EMA proposes reflection paper on using external controls to generate evidence

The European Medicines Agency (EMA) plans to release a reflection paper regarding when external controls can be used to generate evidence to support regulatory decisions on drug approvals. The agency noted that there is currently a lack of regulatory guidance in this area within Europe.

The paper states that while randomized controlled trials are considered the "gold standard" for evaluating the benefits and risks of medicines in regulatory decision-making, there are circumstances where conclusions can be drawn from data collected under a clinical trial protocol where the control group was not randomized. In these cases, an external control may be derived from data from other clinical trials or real-world data (RWD).

EMA said that “the aim of the reflection paper is 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.”

It further noted that advancements have been made in data availability and statistical and pharmacoepidemiological methods, which have led to an increase in proposals for using external controls to support regulatory decisions. However, there is a need for more information on the methodological reliability and operational aspects of this approach. The agency also notes that there is not a standard definition of external controls.

The reflection paper will define what is meant by an external control; the appropriate clinical and regulatory setting and minimal requirements for external controls; operational and feasibility aspects; planning, design, conduct, analysis and reporting of studies for which external controls are used; and considerations on minimizing bias and confounding.

EMA said it plans to release a draft reflection paper for public consultation in the fourth quarter of 2026, followed by a three-month consultation, and to adopt a guideline in the second quarter of 2027.

EMA said that a temporary drafting group (tDG) is being co-led by two Methodology Working Group (MWP) members and consists of experts from the European Specialized Expert Community (ESEC) for Methodology. In addition, the tDG may leverage expertise from the Scientific Advice Working Party (SAWP), the Committee for Human Medicinal Products (CHMP), the Pharmacovigilance Risk Assessment Committee (PRAC) and relevant clinical Working Parties.

EMA said that a scientific workshop will take place on 3 November 2025, as the upcoming guidance is considered "highly relevant" to industry stakeholders. During this workshop, representatives from the industry will be invited to share their challenges, opportunities, and perspectives on the topic.

The concept paper was issued two months after the UK Medicines and Healthcare Products Regulatory Agency (MHRA) issued a draft guideline on a similar topic. The guidelines proposed the use of external control arms based on real-world data (RWD) to support regulatory decisions. (RELATED: Euro Roundup: MHRA seeks feedback on using external control arms based on RWD, Regulatory Focus 22 May 2025)

Reflection paper

EMA proposes reflection paper on using external controls to generate evidence

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