1. International Research Ethics: Issues in Prevention Trials Steve Morin, Ph.D. AIDS Policy Research Center AIDS Research Institute University of California, San Francisco http://ari.ucsf.edu/policy/policy.htm

2. NIH Funding for International AIDS Research, FY 1996-2004 Source: Fauci, NIAID, 2003

3. The Community-Based VCT Prevention Trial F HPTN 043: A Phase IIB Randomized Trial to Evaluate the Efficacy of Community-Based HIV Voluntary Counseling and Testing to Reduce HIV Seroincidence (funded by NIMH). F 32 communities in Africa (Tanzania, Zimbabwe, and South Africa) and 14 communities in Thailand will be randomized to either a community-based HIV voluntary counseling and testing (CBVCT) intervention or clinic-based standard VCT (SVCT).

4. Background F Most HIV infections are in sub-Saharan Africa, yet only a small fraction of Africans know their HIV status. F Voluntary HIV Counseling and Testing (VCT) is an effective method of promoting behavior change, but utilization of VCT is still low in African communities with a high prevalence of HIV.

5. Zimbabwe Harare ~25% of sexually active Zimbabwean adults are infected with HIV, yet a small percentage know their HIV status

6. Community-Based VCT F Intervention has three major strategies: v to make VCT more available in community settings v to engage the community through outreach; and v to provide post-test support. F These three strategies are designed to change community norms and reduce risk for HIV infection among all community members, irrespective of whether they participated directly in the intervention.

7. The road to market in Epworth

8. Mobile VCT Pilot Study F Offered free, anonymous VCT from a mobile caravan F Rotated once a week to 6 sites in Epworth F Rapid tests were performed (15 minutes) F Testers were offered the option to wait for results outside the caravan or return on another day

9. “Plan for Tomorrow -- Get HIV Tested Today”

10. Setting up the caravan for VCT at the Solani Marketplace in Epworth

11. Counselors and outreach worker ready for action

12. What’s different about international research? F Vast disparities in wealth between sponsor and host countries F Limited resources in host country F History of exploitation

13. Anticipating Ethical Issues

14. What are the ethical issues? F Research questions and priorities F Interventions for control group F Post-trial access to interventions F Informed consent F IRB review

15. Research questions and priorities F Helsinki v“a reasonable likelihood that [study populations] stand to benefit from the results” F NBAC v“limited to those studies that are responsive to the health needs of the host country”

16. Response F The CBVCT question emerged from prior research in Tanzania and Kenya. F Issue is considered important to key stakeholders in revising the National AIDS Control Plan. F It addresses both an important behavioral science question and a need of the host country.

17. Interventions for control group F Helsinki v“Best current prophylactic, diagnostic, and therapeutic methods” vRejected “highest attainable and sustainable” standard F NBAC vEffective treatment preferred, but current (no) care may be justified to meet host country health needs

18. Response F The standard of care (SOC) for VCT as a prevention intervention was established in the Tanzania and Kenya trial. F In the control arm of this trial, we establish the same clinic-based VCT as SOC. F SOC was chosen over “available care” for scientific as well as ethical reasons.

19. Post-trial access to interventions F Helsinki vSubjects “should be assured of access to the best proven prophylactic, diagnostic, and therapeutic methods identified by the study F NBAC v“Reasonable, good faith efforts” to provide access to participants vAddress access issues in planning vNegotiate agreements in advance

20. Response F Representative from the Zimbabwe Ministry of Health National AIDS Control Program serves as an investigator. F USAID involved in planning and primary VCT contractor serves as technical advisor. F CDC involved in planning and developing laboratory measures for assessing primary endpoint.

21. Informed Consent F Communicate information von multiple levels (community, family, individual) vin multiple formats (oral, written) vover time F Assess participant’s understanding

22. Response F Involved local researchers in developing the informed consent documents. F Developed Community Advisory Board that reviewed consent documents and process. F Modified US approaches to be reduce miscommunication. F Integrated concepts of informed consent into pre-test counseling.

