Considerations for Topical Microbicide Phase 2 and 3 Trial Design: A Regulatory Perspective

1. Considerations for Topical Microbicide Phase 2 and 3 Trial Design: A Regulatory Perspective Teresa C. Wu, M.D., Ph.D. Division of Antiviral Drug Products Food and Drug Administration

2. Pipeline Regulatory Tools Development Nonclinical Phase 1 Phase 2 & 3 Phase 2 & 3 Design Populations Endpoints Controls Level of Effectiveness Statistical Issues (duration,sample size etc): Dr. Bhore Outline

3. Microbicides in Pipeline

4. Mode of Action • Pathogen destruction by detergent-like chemicals • Maintenance of normal vaginal defenses by enhancing natural acidity • Blocking attachment of pathogens to target cells • Inhibition of HIV attachment, entry, reverse transcriptase • Unknown mechanisms

5. Microbicides in Development • ~60 products in the pipeline • ~20 products either planned for or tested in early phases of human testing (Source: Alliance for Microbicide Development, March 2003) • 9 INDs filed • 4 products planned for phase 2 or 3 trials

6. Regulatory Tools for Expediting Development

7. Topical Microbicides Federal Food, Drug, and Cosmetic Act: section 506 (a) Eligible for Fast Track Drug Development Program • Ability to prevent a serious or life-threatening condition • Potential to address unmet medical needs

8. Fast Track Drug Development Program • (Pre-IND consultation), end-of-phase 1, 2-meetings, pre-NDA meeting • Rolling submission of NDA • Priority review (6 months, vs. standard 10 months)

9. Development of Microbicide Products

10. Development Guidelines • The International Working Group on Microbicides (IWGM) Mauck C. et al. AIDS 2001, 15, 857-868 • Rockefeller Microbicide Initiative. Rockefeller Foundation, 2002:84 http://www.rockfound.org

11. Nonclinical Studies • In vitro antiviral activity, cytotoxicity, mode of action, resistance and cross-resistance; impact on vaginal microflora, pathogens causing STIs. • Animal models for demonstrating microbicide antiviral activity have limited utility in selecting compound. • Nonclinical studies to assess safety, general and reproductive toxicity and pk. • Formulation identification, stability, purity and strength

12. Phase 1 Trials • Total ~150-200 • Local and systemic safety • Selection of dose, formulation; assessment of product acceptability • Once, twice daily use for 7-14 days • HIV-negative women; sexually abstinent; then sexually active

13. Phase 2 Trials • Conventionally, several hundred women • Expanded local & systemic safety, acceptability • Microbicide Activity:Proof-of-concept

14. ‘Proof-of-Concept’ • No validated clinical correlates • In microbicide trials, ‘proof-of-concept’ for HIV prevention can only be measured in studies with very large numbers of participants (several thousand)

15. Low HIV Incidence Rates In commercial sex workers (high-risk women) receiving condom counseling: • 3-5/100 person-years (India, Zaire,Rwanda) • 7/100 person-years (Cameroon)

16. Male Condom Promotion & Counseling • ‘Standard of care’; services deemed ethically necessary for all participants. • High levels of condom use will likely further reduce HIV incidence rates.

17. Monthly evaluations • Monthly pelvic exam & safety labs • Colposcopy for subset • Quarterly HIV serology • Quarterly evaluations • Quarterly HIV serology DSMB Review Phase 2 Phase 3 Months 0 3 5 12-24 Phase 2 Run-In Phase 3 Trial

18. Populations • HIV-negative, sexually active, non-pregnant women at risk for HIV/STI in regions with high HIV prevalence • Such rates occur predominantly in developing countries, e.g. in Africa • Enrolling only frequent product users, e.g CSW, safety profile may not be representative of other groups of women • Adolescent (13-17 years), cultural and legal constraints

19. Foreign Data 21CFR 314.106: As sole basis for marketing approval: ‘data are applicable to the U.S. population and U.S. medical practice’

20. U.S. Population • Primary goal: safety profile and acceptability; exposure duration comparable to non-US participants • A subset of U.S. participants in phase 2 run-in phase 3 trial, or • U.S. data derived from contraceptive trials, or STIs prevention trials, e.g. chlamydia prevention in US women

21. Endpoints • Primary: HIV seroconversion, Safety • Secondary: Incidence of STIs (chlamydia, gonorrhea, syphilis, trichomoniasis) Incidence of other reproductive tract infections (BV, vulvovaginal candidiasis) - STIs are important co-factors. - The potential to increase susceptibility to one or more STIs should be assessed.

