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Unethical Placebo-Controlled Study in Children with Asthma

vitamin D capsulesA recent episode revives a long-standing debate over the ethics of research involving placebos. As reported in the Washington Post  and discussed at length in an article published in Science, a multicenter clinical study supported by the National Institutes of Health and conducted at major medical centers in the United States involved children with asthma, most of whom lived in relatively disadvantaged communities. The lead institution was the University of Pittsburgh; other prestigious participating medical centers included the University of California at San Francisco, Boston Children’s Hospital (affiliated with Harvard Medical School), and Rainbow Babies and Children’s Hospital in Cleveland.

As described in the Science article, the subjects were children with asthma “who had low or deficient levels of vitamin D—many from urban, minority communities; most were Black. Half of the 400 planned participants would receive a daily high-dose vitamin D supplement for about 1 year. The other half would serve as controls.” That is where the ethical problem arose: the control group received a placebo. The standard practice in clinical medicine, according to medical authorities, is that children with vitamin D deficiency are given a modest dose of the vitamin. But rather than adhere to that usual practice for the control group, the researchers chose to give those children a placebo, contending that “vitamin D testing is not routine” and “the kids’ vitamin deficiency probably wouldn’t have been detected, so they were no worse off in the study” (Science).

It is worth noting that two similar studies conducted in other U.S. institutions involving children with asthma refused to approve the use of placebo for the control group. In one study, published in JAMA in 2017, the control group received the standard dose of vitamin D, consistent with vitamin D guidelines from the American Academy of Pediatrics (AAP). The second study also cited the AAP guidelines, and its investigators refused to consider a placebo control.

There is little doubt that the children in this study came from disadvantaged backgrounds. The high rate of asthma and the number of children with vitamin D insufficiency provide strong evidence for this conclusion. The disproportionate number of children of color enrolled in the study (more than 70 percent, with more than 50 percent being Black) provides further evidence. I argue that the use of a placebo in research that involves a disadvantaged group of subjects is unethical, even when those participants would not receive the usual treatment outside the study. It is unethical for the same reason that it is unethical to conduct placebo-controlled studies in poor countries when those same studies could not have been done in the United States or other wealthy countries. That practice was relatively common in the past, until a major controversy arose over placebo-controlled HIV research in poor countries in the late 1990s. Although leading methodologists consider placebo-controlled trials the “gold standard,” the rationale that “we’re not making them any worse off than they would be outside the study” smacks of exploitation.

The duration of this study was 48 weeks—almost a year. The protocol says: “The risk to study participants is minimal and no greater than that encountered in daily life by healthy community-dwelling children. Moreover, we will provide dietary counseling to parents of study participants.” It is commendable to provide dietary counseling, but that does not guarantee that the children will be provided with vitamin supplementation or better diets. While it is true that research is not designed to provide a benefit to participants when a trial is over, the Declaration of Helsinki and other research ethics guidelines call for arrangements to provide such benefits in resource-poor countries. This has become accepted practice to avoid exploitation and “safari research,” in which researchers would go to a poor country, conduct a study showing some benefit that’s otherwise unavailable to a majority of the population, and leave nothing behind. The situation is analogous for disadvantaged populations in the United States. For the most part, the U.S. healthcare system has proven to be inadequate to meet their needs.

This trial was stopped early for futility. A data and safety monitoring board concluded, during an interim review, that vitamin D supplementation had failed to prevent asthma attacks. The Science article says: “The researchers kept an unspecified number of kids, even if very deficient in the vitamin, on a placebo for up to six more months.” This was done to ensure “an orderly closeout,” according to James Kiley, the director of the Division of Lung Diseases of the National Heart, Lung, and Blood Institute, one of the study’s sponsors. Shouldn’t the trial sponsors have provided for a proper dose of vitamin D during that period? In recent years, clinical trials conducted by rich-country researchers in poor countries have made some arrangements, before a trial is begun, to provide post-trial benefits. Not only did these researchers make no such plans; they kept some children on a placebo for up to six more months.

Strong proponents of so-called placebo orthodoxy might defend this study. But they rarely state one of the underlying reasons: placebo-controlled trials require fewer research subjects; they can be done more quickly, and are therefore cheaper than noninferiority studies (studies designed to demonstrate that an experimental treatment is not substantially worse than a control). I find it surprising—if not appalling—that institutional review boards in these major U.S. medical centers are willing to approve studies in which disadvantaged children are denied the standard treatment by being randomized to placebo. The claim that the children are not being made worse off than they would be if not enrolled in the study is an ethically flawed justification.

Ruth Macklin, Ph.D.

Ruth Macklin, Ph.D.

Dr. Macklin is distinguished university professor emerita at Albert Einstein College of Medicine. She is the 2014 recipient of The Hastings Center’s Henry Knowles Beecher Award, which is given in recognition of a lifetime contribution to ethics and the life sciences.

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