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Randomized Clinical Trial Design for Assessing Noninferiority When Superiority Is Expected

Boris Freidlin, Edward L. Korn, Stephen L. George, Robert Gray

From the Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD; Department of Biostatistics and Bioinformatics and the Cancer and Leukemia Group B Statistical Center, Duke University School of Medicine, Durham, NC; and Eastern Cooperative Oncology Group, Harvard School of Public Health, Boston, MA

Address reprint requests to Boris Freidlin, PhD, Biometric Research Branch, 6130 Executive Blvd, EPN-8122, MSC 7434 National Cancer Institute, Bethesda, MD 20892; e-mail: freidlinb{at}ctep.nci.nih.gov

The randomized clinical trial (RCT) is the gold standard for definitive evaluation of new therapies. RCTs designed to show that the therapeutic efficacy of a new therapy is not unacceptably inferior to that of standard therapy are called noninferiority trials. Traditionally, noninferiority trials have required very large sample sizes. Sometimes, a new treatment regimen with a favorable toxicity and/or tolerability profile is also expected to have some modest improvement in efficacy. In such specialized settings we describe a hybrid trial-design approach that requires a dramatically smaller sample size than that of a standard noninferiority design. This hybrid design can naturally incorporate a formal test of superiority as well as noninferiority.

Supported in part by Grant No. U10CA033601 from the National Cancer Institute (S.L.G.).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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