Pharmaceutical Biotechnology (Drug Discovery and Clinical Applications) || Drug Approval in the European Union and United States

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    Drug Approval in the European Union and United States Gary Walsh

    11.1 Introduction

    The pharmaceutical sector is arguably the most highly regulated industry in existence. Legislators in virtually all world regions continue to enact/update legislation controlling every aspect of pharmaceutical activity. Interpretation, implementation, and enforcement of these laws is generally delegated by the lawmakers to dedicated agencies. The relevant agencies within the European Union ( EU ) and the United States ( USA ) are the European Medicines Agency ( EMA ) and the US Food and Drug Administration ( FDA ), respectively. This chapter focuses upon the structure, remit, and operation of both these organiza-tions, speci cally in the context of the approval of biopharmaceutical products for medical use.

    11.2 Regulation within the European Union

    11.2.1 EU Regulatory Framework

    The founding principles of what we now call the European Union are enshrined in the Treaty of Rome, initially adopted by six countries in 1957. While this treaty committed its signatories to a range of cooperation and harmonization measures, it largely deferred healthcare related issues to individual member states. As a consequence, each member state drafted and adopted its own set of pharmaceuti-cal laws, enforced by its own national regulatory authority (now known as the National Competent Authorities). Although the main principles underpinning elements of national legislation were substantially similar throughout all European countries, details did differ from country to country. As a result pharmaceutical companies seeking product marketing authorizations were forced to apply sepa-rately to each member state. Uniformity of regulatory response was not guaranteed


    Pharmaceutical Biotechnology: Drug Discovery and Clinical Applications, Second Edition. Edited by Oliver Kayser, Heribert Warzecha. 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA.

  • 258 11 Drug Approval in the European Union and United States

    and each country enforced its own language requirements, scale of fees, process-ing times, and so on. This approach created enormous duplication of effort, for companies and regulators alike.

    In response, the European Commission ( EC , Brussels) began a determined effort to introduce European - wide pharmaceutical legislation in the mid - 1980s. The Commission represents the EU body with responsibility for drafting (and subsequently ensuring the implementation) of EU law, including pharmaceutical law. In pursuing this objective it has at its disposal two legal instruments: regula-tions and directives . Upon approval, a regulation must be enforced immediately and without alteration by all EU member states. A directive, in contrast, is a softer legal instrument, requiring member states only to introduce its essence or spirit into national law.

    By the early 1990s some eight regulations and 18 directives had been intro-duced, which effectively harmonized pharmaceutical law throughout the Euro-pean Union. In addition to making available the legislative text, the European commission has also facilitated the preparation and publication of several adjunct document s designed to assist industry and other interested parties to interpret and conform to the legislative requirements. Collectively these documents are known as the Rules Governing Medicinal Products in the European Union and they make compulsory reading for those involved in any aspect of pharmaceutical regulation. The 10 volume (Table 11.1 ) publication is regularly updated and is accessible via the relevant EU website ( ). Volume 2 is particularly noteworthy from the perspec-tive of drug approval (i.e., seeking a product marketing authorization).

    This volume is presented in three parts. Volume 2a overviews the various regula-tory routes available for obtaining marketing authorization for a product. Volume 2b presents the regulatory requirements in terms of presentation and the format of the application, while Volume 2c contains various guidelines designed to assist the applicant.

    Table 11.1 The 10 volumes comprising the rules governing medicinal products within the European Union.

    Volume Title

    1 Pharmaceutical legislation: Medicinal products for human use 2 Notice to applicants: Medicinal products for human use 3 Guidelines: Medicinal products for human use 4 Good manufacturing practices: Medicinal products for human and veterinary use 5 Pharmaceutical legislation: Veterinary medicinal products 6 Notice to applicants: Veterinary medicinal products 7 Guidelines: Veterinary medicinal products 8 Maximum residue limits: Veterinary medicinal products 9 Pharmacovigilance: Medicinal products for human and veterinary use 10 Clinical trials guidelines

  • 11.2 Regulation within the European Union 259

    11.2.2 EMA

    Harmonization of pharmaceutical law made possible the implementation of an EU - wide system for the authorization and subsequent supervision of medicinal products. Central to this was the establishment in 1995 of the European Medicines Agency (EMA, originally termed the European Medicines Evaluation Agency or EMEA ) ( ). The function of the EMA is not to duplicate the activities of national competent authorities, but to coordinate the scienti c resource base found in these competent authorities with a view to the evaluation, supervision, and pharmacovigilance of medicinal products.

