Drug Information Journal, Vol. 33, pp. 969978, 1999 Printed in the USA. All rights reserved.

0092-8615/99 Copyright 1999 Drug Information Association Inc.

THE EUROPEAN AGENCY FOR THE EVALUATION OF MEDICINAL PRODUCTS CENTRALIZED PROCEDURE FOR PRODUCT APPROVAL: CURRENT STATUS
ELAINE M. HEALY, BS
Research Coordinator

KENNETH I. K AITIN, PHD

Director Tufts Center for the Study of Drug Development, Tufts University, Boston, Massachusetts

The European Agency for the Evaluation of Medicinal Products (EMEA) was established in July 1993 to unify regulatory practices and improve market access within the European Union (EU). In February 1995, the EMEA implemented the centralized procedure for drug approval within the EU. The current study explores the history, goals, and implementation of the centralized procedure. We examine the time to obtain product marketing authorization for products that have gone through the process relative to the goals set for the program at its inception, and we compare approval times for a group of products that have been approved by both the EMEA and the United States Food and Drug Administration (FDA). Our data indicate that the goals established by the EMEA for the timeliness of application review have generally been met. Moreover, mean approval times for products approved by both the EMEA and the FDA were similar. Key Words: European Union; EMEA; Centralized procedure; Harmonization

INTRODUCTION THE EUROPEAN UNION represents one of the worlds largest prescription drug markets. Yet, access to its entirety has long been hindered by the different systems for product review and marketing authorization among the member states. In one of the most significant efforts to date at unifying regulatory practices and improving market access within the EU, the European Agency for the

Reprint address: Elaine M. Healy, Tufts Center for the Study of Drug Development, Tufts University, 192 South St., Suite 550, Boston MA 02111. E-mail: ehealy @infonet.tufts.edu.

Evaluation of Medicinal Products was established by Council Regulation (EEC) No. 2309/93 on July 22, 1993. In February 1995, the new EU drug approval system went into operation (1). Prior to the establishment of the EMEA, the European Commission (EC) initiated a number of regulatory protocols in an effort to unify the European pharmaceutical market, but the systems lacked the centralized authority necessary for managing resources and procedures among national regulatory authorities. The establishment of the EMEA amended the legislation surrounding the procedures for mutual recognition of product approval among national authorities and es-

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tablished the first entirely centralized procedure for reviewing and licensing products at the European Community level. The EMEAs centralized procedure has now been in operation for over three years. In the current study, we explore the history, goals, and implementation of the centralized procedure. In particular, we examine the length of time it took to obtain product marketing authorization for products that have gone through the process relative to the goals set for the program at its inception, and we compare approval times for a group of products that have been approved by both the EMEA and the United States FDA. HISTORICAL PERSPECTIVE At its inception, the primary goals of the EMEA were to encourage the development of pharmaceutical products and increase their accessibility on the European market. Ultimately, the EMEAs interest was to contribute to the improvement of public health throughout the EU (a listing of EMEA objectives is provided in Appendix 1). (2) It was also anticipated that establishment of this new system for pharmaceutical regulation would stimulate investment by European companies in research and development in the area of biotechnology. Prior to the introduction of the EMEA, medical products were reviewed and approved for marketing at the national level. Companies seeking marketing authorizations for products in one or more countries within the EU underwent the review and approval process in each country. In 1975, the Committee for Proprietary Medical Products (CPMP) was established as a scientific review committee by Directive 75/319 (1). Made up of representatives of regulatory authorities from each of the participating European countries, the purpose of the CPMP was to ensure the quality, safety, and efficacy of products being introduced for marketing authorization among the EUs member states. The introduction of the mutual recognition process in 1983 (established as an

amendment to directive 75/319) (1), made it possible for a single national review for most pharmaceutical/medicinal products to be used as the basis for marketing authorizations in all EU countries. The goal of mutual recognition was to create a unified standard for product review among national regulatory authorities, while leaving the decision for product marketing authorization in the hands of the national regulatory authorities. Initially, national authorities were not required to accept as authoritative product reviews conducted by other member state agencies. Consequently, national regulatory authorities in each country continued to perform their own product reviews before coming to a decision regarding product approval and marketing authorization. This duplication of effort among the different national regulatory authorities undermined the success of the process. The introduction of the EMEA marked the first time that the mutual recognition procedure was managed by a centralized authority, thus maximizing the potential of the mutual recognition procedure for multinational product approvals. Under the EMEAs management, disputes over the acceptability of a marketing authorization within the decentralized system are handed over to the EMEA, where a centralized and binding decision is made (3). In 1987, the concertation procedure for high-technology or biologically-derived products was established by Directive 87/22 (1). In the concertation procedure, the normal national regulatory review process was preceded by a product assessment completed by the CPMP. The establishment of the EMEA led to the replacement of the concertation procedure with the centralized procedure, whereby all high-tech and biologically-derived products entering the European market are not only reviewed by the EUs CPMP, but are also granted EU-wide marketing authorization by the EC. By granting EU-wide marketing authorization, the need for separate national marketing authorizations is eliminated.

