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European regulatory environment for medicinal products

An an overview of current pharmaceutical legislation in the European Union (EU), with a focus on recent developments regarding legislation of medicinal products

Parminder Kaur

The European Community (EC) was founded with the treaty of Rome by six countries i.e. Belgium, France, Federal Republic of Germany, Italy, Luxembourg and The Netherlands in 1957. The objective was to achieve a single integrated market. With the treaty of Maastricht (1992), not only a new name—European Union (EU)—was introduced, but a movement towards economic and monetary unity was also decided. With the Treaty of Amsterdam (1997), further improvements on EU procedures came into force (for instance, more power was given to the European Parliament). Pharmaceutical legislation in the European Union now covers 27 member states and three associated members (Iceland, Liechtenstein and Norway). In May 2004, eight central and Eastern European countries (Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Slovakia, Slovenia) and Cyprus and Malta joined the European Union. Romania and Bulgaria joined the league in early 2007, thereby extending the community.

The European Union has four main institutions—the European Parliament (EP), the European Commission (EC), the Council of Ministers (CM) and the European Court of Justice (ECJ).

European Medicines Agency (EMEA)

The European Medicines Agency (EMEA) was established by Council Regulation 2309/93/EEC together with the introduction of the centralised procedure in 1995. The EMEA is based in Canary Wharf, London. With Regulation (EC) 726/2004 the name of the EMEA was simplified to European Medicines Agency and the structure has been revised. An executive director heads the agency. Scientific opinions of the agency are prepared by committees i.e. the committee for medicinal products for human use (CHMP), the committee for medicinal products for veterinary use (CVMP), the committee for orphan medicinal products for rare diseases (COMP) and the new committee on herbal medicinal products (HMPC). The HMPC was launched in September 2004 based on directive 2004/24/EC that introduced a simplified registration procedure for traditional herbal medicinal products. The EMEA co-ordinates the scientific evaluation of the quality, safety and efficacy of medicinal products which fall into the scope of the EU licensing centralised procedure. In addition EMEA coordinates the resources for scientific evaluation and assessment regarding products undergoing the mutual recognition procedure and the master files for plasma and vaccine antigens.

Another important task of the EMEA is to provide guidance for companies requesting scientific advice (EMEA/H/4260/01) and providing scientific advice before the application of new marketing authorisation for centralised and mutual recognition procedures. This is done via Scientific Advice Working Party (SAWP), established (SAWP) according to regulation 726/2004. The SAWP is a multidisciplinary group and comprises 21 members. This party takes over the tasks of the Mutual Recognition Facilitation Group (MRFG), an informal group started by the agency with the objective to coordinate and facilitate the mutual recognition procedure. On the other hand the Biotechnology Working Party (BWP) covers the field of plasma-derived medicinal products, vaccines and all biotechnology derived medicinal products, including gene therapy as well as biosimilars. Another recent inclusion in the scientific advice group is the Innovative Task Force (ITF). The ITF—in liaison with the CHMP, and where appropriate, the European Commission—provides regulatory advice on whether new medicinal products for emerging therapies and borderline products are eligible for EMEA procedures. This advice is provided free of charge within 60 days of receipt of a valid request from an applicant.

Committee on Human Medicinal Products (CHMP)

The Committee on Proprietary Medicinal Products (CHMP) was established by directive 75/319/EEC as CPMP and changed to CHMP by regulation 726/2004. The CHMP serves for several functions:

• assesses applications submitted under the mutual recognition or centralised procedure
• acts as a forum for harmonisation of procedures
• examines questions concerning the grant, suspension or withdrawal of a license
• advices the EU commission
• establishes working parties that issue guidance documents on manufacture, quality and safety of pharmaceuticals

Each member state has one delegate, who can be supported by experts, in the CHMP. The CHMP meets once every month at the EMEA in London. The CHMP established several working parties.

European Pharmacopoeia (Ph Eur)

Pharmacopoeias (monographs) are quality specifications for pharmaceutical preparations and their ingredients. The European Pharmacopoeia Commission provides reference standards for tests described in the monographs. Under the roof of the Ph Eur, an official network of national medicines control laboratories (OMCLs) has been established. More information on the European Pharmacopoeia is available under http://www.pheur.org.

