clinical trials: in theory and on the ground (guy de bruyn)

8/7/2019 Clinical Trials: In Theory and On the Ground (Guy de Bruyn)

1/37

Clinical Trials:

Why, What, Wherefore?

Guy de Bruyn

Perinatal HIV Research Unit

University of the Witwatersrand

Chris Hani Baragwanath Hospital

Johannesburg, South Africa


2/37

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


3/37

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


4/37

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


5/37

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


6/37

2. Conduct of the trial

Recruitment

Adherence

Retention

Data collection and processing

Data monitoring committees


7/37

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


8/37

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


9/37


10/37

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


11/37

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


12/37

What about additional HIV prevention

technologies?

Male circumcision

STI treatment

Diagnostics

Directed versus syndromic therapy

Post-exposure prophylaxis


13/37

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


14/37

3. Data Analysis

Interim/final analyses

Definitive/exploratory analyses

4. Reporting Results


15/37

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


16/37

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


17/37


18/37

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


19/37

Phase II/III seamless trial design


20/37

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


21/37

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


22/37

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


23/37

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


24/37

Ethical considerations

Principles of Research Ethics


25/37

Foundational Documents

Nuremberg Code

Declaration of Helsinki

Belmont Report

CIOMS


26/37

How Are Patients Rights Protected?

Informed consent

Scientific review

Institutional review boards (IRBs) Data safety and monitoring boards


27/37

Case Studies

Vaxgen

Thai

SAPIT

Caprisa 004


28/37


29/37

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


30/37

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.


31/37

CAPRISA 004: Study Design


32/37

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.


33/37

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

The SAPIT trial


34/37

SAPIT trial results

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


35/37

Decisions made at the design stage met with

disapproval by in-country experts

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


36/37

Experts say trial was unethical when designed

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


37/37

Summary

Why we need clinical trials

What is involved in designing and

implementing a clinical trial

Ethical considerations

Some examples