Regulatory Considerations for Approval: FDA perspective

1. Regulatory Considerations for Approval: FDA perspective Charu Mullick, MD Medical Officer, Division of Antiviral Products Center for Drug Evaluation and Research, FDA 9th IAS Conference on HIV Science, Paris July 26, 2017

2. Assessing efficacy of investigational PrEP products • Regulatory framework • Adequacy of clinical trial data • Role of in vitro and in vivo data • Considerations for future clinical trial designs

3. Legal Effectiveness Requirement Requirement for “Substantial evidence…that the drug will have the effect it purports or is represented to have… under the conditions of use…as recommended or suggested in the proposed labeling” [FD&C Act sec 505(d)] FDA Guidance for Industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products

4. Substantial evidence in the context of HIV PrEP • Animal models • Currently, no validated model • Ex vivo models • Promising Need for clinical data  PrEP trials • Phase 1 data to assess safety • Sufficient HIV endpoints to discern protective effects in Phase 3 • Safety database to ensure tolerability • Other populations

5. Basis for Approval - Truvada • Large Phase 3 trials • Double-blind RCTs, adequate and well-controlled • Favorable benefit-risk assessment • Overall data from trials supported broad labeling indication for both at-risk men and women

6. Trial Designs • Very large sample size • Long time to recruit, obtain HIV endpoint data  Substantial delays in PrEP development and approval

7. Oral Contraceptive Trials • Single arm trial • Use OC Pearl Index • Measure that is used to summarize contraceptive effectiveness • Based on historical evidence and confidence that vaginal sex leading to pregnancy will be occurring with a reliable frequency in a population/time period

8. PrEP trials Consideration for rectal STI incidence as a correlate or benchmark of HIV incidence in MSM

9. Hypothetical Scenario: Patterns of STI and HIV Incidences 30% 30% Rec STI Rec STI Expected HIV incidence with this rectal STI incidence: ~10% 10% HIV 1% Case 2

10. Rectal STI-HIV Association • Quantify and validateassociation in MSM • Use data from previous trials where individuals were not on prophylaxis • Association will predict the point estimate of HIV incidence that is expected for the observed rectal STI incidence in a future trial Rec STI Rec STI HIV HIV

11. Future Trial Design Implications • HIV incidence on investigational PrEP would be expected to be substantially lower than the lower bound of the quantitative estimate • Active controls could still be used for safety comparisons and an efficacy comparison (although underpowered) • Contingent on validating the rectal STI/HIV association

12. Limitations to Approach • Needs to be validated • Sufficient data to obtain a quantitative association • Manydata points frommultiple databases • Variable frequency of STI testing in older databases • May be less frequent than the current standard • Diagnostic assays for STIs in older databases • ? Less sensitive than currently used • Impact of successful Treatment as Prevention on recent HIV rates

13. Summary • We recognize the challenges with designing HIV PrEP trials • We are interested in working towards designing feasible and scientifically valid trials • Rectal gonorrhea/chlamydia incidence in MSM population can potentially serve as a benchmark that is predictive of HIV incidence – with trial design implications • Currently in exploration phase; the association is not yet validated • Similarly, benchmarks or HIV correlates identified in women could facilitate PrEP trial designs in women

14. Acknowledgements Jeff Murray Debra Birnkrant Kim Struble Pete Miele Thank you