European Union Pharmaceutical Medical Device Regulation

European UnionPharmaceutical

&Medical Device

Regulation

Linda R. Horton, JD

Regulatory Affairs Professionals Society 11300 Rockville Pike, Suite 1000

Rockville, MD 20852 301.770.2920, fax 301.770.2924

ISBN# 0-9673115-8-6

1 .

European Union Pharmaceutical and Medical Device Regulation

Linda R. Horton Partner, Hogan & Hartson

December 2005

©All Rights Reserved, RAPS 2005

RAPS EU Pharmaceutical & Medical Device Regulation 2

European Union: Pharmaceutical and Medical Device Regulation The past few years have seen historic changes in the European Union (EU). On 1 May 2004, the EU grew from 15 Member States to 25. For the pharmaceutical industry, many new laws entered into force, were enacted or were proposed. The legislation put in place lays the foundation for regulation of the industry in an enlarged EU for the foreseeable future. Similarly dramatic changes affected companies developing and selling pharmaceuticals for human use and those in the veterinary pharmaceutical business. For the medical device industry, the situation has been relatively static for a decade but then, in May 2005, the European Commission released two long-awaited official drafts, one to revise the Medical Devices Directive and the other to put in place an EU regulatory scheme for human tissue-engineered products as a specially regulated subset of pharmaceuticals. Certainly, keeping track of old and new requirements is a daunting task, particularly if one considers that almost all regulatory affairs professionals need to pay close attention to requirements of the US Food and Drug Administration as well as the EU authorities, and frequently other countries’ regulations, as well. This book is dedicated to regulatory affairs professionals, around the world, whose job it is to meet requirements and help bring new medical products to market. My aim is to promote understanding of an increasingly complex and impressive statutory framework. Although this publication will be too elementary for regulatory affairs officials already deeply immersed in EU pharmaceutical regulation, it may be helpful to others trying to understand the increasingly complex EU system. I wish to express appreciation to my colleagues in Hogan & Hartson’s global life sciences practice for collaboration on client bulletins that were precursors to several sections of this book. In this regard, I would like to thank Guglielmo Adinolfi, Héctor Armengod, Sharon Benning, Aymeric Dumas-Eymard, Jaime Tomhave Gallimore, Matthew Giles, Klaus Goecke, Catriona Hatton, Jacqueline Mailly, Katlin McKelvie, Kornelia Nagy-Koppany, Wim Nauwelaerts, Elefteria Nearchou, Agnieszka Sucheka-Tarnaka, Delphine Voillemot, April Wimberley and Elspeth Wrigley. My editor, Pamela Jones of the Regulatory Affairs Professionals Society staff, was a huge help with format and substance (and incredibly patient), while Martine Quenum spent many hours helping us overcome some difficult word processing challenges. Last but not least, I am grateful to family members, especially my husband, daughter and son, for their support on this project.


European Union Pharmaceutical and Medical Device Regulation Table of Contents Glossary I. Historical Developments in the European Union A. EU enlargement B. 2004 EU medicinal products legislation 1. The new laws and overview of important changes 2. Effective dates of new laws 3. Summary of key changes in legislation generally 4. Summary of key changes in new EMEA Regulation C. Clearer definitions II. EU Medicinal Products Regulation Summarised III. Authorisation Procedures for Medicinal Products and Related Issues A. Contents of marketing authorisation applications B. Period of marketing authorisation validity C. EMEA jurisdiction D. Decentralised authorisations/Mutual Recognition Procedure (MRP) E. Accelerated product availability and key provisions on access to medicines F. Marketing authorisations for generics (details are provided in chapter VIII) G. Marketing authorisations for biosimilars (details are provided in chapter IX) H. Traditional herbal medicinal products and homeopathic medicines I. Radiopharmaceuticals and related products J. Provisions giving marketing authorisation holders additional flexibility K. Patient information L.EMEA transparency and guidelines procedure M. Scientific advice N. EU initiatives on pharmaceutical access in developing countries O. EMEA “Roadmap to 2010” initiative P. EU competitiveness and the G10 Q. Pricing controls, third-party reimbursements, and health technology assessments, and patient mobility IV. Medical Devices Regulation A. EU medical device regulation summarised B. Recent legislative changes and proposals C. Draft proposed directive to amend the Medical Devices Directive D. Current issues in medical devices compliance V. Preclinical Testing and Clinical Trials Regulation A. Good Laboratory Practices B. Medical device clinical trials


C. Medicinal product clinical trials D. Good Clinical Practices Directive E. Guidelines on clinical trials F. Privacy protection legislation VI. Good Manufacturing Practice Requirements and Inspections: Medicines A. 2003 GMP Directive and related legislation B. Inspections C. Revision of Notice to Applicants and related documents D. Requirements for wholesalers and distributors VII. Medicinal Products: Post-Authorisation Compliance A. Variations B. Extensions C. Special approach for pandemic influenza vaccine D. Renewals E. Pharmacovigilance and risk management VIII. Generic Products A. 2004 legislative changes B. The EMEA Regulation C. Definition of generic D. Types of applications E. Contents of an abridged application based on essential similarity F. Generic submissions to Member States other than Reference Member States G. Impact of new legislation on patent law H. Supplementary Protection Certificates (SPC) I. Regulatory data protection “8+2+1” and “global marketing authorisation” J. Other exclusivity laws K. EU initiative to punish innovators for alleged violations of competition rules L. Controversial issues associated with the new legislation IX. Marketing Authorisations for Products Derived From Biotechnology A. Genetically modified organisms B. Biological medicinal products C. Biosimilars X. Medicinal Products Manufactured from Blood or Plasma XI. Regulation of Human Tissue and Other Advanced Therapies A. Tissue Handling Directive B. Advanced therapies C. Draft proposed human tissue-engineered regulation


XII. Orphans and Paediatric Testing A. Orphan Medicinal Product Regulation B. Applications for orphan designation C. Definition of orphan product D. Incentives E. Review of market exclusivity F. Breaking exclusivity G. Advice and Translations H. Paediatric legislation XIII. Prescription versus Over-the-Counter Products: Classification XIV. Parallel Trade in Medicinal Products A. Background B. Recent developments C. Recent case law XV. Veterinary Medicinal Products A. Veterinary Code Amendment Directive and new EMEA Regulation B. Overview C. Centralised procedure D. Mutual recognition procedure E. EU framework for Maximum Residue Levels for veterinary medicinal products in food F. Recent EU initiatives on veterinary medicinal products XVI. Food Supplements A. Background B. Advocate General’s opinion C. The ECJ judgment D. Effect of judgment XVII. Borderline and Combination Products A. Recent legislative changes and proposals B. Medical Devices Directive C. Demarcation guidelines D. Steps toward greater clarity XVIII. Cosmetics XIX. Enforcement: Medicinal Products A. Community Code provisions B. EMEA Regulation and draft Penalties Regulation C. Proposed anti-counterfeiting directive D. European Healthcare Fraud and Corruption Office


XX. Advertising and Promotion A. Community Code provisions B. Increased enforcement C. Situation in various countries D. EFPIA’s new Marketing Code of Practice E. Eucomed Code XXI. National Authorities A. EU Member State responsibilities under new legislation B. New Member States’ implementation steps as of the 1 May 2005, date of accession C. Provisions in accession treaties on parallel trade D. New Member States: contact information for drug regulatory authorities


