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September 01, 2004

Ethical and Legal Issues in AIDS Vaccine Trials

Despite increased interest in HIV/AIDS prevention and treatment in recent years, developing a safe and effective vaccine has proceeded far more slowly than hoped or imagined. Only one vaccine has completed efficacy testing during the epidemic’s twenty-two years. Seth Berkley, Thorny Issues in the Ethics of AIDS Vaccine Trials, 362 THE LANCET 992 (2003). Unfortunately, the results did not warrant the production of the vaccine. Since no disease of global proportions has been eradicated or effectively controlled without a vaccine, implementing a successful AIDS vaccine program is critical. The effort poses not only scientific challenges, however, but also ethical and legal issues.

Ethical Issues

Multicenter AIDS vaccine trials are most efficient where the rates of HIV infection are high. Since more than 95 percent of HIV-positive people live in the developing world, vaccine trial sites must include developing countries in Africa, Asia, and Latin America. Chari A. Maddren, AIDS Vaccines: Balancing Human Rights with Public Health 17 TEMP INT’L & COMP. LJ 277 (2003). In both developed and developing countries, researchers must confront the question of providing medical treatment for vaccinees who become HIV-infected during the trial through normal means of transmission. At issue is the ethical principle of “beneficence,” the obligation to minimize possible harms and maximize possible benefits of medical intervention. At a World Health Organization and United Nations Program on HIV/AIDS (UNAIDS) meeting last year, HIV-1 vaccine researchers supported the notion that antiretrovirals should be provided to trial participants who become infected, but they could not agree on how this should be done. Should the best standard of care be provided, or the best available standard of care? Moreover, if antiretrovirals were provided only to infected trial participants, would that create inequities in host communities and/or an unreasonable inducement to participate in clinical trials? If sponsors are required to provide lifetime care to study participants who become infected, will that reduce sponsors’ interest in doing research in developing countries? Furthermore, will other, less well-financed AIDS research foci, such as microbicide research or research aimed at improving barrier methods, be held to the same standards with respect to care for participants who become infected?

Responding to these questions, some suggest that governments should provide support for follow-up care to communities that participate in this research. Seth Berkley, of the International AIDS Vaccine Initiative, argues that a number of advantages adhere to this community support approach, including (1) avoiding difficult decisions about whether individual patients, as opposed to families, should receive treatment; (2) providing incentives to communities to participate in research; and (3) diminishing the risks that people will be unreasonably induced to participate in research. Berkley, supra.

Informed consent presents other ethical issues with trials in developing countries. In the United States, this doctrine protects and promotes the ethical principle of “autonomy,” or self-governance, by requiring researchers to obtain voluntary informed consent before enrolling participants in research protocols. Informed consent concepts are interpreted differently in other parts of the world, however. In traditional, rural African communities, a form of communitarianism dominates. K. Moodley, HIV Vaccine Trial Participation in South Africa: An Ethical Assessment, 27 J MED. & PHILOS. 197–215 (2002). In this context, research is an altruistic endeavor that benefits communities and societies. Western ethical consent guidelines that emphasize the individual over the community may be difficult to transpose to such a setting.

Language barriers may cause other concerns. One South African study suggested that language may create barriers to informed consent by prospective research participants when there are no local words for “randomization,” “placebo,” or other concepts involved in the scientific design of the research. Salim S. Abdool Karim, Globalization, Ethics and AIDS Vaccines, 288 SCIENCE 2129 (2000).

To address informed consent issues such as language and cultural barriers, the UNAIDS guidelines for HIV vaccine research recommend a process of consultation between community representatives, researchers, sponsors, and regulatory bodies to design an effective informed consent strategy and process. An example of this approach is the advisory board established in rural Hlabisa, South Africa, which has employed eight local people as community liaisons to develop education materials, consult with and inform the community about new research projects, and provide advice to researchers about local needs for the ethical conduct of research. Abdool Karim, supra.

In the United States, additional issues arise with respect to informed consent and especially vulnerable populations—for example, pregnant women and prisoners. Federal regulations governing informed consent in research carry special requirements that must be followed for inclusion of these people in vaccine clinical trials.

