Читать книгу Cobert's Manual Of Drug Safety And Pharmacovigilance (Third Edition) - William Gregory - Страница 68

The EU situation is different from the US situation, in particular because the EU is composed of 27 separate Member States (formerly 28 before the UK left the EU — Brexit) plus three affiliated states that are organized differently from the 50 United States. The EU member states are sovereign countries, whereas the states that make up the US are not. The EU member states are Austria, Belgium, Bulgaria, Cyprus, the Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, the Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, and Sweden.

Britain’s situation after Brexit remains unclear at this writing.

The European legislation often refers to and applies to the European Economic Area (EEA), which consists of the 27 EU member states plus Iceland, Liechtenstein, and Norway. These latter three countries are not EU member states, but participate in much of the EU single market and adopt the EU PV legislation. To complicate matters further, one sometimes sees reference to the European Free Trade Association (EFTA), which was set up originally for countries not in the European Union. The EFTA now includes only Iceland, Norway, Switzerland, and Liechtenstein. (Note that Switzerland is not part of the EU.) The Committee for Medicinal Products for Human Use (CHMP — http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000094.jsp) which facilitates scientific evaluation of medicinal products in the EU, includes members from the 27 countries and Iceland and Norway.

EU “primary legislation” derives from treaties and agreements among the member states. This includes the Single European Act (1987), the Maastricht Treaty (1992), the Treaty of Amsterdam (1997), and the Lisbon Treaty (2007). “Secondary legislation” derives from the treaties. There are several types. The ones that touch most on PV are as follows:

Regulations: Directly applicable and binding in all EU member states without the need for any additional national implementation legislation. That is, the regulation as it is published is, word for word, the law in each of the member states. Note that this is different from the use of the word regulation in the United States.

Directives: This legislation binds member states to the objectives of the legislation within a certain time period but allows each member state to create its own form of national law to achieve it. That is, each member state may modify the wording and requirements of the directive as long as the objectives of the directive are met.

Recommendations, guidelines, and opinions: Non-binding and similar to FDA guidances though EU guidelines usually hold the force of law and are obligatory.

When translated into local law, each EU country can include additional requirements which are then country-specific. Thus, this can lead to somewhat different detailed requirements in various member states.

The main EU website is https://europa.eu/european-union/index_en, and the website covering legislation can be found at https://europa.eu/european-union/law_en.

The key EU regulatory and procedural documents relating to PV can be found at http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000258.jsp&mid=WC0b01ac05800241de.

Guidelines can be found at http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000345.jsp. This site contains “Good Pharmacovigilance Practices (GVPs)”, which consist of over a dozen “guidelines” for post-marketing PV, which are referred to as “modules”, as well as multiple other documents and “annexes”. These annexes include other documents and templates. These “guidelines” are soft law in the EU and are obligatory, unlike the FDA “guidances”, as noted above, which are not obligatory. These modules replaced the previous PV requirements which were contained in “Volume 9A”. The modules are discussed in the individual chapters in this manual covering each module’s topics. Each module has requirements for regulators as well as for applicants (companies).

The EU situation regarding drug safety is, in many ways, far more complex than the US situation. In the US, the requirements for drug safety come primarily from the FDA. Some state and local requirements apply to PV for companies, but in practice, these do not touch on drug safety as much as reimbursement, formularies, health insurance, dispensing, and other non-PV areas. There are, occasionally, requirements for registries or other safety obligations imposed by other governmental entities, such as the National Institutes of Health (NIH) and the National Cancer Institute (NCI) for clinical trials, as well as Risk Evaluation and Mitigation Strategies (REMS) and other post-marketing obligations on NDA holders. The US regulations are relatively short and far less detailed than the EU requirements. Many of the US requirements actually fall under guidances which, although strictly non-obligatory, have in fact become standard practices and are obligatory. For example, Data Monitoring Committees (DMCs) are described in a guidance but have become more or less standard in most phase III clinical trials and are expected by FDA.

In contrast, the EU requirements are highly detailed and run to thousands of pages. Many people have said that the US requirements are not detailed enough (“Show me exactly where the regulations say that I have to do this”) while the EU regulations are too highly detailed. Another complaint is that many of the EU modules have been revised several times since their creation in 2012 whereas US regulations are revised far less frequently.

The EU has the supra-national body of directives, regulations, and such from the European Medicines Agency (EMA) (empowered by the European Commission, Parliament, Council of Ministers in Brussels), as well as legal requirements in each member state, which may differ from or add onto the European Union-level requirements. EU documents are generally available in many of the EU languages (of which there are 24 official ones: Bulgarian, Croatian, Czech, Danish, Dutch, English, Estonian, Finnish, French, German, Greek, Hungarian, Irish, Italian, Latvian, Lithuanian, Maltese, Polish, Portuguese, Romanian, Slovak, Slovene, Spanish and Swedish.). Interestingly the working language of the EU has largely been English. Now that the UK is leaving the EU leaving only two small English speaking countries (Malta and Ireland), one wonders if English will be used less frequently.

Member state documents are published in the official language(s) of the member state but are not consistently published in other languages. Most, if not all, EU-level documents are available in English. Summaries of Product Characteristics (SmPCs), for example, are usually available in the official language of each country where the product is approved. National documents may only be available in that country’s language.

Any company dealing in the EU must obtain expertise at the European and member state level to stay in compliance with all safety obligations. In practice, this usually means the creation of affiliates or subsidiaries or the hiring of local companies or agents in the European countries where the drug is sold or studied.

In particular, the EU requires the presence of a Qualified Person for Pharmacovigilance (EU QPPV). See Directive 2010/84/EU: “The qualified person (…) shall reside and operate in the Union and shall be responsible for the establishment and maintenance of the PV system” and GVP Module 1: the EU QPPV “shall have sufficient authority to influence the performance of the quality system and the PV activities and to promote, maintain and improve compliance with the legal requirements”. The QPPV is the first EMA contact person for PV activities as well as for preparing reports and responding to questions on safety matters, including the risk–benefit analyses of the products.