1. Projeto Praça Onze Universidade Federal do Rio de Janeiro Clinical Trials at AIDS Vaccine ‘09 Scientific Journalists Training Program Global HIV Vaccine Enterprise Paris, October 19, 2009 Mauro Schechter Principal Investigator, Projeto Praça Onze Professor of Infectious Diseases Universidade Federal do Rio de Janeiro

2. Development of HIV vaccines Laboratory and animal protection experiments 20–50 HIV-negative volunteers (lower risk); safety and immunogenicity I I II III IV 100s of HIV-negative volunteers (lower and higher risk); safety, immunogenicity; doses, routes of administration, different populations 1000s of HIV-negative volunteers (higher risk); efficacy Effectiveness; operational research Pre-clinical phase Clinical Phases * * * Randomized clinical trials

3. Randomised Controlled Trials (RCTs) Experimental, (usually) longitudinal, prospective Randomised – ensures that treatment groups are similar at start of trial; any differences are due to chance only Controlled – control group allows to conclude that outcome is due to the test vaccine rather than some other factor Comparison is usually between a new regimen or intervention and an existing standard of care or placebo

4. l Generalisability Participants can be different from those that will use the vaccine Eligibility criteria often leads to groups of patients being excluded (e.g. STI co-infection) l Length of trial and primary endpoints Typically 1-3 years long, thus efficacy of over the longer-term is not assessed Surrogate markers versus clinical events Limitations of randomized clinical trials

5. l Follow-up of patients Participants are generally seen more regularly and followed more intensely than in routine practice - this may influence behaviour, etc. Feasibility Potential participants may not want to leave an important decision up to chance Rare events are difficult to assess in RCTs as long follow-up periods and large numbers of patients are required Ethics It may be unethical to withhold an intervention to form a control group Limitations of randomized clinical trials

6. Practical aspects of clinical trials Question being studied Trial population/Control group Trial design Analysis (pre-specified vs. post-hoc)

7. Practical aspects of clinical trials Question being studied Trial population/Control group Trial design Analysis (pre-specified vs. post-hoc)

8. Practical aspects of clinical trials Question being studied Trial population/Control group Trial design Analysis (pre-specified vs. post-hoc)

9. Trial populations Explicit and objective inclusion and exclusion criteria are required for any RCT Narrow and restrictive inclusion criteria can allow to focus on a specific group of people and reduce variability in the outcome However, included participants may not be representative of those who may receive the vaccine in the future

10. The need for a control group ‘ Hawthorn effect ’ : observation that patients in clinical trials generally do better than similar patients on same treatment (closer monitoring, clear treatment plan, enthusiastic team, etc.) Therefore, a control group provides the opportunity to see ‘ what would have happened without the new intervention ’

11. The need for randomisation Patient allocation to new intervention or control groups is determined purely by chance Thus, any differences between the different arms of the trial are due to chance alone This includes both known and unknown factors Thus, provided individuals are treated similarly during the study period, any differences in outcome between the two groups can be attributed to the intervention

12. Practical aspects of clinical trials Question being studied Trial population/Control group Trial design Analysis (pre-specified vs. post-hoc)

13. Blinding Bias can occur if a patient or treatment team are aware of treatment allocation Patient: psychological effect on behaviour Clinical team: intensity of counselling

14. Types of RCTs Parallel group: each patient is randomised to receive only one of the two different strategies Crossover trial: each patient receives first one treatment strategy then the other, but the treatment order is randomised Cluster randomised: each ‘ cluster ’ of patients (hospitals, outpatient clinics) randomised to receive one of the two different treatment strategies

15. Parallel design trials Randomisation New intervention Control group Present time Compare treatment groups Follow individuals Starting point

16. Cross-over trials Randomisation New Intervention Control group Present time Future time Follow individuals Starting point New Intervention Control group Wash out

17. Crossover trial Crossover trials are particularly useful for short term outcomes in chronic conditions The treatment must be one that does not permanently alter the disease or condition under study The main limitation of a crossover trial is that the effect of the first treatment administered may carry over and alter subsequent responses

18. Cluster randomised trials Randomisation of Hospital/Clinic New Intervention All patients at hospital/clinic receive new intervention All patients at hospital/clinic receive new intervention Control group

19. Clinical Trials at AIDS Vaccine ‘09

20. SS01-02 Clinical outcomes from the STEP study Background 3,000 men and women 3 doses of MRKAd5 gag/pol/nef vaccine or placebo Vaccinations stopped after a pre-specified interim analysis in Ad5 seronegative participants demonstrated no protective effect on HIV acquisition or early plasma viral load Further analysis demonstrated an increased hazard ratio (HR) for HIV acquisition among Ad5 seropositive and uncircumcised vaccinees vs. placebo recipients

21. SS01-02 Clinical outcomes from the STEP study Objective To compare rates of HIV acquisition among vaccine vs. placebo recipients Methods Pre-unblinding data were frozen as of Oct 17, 2007; Post-unblinding data are from Oct 18, 2007 through January 23, 2009

22. SS01-04 Interim efficacy analysis of Phambili study Background Step sister study conducted in South Africa In September 2007, because of results of the Step study, vaccinations were suspended but follow up Objective To compare rates of HIV acquisition among vaccine vs. placebo recipients Methods Pre-unblinding and post-unblinding data 801 participants enrolled, 7% received all 3 study injections; 66% received two; and 27% received one

23. OA04-01 Safety and immunogenicity of LIPO-5, a HIV-1 lipopeptide vaccine Background The vaccine includes 5 long peptides, containing multiple CD8+ and CD4+ T-cell epitopes Phase 1 studies have shown that vaccine dosage at 500µg/lipopeptide elicits cellular immune responses Objective Investigate if HIV-LIPO5 immunogenicity varies with the dosage Methods ELISpot and PBMC lymphoproliferation were assessed at baseline, two weeks after each injection, and at week 48

24. OA04-02 Strong HIV-specific CD4 and CD8 T-lymphocyte proliferation in HIV-1 DNA prime/ modified vaccinia virus Ankara (MVA) heterologous boost vaccinees OA04-03 Characterization of cell-mediated immune responses generated by recombinant modified vaccinia Ankara (rMVA)-HIV-1 in a phase I vaccine trial

25. OA04-05 Safety and viral load changes in HIV-1 infected subjects treated with autologous dendritic immune therapy following ART discontinuation Background In a phase 1 trial, immunotherapy consisting of a monocyte-derived dendritic cells and RNA encoding autologous HIV antigens derived from the patient’s own pre-ART plasma induced immunogenicity in most patients Objective Assess the safety and proportion of patients demonstrating viral load < 1000, <5000 and <10,000 copies/mL during the 12 week ART structured treatment interruption (STI)

26. TAKE HOME MESSAGES

27. Take home message # 1 How to interpret what scientists predict a trial will show

28. “ All predictions are difficult, particularly when they involve the future ” Dan Quayle Former US Vice-President

29. Take home message # 2 How to interpret what reputable scientists mean when they criticize trials that will be conducted by other reputable scientists

30. “If we knew what we are doing, we wouldn't call it research.” – Albert Einstein

31. Take home message # 3 How to interpret what scientists say they have learned from a trial

32. “Half of what we have taught you is wrong. Unfortunately, we do not know which half.” – C. Sidney Burwell, M.D. Address to the graduation class Harvard Medical School

33. Merci ! Thank You ! Obrigado !