Bayesian Safety and Futility Monitoring in Phase II Trials Using One Utility-Based Rule.

Abstract

For phase II clinical trials that determine the acceptability of an experimental treatment based on ordinal toxicity and ordinal response, most monitoring methods require each ordinal outcome to be dichotomized using a selected cut-point. This allows two early stopping rules to be constructed that compare marginal probabilities of toxicity and response to respective upper and lower limits. Important problems with this approach are loss of information due to dichotomization, dependence of treatment acceptability decisions on precisely how each ordinal variable is dichotomized, and ignoring association between the two outcomes. To address these problems, we propose a new Bayesian method, which we call U-Bayes, that exploits elicited numerical utilities of the joint ordinal outcomes to construct one early stopping rule that compares the mean utility to a lower limit. U-Bayes avoids the problems noted above by using the entire joint distribution of the ordinal outcomes, and not dichotomizing the outcomes. A step-by-step algorithm is provided for constructing a U-Bayes rule based on elicited utilities and elicited limits on marginal outcome probabilities. A simulation study shows that U-Bayes greatly improves the probability of determining treatment acceptability compared to conventional designs that use two monitoring rules based on marginal probabilities.