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In a non-inferiority trial, investigators seek to demonstrate that a new treatment is at least as good as or better than an existing treatment. Non-inferiority trials are a staple of neuroendovascular research.1 Many of the tools neurointerventionalists employ daily received regulatory approval and guideline support through performance of non-inferiority trials, including stent retriever and aspiration mechanical thrombectomy devices for acute ischemic stroke,2–4 coils and flow diverter stents for intracranial aneurysms,5 6 and liquid embolic agents for cerebral arteriovenous malformations.7
However, performance of a non-inferiority trial requires that investigators select a ‘non-inferiority margin’—a prespecified margin of difference that is considered acceptable for the new treatment to be considered not worse than the standard treatment. Few aspects of clinical trial design for neurointerventional and other therapies create as much confusion and consternation as the selection of non-inferiority margins for randomized clinical trials. Systematic reviews of the reporting of non-inferiority clinical trials have shown remarkable deficiencies. Three-quarters of trial reports failed to provide any justification for the selection of the non-inferiority margin.8 9 Only one-seventh used non-inferiority margins that preserved at least 50% of the active comparator’s historical treatment effect.10 In fully one-fifth, conclusion passages were assessed as wrong or incomprehensible.9 In one of every eight trials, current reporting guidelines recommended an interpretation of inconclusive or non-inferior even though the new therapy was statistically significantly worse than the active control.11
An important source of this disarray is that almost all authorities discuss the non-inferiority margin as though it were a single conceptual entity, but really there are three distinct foundations for non-inferiority margin selection. Further, the interpretation of positive non-inferiority trials varies depending on which approach to margin selection was used. Conflating them into a unitary concept distorts their particular features and purposes and promotes …
Contributors JLS wrote the first draft. EM provided critical draft revision comments.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests JLS: Medtronic, Cerenovus, Boehringer Ingelheim (prevention only): contracted hourly payments for clinical trial steering committee service advising on rigorous study design and conduct; Rapid Medical: contracted stock option for clinical trial steering committee service advising on rigorous study design and conduct; MIVI, Occlutech: contracted hourly payments for data and safety monitoring board service. EM: NIH-NINDS: grant; American Heart Association/American Stroke Association: payment for editorial activities; Clinical Neurological Society of America: Scientific Planning Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
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