Estimands in Real-World Evidence Studies

Abstract

A Real-World Evidence (RWE) Scientific Working Group (SWG) of the American Statistical Association Biopharmaceutical Section (ASA BIOP) has been reviewing statistical considerations for the generation of RWE to support regulatory decision-making. As part of the effort, the working group is addressing estimands in RWE studies. Constructing the right estimand—the target of estimation—which reflects the research question and the study objective, is one of the key components in formulating a clinical study. ICH E9(R1) describes statistical principles for constructing estimands in clinical trials with a focus on five attributes—population, treatment, endpoints, intercurrent events, and population-level summary. However, defining estimands for clinical studies using real-world data (RWD), that is, RWE studies, requires additional considerations due to, for example, heterogeneity of study population, complexity of treatment regimes, different types and patterns of intercurrent events, and complexities in choosing study endpoints. This article reviews the essential components of estimands and causal inference framework, discusses considerations in constructing estimands for RWE studies, highlights similarities and differences in traditional clinical trial and RWE study estimands, and provides a roadmap for choosing appropriate estimands for RWE studies.

Keywords:

• Estimand
• Estimand framework
• Real-world data
• Real-world evidence

Acknowledgments

We would like to thank Dr. Heng Li at the FDA and Dr. Tricia Luhn at Roche for their valuable contribution to this work. Our gratitude also goes to Dr. Mark Levenson and two anonymous referees whose constructive comments and suggestions help improve the presentation of our article.

Disclosure Statement

The authors report there are no competing interests to declare. The FDA had no role in data collection, management, or analysis. The views expressed are those of the authors and not necessarily those of the US FDA.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.