
Exposure
Cohort
study
Descriptive
study
Direction?
Exposure and
outcome at
the same time
Outcome
Exposure
No
Outcome
Casecontrol
study
Grimes and Schulz, Lancet, 359:57-61, 2002.
Crosssectional
study
Hierarchy of Evidence
Coherence of evidence from multiple sources
Systematic review of well-designed, large randomized trials
Strong evidence from one large randomized trial
Systematic review of small trials (e.g., surrogate outcome studies)
Systematic review of from well-designed cohort studies
Strong evidence from one cohort study
Unsystematic observations (expert opinions)
Adapted from Devereaux PJ et al, Evidence-Based Cardiology,
2nd Edition, BMJ Books, 2003.
10
Oxford Center for Evidence-Based
Medicine Levels of Evidence+
Grade of
Recommendation
Level of
Evidence
Type of Study
A
1a
Systematic review (SR) (with homogeneity) of RCTs
1b
Individual RCT with narrow confidence interval
1c
All or none studies++
2a
SR (with homogeneity) of cohort studies
2b
Individual cohort study
2c
Outcomes research, ecological studies
3a
SR of case control studies
3b
Individual case control study
C
4
Case/series case report, poor quality cohort or case-control
studies
D
5
Expert opinion, or based on physiology, bench research, or
“first principles”
B
+ www.cebm.net/index.aspx?o=1025
++ e.g., all died before treatment became available and now some survive
11
Rating Schemes for Clinical Guidelines
• Quality of Evidence
– I: One or more trials with clinical outcomes
– II: One or more well-designed, non-randomized
trials or cohort studies with clinical outcomes
– III: Expert opinion
• Strength of Recommendation+
– A: Strong
– B: Moderate
– C: Optional
+
from DHHS guidelines for the treatment of HIV
http://www.aidsinfo.nih.gov/Guidelines
12
Rating Schemes Are Used in Guidelines for
the Prevention and Treatment of Disease
• Guideline panels regularly, systematically
develop statements to assist practitioners and to
avoid inappropriate heath care variation
• Guidelines are used to develop performance
measures and benchmarks for quality of care
13
A Review of American College of
Cardiology/American Heart Association
(ACC/AHA) Guidelines
• 16 guidelines with an increasing number of
recommendations over time
• 314/2711 were Level A (median = 11%)
• 1246/2711 were Level C or D (median = 48%)
A = multiple randomized trials or meta-analysis
C = case studies, standard of care or expert
opinion
Tricoci P et. al. JAMA 2009; 301: 831-841
14
Recent Reports of Interest
• Updated guidelines for management of high
blood pressure
– JNC 8: JAMA, published online December 18,
2013 with 2 editorials
– ASH: J Clin Hyper, published online December
17, 2014.
– JNC 8 Minority View, published online January
14, 2014 in Ann Intern Med
• Review of WHO expert guidelines
– “WHO recommendations are often strong based
on low confidence in effect estimates”.
15
Types of Clinical Research in
Journals and Press
• Fletcher and Fletcher (N Engl J Med 1979)
– Review of articles published from 1946-1976
– In 1976, 44% cross-sectional, 34% cohort
studies, 5% randomized trials
– “Predominant designs in 1976 were less
accurate ways of conducting clinical research”.
• Lai and Lane (PLoS One 2009)
– Of 734 front-page stories 43% were
presentations/abstracts
– Of the journal articles reported, 3% were
overviews of trials and 21% were randomized
trials, 42% cohort studies and 31% expert
opinions
16
Chance Observations
Examples
• Bleeding among children chewing
gum containing aspirin to relieve
the pain from tonsillectomies
(Dr. Lawrence Craven) (see Dalen J,
Arch Int Med 1991; 151:1066-1069)
• Discovery of penicillin (Fleming)
and digitalis (purple foxglove)
(Withering)
17
Case Histories (or Case Report)
1. Most ancient and widely used method of clinical
investigation
2. Most useful for disease with a specific etiologic
agent
3. Standard for comparison is usually implicit
The New England Journal of Medicine usually has a
case described in each issue
http://www.nejm.org/browse?category=clinicalcases
18
Case Series
• Def. – aggregation of individual cases in one
report; the series may include all persons with an
outcome or all persons with an exposure and
outcome, e.g., an epidemic or spontaneously
reported adverse events
Weaknesses
• No concurrent control
• Usually inadequate information about persons not
developing the disease
• Cases may not be representative; persons with
disease are survivors of unknown population
19
Example: Case Series
Jaffe et al. Acquired immune deficiency
syndrome in the United States: The first 1,000
cases. J Inf Dis 148:339-45, 1983.
