Using instrumental variables to disentangle treatment and placebo effects in blinded and unblinded randomized clinical trials influenced by unmeasured confounders

TL;DR

This paper introduces a method using instrumental variables to separate treatment and placebo effects in both blinded and unblinded randomized clinical trials, addressing unmeasured confounders to improve effect estimation.

Contribution

It presents a novel approach leveraging instrumental variables to disentangle treatment and placebo effects, applicable even in unblinded trials with confounders.

Findings

Improves treatment effect estimation in blinded trials.

Enables accounting for placebo effects in unblinded trials.

Uses randomization to manipulate treatment and psychological encouragement independently.

Abstract

Clinical trials traditionally employ blinding as a design mechanism to reduce the influence of placebo effects. In practice, however, it can be difficult or impossible to blind study participants and unblinded trials are common in medical research. Here we show how instrumental variables can be used to quantify and disentangle treatment and placebo effects in randomized clinical trials comparing control and active treatments in the presence of confounders. The key idea is to use randomization to separately manipulate treatment assignment and psychological encouragement messages that increase the participants' desire for improved symptoms. The proposed approach is able to improve the estimation of treatment effects in blinded studies and, most importantly, opens the doors to account for placebo effects in unblinded trials.