Challenges and regulatory experiences with non-inferiority trial design without placebo arm

For a non-inferiority trial without a placebo arm, the direct comparison between the test treatment and the selected positive control is in principle the only basis for statistical inference. Therefore, evaluating the test treatment relative to the non-existent placebo presents extreme challenges an...

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Bibliographic Details
Published in:Biometrical journal. Biometrische Zeitschrift, Vol. 51, No. 2 (2009), p. 324-34
Main Author: Hung, H M James
Other Involved Persons: Wang, Sue-Jane ; O'Neill, Robert
Format: electronic Article
Language:English
ISSN:0323-3847
Item Description:Date Completed 04.06.2009
Date Revised 13.04.2009
published: Print
Citation Status MEDLINE
Copyright: From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Physical Description:Online-Ressource
DOI:10.1002/bimj.200800219
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  • For a non-inferiority trial without a placebo arm, the direct comparison between the test treatment and the selected positive control is in principle the only basis for statistical inference. Therefore, evaluating the test treatment relative to the non-existent placebo presents extreme challenges and requires some kind of bridging from the past to the present with no current placebo data. For such inference based partly on an indirect bridging manipulation, fixed margin method and synthesis method are the two widely discussed methods in the recent literature. There are major differences in statistical inference paradigm between the two methods. The fixed margin method employs the historical data that assess the performances of the active control versus a placebo to guide the selection of the non-inferiority margin. Such guidance is not part of the ultimate statistical inference in the non-inferiority trial. In contrast, the synthesis method connects the historical data to the non-inferiority trial data for making broader inferences relating the test treatment to the non-existent current placebo. On the other hand, the type I error rate associated with the direct comparison between the test treatment and the active control cannot shed any light on the appropriateness of the indirect inference for faring the test treatment against the non-existent placebo. This work explores an approach for assessing the impact of potential bias due to violation of a key statistical assumption to guide determination of the non-inferiority margin