Blinded Sample Size Recalculation in Noninferiority Trials: A Case Study in Dermatology

Abstract

When designing a clinical trial, a number of design features including the sample size have to be decided upon. The sample size calculation usually requires some discussion of relevant effect sizes and information about nuisance parameters such as standard deviations or overall event rates, with nuisance parameters being estimated from previous studies. Using a novel endpoint or moving into a new indication, no or only very limited information might be available and the sample size calculation is therefore subject to considerable uncertainty. Internal pilot study designs that allow sample size reestimation midcourse of the ongoing study have been proposed to make trials more robust to misspecifications of nuisance parameters in the planning phase. In this article we present the design of a recently completed randomized active controlled trial in dermatology as a case study. Furthermore, we demonstrate how type I error rate control can be achieved when testing for noninferiority and explore operating characteristics such as power and sample size distributions through simulations motivated by the case study. Finally, relevant regulatory guidelines on sample size reestimation are referred to.