Identifying treatment effect heterogeneity in dose-finding trials using Bayesian hierarchical models

An important task in drug development is to identify patients, which respond better or worse to an experimental treatment. Identifying predictive covariates, which influence the treatment effect and can be used to define subgroups of patients, is a key aspect of this task. Analyses of treatment effect heterogeneity are however known to be challenging, since the number of possible covariates or subgroups is often large, while samples sizes in earlier phases of drug development are often small. In addition, distinguishing predictive covariates from prognostic covariates, which influence the response independent of the given treatment, can often be difficult. While many approaches for these types of problems have been proposed, most of them focus on the two-arm clinical trial setting, where patients are given either the treatment or a control. In this article we consider parallel groups dose-finding trials, in which patients are administered different doses of the same treatment. To investigate treatment effect heterogeneity in this setting we propose a Bayesian hierarchical dose-response model with covariate effects on dose-response parameters. We make use of shrinkage priors to prevent overfitting, which can easily occur, when the number of considered covariates is large and sample sizes are small. We compare several such priors in simulations and also investigate dependent modeling of prognostic and predictive effects to better distinguish these two types of effects. We illustrate the use of our proposed approach using a Phase II dose-finding trial and show how it can be used to identify predictive covariates and subgroups of patients with increased treatment effects.