  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.
