The Johns Hopkins Gazette: January 5, 1998

Jan. 5, 1998
VOL. 27, NO. 16


Ethics Of Clinical Trials Are Debated

Controversy: Tests in developing countries subject of town meeting held by School of Public Health

Rod Graham
School of Public Health

Johns Hopkins Gazette Online Edition

The still-simmering issue of using placebos for clinical trials in developing countries was the subject of an in-depth town meeting at the School of Public Health on Dec. 16, 1997. Dean Alfred Sommer decided to hold the town meeting in partnership with the student Health and Human Rights Group after months of controversy in the press over the use of a placebo arm in several trials that dealt with the use of AZT for pregnant women who were HIV positive.

A group known as Public Citizen had alleged that the use of placebos was unethical because the women who received them would have no treatment, and the treatment was known to be effective in reducing the rate of transmission from mother to baby.

The town meeting looked at the broader issue of ethics and clinical trials as a way to educate all interested parties about how trials are conducted, controlled and evaluated. Speakers addressed the general ethical and design issues of clinical trials, as well as the HIV transmission studies. The audience then questioned a panel of experts.

Steven Goodman, associate professor of oncology in the School of Medicine, discussed how clinical trials are designed. He said, "In any clinical trial, here or abroad, there is a tension between the individual's need to get the best possible treatment, and the need of the community to discover the best therapy for the whole population." Any clinical trial, he said, must balance personal and communal needs.

Nancy Kass, associate professor and director of the Program in Law, Ethics and Health in the School of Public Health, laid out three principles to be considered in the design of clinical trials. First, she said, investigators must be guided by a sense of beneficence, assessing risks and potential benefits to the individual subjects and to society. Second, there must be informed consent; since every clinical trial involves risk, all study participants must decide for themselves whether to join a study. Third, justice and fairness must be exercised.

Kass said that performing clinical trials in developing countries is ethical if there is reason to believe that conditions within the study country are so different from those in the sponsoring country that a Western population could not logically be used as subjects, and if findings are to be used to help the population of the developing country. Also, if the standard of care in the study country is so lacking that a "no treatment" arm would harm no one, then placebo-controlled trials are ethical. Clinical trials performed in developing nations would also be ethical, Kass said, if a local government were to ask Western scientists to come in and identify the most expedient treatment for a devastating epidemic.

Jack Killen, director of the Division of AIDS at NIH, who decides which AIDS studies around the world should be funded, said that the developing nations which took part in the AZT trials realized they could not afford an expensive protocol for their populations. They petitioned the World Health Organization to help organize trials that would identify inexpensive and practical solutions.

In a telling example of the vagaries of clinical testing, Killen then described a study in Thailand where a much less-expensive short course of AZT was tested. The transmission rate between the participating Thai mothers and their babies, which usually ranged from 25 to 30 percent, was only 15 percent in the group receiving the short course. But the study had also included a placebo arm, and the mothers who received placebo also had a 15 percent transmission rate.

"Without that placebo group," Killen said, "we might have assumed that the short course had cut transmission rates in half. We might then have gone on giving that particular SC regimen to mothers for years, thinking that it was dramatically reducing HIV transmission when, in fact, it was no better than placebo."

The next speaker, Peter Lurie, visiting assistant research scientist at the University of Michigan's Institute for Social Research, has long criticized CDC, NIH and Johns Hopkins for using placebos when short-course regimens of AZT are known to reduce HIV transmission rates.

At the crux of Lurie's argument was his belief that Western researchers should provide care that is comparable to that offered in the sponsor's home country. The standard of care, he insisted, is the best treatment available, not merely what people in a particular developing country can afford. Otherwise, he said, the sponsoring country is taking advantage of the social predicament of its study subjects.

As for the informed consent gotten by AIDS researchers in Africa, Lurie said that patients in Cote d'Ivoire, for example, were approached to take part in placebo-controlled studies just minutes after learning they were HIV-seropositive, and many participating women believed they were receiving drugs that would cure them of AIDS. He added that the institutional review boards in some developing nations are inexperienced, often vote without a quorum and, as happened in Ethiopia, approve studies by slim margins. Lurie stated that some scientists from developing countries disagreed with placebo studies but were silenced by their awe of foreign researchers and by fear of losing their jobs.

Norman Fost, professor of pediatrics and director of the Program in Medical Ethics at the University of Wisconsin, rebutted Lurie's argument. Fost said, "Dr. Lurie has said that even though no randomized clinical trial of SC AZT has been done, we have 'every reason to believe' that a short course of AZT is beneficial. But when you have every reason to believe something, that's exactly when you must do a controlled clinical trial." Fost noted that years ago Johns Hopkins physicians had had every reason to believe that giving struggling pre-term babies oxygen to breathe would be beneficial, and yet oxygen therapy blinded many of those babies.

The question of whether standard of care can be linked to standard of living or whether a single universal standard of care must be applied in every situation was a chief sticking point through the evening.

In the end, the participants seemed to be divided into two camps: idealists who saw clearly what justice would dictate in an ideal world, and their more realistic colleagues who must find partial solutions by carrying out clinical drug trials under conditions found in the developing world.