Evolution of the European Medicines Agency clinical guidelines for epilepsy drug development between 2010 and 2025: A comparative analysis by the ILAE Task Force on Regulatory Affairs

OBJECTIVE: The latest European Medicines Agency (EMA) guideline on the clinical investigation of medicines to treat epileptic disorders was adopted by the EMA Committee for Medicinal Products for Human Use in 2025. We compared this guideline with the previous version (2010), highlighting areas where significant revisions were introduced. METHODS: The 2025 and 2010 versions of the guideline were systematically analyzed to identify significant modifications. RESULTS: The latest EMA guideline incorporated terminology from the 2017 International League Against Epilepsy (ILAE) classification of seizures and epilepsy and the 2022 classification of syndromes and replaced the older term "antiepileptic drug (AED)" with "antiseizure medication (ASM)." Recommendations for add-on studies in common epilepsies have remained substantially unchanged, the main revision being the acceptability of the time-to-event design also for confirmatory trials, provided it is not the only design in the clinical development plan. A major novelty is the feasibility of extrapolating data from add-on trials to the monotherapy indication, provided specific conditions are met. Guidance on pediatric ASM development has been expanded, addressing extrapolation of efficacy from data in adults and older children and options for studies in developmental and epileptic encephalopathies and other rare epilepsies. Compared with the previous guideline, greater emphasis is placed on nonseizure outcomes, including functional, quality of life, and patient-reported outcomes. Two new sections have been introduced, addressing studies in neonates and clinical trials in status epilepticus and other seizure emergencies. Options for innovative designs, including registry-based studies, are also discussed in situations where randomized controlled trials are unfeasible. SIGNIFICANCE: The updated guideline reflects the changing scenario in epilepsy treatment development, with a greater focus on pediatric epilepsies, rare epilepsies, and other indications with high unmet needs. The updates also reflect the contribution during the consultation process by a wide range of stakeholders, including the ILAE Task Force on Regulatory Affairs.