arXiv subjects

Helle Lynggaard

Publications and source records attributed to Helle Lynggaard.

2 recordsLinked to original sources

arXiv2026

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

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.

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arXiv2025

Incorporating estimands into meta-analyses of clinical trials

The estimand framework is increasingly established to pose research questions in confirmatory clinical trials. In evidence synthesis, the uptake of estimands has been modest, and the PICO (Population, Intervention, Comparator, Outcome) framework is more often applied. While PICOs and estimands have overlapping elements, the estimand framework explicitly considers different strategies for intercurrent events. We propose a pragmatic framework for the use of estimands in meta-analyses of clinical trials, highlighting the value of estimands to systematically identify and mitigate key sources of quantitative heterogeneity, and to enhance the applicability or external validity of pooled estimates. Focus is placed on the role of strategies for intercurrent events, within the specific context of meta-analyses for health technology assessment. We apply the estimand framework to a network meta-analysis of clinical trials, comparing the efficacy of semaglutide versus dulaglutide in type 2 diabetes. We explore the impact of a treatment policy strategy for treatment discontinuation or initiation of rescue medication versus a hypothetical strategy for the corresponding intercurrent events. The specification of different target estimands at the meta-analytical level allows us to be explicit about the source of heterogeneity, the intercurrent event strategy, driving any potential differences in results. We advocate for the integration of estimands into the planning of meta-analyses, while acknowledging that potential challenges exist in the absence of subject-level data. Estimands can complement PICOs to strengthen communication between stakeholders about what evidence syntheses seek to demonstrate, and to ensure that the generated evidence is maximally relevant to healthcare decision-makers.

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