EMA Guidance: Procedural Advice for Orphan Medicinal Product Designation

The European Medicines Agency (EMA) provides structured guidance for sponsors aiming to secure orphan medicinal product designation within the European Union. In July 2025, EMA released the 18th revision of its detailed guidance document: Procedural advice for orphan medicinal product designation. This comprehensive resource explains every procedural step—from application to appeal—using the IRIS portal, and clarifies how sponsors can prepare robust submissions.

Orphan designation in the EU is governed by Regulation (EC) No 141/2000, in effect since 2000, and several supporting regulations and guidelines. These collectively define what qualifies as an orphan condition (affecting ≤5 in 10,000 people in the EU) and what sponsors must demonstrate:

• Life-threatening or chronically debilitating nature of the disease

• Medical plausibility of the product for the condition

• Significant benefit over existing methods, if any exist

• Prevalence justification or proof of insufficient return on investment without incentives

This framework ensures orphan incentives go only to products targeting genuinely rare, underserved conditions.

EMA now requires all orphan designation applications to be submitted and tracked via the IRIS portal, a secure digital platform launched to standardize submissions and communication.

Key procedural steps include:

• Pre-submission meeting (recommended): Free, virtual discussion with EMA to clarify questions and improve dossier quality. Sponsors should share drafts and presentation materials in advance.

• Formal submission: Through IRIS, sponsors upload scientific evidence (non-clinical and/or clinical), prevalence calculations, proof of establishment in the EEA, translations, and literature references.

• Validation phase: EMA checks completeness and compliance with format/content guidelines (2022/C 440/02). Missing data triggers a supplementary information (VSI) request.

• Evaluation by COMP: The Committee for Orphan Medicinal Products (COMP) reviews data, may consult external experts, and drafts a critical summary report.

• Oral explanation: Sponsors may be invited to answer COMP questions during a scheduled video call, focusing only on identified concerns.

Timelines

• Evaluation period: Max 90 days (excluding clock stops)

• COMP opinion: Issued before day 90 (favourable or unfavourable)

• Follow-up: EMA forwards the opinion to the European Commission, which adopts the final decision—usually within 30 days.

If a negative opinion seems likely, sponsors may withdraw the application before formal adoption, rework data, and resubmit later.

• They can appeal via IRIS within 90 days, using the original data but adding new analyses

• COMP re-evaluates and may revise its opinion

Sponsors can also seek reassessment later if new data emerges supporting the product’s orphan eligibility.

The new Regulation (EU) 2024/568 updates EMA’s fee structure:

• SMEs benefit from full fee waivers (except for small administrative charges)

• Non-SMEs may still get partial fee reductions

• Fee reductions cover not only designation but also protocol assistance and pre-authorisation activities

EMA encourages SMEs to register early to maximise benefits, and provides guidance on SME registration and ATMP classification.

Once a product has orphan designation:

• It must be authorised centrally via the EMA

• It may qualify for conditional approval or approval under exceptional circumstances if evidence is limited due to rarity

• Annual re-evaluations ensure ongoing compliance

EMA’s updated 2025 guidance provides sponsors with a transparent, structured roadmap to navigate the complex orphan designation process, benefiting both industry and patients. For detailed requirements, always consult the full guidance "Procedural advice for orphan medicinal product designation – Guidance for sponsors: EMA official document link"