Standard of Care

The Ethical Debate

As important as the scientific arguments were, it was the ethics of using placebos that dominated the debate over the clinical trials to reduce perinatal transmission of HIV. As both sides sought to elucidate the ethical principles underpinning their position, they had recourse to a number of international guidelines to make their case. The guidelines were essentially voluntary codes, with no mechanism for policing or enforcement; nonetheless, they played a key role--though not necessarily a clarifying one--in the controversy.

The Guidelines.

The bedrock of ethical guidelines was the Nuremberg Code, published in 1947 in the aftermath of shocking revelations of Nazi medical experiments on human subjects. The code, says Dr. Michael Grodin of the Health Law Department of Boston University School of Public Health, was "a very, very important document, a grounding document, which talked about respect for individuals. . . ."

Perhaps the most important of the ten principles articulated in the Nuremberg Code was the notion of "informed consent," which required that human subjects be apprised of the nature and risks of the research, and that their participation be strictly voluntary. All subsequent guidelines included the principle of informed consent, although they also incorporated language permitting researchers to seek the proxy consent of authorized representatives in cases where subjects were deemed incapable of giving informed consent on their own. Other key tenets of the Nuremberg Code sought to protect subjects from undue harm and risk.

About two decades later, the World Medical Association (not to be confused with the World Health Organization) issued a series of "recommendations," known as the Declaration of Helsinki to guide research on human subjects. First adopted in 1962 and revised at regular intervals in subsequent decades, these guidelines included two principles in particular that became focal points in the debate over the placebo-controlled trials in developing countries. One stated that "[c]oncern for the interests of the subject must always prevail over the interests of science and society." The other declared that "[i]n any medical study, every patient--including those of a control group, if any--should be assured of the best proven diagnostic and therapeutic method."

Still later, the Council for International Organizations of Medical Sciences (CIOMS), in collaboration with WHO, issued the International Ethical Guidelines for Biomedical Research Involving Human Subjects. Published in 1993, these guidelines were written to address ethical issues that arose in research involving developed and developing countries, in particular when the host country did not have guidelines of its own. In the course of the controversy over the clinical trials in sub-Saharan Africa, two of the fifteen CIOMS guidelines were frequently invoked.

Guideline 8 set out a series of principles for research involving subjects in "underdeveloped countries." Under these rules, researchers were required to ensure, among other things, that "persons in underdeveloped communities will not ordinarily be involved in research that could be carried out reasonably well in developed communities," and that the research was "responsive to the health needs and the priorities of the community in which it is to be carried out. . . ." Guideline 15 set out the obligations of both sponsoring and host country. In the former, the guideline stated, the proposed study should be submitted for ethical and scientific review, and the ethical standards applied "should be no less exacting than they would be" for research in the sponsoring country itself. Following that review, the study would be subject to the scrutiny of the "appropriate authorities of the host country, including a national or local ethical review committee or its equivalent. ..."

In addition to these international codes, researchers in the US were governed by federal regulations on the protection of human subjects, promulgated by the Department of Health and Human Services. Apart from provisions concerning informed consent, these were largely devoted to detailing the make-up and duties of "institutional review boards" (IRBs)--essentially, local review committees established by a university, hospital, or research organization--which were authorized to scrutinize research proposals to ensure they afforded adequate protections for human subjects. IRBs, which were required to include at least one member unaffiliated with the host institution and one with a non-scientific background, were provided with specific criteria to guide their reviews of research proposals.

But they were expected to be informed as well by the principles and guidelines contained in the Belmont Report , issued in 1979 by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, which was established in the wake of the Tuskegee scandal. The Belmont Report was notable for delineating three "basic ethical principles," frequently cited in the debate over the clinical trials: "respect for persons," which recognized the autonomy of individuals, primarily through the mechanism of informed consent; "beneficence," which sought to minimize the risks and maximize the benefits of research; and "justice," in the sense of equitable distribution of the burdens and benefits of research, which included the stricture that research should not "unduly involve persons from groups unlikely to be among the beneficiaries of subsequent applications of the research."

In the case of research conducted in a foreign country, federal policy did make allowances for differences in procedures to safeguard human subjects in the host nation. It was permissible, according to HHS regulations, to observe the standards of the host country, if it was determined that they "afford protections that are at least equivalent to those provided in this policy. . . ."

The Arguments.

To critics, the placebo-controlled trials in sub-Saharan Africa and Thailand violated some tenets of all the major international ethical guidelines, as well as US regulations. Lurie and Wolfe, for example, charged that the trials violated principles 2, 4, 5, and 7 of the Nuremberg Code, which largely dealt with the obligation to shield research subjects from unnecessary harm, as well as CIOMS guideline 15, which set ethical standards for international research. In her editorial, Marcia Angell cited portions of the Declaration of Helsinki in support of her contention that the trials were unethical.

To advocates, on the other hand, the placebo-controlled trials met the test of ethical standards that guided US-sponsored research on human subjects. Writing in The New England Journal of Medicine, David Satcher of CDC and Harold Varmus of NIH cited the principles of the Belmont Report, in particular those of beneficence and justice, in defense of their agencies' research practices in developing nations. They and others also pointed to guideline 8 of the CIOMS code, which called for responsiveness to local needs in research conducted in developing nations.

Within the overarching argument about which ethical principles should inform the conduct of the trials, certain themes consistently emerged: the definition of the term "standard of care"; the charge of "ethical imperialism"; and finally, the equitable distribution of the benefits of research.   



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