ART and Medical Care in the Context of Prevention Trials: Who Is Responsible?

United States Department of Health and Human ServicesNational Institutes of Health ART and Medical Care in the Context of Prevention Trials: Who Is Responsible? Paolo G. Miotti, M.D. 3rd IAS Conference Rio De Janeiro July 26, 2005

DHHS/NIH/OD/OAR Main Points • Background • Positions and Guidelines • Issues

DHHS/NIH/OD/OAR • Background

DHHS/NIH/OD/OAR HIV Prevention Trials • Examples of HIV prevention trials: • Behavioral and social interventions • Microbicides • Vaccines • MTCT • Male circumcision • Other biomedical interventions (PEP, PrEP, etc.)

DHHS/NIH/OD/OAR Issue of ART/Medical Care: Not Limited to Trials • Randomized controlled trials (experimental) • Other types of studies (observational)

Antiretroviral Treatment (ART) and Medical Care • Expansion in number of treatment and care programs for people with HIV/AIDS • More treatment and prevention research • Changing relationship between health research and health care

Four Principles That Guide Bioethical Decision-making • Beneficence • Non-maleficence • Autonomy • Justice

DHHS/NIH/OD/OAR • Positions and Guidelines

“…it is necessary during the study planning process to identify post-trial access by study participants to prophylactic, diagnostic and therapeutic procedures identified as beneficial in the study or access to other appropriate care.” Declaration of HelsinkiClarification to paragraph 30, 2004

“…researchers should endeavour before the initiation of a trial to secure post-trial access for effective interventions for participants in the trial and that the lack of such arrangements should have to be justified to a research ethics committee.” Nuffield Council on Bioethics, 2005

“People who seroconvert during the course of HIV prevention trials should be assured access to high quality HIV care, including antiretroviral treatment (ART) when they need it. Trial sponsors should commit to assuring the availability of such care either directly or through explicit and durable partnerships with other care providers. Such agreements should be formalized before a trial starts in consultation with host governments, sponsors, and trial communities.” Global Campaign forMicrobicides, 2005* *Draft Consensus Points

“As an initial commitment, IAVI will support the provision of ART, when clinically indicated for participants who become infected during the trial, for a period of 5 years after the start of such treatment is recommended. ART and care will be supported through the establishment of an Escrow Account. IAVI will actively seek collaborations with and commitments from other stakeholders to sustain long-term treatment and care.” International AIDS Vaccine Initiative (IAVI), 2005

ANRS • Commitment that participants during trials will receive treatment and care (also for illnesses that may not be focus of trial) • National country programs will provide ART when required • People becoming HIV infected during trials must be eligible for ART through national programs; if this is not assured, trial will not be funded by ANRS

Medical Research Council (MRC) • Will only choose sites where infrastructure exists to complement study concerning ART and care • Participants identified as HIV infected at enrolment or during study will be referred to local structures

U.S. Department of Health and Human Services: CDC, NIH • CDC: • For research in developing countries, ART is provided when part of addressing the scientific question. • For other situations, research participants are referred to treatment programs. • NIH: • For research in developing countries, ART is provided when part of addressing the scientific question. • Guidance and Q&A for grant/contract applicants available in NIH Guide. It specifically applies to provision of ART after the end of NIH-supported ART trials in developing countries.

“The Wellcome Trust expects the research protocol to include proposals for any necessary post-research health monitoring related to the volunteer’s participation and considers this a responsibility of the principal investigator.” Wellcome Trust, 2005

DHHS/NIH/OD/OAR • Issues

Misconceptions About Medical Care and Research • A large proportion of people think that joining a research trial will provide a direct therapeutic benefit (“therapeutic misconception”) • The “therapeutic misconception” blurs the dividing line between research and health care

ART/Health Care in Context of Prevention Trials • The issue: • long-term provision of ART/care after the end of a prevention trial to participants acquiring HIV during trial

Providing and Securing Access to ART/Health Care After End of Trials • For whom: • Participants in entire HIV prevention trial? • Participants in prevention trial for any length of time? • HIV infected mothers in MTCT prevention trials? • Partners, family members? • Individuals screened for HIV prevention trial, but not enrolled because found HIV positive? • For how long: • Lifetime? • 5 years, 10 years, use situation-specific criteria?

Whose responsibility? • Trials funders (public and/or private)? • Host country governments? • Researchers? • International organizations (e.g., GFATM, PEPFAR)? • All of the above?