Purpose: To describe characteristics of the
cases.
20
21
Case Definition
Eligibility Criteria:
1. Biopsy proven Kaposi sarcoma (KS) or
2. Biopsy, histology, or culture proven infection moderately
predictive of cellular immune deficiency
a. Protozoal and helminthic (parasitic worms) infections,
e.g.,
Pneumocystis carinii pneumonia (now
Pneumocystis jiroveci and recognized to be a fungal
disease)
b. Fungal infections, e.g., esophageal candidiasis
c. Bacterial infections, e.g., atypical mycobacterial
disease
d. Viral infections, e.g., cytomegalovirus disease
Exclusion Criteria:
1. Previous immunosuppressive therapy
2. Illness associated with immunosuppression
3. Persons with KS over 60 years of age
4. Persons under 10 years of age
22
Surveillance
1. Review of selected cancer tumor registries
2. Contact with selected physicians in 18
communities
3. Review of request for pentamidine
isethionate by CDC Parasitic Diseases
Drug Service
4. Reports from individual physicians and
state health departments
23
Results
• 727 cases were homosexual or bisexual males; of
remaining cases 155 were IV drug users
• 75% of homosexual men were from New York or
California
• 48% of cases were 30 - 39 years of age
• There was an excess of KS among homosexual /
bisexual men
• Distribution of cases by risk group changed over
time
24
Case Series Summary
• A descriptive study, i.e., not designed to address a
specific hypothesis or estimate absolute risk of an
outcome.
• Key feature: Clear, reproducible case definition
with a focus on person, place and time
• Addresses 5 “W” questions: who, what, why,
when, and where
• Often the 1st approach taken and the results are
used to generate specific hypotheses
25
Other Examples of Case Series:
Pandemic Influenza A (H1N1v)
• Pneumonia and respiratory failure from swineorigin influenza A (H1N1) in Mexico (N Engl J Med
2009;361:680-689)
• Critically ill patients with 2009 influenza A(H1N1)
in Mexico (JAMA 2009; 302:1880-1887)
• Hospitalized patients with 2009 H1N1 influenza in
the United States, April-June 2009 (N Engl J Med
2009;361:1935-1944)
• Emergence of a novel swine-origin influenza A
(H1N1) virus in China (N Engl J Med
2009;360:2605-2615)
26
Case Series Helped Define Prospective
Cohort Studies with Specific Hypotheses
• INSIGHT H1N1v Outpatient Study
– Characterize patients with influenza-like illness,
influenza A and H1N1v
– Identify risk factors for hospitalization within 14 days of
diagnosis
• INSIGHT H1N1v Hospitalization Study
– Characterize patients hospitalized with influenza A and
H1N1v
– Identify risk factors for death within 60 days of
admission
• For both studies:
– Molecularly characterize the virus
– Establish a repository of serum to study biomarkers.
Dwyer D et al. Vaccine 2011;295:B56-B62.
27
Example: Uncontrolled Trial of an Intervention
Moertel et al. A clinical trial of amygdalin
(laetrile) in the treatment of human cancer.
NEJM 306:201-6, 1982.
Purpose: To determine if laetrile was an
effective and safe treatment for cancer.
Study preceded by retrospective analysis of
laetrile users (estimated 70,000 people, 93
cases submitted, 67 with medical records, 6
“responders”). NEJM 299:549-552, 1978.
