Public Health and Clinical Research

The HIV epidemic provided the circumstances for the emergence of a broad and potent political movement that sought to reshape radically the conditions under which research was undertaken. Brought into question were the role of the randomized clinical trial, the importance of placebo controls, the centrality of academic research institutions, the dominance of scientists over subjects, the sharp distinction between research and therapy, and the protectionist ethos of The Belmont Report (the landmark formulation of research ethics published in 1979 by the U.S. National

Commission for the Protection of Human Subjects of Biomedical and Behavioral Research). Although scholars concerned with the methodological demands of sound research and ethicists committed to the protection of research subjects played a crucial role in the ensuing discussions, both as defenders of the received wisdom and as critics, the debate was largely driven by the articulate demands of those most threatened by AIDS (Epstein). Most prominent were groups such as the People with AIDS Coalition and ACT UP, organizations made up primarily of white, gay men. They were joined by community-based physicians who identified closely with the plight of their patients.

What was so stunning—disconcertingly so to some, exciting to others—was the rhythm of challenge and response. Rather than the careful exchange of academic arguments, there was the mobilization of disruptive and effective political protest. Most remarkable was the core demand. As Carol Levine noted in 1988, "The shortage of proven therapeutic alternatives for AIDS and the belief that trials are, in and of themselves, beneficial have led to the claim that people have a right to be research subjects. This is the exact opposite of the tradition started with Nuremberg—that people have a right not to be research subjects" (Levine, p. 172). That striking reversal resulted in a rejection of the model of research conducted at remote academic centers, with restrictive (protective) standards of access and strict adherence to the "gold standard" of the randomized clinical trial.

Having blurred the distinction between research and treatment—expressed forcefully through the slogan "A Drug Trial Is Health Care Too"—those insistent on radical reform sought to open wide the points of entry to new "therapeutic" agents both within and outside of clinical trials; they demanded that the paternalistic ethical warrant for the protection of the vulnerable from research be replaced by an ethical regime informed by respect for the autonomous choice of potential subjects who could weigh, for themselves, the potential risks and benefits of new treatments for HIV infection. Moreover, the revisionists demanded a basic reconceptualization of the relationship between researchers and subjects. In place of protocols imposed from above, they proposed a more egalitarian and democratic model in which negotiation would replace a scientific authority. Indeed, research "subjects" were now thought of as "participants." Furthermore, the role of the carefully controlled clinical trial as providing protection against the wide-scale use of drugs whose safety and efficacy had not been proven no longer commanded unquestioned respect (Bayer, 1990).

The new perspective did not go without challenge, of course. Some were concerned that the proposed regime would make all but impossible the conduct of research so crucial to the needs of those with HIV/AIDS ("Parallel Track," 1989), while others feared that desperate individuals would, in the absence of the now discredited (paternalistic) ethos, be subject to deception (Annas).

The AIDS-inspired challenge to the ethics of research was not restricted to issues within the United States. Just as the protective regime surrounding research in the United States was a product of a history of abuse, efforts to enunciate ethical standards for the conduct of research in Third World nations was shaped by a history of exploitation, a history characterized by investigations on the poor designed to serve the interests of the privileged. Central to those efforts was the belief that the ethical principles first encountered in industrialized nations had direct bearing on the norms that should govern research in very different settings (IJsselmuiden and Faden). Such universalism took as a given the need to assume that insights regarding cultural differences not serve as the basis for moral relativism.

Just as individual informed consent was the first principle of the ethics of research in advanced industrial nations, it was at the heart of the codes designed to guide research in the poorest nations. To preclude exploitation, international consensus also existed on the extent to which it was critical that research be responsive to the health needs and priorities of the community in which it is to be carried out (CIOMS). What would remain a matter of uncertainty, however, was whether the needs of the poorest and the requirement of responsiveness could justify research that would be unacceptable in the richest nations—whether the principle of universalism could accommodate research in Burundi that would be prohibited in Brooklyn.

