Adaptive Randomization to Improve Utility-Based Dose-Finding with Bivariate Ordinal Outcomes

• Published in: Journal of biopharmaceutical statistics Vol. 22; no. 4; pp. 785 - 801
• Main Authors: Thall, Peter F., Nguyen, Hoang Q.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis Group 01.07.2012; Taylor & Francis Ltd
• Subjects: Adaptive design; Algorithms; Bayes Theorem; Bayesian analysis; Bayesian design; Brain Stem Neoplasms - radiotherapy; Child, Preschool; Clinical trial; Clinical Trials, Phase I as Topic - standards; Clinical Trials, Phase II as Topic - standards; Dose-finding; Dose-Response Relationship, Radiation; Epsilon-greedy algorithm; Humans; Phase I/II clinical trial; Pons; Probability distribution; Radiotherapy - standards; Randomized Controlled Trials as Topic - standards; Risk assessment; Sample Size; Simulation; Toxicity; Treatment Outcome; Utility
• ISSN: 1054-3406; 1520-5711
• DOI: 10.1080/10543406.2012.676586

A sequentially outcome-adaptive Bayesian design is proposed for choosing the dose of an experimental therapy based on elicited utilities of a bivariate ordinal (toxicity, efficacy) outcome. Subject to posterior acceptability criteria to control the risk of severe toxicity and exclude unpromising doses, patients are randomized adaptively among the doses having posterior mean utilities near the maximum. The utility increment used to define near-optimality is nonincreasing with sample size. The adaptive randomization uses each dose's posterior probability of a set of good outcomes, defined by a lower utility cutoff. Saturated parametric models are assumed for the marginal dose-toxicity and dose-efficacy distributions, allowing the possible requirement of monotonicity in dose, and a copula is used to obtain a joint distribution. Prior means are computed by simulation using elicited outcome probabilities, and prior variances are calibrated to control prior effective sample size and obtain a design with good operating characteristics. The method is illustrated by a Phase I/II trial of radiation therapy for children with brainstem gliomas.