Clinical Trials: In Theory and On the Ground (Guy de Bruyn)
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Transcript of Clinical Trials: In Theory and On the Ground (Guy de Bruyn)
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Clinical Trials:
Why, What, Wherefore?
Guy de Bruyn
Perinatal HIV Research Unit
University of the Witwatersrand
Chris Hani Baragwanath Hospital
Johannesburg, South Africa
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Why we need clinical trials
Health care challenge: addressing the need forinterventions providing greater efficacy andreduced toxicity Improved benefit/risk
Broader access
Less costly
Scientific challenge: evaluating efficacy and sideeffects of promising interventions in a mannerthat is
Timely Efficient
Reliable
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Drug Discovery, Development
and Review Process
Adapted from:Pharmaceutical Research and Manufacturers of America, 2006
Phase I Phase IIIPhase II
Stage 1
Drug discovery
Stage 2
Pre-clinical
Stage 3
Clinical trials
Stage 4
Regulatory
review
7 years7 years6.5 years 1.5 years
5 compounds
250 compounds1
approved
drug
10,000
compounds
Firstclin
icaltrialapplic
ationsubm
itted
Marketin
ga
pplication
submitted
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Types of Clinical Studies
Four Phases of Clinical
Experimentation
0 preclinical
1 Dose seeking/PK
2 Biologic activity
3 Clinical Efficacy, Safety
4 Post-marketing, extended evaluation
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What is involved in doing a clinical trial
Steps in Experimentation: 1. Formulating the Problem (Designing the
Study) Formulating specific hypotheses
Choice of populations (eligibility criteria)
Choice of treatments
Choice of endpoints
Defining degree of precision required (sample size)
Developing a written study protocol Operations Manual
Scientific Design
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2. Conduct of the trial
Recruitment
Adherence
Retention
Data collection and processing
Data monitoring committees
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Trial Procedures
Recruitment Screening / determination of eligibility Vaccination
Safety assessments Reactogenicity (local and systemic) Clinical evaluation Laboratory measures
HIV prevention Immunological endpoints / Correlates Trial endpoints
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Access to care -modified from Grady
Care which is part of the scientificdesign
Care needed to safely complete the trial
Care for injuries and adverse events
Post trial access
Ancillary care Care that some participants will
predictably need
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Care needed to safely complete the trial
Resuscitation equipment
Laboratory monitoring of haematologic
parameters and other clinical
laboratory values of potential interest Anaemia
Leukopaenia
Alteration of hepatic enzyme tests
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Ancillary care some examples
Hypertension May be diagnosed incidentally during the conduct
of trial procedures Treatment is lifelong
Management is multi-modal, i.e. requires attentionto weight, nutrition, exercise, in addition topossible pharmacotherapy
Facilitating access to services TOP
Psychosocial support rape/trauma/DV Mental illness
Dental care
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What about additional HIV prevention
technologies?
Male circumcision
STI treatment
Diagnostics
Directed versus syndromic therapy
Post-exposure prophylaxis
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DSMB Review Process
Safety Adverse events Laboratory tests HIV infection
Trial conduct Accrual Retention Adherence
DSMB Decision
Continue Continue with study
Modification: Drop a study arm
Pause/stop study
Futility Success Safety concerns
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3. Data Analysis
Interim/final analyses
Definitive/exploratory analyses
4. Reporting Results
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1990 1995 2000 2005 2010
VaxGen USA
VaxGen Thai Trial
Step Trial
Thai Trial
Trial start/end
Trial analysis/results
First correlates
Timeline of Efficacy Trials
1 year
1 year
6 months
3 months
Phambili 6 months
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Need for more efficient approaches
Current trial designs have numerousinefficiencies
Enhance/accelerate the vaccine development
process by requiring fewer participants and a
reduced time to meet study endpoints
Adaptive designs offer an alternative to thecurrent approach
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Adaptive design
Not uncommon to modify a trial/ statistical procedures during
the conduct of a clinical trial based on interim data
Trial Procedure Statistical Procedures
eligibility criteria
study dose treatment duration study endpoints lab testing procedures diagnostic procedures criteria for evaluability
assessment of clinicresponses
randomization
study design study objectives hypotheses sample size data monitoring and interimanalysis
statistical analysis plan methods for data analysis
Chow S-C, Orphanet Journal of Rare Diseases, 2008
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Phase II/III seamless trial design
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Interpreting Results
"It ain't so much the things we don't
know that get us into trouble. It's the
things we do know that just ain't so." Artemus Ward
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Interpretation of a p-value
Which of these interpretations of p = 0.04is correct?
