Mapping standards of care in trials Mapping standards of care in trials of microbicides or the diaphragmof microbicides or the diaphragm

Global Campaign for MicrobicidesGlobal Campaign for Microbicides

Katharine ShapiroKatharine Shapiro

Microbicides 2008Microbicides 2008

February 24-27February 24-27New Delhi, IndiaNew Delhi, India

Thanks…Thanks…

International and site International and site level investigators level investigators and staff and staff

Katie West, Lori Heise, Katie West, Lori Heise,

Sean PhilpottSean Philpott

U.S. Agency for U.S. Agency for

International International

DevelopmentDevelopment

OverviewOverviewINTRODUCTIONINTRODUCTION The Global CampaignThe Global Campaign Standards of care (SOC) definitions and debatesStandards of care (SOC) definitions and debates

THE SOC MAPPING EXERCISETHE SOC MAPPING EXERCISE GoalsGoals MethodsMethods FindingsFindings Conclusions and recommendationsConclusions and recommendations

The Global Campaign for The Global Campaign for Microbicides works to:Microbicides works to:

Mobilize demand and investment for research Mobilize demand and investment for research and development of new HIV prevention and development of new HIV prevention technologies, especially for womentechnologies, especially for women

Conduct policy advocacy for development, Conduct policy advocacy for development, testing, access, and usetesting, access, and use

Ensure accountability - that as science proceeds, Ensure accountability - that as science proceeds, public and community interests are fully protectedpublic and community interests are fully protected

The evolution of standard of careThe evolution of standard of care

A concept imported from medicine - what a reasonable A concept imported from medicine - what a reasonable physician should provide in order not to be negligent physician should provide in order not to be negligent

Applied to research, especially to describe care Applied to research, especially to describe care provided to people in control arm of a RCTprovided to people in control arm of a RCT

While ethics debate on SOC has been primarily about RCTs While ethics debate on SOC has been primarily about RCTs or provision of ART to seroconverters, we use SOC here or provision of ART to seroconverters, we use SOC here to describeto describe

1.1. the care and prevention services offered during a the care and prevention services offered during a clinical trial (study-related and ancillary care)clinical trial (study-related and ancillary care)

2.2. the care available in the local community/host countrythe care available in the local community/host country

The importance of contextThe importance of context

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

What defines standards?What defines standards?

‘‘Best available care’ has never been well-defined Best available care’ has never been well-defined in medicine.in medicine.

Standards of care vary within and between Standards of care vary within and between developed and developing countries according todeveloped 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.

The SOC debatesThe SOC debates

Erupted in 1997 over controversial trials of Erupted in 1997 over controversial trials of nevirapine to prevent mother to child nevirapine to prevent mother to child transmission of HIV in developing countriestransmission of HIV in developing countries

The ethics of using a placebo when a proven The ethics of using a placebo when a proven regimen to prevent transmission existed in the regimen to prevent transmission existed in the United States were questionedUnited States were questioned

Debate is embedded in unequal distribution of Debate is embedded in unequal distribution of wealth between countries sponsoring research wealth between countries sponsoring research and those hosting it.and those hosting it.

Ethical questions that plague HIV Ethical questions that plague HIV prevention trialsprevention trials

Is it ethically obligatory for trials to improve SOC Is it ethically obligatory for trials to improve SOC while conducting research?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 What is the obligation to provide care to women found HIV+ at screening who cannot enroll?found HIV+ at screening who cannot enroll?

Are dual SOC are problem?Are dual SOC are problem?

Dual standards of careDual standards of care

Dual SOC between sponsoring and host Dual SOC between sponsoring and host countrycountry

Dual SOC between sites within one multi-site Dual SOC between sites within one multi-site trialtrial

Dual SOC between what the research facility Dual SOC between what the research facility provides and what the local community can provides and what the local community can provideprovide

Conflicting ethics guidanceConflicting ethics guidance Declaration of Helsinki:Declaration of Helsinki: Best current standardBest current standard

should be used, but a placebo can be justified in should be used, but a placebo can be justified in certain specific circumstances.certain specific circumstances.

NBACNBAC: Recommends : Recommends established, effective established, effective treatmenttreatment regardless of local availability. (U.S.) regardless of local availability. (U.S.)

Nuffield CouncilNuffield Council: : Emphasizes current standard localEmphasizes current standard local treatment. (U.K.)treatment. (U.K.)

