Through the looking glass: understanding non-inferiority

Abstract

Non-inferiority trials test whether a new product is not unacceptably worse than a product already in use. This paper introduces concepts related to non-inferiority, and discusses the regulatory views of both the European Medicines Agency and the United States Food and Drug Administration.

Follow-up care by a genetic counsellor for relatives at risk for cardiomyopathies is cost-saving and well-appreciated: a randomised comparison

“…One is that noninferiority allows the study power to depend on the selected noninferiority margin (ie, the range with which the trained GC/nurse is allowed to perform 'minimally' worse than the cardiologist and still be regarded as about comparable to the cardiologist). Non-inferiority tends to reward the careless, 14 as the statistical test result may partially depend on the optimality of cardiologists' performance. Although not our aim, it should be noted that the alternative approach of superiority testing would produce a post-hoc power of 499%.…”

Design and interpretation of non-inferiority studies: A clinician’s perspective

“…[1][2][3][4][5][6][7][8] The noninferiority margin is the degree to which the new therapy can be less efficacious than the established treatment and still be considered non-inferior. [1][2][3][4][5][6][7][8] The reason for allowing some degree of decreased efficacy and yet consider the new treatment to be non-inferior is that the other advantages (ease of administration, lower cost, or a better side effect profile) would be so beneficial that it would be reasonable to give up a small amount of efficacy to obtain these other benefits. The challenge, however, is that there is no standard criteria to use to establish this non-inferiority margin.…”

“…Although investigators may choose to attempt to demonstrate superiority of the experimental treatment over the active comparison, in recent years, there has been an increase in the number of clinical trials that simply attempt to demonstrate the non-inferiority of this new therapy. [1][2][3][4][5][6][7][8] In this manuscript, I will summarize the role, design, and interpretation of this type of a clinical trial.…”

New EMA report on paliperidone 3-month injections: taking clinical and policy decisions without an adequate evidence base

“…After 48-weeks of follow-up, at least one relapse occurred in about 8% of patients taking PP3M and 9% of patients taking PP1M, and the differential rate of relapse-free patients was 1.2% (95% CI −2.7 to 5.1). This would demonstrate that PP3M is non-inferior in comparison with PP1M, as the lower limit of the CI does not cross a prespecified 'non-inferiority margin' (Schumi & Wittes, 2011). Such a study design shows some of the prototypical weaknesses of non-inferiority trials.…”

“…First, as the sample size is calculated on the basis of the sole non-inferiority margin, we cannot establish whether PP3M is better than PP1M (Cipriani et al 2009). Second, a demonstration of non-inferiority leaves uncertainty on whether the two drugs are really equivalent, as there is no validated and shared methodology for reliably choosing the non-inferiority margin, and this is reflected by a lack of clear regulatory advice (Schumi & Wittes, 2011;Wangge et al 2013b). Third, exposing patients to studies that do not aim at establishing whether a new drug is associated with additional benefits over a control one may be regarded not only as a waste of resources, but also as a matter of ethical concern (Garattini & Bertele', 2007;Wangge et al 2013a).…”