    An outline structure of the EMA is provided in Figure 11.1 . The agency is gov-erned by a management board, with an executive director being responsible for all operational matters. It directly employs a relatively modest number of staff (approximately 500) and these staff are largely organized into three units (pre - and post - authorization units for human medicines, as well as a unit concerned with veterinary medicines; Figure 11.1 ). The staff are responsible for undertaking administrative and procedural aspects of EMA activities.

    The bulk of the EMA s actual scienti c work is undertaken by one of six key committees:

    Committee for Medicinal Products for Human Use ( CHMP ) Committee for Medicinal Products for Veterinary Use ( CVMP ) Committee for Advanced Therapies ( CAT )

    Figure 11.1 Simpli ed structural overview of the EMA.

    Management Board Governance

    Executive director


    Pre-authorizationevaluation of medicinesfor human use

    Post-authorizationevaluation of medicines

    for human use

    Veterinary medicinesand inspections

    Committee for medicinalproducts for human use


    Committee for medicinalproducts for veterinary use


    Committee foradvanced therapies


    Committee on orphanmedicinal products


    Committee on herbalmedicinal products



  • 260 11 Drug Approval in the European Union and United States

    Committee on Orphan Medicinal Products ( COMP ) Committee on Herbal Medicinal Products ( HMPC ) Paediatric Committee ( PDCO ).

    Each committee is composed of a number of (mainly technical) experts, the majority of whom are drawn from the National Competent Authorities of each EU member state. The committees meet regularly (often monthly) at EMA headquar-ters in London. From a drug approval standpoint, the critical committees are the CHMP and the CVMP (focusing upon human and veterinary drugs, respectively) and the function of these committees in the context of new biotechnology drug approvals will be discussed in the next section. Additionally, the EMA has at its disposal a bank of some 4500 European technical experts (the majority of whom, again, are drawn from the national regulatory authorities). The EMA draws upon this expert advice as required.

    11.2.3 New Drug Approval Routes

    Regulatory mechanism s exist which allow national authorization of a medicine in individual member states. The rules governing medicinal products in the Euro-pean Union also provide for various routes by which new potential medicines may be evaluated with a view to gaining approval throughout the entire EU. These are termed the centralized and decentralized procedures, respectively, and the EMA plays a role in both. The centralized procedure is compulsory for biotech medi-cines and as such is the sole focus of the discussion below. It is also worth noting that approval and regulation of clinical trials in Europe is regulated not by the EMA, but by the National Competent Authority of the countries in which the trials are actually undertaken. Centralized Procedure Under the centralized route, Marketing Authorization Application s ( MAA s) for proposed new medicinal products are submitted directly to the EMA. The drug sponsor will have given several months advance notice to the EMA of their intention to submit such an application. This allows some preparatory work to be undertaken, including the appointment of rapporteur s members of the CHMP (or CVMP if the product is intended for veterinary use) who will coor-dinate evaluation of the application. Before evaluation begins, EMEA staff rst validate the application, by scanning through it to ensure that all necessary information is present and presented in the correct format. This procedure usually takes one to two working weeks to complete. The basic regulatory fee charged for evaluating a full marketing authorization application via the central-ized procedure is in the region of 259 000 (the overall EMA annual budget is in the region of 200 million, of which approximately three quarters is raised via fees).

