Cobert's Manual Of Drug Safety And Pharmacovigilance (Third Edition). William Gregory
suicide in pediatric patients on antidepressants, and contaminated heparin, among others (see other chapters). The FDA and the industry would (probably) counter by saying, quite the contrary that these episodes have shown that the drug safety system in place is indeed functioning and functioning well; the real challenge is to identify these problems earlier and manage the emerging risks.
These criticisms have been made for many other federal agencies, including regulators of banks, insurance companies, Wall Street, the airline industry, and car manufacturers. This is a fascinating and controversial area that is and will remain a work in progress for the foreseeable future.
Q: Should the FDA be broken up into an approving body and a safety body, similar to some other federal regulatory agencies?
A: This proposal has been advanced in the last several years. The argument is that the people who approve a drug have a vested (and emotional) interest in seeing their drug stay on the market and may not act vigorously on safety matters as this might be a tacit admission that their original approval decision was incorrect or too hasty. Organizationally, these functions are already split, but within CDER. It is claimed that separate reviewers should oversee safety, as they have no interest in defending an approval decision and they would be able to better interpret real world evidence, i.e., understand impact of bias and confounders, in data from the post-marketing phase. Thus, the medical skill set involved in post-marketing safety review is arguably different from that required in pre-approval safety review, which focuses on controlled clinical trial data. In all instances, however, safety assessment must always be considered in the context of benefit. Separating the functions would discount the knowledge the reviewing group has obtained over months and years of review of a product, moving post-marketing follow-up to people unfamiliar with the drug. This also would increase the bureaucracy and be more costly. In addition, complete separation would introduce additional challenges in the pre-approval phase when non-routine safety interventions, e.g., REMS, are under discussion. Clearly, each side has valid points. What will evolve will most likely be a political decision. There has also been talk of separating the food part of FDA into a separate agency. This too is under evaluation.
CHAPTER
9
The European Medicines Agency
In 1995, the European Medicines Evaluation Agency (EMEA) now called European Medicines Agency (EMA) but also “the Agency” was created and based in London, England but has moved to Amerstdam, The Netherlands. Now, over two decades later, the face of drug regulation in Europe has totally changed. In 2010, a new PV Regulation was issued generating hundreds of associated Directives, Guidances, Q&A etc. This “tsunami” continues to evolve with ongoing new or updated regulatory documents which continue to be published. In addition, Brexit and the EMA move to Amsterdam — is generating further turbulence in both the EMA organization and its functioning. See the very extensive website of the EMA (http://www.ema.europa.eu/ema/). We will examine the EMA in detail and take a brief look at one member state’s Health Agency: France.
Introduction
Like the US FDA, the EMA’s main responsibility is the protection and promotion of public and animal health through the evaluation, supervision and safety monitoring of medicines throughout the European Union. The EU comprises 27 countries (Member States), as well as the three European Free Trade Area (EFTA) nations of Iceland, Liechtenstein, and Norway. These 31 countries are also referred to as the European Economic Area (EEA).
Switzerland also works closely with the EMA, particularly in areas regarding inspections, but is not within the EU.
Due to Brexit, the EMA moves to Amsterdam, The Netherlands and the number of EU countries will be back to 27. Even if all players are working for a smooth transition, we can expect some difficulties in the functioning of the EMA for a few years.
Registration Procedures in the EU
All medicines must be authorized (=approved) before they can be marketed. There are two main ways for authorizing medicines: a centralized and a national one (that is, non-centralized).
Centralized Authorization Procedure (CAP): Pharmaceutical companies submit one single marketing-authorization application (MAA) to EMA. EMA’s Committee for Medicinal Products for Human Use (CHMP) then, using scientific resources provided by the Member States), carries out a scientific assessment of the application and makes a recommendation (an “opinion”) to the European Commission on whether the medicine should be marketed or not.
Once granted by the European Commission, the centralized MA is valid in all EU Member States as well as in the European Economic Area (EEA) countries Iceland, Liechtenstein and Norway. The new or innovative medicines pass through the centralized authorization procedure in order to be marketed in the EU. This allows the marketing authorization holder (MAH) to market the medicine throughout the EEA on the basis of one single marketing authorization. The centralized process is required for certain medicines, e.g., biosimilars, gene therapies, etc.
National Authorization Procedures: The majority of medicines available in the EU were authorized at national level, either because they were authorized before EMA’s creation (1995) or they were not within the scope of the centralized procedure. Each EU Member State has its own national authorization procedures. If a company wishes to request an MA in several EU Member States for a medicine that is outside the scope of the centralized procedure, it may use one of the following routes:
Note: For issues that occur after authorization (e.g., safety concerns), the CHMP handles centrally-registered products. The Coordination Group for Mutual Recognition and Decentralized Procedures — human (CMD(h)) handles nationally-registered medicines and reports to the Heads of Medicines Agencies (HMA). The Pharmacovigilance Risk Assessment Committee (PRAC) (see below) is the senior committee that then handles all authorized products and makes recommendations to both CHMP and CMD(h).
European Medicines Agency
European Medicines Agency (EMA) serves a market of over 500 million people living in the EEA. The terminology in Europe can be a bit confusing as the EU/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. They are linked by a variety of treaties. 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 EU/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.
Organization and Structure
The EMA handles human and veterinary medicinal products (but not food, unlike the FDA). Whatever the registration status, the EMA goal is to ensure harmonized safety surveillance for all EU countries.
The EMA principle is based on a central organization (~900 EMA permanent employees), supported by ~4,500 experts, who conduct the detailed, work of the Agency by sitting on scientific and medical committees, working