When Context Is Hard to Come By: External Comparators and How to Use Them

Area of Science:

• Clinical research methodology
• Real-world data (RWD) utilization
• Health economics and outcomes research (HEOR)

Background:

• External comparators, including historical or synthetic controls, provide context for clinical trial results.
• Increased access to quality RWD and advanced methods are driving interest in external comparators.
• Legislative directives encourage broader use of RWD by regulatory bodies.

Purpose of the Study:

• To describe methodological considerations for designing studies using external comparators.
• To illustrate the application of RWD-based external comparators in regulatory and reimbursement decision-making.
• To highlight the potential of external comparators for enhancing generalizability and accelerating research.

Main Methods:

• Review of methodological approaches for constructing and validating external comparators.
• Case examples of RWD comparator application in regulatory submissions.
• Discussion of scientific rigor required for RWD-based external control arms.

Main Results:

• External comparators, particularly those derived from RWD, can support regulatory and reimbursement evaluations.
• Methodological tailoring is essential for the successful implementation of external comparators.
• RWD-based external comparators offer opportunities for broader generalizability and faster learning in clinical development.

Conclusions:

• The strategic application of tailored scientific methodology is key to leveraging external comparators effectively.
• Real-world external comparators are increasingly important tools in clinical development and decision-making.
• Further standardization and methodological refinement will enhance the utility of RWD in clinical research.