28
“New Laetrile Study Leaves
Cancer Institute in the Pits”
Science, October 1978
29
Did Investigator Assign Exposures?
Yes
No
Experimental study
Observational study
Random allocation?
Comparison group?
Yes
No
Yes
Analytical
study
Nonrandomised
controlled
trial
Randomised
controlled
trial
Exposure
Cohort
study
Descriptive
study
Direction?
Outcome
Exposure
No
Outcome
Casecontrol
study
Grimes and Schulz, Lancet, 359:57-61, 2002.
Exposure and
outcome at
the same time
Crosssectional
study
Eligibility Criteria
1. Histologically proven cancer
2. No surgery, radiation or chemotherapy in past
month
3. Good general condition (able to eat and get
about alone)
4. No known cure
5. Measurable tumors
Treatment: Naturally derived laetrile
– 21-day intravenous schedule followed by oral
dose
– High doses of vitamins
– Restricted diet
31
Response Variables (Endpoints):
• Tumor size
– Regression
– Stable
– Progression
• Weight
• Performance status
• Side effects
• Mortality
32
Results
179 patients entered; 178 followed
– 1 partial responder
– 54% with progression at end of IV schedule
– All had progression after 7 months
– Median survival: 4.8 months
33
Conclusion
“It must be concluded that amygdalin
(Laetrile) in combination with high doses of
vitamins, pancreatic enzymes, and a diet of
the type employed by ‘metabolic therapists’
is of no substantive value in the treatment of
cancer. Further investigation of clinical use
of such therapy is not justified.”
34
Important Features of This Study
• Well-defined cases and treatment
• Protocol for patient evaluation and analysis
• Objective endpoints
• Complete data with nearly all patients
meeting evaluability criteria; and
• The study was described in sufficient detail
so that it could be replicated
35
Laetrile Study: What is the
Comparison Group?
Partial
Response
Laetrile
No
Response
1
174
175*
* One patient was ineligible and
3 could not be evaluated
36
Remarks by Commentators:
“From a public health standpoint, it was
unethical to conduct a clinical study that would
supposedly test orthodox versus unorthodox
treatments to resolve the laetrile controversy,
but could not do so scientifically.”
“These conclusions are not justified … there
was no control group with which the group of
treated patients could be compared.”
37
Uncontrolled Trial of ART Interruption
Skiest DJ et al. JID 2007; 195:1426-1436.
Purpose: To determine safety of ART
interruption.
38
Eligibility Criteria
1.
2.
3.
4.
CD4+ > 350 cells/mm3 before 1st ART and currently
HIV RNA <55,000 copies/mL
Combination ART for at least 6 months
No prior AIDS events
Treatment: ART interruption (TI) with strong
recommendation to resume when CD4+ declined to
< 250 cells.
39
Outcomes:
• Symptomatic HIV, AIDS, death or CD4+ <250
• Changes in CD4+ and HIV RNA
• Signs, symptoms and laboratory abnormalities
40
Results
167 patients entered; 144 completed 96 weeks of
follow-up
– 5 deaths
– 2 patients with AIDS events
– 2 with symptomatic (Category B) events
– 54 patients with death, AIDS, Cat B, or CD4+ <250
– 26 grade ¾ symptoms or lab abnormalities
41
Conclusion
“In summary, …TI was not associated with
rapid disease progression. TI in selected
patients could avoid drug toxicity…but this
possibility must be weighed against
concerns about infrequent adverse events.”
42
TI Study
AIDS or Death
TI
7
No
AIDS or Death
160
167
43
Special Situations When Uncontrolled
Study May Be Appropriate
• No other treatment to use as control
• Untreated patients have very poor prognosis
• Treatment not expected to have serious side
effects
• Potential benefit to patients large and
unambiguous
• Result of study likely to be widely accepted
Byar D, et al. NEJM, Vol 323, 1990.