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IMPLEMENTATION AND GOALS OF THE CENTRALIZED PROCEDURE Marketing authorizations granted though the EMEA are valid for five years, after which time the sponsoring company must apply for a renewal (1). The EMEAs centralized procedure is required for some but not all products (Regulation 2309/93). For example, whereas the process is mandatory for all high-tech products (List A), it is optional for other new and innovative products (List B) (3). (A complete description of List A and List B product categories is provided in Appendix 2.) One of the primary goals for the establishment of a unified system of product approval was to invigorate biotechnology product development. It was hoped that the creation of a unified regulatory system, in which product review and approval leads to a single marketing authorization recognized by all countries within the EU, would significantly improve market access for developers, thereby stimulating research and development within the biotechnology industry. The centralized procedure was created with specific performance goals for review and approval timeliness. These goals specify that the CPMPs validation of a product application, marking the start of the scientific review, will not exceed 15 days from the date that the sponsoring company submits the product application. The total number of active CPMP scientific review days (ie, validation date to positive opinion by the CPMP) will not exceed 210 days. After a positive opinion, the EMEA has 30 days to finalize the initial product assessment report and forward it to the EC, resulting in a total time for EMEA application review of 240 days (4). The application and scientific assessment report are then submitted to the EC for final marketing authorization, which generally requires another 60 to 80 days (2). Both List A (mandatory) and List B (optional) products are subject to the same review procedure. In some cases, products may receive the designation of approval under

exceptional circumstances, whereby the CPMP delivers a conditional approval. When this happens, the marketing authorization is granted with the condition that the sponsoring company submit postapproval information concerning ongoing studies for the product. Such conditional approvals are granted only for products that are considered of particular urgency to a targeted patient population (3). METHODS Level of Measurement Analyses in this study were performed at the product level. The primary means by which products are categorized for review within the centralized procedure is by the list designation (ie, List A or List B, described above) each product receives prior to application submission (Appendix 2). This designation separates the biotechnology product applications, whose review through the centralized procedure is mandatory, from those products for which review via the centralized procedure is optional. In a limited comparison of the review processes of the same drugs through both the EMEA and the FDA, we compared the reviews of products approved under exceptional circumstances within the centralized procedure to those approved under the accelerated approval regulations of the FDA. Accelerated approval is part of the FDAs fast-track initiative aimed at speeding access to drugs intended to treat life-threatening and severely debilitating illnesses. The FDAs accelerated approval regulations provide mechanisms for compressing the clinical development process and accelerating FDA review (5). Procedures for granting approval under exceptional circumstances in the EMEA and under accelerated approval in the FDA were designed to increase the speed at which therapeutically important products reach the relevant patient populations. Both the EMEA and the FDA require postapproval research from the sponsoring companies for approvals un-

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der these conditions, but while the EMEA considers approval under exceptional circumstances conditional approval, the FDA has avoided that designation for products approved under the accelerated approval regulations (5). Two Tufts Center for the Study of Drug Development (CSDD) databases were used in our analyses. The primary database was developed for the purpose of tracking marketing authorizations granted through the EMEAs system for centralized approval. This database has been created and maintained primarily from information published online by the EMEA. For example, we used European Public Assessment Reports (EPARs), which contain product and review information, and are published on the EMEA website (www.eudra.org) for each product that receives approval through the centralized procedure. We also used annual reports and monthly newsletters, which document the various stages of the review process, including the number of days the clock is stopped during the review process for the company to address issues brought up during scientific review. This information was supplemented with information from other public data sources (eg, NDA Pipeline, Scrip Reports, Pharmaprojects). The information on products having received FDA marketing approval in the United States was obtained from Tufts CSDDs database of approved new chemical and new biological entities, maintained primarily by means of an annual survey conducted by Tufts CSDD, and supplemented with data from publicly available information sources (eg, Pink Sheet, Federal Register, Pharmaprojects, PhRMA bulletins and reports). Analyses The following intervals were calculated for the analyses: Total Approval Time (date of application validation to final decision by the EC for marketing authorization); Total Review Time (date of application validation to the end of the CPMPs scientific review); Stopclock Time (the portion of the total re-

