1. www.global-campaign.org Lori Heise Background and Purpose of Consultation

2. www.global-campaign.org Overview Intro to GCM and our role in ethics and accountability Overview of microbicides and the challenges of HIV prevention trials Evolution of ethical thinking on access to HIV care and treatment in trials Goals and ground rules for today’s meeting

3. www.global-campaign.org The Global Campaign for Microbicides works to: Mobilize demand and investment for research and development of new HIV prevention technologies, especially for women Conduct policy advocacy for development, testing, access, and use Ensure that as science proceeds, public and community interests are fully protected -- Accountability

4. www.global-campaign.org

5. GCM’s unique role We are independent and non-aligned with any product or sponsor We focus on community and user needs and perspectives We are dedicated to building a new model for how to do ethical research in partnership with community Capacity building of civil society is a key part of our mission

6. www.global-campaign.org GCM Role in Trial Ethics Forge consensus around ethical debates that could delay progress Help negotiate the fine line between urgency of the HIV epidemic and need for rigorous ethical standards Build capacity in the activist/civil society sector for ethical deliberation and debate

7. www.global-campaign.org Prior Consultations Ethical Challenges in Microbicide Trials (1997) Ethical Roadmap (2002) Access to HIV treatment GCM/IAVI (2003) Enrolling adolescents in trials (2007)

8. www.global-campaign.org That gel is doing wonders for my complexion! I’m sure that gel is protecting me. It is even giving me more energy ! I know that nice nurse must be giving me the real gel! Training of advocates & community

9. www.global-campaign.org What type of HIV prevention interventions are being tested? Microbicides –Substances that can reduce the transmission of HIV and other STD pathogens when applied vaginally and, possibly, rectally Vaccines PrEP –Once a day prophylactic pill (tenofovir or Truvada) Herpes treatment (acyclovir)

10. www.global-campaign.org HIV Prevention Trial Results 2006 2008200920102007 Microbicide - BufferGel, PRO2000 Oral TDF - IDU HSV-2 Treatment - Infectiousness 2013 Index Partner Treatment Vaccine - Prime/Boost Oral Truvada - Heterosexual Oral TDF -MSM (Phase II) Microbicide - Tenofovir Gel Microbicide - Savvy Microbicide - Cellulose Sulfate Male Circumcision - Infectiousness Oral TDF - West Africa (Phase II) Vaccine - Adenovirus Step/Phambili Female Barrier - Diaphragm HSV-2 Treatment Oral Truvada - MSM Male Circumcision - Susceptibility HSV-2 Treatment - Susceptibility Microbicide - Carraguard Microbicide - PRO2000 IPM Dapivirine Launch

11. www.global-campaign.org Update on Microbicides

12. www.global-campaign.org Eventually, microbicides could come in many forms First generation products will be gels applied with an applicator Future formulations could include vaginal rings or sponges that could be left in for weeks at a time

13. www.global-campaign.org Laboratory Testing 2-6 Years Phase 3 (efficacy) 1 to 4 Years Simultaneous studies in some cases: HIV+, penile & rectal safety 10 or more years Multiple Phase 1 (safety / PK) 2 weeks to 3 months Phase 2 (safety) 6-12 month 25 –200 people 200-800 people 3,000-10,000 people The Microbicide Clinical Trial Process Phase 2B (intermediate) Up to 2-3 Years 1500-3,000 people

14. www.global-campaign.org Early-stage concepts Pre-clinical development (~30 candidates) 5 in early human safety trials 3 in large-scale efficacy trials Adapted from Alliance for Microbicide Development, Microbicide Watch 2006 The Product Pipeline May 2008

15. www.global-campaign.org Multiple Mechanisms of Action Broad Spectrum Blocking Agents Vaginal Defense Enhancers Membrane Disrupting Agents HIV-Specific (ARVs) Entry inhibitors Replication inhibitors Early GenerationNext Generation

16. www.global-campaign.org Next Generation ARV-based Microbicides Advantages –Highly potent and HIV specific –Documented safety and efficacy as treatment –Can be formatted for sustained protection Monthly vaginal ring; daily gel Disadvantages –Potential for resistance –Not contraceptive or effective against other STIs Could create need for 2 nd line therapies

17. www.global-campaign.org Special Challenges of HIV Prevention Trials Complex clinical trial design Healthy individuals -- yet at “high risk” Often involved marginalized or stigmatized populations (sex workers, IDU, MSM) Stigma associated with HIV and sexual activity Transnational research collaborations

