Rising concerns about placebos.

The gold standard of medical research is the double-blind randomize placebo-controlled trial: a test in which researchers randomly assign volunteers to one of at least two groups. People in one group get the drug other treatment being tested, and people in another group get an inactive treatment--and during the trial, neither researcher nor volunteer knows which is which. Such procedures rule out inadvertent bias in assessing an experimental drug and can give clear-cut proof that a drug is effective.

In the United States; the Food and Drug Administration usually asks companies to perform such studies to prove the safety and efficiency of new drugs and some medical procedures. Placebo use is generally required when there's no current treatment for a condition. Further, researchers often use placebos to test new treatment for high blood pressure, allergies and depression and some other mental disorders--conditions for which the risk of serious harm is low it patients briefly discontinue currently available treatments. However for ethical reasons, researcher must avoid using placebos when currently available drugs are known to save lives--such as in test of drugs to prevent heart failure.

Last October, however, scientist assembled in Edinburgh under the aegis of the World Medical Association amended the Declaration of Helsinki, a document that has defined medical ethics internationally since World War II. This amendment calls for new drugs to be tested against the best current treatment--a statement that many researchers say implies that using placebos is unetbical even when the risk of harm is low.

While the document has no legal authority in any country it exerts considerable moral sway over national government and ethical-review boards around the world according to Kenneth J. Rothman of the Boston University School of Public Health.

"If there were no ethical concerns with placebo use we would all endorse it" because of the scientific benefits of placebo-controlled trials he says. However even brieftly taking people off drugs that lower blood pressure or prevent psychotic episodes may in fact be harmful, he says. In such cases, informed consent from a volunteer--saying he or she understands and accepts the risks of participating in a clinical trial--may be ethically meaningless. Rothman adds.

The Helsinki amendment suggests that "the rights of the individual patient [to the best available treatment] take precedence over the rights of science and society in genera," Rothman concludes.

Many researchers--and biothicists--disagree. In July 2000, before the Helsinki declaration was amended, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use released a guidance document explicitly stating that placebo use is, in general, ethically acceptable. This group of respresentatives from the drug industry and regulatory agencies, in contrast to the Helsinki group, concluded that placebo-controlled trials are justifiable when researchers can reasonably assume that patients will experience, discomfort but not serious harm.

"There a lot of anger about the Helsinki document," says medical anthropologist Arthus Kleinman of Harvard Medical School in Boston. "These ethical issues go to the heart of biomedical research."

As alternatives to using placebos, researchers can study different doses of the drug being investigated or compare an experimental drug with a currently approved drug. However, such trial designs have limitations, says Robert J. Temple, director of medical policy at the FDA's Center for Drug Evaluation and Research in Rockville, Md.

If poor study design--such as not enrolling enough patients to show a significant difference--causes the study to show no differences between two treatments when there actually is one, a placebo-controlled trial would be regarded as showing no benefit of the experimental treatment but a test of a current drug versus an ineffective new treatment might be interpreted as proving that the treatments are equal in value, "You don't have to be cynical to think that's risky," Temple says.

--D.C.