Optimal unplanned design modification in adaptive two-stage trials

Adaptive planning of clinical trials allows modifying the entire trial design at any time point mid-course. In this paper, we consider the case when a trial-external update of the planning assumptions during the ongoing trial makes an unforeseen design adaptation necessary. We take up the idea to construct adaptive designs with defined features by solving an optimization problem and apply it to the situation of unplanned design reassessment. By using the conditional error principle, we present an approach on how to optimally modify the trial design at an unplanned interim analysis while at the same time strictly protecting the type I error rate. This linking of optimal design planning and the conditional error principle allows sound reactions to unforeseen events that make a design reassessment necessary.

Automated summary

Adaptive planning of clinical trials allows modifying the entire trial design at any time point mid-course. In this paper, we propose an approach to construct adaptive designs with defined features by solving an optimization problem for unplanned design reassessment. By using the conditional error principle, we present a method to optimally modify the trial design at an unplanned interim analysis while protecting the type I error rate.