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

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

Responsibilities of state, community and private sector on research ethic Policy : looking back on recent CCR5 antagonists 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> is correlated with bad prognosis Concording results were found in other cohorts (MACS, Eurosida, ANRS CO4 / FHDH) CD : these patients must benefit from both a validated HAART and a thorough follow up Naive patients : generic denomination, but heterogenous situations Early testing, high CD4 level, moderate viral load (Stage A) More advanced patients, 200<CD4<350 VL< (Stage B) Late testing, advanced patients with CD4<200 High viral load (StageC)

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 Lab and drug Inclusion criteria limits CD4 countViral load Shering Plough « vicriviroc » >150 CD4/mm3no Pfizer « maraviroc » No criteriano GSK « aplaviroc » >100 CD4/mm3no

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 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

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)

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.

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

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