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HIV Vaccine Clinical Trials: The Standard of Care Debate Standards of ethical conduct in research involving human subjects are centered on three central principles. They are: respect for persons, which includes issues of autonomy and self-determination; beneficence, which seeks to maximize potential benefit to the research subject while minimizing harm; and justice, which includes distributive justice – “the equitable distribution of both the burdens and the benefits of participation in research.”1 One of the most contentious debates in HIV vaccine research pertains to the application of these principles to clinical trials held outside the U.S., primarily those in developing countries. Worldwide, scientists, ethicists, research sponsors, and governments have been unable to agree on an accepted standard of care for trial participants who contract HIV during the course of a clinical trial, an all-but-inevitable occurrence among the high-risk populations in which much of HIV vaccine research is conducted. In general, factors such as time, duration, and severity of the disease are considered when researchers explore the provision of medical care during a clinical trial. The situation is complicated when the disease is a chronic rather than acute condition and when the trials are held in resource-constrained environments, as is the case with HIV.2 Since the late 1990s, researchers and the international scientific community have been striving to reach a consensus on what standard of care is appropriate in this context, how long it should be provided, and who has the obligation to ensure that protocols concerning standard of care are implemented.3 Overview of the Debate Researchers holding clinical trials of HIV vaccine candidates face a great deal of uncertainty in their work. In the process of conducting early-stage vaccine research and using a product of unknown efficacy, they are working with study populations in which some participants will inevitably become naturally infected with HIV during the course of the trial. Thus, decisions regarding the provision of care to research subjects infected with HIV must be made. Virtually all parties believe that some medical care beyond the specific requirements of the research protocol should be provided to clinical trial participants. As Seth Berkley writes, the predominant opinion is that because communities and individuals participating in trials “are contributing to knowledge that is a global public good, [they] should benefit in return.”4 The issue is what level of care should be provided, by whom, and for how long. Recommendations range from providing the same services that are available to patients in the country where the trial is occurring to the best treatment currently in existence worldwide – namely antiretroviral drugs (ARVs). What is clear, however, is that “no country in Africa, and few countries elsewhere in the developing world, can afford Western levels of treatment.”5 As of 2006, the current cost of highly active antiretroviral treatment (HAART), the standard drug regimen for those infected with HIV, was estimated to be $730 per patient-year, although many sources cite higher numbers.6 Use of certain generic combinations lowers this figure to approximately $300 per person per year.7 Market prices for these drugs are often many times higher, particularly in the United States. Although drug prices have dropped for some of the drugs included in HAART regimens, spending $300 for a single patient’s HIV treatment is beyond the reach of most developing countries. In 2002, only 39 out of the 160 countries for which data were available had per capita health expenditures over $730. 85 of those 160 countries spent under $300 per capita in health expenditures.8 In 2006, India’s total per capita health expenditure amounted to only $23.9 Additionally, treatment of HIV/AIDS encompasses more than purchasing and supplying medications. Frequent follow-up and monitoring of patients are required due to the high prevalence of side effects from HAART and the inevitable development of drug resistance. Developing countries and even clinical trial sites may lack the infrastructure to carry out this type of surveillance on a sustainable basis. Once the trial concludes and researchers return to their home countries, ongoing treatment would have to be continued by another entity, the identity of which is unclear. The question of “appropriate treatment” gives rise to heated debates over extremely sensitive issues. Because many clinical trials for HIV candidate vaccines are performed in developing countries, one of the main fears is of the creation of a “double standard” for developed and developing countries owing to funding and infrastructure capacities. Those observing the progress and protocols of clinical trials may ask if appropriate treatment in a rural African community can be equated to appropriate treatment in a major U.S. city. Clinical trials conducted in America or Europe would require that infected participants receive the best available care, a lifetime regimen of anti-retroviral drugs, but for similar trials held in developing countries, the prospect of such care is dim at present.10 Many argue that it is morally unacceptable to allow patients to receive minimal treatment, particularly when treatments are known to be safe and effective. Responsibilities of developed world research organizations may go even further than the provision of treatment for HIV/AIDS. Behavioral scientist Kathy Shapiro and ethicist Solomon Benatar maintain that rich countries sponsoring research in poorer countries have greater access to resources and are therefore ethically obligated to contribute to sustainable improvements in the health of developing nations, not simply tending to health outcomes of research subjects.11 Another viewpoint focuses on the many economic and logistical difficulties