1. Clinical Trials: Why, What, Wherefore? Guy de Bruyn Perinatal HIV Research Unit University of the Witwatersrand Chris Hani Baragwanath Hospital Johannesburg, South Africa

2. 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

3. Drug Discovery, Development and Review Process Adapted from: Pharmaceutical Research and Manufacturers of America, 2006 Phase IPhase IIIPhase II Stage 1 Drug discovery Stage 2 Pre-clinical Stage 3 Clinical trials Stage 4 Regulatory review 7 years 6.5 years1.5 years 5 compounds 250 compounds 1 approved drug 10,000 compounds First clinical trial application submitted Marketing application submitted

4. 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. 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. 2. Conduct of the trial Recruitment Adherence Retention Data collection and processing Data monitoring committees

7. 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. 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

9. 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

10. 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. 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

12. What about additional HIV prevention technologies? Male circumcision STI treatment –Diagnostics –Directed versus syndromic therapy Post-exposure prophylaxis

13. DSMB Review Process Safety Adverse events Laboratory tests HIV infection Trial conduct Accrual Retention Adherence DSMB Decision ContinueContinue with study Modification: Drop a study arm Pause/stop study Futility Success Safety concerns

14. 3. Data Analysis –Interim/final analyses –Definitive/exploratory analyses 4. Reporting Results

15. 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 6 months 3 months Phambili 6 months

16. 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

18. Adaptive design Not uncommon to modify a trial/ statistical procedures during the conduct of a clinical trial based on interim data Trial ProcedureStatistical 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

19. Phase II/III seamless trial design

20. 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. 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

22. 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

23. 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

24. Ethical considerations Principles of Research Ethics

25. Foundational Documents Nuremberg Code Declaration of Helsinki Belmont Report CIOMS

26. How Are Patients’ Rights Protected? Informed consent Scientific review Institutional review boards (IRBs) Data safety and monitoring boards

27. Case Studies… Vaxgen Thai SAPIT Caprisa 004

28. ARV-Based Microbicides Tenofovir UC-781 MIV TMC120 (Dapivirine)

29. 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

30. 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.

31. CAPRISA 004: Study Design

32. HIV Infections Over Time 1 CAPRISA 004: Results TDF prevents incident HSV infections 2 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+ Women 3 10 9 10 8 10 7 10 6 10 3 10 2 10 1 10 0 10 4 10 5 TFV Concentration (ng/mL) Proportion with Detectable Concentrations 45%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 GelPlacebo Months of Follow-up 612182430 Effectiveness (P-value) 47% (0.069) 50% (0.007) 43% (0.004) 40% (0.013) 39% (0.017) 1. Abdool Karim Q, et al. 18 th 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. Abdool Karim SS. N Engl J Med 2010;362:697-706. The SAPIT trial

34. SAPIT trial results Abdool Karim SS. N Engl J Med 2010;362:697-706.

35. Decisions made at the design stage met with disapproval by in-country experts Boulle A. SAMJ 2010, Vol. 100, No. 9

36. Experts say trial was unethical when designed Boulle A. SAMJ 2010, Vol. 100, No. 9

37. Summary Why we need clinical trials What is involved in designing and implementing a clinical trial Ethical considerations Some examples