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	Outline 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
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
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	2 Parallel Controls Advantages Disadvantages 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
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
29
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
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	2 Parallel Controls Advantages Disadvantages 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
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?