Placebo orthodoxy and the double standard of care in multinational clinical research

Abstract

It has been almost 20 years since the field of bioethics was galvanized by a controversial series of multinational AZT trials employing placebo controls on pregnant HIV-positive women in the developing world even though a standard of care existed in the sponsor countries. The trove of ethical investigations that followed was thoughtful and challenging, yet an important and problematic methodological assumption was left unexplored. In this article, I revisit the famous “double standard of care” case study in order to offer novel consideration of the placebo orthodoxy that underlies much of the ethical debate. This majority view found in medical research is that placebo-controlled trials are methodologically superior to comparative trials that use active controls. I challenge this orthodoxy and argue that lives were unnecessarily lost in these trials as a result. Furthermore, current HIV research on vaccines and microbicides is now poised to repeat the error of subscribing to the placebo orthodoxy.

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Fig. 1

Notes

  1. 1.

    PCTs, by contrast, are typically superiority trials, which determine the difference between two interventions.

  2. 2.

    Spencer P. Hey and Charles Weijer [54] similarly called for totality of evidence in properly inferring both claims of efficacy and efficiency in clinical trials. They proposed that “what is needed … is a series of trials, whose various designs are perturbed to optimally contribute toward demonstrating a robust pattern of evidence” [54, p. 3]. This convergence of conclusions is not surprising, as the “totality of evidence argument” follows from Anderson’s observation [53] that Temple and Ellenberg’s [39] concern that ACETs rely on external information is just an instance of Duhemian under-determination.

  3. 3.

    While this patchwork of inferential information made a sufficiently strong case against the need for PCTs, it was not strong enough to preclude the need for further experimentation all together. Before implementing large-scale health interventions that impact the lives of many and utilize considerable resources, one needs more secure data than reasonable sounding inferences. Direct experimentation is generally more trustworthy. The inferential data, however, was compelling enough to help determine what kind of direct experimentation should be undertaken.

  4. 4.

    One might object that the NIH and CDC could have been genuinely motivated by cost considerations rather than placebo orthodoxy in their promotion of PCTs, given that my arguments regarding the limits of statistical significance testing only make the case that PCTs should not be cheaper that ACETs if the former are conducted well. Instead, PCTs are cheaper when their evidentiary limits are accepted or ignored. It is not known what knowledge the NIH and CDC had regarding those design limits at the time of this controversy, and how that knowledge had impacted institutional practice. I thank an anonymous reviewer for bringing this point to my attention.

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Correspondence to Maya J. Goldenberg.

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Goldenberg, M.J. Placebo orthodoxy and the double standard of care in multinational clinical research. Theor Med Bioeth 36, 7–23 (2015). https://doi.org/10.1007/s11017-015-9317-9

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Keywords

  • Placebo
  • Randomized controlled trials
  • Multinational clinical trials
  • Developing world bioethics
  • HIV/AIDS
  • Active-controlled trials