A tutorial on the use of exploratory efficacy outcomes in uncontrolled phase I cell therapy trials

Phase I cell therapy clinical trials evaluate the safety of novel biologic treatments and are often uncontrolled. Many of these studies also include exploratory efficacy outcome measures, which are frequently continuous measures of disease state or severity, or participant‐reported measures of symptom burden or quality of life. When such outcomes are included in uncontrolled phase I trials, they are typically serially assessed on the participants over time, and any improvement from baseline is interpreted as preliminary evidence of efficacy justifying a future, controlled trial. However, it is challenging to distinguish true improvement from regression to the mean in this design. The problem is exacerbated when trial entry criteria are based on extreme values of the outcome measure used to assess efficacy. It is possible to estimate the expected effect of regression to the mean when the natural history of the outcome measure is known, yet this is rarely done in practice. This article provides a refresher on regression to the mean for investigators designing early phase clinical trials in cell therapy and evaluates the potential for regression to the mean to have influenced conclusions drawn from recently conducted phase I cell therapy trials.