1. Mapping standards of care in trials of microbicides or the diaphragm Global Campaign for Microbicides Katharine Shapiro Microbicides 2008 February 24-27 New Delhi, India

2. Thanks… International and site level investigators and staff International and site level investigators and staff Katie West, Lori Heise, Sean Philpott U.S. Agency for International Development

3. Overview INTRODUCTION The Global Campaign The Global Campaign Standards of care (SOC) definitions and debates Standards of care (SOC) definitions and debates THE SOC MAPPING EXERCISE Goals Goals Methods Methods Findings Findings Conclusions and recommendations Conclusions and recommendations

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

5. The evolution of standard of care A concept imported from medicine - what a reasonable physician should provide in order not to be negligent A concept imported from medicine - what a reasonable physician should provide in order not to be negligent Applied to research, especially to describe care provided to people in control arm of a RCT Applied to research, especially to describe care provided to people in control arm of a RCT While ethics debate on SOC has been primarily about RCTs or provision of ART to seroconverters, we use SOC here to describe 1. the care and prevention services offered during a clinical trial (study-related and ancillary care) 2. the care available in the local community/host country

6. The importance of context “A suitable SOC can only be defined in consultation with those who work in country…and should reflect SOC that can be effectively delivered in host country during research and on sustainable basis” Nuffield Council, 2002. “A suitable SOC can only be defined in consultation with those who work in country…and should reflect SOC that can be effectively delivered in host country during research and on sustainable basis” Nuffield Council, 2002.

7. What defines standards? ‘Best available care’ has never been well-defined in medicine. ‘Best available care’ has never been well-defined in medicine. Standards of care vary within and between developed and developing countries according to Standards of care vary within and between developed and developing countries according to provider knowledge, comfort, training and belief, provider knowledge, comfort, training and belief, local resources and context local resources and context ability of the patient to pay. ability of the patient to pay.

8. The SOC debates Erupted in 1997 over controversial trials of nevirapine to prevent mother to child transmission of HIV in developing countries Erupted in 1997 over controversial trials of nevirapine to prevent mother to child transmission of HIV in developing countries The ethics of using a placebo when a proven regimen to prevent transmission existed in the United States were questioned The ethics of using a placebo when a proven regimen to prevent transmission existed in the United States were questioned Debate is embedded in unequal distribution of wealth between countries sponsoring research and those hosting it. Debate is embedded in unequal distribution of wealth between countries sponsoring research and those hosting it.

9. Ethical questions that plague HIV prevention trials Is it ethically obligatory for trials to improve SOC while conducting research? Is it ethically obligatory for trials to improve SOC while conducting research? Whose obligation is it? Whose obligation is it? Should trials fund ART for seroconverters? Should trials fund ART for seroconverters? What is the obligation to provide care to women found HIV+ at screening who cannot enroll? What is the obligation to provide care to women found HIV+ at screening who cannot enroll? Are dual SOC are problem? Are dual SOC are problem?

10. Dual standards of care Dual SOC between sponsoring and host country Dual SOC between sponsoring and host country Dual SOC between sites within one multi-site trial Dual SOC between sites within one multi-site trial Dual SOC between what the research facility provides and what the local community can provide Dual SOC between what the research facility provides and what the local community can provide

11. Conflicting ethics guidance Declaration of Helsinki: Best current standard should be used, but a placebo can be justified in certain specific circumstances. Declaration of Helsinki: Best current standard should be used, but a placebo can be justified in certain specific circumstances. NBAC: Recommends established, effective treatment regardless of local availability. (U.S.) NBAC: Recommends established, effective treatment regardless of local availability. (U.S.) Nuffield Council: Emphasizes current standard local treatment. (U.K.) Nuffield Council: Emphasizes current standard local treatment. (U.K.)

12. Conflicting ethics guidance CIOMS: While care essential to the research is obligatory; other care is “morally praiseworthy” CIOMS: While care essential to the research is obligatory; other care is “morally praiseworthy” UNAIDS Ethical considerations in biomedical HIV prevention trials (2007): Participants who seroconvert should be provided access to treatment from among regimens internationally recognized as optimal. UNAIDS Ethical considerations in biomedical HIV prevention trials (2007): Participants who seroconvert should be provided access to treatment from among regimens internationally recognized as optimal. And… prevention trials ought to contribute constructively to development of HIV service provision in participating countries for sustainable provision of care and treatment after a trial. And… prevention trials ought to contribute constructively to development of HIV service provision in participating countries for sustainable provision of care and treatment after a trial.

