Lynggaard, Helle, Oliver, Keene, Muetze, Tobias and Rehal, Sunita (2024) Applying the Estimand Framework to Non-inferiority Trials. Pharmaceutical Statistics. ISSN 1539-16041539-1612

Abstract

Most published applications of the estimand framework have focused on superiority trials. However, non-inferiority trials present specific challenges compared to superiority trials. The ICH E9(R1) addendum on estimands and sensitivity analysis in clinical trials notes there may be special considerations to the implementation of estimands in clinical trials with a non-inferiority objective yet provides little guidance.

This paper discusses considerations that trial teams should make when defining estimands for a clinical trial with a non-inferiority objective. We briefly introduce non-inferiority trials and discuss how the pre-ICH E9(R1) way of establishing non-inferiority can be embraced by the estimand framework. We discuss the use of the Per Protocol analysis set given the ICH E9(R1) guidance and how the estimand can be constructed for a non-inferiority objective. We examine what clinical questions of interest can be formulated in the context of non-inferiority trials and outline why it is not sensible to describe an estimand as “conservative”.

Key considerations in non-inferiority trials are whether trials should have more than one primary estimand and the choice of non-inferiority margin. Other important issues relate to assay sensitivity, switching from non-inferiority to superiority and estimation. We conclude by providing a list of recommendations, and important considerations for defining estimands for trials with a non-inferiority objective.

Item Type:	Article
Keywords:	clinical question of interest, estimand, estimand framework, estimand thinking, ICH E9(R1), intercurrent event, non-inferiority, regulatory guidance, superiority
Date Deposited:	22 Aug 2024 00:46
Last Modified:	22 Aug 2024 00:46
URI:	https://oak.novartis.com/id/eprint/51963