Optimal group-sequential designs for simultaneous testing of superiority and non-inferiority.

Confirmatory clinical trials comparing the efficacy of a new treatment with an active control typically aim at demonstrating either superiority or non-inferiority. In the latter case, the objective is to show that the experimental treatment is not worse than the active control by more than a pre-specified non-inferiority margin. We consider two classes of group-sequential designs that combine the superiority and non-inferiority objectives: non-adaptive designs with fixed group sizes and adaptive designs where future group sizes may be based on the observed treatment effect. For both classes, we derive group-sequential designs meeting error probability constraints that have the lowest possible expected sample size averaged over a set of values of the treatment effect. These optimized designs provide an efficient means of reducing expected sample size under a range of treatment effects, even when the separate objectives of proving superiority and non-inferiority would require quite different fixed sample sizes. We also present error spending versions of group-sequential designs that are easily implementable and can handle unpredictable group sizes or information levels. We find the adaptive choice of group sizes to yield some modest efficiency gains; alternatively, expected sample size may be reduced by adding another interim analysis to a non-adaptive group-sequential design.