The referral procedure is a Union-law procedure for clarifying regulatory questions concerning authorised or applied-for medicinal products. A question relating to quality, safety, efficacy, or the benefit–risk balance is submitted to the EMA for scientific assessment so that Member States can implement a uniform position. It serves in particular to address divergent national measures or a Union-wide concern in an orderly manner.
Purpose and Parties Involved
In the referral procedure, not every medicinal product is re-examined in full as in a marketing authorisation application. The starting point is a specific regulatory question, such as a safety risk, a quality or manufacturing issue, or a divergent assessment among Member States. Depending on the legal basis, either the Committee for Medicinal Products for Human Use or the Pharmacovigilance Risk Assessment Committee evaluates the question. The scientific recommendation is in many cases followed by a decision of the European Commission, which must be implemented by the Member States.
The procedure thus contributes to the harmonisation of the medicinal products market. Its consequences may include changes to the product information, additional risk-minimisation measures, a suspension, or a withdrawal. Which measure is appropriate depends on the individual case and on the applicable legal basis. Public information is made available by the EMA after completion of the procedure; in safety-related procedures, details of public involvement may also be published.
Procedure Types under Article 31, Article 20, and Article 107i
A procedure under Article 31 of Directive 2001/83/EC concerns questions of Union interest relating to quality, safety, or efficacy. It may be used when a harmonised scientific assessment is required for medicinal products not exclusively subject to the centralised framework. The focus is not solely on pharmacovigilance but may also cover quality, manufacturing, and efficacy.
Article 20 of Regulation (EC) No 726/2004 concerns centrally authorised medicinal products. Here too, safety, quality, manufacturing, or efficacy may give rise to consolidating the scientific assessment at EU level. The procedure under Article 107i of Directive 2001/83/EC, by contrast, is an urgent Union procedure for safety questions. It is embedded in the pharmacovigilance framework and becomes relevant in particular for measures addressing safety risks. The choice of legal basis thus determines product scope, responsible committee, and procedural course.
Distinction from Marketing Authorisation Application and Variations
A referral procedure is not an ordinary application route by which a manufacturer applies for a new authorisation. It is a clarification procedure that may be initiated by Member States, the European Commission, or in certain constellations by the marketing authorisation holder. The aim is a coordinated regulatory response to an existing question, not the initial grant of a marketing authorisation.
A variation to the authorisation also pursues a different purpose. With a variation, the marketing authorisation holder applies for a change to the terms of a specific authorisation. A referral procedure may indeed lead to changes, but its cause is a higher-level assessment of risks or substantive questions. It is therefore not to be understood as a substitute for the regular maintenance of a marketing authorisation dossier.
The choice between procedures is therefore not a merely formal act. It determines whether a safety aspect is addressed in an urgent pharmacovigilance framework, whether a Union-wide question relating to quality or efficacy is assessed, or whether a centrally authorised product is concerned. For marketing authorisation holders, it is important to follow the publication and the formal procedural steps at the EMA. A uniform EU position may have implications for multiple national presentations, summaries of product characteristics, and risk-management measures simultaneously.
Technical preparation should therefore comprehensively capture the affected authorisations, countries, data sources, and possible implementation measures.
Relevance for clinical trials
Clinical data may be decisive in a referral procedure when they concern the efficacy, safety profile, or benefit–risk balance of a medicinal product. For sponsors and marketing authorisation holders, this means that study reports, safety data, analyses, and product information must be consistently available. The operational challenge lies in translating the regulatory question precisely into data queries, scientific justifications, and, where applicable, risk-minimisation measures.
Full-service CROs such as Mediconomics support the preparation of clinical and safety-relevant evidence through data management, biostatistics, pharmacovigilance, medical writing, and regulatory affairs. They can structure information flows between trial operations and authorisation documentation, coordinate responses to regulatory questions technically, and support the documentation of safety assessments, product information changes, or additional trial measures.
Frequently Asked Questions (FAQ)
Who can initiate a referral procedure?
Depending on the legal basis, Member States, the European Commission, and in certain cases marketing authorisation holders may initiate or be involved in a procedure.
Does every referral procedure lead to a withdrawal?
No. Possible outcomes range from unchanged terms through adjustments to the product information to suspension or withdrawal.
What is the core difference between Article 31 and Article 107i?
Article 31 covers Union-wide questions relating to quality, safety, or efficacy, whereas Article 107i is an urgent procedure for safety questions.
Regulatory References
- Directive 2001/83/EC, Article 31 – governs referrals for questions of Union interest.
- Directive 2001/83/EC, Article 107i – governs the urgent Union procedure for safety questions.
- Regulation (EC) No 726/2004, Article 20 – concerns referrals for centrally authorised medicinal products.
- Directive 2001/83/EC, Article 30 – concerns the harmonisation of divergent national decisions.