The Drug Registration Process in Europe

Since the creation of the European Union (EU), formed with the intent to create a single market without trade barriers, the community of member countries has become the second largest pharmaceutical market in the world. Consequently, access to information regarding drug approvals within its jurisdiction is important to global manufacturers. Since 1995, there are two alternative routes to achieving marketing authorization in any or all EU countries: Centralized Registration or

Mutual Recognition. The European Medicines Agency (still abbreviated as EMEA, based on its previous name) oversees the process by co-ordinating evaluation of scientific evidence conducted by representatives from all member states convened in the Committee for Human Use Medical Products (CHMP).

Under the Centralized Procedure, drug sponsors submit preregistration documents directly to the EMEA. Final marketing authorization by CHMP is binding on all member states, resulting in mandatory and automatic approval for commercial introduction throughout the EU. Registrations are valid for five years and are renewable, upon application, for an additional five years. The Centralized Procedure is required for all candidate products produced by biotechnology or for veterinary products designed to boost animal production. Other, nonbiotech medicines may seek approval through either the Centralized Procedure or Mutual Recognition.

Under the EU's Mutual Recognition agreement, applicant companies can achieve multistate clearance within Europe after just one member state approves their product. This decentralized approach enables applicants to choose which national authority will handle preregistration documents and to designate where and when subsequent marketing authorization will be sought (specified countries versus the pan-European mandate).

An abridged approval procedure is possible for "essentially similar products'' (i.e., generic copies of previously authorized branded products, following their patent or market exclusivity expiration). Similar to U.S. ANDAs, abridged applications in the EU focus on proof of bioequivalence and rely on pharmacology, toxicology, and clinical data submitted in applications by the original marketing authorization holder as evidence of safety and efficacy.

Several major changes in the EU approval process can be anticipated in the future as a result of a massive pharmaceutical legislative review completed in December 2003. Revisions scheduled for implementation by the end of 2005 provide for the extension of product categories for which the Centralized Procedure will be mandatory. These categories include new drugs designed to treat AIDS, cancer, diabetes, and neurodegenerative disorders, as well as all new Orphan Drugs. Treatments for immune and viral diseases will be added to the compulsory Centralized list by 2007.

New regulations also define "biosimilar" products as a separate category of generic drugs that may not be eligible for abridged applications to gain marketing authorization (required testing will be decided on a case-by-case basis). Efforts to harmonize widely divergent approval mechanisms for herbal medications have also begun, with the establishment of a separate committee within the EMEA. This group will be responsible for Community-wide scientific guidance on quality, safety, and efficacy issues related to plant-derived preparations. This will involve development of a draft list of phytomedicines with well-established traditional uses, as well as the eventual publication of Community Herbal Monographs compiling available scientific evidence, to be used as a basis for abridged approval applications under the Mutual Recognition system.

Databases

The Community Register of Medicinal Products (from EUDRA). 1995- . URL: http://pharmacos.eudra.org/F2/register/index.htm. The consortium of European Union Drug Regulatory Authorities (EUDRA) Web site provides access to the complete list of drugs approved under the Centralized Procedure that began in 1995. Separate HTML tables, arranged alphabetically by brand name or chronologically by EU number, are available for human drugs, veterinary medicines, and orphan drugs. Tabular lists identify nonproprietary names of the active ingredients in each product, as well as the marketing authorization holder (company name) and approval date. Hyperlinks from each brand name lead to information on approved indications (uses, medical applications), dosage form, strengths, and route of administration. Unlike the EMEA version of the Community Register (see below), the EUDRA database lacks links to supplementary information (annexes), such as labeling and product leaflets. There is no search engine to isolate customized lists of products (e.g., by company name or indications) from the Community Register online.

The Community Register of Medicinal Products (from EMEA). URL: http://www.emea.eu.int/index/indexh1.htm. The EMEA Web site offers, in both HTML and downloadable PDF format, a cumulative list of human drugs authorized under the centralized EU registration system. The HTML version, arranged alphabetically by brand name, provides links to European Public Assessment Reports (EPARs) issued postapproval. Comparable to Drug Review Packages issued by the U.S. FDA, EPARs summarize scientific evidence submitted in support of product authorizations and include other background information used in evaluating safety, quality, and efficacy. The table of contents found under each EPAR link enables downloads of separate modules within each report, such as the product information leaflet (PIL), official labeling, summary of product characteristics (SmPC), and "Steps taken after authorisation.'' The latter section includes any changes to the terms and conditions originally approved, such as variations in product labeling, pharmacovigilance issues, and additional obligations imposed on the manufacturer. The EPAR interface also provides a choice of modules available in any of 20 EU languages.

