International Research Ethics: Issues in Prevention Trials

International Research Ethics: Issues in Prevention Trials

Steve Morin, Ph.D.Steve Morin, Ph.D.

AIDS Policy Research CenterAIDS Policy Research Center

AIDS Research InstituteAIDS Research Institute

University of California, San FranciscoUniversity of California, San Francisco

http://ari.ucsf.edu/policy/policy.htmhttp://ari.ucsf.edu/policy/policy.htm

NIH Funding for International AIDS Research, FY 1996-2004

NIH Funding for International AIDS Research, FY 1996-2004

Source: Fauci, NIAID, 2003

The Community-Based VCT Prevention Trial

The Community-Based VCT Prevention Trial

HPTN 043: A Phase IIB Randomized Trial to HPTN 043: A Phase IIB Randomized Trial to Evaluate the Efficacy of Community-Based HIV Evaluate the Efficacy of Community-Based HIV Voluntary Counseling and Testing to Reduce HIV Voluntary Counseling and Testing to Reduce HIV Seroincidence (funded by NIMH).Seroincidence (funded by NIMH).

32 communities in Africa (Tanzania, Zimbabwe, 32 communities in Africa (Tanzania, Zimbabwe, and South Africa) and 14 communities in Thailand and South Africa) and 14 communities in Thailand will be randomized to either a community-based will be randomized to either a community-based HIV voluntary counseling and testing (CBVCT) HIV voluntary counseling and testing (CBVCT) intervention or clinic-based standard VCT (SVCT). intervention or clinic-based standard VCT (SVCT).

BackgroundBackground

Most HIV infections are in sub-Saharan Africa, yet Most HIV infections are in sub-Saharan Africa, yet only a small fraction of Africans know their HIV only a small fraction of Africans know their HIV status. status.

Voluntary HIV Counseling and Testing (VCT) is an Voluntary HIV Counseling and Testing (VCT) is an effective method of promoting behavior change, effective method of promoting behavior change, but utilization of VCT is still low in African but utilization of VCT is still low in African communities with a high prevalence of HIV. communities with a high prevalence of HIV.

Zimbabwe

Harare

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

Community-Based VCTCommunity-Based VCT

Intervention has three major strategies: Intervention has three major strategies:

to make VCT more available in community settingsto make VCT more available in community settings

to engage the community through outreach; and to engage the community through outreach; and

to provide post-test support. to provide post-test support.

These three strategies are designed to change These three strategies are designed to change community norms and reduce risk for HIV infection community norms and reduce risk for HIV infection among all community members, irrespective of whether among all community members, irrespective of whether they participated directly in the intervention. they participated directly in the intervention.

The road to market in Epworth

Mobile VCT Pilot StudyMobile VCT Pilot Study

Offered free, anonymous VCT from a mobile Offered free, anonymous VCT from a mobile caravancaravan

Rotated once a week to 6 sites in EpworthRotated once a week to 6 sites in Epworth

Rapid tests were performed (15 minutes)Rapid tests were performed (15 minutes)

Testers were offered the option to wait for results Testers were offered the option to wait for results outside the caravan or return on another dayoutside the caravan or return on another day

“Plan for Tomorrow -- Get HIV Tested Today”

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

Counselors and outreach worker ready for action

What’s different about international research?

What’s different about international research?

Vast disparities in wealth between Vast disparities in wealth between sponsor and host countriessponsor and host countries

Limited resources in host countryLimited resources in host country

History of exploitationHistory of exploitation

Anticipating Ethical Issues

What are the ethical issues?What are the ethical issues?

Research questions and prioritiesResearch questions and priorities

Interventions for control groupInterventions for control group

Post-trial access to interventionsPost-trial access to interventions

Informed consentInformed consent

IRB reviewIRB review

Research questions and prioritiesResearch questions and priorities

Helsinki Helsinki ““a reasonable likelihood that [study a reasonable likelihood that [study

populations] stand to benefit from the results”populations] stand to benefit from the results”

NBAC NBAC ““limited to those studies that are responsive to limited to those studies that are responsive to

the health needs of the host country”the health needs of the host country”

ResponseResponse

The CBVCT question emerged from prior The CBVCT question emerged from prior research in Tanzania and Kenya.research in Tanzania and Kenya.

Issue is considered important to key Issue is considered important to key stakeholders in revising the National AIDS stakeholders in revising the National AIDS Control Plan.Control Plan.

