Testing multiple primary endpoints in clinical trials with sample size adaptation

Abstract

In this paper, we propose a design that uses a short-term endpoint for accelerated approval at interim analysis and a long-term endpoint for full approval at final analysis with sample size adaptation based on the long-term endpoint. Two sample size adaptation rules are compared: an adaptation rule to maintain the conditional power at a prespecified level and a step function type adaptation rule to better address the bias issue. Three testing procedures are proposed: alpha splitting between the two endpoints; alpha exhaustive between the endpoints; and alpha exhaustive with improved critical value based on correlation. Family-wise error rate is proved to be strongly controlled for the two endpoints, sample size adaptation, and two analysis time points with the proposed designs. We show that using alpha exhaustive designs greatly improve the power when both endpoints are effective, and the power difference between the two adaptation rules is minimal. The proposed design can be extended to more general settings.

Keywords: family-wise error rate; group sequential design; multiple primary endpoints; sample size adaptation.