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Clin Cancer Res. 2012 Apr 1;18(7):1837-47. doi: 10.1158/1078-0432.CCR-11-1653. Epub 2012 Feb 8.

Statistical issues and recommendations for noninferiority trials in oncology: a systematic review.

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Department of Clinical Trial Design and Management, Translational Research Center, Kyoto University Hospital, 54 Shogoin Kawahara-Cho, Sakyo-ku, Kyoto 606-8507, Japan.


To provide an overview of noninferiority trials in oncology with a special emphasis on methodologic issues, we conducted a systematic review of randomized trials assessing noninferiority of antineoplastic treatments. We identified 72 articles, of which 65 were randomized phase III trials with a single control arm, 3 were factorial phase III trials, and 4 were randomized phase II trials. Forty-six were trials in lung, colorectal, or breast cancer. The quality of reporting was improved chronologically (P < 0.01); the major deficiencies were claims of noninferiority when the results did not meet statistical criteria for noninferiority (7 articles) or when the noninferiority margin was not prespecified (5 articles). Four trials (6%) presented plans for switching from superiority to noninferiority. The analysis populations were intent to treat (ITT) in 52, per-protocol set (PPS) in 6, and both ITT and PPS in 11 trials. Noninferiority margins were set in 68 trials (94%); 1 trial used both of the conventional and effect retention methods, 17 trials used the conventional method, 5 trials used the effect retention method, and in 45 trials, the method was not specified. Some trials used margins that possibly were larger than the assured effects of the active controls. No trials explicitly took into consideration uncertainty in historical data. Two trials (3%) specified 2 values of margins. Our findings highlight critical deficiencies in design and reporting of noninferiority trials. Seven practical recommendations are presented.

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