Joint Estimation of Treatment and Placebo Effects in Clinical Trials With Longitudinal Blinding Assessments

Abstract

In some therapeutic areas, treatment evaluation is frequently complicated by a possible placebo effect (i.e., the psychobiological effect of a patient’s knowledge or belief of being treated). When a substantial placebo effect is likely to exist, it is important to distinguish the treatment and placebo effects in quantifying the clinical benefit of a new treatment. These causal effects can be formally defined in a joint causal model that includes treatment (e.g., new versus placebo) and treatmentality (i.e., a patient’s belief or mentality about which treatment she or he has received) as separate exposures. Information about the treatmentality exposure can be obtained from blinding assessments, which are increasingly common in clinical trials where blinding success is in question. Assuming that treatmentality has a lagged effect and is measured at multiple time points, this article is concerned with joint evaluation of treatment and placebo effects in clinical trials with longitudinal follow-up, possibly with monotone missing data. We describe and discuss several methods adapted from the longitudinal causal inference literature, apply them to a weight loss study, and compare them in simulation experiments that mimic the weight loss study.

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

“…It has being pointed out, however, that even blinded studies might be influenced by placebo effects, as the patients perceptions and beliefs about the treatment they think they received are able to trigger strong placebo effects11213. Recently, a number of statistical approaches have been proposed to quantify the contributions of treatment and placebo effects to a clinical outcome232425. These approaches, nonetheless, are tailored to blinded trials, and leverage blinding assessment data to quantify the amount of unmasking taking place during the trial.…”

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

“…It has being pointed out, however, that even blinded studies might be influenced by placebo effects, as the patients perceptions and beliefs about the treatment they think they received are able to trigger strong placebo effects [1,11,10]. Recently, a number of statistical approaches have been proposed to quantify the contributions of treatment and placebo effects to a clinical outcome [22,23,24]. These approaches, nonetheless, are tailored to blinded trials, and leverage blinding assessment data to quantify the amount of unmasking taking place during the trial.…”