view time that the product dossier was back with the sponsoring company to address issues raised during scientific review); Active CPMPdays (the portion of the total review time that the dossier was in the hands of the CPMP; ie, total review time minus stopclock time); and ECdays (the time during which the product dossier and the CPMPs assessment were in the hands of the EC awaiting legally binding authorization; ie, the time between the ECs receipt of the dossier and the date the final marketing authorization was granted). Additionally, we computed the time between application submission and validation, as well as the time between the rendering of a CPMP opinion and the ECs receipt of the marketing authorization application (6). To compare the review process for products having gone through both the FDA and the EMEA, we calculated approval times for FDA-approved products. FDA Approval Time was computed as the time between the date of New Drug Application (NDA) filing and the date of NDA approval. It should be noted that 10 of the submissions to the FDA that were included in our analyses were reviewed by the agency via the rolling NDA process, wherein portions of the NDA are reviewed by the FDA prior to the formal filing of the application. Thus, the approval phase for these new chemical entities (NCEs) underestimates the total regulatory review period by an unquantifiable amount.

RESULTS Approval Times Within the Centralized Procedure There have been 62 marketing authorizations, corresponding to 52 substances, granted through the EMEAs centralized procedure through June 1998. Of these, 25 were for products that were designated for review as List A products (mandatory); the 37 remaining authorizations were for those designated as List B products (optional). Twelve of the 62 marketing authorizations were

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FIGURE 1. Mean times for various stages of the EMEAs centralized procedure for pharmaceutical product marketing authorization, for all products (n = 62), List A products (whose approval via the centralized procedure is mandatory [see text], n = 25), and List B products (whose approval via the centralized procedure is optional, n = 37).

granted for products under exceptional circumstances. The mean total approval times, active CPMP days, stopclock days, and ECdays for all 62 marketing authorizations (in total and by list designation) through the centralized procedure are shown in Figure 1. Medians and ranges for these values are presented in Table 1. The mean total approval time for all 62 marketing authorizations through the centralized procedure was 422 days. For the 25 List

A products, the mean total approval time was 467 days, which is 76 days (19%) longer than the 391-day mean approval time for List B products. The observed difference between the total approval times of List A and List B products is attributable to the differences in the number of stopclock days, during which time companies address issues raised during scientific review; the clock was stopped nearly twice as long (95% longer) during List A product review (160 days) than it was during List B product review (82

TABLE 1 Median and Range Values for Total Approval Times, Active CPMP Days, Stopclock Days, and EC Review Days for Products Approved via the Centralized Procedure CPMP Active Review Days Median (range) Total (n = 62) List A (n = 25) List B (n = 37) 189 (51297) 197 (51297) 186 (71265) Stopclock Days Median (range) 83 (0487) 132 (0398) 56 (0487) EC Review Days Total Approval Time Median (range) Median (range) 75 (51202) 80 (52189) 75 (51202) 398 (166912) 438 (191730) 380 (166912)

Not noted in this table are the median and range values for the 41-day mean period of CPMPs postopinion assessment report preparation which takes place prior to the European Commissions review and Marketing Authorization.

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days), which suggests that the issues addressed by the companies during this time were of a more complex nature for List A products. The three-day difference between the number of active CPMPdays for these two groups is negligible, as is the one-day difference between the time List A and List B product applications spent awaiting final marketing authorization from the EC. There were 12 products that received marketing authorizations under exceptional circumstances (4 List A products and 8 List B products). The mean total approval time for these 12 products was 373 days (median: 338; range: 166651 days), which is 60 days (14%) less than the 433-day mean approval time for the 50 remaining marketing authorizations. The mean active CPMP review period for the 12 authorizations granted under exceptional circumstances was 162 days, (median: 171; range: 71297 days), which is 27 days (14%) shorter than the 189-day mean active review time for the 50 marketing authorizations granted through the centralized procedure without exceptional circumstances. The mean stopclock for these 12 product approvals was 98 days (median: 68; range: 0307), 19 days (16%) shorter than the 117-day stopclock for the remaining 50 marketing authorizations. Table 2 shows mean values for review phase times for all 62 centralized approvals relative to the goals defined at the programs outset. The data suggest that the EMEA has succeeded in meeting the timelines for re-

