Abstract
Randomized clinical trials (RCTs) continue to fail, often because of unexpected results in the placebo arms of studies. Failed RCTs represent a loss of opportunity in multiple ways including the expenditure of finite research dollars on a failed effort, a loss of time for patients who are waiting for cures, and a potential failure to get an effective therapy to patients due to under-powered studies or other design challenges.
There are currently no effective treatments for Alzheimer’s Disease (AD), a progressive neuro-degenerative condition diagnosed in over six million people in the US. (Kim et. al.) AD clinical trials frequently fail because of strong positive results in patients randomized to placebo. Despite extensive characterization of these placebo response trends, the factors that influence them are poorly understood. Here we report findings that suggest that pharmacogenomic influences based on natural history of disease or the mechanism of action of the drug may differentially affect the drug and placebo arms potentially obscuring findings and warrant further investigation of their effects on the outcomes of AD clinical trials.
Structural factors in the design and execution of clinical trails may also impact placebo response. Here we report on a machine-learning led investigation into the sources of variability in a set of COPD confirmatory trials. Variation in response related to patient sequenceing (drug crossover to placebo) was observed, With expectation and conditioning being the most prominent facctors in placebo response, this suggests potential causality.
Understanding factors that influence response to placebo treatment in RCTs can help guide clinical trial design and effective interpretation of efficacy and safety of drug interventions and improve the success rate of drug development. We must seek to understand all aspects of placebo control arms: how genetic variation may impact comparisons, the impact of study/statistical design choices, how disease biology affects patients (natural history of the disease), and the basic physiology of the placebo effect.