Glossary

ABPI: Association of British Pharmaceutical Industry ADI: acceptable daily intake, in context of veterinary medicines for food animals Afssaps: French agency for health products AIMD: Active Implantable Medical Devices Directive acquis communitaire, European Community legislation (“Community achievement”) BfArM: German agency for health products; see DAMA CHMP: Committee on Human Medicinal Products CPMP: Committee on Proprietary Medicinal Products (CPMP); old name for CHMP CMS: Concerned Member States CA: Competent authority; a drug regulatory agency CE: mark on medical devices signifying conformity with applicable EU requirements CEC: European Commission (Commission for the European Communities) CMC: Chemistry and manufacturing controls CRO: Contract Research Organisation CTD: Common Technical Document CFI: Court of First Instance COMP: Committee on Orphan Medicinal Products CVMP: Committee on Veterinary Medicinal Products DAMA: German agency for health products, replacing BfArM EEA: European Economic Area, comprising the EU 25, Iceland, Liechtenstein, Norway EEC: European Economic Community, former name for EC EC: European Community; also, ethics committee in clinical trial context ECJ: European Court of Justice EFPIA: European Federation of Pharmaceutical Industries and Associations EFSA: European Food Safety Authority EFTA: European Free Trade Area; Iceland, Liechtenstein, Norway, Switzerland EMEA: European Medicines Agency ENGAGE: European Network of GCP Auditors and other GCP Experts EP: European Pharmacopoeia; also, EU Parliament EPAR: European Product Assessment Report ERMS: European Risk Management Strategy EU: European Union EUDRACT: EU drug regulatory agency clinical trials database FDA: US Food and Drug Administration FML: Future Medicines Legislation GDPs: Good Distribution Practices GCPs: Good Clinical Practices GHTF: Global Harmonisation Task Force for medical devices GLPs: Good Laboratory Practices GMPs: Good Manufacturing Practices HMA: Heads of Medicines Agencies


HMPC: Committee on Herbal Medicinal Products hTEP: human tissue-engineered product ICH: International Conference for the Harmonisation of the Technical Requirements for the Registration of Pharmaceuticals for Human Use IMP: Investigational medicinal product ISO: International Standards Organisation IVDD: In Vitro Diagnostics Directive MA: Marketing authorisation MAA: Marketing authorisation application MAH: Marketing authorisation holder MDD: Medical Devices Directive MDEG: Medical Device Expert Group MED DEVs: European Commission guidance on medical devices MedDRA: Medical Dictionary for Drug Regulatory Agencies MEP: Member of the European Parliament MHRA: Medicines and Health products Regulatory Agency, UK MoHs: Ministers of Health MRFG: Mutual Recognition Facilitation Group MRLs: Maximum residue levels, in context of veterinary medicines for food animals MRP: Mutual Recognition Procedure MSs: Member States NB: Notified body; an EU medical devices conformity assessment body NICE: UK National Institute for Clinical Excellence NO(A)EL: No adverse effect level, in context of veterinary medicines for food animals NtA: Notice to Applicants—Medicinal Products for Human Use (NtA) OJ: Official Journal of the European Communities OTC: Over-the-counter, referring to non-prescription medicine PhVQP: Pharmacovigilance qualified person designated by a sponsor PhVWP: Pharmacovigilance Working Party PIC/S: Pharmaceutical Inspection Cooperation Scheme PMF: Plasma master file PSUR: Periodic Safety Update Report Q7A: ICH guideline on GMPs for active pharmaceutical ingredients Q&A: Questions and answers QP: Qualified person QRD: Quality Review of Documents R&D: Research and development Rapporteur: Point person RMS: Reference Member State SAWG: Scientific Advice Working Party SmPC: Summary of (medicinal) Product Characteristics; sometimes called “SPC” SOP: Standard Operating Procedure SPC: Supplementary Protection Certificate


SUSARs: Suspected serious adverse events “Third country:” any country that is not a member of the EU or EEA TRIPS: WTO Agreement on Trade-Related Intellectual Property Rights WHO: World Health Organisation WTO: World Trade Organisation


Chapter I. Historical Developments in the European Union A. EU Enlargement The 10 Member States that joined the EU on 1 May 2004 were Cyprus, the Czech Republic, Estonia, Hungary, Latvia, Lithuania, Malta, Poland, Slovakia and Slovenia. The 15 so-called “old” Member States are Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, The Netherlands, Portugal, Spain, Sweden and the United Kingdom. Before their accession on 1 May 2005, the new Member States needed to “transpose” (adopt into their national laws) all the requirements found in EU law (the so-called acquis communitaire, or “Community achievement”). This process was aided by European Commission activities aimed at integrating the new members, including seminars, training and observer status at key meetings. EU enlargement is a controversial issue at present, but most observers believe it will continue. The process is at an advanced stage for Bulgaria and Romania, and other countries whose membership is less straightforward, but is under serious consideration, are Croatia and Turkey. It also needs to be borne in mind that the EU legislation and system described in this chapter applies throughout the European Economic Area (all EU countries plus Iceland, Liechtenstein and Norway) under a treaty governing this relationship. Therefore, EEA-partner countries are entitled to participate in certain of the technical-level pharmaceutical and medical device regulatory development and implementation activities, and their governments have taken on board the requirement to implement and adhere to EU legislation. B. 2004 EU medicinal products legislation For medicinal products for human use, the two main pieces of EU legislation are the Community Code on Medicinal Products for Human Use (Directive 2001/83/EC) and the Regulation on the European Medicines Agency (EMEA Regulation 726/2004). For medicinal products for veterinary use, the two main pieces of legislation are the Community Code on Medicinal Products for Veterinary Use (Directive 2001/82/EC) and the same EMEA Regulation that covers pharmaceuticals for humans. Products for food animals also are subject to EU food and feed legislation. Each of the Community Code Directives emerged from a wise effort to replace a large body of disparate European Community legislation with a single, comprehensive code. The codification was important to the accession countries needing to understand the pharmaceutical acquis that they were required to adopt. Although the codification could not introduce changes beyond the minimum necessary to compile a congruent text, it was recognised that the two Community Code Directives in themselves were not able to deal with a variety of regulatory, industry and patient needs. So, before the ink was even dry on the two Community Code Directives, the European Commission launched a revision effort known variously as the “pharmaceutical review package” or “future medicines legislation” (FML). After much debate among all involved institutions and stakeholders, on 31 March 2004, the pharmaceutical review legislation was enacted and on 30 April 2004, was published in the Official Journal of the European Communities.1 EU authorities met the goal of completing action on the legislation before the Community enlargement on 1 May 2004. The purposes of the legislation were to guarantee high levels of public protection, complete the internal market for pharmaceuticals, boost the competitiveness of EU-based industry and

1 OJ L 136, 30.04.2004, p. 1.; 2 OJ L 136, 30.04.2004, p. 34; 3 OJ L 136, 30.04.2004, p. 58; 4 OJ L 136, 30.04.2004, p. 85.


meet the challenges of enlargement and globalisation. The new laws include many important changes in the EU legislative framework concerning regulation of product quality, safety and efficacy, as well as new provisions seeking to strike a balance between the rights of innovators and opportunities for generic producers. 1. The new laws and overview of important changes Regulation (EC) 726/2004 (new EMEA Regulation): authorisation and supervision of

medicinal products for human and veterinary use and on the European Medicines Agency (EMEA) (complete revision of the 1993 Regulation, Regulation (EC) 2309/93 . (1993 EMEA Regulation2) that created the European Agency for the Evaluation of Medicinal Products, which the new EMEA Regulation renames the European Medicines Agency, but with the same acronym, EMEA).