It addresses both an important behavioral It addresses both an important behavioral science question and a need of the host science question and a need of the host country.country.

Interventions for control groupInterventions for control group

HelsinkiHelsinki ““Best current prophylactic, diagnostic, and Best current prophylactic, diagnostic, and

therapeutic methods”therapeutic methods”

Rejected “highest attainable and sustainable” Rejected “highest attainable and sustainable” standardstandard

NBACNBAC Effective treatment preferred, but current (no) Effective treatment preferred, but current (no)

care may be justified to meet host country care may be justified to meet host country health needshealth needs

ResponseResponse

The standard of care (SOC) for VCT as a The standard of care (SOC) for VCT as a prevention intervention was established in prevention intervention was established in the Tanzania and Kenya trial.the Tanzania and Kenya trial.

In the control arm of this trial, we establish In the control arm of this trial, we establish the same clinic-based VCT as SOC.the same clinic-based VCT as SOC.

SOC was chosen over “available care” for SOC was chosen over “available care” for scientific as well as ethical reasons.scientific as well as ethical reasons.

Post-trial access to interventionsPost-trial access to interventions

HelsinkiHelsinki Subjects “should be assured of access to the best Subjects “should be assured of access to the best

proven prophylactic, diagnostic, and therapeutic proven prophylactic, diagnostic, and therapeutic methods identified by the studymethods identified by the study

NBACNBAC ““Reasonable, good faith efforts” to provide access Reasonable, good faith efforts” to provide access

to participantsto participants

Address access issues in planningAddress access issues in planning

Negotiate agreements in advanceNegotiate agreements in advance

ResponseResponse

Representative from the Zimbabwe Ministry Representative from the Zimbabwe Ministry of Health National AIDS Control Program of Health National AIDS Control Program serves as an investigator.serves as an investigator.

USAID involved in planning and primary VCT USAID involved in planning and primary VCT contractor serves as technical advisor.contractor serves as technical advisor.

CDC involved in planning and developing CDC involved in planning and developing laboratory measures for assessing primary laboratory measures for assessing primary endpoint.endpoint.

Informed Consent Informed Consent

Communicate information Communicate information on multiple levels (community, family, individual) on multiple levels (community, family, individual)

in multiple formats (oral, written)in multiple formats (oral, written)

over time over time

Assess participant’s understandingAssess participant’s understanding

ResponseResponse

Involved local researchers in developing the Involved local researchers in developing the informed consent documents.informed consent documents.

Developed Community Advisory Board that Developed Community Advisory Board that reviewed consent documents and process.reviewed consent documents and process.

Modified US approaches to be reduce Modified US approaches to be reduce miscommunication.miscommunication.

Integrated concepts of informed consent Integrated concepts of informed consent into pre-test counseling.into pre-test counseling.

Where does HIV Prevention

Research Fit in the Big Picture?

Coverage of Antiretroviral Therapy in Developing Countries, 2002

(Adults by Region)

Coverage of Antiretroviral Therapy in Developing Countries, 2002

(Adults by Region)

Source: Fauci, NIAID, 2003

Total Federal HIV/AIDS Spending by CategoryFY 2002

Total Federal HIV/AIDS Spending by CategoryFY 2002

Source: Kaiser Family Foundation, 2003

Total Federal HIV/AIDS Spending by Department of Agency

FY 2002

Total Federal HIV/AIDS Spending by Department of Agency

FY 2002

Source: Kaiser Family Foundation, 2003

The President’s Emergency Plan for AIDS Relief

The President’s Emergency Plan for AIDS Relief

Source: Fauci, NIAID, 2003

The International Mother and Child Prevention Initiative

The International Mother and Child Prevention Initiative

Source: Fauci, NIAID, 2003

President’s Emergency Plan for AIDS Relief: Funding Breakdown

President’s Emergency Plan for AIDS Relief: Funding Breakdown

Source: Fauci, NIAID, 2003

NIH MissionNIH Mission1) 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.

Planning for Unanticipated

Ethical Challenges

Community Advisory BoardsCommunity Advisory Boards

Represent community -- bridge, link, go-between, Represent community -- bridge, link, go-between, liaison -- make suggestions about protocolsliaison -- make suggestions about protocols

Safeguard/protect the community -- clearinghouse Safeguard/protect the community -- clearinghouse for ethical issues -- promote respect for for ethical issues -- promote respect for participants participants

Legitimize research in communities -- respond to Legitimize research in communities -- respond to misinformation, provide accessmisinformation, provide access

““That is why you saw us coming to look in, That is why you saw us coming to look in, when the caravan came … people when the caravan came … people could see that I was also involved in could see that I was also involved in this project and that they should not this project and that they should not try anything because I am here and we try anything because I am here and we are the ones who have brought this are the ones who have brought this project. project.

