1. Peter Karlton 1 Regulatory Challenges A Diversity of Considerations Ethical Cultural Regulatory standards Strained resources Competing priorities Training

2. Peter Karlton 2 The Imperative of Sexual Autonomy Any degree of efficacy is significant if it provides women with increased sexual autonomy, especially in circumstances where a woman has little or no control over the use of condoms.

3. Peter Karlton 3 Tenofovir 1% Gel Unique mechanism of action Absorbed into tissue and blood Prevents virus from growing Applied discretely 12 hours before and after coitus Low dose may reduce chance of resistance May slow progression of disease if women becomes infected

4. Peter Karlton 4 Creams and Gels: Unique Dosage Forms Require specialized training and expertise Unlike solid-oral dosage forms, e.g., Unique physical-chemical properties Specialized manufacturing and controls Compatibility with drug delivery applicators Complex stability characteristics

5. Peter Karlton 5 Opportunity for Collaboration: Academia, Regulatory, Industry Providing regulators with the tools to assess semi-solid dosage forms requires a commitment from both academia and the pharmaceutical industry.

6. Peter Karlton 6 Collaboration with Developing World Health Agencies Major regulatory agencies must work innovatively with developing world health agencies to create uniform guidance on the non-clinical and clinical development of TMs

7. Peter Karlton 7 FDA Guidance on Non-Clinical Development August 20, 2003, Antiviral Drugs Advisory Committee Meeting (Bethesda, MD) Clinical Development of Topical Microbicides: U.S. Regulatory Perspective, Teresa C. Wu, M.D., Ph.D., FDA, March 28-31, 2004, Microbicides 2004 Meeting, London, UK.

8. Peter Karlton 8 Additional Sources of Regulatory Significance Recommendations for the Development of Vaginal Microbicides, International Working Group on Vaginal Microbicides. AIDS. 2001 May 4;15(7):857-68. Recommendations for the Development of Vaginal Microbicides Recommendations for the Nonclinical Development of Topical Microbicides for Prevention of HIV Transmission: An Update. J Acquire Immune Defic Syndr 2004, 36:541-552. Recommendations for the Nonclinical Development of Topical Microbicides for Prevention of HIV Transmission: An Update

9. Peter Karlton 9 Basic Assumptions About ART Registration in the Developing World Abbreviated dossier with summarized information. Known safety and efficacy of Viread and Truvada. Wide use in treatment centers. Physicians made repeated requests. “Not for profit” price structure. FDA approval would have influence.

10. Peter Karlton 10 Impediments to Rapid Review of Registration Dossiers Long delays in review and response time. Iterative and lengthy Q&A process. Requests for detailed CMC information. The unwillingness to accept approval by FDA or pre-qualification by WHO.

11. Peter Karlton 11 Thank you Contact for Peter Karlton: PKARLTON@MSN.COM