Totton, N. orcid.org/0000-0002-1900-2773, Julious, S., Walters, S. et al. (1 more author) (2024) A review of UK publicly funded non-inferiority trials: is the design more inferior than it should be? Trials, 25 (1). 809. ISSN 1745-6215
Abstract
Background
The number of non-inferiority (NI) trials, those aiming to show a new treatment is no worse than a comparator, is increasing. However, their added complexity over superiority trials can create confusion. Most guidance and reviews to date have an industry focus with research suggesting these trials may differ from publicly funded NI trials. The aim of this work is to review the design and reporting characteristics of UK publicly funded NI trials. This assessment will show how well recommendations from industry are translating to publicly funded trials.
Methods
The International Standard Randomised Controlled Trial Number web registry and the National Institute for Health and Care Research’s Funding and Awards Library and Journals Library were searched using the term non-inferiority and logical synonyms. Inclusion requirements were a UK publicly funded NI randomised controlled trial. Characteristics of the design, analyses and results as available were recorded on a dedicated data extraction spreadsheet. Appropriate summary statistics were used to present the results.
Results
Searches completed on the 14th of January 2022 identified 477 potential trials which after exclusions resulted in a database of 114 NI trials to be summarised. Non-inferiority margins were defined for most trials with a median of 8% (IQR: 3–10%) used for risk differences (n = 58) and 0.35 (IQR: 0.26–0.43) standardised mean difference for continuous outcomes (n = 30). Justifications for the margin chosen (n = 62) were more commonly based on the clinical importance (49/62) and less commonly using statistical considerations (13/62). The most prevalent primary analysis population was solely on an intention-to-treat basis (49/114). The superiority of the treatment was well described but not always included as an outcome and only powered for in about a third of cases.
Conclusions
Aspects of NI trial design are well described but not always in line with current recommendations. Of particular note, is the absence of statistical considerations when setting the non-inferiority margin, which eliminates the ability to confirm indirect superiority over placebo for the new treatment. Additionally, despite suggestions that it can increase the type 1 error in NI trials, the use of the intention-to-treat alone is the most common analysis population.
Trial registration
Research on Research ID: 3171 (registration date: 31st May 2023).
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
Keywords: | Non-inferiority trials; Non-inferiority margin; Margin justification; Analysis population; Review |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 12 Dec 2024 08:54 |
Last Modified: | 12 Dec 2024 08:54 |
Status: | Published |
Publisher: | Springer Science and Business Media LLC |
Refereed: | Yes |
Identification Number: | 10.1186/s13063-024-08651-3 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:220612 |