Conflicting ethics guidanceConflicting ethics guidance CIOMSCIOMS: While care essential to the research is : While care essential to the research is

obligatory; other care is “morally praiseworthy”obligatory; other care is “morally praiseworthy” UNAIDS UNAIDS Ethical considerations in biomedical HIV Ethical considerations in biomedical HIV

prevention trialsprevention trials (2007 (2007): Participants who seroconvert ): Participants who seroconvert should be provided access to treatment from among should be provided access to treatment from among regimens internationally recognized as optimalregimens internationally recognized as optimal. .

And… prevention trials ought to contribute And… prevention trials ought to contribute constructively to development of HIV service provision constructively to development of HIV service provision in participating countries for sustainable provision of in participating countries for sustainable provision of care and treatment after a trial.care and treatment after a trial.

The SOC mapping exerciseThe SOC mapping exercise

Despite lengthy debates, information on how Despite lengthy debates, information on how researchers and sites were addressing these researchers and sites were addressing these issues on the ground in different countries and issues on the ground in different countries and contexts has been limitedcontexts has been limited

Empiric evidence from the field could inform Empiric evidence from the field could inform discussion among all stakeholders on trial ethics, discussion among all stakeholders on trial ethics, & generate ideas for future trial design& generate ideas for future trial design

Goals of SOC mappingGoals of SOC mapping

Document progress made by researchers toward Document progress made by researchers toward meeting ethical guidance and aspirationsmeeting ethical guidance and aspirations

Compare context-specific challenges in provision Compare context-specific challenges in provision of care and preventionof care and prevention

Describe different SOC strategies and how sites Describe different SOC strategies and how sites implemented themimplemented them

MethodsMethods Development of survey guide with input from Development of survey guide with input from

investigators and staffinvestigators and staff Desk review of 7 study protocols & international Desk review of 7 study protocols & international

and site-level documents (SOPs, manuals)and site-level documents (SOPs, manuals) In depth interviews with international investigators In depth interviews with international investigators

and sponsorsand sponsors Visits to a sample of 6 sites and community Visits to a sample of 6 sites and community

clinical facilities in 4 countriesclinical facilities in 4 countries In-depth interviews with site trial staffIn-depth interviews with site trial staff Consultation in Johannesburg, SAConsultation in Johannesburg, SA

Sites includedSites included

Site Trial Product

1. Cape Town, S.A. 2. Shoshanguve, S.A.

Population Council Carraguard

3. Cotonou, Benin CONRAD Cellulose 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 GhanaCellulose sulfate in Nigeria

Range of issuesRange of issues

HIV risk reductionHIV risk reduction STI servicesSTI services Cervical screeningCervical screening Contraception Contraception PregnancyPregnancy Seroconverter careSeroconverter care

Screen-out HIV+ careScreen-out HIV+ care Capacity buildingCapacity building Ancillary careAncillary care Research related harmsResearch related harms Continuity of careContinuity of care

Findings: overview of variations - Findings: overview of variations - study and sitestudy and site

SettingSetting urbanurban peri-urbanperi-urban ruralrural

Study facilitiesStudy facilities mobile clinics in rented mobile clinics in rented

roomsrooms stand alone research stand alone research

clinicsclinics within or adjoining within or adjoining

government clinicsgovernment clinics

Findings: overview of variations - Findings: overview of variations - study protocol and sitestudy protocol and site

Study populationsStudy populations primary health care primary health care

clientsclients family planning clientsfamily planning clients bar and hotel workersbar and hotel workers sex workerssex workers

Local health servicesLocal health services health infrastructure health infrastructure

and spendingand spending outside fundingoutside funding

Overview of variations - servicesOverview of variations - services

What services provided:What services provided: study-related care onlystudy-related care only provision of other non study-related care (primary health provision of other non study-related care (primary health

care)care) Who services were for:Who services were for:

participants onlyparticipants only partners and family members of participants; screened out partners and family members of participants; screened out

womenwomen Where services were provided:Where services were provided:

on siteon site by referralby referral nature of referral mechanismsnature of referral mechanisms

Variations in study-related services Variations in study-related services provided provided

