The placebome

Abstract

Placebos in randomized clinical trials (RCTs) control for many nonspecific factors that influence clinical outcomes, beyond the active agent being tested. These include the "placebo effect," regression to the mean, clinician bias, Hawthorne effects, and the natural history of the condition or disease. The impact of these factors together constitute the "placebo response." A key assumption in RCTs is that the placebo response is a discrete component of response to drug, and thus placebo and drug responses are additive. Based on this additivity assumption, the efficacy of a drug is generally determined to be the difference between the drug and placebo responses. There is evidence that genetic variation can influence at least two key components of placebo response in RCTs: placebo effects and the natural history of the disease process. Further, although some drugs, like naloxone, can modify placebo effects, little is known about the potential for genetic variation to modify the effects of these drugs relative to placebo. If genetic influences on patients vary between the drug and placebo arm, potential gene-by-drug/placebo interactions could mask treatment effects. Here, we review evidence that genetic variation in the placebome - the group of genome-related mediators that affect an individual's response to placebo treatments - could confound results of RCTs through differential effects in the drug and placebo treatment arms.

Keywords: Clinical research; Drug development; Genetics; Genomics; Placebo; Placebo genetics.