Bayesian design of clinical trials using joint models for longitudinal and time-to-event data.

Abstract

Joint models for longitudinal and time-to-event data are increasingly used for the analysis of clinical trial data. However, few methods have been proposed for designing clinical trials using these models. In this article, we develop a Bayesian clinical trial design methodology focused on evaluating the treatment's effect on the time-to-event endpoint using a flexible trajectory joint model. By incorporating the longitudinal outcome trajectory into the hazard model for the time-to-event endpoint, the joint modeling framework allows for non-proportional hazards (e.g., an increasing hazard ratio over time). Inference for the time-to-event endpoint is based on an average of a time-varying hazard ratio which can be decomposed according to the treatment's direct effect on the time-to-event endpoint and its indirect effect, mediated through the longitudinal outcome. We propose an approach for sample size determination for a trial such that the design has high power and a well-controlled type I error rate with both operating characteristics defined from a Bayesian perspective. We demonstrate the methodology by designing a breast cancer clinical trial with a primary time-to-event endpoint and where predictive longitudinal outcome measures are also collected periodically during follow-up.