Clinical Trials:

Why, What, Wherefore?

Guy de Bruyn

Perinatal HIV Research Unit

University of the Witwatersrand
Chris Hani Baragwanath Hospital
Johannesburg, 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
Stage 4
Stage 1 Stage 2 Stage 3 Regulatory
Drug discovery Pre-clinical Clinical trials review

First clinical trial application submitted

Phase I Phase II Phase III

Marketing application submitted

250 compounds
1
10,000 5 compounds
approved
compounds drug

6.5 years 7 years 1.5 years

Adapted from: Pharmaceutical Research and Manufacturers of America, 2006

 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 Trial conduct
• Adverse events • Accrual
• Laboratory tests • Retention
• HIV infection • Adherence

DSMB Decision
Continue Continue with study Pause/stop study
Modification: • Futility
• Drop a study arm • Success
• Safety concerns
• 3. Data Analysis
– Interim/final analyses
– Definitive/exploratory analyses
• 4. Reporting Results
 Timeline of Efficacy Trials

1990 1995 2000 2005 2010

VaxGen USA 1 year

VaxGen Thai Trial 1 year

6 months
Step Trial
3 months
Thai Trial
Phambili 6 months

Trial start/end

Trial analysis/results

First correlates
 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
• eligibility criteria
• study dose
• treatment duration
• study endpoints
• lab testing procedures
• diagnostic procedures
• criteria for evaluability
• assessment of clinic
responses
Statistical Procedures
• 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 MIV

UC-781 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-

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
 CAPRISA 004: Results

HIV Infections Over Time1 CVF Concentrations were Lower, and Detected Less
Frequently in HIV+ Women3
0.20
0.18 109
Probability of Infection

Placebo Tenofovir Gel Placebo

0.16 108 HIV+ HIV- Placebo

TFV Concentration (ng/mL)

0.14 P=0.017 107 1 (0-290,734) 520 (0-1,338,079) 0 (0-4,4)
0.12 106
Tenofovir
0.10 105
0.08
104
0.06
103
0.04
0.02 102
0.00 101

Months of Follow- 6 12 18 24 30 100

up Proportion with 45% 96% 7%
Detectable Concentrations
Effectiveness 47% 50% 43% 40% 39% Time post reported 4.5 (1-24) 4.5 (2-28) 6 (1-34)
(P-value) (0.069) (0.007) (0.004) (0.013) (0.017) gel use (days)

Safety
TDF prevents incident HSV infections2
• No TDF resistance
• HSV infection rate: 29/202 vs. 48/224;
• No evidence for renal or bone toxicity
• IRR 0.49 P=0.003
• Increased rate of mild diarrhea in TDF group
(17% vs. 11%)
• No adverse outcomes with pregnancies

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.
The SAPIT trial

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

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