Traditionally, noninferiority studies have been designed to demonstrate that the efficacy of a new compound is not inferior to a standard compound documentedly efficacious. A major argument for performing noninferiority studies is, that a direct comparison versus placebo of the new compound is less ethical with an efficacious standard treatment already available, because half of the patients in such a trial is given an inferior treatment. The solution is given by a direct comparison of the new versus standard treatment. However, the comparison versus standard is at risk of establishing little difference, and, thus, a negative result. Non-inferiority studies are based on arbitrary margins of noninferiority. Generally, there are three possibilities (Fig. 63.1): (1) noninferiority is demonstrated, (2) it is uncertain, or (3) it is excluded, if the 95% confidence interval of a study is respectively (1) entirely on the right side of the margin of noninferiority, (2) crosses the margin, (3) is entirely left from the margin. The margin of noninferiority is of a rather subjective nature, and, usually, defined by expert investigators as the margin of undisputed clinical relevance (Mercola xxxx; Snapinn 2000). From Fig. 63.1 it can be easily perceived that investigators benefit from wide margins, increasing the chance of a positive study, and that, with very wide margins, it becomes virtually impossible to reject noninferiority. Scientists (Mercola xxxx; Snapinn 2000), statisticians (Hung and Wang 2004; Pocock 2003; Allen and Seaman 2007), and regulatory agencies (Anonymous 2010b) have expressed their worries about this practice. Recently, the EMEA (European Medicines Agency) has declared that noninferiority trials will not be accepted as proof of efficacy in Alzheimer’s and Parkinson’s trials, while the FDA (Food & Drug Administration) formally rejected the use of noninferiority trials in the development of antimicrobial drugs for chronic bronchitis (Anonymous 2010b).
KeywordsStandard Treatment Wide Margin Costly Repetition Noninferiority Trial Morning Peak Expiratory Flow
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