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What questions can a placebo answer?

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Abstract

The concept of clinical equipoise restricts the use of placebo controls in clinical trials when there already exists a proven effective treatment. Several critics of clinical equipoise have put forward alleged counter-examples to this restriction—describing instances of ethical placebo-controlled trials that apparently violate clinical equipoise. In this essay, we respond to these examples and show that clinical equipoise is not as restrictive of placebos as these authors assume. We argue that a subtler appreciation for clinical equipoise—in particular the distinction between de facto and de jure interpretations of the concept—allows the concept to explain when and why a placebo control may be necessary to answer a question of clinical importance.

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Notes

  1. “Competent medical care” refers to care that is consistent with the norms of the expert medical community. Typically, it encompasses a range of treatment approaches for a given medical condition. In other words, competent care is treatment consistent with the standard of care. Legally, this refers to treatment that is endorsed by at least a respectable minority of expert practitioners.

  2. It is worth noting that there are many conceptions of “equipoise” and “clinical equipoise”. See London (2007) for an excellent summary of the various conceptions, their moral foundations, and their potential problems.

  3. One could object that even if there is no methodological difference in kind, there may still be a methodological difference in degree—that is, PCTs make background assumptions that are more plausible or verifiable than ACTs. See Hey and Weijer (2013) for further discussion of this objection.

  4. Freedman (1990) also includes an exception for the use of placebos in populations that do not have access to the proven effective treatment. The use of PCT under such conditions is a vigorous debate in its own right, but would take us too far afield to discuss it here.

  5. For example, a decisively negative PCT—which was inconsistent with clinical equipoise—can still be informative for clinical practice. Since the experimental intervention has failed to outperform the placebo under ideal, experimental conditions, then clinicians could justifiably infer that the experimental intervention is unlikely to be effective in the real-world conditions of practice.

  6. It is worth noting, however, that three-arm PCTs of antidepressants are often only statistically powered for the placebo comparison, leaving them underpowered to detect a difference between the experimental agent and the active comparator (Vieta and Cruz, 2012). Therefore, even if the use of placebo is consistent with clinical equipoise, the specific PCT may still be unethical due to weak scientifically validity.

  7. It is also worth noting, as Hey and Truog (2015) do, that response rates for vemurafenib did indeed regress considerably, from 81 % in phase 1 trials, to 53 % in phase 2, to 48 % in phase 3 (Chapman et al. 2011).

  8. The now well-recognized problem of acquired resistance to BRAF inhibition chemotherapies (such as vemurafenib) may make such add-on trials both scientifically and morally prudent (for example, see Flaherty et al. 2012).

  9. It is worth pointing out that placebo-controlled surgical trials are cases of “complex placebos,” which include a “no treatment” component and a non-therapeutic component (the sham surgical procedures). Only the risks from the “no treatment” arm in these trials are justified by clinical equipoise. The risks from the non-therapeutic components must be justified by considerations of sound scientific design and the contribution to generalizable knowledge (Weijer 2002; Weijer and Miller 2004).

  10. Again, see London (2007) for an excellent review of the non-exploitation approach as an alternative to clinical equipoise.

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Authors and Affiliations

  1. Division of Pharmacoepidemilogy and Pharmacoeconomics, Brigham and Women’s Hospital, Harvard Center for Bioethics, Harvard Medical School, Boston, MA, USA

    Spencer Phillips Hey

  2. Rotman Institute of Philosophy, Western University, Stevenson Hall 2150c, London, ON N6A 5B8, Canada

    Charles Weijer

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  1. Spencer Phillips Hey
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Correspondence to Spencer Phillips Hey.

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Hey, S.P., Weijer, C. What questions can a placebo answer?. Monash Bioeth. Rev. 34, 23–36 (2016). https://doi.org/10.1007/s40592-016-0057-z

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