Microbicides in Clinical Trials: A Detailed Look

1. Microbicides in Clinical Trials: A Detailed Look Polly F. Harrison, PhD Director, Alliance for Microbicide Development

2. 3 carefully planned stages of clinical trials are done prior to regulatory approval. Let�s briefly define each clinical trial phase. Phase 1: purpose is to determine the maximum safe dose of drug. Small numbers of participants are used (10-100 people), typically healthy-- Phase 1 trials, in particular are carried out in small numbers of healthy women at low risk of HIV or STI infection who are evaluated for systemic toxicity and local evidence of damage to the vaginal and cervical epithelium. However, these trials provide limited safety info. Because relatively few subjects are used. Phase 2: to evaluate the type and number of people to be included in the final phase of testing; gives preliminary estimates of effective doses and treatment duration. Phase 3: to determine whether treatment is effective and, what side effects are present. Additional clinical phases are a phase 1/2 and a phase 2/2B, the latter unique to microbicides. A Phase I/II study is generally a small study focused only on product safety. Depending on the product being tested, a Phase I/II also may include dose-ranging assessments to try to determine the optimal dosing for the product (e.g., once a day, twice a day, coitally). A Phase II/IIb study includes an initial component (the Phase II portion of the study) that is focused on product safety and then continues into the Phase IIb component that focuses on both product safety and product effectiveness. It is important to note that a Phase IIb study provides a direct estimate of product effectiveness. Since the concept of a Phase IIb study is new to many people, many think that a Phase IIb study is "just a large safety study" but that is not correct. 3 carefully planned stages of clinical trials are done prior to regulatory approval. Let�s briefly define each clinical trial phase. Phase 1: purpose is to determine the maximum safe dose of drug. Small numbers of participants are used (10-100 people), typically healthy-- Phase 1 trials, in particular are carried out in small numbers of healthy women at low risk of HIV or STI infection who are evaluated for systemic toxicity and local evidence of damage to the vaginal and cervical epithelium. However, these trials provide limited safety info. Because relatively few subjects are used. Phase 2: to evaluate the type and number of people to be included in the final phase of testing; gives preliminary estimates of effective doses and treatment duration. Phase 3: to determine whether treatment is effective and, what side effects are present. Additional clinical phases are a phase 1/2 and a phase 2/2B, the latter unique to microbicides. A Phase I/II study is generally a small study focused only on product safety. Depending on the product being tested, a Phase I/II also may include dose-ranging assessments to try to determine the optimal dosing for the product (e.g., once a day, twice a day, coitally). A Phase II/IIb study includes an initial component (the Phase II portion of the study) that is focused on product safety and then continues into the Phase IIb component that focuses on both product safety and product effectiveness. It is important to note that a Phase IIb study provides a direct estimate of product effectiveness. Since the concept of a Phase IIb study is new to many people, many think that a Phase IIb study is "just a large safety study" but that is not correct.

3. Here is a map of current microbicide clinical trial sites.Here is a map of current microbicide clinical trial sites.

4. current microbicide clinical trials This is the same map with all microbicide clinical trials taking place today. This is the same map with all microbicide clinical trials taking place today.

5. Currently, there are 16 unique microbicide candidates in some phase of clinical development. This table depicts each microbicide candidate furthest along. For example, you will see in the next slide that Carraguard� is in both a phase 1 and a phase 3. In this table we only count Carraguard� once, in phase 3 because the purpose of this table is to give a total number of microbicide candidates in clinical development. Currently, there are 16 unique microbicide candidates in some phase of clinical development. This table depicts each microbicide candidate furthest along. For example, you will see in the next slide that Carraguard� is in both a phase 1 and a phase 3. In this table we only count Carraguard� once, in phase 3 because the purpose of this table is to give a total number of microbicide candidates in clinical development.

6. Here we have an overview of all current clinical trials. Going back to my previous example, Carraguard�, you see it is in both a phase 1 and a phase 3.Here we have an overview of all current clinical trials. Going back to my previous example, Carraguard�, you see it is in both a phase 1 and a phase 3.

7. phase 1 clinical trials Let�s take a closer look at these clinical trials. First we have those microbicide candidates in phase 1 or safety studies. Mechanisms of action: categories may be revised; in discussion. Please note a minor error in your presentation handout. For Carraguard� phase 1 it is in Thailand/ Chiang Rai not India. Let�s take a closer look at these clinical trials. First we have those microbicide candidates in phase 1 or safety studies. Mechanisms of action: categories may be revised; in discussion. Please note a minor error in your presentation handout. For Carraguard� phase 1 it is in Thailand/ Chiang Rai not India.

8. phase 1 clinical trials (cont.) Phase 1 continuedPhase 1 continued

9. phase 1 clinical trials (concl.) Phase 1 continuedPhase 1 continued

10. On to phase 1/2. On to phase 1/2.

11. Next we have those in phase 2 or expanded safety studies. Next we have those in phase 2 or expanded safety studies.

12. Now, I would like to take the opportunity to focus on late-stage clinical development which includes phases 2/2B and 3. Now, I would like to take the opportunity to focus on late-stage clinical development which includes phases 2/2B and 3.

