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The European Medicines Agency (EMA, EMEA)

In 1995, the European Medicines Evaluation Agency (EMEA) was created and based in the Canary Wharf section of London, England. Now, over a decade later, the face of drug regulation in Europe has totally changed. In 2004, a new directive changed the name of the EMEA to the European Medicines Agency (EMA, also called, like the U.S. Food and Drug Administration [FDA] and Central Intelligence Agency [CIA], “The Agency”). See its very extensive website (Web Resource 22-1).

Like the FDA, its main responsibility is the protection and promotion of public and animal health through the evaluation and supervision of medicines throughout the European Union, comprising 27 countries (Member States) and their more than 40 national authorities, as well as the three European Free Trade Area (EFTA) nations of Iceland, Liechtenstein, and Norway. Switzerland also works closely with the EMA, particularly in areas regarding inspections. These 30 countries are also referred to as the European Economic Area (EEA).

The terminology in Europe can be a bit confusing as the European Union/EEA is not the European equivalent of the United States. The European Union/EEA is composed of sovereign nations, which still retain many powers and functions. Some governmental functions are devolved in full or in part to the “central” authority (in Brussels and Strasbourg) and others are retained by the national governments. Not all countries devolve the same functions to the central authority. Thus, the European Union/EEA’s handling of drugs and drug safety is similar to but, in many ways, quite different from that of the FDA or other single, national health agencies.

The EMA handles human and veterinary medicinal products (but not food, unlike the FDA). The EMA has the authority to approve the “Marketing Authorisation” (MA) for a product via the “centralized procedure,” thus avoiding the need to gain approval in each of the 30 countries. Some products may still be approved by national authorities on a country-by-country basis.

Six scientific committees, with members from all 30 states, handle the main scientific work of the Agency: the Committee for Medicinal Products for Human Use (CHMP), the Committee for Medicinal Products for Veterinary Use (CVMP), the Committee for Orphan Medicinal Products (COMP), the Committee on Herbal Medicinal Products (HMPC), the Paediatric Committee (PDCO), and the Committee for Advanced Therapies (CAT).

The EMA (with more than 500 employees mainly based in Canary Wharf in London) is headed by an executive director with five reporting divisions, including two that touch on drug safety: the sections on “Human Medicines Development and Evaluation” and the Patient Health Protection. The latter has four subdivisions, including Compliance and Inspection and Pharmacovigilance and Risk Management. The PV and RM group has four subdivisions below it, handling Data Collection and Management, Signal Detection and Data Analysis, Risk Management, and Coordination and Networking. See the organization chart on the EMA website (Web Resource 22-2).

The highest-level committee handling human medicines is the Committee for Medicinal Products for Human Use (CHMP). This committee has created a pharmacovigilance committee called the Pharmacovigilance Working Party (PWP or PVWP) that has experts from each member state. They meet for 2 to 3 days each month (except August) to discuss major safety issues such as standard operating procedures, guidance documents, “points to consider” documents, new procedures, class- or product-specific safety issues, International Conference on Harmonization (ICH) documents, and interactions with other bodies (e.g., the Uppsala Monitoring Centre and non-European Union organizations). In addition, urgent or emergency safety matters may also be brought to the Working Party. Their yearly work schedule is usually published in advance.

The CHMP handles the safety of authorized products via member states’ national medicines agencies by monitoring safety concerns (ADRs) and by making recommendations to the European Commission to change, suspend, or withdraw a product’s marketing authorization.

Under the CHMP’s Pharmacovigilance Working Party is a committee that handles drug safety and has representatives from all member states. Its primary duties include evaluation of potential signals arising from spontaneous reports, advising on risk and risk management (including regulatory options), monitoring regulatory action, setting standards for procedures and methodologies for Good PV Practice, communication and exchange of information between the EMEA and national authorities, and cooperation with ex-European Union agencies (particularly FDA and the World Health Organization). Their domain is largely in the postapproval area, but they do have authority for drugs still under study. They issue work programs in advance of their monthly meetings and publish meeting summaries (Web Resource 22-3), which usually involve safety issues on specific drugs.

In 2001, a European Union-wide central database, called the Eudravigilance System, was created (Web Resource 22-4). This database serves as a “clearinghouse” to ensure that all appropriate cases are transmitted to the appropriate member states. It is used to capture SAEs as Individual Case Safety Reports (ICSRs) both pre- and postauthorization. This allows for a single European database accessible to the member states’ HAs. Industry has limited access, primarily to their own cases only. The public does not have access at this time. See Chapter 8 for further details.

The European Union has developed a comprehensive risk management strategy for all products in the European Union. This is a strategy that covers the entire life cycle of a product, and a risk analysis is required for every product upon approval (or during its marketing). The goal is to create a set of pharmacovigilance activities and interventions designed to identify, characterize, prevent, or minimize risks relating to medicinal products, including the assessment of the effectiveness of these interventions. This is discussed in detail in Chapter 30.

