🤖 AI Summary
Current regulatory guidance for non-inferiority trials inadequately incorporates the ICH E9(R1) estimand framework, leading to non-inferiority margin selection that overlooks how strategies for handling intercurrent events affect treatment effect estimation. This study addresses this gap by simulating patient pathways in a weight management context to systematically evaluate how different intercurrent event handling strategies—and their frequencies—alter the estimand. By reconstructing historical trial data under varying estimands, the research assesses the dependence of the non-inferiority margin \(M_1\) on the specified estimand. It reveals, for the first time, a strict correspondence between the non-inferiority margin and the estimand, demonstrating that even when clinical questions appear similar, historical control treatment effects cannot be directly reused if estimands differ. The findings underscore that margin specification must align precisely with the target estimand.
📝 Abstract
Since the release of the ICH E9(R1) addendum on estimands, its application in non-inferiority trials has received far less attention than in superiority settings. A key conclusion from Lynggaard et al. was that the "choice of non-inferiority margin must reflect the chosen estimand." However, current regulatory guidance predates ICH E9(R1) and therefore does not reflect how the estimand influences the historical evidence and constancy assumption (assay sensitivity) used to derive the non-inferiority margin. This paper investigates the degree to which the non-inferiority margin depends on the estimand. Using simulated patient journeys in a weight-management setting, we illustrate how different intercurrent event strategies and variations in the intercurrent event frequency affect the estimand, and consequently the estimated treatment effect. These results emphasize that the historical treatment effect of the reference treatment versus placebo, and thus the margin $M_{1}$, is specific to an estimand and may differ even when trials formally target similar questions. We further illustrate the process of determining the non-inferiority margin using two examples in non-inferiority trials for a new theoretical weight management treatment. In the first example, we focus on the setting where the historical clinical trials use the estimand framework highlighting that even when they include the estimand framework, determining the non-inferiority margin can be challenging in case the historical trials target an estimand different from the one in the planned study. A second example highlights challenges when historical trials did not employ the estimand framework and the targeted estimand cannot be fully reconstructed.