On 3 June 2026, the European Medicines Agency (EMA) published a concept paper outlining plans to develop a reflection paper on the use of external controls for evidence generation in regulatory decision-making. The document, issued by EMA's Committee for Medicinal Products for Human Use (CHMP), aims to gather stakeholder input on methodological, operational, and regulatory considerations for incorporating external control arms—such as historical data, real-world evidence, or data from other trials—into the evaluation of medicinal products. The initiative responds to growing interest in using external controls to complement or replace traditional randomised controlled trials, particularly in rare diseases, oncology, and other areas where randomised trials are challenging.
The concept paper sets the stage for a formal reflection paper, which will provide guidance on when and how external controls can be used to support marketing authorisation applications, post-authorisation studies, and other regulatory decisions. EMA invites comments from pharmaceutical companies, academic researchers, patient organisations, and other stakeholders by 31 August 2026. The feedback will inform the drafting of the reflection paper, expected to be published in 2027.
Policy orientations and trade-offs
The use of external controls presents both opportunities and risks. On the positive side, it can reduce the time and cost of drug development, enable studies in patient populations where randomisation is unethical or impractical, and leverage existing data sources. However, external controls may introduce bias due to differences in patient populations, disease management, or data collection methods compared to the trial setting. EMA's reflection paper will need to address how to ensure the reliability and validity of evidence generated from external controls, including criteria for selecting appropriate data sources, methods to minimise confounding, and standards for transparency and reproducibility.
Impact on stakeholders - Pharmaceutical companies: Could benefit from faster and cheaper development pathways, especially for rare diseases, but may face stricter requirements for justifying the use of external controls and demonstrating comparability with trial data. - Patients: May gain earlier access to innovative therapies if external controls accelerate approvals, but could be exposed to higher uncertainty about a drug's efficacy and safety if controls are not robust. - Regulatory bodies (EMA, national competent authorities): Will need to develop new expertise and guidelines to evaluate external control evidence consistently, potentially increasing workload during the transition period. - Academic researchers and health technology assessment bodies: May see expanded opportunities for using real-world data in regulatory decisions, but will need to agree on methodological standards to ensure evidence is acceptable for both marketing authorisation and reimbursement decisions.
Expected institutional follow-up After the public consultation closes on 31 August 2026, EMA will analyse the comments and proceed with drafting the reflection paper. The final document is expected to be adopted by the CHMP and published in 2027. It may subsequently inform updates to EMA's scientific guidelines on clinical trials, real-world evidence, and benefit-risk assessment.
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