World Health Organization (WHO)

The WHO issues guidance documents as technical reports that are taken into consideration by EU legislation.

Legal framework

The legal framework of the EU licensing consists of three major columns—regulations, directives and guidelines. The rules governing medicinal products in the European Union are issued by the EU commission and can be found under—http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/index.htm. For human medicinal products, including all biological and biotech products, the relevant volumes are Volume 1- Volume 10.

Regulations

Regulations are directly effective as supranational law and they are addressing the citizens of the EU member states. For example Regulation 726/2004 supersedes Regulation 2309/93/EEC, establishing the European Medicines Agency (EMEA) and Regulations 1084/2003 and 1085/2003 describing the latest variation procedure for licensed medicinal products. All regulations for pharmaceuticals cover for chemical and biological medicinal products.

Directives

Directives addressing the member states have to be implemented in national law by the legislation of the member states. Directive 65/65/ EEC is the historical root of all directives concerning pharmaceuticals because that lays down the framework for medicines regulation in the EU; directive 2001/83/EC on the community code to medicinal products for human use released by the commission in November 2001 summarises all relevant directives from 1965 to 1999 relating to medicinal products for human use; directive 2003/63/EC amended directive 2001/83/EC by implementing the new structure of an application dossier for a marketing authorisation according to the ICH guidance on the Common Technical Document (CTD). Additionally this directive introduces the mater file approach for source plasma and vaccine antigens and includes gene therapy products; directive 2001/20/EC relating to the implementation of good clinical practice (GCP) in the conduct of clinical trials on medicinal products for human use and harmonising clinical trails in the EU; directive 2003/94/EC implementing the principles of good manufacturing practice (GMP) for medicinal products for human use and investigational products for human use; directive 2004/27/EC amending directive 2001/83/EC by implementing several improvements for the licensing procedures; directive 2005/28/EC of 8 April 2005, laying down principles and detailed guidelines for GCP for investigational medicinal products as well as requirements for authorisation of the manufacturing or importation of such products.

General documents and guidelines

Guidelines issued by the CHMP, the European Pharmacopoeia and ICH are not legally binding, but where an applicant chooses not to be compliant with a guideline, that decision must be explained and justified.

Registration procedures

Prior to a Marketing Authorisation Application (MAA) is being submitted, it's required to show the safety and efficacy of the medicinal product taking into consideration the intrinsic and extrinsic factors for the local population. In order to do so, local clinical data should be generated for a new medicinal product, thereby necessitating the need for clinical trials in the EU. In case a product has already been used in other countries for which the safety and efficacy has been proven, a bridging clinical study would suffice the purpose, e.g, in case of old vaccines that have been in use for many years outside EU.

Clinical trials in the EU

Since 1 May 2004, directive 2001/20/EC relating to implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use is fully applicable in all member states. For all clinical trails approval of the clinical trial protocol by an ethics committee and competent regulatory authority is mandatory. The approval of the competent authority is based on information in the investigator's brochure, study protocol and the investigational medicinal product dossier (IMPD) that includes data on pharmaceutical, pre-clinical and clinical development. Approval times for the competent authorities are 60 days and additionally 30 days or more for gene therapy products. For all clinical trials sponsors need to obtain a EUDRACT number from the EUDRACT database.

Additionally, the sponsor shall ensure that all relevant information about Suspected Serious Unexpected Adverse Reactions (SUSARs) are recorded and reported to the competent authorities in all member states concerned and to the ethics committees.

The EU offers three main routes and two exemption routes for authorising medicinal products—

Centralised procedure (CP):

As per regulation 724/2004 and directive 2004/27/EC, Marketing Authorisation Applications (MAA) are made directly to the EMEA and lead to a grant of a European marketing authorisation by the EU Commission within seven months (210 days) after application. One Member State is assigned rapporteur for an application and takes the lead in the evaluation process of the CHMP. The decision of the commission is binding on all EU member states. The product may be marketed in all member states with one common Summary of Product Characteristics (SPC). The procedure is compulsory for medicinal products using biotechnolo-gical processes and may be used for other innovative products on a voluntary basis.

