Considerations for master protocols using external controls.

Area of Science:

• Clinical Trials Methodology
• Oncology Drug Development
• Biostatistics

Background:

• Master protocols are increasingly used in oncology clinical trials for efficiency and flexibility.
• These protocols (e.g., basket, umbrella, platform trials) study multiple drugs and subpopulations under one design.
• Incorporating external controls can further enhance the efficiency of master protocols.

Purpose of the Study:

• To provide an overview of external control types and their features in master protocols.
• To discuss key considerations for using external controls in master protocols, including data assessment and estimand construction.
• To present a causal roadmap for estimating treatment effects in master protocols with external controls.

Main Methods:

• Review of different external control types and their application in master protocols.
• Discussion of challenges and considerations, including fit-for-use real-world data and estimand definition.
• Presentation of a three-step targeted learning-based causal roadmap: estimand definition, efficient estimation, and sensitivity analysis.

Main Results:

• Identified various types of external controls and their unique characteristics within master protocols.
• Outlined critical considerations for constructing estimands and assessing real-world data for external controls.
• Demonstrated a causal roadmap for robust treatment effect estimation, supported by illustrative examples.

Conclusions:

• Master protocols, especially when utilizing external controls, offer an efficient framework for oncology drug development.
• Careful consideration of estimands, data quality, and causal assumptions is crucial for valid inference.
• The proposed causal roadmap provides a structured approach to enhance the reliability of results from master protocols using external controls.