Directive 2004/27/EC (Code Amendment Directive) amending the Community Code on

Medicinal Products for Human Use (Directive 2001/83/EC) (Community Code Directive).3 Directive 2004/24/EC (Herbal Medicinals Directive) on traditional herbal medicinal products,

also amending the Community Code Directive. Directive 2004/28/EC (Veterinary Code Amendment Directive) amending the Community

Code on Medicinal Products for Veterinary Use (Directive 2001/82/EC) (Veterinary Community Code Directive).

2. Effective dates of new laws The three Directives entered into force on the date of publication, 30 April 2004. Member States were required to implement them by 30 October 2005. The new EMEA Regulation entered into force on 20 May 2004 and was fully applied from 20 November 2005. For many new provisions, it is unclear whether they apply only to products approved after 30 October or 20 November, or to all products, regardless of original authorisation date. Pending applications have presented the most challenging issues. To sort out some of these issues, EMEA has issued a guidance document on Practical Considerations on the Impact of the New Pharmaceutical Legislation on Marketing Authorisation Applications via the Centralised Procedure and Centrally Authorised Medicinal Products for Human Use.4 Another key guidance governs the formatting of documents for EMEA review, the Quality Review of Documents (QRD) Product Information Templates.5 Although the latter document applies initially only to applications for marketing authorisations pending under consideration by the EMEA in two months immediately prior to the 20 November 2005 entry into force of the New EMEA Regulation, as already-authorised products go through renewals or variations, they also will be required to comply with the new Product Information Templates. Because products that originally received their marketing authorisations under the 2001 Community Codes or their predecessors will continue to be regulated to a certain degree under 2 Council Regulation 2309/93/EC of 22 July 1993 laying down Community procedures for the authorisation and supervision of medicinal

products for human veterinary use and establishing a European Agency for the Evaluation of Medicinal Products, OJ L214, 24.8.1993.

3 Article 8, Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community Code relating to

medicinal products for human use, OJ L 311, 20.11.2001, as amended by the Community Code Directive 2004/27.

4 EMEA/243280/2005, 8 September 2005. A similar document for veterinary medicines, EMEA/31976/2005, was published 17 October 2005.

5 EMEA CHMP, Quality Review of Documents Group, EMEA/CHMP/245309, 28 July 2005.


those versions, e.g., as to exclusivity periods, regulatory affairs professionals will need to refer to the old laws, as well as new ones, in ascertaining what provisions apply to their companies’ products. 3. Summary of key changes in legislation generally Improving marketing authorisation procedures Streamlining centralised procedures and tightening deadlines for decisions Tackling “non-recognition” in decentralised mutual recognition procedure through a new

decentralised procedure Accelerating access to medicines and providing for compassionate use Enhancing regulatory transparency and patient information Promoting innovation through harmonised regulatory data exclusivity periods (an “8 + 2+ 1”

formula that will harmonise current disparities among Member States in which some had granted six years of data protection and others had provided 10 years)

4. Summary of key changes in new EMEA Regulation EMEA’s mandatory jurisdiction was broadened and will continue to grow through built-in

expansion provisions. EMEA’s optional jurisdiction provisions were revised, opening the door for more applicants

to seek to make use of the centralised review. The Committee on Proprietary Medicinal Products (CPMP) was renamed the Committee for

Medicinal Products for Human Use (CHMP). The CHMP’s composition was immediately revised to accommodate the 10 new Member

States (under the 1993 EMEA Regulation, each Member State had two CPMP members, but a committee with 50 members would be unwieldy, so each Member State now has but one member, and one alternate, on the CHMP).

In addition, up to five additional (“co-opted”) members help round out the CHMP’s expertise. Similar changes were made in the Committee on Veterinary Medicinal Products (CVMP). Shortened timeframes govern decisions (assessments are to be completed within 150 days)

and other changes are meant to speed up access to new therapies. EMEA was given new powers, e.g., to impose conditions and/or restrictions to reinforce an

ongoing benefit-risk assessment; to ask a marketing authorisation holder, at any time, to submit data showing that the benefit-risk ratio remains favourable; and to propose to the European Commission financial penalties for those marketing authorisation holders that do not meet the obligations prescribed in connection with authorisations.


The EMEA CHMP will play a major role in helping resolve the “non-recognition” problem in

the decentralised/mutual recognition procedure. C. Clearer definitions The new Code Amendment Directives clarify key definitions affecting the scope and operation of the two Community Code Directives, 2001/83/EC on human use products and 2001/82/EC on veterinary use products, and in some respects also of the new EMEA Regulation. 1. medicinal product This term now clearly includes new therapies and the growing number of so-called “borderline” products between the medicinal product sector and others.6 The intended broadening of the new medicinal product definition by the Code Amendment Directive is achieved by the following rewording (with changes in italics): a medicinal product is “any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or any substance or combination of substances which may be used in or administered to human beings with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological, or metabolic action, or to making a medical diagnosis.” The Code Amendment Directive explains in its preamble that, based upon “the emergence of new therapies and of the growing number of ‘borderline’ products between the medicinal product sector and other sectors, the definition of ‘medicinal product’ should be modified so as to avoid any doubt as to the applicable legislation” when a product fully falls within the medicinal product and another regulated product definition. Specifically, “this definition should specify the type of action that the medicinal product may exert on physiological functions” and “[t]his enumeration of actions will also make it possible to cover medicinal products such as gene therapy, radiopharmaceutical products, as well as certain medicinal products for topical use.”7 In a 2003 Commission Directive8 (Dossier Harmonisation Directive) that adopted the International Conference on Harmonisation (ICH) Common Technical Document (CTD), the European Commission had already described additional submission requirements for gene therapy and somatic cell therapy, and now the definition of medicinal product likewise reflects the broader scope. The EU’s amended medicinal product legislation also seeks to accomplish a significant clarification and new legal certainty in product classifications—by creating a presumption in favour of regulating borderline products as medicinal products. Article 2.2 of the Community Code as amended by the Code Amendment Directive states that, “In cases of doubt, where, taking into account all its characteristics, a product may fall within the definition of a ‘medicinal product’ and within the definition of a product covered by other Community legislation [such as the Medical Devices Directive] the provisions of this [Community Code] Directive shall apply.” Thus, in the EU, when a product’s status is in doubt, regulators will default to the more robust regulatory approach for medicinal products to protect the public health. In sum, where a given product falls within the definition of more than one regulatory classification, there is a presumption in favour of handling the product as a medicine, unless the product falls clearly under the definition of other categories (food, food supplements, medical

6 Article 1, Community Code, as amended by the Amendment Directive.

7 Directive 2004/27/EC, recital 7, 2004 OJ L 136 34.

8 Directive 2003/63/EC OJ L 159, 27/6/2003 46-94.


devices, biocides, cosmetics, etc.). Chapter XVII on Borderline and Combination Product Issues provides additional details on the borderline product issue. 2. generic medicinal product This term is defined as “a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies.…..”9 This clarification largely codifies EU case law but will provide greater legal certainty in the application of abridged application procedures for generic medicines. Generics are covered in more detail in Chapter VIII. 3. similar biological medicinal products (“biosimilars”) These products are similar to a reference biological product but do not meet the definition of a generic medicinal product. For biosimilars, the results of “appropriate” preclinical tests or clinical trials must be provided, the type and quantity of supplementary data must comply with the “relevant criteria” for full application and “[t]he results of other tests and trials from the reference medicinal product’s dossier shall not be provided.”10 In the 2003 Dossier Harmonisation Directive,11 EU authorities had begun specifying the data requirements for biosimilars, a process that continues through issuance of guidelines. Biosimilars are discussed in Chapter IX.C.

