ASSESSING REGULATORY AND HTA BODY EXPECTATIONS FOR EXTERNAL CONTROL ARM STUDIES UNDER THE EU JOINT CLINICAL ASSESSMENT PROCESS
Author(s)
Georgios Papadakis, PhD1, Katerina Pilou, MSc1, Sebastiao Rodrigues, MSc2, Spyros Kolovos, PhD1, Maximilian Schlueter, MSc2, Jennifer Gaultney, PhD, MPH2.
1IQVIA, Athens, Greece, 2IQVIA, London, United Kingdom.
1IQVIA, Athens, Greece, 2IQVIA, London, United Kingdom.
OBJECTIVES: External control arms (ECAs) may be constructed using individual patient data from real-world data (RWD) or prior trials for comparative effectiveness analyses against pivotal trials. Given ECAs are particularly relevant for regulatory and health technology assessment (HTA) submissions based on single-arm trials, aligning study requirements across agencies is critical, especially under the European Union (EU) Joint Clinical Assessment (JCA) process. We assessed the methodological requirements for ECAs from regulators, the EU HTA Coordination Group, and European HTA bodies.
METHODS: We reviewed ECA-specific guidance or positions from the Food and Drug Administration (FDA, 2023), European Medicines Agency (EMA, 2026), Medicines and Healthcare products Regulatory Agency (MHRA, 2025), EU HTA Coordination Group (2024), Haute Autorité de Santé (HAS, 2021/2023), Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG, 2025), and National Institute for Health and Care Excellence (NICE, 2025).
RESULTS: FDA and MHRA have dedicated ECA guidance, while EMA’s draft paper is expected late 2026. NICE and HAS address ECAs within real-world evidence (RWE) frameworks and published positions (HAS, 2023), while IQWiG and JCA guidance do so indirectly via routine practice data collection and indirect comparison methods, respectively. All agencies and JCA guidance reference target trial emulation and require confounding adjustment for systematically identified prognostic factors and effect modifiers. Unlike HTA bodies, regulators encourage pre-trial engagement for ECA pre-specification. Only FDA covers trial- and RWD-based ECAs, while other agencies focus on RWD and JCA guidance remains data-source agnostic. National HTA bodies prioritize country-specific RWD and provide the most detailed statistical methods guidance.
CONCLUSIONS: Conducting transferable ECAs remains challenging, compounded by the lack of ECA-specific EMA and JCA guidance and an industry-accessible route to the federated DARWIN-EU RWD network. The 2026 draft EMA paper, a dedicated JCA RWE framework, and EU-level joint early engagement, aligned with the NICE-MHRA RWE scientific dialogue, could bridge regulatory and HTA expectations.
METHODS: We reviewed ECA-specific guidance or positions from the Food and Drug Administration (FDA, 2023), European Medicines Agency (EMA, 2026), Medicines and Healthcare products Regulatory Agency (MHRA, 2025), EU HTA Coordination Group (2024), Haute Autorité de Santé (HAS, 2021/2023), Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG, 2025), and National Institute for Health and Care Excellence (NICE, 2025).
RESULTS: FDA and MHRA have dedicated ECA guidance, while EMA’s draft paper is expected late 2026. NICE and HAS address ECAs within real-world evidence (RWE) frameworks and published positions (HAS, 2023), while IQWiG and JCA guidance do so indirectly via routine practice data collection and indirect comparison methods, respectively. All agencies and JCA guidance reference target trial emulation and require confounding adjustment for systematically identified prognostic factors and effect modifiers. Unlike HTA bodies, regulators encourage pre-trial engagement for ECA pre-specification. Only FDA covers trial- and RWD-based ECAs, while other agencies focus on RWD and JCA guidance remains data-source agnostic. National HTA bodies prioritize country-specific RWD and provide the most detailed statistical methods guidance.
CONCLUSIONS: Conducting transferable ECAs remains challenging, compounded by the lack of ECA-specific EMA and JCA guidance and an industry-accessible route to the federated DARWIN-EU RWD network. The 2026 draft EMA paper, a dedicated JCA RWE framework, and EU-level joint early engagement, aligned with the NICE-MHRA RWE scientific dialogue, could bridge regulatory and HTA expectations.
Conference/Value in Health Info
2026-11, ISPOR Europe 2026, Vienna, Austria
Value in Health, Volume 29, Issue 12S
Code
HPR201
Topic
Health Policy & Regulatory, Health Technology Assessment, Real World Data & Information Systems
Topic Subcategory
Reimbursement & Access Policy
Disease
No Additional Disease & Conditions/Specialized Treatment Areas