The Placebo Debate.

The opening salvo in the battle over the clinical trials was an April 22, 1997 letter to US Health and Human Services (HHS) Secretary Donna Shalala, authored by Drs. Peter Lurie and Sidney Wolfe of the Health Research Group--an arm of Public Citizen, the watchdog organization founded by Ralph Nader.

The letter's argument was couched in strong terms. "Unless you act now," it began, "as many as 1,002 newborn infants in Africa, Asia and the Caribbean will die from unnecessary HIV infections they will contract from their HIV-infected mothers in nine unethical research experiments funded by your Department through either [NIH or CDC]." From there, the authors went on to assert that the use of placebos in the nine US-sponsored trials violated international ethical guidelines and HHS's own regulations for the protection of human subjects in international research.

Because the 076 protocol had been proven effective in reducing HIV transmission, they wrote, subjects in the control group of any subsequent clinical trials should be given "effective prophylaxis" to help prevent infection. This standard, they noted, was observed in the US: in two trials of treatments to reduce HIV transmission then being conducted in the US, all the women in the study, including those in the control group, were provided with AZT or other anti-viral drugs.

Urging the HHS secretary to order researchers to provide treatment to all subjects in the trials (and to pressure foreign governments to do the same), the letter concluded, "We are confident that you would not wish the reputation of your department to be stained with the blood of foreign infants."

Several months later, on September 18, 1997, Lurie and Wolfe repeated their charges in a highly visible venue: The New England Journal of Medicine, one of the most respected medical publications in the US. In the same issue in which their "Sounding Board" article appeared, the journal's executive editor, Dr. Marcia Angell, wrote a strongly worded editorial condemning the use of placebos when "effective treatment exists. . . ."

Like Lurie and Wolfe, Angell likened the use of placebos in the clinical trials on HIV transmission to the infamous Tuskegee syphilis study, in which poor African-American men in the rural south were denied effective treatment for syphilis so that researchers for the US Public Health Service could study the natural progress of the disease.

Both the letter to Shalala and, in particular, the pieces in The New England Journal of Medicine sparked a vigorous defense from researchers and health officials in the US and abroad, who strenuously objected to the harsh characterizations and the public manner of the charges of unethical conduct. Many were angered by the press releases, and, in one instance, the press conference Lurie and Wolfe used to accompany their criticism, and by the comparison to the Tuskegee study, which, they argued, was inappropriate and offensive.

More important, they took issue with the substance of the criticism of the clinical trials, countering that the use of placebos accorded with the soundest research principles and established ethical practices.

For the next two years, both sides pursued the debate in professional journals and gatherings, in congressional testimony, and in the media. Almost no one disputed the need to find shorter and cheaper ways to reduce mother-to-infant transmission of HIV in poorer nations, although some lamented the unwillingness of rich ones to subsidize treatment with the 076 regimen in Africa and elsewhere.  

Rather, the disagreement focused largely on the use of placebos as the comparison arm in the clinical trials. Broadly speaking, arguments for and against placebos could be said to fall into two general categories: the scientific and the ethical.



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