Estimands and the Choice of Non-Inferiority Margin under ICH E9(R1)

TL;DR

This paper explores how the choice of estimand influences the non-inferiority margin in clinical trials, emphasizing the importance of aligning the margin with the estimand to ensure valid conclusions, especially in weight-management studies.

Contribution

It demonstrates the impact of estimand selection on non-inferiority margins through simulations and practical examples, highlighting challenges in historical data interpretation.

Findings

Estimand choice significantly affects the non-inferiority margin.

Different intercurrent event strategies alter the estimand and treatment effect.

Historical trial data may not directly inform the margin if estimands differ.

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.