EMA to develop guidance on external controls for regulatory decision-making

The European Medicines Agency (EMA) has adopted a concept paper proposing the development of a reflection paper on the use of external controls in regulatory decision-making. The initiative aims to support a more consistent methodological approach to the assessment of externally controlled evidence.

The Baseline

• Following previous public consultation, the EMA has adopted a concept paper proposing the development of guidance on the use of external controls in regulatory decision-making.
• The planned reflection paper aims to establish more consistent methodological principles for assessing externally controlled evidence, particularly where randomized controlled trials (RCTs) are not feasible.
• The initiative reflects growing use of real-world data (RWD) and external comparator data in medicines development and regulatory assessment.

The initiative comes as the use of RWD and other external data sources continues to expand, prompting growing interest in the use of external controls where RCTs may not be feasible. This is particularly relevant in areas such as rare diseases and small patient populations, where conventional trial designs can present practical or ethical challenges.

In response to these developments, the EMA's Committee for Medicinal Products for Human Use (CHMP) has endorsed plans to develop a reflection paper setting out general principles for assessing the use of external controls in regulatory decision-making. Reflection papers outline the agency's current scientific thinking on emerging topics and are intended to promote discussion and greater consistency in regulatory approaches, rather than establish legally binding requirements. According to the concept paper, recent advances in data availability and statistical methodology have led to “an increase in proposals using external controls to support regulatory decision-making.” However, the agency notes that:

“Specific regulatory guidance on the use of external controls to support regulatory decision-making in Europe is currently lacking.”

The planned reflection paper will address the methodological and operational considerations associated with externally controlled studies, including terminology, data quality, source selection, reproducibility, and feasibility. It will also cover study planning, conduct, and reporting, including the use of the ICH E9(R1) estimand framework to define causal questions and target trial emulation to align study design with the intended estimand and reduce bias. Statistical considerations, including sample size determination and type I error control, will also be addressed.

The development of the reflection paper follows extensive discussion at the recent EMA-HMA Workshop on the use of external controls for evidence generation in regulatory decision-making, where participants highlighted the increasing use of external comparator data and the need for greater methodological transparency and consistency in regulatory assessment.

The EMA's initiative also aligns with broader international efforts to clarify the regulatory use of external controls. Regulatory authorities including the US FDA, the UK MHRA, and Japan's Pharmaceuticals and Medical Devices Agency have all recently published draft guidance or recommendations on these approaches, reflecting growing interest in alternative evidence-generation strategies where randomization may not be practical.

Under the proposed timetable, a drafting group will be established during 2026, with a draft reflection paper expected to enter public consultation before final adoption by the CHMP in 2027. According to the concept paper, the guidance is expected to support more transparent and consistent assessment of externally controlled evidence and contribute to better informed regulatory decision-making.