Multiple Testing of Noninferiority Hypotheses in Active Controlled Trials

Abstract

For noninferiority testing with the maximum allowable noninferiority margin being prespecified, one can perform valid statistical testing at the same alpha level for multiple noninferiority hypotheses with margins being smaller than this maximum margin. This is easily comprehensible because only one confidence level is used to assess which margins within the interval bounded by the maximum margin can be ruled out. If different confidence intervals are used, e.g., the interval generated from the intent-to-treat population is used for testing superiority and the interval generated from the per-protocol population is used for testing noninferiority, the problem of multiplicity will surface and the adjustment of alpha for each testing may be needed. All these predicate on the condition that at least a certain element of the maximum allowable noninferiority margin, whether it is the entire margin or the fraction of the active control effect to be retained, must be fixed in advance. None of these elements can be allowed to be influenced directly or indirectly by any analysis of the noninferiority trial data. Otherwise, the noninferiority analysis may be invalid.

Key Words:

• Multiple testing
• Maximum allowable noninferiority margin
• Active controlled clinical trial

Acknowledgments

This research was supported by the Review Science Research Funds #RSR- 096-10A and #RSR-FY99/00-08, #RSR-FY01-20, #RSR-FY02-19 granted by the Center for Drug Evaluation and Research, US Food and Drug Administration.

Notes

^#The opinions expressed are those of the authors and not necessarily those of the US Food and Drug Administration.