September 22, 2020

COVID-19 has had a devastating impact on healthcare systems and the global economy. The search for drugs to treat and prevent SARS-CoV-2 infection is ongoing, with more than 1200 drugs in the pipeline and more 3,200 clinical trials planned or initiated as of 21 September 2020 (GlobalData). The success of these studies, however, may be at risk due to an invisible threat – the placebo response.  

The recent FDA Guidance on Developing Drugs and Biological Products for Treatment or Prevention of COVID-19 indicates that “the extent of clinical benefit of how a patient feels, functions, or survives” is critical as a primary endpoint, while virologic measures should only be used as secondary endpoints. This emphasizes the importance of measuring clinical improvement based on the presence, severity or duration of symptoms and functional limitations when developing drugs to treat COVID-19.  Even COVID-19 vaccine trials use the prevention of symptomatic COVID-19 disease as a primary endpoint. Beyond this, drug development for COVID-19 has been focusing on improving survival and reducing ventilator usage in severely ill patients; however, improved medical management of severe COVID-19 patients and more therapeutic options are shifting attention to treating patients with mild-to-moderate COVID-19 to reduce hospitalizations, cost and the overall burden to healthcare systems.

As COVID-19 trials focus on clinical symptoms, they will rely on self-reporting of body aches, cough, dyspnea, malaise and the ability to conduct daily activities. These endpoints are subjective, highly variable and have been associated with significant placebo response rates.  For example, up to 2/3 of demonstrabletreatment efficacy has been attributed to the placebo response in trials for pain1 and up to 85% in trials for cough2. The placebo response is a complex phenomenon that is influenced by factors including patient personality and expectation3. In fact, significant placebo response rates have been reported in clinical trials that use clinical signs such as pain, discomfort, fatigue, cough, dyspnea and quality of life as primary endpoints.  A high placebo response reduces the ability to demonstrate therapeutic efficacy thus jeopardizing success rate or increasing the number of patients needed. High placebo response rates have led to clinical trial failures in areas like pain and depression, among many others4

When present, a high placebo response can compromise the ability to detect treatment efficacy. The placebo response is highly variable among clinical trial subjects and relates to unique characteristics intrinsic to the subject that can be a major contributing factor to clinical data variability. The high profile and media attention dedicated to clinical trials for COVID-19 may likely accentuate the placebo response in these studies. The great societal need for efficacious therapies for COVID-19 has understandably led to tremendous expectations, desire, hope and need for treatment efficacy in individual clinical trial patients. Indeed, recent Phase 1 data on tolerability of BNT162b2 released by Pfizer to investors showed similar incidence of adverse events like headache and fatigue in subjects after the first dose of either active vaccine and placebo, suggesting a marked placebo response in this trial.COVID-19 is associated with significant mortality and has had a devastating impact on healthcare systems, the global economy, and society in general. Improved medical management of severe COVID-19 patients will ultimately shift attention to diagnosing and treating patients with mild-to-moderate COVID-19 to reduce hospitalizations, cost and the overall burden to healthcare systems. The need for efficacious drugs for mild to severe COVID-19 in early to late-stage patients has never been greater. Any opportunity to mitigate factors that derail or delay the evaluation of experimental therapies for COVID-19 must be seriously considered. As such, scientists and clinicians must address the placebo response when designing trials that evaluate COVID-19 symptom presence, duration and severity as endpoints to limit the risk of clinical trial failure. The critical importance of introducing new therapies to fight COVID-19 compels the consideration of sophisticated methods like Placebell©™ for reducing the impact of the placebo response.


1.         Häuser, W., Bartram-Wunn, E., Bartram, C., Reinecke, H. & Tölle, T. Systematic review: Placebo response in drug trials of fibromyalgia syndrome and painful peripheral diabetic neuropathy – Magnitude and patient-related predictors. Pain 152, 1709–1717 (2011).

2.         Eccles, R. The Powerful Placebo Effect in Cough: Relevance to Treatment and Clinical Trials. Lung vol. 198 13–21 (2020).

3.         Weimer, K., Colloca, L. & Enck, P. Age and sex as moderators of the placebo response – An evaluation of systematic reviews and meta-analyses across medicine. Gerontology 61, 97–108 (2015).

4.         Dumitrescu, T. P., McCune, J. & Schmith, V. Is Placebo Response Responsible for Many Phase III Failures? Clinical Pharmacology and Therapeutics 106, 1151–1154 (2019).


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