Clinical Trials: Why, What, Wherefore?

Guy de Bruyn

Perinatal HIV Research UnitUniversity of the Witwatersrand

Chris Hani Baragwanath HospitalJohannesburg, South Africa

Why we need clinical trials

• Health care challenge: addressing the need for interventions providing greater efficacy and reduced toxicity– Improved benefit/risk– Broader access– Less costly

• Scientific challenge: evaluating efficacy and side effects of promising interventions in a manner that is– Timely– Efficient– Reliable

Drug Discovery, Development and Review Process

Adapted from: Pharmaceutical Research and Manufacturers of America, 2006

Phase I Phase IIIPhase II

Stage 1Drug discovery

Stage 2Pre-clinical

Stage 3Clinical trials

Stage 4Regulatory review

7 years7 years6.5 years 1.5 years

5 compounds250 compounds

1approved

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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

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

2. Conduct of the trial

• Recruitment

• Adherence

• Retention

• Data collection and processing

• Data monitoring committees

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

Access to care - modified from Grady

• Care which is part of the scientific design

• 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

Protocol mandates

• Avoiding pregnancy during the vaccination period

• Assessing symptoms of illness

• Ensuring adequate standard of care to control participants– Counselling – pre/post-test, risk reduction,

safer sex– Providing condoms

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

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 attention

to weight, nutrition, exercise, in addition to possible pharmacotherapy

• Facilitating access to services– TOP– Psychosocial support – rape/trauma/DV– Mental illness

• Dental care

What about additional HIV prevention technologies?

• Male circumcision

• STI treatment – Diagnostics– Directed versus syndromic therapy

• Post-exposure prophylaxis

DSMB Review Process

Safety• Adverse events• Laboratory tests• HIV infection

Trial conduct• Accrual• Retention• Adherence

DSMB Decision

Continue Continue with studyModification:• Drop a study arm

Pause/stop study• Futility• Success• Safety concerns

• 3. Data Analysis– Interim/final analyses– Definitive/exploratory analyses

• 4. Reporting Results

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

Need for more efficient approaches

Current trial designs have numerous inefficiencies

Enhance/accelerate the vaccine development process by requiring fewer participants and a reduced time to meet study endpoints

Adaptive designs offer an alternative to the current approach

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 clinic responses

• randomization• study design• study objectives• hypotheses• sample size• data monitoring and interim analysis • statistical analysis plan• methods for data analysis

Chow S-C, Orphanet Journal of Rare Diseases, 2008

Phase II/III seamless trial design

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

Interpretation of a p-value

• Which of these interpretations of p = 0.04 is 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

Main threats to achieving a reliable evaluation

• Variability: if same experiment is done several times, 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

Main threats to achieving a reliable evaluation

• Bias: tendency of a statistical estimate to deviate in one direction from a true value– Example: high risk patients may receive

more intensive intervention– Methods to control bias:

• Randomization• Adherence to interventions• Intention to treat analyses• High levels of retention / follow-up

Ethical considerations

• Principles of Research Ethics

Foundational Documents

• Nuremberg Code

• Declaration of Helsinki

• Belmont Report

• CIOMS

How Are Patients’ Rights Protected?

• Informed consent

• Scientific review

• Institutional review boards (IRBs)

• Data safety and monitoring boards

Case Studies…

• Vaxgen

• Thai

• SAPIT

• Caprisa 004

ARV-Based Microbicides

Tenofovir

UC-781

MIV

TMC120 (Dapivirine)

                                           

     

1% Tenofovir Vaginal Gel

• Active ingredient is tenofovir, an antiretroviral

• Has specific action against HIV and proven safety and activity as a therapeutic agent

• Provided in pre-filled applicators• Low levels of drug in the blood• Low frequency of side effects

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 sex act

• Participants asked to apply the first dose of the assigned gel within 12 hours prior to coitus and to 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.

CAPRISA 004: Study Design

0.000.020.040.060.080.100.120.140.160.180.20

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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

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Proportion withDetectable Concentrations

45% 96% 7%

4.5 (1-24) 4.5 (2-28) 6 (1-34)Time post reportedgel 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.

Abdool Karim SS. N Engl J Med 2010;362:697-706.

The SAPIT trial

SAPIT trial results

Abdool Karim SS. N Engl J Med 2010;362:697-706.

Decisions made at the design stage met with disapproval by in-country experts

Boulle A. SAMJ 2010, Vol. 100, No. 9

Experts say trial was unethical when designed

Boulle A. SAMJ 2010, Vol. 100, No. 9

Summary

• Why we need clinical trials

• What is involved in designing and implementing a clinical trial

• Ethical considerations

• Some examples