What Health Care Should Be Provided to Research Participants? • Same level available to general population • Often inadequate • Higher level • Possible undue inducement • Research used as a conduit to health care

Gradations of EngagementExamples • Minimal engagement: • Screening only (for example) • Medium engagement: • Screening, one intervention, one or two follow-ups • High engagement: • Long-duration study with many interactions From: Henry S. Richardson, Ph.D., Georgetown University

Grading Ancillary Care Responsibility - Examples Vaccine trial participants Maternal-fetal trial subjects Importance of HIV status to trial Microbicide trial participants Those screened out Degree of Engagement From: Henry S. Richardson, Ph.D., Georgetown University

Complex Research Environment: Interaction of All Stakeholders Is Needed Community Researchers Research participants Funders

“No guidance document can eliminate the necessity of identifying relevant issues on the ground and then engaging in a process of description, analysis, and balancing of the ethical tension inherent to them.” MacQueen, et al. (HPTN), BMJ, 2003 Ethics Guidance for HIV Prevention Trials

Thank you

U.S. Department of Defense • $1 million for treatment and care of HIV seroconverters in the Thai vaccine trial. • First funds have been placed in account to go to Thai MOH for eventual years of therapy

“…trial participants must be provided with treatment and care for HIV/AIDS and its associated complications if they become HIV infected during the course of an HIV preventive vaccine trial.” MRC South Africa, 2005

Council for International Organizations of Medical Sciences (CIOMS), 2002 “…The sponsors' obligations in particular studies should be clarified before the research is begun. The research protocol should specify whathealth-care serviceswill be made available, during and after the research, to the subjects themselves, to the community from which the subjects are drawn, or to thehost country, and for how long. Although sponsors are, in general, not obliged to provide health-care services beyond that which is necessary for the conduct of the research, it is morally praiseworthy to do so. Such services typically include treatment for diseases contracted in the course of the study. It might, for example, be agreed to treat cases of an infectious disease contracted during a trial of a vaccine designed to provide immunity to that disease, or to provide treatment of incidental conditions unrelated to the study.”

NIH Guidance for Post-ART Trials • In selection of sites for ART trials, priority may be given “to sites where sources are identified for the provision of ART following the completion of the trial” • Limited to HIV treatment trials assessing the safety and efficacy of ART (not prevention or co-infection trials) • Applies after participant’s completion of the trial • Objective: to prevent negative health effects, which include increased risk of death

NIH Guidance - Implementation • Guidance published on the NIH Guide for Grants and Contracts • Questions & Answers posted on web site maintained by NIH • OAR Work Group will periodically review submitted plans to assure consistency across NIH institutes

Ancillary Care • “Ancillary care” • Care not required to address scientific questions or assess safety • Ancillary care for HIV/AIDS • Focus on provision of ARVs in non-treatment trials (trials in which ARVs are not the experimental treatment)

Complex Research Environment: Interaction of All Stakeholders is Needed Research participants Researchers Funders Community

Overview Is the claim within thescopeof entrustment? There is no responsibility to provide ancillary care NO Is the claim sufficiently strong? YES NO YES There is a responsibility to provide ancillary care

Ancillary Care:Two Polar Positions • Researchers as personal physicians: • They owe research participants same care they would provide to their patients • Researchers as pure scientists: • They do not owe ancillary care to research participants, as they are not the researchers’ patients

Council for International Organizations of Medical Sciences (CIOMS), 2002 “…if an investigational drug has been shown to be beneficial, the sponsor should continue to provide it to the subjects after the conclusion of the study, and pending its approval by a drug regulatory authority. The sponsor is unlikely to be in a position to make a beneficial investigational intervention generally available to the community or population until some time after the conclusion of the study, as it may be in short supply and in any case cannot be made generally available before a drug regulatory authority has approved it.”

Gradations of ScopeHIV/AIDS Examples • HIV status is not within scope when no permissions are needed regarding it. • HIV status is minimally within scope when HIV+ status is an exclusion criterion. • HIV status is clearly within scope when the study calls for monitoring it. • HIV status is centrally within scope when it is a study endpoint. From: Henry S. Richardson, Ph.D., Georgetown University

Determine Scope of Entrustment • The nature of a study largely fixes scope. • What is entrusted depends on what permissions must be given for the study to go forward safely and validly. • Scope typically will include: • Dealing with the “subject’s condition” (e.g., HIV/AIDS) • Following up on diagnoses (e.g., of HIV/AIDS). From: Henry S. Richardson, Ph.D., Georgetown University

ART and Medical Care in the Context of Prevention Trials: Who Is Responsible?