Introduction
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Non-inferiority (NI) clinical trials [A non-inferiority trial tests whether the new treatment’s efficacy is not unacceptably lower than the standard of care. Critical to this is the choice of the non-inferiority margin, which is the smallest non-acceptable loss of efficacy. The difference in the primary outcome between the two arms is estimated, together with an associated confidence interval, on a specific scale of interest. The choice of scale is key [Choosing the non-inferiority margin is a fundamental step in the design of a non-inferiority trial, and not a straightforward one [Whatever the strategy used to select the non-inferiority margin, its appropriateness is likely to depend on the assumed control event risk being close to the truth [Few strategies have been proposed to handle unexpected control event risks in non-inferiority trials [The rest of this paper is organised as follows. We present the D3 trial and explain why methodology to handle unexpected event risks might be necessary. Then, in the “