Masterstudiengang "Drug Regulatory Affairs"

Language: English
 

Directive 2001/83/EC and its amendments have set the legal basis and the process for referral procedures within the European Community to resolve disagreement between MSs prior to authorisation and for authorised products. Referrals can be initiated to address any concerns related to medicinal products at the European level. Reasons for a referral can range from concerns over the safety of an approved class of medicinal product to different opinions among Member States on the use of a medicinal product in a certain indication during the review and approval process. The overall aim of a referral is to safeguard public health and to allow free movement and trade of medicinal products in the EU.
Referrals can be initiated by different bodies and organisations within the Community: the EC, any MS or the MAH/applicant, depending on the particular reason for a referral. Any product falling under the scope of a referral will be referred to the CHMP for a scientific evaluation, providing the MSs and the MAH/applicant with the possibility to support their case by relevant information. The CHMP issues an opinion based on their scientific assessment. The final decision is taken by the European Commission and is binding to all MSs in the Community and needs to be implemented at the national level. It can lead to a variation, revocation or suspension of a medicinal product.
Directive 2001/83/EC, as amended, provides for several different referral options. The initiator and the purpose of the referrals differ:

• Article 29(4) - "Mutual Recognition and Decentralised referral" initiated by MS based on any potential serious risk to public health identified during a MRP/DCP.
• Article 30 - "Divergent decision referral" initiated by any MS, EC, applicant/MAH on divergent decisions taken by MSs concerning authorisation, suspension or withdrawal of a medicinal product. Article 30 includes cases where a medicinal product is placed on a list of products to be harmonised, following a request by the EC for harmonisation.
• Article 31 - "Community interest referral" initiate by any MS, EC, applicant/MAH in cases where the interest (public health) of the Community might be affected.
• Article 36(1) - "Follow-up referrals" initiated by any MS or EC to resolve any post-authorisation divergences to protect public health following e.g. a variation.
• Article 107 - "Unilateral action by MSs in urgent cases" initiated by any MS to protect public health, followed by an assessment by the CHMP on an European level.

A referral can lead to full or partial harmonisation of the prescribing information (SmPC / labelling / package leaflet). In most cases, referrals consider the clinical information of a product and therefore could affect the indication, posology, contraindication and special warnings and precautions for use sections of the prescribing information of a particular product. Following the completion of a referral procedure, further action by the MAH/applicant could be required to harmonise the complete dossier (e.g. the quality information). In the case of Article 29(4) referrals, where a new medicinal product is being assessed prior to its authorisation and based on a complete dossier, full harmonisation will be achieved in the reference and concerned MSs taking part in the MRP/DCP, followed by national implementation of the EC Decision in all respective MSs that were part of the procedure.

Harmonisation can have different advantages to the involved stakeholders. The MAH needs to maintain only a single dossier. In addition, based on a harmonised product, the MAH could relatively easily apply for an authorisation of a product in all EU MSs, if not previously done, to fulfill the prerequisite to apply for a 6-month extension of the Supplementary Protection Certificate following completion of a Paediatric Investigational Plan. MSs Competent Authorities have the possibility to raise any potential concern to public health in their territory with a follow-up action on an EU-wide level to ensure the same prescribing information is applicable within the whole EU. In addition, harmonisation could also help to reduce turnaround time as only one dossier would have to be reviewed in case of any post-marketing changes. For generic companies, harmonisation of an originator product information is of benefit as they could apply for an approval in all MSs where a particular product is authorised, as reference can then be made to one originator product with the same prescribing information across the EU. Availability of generic products with the same prescribing information as for an originator product can be of benefit to the Health Insurance System in the different MSs as reimbursement costs could be reduced by substitution of an originator medicinal product by a generic product with identical prescribing information to the originator product but lower price.

In general, referral procedures have a 60-day active review time but due to clock-stops can be a lengthy process. They frequently take more than one year from initiation to completion. There is however one exception, which relates to Article 107 referrals, where urgent action based on critical safety findings, is required. In these cases, the CHMP opinion can be adopted even within one month only, but usually safety measure had been initiated already at earlier times, even before the initiation of such a procedure.