Reweighting estimators to extend the external validity of clinical trials: methodological considerations

Area of Science:

• Clinical Epidemiology
• Biostatistics
• Pharmacoeconomics

Background:

• Randomized controlled trials (RCTs) provide strong internal validity but limited generalizability to target populations.
• Estimating real-world treatment effects requires extending RCT findings beyond trial participants.
• Methods for robust external validity and generalizability are increasingly important in medical research.

Purpose of the Study:

• To enumerate recommended steps for extending inference from RCTs to target populations.
• To discuss viable methodological choices for each step of extended inference.
• To provide recommendations for reliable generalization of treatment effects.

Main Methods:

• The paper outlines a structured approach for extended inference.
• It reviews current statistical and methodological options for each step.
• A case study applies these methods to a pharmaceutical trial for Alzheimer's disease (AD) in European residents.

Main Results:

• The study demonstrates a complete extended inference process from an RCT to a defined target population.
• Practical challenges encountered during the case study are highlighted.
• Limitations in reliably extending trial inference to real-world populations are identified.

Conclusions:

• Extending RCT findings to target populations is feasible but presents practical difficulties.
• Careful methodological choices are crucial for reliable generalization of treatment effects.
• The study underscores the importance of acknowledging limitations in real-world applicability.