9 Article 10.2 (b), Code Amendment Directive.

10 Article 1(8), OJ L 136, 30.04.2004, p. 39; new Article 10.4 of the Community Code Directive.

11 Directive 2003/63/EC OJ L 159, 27/6/2003 46 – 94.


Chapter II. EU Medicinal Products Regulation Summarised Every medicinal product needs an approved marketing authorisation application (MAA) in order to be marketed in the EU.12 The marketing authorisation holder (MAH) needs to be established in the EU.13 To gain permission to market a medicine in the EU, the sponsor (applicant) must submit a dossier to the relevant drug regulatory authority for review. The submission includes information on quality, safety and efficacy (i.e., on the chemistry, manufacturing and pharmaceutical aspects of the product as well as the nonclinical and clinical data). The contents of the submission are being increasingly harmonised and vary to some degree depending upon the product’s nature (much less information is needed for a generic version of a well-established product and, typically, much more is needed for a novel biotechnology-derived treatment). In the EU, there are two different authorisation routes for medicines: centralised and decentralised. Under the centralised route, one marketing authorisation is granted for the entire EU while, under the decentralised route, one or more national marketing authorisations are granted. In the centralised system, the application is made to the European Medicines Agency (EMEA), where it is reviewed by the Committee for Human Medicinal Products (CHMP) or, in the case of animal drugs, by the Committee for Veterinary Medicinal Products (CVMP). An EMEA staff member serves as Product Team Leader, but the actual in-depth review is carried out by a rapporteur, assisted by a co-rapporteur, on behalf of the CHMP or the CVMP and EMEA. Various other committees and working parties may play a role (e.g., therapeutic area expert groups and/or the Committee on Orphan Medicinal Products or COMP). In any case, the CHMP as a whole hears from the applicant and the rapporteur and reviews certain documentation and then provides to EMEA and the European Commission its opinion on whether, in light of the product’s safety, quality and efficacy and its overall benefit-risk ratio for its intended use, the product should be granted a marketing authorisation (MA) in the EU. The decision to grant or refuse an authorisation is made by the European Commission; it rarely overturns a decision of the CHMP/EMEA. In circumstances where use of the centralised route is not mandatory, the applicant can nevertheless, in some cases, request its use. EMEA suggests that sponsors of medicinal products wishing to use the optional centralised route send a letter to the agency justifying this request. The law on the mandatory and optional jurisdiction of EMEA has changed, effective 20 November 2005, as a result of the 2004 pharmaceutical review legislation. Under the decentralised route, the applicant selects an EU Member State’s drug regulatory agency to serve as Reference Member State (RMS). The application is then submitted to that agency for review. The applicant decides which EU Member States’ markets are of commercial interest and, in each such Member State—called a Concerned Member State (CMS)—makes a submission seeking mutual recognition of the RMS’ authorisation decision. The EU law governing decentralised approvals changed, effective 30 October 2005, the date on which extensive changes to the EU Community Code on Medicinal Products took effect. A principal aim of the amendments was to improve the functioning of the decentralised procedure, by restricting the ability of CMSs to refuse to grant Mutual Recognition to the RMS’ authorisation. Such disagreements would be forced into a dispute resolution process involving the Mutual Recognition Facilitation Group and possibly also the CNMP or CVMP. The amendments also prevent marketing authorisation applicants from withdrawing their

12 Article 6, Community Code Directive, 2001/83; Article 3, EMEA Regulation 726/2004.

13 Article 8.1 and 16b, Community Code Directive 2001/83, as amended.


applications from national regulatory bodies, thereby avoiding an arbitration process that has been in place for some years (but little used). Whether a product enters the EU market through the centralised or decentralised route, there is a complex array of requirements and guidelines at both the EU and Member State levels dealing with preclinical testing and Good Laboratory Practices (GLPs), clinical testing and Good Clinical Practices (GCPs), Good Manufacturing Practices (GMPs) and related chemistry and manufacturing controls (CMC), inspections, labelling, advertising and promotion, parallel trade, imports, exports and compliance and enforcement. There has been a rapid expansion of law on these subjects at the EU level, with increased harmonisation in many areas. Still, Member State requirements and guidelines remain essential parts of the EU regulatory picture, especially when the EU-level law is a “Directive,” which by its nature is almost entirely dependent upon Member State implementation to have a direct impact on private parties.


Chapter III. Authorisation Procedures for Medicinal Products and Related Issues Under the new EMEA Regulation, EMEA assessment of new medicines will be quicker, enabling new medicinal products to be placed on the Community market faster. The authorisation procedure is changing to oblige more categories of medicines to use the centralised procedure, instead of seeking authorisation first in a “Reference Member State,” then in other Member States, through the decentralised mutual recognition system. Originally, the centralised procedure was mandated only for the authorisation of biotechnology products. Under the new EMEA Regulation, the centralised procedure becomes mandatory also for medicines to treat AIDS, cancer, diabetes, neurodegenerative disorders and orphan diseases. In 2008, the centralised procedure will be further extended to cover medicines for autoimmune and viral diseases. A general review clause will enable further extension of EMEA’s exclusive jurisdiction to medicines for other diseases. Also, provisions giving sponsors the option to request the EMEA centralised procedure have been revamped. Member State review procedures also have been strengthened and improved. A new Decentralised Procedure aims to put teeth into the mutual recognition procedure, forcing Member State regulators who disagree with their counterparts into a harmonisation and/or arbitration process, and barring the applicants from withdrawing an application, in a Member State reluctant to recognise another’s approval, to avoid the risk of having the matter arbitrated. A. Contents of Marketing Authorisation Applications It should be noted that neither the new EMEA Regulation nor the Code Amendment Directives needed to revise fundamentally the important topic of what goes into an application seeking marketing authorisation. Several obligations were added to an already robust application format, e.g. the requirement of a risk management plan14 and an evaluation of environmental risks.15 Legislation on the actual contents of an application for marketing authorisation—the Commission Dossier Harmonisation Directive16—was published in June 2003, midway between the publication of the Community Code in November 2001, which is modified, and the new revisions to the Code Amendment Directive published 30 April 2004. Importantly, the Dossier Harmonisation Directive brought into full force in the EU the International Conference on Harmonisation (ICH) Common Technical Document (CTD).17 This Annex and its harmonised dossier apply to both centralised and decentralised processes and to applications of all types (full, abridged, etc.). Also, the Dossier Harmonisation Directive contains significant provisions on biological medicinal products, e.g., biosimilars, blood products and gene or somatic cell therapy. The new legislation has required the European Commission in cooperation with EMEA and Member State authorities to revise the Notice to Applicants—Medicinal Products for Human Use (NtA). The Dossier Harmonisation Directive explicitly refers to, and makes mandatory, Volume 2B of the NtA: “The particulars and documents accompanying an application for marketing authorisation… shall be presented in accordance with the requirements set out in this Annex and shall follow the guidance published by the Commission in the rules governing medicinal

14 Article 8.3 (ia).

15 Article 8.3 (ca).

16 Dossier Harmonisation Directive, 2003/63/EC 25 June 2003, (1), L159/52.

17 EMEA, CPMP/ICH/2887/99 Rev. 2—Topic M4; Common Technical Document for the Registration of Pharmaceuticals for Human Use, 20

Nov. 2003.


