Presentation (CTI)

OBJECTIVES: Many medicines are widely used in clinical practice, but remain off-label because regulatory approval was never sought. Obtaining an on-label indication ensures formal evaluation of benefits and risks, enhances safety monitoring and may facilitate reimbursement and access. One pathway for approval is the ‘Well-Established Use’ (WEU) regulatory pathway, where applicants can substitute (non-)clinical studies with a comprehensive review of existing literature. To qualify for WEU, applicants need to demonstrate a positive benefit-risk balance in the claimed indications and show systemic use over at least 10 years; scientific interest; and coherence of scientific assessments. This study describes the assessments of WEU applications by the European Medicines Agency, focussing on the extent of evidence of efficacy and safety.
METHODS: We retrospectively analysed the European Public Assessment Reports (EPARs) of medicinal products submitted via the WEU pathway between 1995 and 2025. We extracted the regulatory characteristics (e.g. approval status, orphan designation) and the types of evidence supporting each application.
RESULTS: Twenty-two applications were identified and 18 EPARS were included: 12 approved, 4 withdrawn, and 2 refused. Indications were diverse, most commonly eye disorders, renal/urinary disorders and surgical/medical procedures (each n=2); 61% held orphan designation. To demonstrate systemic use, applicants primarily cited treatment guidelines (n=10), national approvals (n=5), hospital/patient surveys (n=4), and compassionate use/named-patient programs (n=4). Evidence for benefit-risk assessment varied: 8 applications included retrospective and prospective studies, 6 relied solely on prospective data; 5 on retrospective data and 1 on meta-analyses. Of the withdrawn and refused applications, two failed to meet the WEU criteria and other objections raised were related to safety and quality aspects.
CONCLUSIONS: The WEU pathway offers a viable route for formalising marketing authorisation. Diverse evidence types can support approval, showing that this pathway can be adapted to deal with a variety of studies and evidence. These findings may inform future WEU applications.