A referral is a procedure used to resolve issues such as concerns over the safety or benefit-risk balance of a medicine or a class of medicines.
In a referral, the European Medicines Agency is requested to conduct a scientific assessment of a particular medicine or class of medicines on behalf of the European Union (EU). The medicine, or the class or medicines, is ‘referred’ to the Agency so that it can make a recommendation for a harmonised position across the EU.
There are a number of reasons why a referral may be started, ranging from concerns over the safety of a class of medicine to disagreements among Member States on the use of the medicine:
- safety-related referrals are assessed by the Pharmacovigilance Risk Assessment Committee (PRAC) and then either by the Committee for Medicinal Products for Human Use (CHMP) or, for nationally authorised medicines, by the Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh);
- all other referrals on human medicines are assessed by the CHMP only.
Referrals can be started by the European Commission, any Member State or by the company that markets the medicine.
For most referrals, the European Commission issues a decision to all Member States reflecting the measures to take to implement the Agency's recommendation.
Types of referral
All referrals are described in the legislative texts that govern how medicines are authorised and monitored in the EU.
|Article 107i procedures|
This type of procedure is triggered when a Member State or the European Commission consider that urgent action is necessary because of a safety issue. Situations that fall under this procedure include consideration for suspension or revocation of the marketing authorisation for a medicine, the prohibition of supply of a medicine or major changes to the marketing authorisation such as deletion of indications, reduction of the recommended dose or new contraindications. The procedure is also applicable in case of a safety issue with a class of medicines.
Information for marketing-authorisation holders on this type of procedure is available under questions and answers: Urgent Union procedure (Article 107i).
|Safety, quality, manufacturing or efficacy issues|
|Article 20 procedures|
This type of procedure is triggered for medicines that have been authorised via the centralised procedure in case of manufacturing or safety issues.
Information for marketing-authorisation holders on this type of procedure is available under questions and answers: Article 20 pharmacovigilance procedures.
|Article 31 referrals|
This type of referral is triggered when the interest of the Community is involved, following concerns relating to the quality, safety or efficacy of a medicine or a class of medicines.
Information for marketing-authorisation holders on this type of procedure is available under questions and answers: Article 31 pharmacovigilance referral.
|Paediatric medicine issues|
|Article 29 paediatrics||This type of procedure may be triggered by a marketing-authorisation holder when applying for a new indication, new pharmaceutical form or new route of administration for use in children for a product authorised under Directive 2001/83/EC.|
|Harmonisation, mutual-recognition procedure and decentralised procedure|
|Article 13 referrals||This type of referral is triggered for a medicine that has been authorised by mutual recognition or via the decentralised procedure when there is disagreement between Member States on a variation (type II).|
|Article 29(4) referrals||This type of referral is triggered when there is a disagreement between Member States regarding a medicine being evaluated during a mutual-recognition or decentralised procedure, on the grounds of a potential serious risk to public health.|
|Article 30 referrals||This type of referral is triggered when Member States have adopted different decisions over the years for some medicines (e.g. different indications, contraindications or posology) and there is a need to harmonise across the EU.|
The Agency's Executive Director, the European Commission or a Member State can also ask the CHMP draw up an opinion on any scientific matter related to the evaluation of medicines for use in humans.
- For more information, see Article 5(3) opinions.
Historical referral types
A number of referral types are no longer applicable because of changes in European law. The outcomes of a number of these historical referral types are available on this website.
|Referral type||Description||Applicable prior to|
|Article 5(11) referrals||This type of referral was triggered for a medicine that had been authorised by mutual recognition or via the decentralised procedure when there was disagreement between Member States on a variation (type IB).||January 2010|
|Article 6(12) referrals||This type of referral was triggered for a medicine that had been authorised by mutual recognition or via the decentralised procedure when there was disagreement between Member States on a variation (type II). This referral has been replaced by Article 13 referrals.||January 2010|
|Article 6(13) referrals||This type of referral was triggered by the marketing-authorisation holder for a medicine that had been authorised by mutual recognition or via the decentralised procedure when Member States could not accept the variation (type II).||January 2010|
|Article 36 referrals||This type of referral applied for a marketing authorisation that were granted via the mutual-recognition or decentralised procedure. It was triggered when a Member State considered that action (variation, suspension or withdrawal) was needed on the grounds of the need to protect public health. This referral has been replaced by Articles 107i and 31.||July 2012|
|Article 107 procedures||This type of procedure was triggered when a Member State varied, suspended or revoked the marketing authorisation for a medicine in its territory because of a safety issue. This procedure has been replaced by Article 107i.||July 2012|
Publication of information on referrals
Information on referrals for human medicines is published under referrals. Users can search the database of referrals by medicine name and type of referral.
These pages include information on the referral written in public-friendly language in a question-and-answer format, key facts and all documents related to the referral. For safety-related referrals, it also includes information on how the public can submit data to be considered as part of the assessment and on whether a public hearing is taking place.
In addition, the Agency announces the key steps in referrals:
- for safety-related referrals, the Agency announces the start of the referral in the PRAC meeting highlights. After assessment, the Agency also announces the PRAC's recommendation to the CHMP or CMDh the PRAC meeting highlights;
- for all other referrals, the Agency announces the start of the referral in the CHMP meeting highlights;
For all referrals, the Agency announces their conclusion in the CHMP meeting highlights or the CMDh meeting highlights.
Information on Article 20 procedures was previously published as part of the European public assessment report for the medicine concerned. For Article 20 procedures starting from July 2012, information is available under referrals.
- European Medicines Agency procedural advice for marketing authorisation holders/applicants concerned by referral procedures (human medicines)
- Questions and answers: Article 20 pharmacovigilance procedures
- Questions and answers: Urgent Union procedure (Article 107i)
- Questions and answers: Article 31 pharmacovigilance referral
- Referral procedures: Regulatory and procedural guidance
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