title: A simulation study of methods for selecting subgroup-specific doses in phase 1 trials.
abstract: 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.
authors.affiliation: Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Morita
authors.affiliation: Department of Biostatistics, The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Thall
authors.affiliation: Department of Biostatistics and Epidemiology, Yokohama City University, Yokohama, Japan.|Biostatistics Group,Data Science,Global Development, Astellas Pharma INC, Tokyo, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Takeda
mesh_terms: D001499:Bayes Theorem; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D017408:Guidelines as Topic; D006801:Humans; D015233:Models, Statistical; D004364:Pharmaceutical Preparations / Q000008:administration & dosage; D012107:Research Design; D018401:Sample Size
chemical_list: D004364:Pharmaceutical Preparations
keywords: Bayesian study design; conditionally independent hierarchical model; continual reassessment method; phase 1 clinical trial; subgroup-specific dose-finding