22. 2 Parallel Control Groups • Placebo group • ‘No-treatment’ group (condom-only)

23. Placebo • The choice of comparator when there is no approved microbicide • Providing blinding, maximizing unbiased estimate of efficacy and safety

24. Placebo • Vehicle of the candidate microbicide Some components may have activity against HIV & bacteria,e.g. carbomer • Universal placebo: unrelated ‘inert’ chemical, gel-like substance; can be used for multiple microbicides trials, has been shown: -In vitro no activity against HIV, bacteria -Safe in limited nonclinical testing

25. Placebo: Uncertainties • Placebo gel itself is a barrier which could have an unknown level of efficacy. • Placebo gel may have an unknown level of local toxicity when used in large numbers of women. Both uncertainties need to be addressed in the presence of a no-treatment control.

26. Placebo - blinding - validate the interpretation of data from microbicide arm No-treatment - placebo may have activity/toxicity - validate the interpretation of data from placebo arm ‘No-treatment’ arm cannot be blinded. Differential dropout rates Differential risk behavior levels Potential gel sharing Cost increase 2 Parallel ControlsAdvantages Disadvantages

27. Effect Size • Consistent condom use: decrease HIV risk by ~85% (NIH, 2001) • Measure incremental benefit offered over ‘imperfect’ (actual) use of condom alone. • In the context of ‘imperfect’ (actual) use of condom, most experts have considered an effect size of 30% to 50% to be acceptable for microbicides.

28. Summary • Phase 2 run-in phase 3 trial design • Population enrolled should be generalizable. Data should be applicable to the U.S. population. • Endpoints: HIV incidence, safety, STIs incidences • 2 parallel controls: placebo, no-treatment • Effect size expected to be 30%-50%in the context of condom promotion

30. Question 1: Design Please comment on the following: A. A phase 2 run-in phase 3 design B. A stand-alone phase 2 targeted at high-risk groups (e.g. CSW), followed by a phase 3 trial(s). Please comment on the feasibility. C. Other alternatives

31. Monthly evaluations • Monthly pelvic exam & safety labs • Colposcopy for subset • Quarterly HIV serology • Quarterly evaluations • Quarterly HIV serology DSMB Review Phase 2 Phase 3 Months 0 3 5 12-24 Phase 2 Run-In Phase 3 Trial

32. Question 2: Controls Please discuss and rank the following design options: A. 3-arm design (microbicide, placebo, and no-treatment) B. 2-arm design (microbicide, placebo) C. 2-arm design (microbicide, no -treatment)

33. Placebo: - blinding - validate the interpretation of data from microbicide arm No-treatment: - placebo may have activity/toxicity - validate the interpretation of data from placebo arm ‘No-treatment’ arm cannot be blinded. Differential dropout rates Differential risk behavior levels Potential gel sharing Cost increase 2 Parallel ControlsAdvantages Disadvantages

34. Question 3: ‘Win’/Success Definition If the committee is in favor of the 3-arm design, please comment on FDA’s definition of a ‘win’/success: The microbicide arm has to show a significantly better reduction in HIV seroconversion rate than both the placebo and no-treatment arms.

35. Question 4: Follow-up Duration - How Long? • On-treatment A. 12 months for every participants B. 24 months for every participants C. Follow-up continues until the last participant enrolled completes 12 or 24 months. D. Less than 12 months. • Need an off-treatment follow-up? If yes, how long?

36. Level of Evidence • For a single large well-controlled trial, does the Committee agree with FDA’s specifications that: - P < 0.001 (2-sided) : Convincing - 0.001 < P < 0.01: Possibly persuasive, if results are consistent across subgroups • What other supportive evidence does the Committee like to have?