Response‐Adaptive Randomization Procedure in Clinical Trials with Surrogate Endpoints

Abstract

In clinical trials, subjects are usually recruited sequentially. According to the outcomes amassed thus far in a trial, the response‐adaptive randomization (RAR) design has been shown to be an advantageous treatment assignment procedure that skews the treatment allocation proportion to pre‐specified objectives, such as sending more patients to a more promising treatment. Unfortunately, there are circumstances under which very few data of the primary endpoints are collected in the recruitment period, such as circumstances relating to public health emergencies and chronic diseases, and RAR is thus difficult to apply in allocating treatments using available outcomes. To overcome this problem, if an informative surrogate endpoint can be acquired much earlier than the primary endpoint, the surrogate endpoint can be used as a substitute for the primary endpoint in the RAR procedure. In this paper, we propose an RAR procedure that relies only on surrogate endpoints. The validity of the statistical inference on the primary endpoint and the patient benefit of this approach are justified by both theory and simulation. Furthermore, different types of surrogate endpoint and primary endpoint are considered. The results reassure that RAR with surrogate endpoints can be a viable option in some cases for clinical trials when primary endpoints are unavailable for adaptation.