Estimands and their estimators for clinical trials impacted by the COVID-19 pandemic: a report from the NISS Ingram Olkin Forum Series on unplanned clinical trial disruptions
File(s)2202.03531.pdf (1.1 MB)
Working Paper
Author(s)
Type
Working Paper
Abstract
The COVID-19 pandemic continues to affect the conduct of clinical trials globally. Complications may arise from pandemic-related operational challenges such as site closures, travel limitations and interruptions to the supply chain for the investigational product, or from health-related challenges such as COVID-19 infections. Some of these complications lead to unforeseen intercurrent events in the sense that they affect either the interpretation or the existence of the measurements associated with the clinical question of interest. In this article, we demonstrate how the ICH E9(R1) Addendum on estimands and sensitivity analyses provides a rigorous basis to discuss potential pandemic-related trial disruptions and to embed these disruptions in the context of study objectives and design elements. We introduce several hypothetical estimand strategies and review various causal inference and missing data methods, as well as a statistical method that combines unbiased and possibly biased estimators for estimation. To illustrate, we describe the features of a stylized trial, and how it may have been impacted by the pandemic. This stylized trial will then be re-visited by discussing the changes to the estimand and the estimator to account for pandemic disruptions. Finally, we outline considerations for designing future trials in the context of unforeseen disruptions.
Date Issued
2022-09-14
Date Acceptance
2022-06-22
Citation
Statistics in Biopharmaceutical Research, 2022, 15 (1), pp.94-111
ISSN
1946-6315
Publisher
Taylor and Francis
Start Page
94
End Page
111
Journal / Book Title
Statistics in Biopharmaceutical Research
Volume
15
Issue
1
Is Replaced By
Copyright Statement
©2021 The Author(s)
Identifier
https://arxiv.org/pdf/2202.03531.pdf
Subjects
stat.ME
stat.ME
stat.AP
Publication Status
Published
Date Publish Online
2022-06-27