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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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