Phase III Evaluation of Treatment Combinations in Three-Arm Trials

Abstract

Phase III trials that randomly assign patients to a control treatment (C), an experimental treatment (A), or a combination treatment (AB) should be designed with the goal to recommend the best treatment: AB (if it is better than A and C), A (if it is better than C, and AB is not better than A), or C (if neither AB nor A is better than C). However, this goal can be challenging to achieve with statistical confidence. We performed a survey of cancer trials published in five journals from January 2018 to May 2024 to assess the trial designs being used in this setting and found that three quarters of them did not have a provision for a formal comparison of the AB treatment arm with the A treatment arm, a possible shortcoming. A limited simulation evaluates two analysis strategies that incorporate an AB versus A comparison and is used to formulate some recommendations for designing these types of trials.