Statistical considerations in model-based dose finding for binary responses under model uncertainty.

Abstract

The statistical methodology for model-based dose finding under model uncertainty has attracted increasing attention in recent years. While the underlying principles are simple and easy to understand, developing and implementing an efficient approach for binary responses can be a formidable task in practice. Motivated by the statistical challenges encountered in a phase II dose finding study, we explore several key design and analysis issues related to the hybrid testing-modeling approaches for binary responses. The issues include candidate model selection and specifications, optimal design and efficient sample size allocations, and, notably, the methods for dose-response testing and estimation. Specifically, we consider a class of generalized linear models suited for the candidate set and establish D-optimal designs for these models. Additionally, we propose using permutation-based tests for dose-response testing to avoid asymptotic normality assumptions typically required for contrast-based tests. We perform trial simulations to enhance our understanding of these issues.