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.
Original language | English (US) |
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Pages (from-to) | 143-156 |
Number of pages | 14 |
Journal | Pharmaceutical statistics |
Volume | 16 |
Issue number | 2 |
DOIs | |
State | Published - Mar 1 2017 |
Keywords
- Bayesian study design
- conditionally independent hierarchical model
- continual reassessment method
- phase 1 clinical trial
- subgroup-specific dose-finding
ASJC Scopus subject areas
- Statistics and Probability
- Pharmacology
- Pharmacology (medical)
MD Anderson CCSG core facilities
- Biostatistics Resource Group