An Overview of Statistical and Regulatory Issues in the Planning, Analysis, and Interpretation of Subgroup Analyses in Confirmatory Clinical Trials

Abstract

Whether confirmatory or exploratory in nature, the investigation of subgroups poses statistical and interpretational challenges, yet these investigations can have important consequences for product licensing, labeling, reimbursement, and prescribing decisions. This article provides a high-level, nontechnical summary of key statistical issues in the analysis of subgroups, with a focus on the regulatory context in which drug development and licensing decisions are made. References to specific aspects of regulatory processes are based on the system in Europe, though it is hoped that the principles outlined can be generally applied to other regulatory regions. This article challenges the common assumption that a clinical trial population should be assumed to be homogeneous, with homogeneous response to treatment, and asks whether commonly employed strategies for handling and identifying potential heterogeneity are sufficient. Investigations into subgroups are unavoidable, yet subgroup analyses suffer from fundamental complications and limitations of which those planning and interpreting clinical trials must be aware. Some areas for further methodological work and an improved methodological framework for the conduct of exploratory subgroup analyses are discussed. Above all, the need for an integrated scientific approach is highlighted.

Key Words:

• Clinical trial planning and analysis
• Regulatory decision making
• Subgroup
• Subgroup analysis

ACKNOWLEDGMENTS

The content of this article is based on experiences of giving scientific advice to drug developers and assessing clinical trials in Marketing Authorisation Applications. It is also based on discussions with regulatory colleagues from across the European network and interactions with colleagues in the pharmaceutical industry. The author thanks the constructive comments from the reviewers, which have led to an improved article. The content of this article does not necessarily represent the position of the Medicines and Healthcare Products Regulatory Agency, the European Medicines Agency, or its committees or working parties.

Notes

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