Multiple comparisons in non-inferiority trials: Reaction to recent regulatory guidance on multiple endpoints in clinical trials.

We consider analysis of active control, non-inferiority clinical trials with multiple primary endpoints for assessing efficacy of an investigational treatment. Many of the issues with multiple endpoints for non-inferiority trials are similar to issues for superiority trials, but there are important differences. Because non-inferiority trials typically make decisions with confidence interval bounds instead of p-values, care must be taken in adjusting for multiple hypotheses. Composite endpoints are more difficult to interpret in non-inferiority trials due to difficulties in indirectly comparing the investigational treatment to placebo on each component. Otherwise many of the methods used in superiority trials (including sequential testing, graphical procedures and gatekeeping procedures) can be applied to non-inferiority trials with a little additional care. We focus on the differences between non-inferiority and superiority trials to provide guidance on application of recent regulatory guidance to non-inferiority trials.