1. Topical Microbicides Antiviral Drugs Advisory Committee August 20, 2003

2. Topical Microbicides Definition –Drug or biologic product for the reduction of transmission of HIV and/or other STIs, applied topically –Varied formulations, +/- device –With or without spermicidal activity –Vagina or rectum as route of administration prior to intercourse

3. Topical Microbicides Ideal Characteristics –Non-irritating –Discreet Odorless Tasteless Colorless –Stable in most environments –Affordable Safe and Effective

4. Topical Microbicides Classes of Drugs –Surfactants –Buffering agents –Chemical barriers –Entry inhibitors –Nucleoside and non-nucleoside reverse transcriptase inhibitors

5. Adults and Children Estimated to be Living with HIV/AIDS, end of 2002 Total: 42 million Western Europe 570 000 North Africa & Middle East 550 000 Sub-Saharan Africa 29.4 million Eastern Europe & Central Asia 1.2 million South & South-East Asia 6 million Australia & New Zealand 15 000 North America 980 000 Caribbean 440 000 Latin America 1.5 million East Asia & Pacific 1.2 million

6. Regional HIV/AIDS Statistics and Features, end of 2002 Epidemic started Sub-Saharan Africa North Africa & Middle East South and South-East Asia East Asia & Pacific Latin America Caribbean Eastern Europe & Central Asia Western Europe North America Australia & New Zealand late ’70s early ’80s late ’80s late ’70s early ’80s late ’70s early ’80s early ’90s late ’70s early ’80s late ’70s early ’80s late ’70s early ’80s 29.4 million 550 000 6.0 million 1.2 million 1.5 million 440 000 1.2 million 570 000 980 000 15 000 8.8% 0.3% 0.6% 0.1% 0.6% 2.4% 0.6% 0.3% 0.6% 0.1% 58% 55% 36% 24% 30% 50% 27% 25% 20% 7% Hetero Hetero, IDU IDU, Hetero, MSM MSM, IDU, Hetero Hetero, MSM IDU MSM, IDU MSM, IDU, Hetero MSM Adults & children living with HIV/AIDS Adult prevalence rate * % of HIV- positive adults who are women Main mode(s) of transmission for those living with HIV/AIDS ** Adults & children newly infected with HIV 3.5 million 83 000 700 000 270 000 150 000 60 000 250 000 30 000 45 000 500 Epidemic started

7. Global Summary of the HIV/AIDS Epidemic, end of 2002 Global Summary of the HIV/AIDS Epidemic, end of 2002 Number of people living with HIV/AIDS Total42 million Adults38.6 million Women19.2 million Children under 15 years3.2 million People newly infected with HIV in 2002 Total5 million Adults4.2 million Women2 million Children under 15 years800 000 AIDS deaths in 2002 Total3.1 million Adults2.5 million Women1.2 million Children under 15 years610 000

8. Injection drug use 32% Heterosexual transmission 66% 32% Heterosexual transmission 66% Estimated* AIDS Incidence in Women and Adolescent Girls, by Exposure Category, Diagnosed in 2001, United States * Data adjusted for reporting delays and estimated proportional redistribution of cases initially reported without risk. Data reported through June 2002. ** Includes patients whose medical record review is pending; patients who died, were lost to follow-up, or declined interview; and patients with other or undetermined modes of exposure. † Includes sex with a bisexual male, a person with hemophilia, a transfusion recipient with HIV infection, or an HIV- infected person with an unspecified risk Other/not identified** 3% † Sex with men of other or unspecified risk 50% Sex with injection drug user 16%

9. Topical Microbicides Areas of Discussion –trial design phase 2/3 run-in vs other designs single trial vs 2 adequate and well controlled trials –control arms and criteria of a “win” placebo and no-treatment controls –trial duration capture efficacy endpoints, assess durable treatment effect and have long term safety experience

10. Clinical Trial Design Issues in the Development of Topical Microbicides for the Reduction of HIV Transmission 8 :30 a.m. HIV and STIs in Women: Salim Karim, MBChB, Ph.D. The Urgent Need for an Efficacious University of Natal Microbicide Durban, South Africa 8:50 a.m. Lessons Learned from COL-1492, Lut Van Damme, M.D., MSc. a Nonoxynol-9 Vaginal Gel Trial Contraceptive Research and Development Program (CONRAD) Arlington, VA 9:10 a.m. Considerations for Topical Teresa C. Wu, M.D., Ph.D. Microbicide Phase 2 and 3 Trial Medical Officer Designs, a Regulatory Perspective DAVDP, FDA 9:30 a.m.Considerations for Topical Andrew Nunn, M.D. Microbicide Phase 2 and 3 Trial Medical Research Center Designs, an Investigator’s London, UK Perspective 10:25 a.m.Statistical Considerations for Thomas Fleming, Ph.D. Topical Microbicide Phase 2 and Chair, Department of Biostatistics 3 Trial Designs, an Investigator’s University of Washington Perspective Seattle, WA 10:50 a.m.Statistical Considerations for Rafia Bhore, Ph.D. Topical Microbicide Phase 2 and Mathematical Statistician 3 Trial Designs, a Regulatory Division of Biometrics, FDA Perspective