How should we design future mechanistic and/or efficacy clinical trials?

New molecular targets and novel treatments for neuropsychiatric diseases, including psychedelics and gene and cell therapies, require more efficient clinical trials. This review examines factors that hinder the detection of therapeutic signals, such as excessive placebo or sham responses and imprecise diagnostic and outcome measures. It also presents methodological approaches to improve trial performance, including the sequential parallel comparison design and independent confirmation of subject enrollment, along with designs that increase the precision of mechanistic trials.

Study at a glance

Abstract

The emergence of new molecular targets, together with the development of new approaches to neuropsychiatric diseases, involving psychedelics as well as gene and cell therapies, are creating the need to improve the efficiency of mechanistic and/or efficacy clinical trials. This review article will discuss a number of issues that have hampered our ability to detect therapeutic signals, from excessive placebo/sham response rates to the imprecision of diagnostic and outcome assessments. In addition to reviewing the limitations of current efficacy and mechanistic neuropsychiatric clinical trials, this review presents some of the methodological approaches that may improve the overall performance of our neuropsychiatric trials, including the adoption of novel study designs such as the sequential parallel comparison design and independent confirmation of the appropriateness of subjects' enrollment. In addition, this review will discuss several designs that make mechanistic clinical trials more precise.