Abstract

A central assumption in the design and conduct of non-inferiority trials is that the active-control therapy will have the same degree of effectiveness in the planned non-inferiority trial as it had in the prior placebo-controlled trials used to define the non-inferiority margin. This is referred to as the `constancy' assumption. If the constancy assumption fails, the chosen non-inferiority margin is not valid and the study runs the risk of approving an inferior product or failing to approve a beneficial product. The constancy assumption cannot be validated in a trial without a placebo arm, and it is unlikely ever to be met completely. However, it is often the case that there exist strong, measurable predictors of constancy, such as dosing and adherence, and such predictors can be used to identify situations where the constancy assumption will likely fail. Here we propose a method for using measurable predictors of active-control effectiveness to specify non-inferiority margins targeted to the planned study population, and further use these predictors to adapt the non-inferiority margin at the end of the study. Population-specific margins can help avoid violations of the constancy assumption, and adaptive margins can help adjust for violations that will inevitably occur in real clinical trials, while at the same time maintain pre-specified levels of type I error and power.

Disciplines

Clinical Trials

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