13. The SOC mapping exercise Despite lengthy debates, information on how researchers and sites were addressing these issues on the ground in different countries and contexts has been limited Despite lengthy debates, information on how researchers and sites were addressing these issues on the ground in different countries and contexts has been limited Empiric evidence from the field could inform discussion among all stakeholders on trial ethics, & generate ideas for future trial design Empiric evidence from the field could inform discussion among all stakeholders on trial ethics, & generate ideas for future trial design

14. Goals of SOC mapping Document progress made by researchers toward meeting ethical guidance and aspirations Document progress made by researchers toward meeting ethical guidance and aspirations Compare context-specific challenges in provision of care and prevention Compare context-specific challenges in provision of care and prevention Describe different SOC strategies and how sites implemented them Describe different SOC strategies and how sites implemented them

15. Methods Development of survey guide with input from investigators and staff Development of survey guide with input from investigators and staff Desk review of 7 study protocols & international and site-level documents (SOPs, manuals) Desk review of 7 study protocols & international and site-level documents (SOPs, manuals) In depth interviews with international investigators and sponsors In depth interviews with international investigators and sponsors Visits to a sample of 6 sites and community clinical facilities in 4 countries Visits to a sample of 6 sites and community clinical facilities in 4 countries In-depth interviews with site trial staff In-depth interviews with site trial staff Consultation in Johannesburg, SA Consultation in Johannesburg, SA

16. Sites included SiteTrialProduct 1. Cape Town, S.A. 2. Shoshanguve, S.A. Population CouncilCarraguard 3. Cotonou, BeninCONRADCellulose sulfate 4. Kwa Zulu Natal S.A. 5. Mwanza, Tanzania Microbicides Development Program Pro 2000Gel 6. Harare, Zimbabwe-HIV Prevention Trials Network -MIRA -BufferGel & Pro 2000 Gel -Diaphragm *Not visited: 7. Nigeria, Ghana Family Health International Savvy in Ghana Cellulose sulfate in Nigeria

17. Range of issues HIV risk reduction HIV risk reduction STI services STI services Cervical screening Cervical screening Contraception Contraception Pregnancy Pregnancy Seroconverter care Seroconverter care Screen-out HIV+ care Capacity building Ancillary care Research related harms Continuity of care

18. Findings: overview of variations - study and site Setting urban urban peri-urban peri-urban rural rural Study facilities mobile clinics in rented rooms mobile clinics in rented rooms stand alone research clinics stand alone research clinics within or adjoining government clinics within or adjoining government clinics

19. Findings: overview of variations - study protocol and site Study populations primary health care clients primary health care clients family planning clients family planning clients bar and hotel workers bar and hotel workers sex workers sex workers Local health services health infrastructure and spending health infrastructure and spending outside funding outside funding

20. Overview of variations - services What services provided: What services provided: study-related care only study-related care only provision of other non study-related care (primary health care) provision of other non study-related care (primary health care) Who services were for: Who services were for: participants only participants only partners and family members of participants; screened out women partners and family members of participants; screened out women Where services were provided: Where services were provided: on site on site by referral by referral nature of referral mechanisms nature of referral mechanisms

21. Variations in study-related services provided All studies provided a comprehensive HIV prevention package with All studies provided a comprehensive HIV prevention package with unlimited RR counseling, comprehensive STI care, condoms, some couples counseling offered unlimited RR counseling, comprehensive STI care, condoms, some couples counseling offered Most provided contraception (often added later) Most provided contraception (often added later) Most provided female condoms, cervical cancer screening, diagnosis and treatment Most provided female condoms, cervical cancer screening, diagnosis and treatment Most provided counseling and STI care for men Most provided counseling and STI care for men One provided an HIV support group One provided an HIV support group

22. Variations in non-study related care provided MDP South Africa: Ancillary care for study participants and families - ill children, childhood immunizations, using supplies from the adjacent DOH-run clinic MDP South Africa: Ancillary care for study participants and families - ill children, childhood immunizations, using supplies from the adjacent DOH-run clinic MDP Mwanza, Tanzania: no ancillary care. Study visits take place in rented rooms where a limited mobile clinic is set up MDP Mwanza, Tanzania: no ancillary care. Study visits take place in rented rooms where a limited mobile clinic is set up Pop Council, South Africa: Little ancillary care. Pop Council, South Africa: Little ancillary care. CONRAD Benin: Complete HIV prevention and care (including ART)to all, but no ancillary care - referral for all non-reproductive health problems. CONRAD Benin: Complete HIV prevention and care (including ART)to all, but no ancillary care - referral for all non-reproductive health problems. HPTN 035 Zimbabwe:. Diagnosis and/or treatment for a limited number of ancillary health concerns (e.g., malaria, minor infections, etc.) provided HPTN 035 Zimbabwe:. Diagnosis and/or treatment for a limited number of ancillary health concerns (e.g., malaria, minor infections, etc.) provided FHI Nigeria and Ghana: Virtually no ancillary care FHI Nigeria and Ghana: Virtually no ancillary care