products in the European Community, Volume 2B, Notice to applicants, Medicinal products for human use, presentation and content of the dossier, Common Technical Document (CTD).”18 Accordingly, the revisions of the NtA will need to be carefully monitored by regulatory affairs professionals. Although the NtA itself is described as having only the legal status of a guideline (see chapter III.L. below on the EMEA guidelines procedure), the Dossier Harmonisation Directive makes its Volume 2B a binding rule. Also, the NtA’s contents restate and summarise various legal requirements in a comprehensive manner, along with nonbinding guidance. Thus, the NtA is a valuable resource and reference tool but needs to be read with an eye toward differentiating that which is required from that which is only recommended. Under the CTD as implemented in the Dossier Harmonisation Directive and Volume 2B of the NtA, there are five key modules:19

Module 1, European Community Administrative Information (Annex, Part I)

o 1.1 Table of contents

o 1.2 Application form

o 1.3 Summary of Product Characteristics,20 labelling and package insert and mock-ups and specimens

o 1.4 Information about the experts whose reports are found in other Modules

o 1.5 Specific requirements for different types of applications (Annex Part II)

o 1.6 Environmental risk assessment (where relevant, applications shall include a

risk assessment overview evaluating possible risks to the environment due to the use and/or disposal of the medicinal product and make proposals for appropriate labelling provisions)21

Module 2, quality, nonclinical and clinical summaries

o 2.1 Table of contents o 2.2 Introduction

o 2.3 Quality overall summary

o 2.4 Nonclinical overview

18 Dossier Harmonisation Directive, 2003/63/EC 25 June 2003, (1), L159/52.

19 2003/63/EC (2).

20 The summary of product characteristics is an important EU regulatory document that, among other things, defines what claims can be made

about the product in marketing it to health professionals. See Chapter XX. This book reserves the acronym “SPC” for the Supplementary

Protection Certificate, extending a drug’s patent term, discussed in Chapter VIII.H. The reader should be aware that the “summary of product

characteristics” is sometimes also referred to as the “SPC” or sometimes “SmPC” for “summary of medicinal product characteristics.”

21 Environmental risk associated with the release of medicinal products containing or consisting of genetically modified organisms (GMOs)

within the meaning of Directive 2001/18/EC of 12 March 2001 shall be addressed. Additional details are provided in this section of the Annex as

set forth in the Dossier Harmonisation Directive.


o 2.5 Clinical overview

o 2.6 Nonclinical summary

o 2.7 Clinical summary

Module 3, chemical, pharmaceutical and biological information

o 3.1 Format and presentation (a detailed outline is set forth in the Annex)

o 3.2 Basic principles and requirements (considerable detail is required on ingredients and finished dosage form, relevance of European Pharmacopoeia, good manufacturing practices, products of animal origin, risks from adventitious agents, “where applicable…a CE marking which is required by Community legislation on medical devices,”22 manufacturing process and composition of the active substances and finished medicinal products, excipients, etc.).

Module 4, Nonclinical reports

o 4.1 Format and presentation (table of contents; study reports on pharmacology, pharmacokinetics, toxicology, genotoxicity, carcinogenicity, reproductive and developmental toxicity, local tolerance, antigenicity, immunotoxicity, dependence, metabolites, impurities, etc.; literature references)

o 4.2 Content: the basic principles and requirements (considerable detail is

provided as to each type of toxicity and other information)

Module 5, clinical study reports

o 5.1 Format and presentation

o 5.2 Content: basic principles and requirements

o “The clinical particulars to be provided …must enable a sufficiently well-founded and scientifically valid opinion to be formed as to whether the medicinal product satisfies the criteria governing the granting of a marketing authorisation.”23 Clinical studies must always be preceded by animal studies.24

Records retention requirements are specified, e.g., for at least 15 years after the discontinuation of the clinical trial.25

For each clinical trial, the protocol, audit certificates if available, lists of

investigators, and signed investigator reports must be included.26

22 2003/63/EC Annex at 3.2(11). See Chapter XVII on borderline and combination products.

23 2003/63/EC Annex at 5.2 a).

24 2003/63/EC Annex at 5.2 b).

25 2003/63/EC Annex at 5.2 c).

26 2003/63/EC Annex at 5.2 d)-j).


Reports of biopharmaceutical studies, e.g., bioavailability and

bioequivalence, shall be provided27 as well as of controlled clinical studies: “randomised and as appropriate versus placebo and versus an established medicinal product of proven therapeutic value”28.

As indicated, often a three-arm controlled clinical trial is required with a clinical trial design that includes a placebo arm and a product of “proven therapeutic value.” The CTD presentation is applicable to all types of marketing authorisation applications whether for the centralised, mutual recognition or national procedures and whether an application is full or abridged. It also is applicable regardless of the product types, including new chemical entities, radiopharmaceuticals, plasma derivatives, vaccines, herbal medicinal products, etc.29 In assembling the dossier for an application for marketing authorisation, the applicant also needs to take into account relevant scientific guidelines from the Commission and the EMEA CHMP, European Pharmacopoeia monographs and other documents and EU good manufacturing practice requirements.30 The application must include all information relevant to the evaluation, whether favourable or unfavourable to the product, including in particular, all relevant details about any incomplete or abandoned preclinical or clinical tests whether or not for an indication covered by the application.31 Clinical trials whose results are reported must have been carried out in accordance with the Clinical Trials Directive32 and applicable Member State laws or (if conducted outside the EU) in accord with good clinical practices and ethical principles equivalent to that Directive, e.g., the Declaration of Helsinki.33 Animal tests must have been conducted in accordance with good laboratory practices34and animal protection laws.35 Any new information not in the original application and all pharmacovigilance information shall be submitted to the Competent Authority, and variations shall be submitted in accordance with the relevant regulations,36 national requirements and Volume 9 of the NtA.37 As set forth in the Dossier Harmonisation Directive,38 the Annex to the Community Code Directive is divided into four parts:

Part I, application format, the Summary of Product Characteristics, the labelling, the leaflet and presentation requirements for standard applications (Modules 1 to 5)

Part II, derogations (exceptions) for “Specific applications,” i.e., well-established

medicinal use, essentially similar products, mixed applications (part bibliographic and

27 2003/63/EC Annex at 5.2.1-5.2.5.

28 2003/63/EC Annex at 5.2.5.

29 2003/63/EC Annex (3).

30 2003/63/EC Annex (4)-(6).

31 2003/63/EC Annex (7).

32 2001/20/EC. See Chapter V. 33 2003/63/EC Annex (8).

34 2003/63/EC Annex (9), citing Council Directive 87/18/EC and 88/320EEC.

35 2003/63/EC Annex (10), citing Council Directive 86/609/EEC of 24 November 1986.

36 Commission Regulations (EC) 1084/2003 or 1085/2003. See Chapter VII.A.

37 2003/63/EC Annex (11).

