A Framework for Assessing the Viability of External Control for a Single-Arm Trial

Area of Science:

• Clinical Trial Design
• Regulatory Science
• Real-World Evidence

Background:

• Single-arm trials utilizing external control arms (ECAs) are gaining traction due to practical advantages.
• Regulatory agencies require robust justification for ECA trial designs, including data sources and statistical methods.

Purpose of the Study:

• To introduce the ECA Viability Checklist, a framework for assessing the feasibility of ECA trials.
• To aid study sponsors in preparing for discussions with regulatory bodies like the FDA, EMA, and MHRA.

Main Methods:

• The Checklist is informed by guidance from the FDA, EMA, and MHRA, and data from 40 FDA-approved ECA trials.
• It comprises 10 thematic questions addressing critical design and analytical aspects of using real-world data and historical trials.
• The Checklist was validated using 4 FDA-approved ECA trials.

Main Results:

• The Checklist provides recommendations for addressing potential issues in ECA trial design.
• Affirmative responses to Checklist questions increase confidence in regulatory acceptance.
• Non-affirmative responses necessitate a clear rationale and adherence to recommendations.

Conclusions:

• The ECA Viability Checklist facilitates initial assessments of proposed ECA trial designs.
• It empowers decision-makers to determine the necessary steps for ensuring regulatory acceptance of ECA trials.