Current issues in non-inferiority trials.
ABSTRACT Non-inferiority (NI) trials enable a direct comparison of the relative benefit-to-risk profiles of an experimental intervention and a standard-of-care regimen. When the standard has clinical efficacy of substantial magnitude that is precisely estimated ideally using data from multiple adequate and well-controlled trials, with such estimates being relevant to the setting of the NI trial, then the NI trial can provide the scientific and regulatory evidence required to reliably assess the efficacy of the new intervention. In clinical practice, considerable uncertainty remains regarding when such trials should be conducted, how they should be designed, what standards for quality of trial conduct must be achieved, and how results should be interpreted. Recent examples will be considered to provide important insights and to highlight some of the challenges that remain to be adequately addressed regarding the use of the NI approach for the evaluation of new interventions. 'Imputed placebo' and 'margin'-based approaches to NI trial design will be considered, as well as the risk of 'bio-creep' with repeated NI trials, use of NI trials when determining whether excess safety risks can be ruled out, higher standards regarding quality of study conduct required with NI trials, and the myth that NI trials always require huge sample sizes.
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ABSTRACT: In non-inferiority trials of radiotherapy in patients with early stage breast cancer, it is inevitable that some patients will cross over from the experimental arm to the standard arm prior to initiation of any treatment due to complexities in treatment planning or subject preference. Although the intention-to-treat (ITT) analysis is the preferred approach for superiority trials, its role in non-inferiority trials is still under debate. This has led to the use of alternative approaches such as the per-protocol (PP) analysis or the as-treated (AT) analysis, despite the inherent biases of such approaches.BMJ Open 10/2014; 4(10):e006531. · 2.06 Impact Factor
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ABSTRACT: Active-controlled, “noninferiority” (NI) trials continue to raise many issues and controversies. With placebo-controlled trials becoming increasingly difficult in areas like oncology, infection, arthritis and respiratory illness, the use of active-controlled, “NI” trials to evaluate new treatments is likely to continue to be an important feature of drug development. Such trials continue to pose fundamental issues, many of which remain without broad scientific or regulatory consensus. These issues range from the fundamental purpose of an active-controlled NI trial to determination of the effectiveness of control and sample size, to issues of assay sensitivity and trial quality, to the statistical methodologies to be used. In this article, these matters are reviewed and discussed and observations are offered regarding the relative merits of the most common methodologies currently in use for NI assessment. Opinions are also included occasionally, some perhaps controversial, with the intention of generating discussion and debate.Statistics in Biopharmaceutical Research 08/2013; 5(3):229-238. · 0.70 Impact Factor
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ABSTRACT: NI margins have to be chosen appropriately to control the risk of degradation of treatment effects in non-inferiority (NI) trials. We aimed to study whether the current choice of NI margins protects sufficiently against a degradation of treatment effect on an average.PLoS ONE 07/2014; 9(7):e103616. · 3.53 Impact Factor