All studies provided a comprehensive HIV All studies provided a comprehensive HIV prevention package withprevention package with unlimited RR counseling, comprehensive STI care , unlimited RR counseling, comprehensive STI care ,

condoms, some couples counseling offeredcondoms, some couples counseling offered Most provided contraception (often added later)Most provided contraception (often added later) Most provided female condoms, cervical cancer Most provided female condoms, cervical cancer

screening, diagnosis and treatmentscreening, diagnosis and treatment Most provided counseling and STI care for menMost provided counseling and STI care for men One provided an HIV support groupOne provided an HIV support group

Variations in non-study related care Variations in non-study related care providedprovided

MDP South AfricaMDP South Africa: Ancillary care for study participants and : Ancillary care for study participants and families - ill children, childhood immunizations, using supplies families - ill children, childhood immunizations, using supplies from the adjacent DOH-run clinicfrom the adjacent DOH-run clinic

MDP Mwanza, TanzaniaMDP Mwanza, Tanzania: no ancillary care. Study visits take : no ancillary care. Study visits take place in rented rooms where a place in rented rooms where a limited mobile clinic is set uplimited mobile clinic is set up

Pop Council, South Africa:Pop Council, South Africa: Little ancillary care. Little ancillary care. CONRAD BeninCONRAD Benin: Complete HIV prevention and care (including : Complete HIV prevention and care (including

ART)to all, but no ancillary care - referral for all non-reproductive ART)to all, but no ancillary care - referral for all non-reproductive health problems.health problems.

HPTN 035 Zimbabwe:HPTN 035 Zimbabwe:. Diagnosis and/or treatment for a limited . Diagnosis and/or treatment for a limited number of ancillary health concerns (e.g., malaria, minor number of ancillary health concerns (e.g., malaria, minor infections, etc.) providedinfections, etc.) provided

FHI Nigeria and GhanaFHI Nigeria and Ghana: Virtually no ancillary care: Virtually no ancillary care

Variations within specific Variations within specific servicesservices

Cervical cancer Cervical cancer screeningscreeningHIV CareHIV Care

Cervical screeningCervical screening

Incidence of vaginal & cervical lesions are secondary Incidence of vaginal & cervical lesions are secondary safety endpoints in trialssafety endpoints in trials

Visual examination of vagina and cervix are required Visual examination of vagina and cervix are required & colposcopy of any lesions to determine if product-& colposcopy of any lesions to determine if product-relatedrelated

Some sites offer Pap smears to women at Some sites offer Pap smears to women at enrollment; some to women at study screening, enrollment; some to women at study screening, some don’t offer themsome don’t offer them

Cervical screening is not of much use if a system is Cervical screening is not of much use if a system is not in place to address continuing need for not in place to address continuing need for diagnosis, treatment & follow updiagnosis, treatment & follow up

Variations in cervical screeningVariations in cervical screening

South AfricaSouth Africa: free national screening and treatment : free national screening and treatment program but public system overloaded (long waits, program but public system overloaded (long waits, losses to referral and f/u) --though women with losses to referral and f/u) --though women with abnormal results may get more attentionabnormal results may get more attention

Trial participants with abnormal Paps are ensured Trial participants with abnormal Paps are ensured diagnosis & treatment including transport to referral diagnosis & treatment including transport to referral centers, until trial ends centers, until trial ends

Women who are not participants get free screening Women who are not participants get free screening but are referred on to public systembut are referred on to public system

Variations in cervical screeningVariations in cervical screeningZimbabweZimbabwe: limited public services: limited public services HPTN 035 provides Paps at enrollment and HPTN 035 provides Paps at enrollment and

abnormalities are diagnosed, treated and followed abnormalities are diagnosed, treated and followed by study M.O.by study M.O.

MIRA did not provide Paps routinely but on MIRA did not provide Paps routinely but on participant requestparticipant request

TanzaniaTanzania: no public services: no public services MDP Mwanza does not provide PapsMDP Mwanza does not provide PapsBenin and NigeriaBenin and Nigeria: no public services: no public services FHI & CONRAD trials provided no screening - if FHI & CONRAD trials provided no screening - if

suspicious lesions found, women referred to suspicious lesions found, women referred to private doctors private doctors

Cervical cancer screeningCervical cancer screening Trials improve care for women by raising awareness, Trials improve care for women by raising awareness,

screening, training providers (SA - MDP & PC); by screening, training providers (SA - MDP & PC); by providing new services themselves (Zimbabwe HPTN)providing new services themselves (Zimbabwe HPTN)

Consensus recommendation:Consensus recommendation: Future trials should at Future trials should at a minimum provide cervical screening if some publicly a minimum provide cervical screening if some publicly supported services exist, but where none exist supported services exist, but where none exist investigators should advocate for and support initiation investigators should advocate for and support initiation of services. Trials can contribute by offering training to of services. Trials can contribute by offering training to public sector providers in screening, colposcopy, and public sector providers in screening, colposcopy, and low technology techniques such as VIA where low technology techniques such as VIA where approved.approved.

