Bayesian Utility-Based Designs for Subgroup-Specific Treatment Comparison and Early-Phase Dose Optimization in...

Despite the fact that almost any sample of patients with a particular disease is heterogeneous, most clinical trial designs ignore the possibility that treatment or dose effects may differ between prognostic or biologically defined subgroups. This article reviews two clinical trial designs that make subgroup-specific decisions and compares each to a simpler design that ignores patient heterogeneity. The purpose is to illustrate the benefits of accounting prospectively for treatment-subgroup interactions and how utilities may be used to quantify risk-benefit trade-offs.

Two Bayesian clinical trial designs that perform subgroup-specific decision making and inference based on elicited utilities of patient outcomes are reviewed. The first is a randomized comparative trial of nutritional prehabilitation for patients undergoing esophageal resection that has two prognostic subgroups and is based on postoperative morbidity score. The second is a sequentially adaptive trial of natural killer cells for treating hematologic malignancies that is based on five time-to-event outcomes and that performs safety monitoring and optimizes cell dose within six disease subgroups. Computer simulations under a range of different scenarios are presented for each design to establish its operating characteristics and compare it to a more conventional design that ignores patient heterogeneity.

Each design has attractive operating characteristics, is greatly superior to a simplified design that ignores patient subgroups, is robust to deviations from its assumed statistical model, and is feasible to use for conducting trials.

Bayesian designs that make subgroup-specific decisions in randomized comparative trials or sequentially adaptive early-phase dose-finding trials are superior to designs that ignore patient heterogeneity. Using elicited utilities of complex patient outcomes to quantify risk-benefit trade-offs provides a practical and ethical basis for decision making and treatment evaluation in clinical trials.