38 2003/63/EC Annex at L 159/53.


part the applicant’s own studies),39 similar biological products,40 fixed combinations41 and “exceptional circumstances” relating to conditional authorisations42

Part III, “Particular application requirements” for biological medicinal products (Plasma

Master File, Vaccine Antigen Master File),43 radiopharmaceuticals,44 homeopathic medicinal products, herbal medicinal products45 and orphan medicinal products46

Part IV, “Advanced therapy medicinal products” such as gene therapy medicinal

products (using human autologous or allogeneic system or xenogeneic system) and cell therapy products, both of human or animal origin, and xenogeneic transplantation medicinal products.47

Labelling is also a key part of any application for marketing authorisation. The Community Code on Medicinal Products as well as the NtA and other Commission and EMEA guidelines spell out in great detail what is required for labelling, including the package leaflet for patients.48 B. Period of marketing authorisation validity. Effective 30 October 2005, market authorisations by EMEA or the Member States are valid for an initial five-year period. Then, following that period, market authorisations are unlimited, unless pharmacovigilance leads Competent Authorities to impose an additional five-year renewal requirement.49 The trade-off for this provision replacing the previous five-year term of marketing authorisations was stricter pharmacovigilance rules, as discussed in Chapter VII.E. The revisions to the Community Code also prescribe a “sunset” provision for an authorisation for a product not placed on the market within three years or not used for three consecutive years.50 Therefore, information about the exact product launch date must be submitted to EMEA or the relevant Member State drug regulatory authorities.51 There is also a requirement to inform EMEA or other authorities when a product ceases to be placed on the market.52 EU authorities have issued guidance on these provisions:

39 See chapter VIII on generic products for details on certain of these applications.

40 Details are provided in the Annex in Part II.4. See Chapter IX.C. on marketing authorisations for biosimilar products.

41 Details are provided in the Annex in Part II.5.

42 Annex, Part II.6, which implements Article 22 of the Community Code Directive 2001/83 on conditional marketing authorisations, states that

a marketing authorisation can be granted subject to specific obligations (e.g., post-marketing studies, limiting a product to prescription use-only

or use only under strict supervision, or special labeling alerting the medical practitioners that “the particulars available concerning the medicinal

product in question are as yet inadequate in certain specified respects”).

43 See chapter IX on marketing authorisations for products derived from biotechnology.

44 Details are provided in the Annex in Part II.2.1-2.2.

45 Details are provided in the Annex in Part II.4. See Chapter III.H. on herbal medicinal products.

46 Details are provided in the Annex in Part II.5. See Chapter XII on orphan medicinal products.

47 Details are provided in the Annex in Part IV. See Chapter XI on regulation of advanced therapies.

48 Articles 59-69 of the Community Code on Medicinal Products 2001/83, as amended by the Code Amendment Directive 2004/27.

49 Article 24, Community Code, as amended by Code Amendment Directive.

50 Article 23a, Community Code, as amended by Code Amendment Directive.

51 Article 23a, Community Code Directive 2001/83 as amended by the Code Amendment Directive 2004/27; Article 13(4), EMEA Regulation

726/2004.

52 Id.


European Commission, Application of the “Sunset Clause” in the Review of the

Pharmaceuticals Legislation to Medicinal Products Authorised Before Directives 2004/27 and 2004/28 and Regulation 726/2004, effective 3 October 2005.

EMEA, Draft Post-Authorisation Guidance, Human Medicinal Products, Questions and

Answers on Application of the “Sunset Clause” to Centrally Authorised Medicinal Products, EMEA/180079, 13 October 2005.

EMEA, Draft Post-Authorisation Guidance, Human Medicinal Products, Questions and

Answers on Notification to the EMEA of Actual Marketing and Cessation of Placing on the Market for Centrally Authorised Products, EMEA/180078, 13 October 2005.

C. EMEA jurisdiction 1. Mandatory jurisdiction An Annex to the new EMEA Regulation 726/2004 lists products subject to the agency’s mandatory jurisdiction. The following classes of products may enter the EU market only through the EMEA centralised review procedure:

As required already: Biotechnology products

Amended: Orphan medicinal products (under the new EMEA Regulation, all orphan medicines must go through EMEA and the centralised review process; before, orphan medicines’ sponsors were given the option to elect the centralised procedure, and most did)

New: Medicinal products containing a new active substance for:

o Acquired Immune Deficiency Syndrome (HIV/AIDS)

o Cancer

o Neurodegenerative disorders

o Diabetes

The scope of EMEA review authority will expand again on 20 May 2008 to require manufacturers of medicines for the following conditions to use only the EMEA centralised process:

Auto-immune diseases

Other immune dysfunctions

Viral diseases Furthermore, the legislation mentions the possibility of further extending the list of products subject to mandatory centralised review. This was a compromise between the European


Commission, on the one hand, and the Member States and industry on the other. The Commission had proposed that all new chemical entities be required to use the EMEA centralised process, as has already been required for all new biotech products, and as had worked well during the first decade of EMEA’s operation. Member States were concerned about further erosion of their approval function, while the pharmaceutical industry argued for “full optionality” to enable manufacturers to use Member State approval processes if that is their preference in a given case. The approach of listing products/disease categories for which EMEA would have exclusive review authority was designed as a middle ground. The categories selected are ones for which the centralised procedure had already become dominant. (Indeed, by 2005, some 70% of new pharmaceutical entities reaching the EU market arrived via the centralised process.) To provide additional guidance concerning the scope of the centralised procedure, on 1 June 2005, EMEA issued for public comment a draft guideline53 defining which products must use that procedure as of 20 November 2005. The products that, in addition to biotechnology and orphan products, fall under what is called the "mandatory scope" comprise the four initial therapeutic classes listed earlier and generally will be for the treatment, rather than the prevention, of disease. 2. Optional jurisdiction. As noted above, an Annex to the new EMEA Regulation (EC) No. 726/2004 lists the categories of products subject to EMEA’s newly expanded mandatory jurisdiction. While, under the original EMEA Regulation, the annex also dealt with new chemical entities for which EMEA review was an option for the sponsor but not required (the “Part B list”), from 20 November, 2005 the Part B list no longer exists. Article 3 of the new EMEA Regulation will determine whether EMEA may accept applications for other products where its jurisdiction is not mandatory. The optional jurisdiction categories are:

any product not specifically listed in the Annex (regardless of disease class), if it contains a new active substance not authorised in the EU

any product not listed in the Annex if “the applicant shows that the medicinal product

constitutes a significant therapeutic, scientific or technical innovation or that the granting of authorisation in accordance with the Regulation is in the interests of patients…at Community level.”

D. Decentralised authorisations/Mutual Recognition Procedure (MRP) Effective 30 October 2005, a new decentralised approach applies to all marketing authorisations issued on or after that date that are not authorised through the mandatory centralised procedure. It is not possible for a pharmaceutical company to apply for a product to be authorised by more than one Member State without using either the EMEA centralised process or the newly decentralised MRP.54 The Code Amendment Directive makes extensive changes in the Community Code to address problems in the MRP.

53 EMEA/180921/2005.

54 Articles 17.2, 18, Community Code Directive 2001/83 as amended.


The Mutual Recognition Facilitation Group (MRFG) of Member State regulators now has official status as the “Coordination Group.”55

Under the MRP, an original national marketing authorisation (MA) granted by the Reference

Member State (RMS) is the subject of an application for Mutual Recognition to one or more other Member States (these are referred to as “Concerned Member States” or CMSs).

Parallel applications in all Concerned Member States are possible. However, the applicant is not required to file an application in all Member States, i.e.,

previous law providing the flexibility under the decentralised procedure to pick and choose Member States remains unaffected.56

As for the MRP, the RMS drafts the assessment report, the Summary of Product

Characteristics and the patient information leaflet. The RMS then forwards these documents to the CMSs for the consultation process. Arbitration is now compulsory if one or more CMSs does not grant authorisation, “in specific

cases where the interests of the [European] Community are involved”.57 The disagreement will be referred to the MRFG, which makes its “best endeavours” to reach an agreement within 60 days. If agreement is not reached, the matter is referred to EMEA and its CHMP.

