Referral Procedures

A medicinal product can only be placed on the market in the European Union (EU) when a marketing authorisation (MA) has been issued. There are different types of procedures, national authorisation, centralised procedure (CP), mutual recognition (MRP) and decentralised procedure (DCP). If a MA has granted for particular product by CP, applicant can launch product in entire community at same time. If a MA has granted by particular member state, product can launch in own territory only.

If no MA has been granted in the Community, the applicant can also make use of a DCP and submit an application in all the MSs where he intends to obtain a MA at the same time, and choose one of them as reference MS. The decentralised procedure is to be used in order to obtain marketing authorisations in several Member States where the medicinal product in question has not yet received a marketing authorisation in any Member State at the time of application.

In cases where national authorisations are requested for the same medicinal product in more than one Member State (MS) and the applicant had already received a marketing authorisation in a MS, the applicant can submit an application in the MS concerned using the procedure of mutual recognition. The MSs concerned should then recognise the MA already granted by the reference MS and authorise the marketing of the product on their national territory.

In centralised procedure, product information (SmPC, Labelling and Package leaflet) of the community marketing authorization is same in all countries. But in case of other procedures (DCP & MRP), potential differences are there in product information due to divergent decisions taken by some member states (i.e. medicinal product is approved in different indications in several MSs), could have an impact on the final marketing authorization and free movement of goods in European union.

There are several procedures that involved parties (i.e. MSs, applicant/MAH, the European Commission) have through a referral to address such heterogeneity of MAs and resulting prescribing information following authorisation (via national procedure or MRP) or prior to authorisation (via MRP or DCP), in order to achieve harmonisation of such information.

A referral is an European procedure that allows to address any concerns related to a medicinal product via an arbitration mechanism leading to an EU-wide, binding decision. When a Member State (MS), Applicant, Marketing Authorisation Holder (MAH) or the European Commission (EC) decides to initiate a referral, a notification form is sent to the CHMP/European Medicines Agency Secretariat, clearly identifying its legal basis, the product(s) concerned and a detailed explanation of the issue(s) referred.

Types of Referrals - Legal basis

From Directive 2001/83/EC
Article 29(4) referral ("Mutual Recognition and Decentralized Referral"):  If the MS involved in a MRP/DCP fail to reach an agreement within the 60-day period in the coordination group procedure, a referral according to Article 29(4) shall be triggered. The referral is then triggered by the reference MS in the MRP, on the grounds of potential serious risk to public health, where no agreement was reached during the coordinating group procedure on the assessment report (AR), the SmPC, the labelling or the Package Leaflet (PL), prepared by the Reference Member State (RMS)

Article 30 referral ("Divergent Decision Referral"): An article 30 (1) referral may be initiated when divergent decisions have been adopted by MSs concerning the authorization, suspension or withdrawal of a particular product. For example, where such medicinal product has been nationally authorized in two or more MSs and the authorization diverge (e.g. different indications, contraindications or posology). It may be triggered by the EC, a MS, a MAH or an Applicant.

An article 30(2) referral may be initiated for the same reasons stated above when the medicinal product is on the list laid down yearly by the coordination group.

Article 31 referral ("Community interest referral"): It may be initiated in specific cases where the interest of the community is involved. The expression 'Community interest' has a broad meaning but it refers particularly to the interests of the public health in the Community, for example following concerns related to the the quality, efficacy and/or safety of a medicinal product or new Pharmacovigilance information.

Article 31(1) referral relates to a medicinal product while article 31(2) referral refers to a class/range to medicinal products. Both may be triggered by the EC, a MS, a MAH or an Applicant.

Article 35 and 36 ("Follw-up referrals"): An article 36 referral my be initiated to resolve any post-harmonization divergences that may arise between MSs. It may be triggered by a MS when it is considered that a variation, suspension or withdrawn of a harmonized Marketing Authorization (MA) is necessary for the protection of public health.
These referrals may be triggered by MSs or MAH in the frame of follow-up procedure for medicinal products which have been granted a MA via MRP or which have been subject to complete harmonization in  the frame of a referral procedure.
Article 107 ("Unilateral action by MS in Urgent cases"):  This type of procedure is triggered when a Member state varies, suspends or revokes the marketing authorization for a medicine in its territory because of a safety issue. It informs the CHMP so that a EU-wide decision can be reached.
From Regulation (EC) 1084/2003
Article 5(11): This type of referral is triggered for a medicine that has been authorized by mutual recognition or via the dcentralised procedure when there is disagreement between member states on a variation (type IB)
Article 6(12) and 6(13): This type of referral is triggered for a medicine that has been authorized by mutual recognition or via the decentralised procedure when there is disagreement between Member states on a variation (Type II)
Article 6(12) ------------------------>May be triggered by a MS.
Article 6(13)------------------------>May be triggered by the MAH.
From Regulation (EC) 726/2004
Article 20: This type of procedure is triggered for the medicines that have been authorized via the centralsied procedure.The outcome of these procedures is published with the European public assessment report for the medicine.
From Regulation (EC) 1901/2006:
Article 29 (Paediatric): This type of procedure may be triggered by a marketing authorization holder when applying for a new indication, new pharmaceutical form or new route of administration for use in the paediatric population a product authorized under directive 2001/83/EC.
From Regulation (EC) 1234/2008:
Article 13: This type of referral is triggered for a medicine that has been authorized by mutual recognition or via the decentralized procedure when there is disagreement between MSs on a variation (Type II).

Reference:

1. Chapter 3 : Community referral Procedures, The Notice to Applicants Volume 2A Procedures for marketing authorization
2. Referrals procedures