Noninferiority Trial Design: Opportunities and Challenges

Published:September 28, 2022DOI:
      Defining treatment effectiveness is the foundation of evidence-based practice. Most studies comparing the effectiveness of treatment options involve superiority designs in which a treatment is compared against a placebo, standard care, or an alternative treatment. However, in scenarios in which it is not ethical to consider these options, noninferiority designs can be considered. Noninferiority (NI) trials aim to demonstrate that a new treatment is not unacceptably worse than a standard treatment. Noninferiority is determined relative to a noninferiority margin, which is the difference between the test and active control treatment that is not unacceptably clinically inferior. However, there are important considerations with respect to the design, analysis, and interpretation of NI studies, which differ from superiority trials. This review will outline the key components of NI trials, how to interpret the findings, and understand their nuances and potential limitations.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Hand Surgery
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • U.S. Department of Health and Human Services Food and Drug Administration
        Non-Inferiority Clinical Trials to Establish Effectiveness Guidance for Industry. 2016.
        • Patel M.R.
        • Mahaffey K.W.
        • Garg J.
        • et al.
        Rivaroxaban versus Warfarin in nonvalvular atrial fibrillation.
        N Engl J Med. 2011; 365: 883-891
        • Nijs K.
        • Lismont A.
        • de Wachter G.
        • et al.
        The analgesic efficacy of forearm versus upper arm intravenous regional anesthesia (Bier’s block): a randomized controlled non-inferiority trial.
        J Clin Anesth. 2021; 73110329
        • Flight L.
        • Julious S.A.
        Practical guide to sample size calculations: non-inferiority and equivalence trials.
        Pharm Stat. 2016; 15: 80-89
        • Parekh D.J.
        • Reis I.M.
        • Castle E.P.
        • et al.
        Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3, non-inferiority trial.
        Lancet. 2018; 391: 2525-2536
        • Leung J.T.
        • Barnes S.L.
        • Lo S.T.
        • Leung D.Y.
        Non-inferiority trials in cardiology: what clinicians need to know.
        Heart. 2020; 106: 99-104
        • Hassellund S.S.
        • Williksen J.H.
        • Laane M.M.
        • et al.
        Cast immobilization is non- inferior to volar locking plates in relation to QuickDASH after one year in patients aged 65 years and older: a randomized controlled trial of displaced distal radius fractures.
        Bone Joint J. 2021; 103–B: 247-255
        • Schumi J.
        • Wittes J.T.
        Through the looking glass: understanding non-inferiority.
        Trials. 2011; 12: 106
        • D’Agostino R.B.
        • Massaro J.M.
        • Sullivan L.M.
        Non-inferiority trials: Design concepts and issues - The encounters of academic consultants in statistics.
        Stat Med. 2003; 22: 169-186
        • Wangge G.
        • Klungel O.H.
        • Roes K.C.B.
        • de Boer A.
        • Hoes A.W.
        • Knol M.J.
        Interpretation and inference in noninferiority randomized controlled trials in drug research.
        Clin Pharmacol Ther. 2010; 88: 420-423
        • Wangge G.
        • Klungel O.H.
        • Roes K.C.B.
        • de Boer A.
        • Hoes A.W.
        • Knol M.J.
        Room for improvement in conducting and reporting non-inferiority randomized controlled trials on drugs: a systematic review.
        PLoS One. 2010; 5e13550

      Linked Article