23. Variations within specific services Cervical cancer screening Cervical cancer screening HIV Care HIV Care

24. Cervical screening Incidence of vaginal & cervical lesions are secondary safety endpoints in trials Incidence of vaginal & cervical lesions are secondary safety endpoints in trials Visual examination of vagina and cervix are required & colposcopy of any lesions to determine if product- related Visual examination of vagina and cervix are required & colposcopy of any lesions to determine if product- related Some sites offer Pap smears to women at enrollment; some to women at study screening, some don’t offer them Some sites offer Pap smears to women at enrollment; some to women at study screening, some don’t offer them Cervical screening is not of much use if a system is not in place to address continuing need for diagnosis, treatment & follow up Cervical screening is not of much use if a system is not in place to address continuing need for diagnosis, treatment & follow up

25. Variations in cervical screening South Africa: free national screening and treatment program but public system overloaded (long waits, losses to referral and f/u) --though women with abnormal results may get more attention Trial participants with abnormal Paps are ensured diagnosis & treatment including transport to referral centers, until trial ends Trial participants with abnormal Paps are ensured diagnosis & treatment including transport to referral centers, until trial ends Women who are not participants get free screening but are referred on to public system Women who are not participants get free screening but are referred on to public system

26. Variations in cervical screening Zimbabwe: limited public services HPTN 035 provides Paps at enrollment and abnormalities are diagnosed, treated and followed by study M.O. HPTN 035 provides Paps at enrollment and abnormalities are diagnosed, treated and followed by study M.O. MIRA did not provide Paps routinely but on participant request MIRA did not provide Paps routinely but on participant request Tanzania: no public services MDP Mwanza does not provide Paps MDP Mwanza does not provide Paps Benin and Nigeria: no public services FHI & CONRAD trials provided no screening - if suspicious lesions found, women referred to private doctors FHI & CONRAD trials provided no screening - if suspicious lesions found, women referred to private doctors

27. Cervical cancer screening Trials improve care for women by raising awareness, screening, training providers (SA - MDP & PC); by providing new services themselves (Zimbabwe HPTN) Trials improve care for women by raising awareness, screening, training providers (SA - MDP & PC); by providing new services themselves (Zimbabwe HPTN) Consensus recommendation: Future trials should at a minimum provide cervical screening if some publicly supported services exist, but where none exist investigators should advocate for and support initiation of services. Trials can contribute by offering training to public sector providers in screening, colposcopy, and low technology techniques such as VIA where approved. Consensus recommendation: Future trials should at a minimum provide cervical screening if some publicly supported services exist, but where none exist investigators should advocate for and support initiation of services. Trials can contribute by offering training to public sector providers in screening, colposcopy, and low technology techniques such as VIA where approved.

28. Variations in care for participants who became HIV+ All but 1 trial allowed women to continue in study and receive study related care All but 1 trial allowed women to continue in study and receive study related care All provided ‘assisted referrals’ to govt. HIV/AIDS services - level of assistance varied All provided ‘assisted referrals’ to govt. HIV/AIDS services - level of assistance varied Some trials offered Some trials offered WHO clinical staging WHO clinical staging baseline lab evaluations (CD4, LFTs) baseline lab evaluations (CD4, LFTs) 1 study actually provided funds up front for ART when needed in future 1 study actually provided funds up front for ART when needed in future

29. Variations in care for HIV+ women screened out All studies offered extra post-test counseling and referral; All studies offered extra post-test counseling and referral; All studies but 1 provided STI screening and/or treatment to woman and partner; All studies but 1 provided STI screening and/or treatment to woman and partner; Some provided WHO staging and CD4counts ; Some provided WHO staging and CD4counts ; One provided an HIV+ support group; One provided an HIV+ support group; One provided the same care (incl. ART) to everyone - screened out and seroconverting participants and the community One provided the same care (incl. ART) to everyone - screened out and seroconverting participants and the community All were increasingly concerned and responsive to need for services for women screened out All were increasingly concerned and responsive to need for services for women screened out