Post-trial access to safe and effective vaccines raises questions relating to the ethical principle of “justice,” which refers to the fair distribution of the benefits and burdens of research. To ensure that local communities share any benefit derived from their residents’ participation in studies, some observers have suggested that pharmaceutical companies should commit to a vaccine price of cost plus 10 percent. Abdool Karim, supra. The UNAIDS ethics guidelines recommend that any HIV vaccine demonstrated to be safe and effective should be made available as soon as possible to all research trial participants, as well as other populations at high risk of HIV infection, and that plans at the initial stages of HIV vaccine development ensure the availability of benefits. UNAIDS, ETHICAL CONSIDERATIONS IN HIV PREVENTIVE VACCINE RESEARCH (2000).

Finally, a practical challenge that relates to ethical issues in AIDS vaccine trials abroad is the limited research regulatory framework in some countries. At a recent conference in Cape Town, South Africa, participants from African countries discussed the difficulties they face in creating rigorous ethical review processes, including the lack of research regulation, unavoidable conflicts of interest among the small number of people with skills to be members of research ethics committees, and the lack of opportunities for formal academic training in research ethics. Some have urged the establishment of strong regional and national regulatory bodies to respond to these challenges. Bebe Loff, Africans Discuss Ethics of Biomedical Research, 359 THE LANCET 956 (2000).

Legal Issues

Many of the legal concerns that apply to HIV vaccine trials, and that likely would apply to an approved vaccine, relate to stigma and discrimination against people who are presumed to be infected or are assumed to be at a higher risk for infection because of their participation in vaccine trials. Many countries, including the United States, have legislation that protects people who are HIV infected against discrimination. But what of a person thought to be infected because of a positive test only due to the vaccine? Interpretations of a western blot test—the confirmatory test for HIV—can be read as positive for a person whose vaccine produces antibodies.

Under U.S. law, a person who is perceived to be infected may be protected from certain discriminatory acts under the Americans with Disabilities Act (ADA). However, conflict between agency interpretation of the ADA and the U.S. Supreme Court’s construction of the act leave questions about its protection of AIDS vaccinees with HIV-positive tests stemming from vaccine-induced antibodies. Moreover, even if applicable, the ADA’s protection cannot eliminate the stigma of a positive HIV test, allow blood donation, change travel requirements to countries for which an HIV test is a condition of entry, or override prison system rules that segregate prisoners based on HIV status. Additional concerns relate to the fact that vaccine volunteers may be considered at higher risk for HIV infection merely because of their participation in a vaccine trial. Disability law does not extend to discrimination solely based on trial participation.

These potential concerns might be addressed through various approaches, including the following:

  • vaccine approval criteria that incorporate mandated lifetime availability to trial participants of blood assays capable of distinguishing HIV infection from vaccine-induced antibody response;
  • laws that prevent the disclosure of HIV vaccine trial participation and data without consent; and that prohibit the use of vaccine positivity or participation in an AIDS vaccine trial as a basis for disparate treatment in employment, or in any federally funded or operated program, or as a reason for denial or limitation of insurance coverage; and
  • incentives for research and development of more sophisticated blood screening mechanisms to distinguish natural infection from vaccine response.

Additional legal issues relate to the requirement to provide medical care and other benefits to volunteers in vaccine trials who have adverse reactions to the vaccine. Although the legal requirement is far from firm, these volunteers should be entitled to state of the art medical care for the reaction. The UNAIDS ethical guidelines, among other documents, suggest that such participants should also be compensated for loss of earnings. UNAIDS, supra.

Seth Berkley has observed that “the most profoundly unethical course is to do nothing to prevent or alleviate . . . suffering.” Yet, as research on the AIDS vaccine proceeds, it is critical that we pay close attention to the attendant ethical and legal challenges so as to assure scientific validity as well as individuals’ willingness to participate in clinical studies. Individuals who do not feel respected, or who do not fully comprehend the studies in which they enroll, or who are not confident that their interests and rights are being protected, are less likely to volunteer to participate and less likely to adhere to the research interventions and follow-up. Ethical and legal issues in HIV vaccine research must be comprehensively identified and analyzed and appropriately resolved to assure the scientific success of trials and the protection of individuals’ interests.

As published in Human Rights, Fall 2004, Vol. 31, No. 4, p.20- 22.