Considerations for identifying the “right” subgroup in adaptive enrichment trials

Abstract

Adaptive Enrichment Trials aim to make efficient use of data in a pivotal trial of a new targeted therapy to both (a) more precisely identify who benefits from that therapy and (b) improve the likelihood of successfully concluding that the drug is effective, while controlling the probability of false positives. There are a number of frameworks for conducting such a trial and decisions that must be made regarding how to identify that target subgroup. Among those decisions, one must choose how aggressively to restrict enrollment criteria based on the accumulating evidence in the trial. In this article, we empirically evaluate the impact of aggressive versus conservative enrollment restrictions on the power of the trial to detect an effect of treatment. We identify that, in some cases, a more aggressive strategy can substantially improve power. This additionally raises an important question regarding label indication: To what degree do we need a formal test of the hypothesis of no treatment effect in the exact population implied by the label indication? We discuss this question and evaluate how our answer for adaptive enrichment trials may relate to the answer implied by current practice for broad eligibility trials.