Development of a reflection paper on the use of external controls for evidence generation in regulatory decision-making - Scientific guideline

Randomised controlled trials are the gold standard of evidence to support causal conclusions on the benefits and risks of medicines in regulatory decision making along the lifecycle.

However, in some situations, causal conclusions may be derived from a setting where the investigational medicinal product data was collected under a clinical trial protocol while the control arm was not a randomized arm in that same protocol. In these situations, a so-called external control, may be derived from data from other clinical trials, real-world data (RWD) or other data sources.

A reflection paper shall be drafted to describe the main challenges with external controls and further discuss the circumstances and methodological constraints under which the use of external controls could be considered appropriate for generating pivotal or supportive evidence, either for efficacy, safety or other relevant regulatory decision-making objectives.

This concept paper outlines the scope and content of the reflection paper. It was finalsed based on comments received during the public consultation and the related workshop held in November 2025.

Keywords: Clinical trial design, external controls, regulatory decision-making

Current effective version

Concept paper on the development of a reflection paper on the use of External controls for evidence generation in regulatory decision-making

Adopted Reference Number: EMA/125200/2026

First version

Draft concept paper on the development of a reflection paper on the use of external controls for evidence generation in regulatory decision-making

Draft: consultation closed Consultation dates: 25/07/2025 to 31/10/2025 Reference Number: EMA/CHMP/225255/2025 Summary:

Randomised controlled trials are the gold standard of evidence to support causal conclusions on the benefits and risks of medicines in regulatory decision making along the lifecycle.

However, in some situations, causal conclusions may be derived from a setting where the investigational medicinal product data was collected under a clinical trial protocol while the control arm was not a randomized arm in that same protocol. In these situations, a so-called external control, may be derived from data from other clinical trials, real-world data (RWD) or other data sources.

A reflection paper shall be drafted to describe the main challenges with external controls and further discuss the circumstances and methodological constraints under which the use of external controls could be considered appropriate for generating pivotal or supportive evidence, either for efficacy, safety or other relevant regulatory decision-making objectives.

This concept paper outlines the scope and content of the reflection paper.

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