Article 31 referral: referral in the interest of the Union
An Article 31 referral is an EU-level assessment of a medicine or class of medicines where the interests of the Union are involved, usually on safety.
Article 31 of Directive 2001/83/EC lets a Member State, the Commission, an applicant or a marketing authorisation holder refer a matter to the Committee for Medicinal Products for Human Use in specific cases where the interests of the Union are involved, before any national decision is taken. The referral can concern one product or a whole class of products containing the same substance or sharing a safety concern. Where the referral is based on pharmacovigilance data, the Pharmacovigilance Risk Assessment Committee assesses it first and sends a recommendation to the CHMP, or to the CMDh where only nationally authorised products are involved.
The scope is set in a notification that lists the products and the questions to be addressed, and holders are asked to submit data to a timetable. Outcomes range from no change, through new contraindications, warnings and restrictions on use, to suspension or revocation. For centrally authorised products the Commission adopts a decision; for nationally authorised products the CMDh adopts a position by consensus that Member States implement, or by majority, in which case the Commission decides.
What goes wrong: treating the data call as a formality and submitting a thin response, when the assessment relies heavily on what holders provide; missing that a class referral on one product changes the product information of every product with the same substance, including generics; and not planning for the implementation phase, when product information must be updated in every market within a short deadline and healthcare professionals may need a direct communication.
Holders learn of a referral from the EMA announcement and the notification sent to them, which lists the questions and the dates for submitting data. Each holder answers for its own products, but the assessment treats the substance or class as a whole, so a well-documented response from one company can shape the outcome for all. The published assessment report names the data gaps that were found, which has reputational weight with prescribers and payers.
Article 31 should be distinguished from the urgent Union procedure of Article 107i, used when a Member State or the Commission wants rapid action such as suspension, and from Article 29 referrals that resolve disagreements in mutual recognition and decentralised procedures. Article 20 of Regulation (EC) No 726/2004 covers similar questions for centrally authorised products.
Timing
The CHMP adopts a reasoned opinion within 60 days of the referral under Article 32, which can be extended by up to 90 days, and the timetable usually includes a clock-stop for the holders' responses and an oral explanation. Where the PRAC assesses first, its recommendation precedes the CHMP opinion or CMDh position. Re-examination may be requested within 15 days of the opinion. The Commission decision or CMDh position then sets the deadline for holders to vary their authorisations.
Used in
Pharmacovigilance and regulatory teams watch for new referrals and outcomes published by EMA with Alerts.
Related terms
- Referral: EU-level assessment of a disputed or safety issueA referral is an EU procedure that resolves a scientific or regulatory issue about a medicine, or a class of medicines, in a single EU-level assessment.
- Article 30 referral: harmonisation of divergent national authorisationsAn Article 30 referral asks the CHMP to harmonise the product information of a medicine authorised nationally on differing terms across Member States.
- PRAC: Pharmacovigilance Risk Assessment CommitteeThe PRAC is the EMA committee that assesses the safety of human medicines in the EU, from risk management plans and PSURs to signals and safety referrals.
- USR: urgent safety restrictionAn urgent safety restriction (USR) is a provisional change to a medicine's product information imposed at once because of a risk to public health.
- DHPC: direct healthcare professional communicationA direct healthcare professional communication (DHPC) is a letter agreed with authorities that alerts prescribers and pharmacists to urgent safety issues.
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