Trials Accelerating Research : Approaches that Work XVI International Aids Conference Toronto Canada 13-18 August 2006

1. Responsibilities of state, community and private sector on research ethic Policy : looking back on recent CCR5 antagonistsHugues Fischer, TRT-5 (French Cab), Act Up-Paris, Paris, France Trials Accelerating Research : Approaches that Work XVI International Aids Conference Toronto Canada 13-18 August 2006

2. Responsibilities of state, community and private sector on research ethic Policy : looking back on recent CCR5 antagonists Issues : • The early years of the fight against AIDS saw a redefinition of roles and responsibilities between state, civil society and private sector on research priorities and research ethics • Yet, though greatly improved, the resulting compromise system created for ensuring appropriate protection of research participants is not perfect • This poster will explore activities and changes needed to reach a higher level of protection assurance for clinical research participants looking back on recent CCR5 antagonist polemic that opposed the French CAB TRT-5, to 3 pharmaceuticals companies : Pfizer, Schering-Plough and GSK

3. Responsibilities of state, community and private sector on research ethic Policy : looking back on recent CCR5 antagonists Naive patients : generic denomination, but heterogenous situations • Art Cohort Collaboration : Higher risk of clinical evolution (on a 3 years comparison basis) in patients initiating validated HAART with CD4<200 • British Columbia cohort : Initiation of HAART when VL> 100 000 is correlated with bad prognosis Concording results were found in other cohorts (MACS, Eurosida, ANRS CO4 / FHDH) • CD4 <200 and/or VL > 100 000 : these patients must benefit from both a validated HAART and a thorough follow up

4. Responsibilities of state, community and private sector on research ethic Policy : looking back on recent CCR5 antagonists Phase II CCR5-antagonist trials in 2005 Dose determination trials

5. Responsibilities of state, community and private sector on research ethic Policy : looking back on recent CCR5 antagonists Phases II trials : At this step, what was known on ARV associations including anti-CCR5 drugs? KNOWN • In vitro data and animal testing results • Tolerability in healthy volunteers • Phase I results : drop of viral load following a 7-10 days anti-CCR5 monotherapy (same order of magnitude as observed with other ARV) among 60-80 patients with high CD4 (>400) • In vitro, evidence of resistance mutations UNKNOWN • Efficacy and tolerance of anti-CCR5 in combination with other ARV; drug interactions with anti-OI medicines • Anti-CCR5 efficay and tolerance on periods longer than 10d • Appropriate doses and administration schedule • CCR5/CXCR4 switch and consequences on clinical evolution

6. Responsibilities of state, community and private sector on research ethic Policy : looking back on recent CCR5 antagonists Were there enough data to include advanced naive patients in Phase II trials? • Due to the lack of mid-term data concerning association of anti-CCR5 and other ARV, there was a clear risk of sub-optimal treatment administration in these clinical trails, mainly implying following risks : • Early failure for naive advanced patients initiating treatment in the late phase of the disease • Clinical degradation/ resistance appearance • Psychological impact following first treatment failure : • Discouragment and depression • Loss of confidence in therapy • Lack of adherence • Risk of increased Serious Adverse Events (IRS, drug interactions with OI medicines)

7. Responsibilities of state, community and private sector on research ethic Policy : looking back on recent CCR5 antagonists TRT-5 position • Evaluation of putative risk/benefit ratio based on available data suggested that inclusion of naive advanced patients in these phase II clinical trials was far too risky. • Patients’ interest did not favor their participation in these early trials. More insight should be gained in stage A patients before inclusion of naive advanced patients in new class products trials.

8. Responsibilities of state, community and private sector on research ethic Policy : looking back on recent CCR5 antagonist Recommendations « There is no good science where there is no good ethics » • In medical research on human, considerations related to the well-being of the human subject should take precedence over the interests of science and society.(Declaration of Helsinki, article 5)… Although these interests are not necessarily antagonistic. • There is no contradiction between the TRT-5 position and the fight of this group for early drug access for experienced patients with complete therapeutic failure. • French ethics and expertise in HIV field should promote guidelines which could be internationally called and used • Although in this presentation, we focused on entry criteria, there were many more parameters in these trials which compromised people security

9. Meet the TRT5 : Exibition hall, booth G-471, FRANCE this afternoon from 2:30 to 4:30