A simulation study of methods for selecting subgroup-specific doses in phase 1 trials.

Patient heterogeneity may complicate dose-finding in phase 1 clinical trials if the dose-toxicity curves differ between subgroups. Conducting separate trials within subgroups may lead to infeasibly small sample sizes in subgroups having low prevalence. Alternatively,it is not obvious how to conduct a single trial while accounting for heterogeneity. To address this problem,we consider a generalization of the continual reassessment method on the basis of a hierarchical Bayesian dose-toxicity model that borrows strength between subgroups under the assumption that the subgroups are exchangeable. We evaluate a design using this model that includes subgroup-specific dose selection and safety rules. A simulation study is presented that includes comparison of this method to 3 alternative approaches,on the basis of nonhierarchical models,that make different types of assumptions about within-subgroup dose-toxicity curves. The simulations show that the hierarchical model-based method is recommended in settings where the dose-toxicity curves are exchangeable between subgroups. We present practical guidelines for application and provide computer programs for trial simulation and conduct.