view specified for the centralized procedure for all categories except the preparation of the assessment report preceding the ECs final decision. Comparison of Approval Times for Products Approved by both EMEA and FDA Of the 52 new substances that have been approved through the centralized procedure since 1995, 32 were also approved by either the Center for Drug Evaluation and Research (CDER) or the Center for Biological Evaluation and Research (CBER) of the FDA. We excluded two products from the analysis having approval times through one or both of the agencies that were clear outliers (ie, arcitumomab, whose total approval time was 1901 days in the FDA and 642 days in the EMEA, and levacetylmethadol, whose total approval time was 18 days in the FDA and 912 days in the EMEA). The mean total approval time for the 30 remaining products was 370 days through the EMEAs centralized procedure (median: 361; range: 166 651) and 366 days (median: 364; range: 42 907 days) through the FDA. Figure 2 shows a scatterplot for the approval times of these 30 products by both the EMEA and the FDA. The scatterplot reflects the degree to which approval times within these systems vary. Approval times by the FDA are represented along the X-axis, while those by the EMEA are shown on the

TABLE 2 Comparison of Actual Approval Times by Centralized Procedure With Performance Goals CPMP Active Review Days Goal time Total (n = 62) List A (n = 25) List B (n = 37) 210 184 182 185 Preparation of Assessment Report 30 41 41 41 EMEA Processing Time 240 225 223 226 European Commission Total Review Review Time 60* 83 84 83 300 days 308 307 309

*The review by the EC resulting in the final decision and marketing authorization is expected although not strictly defined as 60 days. Depending on the availability of the Commission Directorate, the length of this part of review may vary.

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FIGURE 2. Scatterplot of approval times for 30 products approved by both the EMEA and the FDA. The 14 dots on the right side of the bisection line represent those products whose approval time was shorter in the EMEA than in the FDA. The 16 dots on the left side of the bisection line represent those products whose approval times were shorter in the FDA than in the EMEA.

Y-axis. A line has been drawn to bisect the graph, allowing visual comparison of the approval times through each agency. The 14 dots on the right side of the bisection line represent those products whose approval times were shorter in the EMEA than in the FDA, while the 16 dots on the left side of the bisection line represent the products whose approval times were shorter in the FDA than in the EMEA. The dispersion of dots representing the approval time for individual products by both agencies reflects a smaller range of approval times by the EMEA than by the FDA (166 to 651 days vs. 42 to 907 days, respectively). Of the 30 products reviewed by both regulatory agencies, 17 were assigned a priority review rating within the FDA, eight of which were granted accelerated approval (note that

Betaseron was granted accelerated approval but was reviewed by CBER, where no priority ratings were assigned at that time), and 10 of the 30 products were submitted as rolling NDAs. Within the EMEA, 11 of the 30 products were granted approval under exceptional circumstances. To provide a direct comparison of approval times for individual products approved by the EMEA and the FDA, we compared review times for those products that had similar submission dates in each agency (ie, within 32 days of one another) and whose regulatory status (ie, exceptional and accelerated approval status in the EMEA and FDA, respectively, vs. standard review) were comparable. There were 10 such products. EMEA and FDA approval times for each of these products are shown in Figure 3. The

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FIGURE 3. Comparison of approval times (time from application submission to date of product approval) for products with similar review priority status and submission dates in both the EMEA and the FDA.

mean approval time for the 10 products was 372 days (range: 301438 days) for the EMEA and 354 days (range: 92877 days) for the FDA, a difference of 5%. DISCUSSION The creation of the EMEA is the most recent in a long line of efforts to coordinate the individual national regulatory authorities within the EU. A relatively new system, it is likely to evolve further in the years to come. The EMEA, in general, and the centralized procedure, in particular, reflect the continued and growing desire for international regulatory harmonization within the biotechnology and pharmaceutical industries. To the extent that the unified regulatory efforts of the EMEA improve access to the entire European market, the biotechnology and pharmaceutical industries benefit. Furthermore, if the EMEA effectively improves public access to new medicines within the EU, there will ultimately be a benefit to the public health.

