(C-195) External Control Arm Studies in Marketing Authorisation Applications Submitted to the European Medicines Agency: A Review of Study Design Features and Methods

Background: The increasing availability of observational data and the recently published guidelines on external control arm (ECA) studies present an opportunity for their use in regulatory applications.

Objectives: To characterise the study design features and methods of ECA studies in recently submitted marketing authorisation (MA) applications to the European Medicines Agency (EMA) and summarise EMA's opinion on the ECA evidence
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Methods: EMA medicines’ assessment documents from 01-01-2022 to 31-12-2024 were screened for ECA design. We double-extracted data and classified ECA evidence as acceptable, supportive or unsupportive for the final MA recommendation according to the EMA’s feedback.

Results: Of 281 medicines, 27 (9.6%) included evidence based on an ECA. The motivation for using ECA evidence was to provide a control arm for clinical trials, either single-arm (21) or randomised (3), or to compare long-term outcomes in open-label extension phases (3).

In acceptable cases (4/27), ECA evidence formed the basis for the final recommendation. A strong justification for the ECA in scenarios of extremely rare diseases or unethical placebo arms, in addition to providing sensitivity analyses with consistent results were highlighted by the EMA as decisive factors.

In supportive cases (14/27), the EMA considered ECA evidence useful to contextualise results in the absence of placebo arms, alternative data, or existing treatment options, particularly in studies with large treatment effects, objective endpoints, and predictable disease courses, but still insufficient to replace controlled trial results due to “inherent biases”.

For applications with unsupportive ECA evidence (9/27), EMA’s concerns included insufficient methodological details, post hoc data-driven decisions, differences between the trial and external cohorts in terms of their baseline characteristics, calendar time, disease stage, and endpoint characterisation, as well as the risk of residual confounding and selection bias.

Conclusions: While ECA evidence can meaningfully contribute to regulatory decisions, especially in rare diseases with limited patient numbers, it must be backed by a strong rationale, be preplanned and methodologically robust, and demonstrate population comparability. These findings can inform the design of future ECA studies to improve their likelihood of acceptance in regulatory decisions.