30. Different strategies for care Population Council Carraguard SA - independent research clinics, study-related care, only for participants (except STIs); relied on referral, implemented a SOC study Population Council Carraguard SA - independent research clinics, study-related care, only for participants (except STIs); relied on referral, implemented a SOC study MDP SA Pro2000 - research clinics co-located with govt. services, benefited from PEPFAR funding secured by the research center, directly provided PHC for women and families MDP SA Pro2000 - research clinics co-located with govt. services, benefited from PEPFAR funding secured by the research center, directly provided PHC for women and families MDP Tanzania Pro2000 - mobile clinics for high risk mobile women - study related-care only, primarily for participants MDP Tanzania Pro2000 - mobile clinics for high risk mobile women - study related-care only, primarily for participants MIRA diaphragm Zimbabwe - largely study-related care only in a research only clinic; implemented SOC study MIRA diaphragm Zimbabwe - largely study-related care only in a research only clinic; implemented SOC study

31. Strategies for care (2) HPTN 035 BufferGel & Pro2000 Zimbabwe - research clinics on government clinic grounds; some PHC (ancillary care) provided HPTN 035 BufferGel & Pro2000 Zimbabwe - research clinics on government clinic grounds; some PHC (ancillary care) provided CONRAD CS Benin - complete study related and HIV/AIDS care to all high risk women and men including ART, regardless of study participation. Referrals for all other care, in most cases not paid for by study. ART for seroconverters funded before study began. CONRAD CS Benin - complete study related and HIV/AIDS care to all high risk women and men including ART, regardless of study participation. Referrals for all other care, in most cases not paid for by study. ART for seroconverters funded before study began. FHI Nigeria CS and Ghana Savvy - most study visits in health posts with limited study-related care, no ancillary care. FHI Nigeria CS and Ghana Savvy - most study visits in health posts with limited study-related care, no ancillary care.

32. Some cross-cutting issues Fragile health systems Fragile health systems Sensitivity about dual SOC and ‘undue inducement’ Sensitivity about dual SOC and ‘undue inducement’ Weak referral mechanisms Weak referral mechanisms Partnerships to provide care Partnerships to provide care Location of trial sites - co-location with other facilities vs. stand-alone research clinics or mobile clinics Location of trial sites - co-location with other facilities vs. stand-alone research clinics or mobile clinics Male partner involvement Male partner involvement

33. Conclusion (1) Sites providing the most comprehensive care allocated resources from the start, formed working partnerships with government, and co-located research with public facilities. Sites providing the most comprehensive care allocated resources from the start, formed working partnerships with government, and co-located research with public facilities.

34. Recommendation (1) Future trials should seek opportunities to co- locate or partner with existing local care facilities before a trial begins. This can facilitate easier access to referral services for participants, strengthen opportunities for care- related synergies and build long-term SOC capacity in the host community. Future trials should seek opportunities to co- locate or partner with existing local care facilities before a trial begins. This can facilitate easier access to referral services for participants, strengthen opportunities for care- related synergies and build long-term SOC capacity in the host community.

35. Conclusion (2) Microbicide trials provide an example of high quality integrated SRH, HIV/AIDS and often primary care within deprived settings that can ‘ratchet up’ SOC in communities, and help meet ethical aspirations. Microbicide trials provide an example of high quality integrated SRH, HIV/AIDS and often primary care within deprived settings that can ‘ratchet up’ SOC in communities, and help meet ethical aspirations.

36. Recommendation (2) HIV prevention researchers, sponsors and donors should make every effort to use microbicide trials as an opportunity to strengthen and improve local standards of care and services in host communities, and host countries where possible. The minimum objective should be to incrementally improve care in a sustainable fashion to reduce global disparities in health. HIV prevention researchers, sponsors and donors should make every effort to use microbicide trials as an opportunity to strengthen and improve local standards of care and services in host communities, and host countries where possible. The minimum objective should be to incrementally improve care in a sustainable fashion to reduce global disparities in health.

37. Conclusion (3) There were no sites where community was consulted about what SOC should be provided until after a study had been designed and implemented. There were no sites where community was consulted about what SOC should be provided until after a study had been designed and implemented.

38. Recommendation (3) All future studies should explicitly define standard of care that will be provided - the broad elements of care can be described in the protocol, while site specific elements can be written into site standard operating procedures. Community voices should be sought and integrated into SOC decision making at every stage of the trial design and implementation. All future studies should explicitly define standard of care that will be provided - the broad elements of care can be described in the protocol, while site specific elements can be written into site standard operating procedures. Community voices should be sought and integrated into SOC decision making at every stage of the trial design and implementation.

39. Thank you!