44
Planned Observational Studies
1. Cross-Sectional – data collected at a single
point in time (risk factors and disease endpoints
measured simultaneously).
2. Case-Control - controls (non-cases) sampled
from base population.
3. Prospective Follow-up (cohort) - controls (noncases) not sampled; risk factor measurements
made before endpoints occur.
45
Did Investigator Assign Exposures?
Yes
No
Experimental study
Observational study
Random allocation?
Comparison group?
Yes
No
Yes
Analytical
study
Nonrandomised
controlled
trial
Randomised
controlled
trial
Exposure
Cohort
study
Descriptive
study
Direction?
Outcome
Exposure
No
Outcome
Casecontrol
study
Grimes and Schulz, Lancet, 359:57-61, 2002.
Exposure and
outcome at
the same time
Crosssectional
study
Cross-Sectional Study
• National Health and Nutrition Examination
Survey (NHANES) – ongoing national
survey conducted by the National Center for
Health Statistics
In 2007-2008 almost 17% of children and
adolescents aged 2-19 years were obese
http://www.cdc.gov/nchs/nhanes.htm
47
Cross-Sectional Study
MRFIT: Association of left ventricular hypertrophy (LVH)
by ECG and hypertensive status at baseline of trial
LVH
Hypertensive
Normotensive
No LVH
231
7,781
8,012
43
4,811
4,854
274
12,592
12,866
Prevalence of LVH among hypertensives =
231 / 8,012 = 2.9%
Prevalence of LVH among normotensives =
43 / 4,854 = 0.9%
Cross-sectional study + follow-up = cohort study.
48
Cross-Sectional Study
Association of PCP and gender
at baseline in trials and cohort studies carried out by the
Community Programs for Clinical Research on AIDS (CPCRA)
PCP
Men
Women
No PCP
371
1,189
2,260
58
493
551
429
2,382
2,811
History of PCP among men = 371 / 2,260 = 16.4%
History of PCP among women = 58 / 551 = 10.5%
P-value = 0.001 for difference
49
CD4+ Percent Distribution for Men and
Women
CD4+
Men
Women
Total
< 50
22
13
20
50 - 99
11
6
10
100 - 149
8
7
8
150 - 199
7
8
8
52
66
54
Total
100
100
100
Median
213
328
232
≥ 200
50
Interrelationship Between Gender, CD4+
Count, and PCP
Gender
(risk factor)
PCP
(disease
endpoint)
CD4+
(confounder)
51
Percent of Patients with History of PCP
According to CD4+ Count
CD4+
(cells/mm3)
Total
Percent with
PCP
< 50
561
43.3
50 - 99
272
27.6
100 - 149
226
15.5
150 - 199
212
8.5
1,541
3.8
≥ 200
52
Confounding
Confounder (def.)
• A variable whose effect is entangled with the
effect of other variables under study
• A factor related to the disease endpoint
being studied and to the risk factor being
investigated
53
Modified Question
To what extent do differences in the
CD4+ distribution between men and
women explain the difference (or lack of
difference) in the prevalence of PCP
between men and women?
54
Percent of Patients with History
of PCP by CD4+ Count and Gender
CD4+
< 50
50 - 99
100 - 149
150 - 199
≥ 200
Total
Percent with PCP
Men
Women
43.9
28.9
16.1
10.7
3.3
39.4
18.2
12.5
0.0
5.2
16.4
10.5
55
Unadjusted and CD4+ Adjusted Percent with
History of PCP by Gender
Men
Women
P-value
Unadjusted
16.4
10.5
0.001
CD4+ adjusted
(direct method)
15.6
13.5
0.22
56
Common Problems with Inferences from
Cross-Sectional Surveys
• Chicken/egg dilemma (except for genetic factors)
• By definition must consider prevalent cases rather
than incident cases, thus data reflect determinants
of death/recovery as well as etiology (Neyman
bias or incidence-prevalence bias).
Primary Utility: descriptive; hypothesis generation
57
Incidence and Prevalence
Incidence
Prevalence
Recovery/Death
58