That was the issue that would animate a furious international debate occasioned by the 1994 finding that AZT administered to infected women in the second and third trimesters and to their infants for six weeks could reduce by two-thirds the rate of mother-to-child HIV transmission (Connor, Sperling, and Gelber). Although superficially a conflict over a technical matter involving research design— the role of placebos—the dispute touched on the deepest questions of what ethical conduct meant in a world characterized by great inequalities and profound inequities.

Given the burden of pediatric AIDS in Africa and Asia, it was a matter of some urgency that trials begin to determine whether radically cheaper alternatives to the standard regimen could achieve at least some measure of reduced maternal-fetal HIV transmission. In June 1994 a special consultation of the World Health Organization (WHO) considered the challenge and called for the launching of studies to achieve that goal. The consultation made clear its conclusion that placebo-controlled trials—trials in which a comparison is made between an inert substance and the potentially active agent—"offer the best option for obtaining rapid and scientifically valid results."

There was no question that a placebo-controlled trial would have been considered unethical in the United States or any other advanced industrial nation. No trial that denied access to the effective standard, or to an intervention thought to hold the promise of being at least as effective as, if not more effective than, the prevailing standard of care, would have satisfied the requirements of ethical review. The question posed by the furious controversy that unfolded was whether it was ethical to conduct such a trial in a poor country. In 1997 the New England Journal of Medicine gave its answer unambiguously: "Only when there is no known effective treatment is it ethical to compare a potential new treatment with a placebo. When effective treatment exists, a placebo may not be used. Instead, subjects in the control group of the study must receive the best known treatment" (Angell, p. 847).

Given this premise, the Journal rejected as irrelevant the fact that healthcare available in most Third World countries provided nothing like healthcare available in industrialized countries. Citing for authority the Declaration of Helsinki— the international code of research ethics adapted by the World Medical Association in 1964—the editorial noted that control groups had to be provided with the best current therapy, not simply that which was available locally. "The shift in wording between 'best' and 'local' may be slight, but the implications are profound. Acceptance of this ethical relativism could result in widespread exploitation of vulnerable Third World populations for research programs that could not be carried out in the sponsor country" (Angell, p. 848).

Those who rejected the Journal's viewpoint made clear that placebo-controlled trials were dictated by the urgency of the situation. Only placebo-controlled trials could provide "definitive," "clear," "firm" answers about which interventions worked, thus allowing governments to make "A sound judgment about the appropriateness and financial feasibility of providing the intervention" (Varmus and Satcher, p. 1004). The failure to employ a placebo would have made it difficult to clearly determine whether the affordable but less effective intervention was better than no intervention at all. In short, they concluded that placebos were crucial to policymakers required to make relatively costly decisions under conditions marked by profound poverty and scarce public health resources (Varmus and Satcher).

Paralleling the debates over maternal—fetal transmission of HIV were those that surfaced over the ethics of AIDS vaccine trials. In this case the focus was on those research participants who might become infected with HIV during a trial. On the one hand there were those who argued that such individuals be provided with optimal care—the retroviral therapy available in the developed countries. On the other hand there were those who asserted that care should reflect that which was consistent with what was available in the host nation (Bayer, 2000). So divisive was this controversy that the Joint United Nations Programme on HIV/AIDS (UNAIDS) could not come to an agreement on the appropriate ethical norm and indeed had to settle for a procedural rather than substantive solution, a solution that focused on how to reach acceptable agreement rather than one that put forth a standard to guide such deliberations (UNAIDS).

Thus were the issues joined. These controversies ultimately provoked an international effort to consider ethical standards of research in the Third World. The World Medical Association undertook a series of consultations on the revision of the Declaration of Helsinki; the Council for International Organizations of Medical Sciences (CIOMS) did so as well. Finally, within the United States, which funded much of the international research that had been subject to scrutiny, the National Bioethics Advisory Commission took up the issue of studies in poor nations.

Whereas those who saw in any effort to craft "flexible" standards that reflected the uniquely pressing context of international poverty and inequality the treacherous embrace of moral relativism, their opponents persisted in arguing that a failure to consider the context of investigation was a failure of moral understanding. Principles could be universal; their application could not be rigid. (Singer and Benatar; Benatar and Singer).

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