Under the prior law, applicants sometimes withdrew applications under these circumstances

rather than go through arbitration. This is no longer permitted. Once an applicant has selected a CMS, the applicant can no longer withdraw the

application. In other words, the new statute does not permit withdrawals by manufacturers in case of a

CMS’s objection. Non-objecting countries can “provisionally” authorise the product, under Article 29 (6). Under Article 30, “divergent decision referrals,” the CHMP arbitrates divergent decisions on

authorisations while the MRFG prepares an annual list of proposed medicinal products for which harmonisation of the summary of product characteristics is necessary.

Member States, the Commission, and industry can nominate candidates for the

harmonisation list. For Article 31, “Community interest referrals,” special provisions are made for participation

by the Marketing Authorisation holder in the proceeding.

55 Article 27, Community Code Directive 2001/83, as amended by Code Amendment Directive 2004/27.

56 Article 28, Community Code, as amended. However, once an application is filed, it may not be withdrawn, as is discussed in the text. Also,

under new Article 126a, a Member State may authorise a product even if such authorisation was not requested by the sponsor.



After the CHMP makes a reasoned decision,58 the Commission issues a decision on the matter.59.

The decentralised MRP process for veterinary medicinal products is almost identical to that for medicinal products for human use and is discussed in Chapter XVII.D. The grounds for a CMS to object to mutual recognition of an authorisation granted by a RMS are a “potential serious public health risk.”60 In an effort to prevent over-reliance on this provision, and to make the MRP process more effective, Article 29(2) of the 2004 Code Amendment Directive calls on the Commission to adopt a guideline defining “potential serious risk to public health.” A draft proposal was published on the Commission’s website for comment on 22 February 2005. The draft proposed Guideline on the definition of a potential serious risk to public health takes as a starting place the definition of “risk” in Article 1(28, first indent) of the Community Code Directive and states that a “potential serious risk to public health” is where there is a high probability that a serious hazard could result in severe negative effects with regard to the use of the human medicinal product that cannot be presented, reversed or avoided.”61 As is evident, the intended threshold is quite high and other details indicate that the European Commission expects Member States to recognise one another’s authorisations. Also, Member States may not object to a product authorised in another Member State on the basis of its labelling.62 The Community Code as amended along with the new EMEA Regulation expands the power of the EMEA to order safety measures even as to products originally approved through national procedures.63 It remains to be seen whether, under the new legislation, the decision of the European Court of Justice (ECJ) in the Anorectics Case64 has continued vitality to limit the ability of the European Commission to intervene in Member State authorisation decisions. In that case, the Commission had ordered Member States to withdraw the national marketing authorisations of an entire category of medicinal products containing anorectic substances, i.e., diet drugs. The Commission based its request upon its responsibility to protect public health in the single market, notwithstanding the responsibilities of the individual Member States for the national marketing authorisations. Thus, the EU Commission based its action not on “Community interest referrals” but on “protection of public health interests.” In its 24 July 2003 judgment, the ECJ annulled the Commission’s action on the grounds that, where a marketing authorisation was “granted purely under national procedures,” the European Commission was not legally entitled to make a decision of withdrawal on grounds of “public health interests.” The case called into question the legality of the Commission’s “forced harmonisation” efforts, in which the Commission had cited Articles 30 and 31 of the Community Code to force the harmonisation of Summaries of Product Characteristics for products that had gone through the national approval process, emerging with differing Summaries depending upon the Member State.

58 Article 32, Community Code Directive, 2001/83 as amended.

59 Articles 33 and 34, Community Code Directive 2001/83, as amended.


61 Proposal, page 3.

62 Article 60, Community Code Directive 2001/83, as amended.

63 See articles 33, 34 and 127a, Community Code Directive 2001/83, as amended.

64 Commission of the European Communities v. Artegodan and others. C-39/03, ECR 2003; I-07885 (ECJ 2003).


The new 2004 legislation increases the authority of the European Commission to request a Member State to take urgent safety measures. It is unclear that this new authority will overcome the ECJ’s holding in the Anorectics Case. E. Accelerated product availability and access to medicines 1. Tighter timeframes and “fast track” Review timeframes have been shortened. An accelerated authorisation process is provided for products of significant therapeutic interest under EMEA’s centralised procedure: the review period of 210 days has been shortened to 150 days.65 As before, the clock stops while EMEA is awaiting a sponsor’s reply to an agency request. EMEA is developing a guideline on the procedure for accelerated assessment. Member States still have 210 days to act on applications submitted under the decentralised procedure.66 An August 2005 Note to Applicants describes how the tighter time frames will apply to products going through the centralised procedure.67 2. Conditional marketing authorisation A conditional marketing authorisation is possible in certain cases for important therapies, under the EMEA centralised procedure.68 This process is analogous to the FDA’s accelerated approval process and is not to be confused with the authority of the EMEA or Member State drug regulatory authority to authorise products subject to “conditions to authorisation.” Where a conditional marketing authorisation is granted, a renewable one-year authorisation may be available, provided there is an important expected health benefit for the patients concerned and the company agrees to carry out additional monitoring and clinical studies, which will be reviewed at the end of the year. Conditional authorisations are also possible under the Community Code Directive.69 In late 2004, the European Commission issued a draft Regulation70 explaining how pharmaceutical companies can apply for a conditional marketing authorisation under the new EMEA Regulation. Products eligible for the procedure are those for the treatment, prevention or diagnosis of chronically or seriously debilitating diseases; orphan medicines; and those for use in emergency situations or in response to public health threats recognised by the World Health Organisation or EU institutions. A company may apply for a conditional authorisation either when it submits its application for authorisation or during the assessment procedure. Any such request shall be made publicly available. The applicant must provide detailed justification for the use of the procedure, i.e., that a conditional approval is in the public interest and that the presumed benefit-risk ratio of the product is favourable, based upon scientific evidence, pending the completion of additional studies. The sponsor also must supply quality and nonclinical safety data.

65 Article 14.9, New EMEA Regulation, Reg. 726/2004; Article 22, Community Code Directive 2001/83 as amended by code Amendment

Directive 2004/27.

66 Article 17, Community Code Directive 2001/83 as amended.

67 Note to Applicants, Implementation Review 2001, Linguistic review process and decision making phase – implementation of Article 10 of

Regulation (EC) No 726/2004.

68 Article 14.8, New EMEA Regulation Reg. 726/2004.

69 Article 22, Community Code Directive 2001/83 as amended.

70 Draft Commission Regulation (EC) No. …/…of […] on the conditional marketing authorisation for medicinal products falling within the

scope of Regulation (EC) No 726/2004 of the European Parliament and the Council of 31 March 2004.