The PDF version of the EMEA's Community Register lacks links to EPARs, but does include brand and nonproprie-tary names for each product, company and country of origin, anatomic/therapeutic classification codes, and indication keywords. It also contains "presentation" details (dosage form, strength), dates of application validation and opinion by the CHMP, and elapsed time (number of days) spent in review.

There is no search capability incorporated into this database for retrieving subsets of product entries that match specified criteria. The EMEA Web site also includes separate databases for orphan medicinal products and for veterinary medicines; each is accessible from the home page URL.

CHMP Summaries of Opinion. URL: http://www.emea.eu.int/ index/indexl.htm. Summaries of Opinion from the CHMP provide detailed product information two to three months prior to official EU marketing authorization and before publication of an EPAR (see above). These brief summaries, presented in textual format as downloadable PDF files, describe indications recommended for approval, anticipated therapeutic benefits, and known side effects. Opinions are hyperlinked from nonproprietary names found in a table at the URL cited here. The table is organized in reverse chronological order by CHMP Opinion adoption date (i.e., latest issue listed first) and cites proposed brand names, dosage forms, and strengths. This database identifies human drugs in the final stage of preregistration under the Centralized Procedure for entry into the European market.

MRI—European Product Index. URL: http://mri.medagencies. com/prodidx. The European Product Index pools together new drug authorization information supplied by each of the European Union member states to provide a gateway to all products registered under the Mutual Recognition system. A pull-down menu on the opening screen's search form offers several options for viewing data, including alphabetical product lists by proprietary name or by specific country of registration. Users can qualify country product lists by limiting output to a selected Reference Member State (RMS, originally evaluates and approves) and/ or a specified Concerned Member State (CMS) that has authorized marketing based on the RMS decision. Results of searches identify product brand names, dosage form and strength, and active ingredients. Brand names link to further information about each drug, including RMS and CMS, marketing authorization holder (company), and pertinent approval dates. Product records typically provide hyperlinks to SmPCs and PILs, but access to Public Assessment Reports (lengthier summaries of scientific evidence submitted) is limited.

OTC Ingredient Classification Tables. URL: http://www.aesgp. be/publications/otcIngredient Tables.asp. Regulations regarding nonprescription drug authorizations in Europe are still undergoing harmonization, but the routes to market rely on product characteristics comparable to those required by the U.S.: novelty versus long-term established safe use. There is no direct EU counterpart to the U.S. OTC Monographs. However, the OTC Ingredient Classification Tables cited here identify active constituents in approved drug products marketed worldwide. Compiled by the Association of the European

Self-Medication Industry, the PDF list enables at-a-glance comparisons of availability and Rx versus OTC status in various countries (not limited to Europe). Tables organize ingredients by therapeutic class and identify dates of initial Rx-to-OTC switches, when known.

Books

Lofgren M, Dreesen M. New Drug Approval in the European Union. Waltham, MA: PAREXEL International, 2002. The authors provide invaluable background information on Centralized Registration and the Mutual Recognition Procedure. EU expansion in 2004 and forthcoming changes mandated by the 2003 legislative review will, no doubt, lead to publication of a new edition. Meanwhile, the in-depth discussion of regulatory requirements characteristic of books from this publisher offers a solid foundation on which to build knowledge of changes effective during the next few years.

Kanavos P. World Generics: Impact of Regulation and Market Development. Richmond, Surrey, U.K.: PJB Publications, 2003. The author examines the current status of the generics market, in both developed and developing countries, and discusses key intellectual property, antitrust, and supply/demand issues that affect it. This Scrip Report also provides details regarding European Commission amendments and devotes three chapters to the differences among price-regulated nations. As an alternative to hardcopy format, PJB also offers electronic (HTML or PDF) subscriptions to this publication.

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