March 5, 2020

The Placebo response in drug development. Part 1: Rheumatoid Arthritis

Placebo-controlled clinical trials are the gold standard in drug development, in part to ensure that the efficacy of a new therapy exceeds the placebo response in the indication being studied. The placebo response is a measured improvement in clinical signs and/or symptoms that occurs in patients receiving a sham or “dummy” treatment. The placebo response is a complex psychological, biological and sociological phenomenon that confounds clinical data analysis, particularly for subjective and patient-reported outcomes. The placebo response is widely known to compromise evaluation of pain endpoints and has been suggested to contribute to as much as ~2/3 of the measured treatment effect in  pain from various etiologies1, contributing to the high rate of Phase II and III clinical trial failure in this indication2. The placebo response is, however, not limited to pain trials; in fact, the understanding of the impact of this phenomenon in a wide variety of therapeutic areas is growing steadily. This article is part of a series that will examine the impact of the placebo response in drug development in areas beyond pain.

Evidence has accumulated in recent years that the placebo response is a significant issue in evaluating efficacy of drugs for rheumatoid arthritis (RA). RA is a chronic disease characterized by inflammatory synovitis and progressive joint destruction. It can be severely disabling with a an annual incidence of up to 40 per 100,000 in the United States and a prevalence of 1.3 million in the United States and between 0.24 and  1% worldwide3. Historically, treatments were limited to conventional disease-modifying antirheumatic drugs (DMARDs) such as methrotrexate, but more recently biological DMARDs – such as those targeting tumor necrosis factor (TNF-) – have significantly increased the number of patients reaching clinical remission4. Efficacy of disease-modifying drugs in RA is primarily demonstrated by reduction in the RA Disease Activity Score (DAS-28) and American College of Rheumatology (ACR) response criteria. These efficacy endpoints are composite scores combining objective evidence of inflammation as well as subjective measures of disease activity (e.g. pain).

Recently Bechman et al., have conducted a meta-analysis to characterize the placebo response in RA5. Initially, 1828 trials were identified (published up to July 2018) but only 32 Phase II and III trials were selected (based on similarity in study designs, previous exposure to RA treatment and patient population), including trials for both biologics and JAK inhibitors. From 1999 to 2018, there was a statistically significant increase in placebo ACR50 and ACR70 responses (ACR50 ß=0.41, 95 CI of 0.09 to 0.74, with a p-value of 0.01; ACR70 ß=0.18, 95 CI of 0.04 to 0.31, with a p-value of 0.01) that remained significant after controlling for potential confounding factors. The authors did not observe a change in treatment response in the active therapeutic arm over time. According to them, this increase in placebo response may be related to changes over time in trial design, study population, and expectation bias. The authors also mentioned geography as a potential source of placebo response inflation. A similar meta-analysis performed by Tuttle, et al6 in pain examining studies conducted in the US only reached a similar conclusion: the placebo response was increasing over time. 

Unfortunately, this increasing placebo response over time may lead to further decreases in effect size and thus continue to present a significant obstacle to the development of new drugs for RA. The authors of this meta-analysis5 noted that the ability to measure expectation bias and predict placebo responders could substantially improve the design and interpretation of trials. At Tools4Patient, we have developed a platform solution called Placebell©™ to reduce the impact of the placebo response in clinical trials that can be applied to virtually any therapeutic area.  This approach considers multiple factors on an individual patient basis, including demographics, medical history, baseline disease intensity and certain previously identified psychological traits.  Initial data in pain suggest that the Placebell©™ approach can reduce data variability related to the placebo response by as much as 30%. Placebell©™ is currently being applied to clinical trials in pain and being evaluated in neurology, psychiatry and ophthalmology. It can easily be adapted for use in inflammatory disease.  Furthermore, implementation of Placebell©™ only requires that our proprietary psychological questionnaire be administered to patients at screening or baseline. For more information on scientific collaboration in diseases beyond pain, please contact us.


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. 2011;152(8):1709-1717. doi:10.1016/j.pain.2011.01.050

2.        Dumitrescu TP, McCune J, Schmith V. Is Placebo Response Responsible for Many Phase III Failures? Clin Pharmacol Ther. 2019;106(6):1151-1154. doi:10.1002/cpt.1632

3.        RA Facts: What are the Latest Statistics on Rheumatoid Arthritis? –

4.        Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P. New therapies for treatment of rheumatoid arthritis. Lancet. 2007;370(9602):1861-1874. doi:10.1016/S0140-6736(07)60784-3

5.        Bechman K, Yates M, Norton S, Cope AP, Galloway JB. Placebo response in rheumatoid arthritis clinical trials. J Rheumatol. 2020;47(1):28-34. doi:10.3899/jrheum.190008

6.        Tuttle AH, Tohyama S, Ramsay T, et al. Increasing placebo responses over time in U.S. clinical trials of neuropathic pain. Pain. 2015;156(12):2616-2626. doi:10.1097/j.pain.0000000000000333

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