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. 2024 Jun 17:385:e078000.
doi: 10.1136/bmj-2023-078000.

Exploring different objectives in non-inferiority trials

Conor D Tweed  1 , Matteo Quartagno  1 , Michelle N Clements  1 , Rebecca M Turner  1 , Andrew J Nunn  1 , David T Dunn  1 , Ian R White  1 , Andrew J Copas  1
Affiliations

Exploring different objectives in non-inferiority trials

Conor D Tweed et al. BMJ. .

Abstract

Non-inferiority trials compare the efficacy of a new treatment with an existing one where the new treatment is expected to have broadly similar efficacy to the existing treatment, but where other benefits might make the new treatment desirable. These trials might aim to demonstrate that a new treatment is either an alternative to, or a replacement for, the current treatment. In this article, how treatment comparisons can be based only on efficacy, or on both efficacy and other benefits, is explained, and guidance on how to choose the correct objective for a trial is given. This choice should influence the design of the trial (eg, choosing the non-inferiority margin and secondary outcomes), analysis, and reporting of the trial. Most non-inferiority trials aim to show only that a new treatment is an alternative to the standard of care. Being more transparent about the trial objective, however, could mean that more trials are conducted with an emphasis on the risk-benefit trade-off for a new treatment and generate more clinically meaningful trial results with a greater effect on practice.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: core support from the Medical Research Council (MRC) UK to the MRC Clinical Trials Unit for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Figures

Fig 1
Fig 1
Illustration of non-inferiority based on difference in treatment effect on the risk ratio scale comparing a new intervention with an active control. Point estimates are shown with 95% confidence intervals (CI)
Fig 2
Fig 2
Example of hypothetical risk-benefit frontier. The Bullous Pemphigoid Steroids and Tetracyclines (BLISTER) trial proposed using different non-inferiority margins (% absolute difference) depending on the observed reduction in mortality (% absolute difference) in the new treatment arm compared with the control arm (with a greater difference allowing a wider margin). Margin values were obtained at two values of the difference in mortality (circles, one for declaration of the new intervention as an alternative option and one for replacement). Lines between the two points were plotted to show a hypothetical frontier of proposed margins at intermediate values for difference in mortality, illustrating how a more granular range for the non-inferiority margin could be used. Each measured value for the additional benefit could be associated with a non-inferiority margin, or with two non-inferiority margins, by agreeing values for an alternative option and for a replacement, as shown here, and plotting the curve. Data from Williams et al
See this image and copyright information in PMC

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