Multiple testing strategies for clinical trials with co-primary endpoints in all comers and a subgroup.

e14041Background: In this new era of precision medicine, subgroup analyses have become increasingly critical for the success of oncology drug development. When the treatment benefit is still uncertain in the subgroup, sometimes registrational trials are designed to have co-primary endpoints, e.g. the same endpoint tested in both the all comer population and a (biomarker specified) subgroup with the family-wise Type 1 error being strongly controlled. Many multiple testing methods have been proposed and applied to address multiplicity issues for such designs. In this work we did a comprehensive review of current methods and compared their advantages and disadvantages. Methods: In a simple scenario of testing one endpoint in an oncology trial, assuming known sample size, randomization ratio and hazard ratio in subgroup and all comers, respectively, we reviewed six alpha spending methods including Bonferroni's method, fixed sequence method, Hochberg's step up method, Holm's step-down method, alpha fall back m...