DOI
https://doi.org/10.25772/123Z-6P95
Defense Date
2020
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Biostatistics
First Advisor
Robert A. Perera, PhD
Abstract
Historically, clinical trials have been performed based on decisions made prior to the start of the trial. Adaptive designs have been developed to provide increased flexibility, allowing pre-specified changes to occur based on interim data. Each adaptive design addresses a unique pitfall of a non-adaptive design, such as minimizing the chance of an under- or over-powered study by utilizing interim data to update the sample size estimate (sample size re-estimation) or increasing the ethical benefit of a trial by allocating more participants to the better performing treatment group ([covariate-adjusted] response-adaptive randomization). Additional benefit is attainable by combining more than one adaptive design within a single clinical trial to form a multiple adaptive design. The current multiple adaptive design literature, however, performs the designs independently and sequentially, negating the flow of information between each design. In this work, we develop integrated multiple adaptive designs that allow the two considered adaptive designs to be simultaneously optimized. Specifically, integrated multiple adaptive designs combining sample size re-estimation (SSR) and response-adaptive randomization (RAR) are developed for continuous and binary outcomes to allow for the balance between allocating participants in a manner that minimizes the total sample size required and ethically allocating participants. For continuous outcomes, we extend the framework from the integration of SSR and RAR to allow for increased personalization by allocating participants based on their covariate profile (covariate-adjusted response-adaptive randomization) while simultaneously considering the impact of the resultant allocation on the sample size re-estimation. The developed methods show benefit in terms of ethics and efficiency when compared to a fixed design, with no adaptive elements; singly adaptive designs, where only one adaptive design is included; and a sequential multiple adaptive design, where the two adaptive elements are included but not integrated.
Rights
© Christine M. Orndahl
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
12-18-2020