In this study we report on several measurable outcomes of the EMEAs centralized procedure, assessing the type of products that have been approved and the agencys adherence to its performance goals. To date, the majority of the marketing authorizations granted have been for products whose review through this system was optional (ie, List B). This likely indicates a certain level of industry satisfaction with the centralized procedure (7). With regard to the EMEAs adherence to its performance goals, our data indicate that the goals established for the timeliness of application review have generally been met. The system for centralized approval is set up such that an applications progress through the various stages of review is determined, in part, by the CPMP meeting schedule formulated by the EMEA at the beginning of the year. Therefore, review and total approval times within this system are somewhat dependent on the degree to which review progress coincides with such meeting schedules. The limited variability in the EMEA review

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times observed in our study may be due to the fact that application review is subject to a predetermined meeting schedule. The similarity of mean approval times for the 30 products approved by both the EMEA and the FDA masks the disparity of individual product review times. These disparities may reflect such factors as differences in submissions to each agency, resources devoted to review, priority of review, and differences in the questions and concerns about the application raised by the two agencies. The EMEA represents the culmination of more than 20 years of effort to consolidate resources and improve efficiency among European regulatory authorities, but the process is still evolving. Despite general industry satisfaction, some have complained about the lack of business efficiency and flexibility in the system and have called for greater availability of comprehensive and consistent regulatory advice (8). Undoubtedly, further efforts to cultivate a more unified and efficient system for medical product development and regulation will be proposed and implemented in coming years. The upcoming release of the EMEAs 2001 Review will provide a more complete perspective on the system and what can be anticipated for its future application. Tufts CSDD will continue to monitor and report on the EMEAs activities. REFERENCES
1. Friedel E, Freundlich M. European Community harmonization of the licencing and manufacturing of medicinal products. Food Drug Law J. 1994;49(1):141 170. 2. European Agency for the Evaluation of Medicinal Products. Work programme 199798EMEA. Luxembourg: Office for Official Publications of the European Community; 1997. 3. Currie WJC, Lo fgren M. A Practical Guide to the EMEA. Waltham MA: Parexel; 1996. 4. Bass R. Why have targets for the review process? The view of the EMEA. Improving the Regulatory Review Process: Assessing Performance and Setting Targets. Proceedings of a CMR International Workshop held at Nutfield Priory, Nutfield, UK, January 1997. McAuslane N, Walker S, editors. Dordrecht: Boston, Kluwer; 1997. 5. Shulman SR, Brown JS. The Food and Drug Adminis-

trations early access and fast-track approval initiatives: how have they worked? Food Drug Law J. 1995;50(4):503531. 6. European Agency for the Evaluation of Medicinal Products. Second General Report 1996. Luxembourg: Office for Official Publications of the European Community, 1997. European Agency for the Evaluation of Medicinal Products. Third General Report 1997. Luxembourg: Office for Official Publications of the European Community; 1997. 7. Sauer F. A new and fast drug approval system in Europe. Drug Inf J. 1997;31(1):16. 8. Europe Should Move to Centralized Review of All DrugsCPMPs Winkler. Pink Sheet. November 30, 1998;60(48):1718.

APPENDIX 1*
EMEA Objectives: To protect public health by mobilizing the best scientific resources existing within the European Union To promote health care through the effective regulation of new pharmaceuticals and better information for users and health professionals To facilitate the free circulation of pharmaceuticals within the European single market To support the European pharmaceutical research and development industry by developing efficient, effective and responsive operating procedures To support effort in international cooperation

APPENDIX 2
List A products include those medicinal products developed by means of: 1. Recombinant DNA technology, 2. Controlled expression of genes coding for biologically active proteins in prokaryotes and eukaryotes, including transformed mammalian cells, and 3. Hybridoma and monoclonal antibody methods. List B products include: 1. Medicinal products developed by other biotechnological processes which, in the opinion of the agency, constitute a significant innovation, 2. Medicinal products administered by means of new

*The European Agency for the Evaluation of Medicinal Products Work Programme 199798 (2). Regulation 2309/93 (3)

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delivery systems which, in the opinion of the agency, constitute a significant innovation, 3. Medicinal products presented for an entirely new indication which, in the opinion of the agency, are of significant therapeutic interest, 4. Medicinal products based on radio-isotopes which, in the opinion of the agency, are of significant therapeutic interest, 5. New medicinal products derived from human blood or human plasma,

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6. Medicinal products the manufacture of which employs processes which, in the opinion of the agency, demonstrate a significant technical advance such as two-dimensional electrophoresis under micro-gravity, and 7. Medicinal products intended for administration to human beings, containing a new active substance which, on the date of entry into force of this regulation, were not authorized by any Member State for use in a medicinal product intended for human use.