9

Regulations, Directives, Guidances, and Laws

Pharmacovigilance (PV) is governed by a large body of requirements. Some are written and rigid. Others are written and far less rigid. Others are not requirements but only guidances or guidelines, and still others are unwritten customs and (best) practices. Obviously, laws and regulations vary from country to country. The sections that follow summarize briefly the obligations in the United States and the European Union (EU) for drugs and over-the-counter (OTC) products.

Legal requirements for drug safety come from multiple areas. There are laws, regulations, and guidances issued by the United States federal government. These are the predominant formal requirements governing drug safety. In the United States, a “law” is a written statute, requirement, or ordinance that has been passed by a legislature and then signed into law (where required) by the executive. That is, a federal law is passed by Congress in Washington, D.C., and signed by the president. Laws may be created at multiple levels of government (federal, state, and local).

The law governing investigational drugs (“New Drugs”) is found in Section 505(i) [21 U.S.C. 355], and the law governing marketed drugs is found in Section 505(k) of the Food Drug and Cosmetic Act (Web Resource 9-1).

In addition to laws, the United States Food and Drug Administration (FDA) is empowered to create regulations. Regulations are rules issued by government authorities under the power of laws. Regulations thus have the force of law. To create a regulation, the FDA publishes the proposed version of the new or amended regulation in the Federal Register (Web Resource 9-2). A period is defined during which time the public may send written comments on the proposal to the FDA. After review, a final regulation is published in the Federal Register and in the Code of Federal Regulations (Web Resource 9-3). A long period may elapse between publishing the draft and the final regulation; also, the draft regulation may be withdrawn.

Finally, the FDA issues guidances that contain the FDA’s preferences on laws and regulations. As the FDA states on its Center for Drug Evaluation and Research Guidance website (Web Resource 9-4): “Guidance documents represent the Agency’s current thinking on a particular subject. They do not create or confer any rights for or on any person and do not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both.” However, it is generally held in practice in the industry to be a wise course of action to follow FDA guidances.

Many of the applicable pharmacovigilance guidances can be found at Web Resource 9-5. Clinical trial guidances may be found at Web Resource 9-6. A more complete listing of FDA guidances can be found at Web Resource 9-7.

The European Union situation is different from the United States’, in particular because the European Union is composed of 27 separate member states (countries) and 3 affiliated states that are different from the 50 United States. The European Union member states are sovereign countries; the United States are not. The 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, Sweden, and the United Kingdom.

The European legislation often refers to and applies to the European Economic Area (EEA), which consists of the 27 European Union member states plus Iceland, Liechtenstein, and Norway, which are not European Union member states but which participate in much of the European Union single market and adopt the European Union 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 (then called the Common Market). The EFTA now includes only Iceland, Norway, Switzerland, and Liechtenstein. The Committee for Medicinal Products for Human Use (CHMP), which handles drug regulation for the European Union, includes members from the 27 countries and Iceland and Norway.

European Union “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 (2009). “Secondary legislation” derives from the treaties. There are several types. The ones that touch most on pharmacovigilance are as follows:

• Regulations: Directly applicable and binding in all European Union 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.

The main European Union website is Web Resource 9-6, and the website covering European Union legislation can be found at Web Resource 9-8.

The key European Union regulatory and procedural documents relating to pharmacovigilance can be found at Web Resource 9-9. This site contains Volume 9A, Volume 10, The Rapid Alert System document, Eudravigilance and risk, and management documents. Additional guidelines for Marketing Authorization (MA) holders, health authorities, and PV practices are found at Web Resource 9-10.

The European Union situation regarding drug safety is, in many ways, far more complex than the United States’. In the United States, the requirements for drug safety come primarily from the FDA. A few state and local requirements apply to pharmacovigilance 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, at rare times, 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. In contrast, the European Union has the supranational 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. European Union documents are generally available in many of the European Union languages (of which there are 23 official ones). Member state documents are published in the language of the member state but are not consistently published in other languages. Most, if not all, European Union-level documents are available in English. Summaries of Product Characteristics (SPCs), 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 European Union 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 European Union requires the presence of a “Qualified Person” (Directive 2001/83/EC and Volume 9A). This person must be physically in one of the European Union member states and is responsible for pharmacovigilance. The person is responsible for “the establishment and maintenance of a system which ensures that information about all suspected adverse reactions which are reported to the personnel of the company, and to medical representatives, is collected and collated in order to be accessible at least at one point in the Community” (i.e., the European Union) as well as for preparing reports and responding to questions on safety matters, including the risk–benefit analyses of the products. See the directive (articles 103 and 104 in particular) and Volume 9A (see Chapter 23).

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