Clinical Trials in Developing Countries Should Be Held to Ethical Standards, Panel Says
When designing and conducting clinical trials of drug therapies in developing countries, scientists should not enroll people who "would be unable to afford" the medicines and should not give study volunteers placebos in place of drugs "that are known to work," members of the National Bioethics Advisory Commission write in a New England Journal of Medicine article. Reuters/Contra Costa Times reports that the article represents the "latest round in a debate over" the ethical questions surrounding clinical trials in developing nations. Concern over these studies was raised in 1997, when members of Public Citizen's Health Research Group cited 15 government-funded studies that were testing "various" treatments aimed at halting mother-to-child transmission of HIV. Group members Drs. Sidney Wolfe and Peter Lurie said that these studies -- all of which were being conducted in developing nations -- were "unethical" because some of the women enrolled in the study were given placebos, despite the fact that AZT had been shown to prevent vertical transmission. Distribution of a placebo in place of an established treatment was perceived as unethical in the United States and several other countries at the time (Emery, Reuters/Contra Costa Times, 7/11).
In their NEJM article, Harold Shapiro and Eric Meslin, chair and executive director of the commission, respectively, write that the United States has developed "substantive ethical standards" for clinical trials that include a "required set of procedures" for their implementation. Shapiro and Meslin write that these standards were developed on "the principles of justice and individual autonomy" and that the standards apply to all research in the United States on human subjects that is financed by a variety of federal agencies or regulated by the FDA. This system has "worked reasonably well for clinical research in the United States" and the same standards should be applied to all clinical trials conducted abroad, they add. They write that clinical trials conducted at home and abroad should not "exploit" study participants, should include prior review and approval by ethics review committees, should "minimiz[e]" the risk to participants, should present a "favorable risk-benefit ratio" to participants and should require informed consent from "all competent adult participants." Participants also should receive "adequate medical care" during the trial, Shapiro and Meslin state, adding that although these provisions are not required in the United States, they could be adopted separately by developing countries. However, the authors state that one "important" standard is a requirement that clinical trials sponsored or regulated by U.S. groups be "responsive to the host country's health needs" and not conduct tests of drugs in countries that cannot afford them. "If the intervention being tested is not likely to be affordable in the host country or if the health care infrastructure cannot support its proper distribution and use, it is unethical to ask persons in that country to participate in the research, since they will not enjoy any of its potential benefits," they write. Thus ethics review panels and researchers will have to decide if a trial in another country is "justifi[able]." Justifiable studies could include research addressing an "important health problem" in the country where the trial is being conducted, trials that are a joint effort by the country sponsoring the study and the host country and studies that address important health problems occurring in both the sponsoring and host countries.
Shapiro and Meslin write that clinical trials involving treatment for a "life-threatening" disease for which "an established, effective treatment is available" should not use a placebo control group. "Moreover, such a trial is not ethical if patients in the developed country would be the primary beneficiaries and if it is not clear that the trial would be responsive to the health care needs of the host country," they state. The authors add that trial sponsors have an "ethical obligation" to make any treatments found to be successful during the trial available to participants after the study's conclusion. "There is a related obligation to ensure that participants are no worse off during the trial than they were before it," they write, adding that participants should not suffer after the trial as a result of not being able to access the drugs they were given during the study (Shapiro/Meslin, NEJM, 7/12).
In a related op-ed, Drs. Greg Koski and Stuart Nightingale of HHS write that to "a large extent, the appropriateness of a clinical trial and of the control group used is based on two considerations." First, they write that "the research question should be posed in a manner that is relevant and meaningful to the host country, such as a comparison of an available treatment with the current standard of care in the host country (which might be no intervention in some cases)." Second, the trial "should be designed to achieve maximal efficiency in producing meaningful data that could lead to improvements in health in the host country without leaving the study participants worse off at the end of the trial than they were when they entered it," they state. However, they note that the Declaration of Helsinki -- which would "prohibit almost all placebo-controlled clinical trials and would require that the best proved therapy be provided to the participants" after its conclusion -- is "too rigid" because "[o]ne trial rarely demonstrates that a given treatment is superior to all others, and there is often considerable disagreement about what the best methods are." Koski and Nightingale conclude, "Our greatest challenge is to realize and fully accept that in all research involving human subjects, ethics and science are not separable -- a given study must conform to ethical standards or it should not be performed, and it must be scientifically sound or it cannot be ethical" (Koski/Nightingale, NEJM, 7/12).