that would be incurred in providing the best available medical care. A particularly provocative analysis of the situation concludes that “if the rules of clinical trials required participants to receive the best care on earth, there would be no clinical trials.”12 As a result, proponents of this view argue that the world as a whole would benefit more from continued scientific advances and furthering of medical knowledge than from implementing guidelines that would make HIV vaccine trials and other scientific research impossible to conduct. Lastly, a minority opinion is that research scientists should focus their attention and resources on attaining the highest quality research outcomes possible. Drawing a clear line between research and treatment, proponents of this view argue that issues such as care and treatment outside the confines of the trial are beyond their scope of duty.13 Challenges The logistic, economic, and ethical barriers involved in providing medical care during clinical trials are both formidable and numerous. One potential consequence of providing lifetime ARV therapy to infected trial participants is a sharp decrease in the scientific community’s ability or willingness to conduct HIV vaccine clinical trials. Funding and infrastructure are insufficient for full provision of such care. Furthermore, manufacturers’ and other trial sponsors’ incentives to conduct essential research in developing countries would be eroded.14 High costs are likely to deter sponsors, researchers, and local health authorities from initiating innovative and more ambitious projects.15 If combination antiretroviral therapy, currently the most effective treatment available, is to be provided regardless of the geographical location and economic status of the trial site, it is crucial to recognize the burden clinical trials could place on over-stressed local health systems. Developing countries often struggle with have poor health infrastructures, and delivering ARVs may exceed local capacity. Without the ability to guarantee long-term sustainability, provision of care through clinical trials could jeopardize the quality and outcome of the treatment.16 Patients who become infected with HIV will need ARVs for the rest of their lives, since the drugs only delay progression to AIDS. These drug regimens are not only extremely expensive but also complex to administer. Without the proper infrastructure in place for monitoring individuals who are taking the ARVs, patients are put at significant risk of harmful side effects resulting from treatment.17 Drug resistance to HIV is common and has resulted in the development of more costly, second-line drugs to replace first-line therapy. Access to and administration of second-line drugs poses yet another challenge to the health systems of developing countries. Additionally, an array of equity issues arises from provision of treatment. Community and familial relations could become strained if research volunteers receive better medical care than their neighbors or relatives, receiving such care for free. In fact, the promise of superior medical care could become an undue inducement to participate in clinical trials. Shapiro and Benatar caution that “despite good intentions, well resourced, research sponsored care in an otherwise impoverished healthcare facility is a microcosm of global health inequities.”18 Addressing these inequities is far beyond the abilities of any individual research group developing a new vaccine. Current Developments In recent years, stakeholders in HIV research have developed novel programs in their efforts to actively confront and resolve the standard of care dilemma. For U.S. researchers, the situation has proven particularly challenging in light of National Institutes of Health (NIH) regulations dictating that research funds cannot be used to pay for treatment that is not the specific focus of the research being undertaken.19 However, in 2003, the HIV Vaccine Trials Network (HTVN), a collaboration of scientists from 28 research sites, announced that participants who become infected during HTVN trials will receive long-term antiretroviral treatment. Some factors involved in this decision include the belief that provision of ARVs is now feasible in many locations, more robust ethics guidance from the international community, and the view that providing treatment may aid research by assuring parity between participants at all stages of the trials.20 Another example of efforts to provide treatment comes from Haiti, where prior to the start of the clinical trials, private donors are identified and money is placed in a fund to pay for treatment for volunteers who become infected. Considerations such as the number of trial participants, anticipated infection rates, current price of providing ARVs, and predicted survival time of patients are used to estimate the amount of money that will be required. The fund is then overseen by investigators, the local institutional review board (IRB), and community leaders. Counseling is also provided to prevent volunteers from believing that antiretroviral treatment is a cure and from engaging in risky behaviors.21 These initiatives, along with several others, such as those created by IAVI and the South African AIDS Vaccine Initiative (SAAVI), are promising steps taken toward greater international consensus on HIV vaccine research. While these programs continue to struggle with funding shortages and logistical barriers to overcome, they are indicative of researchers’ noteworthy efforts to actively apply the products of ethical deliberation to their work and to ensure that the generosity of HIV vaccine research volunteers is adequately respected.22 -- By Jessica Ho, University of Pennsylvania (yjho@sas.upenn.edu)
1 Bloom, Barry R. “The Highest Attainable Standard: Ethical Issues in AIDS Vaccines.” Science 279.5348(1998): 186. |
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