Mutual recognition procedure (MRP)

The basis of this procedure has been laid down in council directive 2004/27/EC. Pre-requisite to enter in this procedure is a marketing authorisation in one of the EU member states (reference member state, RMS). To obtain such initial national marketing authorisation may take six to nine months. An application for mutual recognition may be addressed to any number of member states (concerned member states, CMS). The RMS compiles an assessment report within 90 days and sends this report to all CMS who have 90 days to recognise the decision of the RMS by granting a marketing authorisation with an identical SPC. Concerned member states have additional 30 days for granting the national licenses. Thus, the total MR procedure takes nine months for the first national marketing authorisation plus seven months for the mutual recognition part.

Decentralised procedure (DCP)

This had been laid down in directive 2004/27/EC, and is applicable where a medicinal product has not received the marketing authorisation in any of the member state. The applicant requests one country to be the Reference Member State (RMS) in the procedure. On the 120th day of the assessment procedure, the RMS circulates the draft assessment report, including comments on the SPC, package leaflet and labelling texts. A clock stop is observed until the applicant has submitted a response document. Then the draft assessment report is issued by the RMS and it needs to be agreed on during a 90 day 'European' period; a mutual recognition procedure in which other member states generally adopt the RMS's assessment, unless they have important objections on the grounds of a potentially serious risk to public health. In such situations, further discussions will also be held in the co-ordination group for mutual recognition and decentralised procedures. The procedure has to be finalised after 210 days. Concerned member states have additional 30 days for granting the national licenses which adds up to eight months for the DCP. New for both the mutual recognition and the decentralised procedure is a public assessment report and the fact that package leaflet and labelling is part of the approval i.e. a ‘blue’ box is required as for the centralised procedure. An additional novelty is the introduction of a forced negotiation period guided by the co-ordination group (CMD) of 60 days in case CHMP cannot reach a positive agreement after the 90 days assessment period. Only after failure of these additional negations the arbitration procedure can start. The applicant cannot withdraw the application in selected member states after the assessment report has been issued.

National marketing authorisation

This could be filed in one member state, but stays restricted to this particular member state. As soon as the license holder applies for a marketing authorisation in a second EU member state the mutual recognition procedure applies.

Orphan drug designation

EU regulation on orphan medicinal products EC 141/2000 and EC 847/2000 apply for products intended for treatment of rare diseases. If a medical condition does not affect more than five in 10,000 persons in the community (i.e. approximately 225,000 persons as of April 01, 2004) an orphan designation may be applied for. Prove of the prevalence of a rare condition should follow COMP/436/01. The designation procedure with the COMP takes 90 days plus 30 days for commission approval. Additionally, the sponsor has to file an application for a marketing authorisation through the centralised procedure and only after approval may bring the orphan drug product on the EU market. The approval includes a 10 years exclusive marketing right.

Post marketing requirements—renewal and pharmacovigilance

In accordance with article 24 of directive 2001/83/EC, as amended, a marketing authorisation may be renewed after five years on the basis of a re-evaluation of the risk—benefit balance by the competent authority of the authorising member state. Once renewed, the marketing authorisation shall be valid for an unlimited period unless the competent authority decides, on justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal. In some cases, especially in case of conditional approval, a follow-up, long-term safety study is required. Upon submission of additional safety data, the approval is being granted with no further conditions applied.

The surveillance of drug safety of licensed medicinal products (pharmacovigilance) is regulated by council regulation 726/2004 and directive 2004/27. Companies must provide individual adverse reaction case reports, periodic safety update reports (bi-annually and annually during the first five years of a marketing authorisation) and every three years after the renewal. Data are collected in the EudraVigilance post-authorisation module of the database.

Conclusion

The EU pharmaceutical legislation provides extensive rules and guidance on licensing procedures for medicinal products for human use that ensure high quality and safe therapies. The new legal basis will facilitate the integration of the new accession countries and will strengthen the procedures further.

References
1. http://europa.eu.int/eur-lex
2. http://www.emea.eu.int/index/-indexh1.htm
3. European Pharmacopoeia, Edition 4.6 2003 and http://www.pheur.org
4. http://pharmacos.eudra.org/F2/-eudralex/vol-2/home.htm
5.http://pharmacos.eudra.org/F2/-eudralex/vol-1/new_v1/Dir2002-98_EN.pdf
6. http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-2/c/renewal_guid_final_oct2005.pdf

(The author is a global regulatory consultant and can be contacted at parminder.kaur@consultant.com)