Transcript

257

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, specifi 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

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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 ( http://ec.europa.eu/health/documents/eudralex/index_en.htm ). 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 ) ( http://www.ema.europa.eu ). The function of the EMA is not to duplicate the activities of national competent authorities, but to coordinate the scientifi 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 scientifi 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 Simplifi ed structural overview of the EMA.

Management Board Governance

Executive director

Operational

Pre-authorizationevaluation of medicinesfor human use

Post-authorizationevaluation of medicines

for human use

Veterinary medicinesand inspections

Committee for medicinalproducts for human use

(CHMP)

Committee for medicinalproducts for veterinary use

(CVMP)

Committee foradvanced therapies

(CAT)Scientific

Committee on orphanmedicinal products

(COMP)

Committee on herbalmedicinal products

(HMPC)

Paediatriccommittee(PDCO)

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.

11.2.3.1 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 fi 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 effi 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 scientifi c opinion on the product, either recommending acceptance or rejection of the marketing application. The EMA then transmits this scientifi 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 fi 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 scientifi c opinion. However, during the application process, if the EMEA offi cials seek further information/clarifi 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 fi 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 ( http://www.fda.gov/ ). 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 signifi 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.

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 effi 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 lower molecular weight and often manufac-tured by direct chemical synthesis). Included are prescription, generic, and over the counter drugs. CDER has now also been assigned regulatory responsibility for the majority of pharmaceutical biotechnology products (Table 11.3 ).

The Center for Biologics Evaluation and Research (CBER) undertakes many activities similar to that of CDER, but it focuses upon biologics and related prod-ucts. The term “ biologic ” historically has a specifi c meaning, relating to “ a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood components or deriva-tives or allergenic products which are used in the prevention, treatment or cure of diseases of human beings ” ( http://www.fda.gov/Drugs/default.htm ). CBER therefore regulates products such as vaccines and blood factors, be they produced by traditional or modern biotechnological means (i.e., by non - recombinant or recombinant means). Additional “ biological product s, ” including cell, gene therapy, and tissue - based products also fall under the auspices of CBER.

11.3.2 Approvals Procedure

The overall procedure by which biotechnology and other drugs are evaluated and approved by CDER or CBER are, predictably, very similar, although some of the

Table 11.3 Major biotechnology/biological - based drug types regulated by CDER and CBER .

CDER regulated CBER regulated

Monoclonal antibodies for in vivo use Blood

Cytokines (e.g., interferons and interleukins) Blood proteins (e.g., albumin and blood factors)

Therapeutic enzymes Vaccines

Thrombolytic agents Cell and tissue based products

Hormones Gene therapy products

Growth factors Antitoxins, venoms, and antivenins (antivenoms)

Additional miscellaneous proteins Allenergic extracts

264 11 Drug Approval in the European Union and United States

regulatory terminology used by these two centers differ. A summary overview of the main points along the drug development/approval road in which CDER/CBER play key regulatory roles is provided in Figure 11.4 .

Once a sponsor (company, research institute, etc.) has completed preclinical evaluation of a proposed new drug, it must gain FDA approval before instituting clinical trials. The sponsor seeks this approval by submitting an Investigational New Drug Application (an IND ) to either CDER or CBER, as appropriate. The application, which is a multi - volume work of several thousand pages, contains information detailing preclinical fi ndings, methods of product manufacture, and proposed protocols for initial clinical trials. The regulatory offi cials then assess the data provided, and may seek more information/clarifi cation from the sponsor if necessary. Evaluation is followed by a decision to either permit or block clinical trial s. Should clinical trials commence, the sponsor and regulatory offi cials hold regular meetings in order to keep the FDA appraised of trial fi ndings.

Upon successful completion of clinical trials, the sponsor then usually applies for drug approval . In CDER terminology this application is termed a New Drug Application (an NDA – the analogous term in Europe being the Marketing Authori-zation Application, MAA). NDAs usually consist of several hundred volumes containing over 100 000 pages in total. The NDA contains all the preclinical as well as clinical fi ndings and other pertinent data/information. FDA fees in respect of evaluating a full application stand in the region of $1.5 million. Upon receipt of an NDA, CDER offi cials check through the document ensuring completeness (a process similar to the EMEA ’ s validation phase). Once satisfi ed, they “ fi le ” the application and evaluation begins.

The NDAs are reviewed by various FDA regulatory experts, generally under topic headings such as “ medical, ” “ pharmacology, ” “ chemistry, ” “ biopharmaceuti-cal, ” “ statistical, ” and “ microbiology ” reviews. Reviewers may seek additional infor mation/clarifi cation from the sponsor, as they feel necessary. The regulators are allowed 60 days to ensure that the dossier is complete, and a further 180 days to conduct the scientifi c evaluation of the product. The review process is coordi-nated by a specifi c project manager. Upon review completion, the application is either approved or rejected.

The review process undertaken by CBER offi cials upon biologic and related prod-ucts is fairly similar to that described above for CDER regulated products. CBER

Figure 11.4 Summary overview of the main points during a drug ’ s development at which the FDA plays a key regulatory role.

Pre-clinical testing

ApprovalClinical trials

IND application

Regular regulatory meetings

NDA/BLAapplication

11.4 International Regulatory Harmonization 265

regulated investigational drugs may enter clinical trials subject to gaining IND status. The application process for drug approval is undertaken by the sponsor sub-sequent to completion of successful clinical trials is termed the licensure phase in CBER terminology. The actual product application is known as a Biologics License Application ( BLA ). Overall, the content and review process for a BLA is not dissimi-lar to that of the analogous CDER NDA process, as discussed above. The bottom line is that the application must support the thesis that the product is both safe and effec-tive, and that it is manufactured and tested to the highest quality standards.

