A simulation study of methods for selecting subgroup‐specific doses in phase 1 trials |
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| Authors: | Satoshi Morita Peter F. Thall Kentaro Takeda |
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| Affiliation: | 1. Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan;2. Department of Biostatistics, The University of Texas, Houston, TX, USA;3. Department of Biostatistics and Epidemiology, Yokohama City University, Yokohama, Japan;4. Biostatistics Group,Data Science,Global Development, Astellas Pharma INC, Tokyo, Japan |
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| 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. |
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| Keywords: | Bayesian study design conditionally independent hierarchical model continual reassessment method phase 1 clinical trial subgroup‐specific dose‐finding |
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