The Declaration of Helsinki has been clarified to state that the use of placebos is unethical in nearly all clinical trials involving diseases for which there are existing treatments.

The revision was approved last month by the World Medical Association (WMA), made up of representatives of the medical profession from 45 countries, including delegates from the American Medical Association (AMA). The delegates met in Edinburgh, Scotland, for the WMA’s 52nd General Assembly.

The Declaration of Helsinki traces its roots to the worldwide horror generated in response to the involuntary and inhumane research that Nazi medical officers performed on prisoners during World War II. For four decades this legendary document has guided ethical concerns within the realm of medical research.

In the fifth revision since the ratification of the original declaration in 1964, the language was changed to say that any new method of treatment should be tested against the "best current prophylactic, diagnostic, and therapeutic methods." The declaration goes on to clarify, "This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic, or therapeutic method exists."

Although the declaration has no legally binding authority, its influence over the last 40 years has been profound as one of a handful of postwar documents that set out to determine international standards for medical research. Its effects on national governments, including the U.S., ethical review boards, and individual researchers has been considerable. However, the effect of the new revision on medical research in the United States may not be clear for some time.

"I believe that it is a mistake to rule out the use of placebos in well-designed research," said Greg Koski, M.D., director of the U.S. Department of Health and Human Services’ Office for Human Research Protections. "The Declaration of Helsinki has been viewed as a very important set of guiding principles for the ethical conduct of research; however, I don’t believe we would take the declaration as the literal basis for new regulations."

Margaret Dotzel, Ph.D., the associate commissioner for policy at the Food and Drug Administration (FDA), agreed. "The agency would have to look at the language within the revision," she said in an interview, "and really study it to make a determination of how we would want to react, if at all. And that will take time."

Controversy is sure to surround the revision. The FDA requires that most new medications, including psychotropic medications, be tested against placebos. The same is true of many other countries, including the United Kingdom’s Medicines Control Agency. The new language would potentially place thousands of such clinical trials in the U.S. and U.K. outside the bounds of "ethical" conduct.

The controversy surrounding placebo use in clinical trials has been brewing for some time, including in the psychotropic arena. The rationale for using placebos is based on the premise that the period of time in which a person takes a placebo, rather than the best-known available treatment, is short and that the risk of serious harm is low. However, critics argue that effective treatments are available for psychiatric illnesses such as depression, schizophrenia, and anxiety and bipolar disorders. Critics maintain that it is unethical to deprive patients, even for a short period, of the potential benefits of the best currently available treatment.

"The WMA’s main objective," said Delon Human, M.D., secretary general of the WMA, "is to serve and protect our patients, especially those who are involved in potentially harmful research projects. At the same time, we applaud and encourage the use of ethical research to find new ways to cure disease."