We were giving ourselves accolades...you We were giving ourselves accolades...you thought you had the accolades but we thought you had the accolades but we were the ones who had them! were the ones who had them!

We want to tell you … we were telling We want to tell you … we were telling people we brought the project so that people we brought the project so that they could embrace it, there was no they could embrace it, there was no problem my children (referring to problem my children (referring to staff).”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.

BreadBread

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

Should the research study feed them?Should the research study feed them?

ResponseResponse Extensive discussion in counseling supervision Extensive discussion in counseling supervision

session and consultation with other projects. session and consultation with other projects.

Determined that offering food would be coercive Determined that offering food would be coercive under the circumstances; referral to food under the circumstances; referral to food programs would be more appropriate.programs would be more appropriate.

Providing food (incentive) would also change the Providing food (incentive) would also change the study -- would no longer be testing whether study -- would no longer be testing whether changing community norms leads to increased changing community norms leads to increased awareness of status and decreased new awareness of status and decreased new infections.infections.

Antiretroviral TherapyAntiretroviral Therapy Challenge:Challenge: HIV drugs are not generally available. HIV drugs are not generally available.

Referral options are limited. Treatment advocates, Referral options are limited. Treatment advocates, some developing country researchers, and some some developing country researchers, and some at NIH have suggested it is “unethical” to conduct at NIH have suggested it is “unethical” to conduct HIV testing if the researchers do not provide HIV testing if the researchers do not provide treatment.treatment.

What should the researchers do?What should the researchers do?

ResponseResponse Conducted focused discussion of the issue with Conducted focused discussion of the issue with

local CAB. local CAB. Consensus was that VCT was of benefit to Consensus was that VCT was of benefit to

participants and community even in absence of participants and community even in absence of treatment.treatment.

Providing treatment would also change the study Providing treatment would also change the study -- would no longer be testing whether changing -- would no longer be testing whether changing community norms leads to increased awareness community norms leads to increased awareness of status and decreased new infections.of status and decreased new infections.

HPTN GuidanceHPTN Guidance

Prevention trials should make “practically Prevention trials should make “practically achievable” effective prevention methods achievable” effective prevention methods “reasonably available” to all people screened or “reasonably available” to all people screened or enrolled -- VCT & condom availability.enrolled -- VCT & condom availability.

In conducting research in settings where In conducting research in settings where standards of HIV care are poor, consider standards of HIV care are poor, consider opportunities to contribute to the local opportunities to contribute to the local infrastructure.infrastructure.

What should investigators do?What should investigators do?

Raise and address issuesRaise and address issues Expect close scrutiny and harsh criticismExpect close scrutiny and harsh criticism Justify design proactivelyJustify design proactively Plan for potential criticismsPlan for potential criticisms

Make good-faith, reasonable effortsMake good-faith, reasonable efforts Involve host country scientists, community leaders, Involve host country scientists, community leaders,

political leaderspolitical leaders

Seek US and host country review and consider Seek US and host country review and consider community consultationcommunity consultation

AcknowledgementsAcknowledgements

National Institute of Mental Health (NIMH) and Office of National Institute of Mental Health (NIMH) and Office of AIDS Research (OAR) AIDS Research (OAR)

Leslie Wolf, JD & Bernard Lo, MD, UCSF Program in Leslie Wolf, JD & Bernard Lo, MD, UCSF Program in Medical Ethics and CAPS Policy & Ethics CoreMedical Ethics and CAPS Policy & Ethics Core

Epworth Community Advisory Board and Epworth Epworth Community Advisory Board and Epworth Local BoardLocal Board

Community Working Group & Ethics Working Group, Community Working Group & Ethics Working Group, HIV Prevention Trials NetworkHIV Prevention Trials Network

Zimbabwe Investigators: Gertrude Khumalo-Zimbabwe Investigators: Gertrude Khumalo-Sakutukwa, Katherine Fritz, Tinofa Mutevedzi, Taurai Sakutukwa, Katherine Fritz, Tinofa Mutevedzi, Taurai Vaki and Owen MapfumoVaki and Owen Mapfumo