The Issue of Multiplicity in Noninferiority Studies

• Activity Number: 245
• Type: Contributed
• Date/Time: Monday, July 30, 2012 : 2:00 PM to 3:50 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Chunlei Ke*+ and Beiying Ding and Qi Jiang and Steven Michael Snapinn
• Companies: Amgen, Inc. and Amgen, Inc. and Amgen, Inc. and Amgen, Inc.
• Keywords: Non-inferiority ; family-wise type I error ; Closed testing principle

Abstract

In a clinical study evaluating non-inferiority (NI) of an experimental drug relative to an established therapy, it is common to further test superiority of the experimental drug after NI is established. It has been shown that no multiplicity issue exists between NI and superiority tests of the primary endpoint. However, when there is an additional, or secondary, endpoint that will be tested subsequent to the NI testing of the primary endpoint, it is not immediately clear whether the overall type I error rate is strictly controlled among all the tests. We will first demonstrate that the family-wise type I error rate is not controlled unless a multiplicity adjustment procedure appropriately takes into account both NI and superiority tests of the primary endpoint. Some simulations are performed to appreciate the magnitude of the potential inflation of the type I error rate. We also evaluate a multiplicity adjustment method using the popular Hochberg procedure and show that it tends to be conservative when used in the setting for both NI and superiority tests. Potential modification and extensions to more complex study design will be discussed.