Ethical Controversy in Human Subjects Research

Assortment of blue-colored pills

Public attention to ethics in research involving human subjects typically emerges from shocking scandals.

The best-known examples include the Tuskegee syphilis study, the Willowbrook hepatitis experiments and the Jewish Chronic Disease Hospital case. In the Tuskegee study, poor black men in Alabama were observed for more than 40 years to study the natural history of syphilis, and medication was withheld even when effective treatment became available. In the Willowbrook case, mentally retarded children residing in an overcrowded state institution formerly located on Staten Island were deliberately infected with hepatitis to help researchers seeking an effective preventive vaccine. In the Jewish Chronic Disease Hospital experiment, elderly hospitalized patients at the former Brooklyn facility were told they were in a research study, but were not told they were being injected with live cancer cells to study the mechanism of immune reaction.

A recent discovery revealed bioethical breaches that extended beyond U.S. borders. In the 1940s, doctors from the U.S. Public Health Service deliberately infected Guatemalan prisoners, mental patients and soldiers with sexually transmitted disease material.

While a few scholars defended some aspects of these experiments, the studies were almost universally condemned as unethical and these cases are featured in bioethics courses for medical students, undergraduates and those pursuing continuing medical education.

In all these cases, the subjects were not offered the same protections and considerations as other populations. They were worse off than if they had never been included in the studies. Beyond harming the participants, these studies also damaged the reputation of scientific research in the eyes of the participant communities.

Today, medical research faces similar questions surrounding the issue of placebo controls in tests of HIV treatments in resource-strapped nations unable to provide proven preventive methods of treatment.

A leading example is that of clinical trials in developing countries in the late 1990s, designed to study the efficacy of a short-course regimen to prevent transmission of HIV from an infected pregnant woman to her offspring. At the time, a proven, effective way to prevent mother-to-child transmission existed in the United States and other industrialized countries. But for reasons of feasibility and cost, that method could not be introduced in resource-poor countries lacking the necessary infrastructure. The ethical controversy arose over the use of a placebo control in the experimental design of the short-course treatment. A placebo control would have been unethical in a similar study in the United States because pregnant women could have had access to an effective preventive method outside the study.

Critics argued that a placebo-controlled design was unethical in developing countries, as it deprived women in that arm of the study of a method having a high probability of preventing HIV transmission. Study defenders replied that the women in the trial lacked access to an effective preventive method outside the trial, so they were not being made worse off by enrolling. The defenders also argued that this was the “standard of care” in the countries where the trial was carried out.

Now, given recent scientific advances in HIV prevention, we are likely to see a resurgence of that debate. A method of HIV prevention called pre-exposure prophylaxis (PrEP) has been shown to be effective in three clinical trials in the past couple of years. In July 2012 the Food and Drug Administration (FDA) approved a combination drug (brand name Truvada) for PrEP.

Arguably, it would be unethical to study a new preparation for pre-exposure prophylaxis with a design using a placebo control in the United States, since participants in such a trial could obtain Truvada outside the trial. In effect, individuals randomized to the control arm would be worse off after joining the study than they would be if they received a proven method of prevention from their physicians.

But what about members of at-risk populations in developing countries with a high burden of HIV disease? Approval of Truvada by the FDA does not ensure that regulatory authorities in Africa will consider the drug the “standard of care” in their countries. Besides, the drug is unlikely to be readily available outside clinical trials, at least initially, in most resource-poor countries.

So the question arises: should there be one global ethical standard for future research on biomedical HIV prevention? Or is it ethically acceptable to allow double standards—one for wealthy countries, in which a proven preventive method should be used as a comparator, and one for resource-poor countries, using a placebo control?

As an opponent of double standards in global health research, I contend that adherence to a single, universal standard is ethically the best option. Ultimately, it is the highest standard of care available anywhere, not the highest standard of care in the countries where the trials take place, that must be met to protect and serve the needs of study participants as well as medical research itself.

Ruth Macklin, Ph.D.

Ruth Macklin, Ph.D.

Ruth Macklin, PH.D. is professor, Department of Epidemiology & Population Health at Albert Einstein College of Medicine.

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