18. www.global-campaign.org Basic Design for Microbicide Effectiveness Trials (Phase III) Recruit Condoms, STD treatment + product Condoms, STD treatment + placebo Screening visit: HIV, PAP, pregnancy testing Randomize Informed Consent Enrollment visit: STD treatment Informed Consent 1 2

19. www.global-campaign.org Typical phase HIV prevention trial Background HIV prevalence among population being enrolled –30 to 40 percent Ratio of those screened to enrolled –4 or 5 to 1 Expected HIV endpoints in trial –70 to 250 Most participants who seroconvert in HIV prevention trials will not need ARVs for many years until after the trial is over

20. www.global-campaign.org Access to HIV Care and Treatment At GCM ethics meeting in 1997, the issue of access to HIV treatment was not even on the agenda No viable government-run treatment programs existed in resource-poor countries Assumption was that women who became infected during a trial (or screened out as positive) would be referred for counseling, and palliative care.

21. www.global-campaign.org Changing Expectations and Opportunities What changed between 1997 and 2007? –Global commitment to expand treatment coverage to developing world (WHO 3x5; PEPFAR) –Creative agreements to lower cost of drugs for resource-poor countries –Easier to tolerate drugs & regimens –Global debate on the ethics of transnational research trials

22. www.global-campaign.org Challenging Questions for HIV Prevention Trials Is it ethically obligatory for trials to provide access to HIV treatment and care while conducting research? How long does this obligation last? Who should pay for treatment and care of those who seroconvert? What is the obligation to provide care to women found to be HIV-positive at screening?

23. www.global-campaign.org Back drop of ethical debate Controversy over peri-natal AZT trials UNAIDS consultations on ethics of HIV vaccine trials –Regional consultations reaching different conclusions Extensive discussion among ethicists & academics (obligatory or praiseworthy?) Uneven (and evolving) availability of ART in Africa

24. www.global-campaign.org r “ “We will not let Cambodians be used as guinea pigs…” Cambodian prime minister

25. www.global-campaign.org What does ethical guidance say? CIOMS (2002) Guideline 21 Comments : Seroconverters: Sponsors are … not obliged to provide health care services beyond that which is necessary for the conduct of the research…[nonetheless], it is morally praiseworthy to do so. Screened-Out: [Volunteers] who cannot be enrolled in a study because they do not meet health criteria … should be advised to obtain or should be referred to appropriate care.

26. www.global-campaign.org Early UNAIDS guidance reflects lack of consensus UNAIDS Vaccine Guidance (2000) –“Care and treatment for HIV/AIDS and its associated complications should be provided to participants in HIV preventive vaccine trials, with the ideal being to provide the best proven therapy and the minimum to provide the highest level of care attainable in the host country”

27. www.global-campaign.org GCM Consensus meeting on Standard of Care (2003) Researchers should ensure access to HIV care & treatment, including ARVs HIV care should extend beyond ARVs Special obligation to attend to SRH needs of participants

28. www.global-campaign.org WHO/UNAIDS Inter-current Infections Meeting (2003) Funding mechanisms that will ensure continued treatment and care should be fully discussed and agreed on by the participating organizations

29. www.global-campaign.org UNAIDS/WHO Guidance (2007) UNAIDS (2007) Guidance Point 16: Seroconverters: Participants who seroconvert should be provided access to treatment from among regimens internationally recognized as optimal.. All Participants and the Community: Prevention trials ought to contribute … to development of HIV service provision in participating countries for sustainable provision of care and treatment after a trial.

30. www.global-campaign.org Needs of HIV positive Individuals Counseling & support Viral load/CD4 OI prophylaxis Nutritional support ART Drug monitoring All immediately Screened out Some immediately

31. www.global-campaign.org Needs of HIV positive Individuals Counseling & support Viral load/CD4 OI prophylaxis Nutritional support ART Drug monitoring During trial Seroconvert After trial

32. www.global-campaign.org Focus of this meeting Operational questions –Not here to debate limits of ethical obligation –Focus on how to operationalize care Special emphasis on: –Access to ART (although we recognize the full continuum of care needs) –Care needs after the end of a trial

33. www.global-campaign.org Options we will Explore Referral Buying into existing care system (e.g. workplace program) Insurance Enrolling in other trials Trust funds Others?

34. www.global-campaign.org Meeting Assumptions We are here in an open spirit of exploration No one has the answers yet… Everyone is committed to participant well being