Placebo Controls, Ethics in Multinational Clinical Trials

Historical Considerations: The Problem as it Stood in 1996

The Declaration of Helsinki, the code of research ethics promulgated by the World Medical Association (WMA) in 1964 and since recognized widely as a leading code of ethics for biomedical research involving human subjects, contained in its 1996 iteration the following article on the use of placebos; this established the “best proven therapeutic method” as the standard requirement for all patients who serve as research subjects:

The implications of this article, which has come to be known as the notorious “Article II.3,” extend far beyond the use of placebo controls in clinical trials.

This article, if strictly applied, would rule out the development of all new therapies for conditions for which there are already existing “proven” therapies. One cannot evaluate a new therapy unless one withholds those that have already been demonstrated safe and effective for the same indication. (There are a few exceptions, most notably drugs having mechanisms of action different from the existing proven therapy.)

Article II.3 also forbids placebo controls in clinical trials in which there is virtually no risk from withholding proven therapy. Consider research in the field of analgesics and antihistamines. No experienced clinical trialist would ever employ an active control for an evaluation of a new analgesic. Article II.3 also rules out the use of placebo controls where there is a very remote possibility of a serious adverse consequence of withholding the active drug, such as trials of new antihypertensives and of new oral hypoglycemic agents. Insisting on active controls in these areas would introduce major inefficiencies with virtually no compensating benefit; the amount of injury to research subjects that would be prevented by requiring active controls is so small that it can be, and generally is, considered negligible.

The most controversial interpretation of Article II.3 was that it required the provision of the best proven therapeutic method that is available in the wealthy countries even when conducting research in countries in which such therapy is not available. This interpretation provoked the most acrimonious debate in the field of research ethics since the 1970s. The debate began with the publication in The New England Journal of Medicine of an article that denounced as unethical the clinical trials that were being carried out in several countries to evaluate the effectiveness of the short-duration regimen of AZT (azidothymidine) in preventing perinatal transmission of HIV infection. [Page 836]The editor of the New England Journal opined that these trials were, in certain respects, reminiscent of the notorious Tuskegee Syphilis Studies. In contemporary American culture, Tuskegee is one of the most powerful metaphors for symbolizing evil in the field of research ethics. The other side of the controversy is exemplified by a statement of a physician-researcher from Uganda, one of the countries in which the trials were conducted. He accused the editor of a form of “ethical imperialism” that asserts that the American vision of research ethics must dominate the conduct of research everywhere in the world.

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