23. Where does HIV Prevention Research Fit in the Big Picture?

24. Coverage of Antiretroviral Therapy in Developing Countries, 2002 (Adults by Region) Source: Fauci, NIAID, 2003

25. Total Federal HIV/AIDS Spending by Category FY 2002 Source: Kaiser Family Foundation, 2003

26. Total Federal HIV/AIDS Spending by Department of Agency FY 2002 Source: Kaiser Family Foundation, 2003

27. The President’s Emergency Plan for AIDS Relief Source: Fauci, NIAID, 2003

28. The International Mother and Child Prevention Initiative Source: Fauci, NIAID, 2003

29. President’s Emergency Plan for AIDS Relief: Funding Breakdown Source: Fauci, NIAID, 2003

30. NIH Mission 1) Foster fundamental creative discoveries, innovative research strategies, and their applications as a basis to advance significantly the Nation’s capacity to protect and improve health; 2) Develop, maintain, and renew scientific human and physical resources that will assure the Nation’s capability to prevent disease; 3) Expand the knowledge base in medical and associated sciences in order to enhance the Nation’s economic well- being and ensure a continued high return on the public investment in research; and 4) Exemplify and promote the highest level of scientific integrity, public accountability, and social responsibility in the conduct of science.

31. Planning for Unanticipated Ethical Challenges

32. Community Advisory Boards F Represent community -- bridge, link, go-between, liaison -- make suggestions about protocols F Safeguard/protect the community -- clearinghouse for ethical issues -- promote respect for participants F Legitimize research in communities -- respond to misinformation, provide access

33. “That is why you saw us coming to look in, when the caravan came … people could see that I was also involved in this project and that they should not try anything because I am here and we are the ones who have brought this project. We were giving ourselves accolades...you thought you had the accolades but we were the ones who had them! We want to tell you … we were telling people we brought the project so that they could embrace it, there was no problem my children (referring to staff).” Barbara Mangwende, Chair of the Epworth CAB Community leaders play an important role, as they facilitate access to the local community, as well as understanding and acceptance of research.

34. Bread F Challenge: Many participants coming for pilot study were weak from hunger. Nurse raised issue of whether we can feed them bread? F Should the research study feed them?

35. Response F Extensive discussion in counseling supervision session and consultation with other projects. F Determined that offering food would be coercive under the circumstances; referral to food programs would be more appropriate. F Providing food (incentive) would also change the study -- would no longer be testing whether changing community norms leads to increased awareness of status and decreased new infections.

36. Antiretroviral Therapy F Challenge: HIV drugs are not generally available. Referral options are limited. Treatment advocates, some developing country researchers, and some at NIH have suggested it is “unethical” to conduct HIV testing if the researchers do not provide treatment. F What should the researchers do?

37. Response F Conducted focused discussion of the issue with local CAB. F Consensus was that VCT was of benefit to participants and community even in absence of treatment. F Providing treatment would also change the study - - would no longer be testing whether changing community norms leads to increased awareness of status and decreased new infections.

38. HPTN Guidance F Prevention trials should make “practically achievable” effective prevention methods “reasonably available” to all people screened or enrolled -- VCT & condom availability. F In conducting research in settings where standards of HIV care are poor, consider opportunities to contribute to the local infrastructure.

39. What should investigators do? F Raise and address issues vExpect close scrutiny and harsh criticism vJustify design proactively vPlan for potential criticisms F Make good-faith, reasonable efforts vInvolve host country scientists, community leaders, political leaders F Seek US and host country review and consider community consultation

40. Acknowledgements F National Institute of Mental Health (NIMH) and Office of AIDS Research (OAR) F Leslie Wolf, JD & Bernard Lo, MD, UCSF Program in Medical Ethics and CAPS Policy & Ethics Core F Epworth Community Advisory Board and Epworth Local Board F Community Working Group & Ethics Working Group, HIV Prevention Trials Network F Zimbabwe Investigators: Gertrude Khumalo- Sakutukwa, Katherine Fritz, Tinofa Mutevedzi, Taurai Vaki and Owen Mapfumo