Variations in care for participants Variations in care for participants who became HIV+who became HIV+

All but 1 trial allowed women to continue in study and All but 1 trial allowed women to continue in study and receive study related carereceive study related care

All provided ‘assisted referrals’ to govt. HIV/AIDS All provided ‘assisted referrals’ to govt. HIV/AIDS services - level of assistance variedservices - level of assistance varied

Some trials offeredSome trials offered WHO clinical stagingWHO clinical staging baseline lab evaluations (CD4, LFTs)baseline lab evaluations (CD4, LFTs)

1 study actually provided funds up front for ART 1 study actually provided funds up front for ART when needed in futurewhen needed in future

Variations in care for HIV+ women Variations in care for HIV+ women screened outscreened out

All studies offered extra post-test counseling and All studies offered extra post-test counseling and referral;referral;

All studies but 1 provided STI screening and/or All studies but 1 provided STI screening and/or treatment to woman and partner;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 - One provided the same care (incl. ART) to everyone -

screened out and seroconverting participants and the screened out and seroconverting participants and the communitycommunity

All were increasingly concerned and responsive to All were increasingly concerned and responsive to need for services for women screened outneed for services for women screened out

Different strategies for careDifferent strategies for care Population Council Carraguard SAPopulation Council Carraguard SA - independent - independent

research clinics, study-related care, only for participants research clinics, study-related care, only for participants (except STIs); relied on referral, implemented a SOC study(except STIs); relied on referral, implemented a SOC study

MDP SA Pro2000MDP SA Pro2000 - research clinics co-located with govt. - research clinics co-located with govt. services, benefited from PEPFAR funding secured by the services, benefited from PEPFAR funding secured by the research centerresearch center,, directly provided PHC for women and directly provided PHC for women and familiesfamilies

MDP Tanzania Pro2000MDP Tanzania Pro2000 - mobile clinics for high risk mobile - mobile clinics for high risk mobile women - study related-care only, primarily for participantswomen - study related-care only, primarily for participants

MIRA diaphragm ZimbabweMIRA diaphragm Zimbabwe - largely study-related care - largely study-related care only in a research only clinic; implemented SOC studyonly in a research only clinic; implemented SOC study

Strategies for care (2)Strategies for care (2)

HPTN 035 BufferGel & Pro2000 ZimbabweHPTN 035 BufferGel & Pro2000 Zimbabwe - research - research clinics on government clinic grounds; some PHC (ancillary clinics on government clinic grounds; some PHC (ancillary care) provided care) provided

CONRAD CSCONRAD CS BeninBenin - complete study related and HIV/AIDS - complete study related and HIV/AIDS care to all high risk women and men including ART, care to all high risk women and men including ART, regardless of study participation. Referrals for all other care, regardless of study participation. Referrals for all other care, in most cases not paid for by study. ART for seroconverters in most cases not paid for by study. ART for seroconverters funded before study began.funded before study began.

FHI Nigeria CS and Ghana SavvyFHI Nigeria CS and Ghana Savvy - most study visits in - most study visits in health posts with limited study-related care, no ancillary care.health posts with limited study-related care, no ancillary care.

Some cross-cutting issuesSome 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 mechanismsWeak referral mechanisms Partnerships to provide carePartnerships to provide care Location of trial sites - co-location with other facilities Location of trial sites - co-location with other facilities

vs. stand-alone research clinics or mobile clinicsvs. stand-alone research clinics or mobile clinics Male partner involvementMale partner involvement

Conclusion (1)Conclusion (1)

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

Recommendation (1)Recommendation (1)

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

Conclusion (2)Conclusion (2)

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

Recommendation (2)Recommendation (2)

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

Conclusion (3)Conclusion (3)

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

Recommendation (3)Recommendation (3)

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

Thank you!Thank you!