Clinical trials with multiple outcomes: a statistical perspective on their design, analysis, and interpretation

Abstract

This article tackles both practical and statistical issues in the handling of multiple outcomes in clinical trials, with relevance to trial design, analysis, and reporting. Specific topics illustrated by examples include: the advantage of prespecifying priorities amongst outcomes and analyses, corrections for multiple significance testing and their limited value, problems with adverse event data, the use of a single global test of significance for clinically related outcomes, the use of a combined outcome for clinical event data, and the value of exploring interrelationships amongst outcomes. The problems in handling multiple outcomes are enhanced by trials being too small, dichotomous attitudes (is the trial "positive" or not?), obsession with p-values, and the manipulative instincts of human nature. While predeclarations of priorities in analysis and reporting of multiple outcomes are important in suppressing distortive claims, it would be unfortunate if too inflexible an approach suppressed unpredictable findings from being seriously considered.