13. overview of late-stage clinical trials 5 microbicide candidates, entering into 6 large-scale clinical trials mechanisms of action: 1 acid buffer (BufferGel�) 1 entry & fusion inhibitor (PRO 2000) 2 adsorption inhibitors (Carraguard�, Cellulose sulfate) 1 surfactant (Savvy�) total of 30,458 women to be enrolled This is a pivotal year for microbicide research and development- we have 5 microbicide candidates entering into 6 large-scale clinical trials. Of those 5, there are one each of an acid buffer- maintains an acidic vaginal pH, entry & fusion inhibitor- prevent virus attachment and adhesion, fusion with target cells, and a surfactant or surface-active agent- inactivates or destroys viruses or bacteria by disrupting their outer envelopes or membranes. The remaining 2 microbicide candidates are adsorption inhibitors- prevent the entry into host target cells (coat the virus and/or target cell through charged interactions). The total number of women to be enrolled in all 6 trials is 30,458. This is a pivotal year for microbicide research and development- we have 5 microbicide candidates entering into 6 large-scale clinical trials. Of those 5, there are one each of an acid buffer- maintains an acidic vaginal pH, entry & fusion inhibitor- prevent virus attachment and adhesion, fusion with target cells, and a surfactant or surface-active agent- inactivates or destroys viruses or bacteria by disrupting their outer envelopes or membranes. The remaining 2 microbicide candidates are adsorption inhibitors- prevent the entry into host target cells (coat the virus and/or target cell through charged interactions). The total number of women to be enrolled in all 6 trials is 30,458.

14. late-stage clinical trials (concl.) primary endpoint is HIV secondary endpoints: BV (BufferGel�, PRO 2000) chlamydia (BufferGel�, Cellulose sulfate, PRO 2000, Savvy�) genital ulcer disease (BufferGel�, PRO 2000) gonorrhea (BufferGel�, Cellulose sulfate, PRO 2000, Savvy�) HSV-2 (BufferGel�, PRO 2000) syphilis (BufferGel�, PRO 2000) trichomoniasis (BufferGel�, PRO 2000) 3 are contraceptive: BufferGel�, PRO 2000, Savvy� clinical trial sites: 11 Africa countries, India (Pune and ?), 1 US site (Philadelphia) All current microbicide candidates in late-stage clinical trials have an HIV primary endpoint. With several secondary endpoints being observed such as bacterial vaginosis (BV), chlamydia, genital ulcer disease, gonorrhea, HSV-2, syphilis, and trichomoniasis. Of the 5 candidates, 3 are contraceptive therefore pregnancy will be an additional secondary endpoint (?) Referring to the clinical site map I showed at the beginning of my presentation these late-stage trials are taking place in 11 African countries, India and 1 US site. All current microbicide candidates in late-stage clinical trials have an HIV primary endpoint. With several secondary endpoints being observed such as bacterial vaginosis (BV), chlamydia, genital ulcer disease, gonorrhea, HSV-2, syphilis, and trichomoniasis. Of the 5 candidates, 3 are contraceptive therefore pregnancy will be an additional secondary endpoint (?) Referring to the clinical site map I showed at the beginning of my presentation these late-stage trials are taking place in 11 African countries, India and 1 US site.

15. phase 2/2B clinical trials More detail about those microbicides in phase 2/2BMore detail about those microbicides in phase 2/2B

16. More detail about those microbicides in phase 3 More detail about those microbicides in phase 3

17. phase 3 clinical trials (concl.) More on phase 3 clinical trials. More on phase 3 clinical trials.

18. PH YOU NEED TO LOOK AT THIS SLIDE AND EDIT IT!!PH YOU NEED TO LOOK AT THIS SLIDE AND EDIT IT!!

19. ethical issues equitable distribution of burdens and benefits -- avoiding exploitation avoiding �wishful thinking� � also known as the �therapeutic misconception� standard of care for trial participants What package of prevention and care should be provided to trial participants? What obligation do we have to those who seroconvert during a trial? �Therapeutic misconception� is refers to the tendency of some research participants to wrongly assume that whatever drug or intervention they are offered must work or be beneficial (or why would it be offered?) �Therapeutic misconception� is refers to the tendency of some research participants to wrongly assume that whatever drug or intervention they are offered must work or be beneficial (or why would it be offered?)

20. brief background and update tenofovir gel in two phase 2 trials in the microbicide pipeline: PRO 2000 and tenofovir gel trial in South Africa tenofovir gel (HPTN 059) trial in Pune, India and Bronx, NY an example: tenofovir PH- REVIEW THE BACKGROUNDER ON TENOFOVIR PH- REVIEW THE BACKGROUNDER ON TENOFOVIR

21. conclusions Conclusions: PH this is what Zeda closed with in her BKK presentation. I assume she will say the same thing. Conclusions: PH this is what Zeda closed with in her BKK presentation. I assume she will say the same thing.

22. acknowledgments Franka N. des Vignes, PhD Program Officer Trisha L. Lamphear, MPH Research Associate Jana C. Bowcut, MPH Research Associate Cecilia D. Fox Administrative Associate Pamela Norick Senior Legislative and Policy Adviser The work of the Alliance has been made possible by the dedication of its participants and contributions from the: � William and Flora Hewlett Foundation, � International Partnership for Microbicides, � Moriah Fund, � Rockefeller Foundation, � Bill and Melinda Gates Foundation through the � Global Microbicide Project, and the generosity of private contributors.

23. visit our continually updated website at: www.microbicide.org or contact the Alliance directly: 8484 Georgia Avenue, Suite 940 Silver Spring, MD 20910 tel: 301-587-9690; fax: 301-588-8390 email: info@microbicide.org