The response to the Covid-19 pandemic by drug and vaccine developers has been swift. BioCentury lists more than 400 unique compounds — small molecules, antibodies, and vaccines — that are currently in clinical development for Covid-19.
Yet the success of this work is at risk due to an invisible threat: the placebo response. It could contribute to clinical trial failures and delay the delivery of medications and vaccines to mitigate this global public health disaster.
The placebo response is a complex psychobiological phenomenon that describes the clinical improvement seen in patients taking dummy or sham medicines. It can also comprise some proportion of the measured effect among patients receiving active drugs. Multiple behavioral, psychophysiological, and neuroimaging studies have shown that the placebo response is a real, multifactorial effect associated with changes in biochemical pathways in the brain. The effect is patient specific and is influenced by patient expectations and certain well-defined personality traits.
While drug developers are attuned to considering the placebo response in areas like pain and depression, it may not be immediately apparent why it is so critical for the development of Covid-19 therapies and vaccines. What set the stage was the FDA’s regulatory guidance, released in May, directing how the biopharma industry should evaluate drugs and vaccines being developed to fight the pandemic.
The FDA indicated that Phase 3 trials will need to go beyond measuring survival or viral load and evaluate how patients feel and function. This emphasizes the importance of evaluating clinical improvement based on the presence, severity, or duration of symptoms and functional limitations. Even Covid-19 vaccine trials use the prevention of symptomatic Covid-19 disease as a primary endpoint.
Recent data released by Eli Lilly on its therapeutic antibody show that a reduction in viral load does not necessarily translate into improvement in clinical signs and symptoms for Covid-19 patients. In that Phase 2 trial, there were encouraging reductions in patients’ levels of SARS-CoV-2, the virus that causes Covid-19, yet the degrees to which patients actually experienced clinical benefit was unclear.
In the early days of the pandemic, drug development focused on improving survival and reducing ventilator usage in the sickest patients. In the wake of improved medical management of severe Covid-19 patients and more therapeutic options, the industry’s sights are now being set on developing medicines for people with mild-to-moderate Covid-19. This means focusing on reducing the severity of symptoms, with the goal of reducing hospitalizations, costs, and the overall burden to health care systems. Here again, the placebo response may be influential.
As Covid-19 trials focus on clinical symptoms, they will rely on self-reporting of body aches, cough, shortness of breath, and the burden on everyday life. These endpoints are subjective, highly variable, and have been associated with significant placebo response rates. To illustrate, in pain trials, up to two-thirds of treatment efficacy has been attributed to the placebo response, and the rate is as high as 85% in trials for cough.
The placebo effect is, in fact, arising in studies for Covid-19 vaccines. Pfizer discussed the tolerability profile of its vaccine candidate in a recent investor presentation, and participants receiving placebo showed significant increases in fatigue and headache (see slide 17 of the presentation). This phenomenon is specifically related to the placebo response.
The urgency to develop Covid-19 therapies and vaccines may actually make matters worse. The tremendous societal need for and media attention on clinical development of these agents is likely to increase patients’ expectations of — or pressure for — an effective treatment, which substantially increases the likelihood of a high placebo response rate.
Covid-19 has also forced the industry to conduct clinical trials remotely so patients can stay home instead of traveling to study sites. That introduces new variables with respect to the psychology of participants. Interactions between clinical trial participants and trial physicians influence the placebo response, so shifting to virtual health trial visits will almost certainly affect how some participants respond to either drug or placebo.
A high placebo response has undermined hundreds of clinical trials over the last several decades and is a major cause of failure in Phase 3 trials. Just last year, Lundbeck announced the failure of its Phase 3 trial for brexpiprazole, an antipsychotic drug candidate. The drug did not meet statistical significance versus placebo in the primary endpoint; a higher-than-expected placebo response was cited as a major factor.
Awareness of the phenomenon in the context of the many ongoing Phase 3 clinical trials for Covid-19 therapies and vaccines will be crucial to understanding their true benefits.
Erica Smith is a vice president of Tools4Patient, a Belgium-based company focused on de-risking clinical drug development. Dominique Demolle is the company’s CEO.
I would like to commend the authors for drawing attention to the placebo response in COVID-19 trials, a phenomenon which is indeed prominent in trials with subjective endpoints. It is also worth recognizing a related phenomenon, that many patients do not naturally report symptoms accurately, and that both placebo responsiveness and accuracy of symptom reporting can be improved with training (Treister et al 2018, 2019).