  • 11.2 Regulation within the European Union 261

    The validated application is then formally presented at the next meeting of the CHMP (human medicine applications) or CVMP (veterinary medicines) and the rapporteur organizes technical evaluation of the application (product safety, quality, and ef cacy). Much of this evaluation is often carried out in the rapporteur s home national regulatory agency. Another member of the com-mittee (the co - rapporteur) assists in this process. Upon completion of the eval-uation phase the rapporteurs draw up a report, which they present, along with a recommendation, at the next CPMP (or CVMP) meeting. After discussion, the committee issues a scienti c opinion on the product, either recommending acceptance or rejection of the marketing application. The EMA then transmits this scienti c opinion to the European Commission in Brussels (the only body with the legal authority to actually grant marketing authorizations). Legally the Commission must ensure that the potential marketing authorization is in com-pliance with the regulations, and it issues a nal, binding decision on the product (Figure 11.2 ).

    Regulatory evaluation of Marketing Authorization Applications must be com-pleted within strict time limits. The EMA is given a 210 - day window to evaluate an application and provide a scienti c opinion. However, during the application process, if the EMEA of cials seek further information/clari cation on any aspect of the application this 210 - day clock stops until the sponsoring company provides satisfactory answers. The average duration of active EMEA evaluation of biotech product applications is in the region of 160 days, well within this 210 - day timeframe. Duration of clock stops can vary widely from 0 days to well over 300 days. Upon receipt of the EMA opinion, the Commission is given a maximum of 90 days in which to translate this opinion into a nal decision. Overall therefore, the centralized process should take a maximum of 300 active evaluation days.

    Figure 11.2 Overview of the EU centralized procedure.

    Marketing aurthorizationapplication submitted

    Final Commission decision

    Validation & presentation atnext CHMP or CVMP meeting

    CHMP (or CVMP)scientific opinion issued

    Opinion transmitted toEuropean Commission

    Evaluation,210 days, maximum

    Commission evaluation,90 days, maximum

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    11.3 Regulation in the United States of America

    The Food and Drug Administration (FDA) is the US regulatory authority ( ). Its primary function is to protect public health by assuring the safety, effectiveness, and security of human and veterinary drugs, medical devices, cosmet-ics, products that give off radiation as well as food and selected other products (Table 11.2 ). Founded in 1930, it now forms part of the US Department of Health and Human Services, and its Commissioner is appointed directly by the US President.

    The FDA derives its legal authority from the federal Food, Drug, and Cosmetic ( FD & C ) Act. Originally passed into law in 1930, the act has been updated/amended several times since. The FDA interprets and enforces these laws. Although there are many parallels between the FDA and the EMA, its scope is far broader than that of the European agency and its organizational structure is signi cantly differ-ent. Overall the FDA now directly employs some 11 500 people, has an annual budget in the region of $1 billion and regulates over $1 trillion worth of products annually. A partial organizational structure of the FDA is presented in Figure 11.3 . In the context of pharmaceutical biotechnology the Center for Drug Evaluation and Research ( CDER ) and the Center for Biologics Evaluation and Research ( CBER ) are the most relevant FDA bodies.

    Table 11.2 Product categories regulated by the FDA .

    Foods, nutritional supplements Drugs chemical and biotech based The blood supply and blood products Cosmetics and toiletries Medical devices All radioactivity - emitting substances Microwave ovens

    Figure 11.3 Partial organizational structure of the FDA.


    Center for Dug Evaluation & Research (CDER)

    Center for Biologics Evaluation & Researh (CBER)

    Center for Veterinary Medicine (CVM)

    Center for Devices& Radiological Health (CDRH)

    Center for Food Safety &Applied Nutrition

  • 11.3 Regulation in the United States of America 263

    11.3.1 CDER and CBER

    A major activity of the Center for Drug Evaluation and Research is to evaluate new drugs and decide if marketing approval should be granted or not. (Note the differ-ence in regulatory terminology the term medicinal product being used in Europe, whereas the term drug is favored in the US.) Additionally, CDER also monitors the safety and ef cacy of drugs already approved (i.e., post - marketing surveillance and related activities). Traditionally CDER predominantly regulated chemical - based drugs (i.e., drugs that are usually of lowe...