Doubting the Placebo in a Placebo-Controlled Study
(Thursday, February 25, 2021)
Placebo-controlled studies are the global gold standard to evaluate the safety and effectiveness of new drugs. However, can placebo make a new product look better than it actually is by causing adverse effects not otherwise seen or inducing other artifacts that make the active drug look better? An interesting commentary in the Journal of American Medical Association this week lists several concerns with placebos using examples from well-known clinical trials where the placebo was found to confound or conflate the benefits of the test drug. A placebo is intended to be an inert neutral compound that looks and feels like the active drug but has no biological effect. That said, a placebo is still known to cause a well-defined biological effect, despite being inert, called the “placebo-effect” where the mere use of an intervention causes the patients participating in clinical trials to feel better. Such placebo-effect is very prominent in indications that rely on patient-reported outcomes. However, for trials with objective endpoints based on unbiased measures, the placebo is critical to measure the true effect of a drug compared to a “fake” treatment. The use of placebo is considered so critical that regulators have rarely approved a new drug without data from placebo-controlled studies. There have been a few cases where the placebo was suspected to enhance the benefits or safety of a drug, as listed in the JAMA report this week,  but those are rare cases among a very robust evidence to the contrary. The authors of the commentary urge that developers and regulators should disclose the complete identity of the placebo for independent analysis by the scientific community and confirmation of the benefits. However, that’s not how new drugs are approved. The developers are required to disclose the complete certificate of analysis of their placebo to FDA and other regulators, who in turn make the assessment regarding the appropriateness of the choice of the placebo. Any results presented by the developers in support of their market approval application are reviewed, both in the active and placebo arms, to decide whether or not to approve a new drug. While the examples cited by the authors in this commentary raise important questions, but they fail to acknowledge that the examples selected by them present rare occurrences and not the norm. There is no reason to assume that the placebo-controlled studies are a reliable and robust measure of the safety and effectiveness of a new drug.

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AUTHOR               

 Dr. Mukesh Kumar
​ Founder & CEO, FDAMap

 Email: mkumar@fdamap.com
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