(a) There is a 4% chance that the positive
result was a fluke (b) If the trial were repeated 100 times in the
same population, under identical conditions,
and in reality the vaccine is worthless, then
only 4 of the trials on average would produce
p-values 0.04
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Main threats to achieving a reliable evaluation
Variability: if same experiment is done severaltimes, the results will be different each time
Variability depends on:
How similar the participants are
How consistently treatment is administered
Sample size
Methods to limit variability:
Eligibility criteria
Careful protocol specifications for treatment
Adequate sample size
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Main threats to achieving a reliable evaluation
Bias: tendency of a statistical estimateto deviate in one direction from a truevalue
Example: high risk patients may receivemore intensive intervention
Methods to control bias: Randomization
Adherence to interventions Intention to treat analyses
High levels of retention / follow-up
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Ethical considerations
Principles of Research Ethics
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Foundational Documents
Nuremberg Code
Declaration of Helsinki
Belmont Report
CIOMS
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How Are Patients Rights Protected?
Informed consent
Scientific review
Institutional review boards (IRBs) Data safety and monitoring boards
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Case Studies
Vaxgen
Thai
SAPIT
Caprisa 004
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1% Tenofovir Vaginal Gel
Active ingredient is tenofovir, anantiretroviral
Has specific action against HIV and
proven safety and activity as atherapeutic agent
Provided in pre-filled applicators
Low levels of drug in the blood Low frequency of side effects
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Coital Dosing in CAPRISA 004
Participants advised to use gel which is in single-Participants advised to use gel which is in single-use, pre-filled applicators, as follows:use, pre-filled applicators, as follows:
Coitally dependent use - 2 doses of gel per sexact
Participants asked to apply the first dose of theassigned gel within 12 hours prior to coitus andto apply a second dose as soon as possible,
within 12 hours, after coitus. Not more than two doses of gel in a 24-hour
period.
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CAPRISA 004: Study Design
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0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0.16
0.18
0.20
ProbabilityofInfection
HIV Infections Over Time1
CAPRISA 004: Results
TDF prevents incident HSV infections2
HSV infection rate: 29/202 vs. 48/224;
IRR 0.49 P=0.003
Safety
No TDF resistance
No evidence for renal or bone toxicity
Increased rate of mild diarrhea in TDF group
(17% vs. 11%)
No adverse outcomes with pregnancies
Placebo
Tenofovir
P=0.017
CVF Concentrations were Lower, and Detected Less
Frequently in HIV+ Women3
109
108
107
106
103
102
101
100
104
105
TFVConcent r
ation(ng/mL)
Proportion with
Detectable Concentrations45% 96% 7%
4.5 (1-24) 4.5 (2-28) 6 (1-34)Time post reported
gel use (days)
1 (0-290,734) 520 (0-1,338,079) 0 (0-4,4)
HIV+ HIV- Placebo
Tenofovir Gel Placebo
Months of Follow-up
6 12 18 24 30
Effectiveness(P-value)
47%(0.069)
50%(0.007)
43%(0.004)
40%(0.013)
39%(0.017)
1. Abdool Karim Q, et al. 18th IAC; Vienna, July 18-23, 2010; Abst TUSS0502; 2. Kashuba A, et al. ibid. Abst. TUSS0503; 3. Sokal D, et al. ibid. Abst. TUSS0504.
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Abdool Karim SS. N Engl J Med 2010;362:697-706.
The SAPIT trial
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SAPIT trial results
Abdool Karim SS. N Engl J Med 2010;362:697-706.
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Decisions made at the design stage met with
disapproval by in-country experts
Boulle A. SAMJ 2010, Vol. 100, No. 9
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Experts say trial was unethical when designed
Boulle A. SAMJ 2010, Vol. 100, No. 9
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Summary
Why we need clinical trials
What is involved in designing and
implementing a clinical trial
Ethical considerations
Some examples