A Bayesian predictive framework for adaptive interim-analysis timing with robust borrowing in confirmatory trials

Abstract

Confirmatory phase III trials require rigorous evidence, yet for first-in-class (FIC) therapies they must often be designed when same-mechanism evidence is scarce. This uncertainty motivates planned interim analyses and makes phase II data from the same therapy a relevant source of prior evidence. However, both borrowing and repeated interim analyses must be calibrated to control the overall type I error rate. Because borrowing changes the evidence available at interim analyses relative to a non-borrowing group sequential design (GSD), it also raises the question of whether interim analysis timing should be prospectively adapted to the borrowing-adjusted evidence base. We propose a prespecified adaptive interim-timing framework based on Bayesian information borrowing and Bayesian predictive probability $B^2$-FIC. The borrowing model is calibrated against phase II--phase III discrepancy scenarios to control overall type I error rate. At the first interim analysis (IA1), the calibrated model combines phase II information with accumulating phase III data to update the posterior. Bayesian predictive probabilities from this posterior select the earliest information fraction for the second interim analysis (IA2) that meets the efficacy criterion. In simulations, $B^2$-FIC maintained empirical type I error and improved interim power across different scenarios. Predictive probabilities derived from phase II and phase III IA1 data selected earlier IA2 than GSD when evidence was favorable. Two oncology case studies illustrate the framework. Overall, $B^2$-FIC provides a calibrated framework for adapting interim timing to borrowing-adjusted evidence, an emerging design problem in confirmatory trials.