While the majority of biotech - based drugs are regulated in the United States by either CBER or CDER, it is worth noting that some such products fall outside their auspices. Bone morphogenic protein s ( BMP s) for example, function to stimulate bone formation. As such several have been approved for the treatment of slow healing bone fractures. Product administration requires surgical implantation of the BMP in the immediate vicinity of the fracture, usually as part of a supporting device. As such, in the United States, these products are regulated by the FDA ’ s Center for Devices and Radiological Health ( CDRH ) ( http://www.fda.gov/Medi-calDevices/default.htm ). Drugs (both biotech and non - biotech) destined for veteri-nary use also fall outside the regulation of CBER or CDER. Most such veterinary products are regulated by the FDA ’ s Center for Veterinary Medicine ( CVM ) although veterinary vaccines (and related products) are regulated not by the FDA, but by the Center for Veterinary Biologics, which is part of the US Department of Agriculture ( http://www.aphis.usda.gov/animal_health/vet_biologics/vb_about.shtml ).

11.4 International Regulatory Harmonization

Europe, the United States, and Japan represent the three main global pharmaceuti-cal markets. As such, pharmaceutical companies usually aim to register most new drugs in these three key regions. Although the underlining principles are similar, detailed regulatory product authorization requirements vary in these different regions, making some duplication of registration effort necessary. The Interna-tional Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (the ICH process) is an initiative aimed at harmonizing regulatory requirement s for new drug approvals in these regions. The project was established in 1990 and brings together both regulatory and industry representatives from Europe, the United States, and Japan. ICH is administered by a steering committee, consisting of representatives of the above mentioned group-ings. The steering committee in turn is supported by an ICH secretariat, based in Geneva, Switzerland ( http://www.ich.org/ ). The main technical workings of ICH are undertaken by expert working groups charged with developing harmonizing guidelines. The guidelines are grouped under one of the following headings:

• Effi cacy (clinical testing and safety monitoring related issues) • Quality (pharmaceutical development and specifi cations)

266 11 Drug Approval in the European Union and United States

• Safety (preclinical toxicity and related issues) • Multidisciplinary (topics not fi tting the above descriptions).

Thus far, in excess of 60 guidelines aimed at both traditional and biotechnology based products have been produced and are being implemented. One of the ICHs most signifi cant initiatives to date has been the development of the Common Tech-nical Document . This provides a harmonized format and content for new product authorization applications within the EU, United States, and Japan. Such regula-tory streamlining will make more economical use of both company and regulatory authorities ’ time, should reduce the cost of drug development and also speed up the drug development procedure, ensuring faster public access to new drugs.

11.5 Regulation of Biosimilars

The advent of biosimilar s possibly represents the most contentious regulatory issue to arise in recent years in the context of biotech drug approval. Once patent protec-tion on any drug expires, alternative pharmaceutical companies are free to develop and seek marketing approval for a copy of the original product – that is, to market a generic product . Traditional targets for generic manufacturers are invariably low molecular weight organic molecules, which are manufactured by well defi ned, precisely controlled chemical pathways. Hence, it is possible to routinely produce a product identical in every way to the original drug. Legislative frameworks for the approval of such generic pharmaceuticals were established in many regions of the world from the 1980s onwards, and are generally non - contentious.

The fi rst recombinant biotech products ( biopharmaceutical s) entered the mar-ketplace in the 1980s, thus many of the original products have lost patent protec-tion only in the last decade. Collectively somewhere in the region of $12 – 15 billion worth of products are now off patent and it is not surprising that many such origi-nator products would become the target of generic producers. Biopharmaceuticals, however, differ fundamentally from traditional, chemically synthesized, low molecular weight pharmaceutical products. They are hundreds, usually thousands, of times larger and are synthesized by biological processes, with all of the inherent variability that this entails. While genetic engineering can ensure the production of a recombinant protein with an amino acid sequence identical to any approved product, the exact details of manufacture (upstream and downstream processing) can and will infl uence the impurity profi le of the product, as well as the exact detail of any post - translational modifi cations (e.g., glycosylation) present. Moreover, their complexity renders full analytical characterization of any such product extremely challenging.

As such, it is highly improbable that a generic version of a biopharmaceutical would be absolutely identical to the originator. What is achievable is the production of a product very substantially similar to the originator, hence the term biosimilar.

The EU developed legislative provisions for the approval of biosimilars almost a decade ago and the EMA subsequently developed a suite of associated regulatory

References 267

guidelines ( http://www.ema.europa.eu ). This has thus far facilitated the approval of 14 such biosimilar products within Europe. EU biosimilar regulation s neces-sitate the generation of comparative data between the proposed new biosimilar product and the original (reference) product, to which it claims biosimilarity. The reference product must already be approved for general medical use within the EU. The sponsor seeking biosimilar approval must submit the data generated as a Marketing Application directly to the EMA for consideration via the centralized procedure. The Marketing Authorization Application (relative to the one for the original reference product) will contain a full quality module (containing details of product development, manufacture, specifi cations, and analysis, etc.), as well as reduced clinical and non - clinical data modules.

Regulators in several other world regions (e.g., Australia, Canada, Japan, Swit-zerland) have developed regulatory frameworks for the approval of biosimilar products. In most cases these regulatory provisions are substantially similar to European regulations. Development of a biosimilar pathway in the United States has been signifi cantly slower, although a legal framework for such approvals was fi nally implemented with the ratifi cation of the US Biologics Price Competition & Innovation Act ( BPCI Act ) in 2010. With the legal framework in place it is effec-tively now up to the FDA to implement its contents. A Biosimilar Implementation Committee has been established and an Associate Director for Biosimilars has been appointed, and the FDA are currently in the process of developing biosimilar guidelines. It is therefore likely that biosimilar products will fi nally become avail-able on the US market over the next few years.


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