In addition to the EMA, each European country has its own national health authority (HA) or authorities that handle drug safety. They are often called “competent authorities (CA)” in European Union regulatory jargon. The European Union is still evolving and the recently enacted Lisbon Treaty has altered some of the basic structures and functions of the European Union governing bodies. The European Union remains still a work in progress. The interplay between the central authority (primarily in Brussels but with various agencies scattered throughout the European Union, such as the EMA in London and the European Central Bank in Frankfurt, Germany) and the individual countries is dynamic and often changing. Note also that the EMA does not have jurisdiction over food. The European Food Safety Authority in Parma, Italy handles those matters.

As noted, for drug safety, some functions are primarily centralized in London and some remain in each member state. Some national authorities are very large and powerful and exert strong influence over smaller member states. This division and, in many cases, duplication of labor, as well as the multitude of languages involved in the European Union, produce a challenge for safety reporting both for the pharmaceutical industry and for the member states themselves. Most of the work in drug safety is done at the international level in English, but, obviously, at the local level the national languages are still used. The comparison with other countries, particularly the United States, where the drug safety function is clearly centralized, is striking. The closest analogy would be if each of the 50 states in the United States had its own mini-FDA and used languages other than English.

In terms of pharmacovigilance the EMA has largely harmonized along the lines of ICH. They have codified the premarketing requirements in a document known as Volume 10 and the postmarketing requirements in Volume 9A. Each is discussed in detail below. Nonetheless, there are still many differences, particularly for clinical trial pharmacovigilance, from country to country.

The European Union has issued its postmarketing safety regulations and requirements in a single document known as Volume 9A. The latest version was issued in September 2008. It is available online (Web Resource 22-5) in a PDF file. It is 229 pages long with links in the Annexes (appendices) to multiple other useful documents (e.g., guidelines, ICH documents, the Risk Management Plan template). There is a detailed table of contents and, perhaps more importantly, the document (as a PDF file) is easily searchable using the free Adobe Reader (Web Resource 22-6) or other software, making it easy to find specific references to topics of interest. Unlike the regulations and requirements in other countries, this document is exceptionally readable, clearly written, and comprehensive. It has been updated periodically and will likely be so in the near future.

Here is a brief summary of the contents:

The legal basis for PV in the European Union dates back to 1993 and the Council Regulation (EEC) 2309/93 and Regulation 726/2004. These are all available on Eudralex (Web Resource 22-7). These documents require the EMA, the member states, and others to set up systems to handle the collection, verification, exchange, and presentation of adverse reaction reports within the European Union.

Part I covers guidelines for Marketing Authorization holders (MAHs).

The roles and responsibilities of the MAH are spelled out and require that an appropriate system of PV is put in place by the MAH. All information regarding the benefit–risk profile must be promptly and fully sent to the competent authorities. And most critically, it describes the role of the Qualified Person for Pharmacovigilance (QPPV or QP), to be appointed by the MAH and to be continuously (24/7) available for safety matters. In brief, the QP establishes and maintains the PV system, has an overview of all the products and safety issues pending, and makes sure all safety functions are handled properly. The QP’s roles are discussed in detail in Chapter 23. The QP must ensure that all suspected ADRs are collected, collated, reported, and accessible within the European Union. The MAH must prepare, update, and provide a “Detailed Description of the PV System.” This (along with the United Kingdom equivalent, the “Summary of PV Systems”) is covered in Chapter 49. This section of Volume 9A further covers the requirements for risk management systems, expedited reporting, PSURs, special situations, databases, documentation, company postmarketing safety studies, and regulatory matters. These topics are covered in detail in this manual in the individual chapters.

Part II covers guidelines for the EMA and health agencies (“competent authorities”).

This section covers the obligations of the member states’ national health agencies; how PV is to be done; handling of ICSRs, PSURs, signal detection, medication errors, benefit–risk analyses, communication, data exchange, crisis management plans relating to safety matters, inspections, creation, and a rapid-alert and nonurgent information communication system; how referrals to the EMA are to be done; and how the European Union and member states work with the World Health Organization in international PV.

Part III covers the electronic exchange of information.

This section describes the handling, format, transmission, and details of ICSRs and EudraVigilance.

Part IV covers pharmacovigilance communication.

This section describes the principles for communication to healthcare professionals and others.

The Annexes include a glossary, abbreviations, terminology, references to guidelines and templates for the European Union Risk Management Plan, the PSUR sections, and distribution requirements for reporting to competent authorities.

In summary, this is a complete and well-prepared document that is easy to handle and absorb, though it is highly detailed and exacting. The document is rich in explanations and background and anyone in the field of PV, whether in the European Union or not, should read and be familiar with this document. Many of its principles and procedures are used throughout the rest of the world as they are based on the common seminal antecedent documents of PV, namely, the Council for International Organizations of Medical Sciences (CIOMS) and ICH documents.

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