Another requirement is that the sponsor continue and complete all studies underway or conduct new ones to demonstrate the product’s positive benefit-risk profile. The conditional marketing authorisation would contain a statement concerning the specific obligations and timeframes that comprise the conditions to the authorisation. Products marketed through the conditional approval mechanism must contain information to this effect in their labelling. The term of a conditional authorisation would be one year, on a renewable basis. If the company wishes to extend this period, it must apply for renewal. The CHMP would assess the application and decide whether the conditions have been met or need to be modified. The CHMP also will review the specific obligations and timeframe for their completion annually and make the results of its review public. If the CHMP believes commitments have been met, it may proceed to issue an opinion on the marketing authorisation itself; indeed, the CHMP can take this step anytime during the conditional authorisation period. Once the CHMP has issued an opinion, the normal procedure applies and ordinarily the European Commission will issue a marketing authorisation decision. The CHMP will prepare guidelines on the operation of the new Conditional Authorisations Regulation after it has been adopted. 3. Compassionate use A European-wide system to make medicinal products available prior to authorisation for a “compassionate use” will also be possible.71 This will help ensure that certain patients―those with a chronically or seriously debilitating disease or whose disease is considered to be life-threatening, and who cannot be treated satisfactorily by an authorised product―are allowed access to products still undergoing investigation. This provision will be particularly helpful where no clinical trials of the product are being performed in the country in which a patient lives. The new pan-EU system makes medicines available in advance of authorisation for “compassionate use,” provided that:

An application for MA has been filed

A clinical trial is underway EMEA is preparing a guideline on compassionate use in the European Community.72 Although responsibility to allow compassionate use lies with Member State authorities, it is possible to obtain a CHMP opinion supporting such use. The company seeking a means to make products available on a compassionate use basis, pending authorisation, must take steps to ensure supply to those patients participating in the plan, between the granting of the marketing authorisation and the actual placement of the product on the market. The legislation does not disturb named-patient sales under the Community Code Directive or various Member State laws.73 4. Response to emergencies Member States may temporarily authorise the distribution of an unauthorised medicinal product in response to a suspected or confirmed spread of pathogenic agents, toxins, chemical agents

71 Article 83, New EMEA Regulation 726/2004; EMEA/D/936/04/Final; EMEA/H/34163/03/Rev 2.0.

72 EMEA/CHMP/5579/04.

73 Article 5.1, Community Code on Medicinal Products Directive 2001/83, as amended.


or nuclear radiation any of which could cause harm.74 Marketing authorisation holders, manufacturers and health professionals would be shielded from civil or administrative liability for any consequences resulting from the use of a medicinal product for other than the authorised indications or from the use of an unauthorised medicinal product, when the use is recommended or required by a competent authority in response to the suspected or confirmed spread of pathogenic agents or nuclear radiation that could cause harm.75 Marketing authorisation holders or manufacturers still would be liable if the products in question are defective.76 5. Single Market Authorisation: “Cyprus Clause” This Single Market Authorisation provision states that, even if a pharmaceutical company has not submitted a marketing authorisation application to a Member State, that Member State may authorise the product on its market on the basis of an authorisation by another EU Member.77 In these cases, the Member State shall notify the marketing authorisation holder and may request a copy of the assessment report and the marketing authorisation. This provision is a source of concern in industry. A myriad of questions about the marketing authorisation provisions of the new laws confound regulators and industry. Here are just a few. 1. How will conditional authorisations work? See Chapter III.E.2. 2. Will recent controversies over drug safety affect implementation of this

provision? 3. Are Member State authorities justified in their insistence that sponsors update

their authorisations once more, despite the new provision that could be interpreted as applying just one five-year renewal (in most cases) immediately after the initial authorisation? See Chapter VII.D.

4. Is industry justified in its concern that this process will enable each

affected Member State to make burdensome and unnecessary data requests that might jeopardise continued marketing of products, where a company decides that the benefits of continued authorisation would not justify the expense of answering the regulatory demands?

5. How will the new requirement that certain information on the outer package

appear in Braille work in practice? 6. How will authorities and companies deal with the Single Market Authorisation,

also known as the “Cyprus Clause?” See Chapter III.E.5.

74 Article 5.2.

75 Article 5.3.

76 Article 5.4.

77 New Article 126a, Community Code Directive 2001/83, as amended by Code Amendment Directive 2004/27.


F. Marketing authorisations for generics This topic is covered in more detail in chapter VIII. G. Marketing authorisations for biosimilars This topic is covered in more detail in chapter IX.C. For purposes of the current discussion, it is important to note that the European Commission has stated that, within the EU, only EMEA has authority to assess applications for biotechnology-derived applications, whether these are original applications or for biosimilars. H. Traditional herbal medicinal products and homeopathic medicines 1. Herbal medicines The Herbal Medicinals Directive 2004/24/EC provides a simplified registration procedure for traditional herbal medicinal products requiring fulfilment of European standards of quality, safety and efficacy.78 This harmonised procedure is aimed at safeguarding public health while ensuring free product movement in the EU market. The Directive enacts a new legislative framework for traditional herbal medicines. The Community Code had dealt already with well-established herbal medicines, some supported with modern clinical trials. Under the amendments to the Community Code effected by the new Herbal Medicinals Directive, there also will be a complementary category of herbal medicines that have been in traditional use. This legislation is not meant to affect the use of plants in other product categories. The possibility for plants to be used in foods and food supplements continues to exist, depending upon EU Member States’ national legislation. According to an EU parliamentary report, there may be future harmonisation of food and food supplement herbal plant use via an amendment to the EU Food Supplement Directive or a regulation on food fortification. Herbal medicines are widely used in a few large Member States. It is estimated that Germany and France comprise up to 75% of the European market for herbal medicines. Indeed, in Germany, 30% of all OTC drugs are herbals. The new Directive treats certain herbal remedy classes as drugs rather than food supplements. When the legislation is fully implemented, no herbal medicinal product may be placed on the market unless a market authorisation has been issued. Monographs will be prepared to simplify the process. Other herbal products, referred to as "borderline" products or food supplements, remain unregulated at the EU level but are in many cases subject to highly divergent Member State laws. However, only those herbal “remedies" that have complied with medicinal product requirements may make medicinal claims on their packages. There also are advertising restrictions. In order to receive market authorisation in EU Member States, herbal medicinal product manufacturers are required to provide extensive product safety, efficacy and quality data. A dossier included in the marketing authorisation application details the finished product’s composition and manufacturing processes, as well as a report on how starting materials, intermediate and finished products are controlled. Stability information also is required on active substances and the finished product.

78 Articles 16a through 16i of Community Code Directive, 2001/83 as amended by Directive 2004/24.


Herbal products must be produced under GMPs and meet expected quality levels as to the purity, content and other properties of the substances used. For new herbal substances, clinical trials will be required. The key EMEA documents to date on herbal medicines are:

Rules of procedure for the new EMEA Committee on Herbal Medicinal Products (HMPC)79

Guideline on the documentation to be submitted for inclusion into the list of herbal

substances, preparations and combinations thereof80

Structure of the list of herbal substances, preparations and combinations thereof81

Timetable for the finalisation of a Community herbal monograph82

Procedure for the preparation of community monographs for traditional herbal medicinal products83

Procedure for the preparation of community monographs for traditional herbal medicinal

products with well established medicinal use,84 which sets forth a somewhat abridged procedure for these products, as compared with the latter document

The Procedure for the preparation of community monographs for traditional herbal medicinal products describes the content of each Community monograph for traditional herbal medicinal products containing herbal substance/herbal preparation. The title of each monograph would refer to the plant’s botanical name according to the binomial system, followed, in brackets, by the plant part. The headings of each section of a monograph would be:

medicinal product name

qualitative and quantitative composition

pharmaceutical form

clinical particulars (including therapeutic indications, posology and method of administration, contraindications, special warnings and precautions for use, interaction with other medicinal products and other forms of interaction, pregnancy and lactation, effects of ability to drive and use machines, undesirable effects and information about overdoses)

pharmacological properties

79 EMEA/HMPC/139800/2004.

80 EMEA/HMPC/107399/2005.

81 EMEA/HMPC/100824/2005.

82 EMEA/HMPC/126542/2005.

83 EMEA/HMPC/182320/2005 (15 July 2005).

84 EMEA/HMPC/182352/2005 (15 July 2005).


date of compilation The herbal medicines legislation was somewhat overshadowed by the new EMEA Regulation and the Code Amendment Directives. Nevertheless, a number of interesting issues arose during its parliamentary consideration: the composition of a traditional herbal medicine, the acceptance of non-EU tradition, the mutual recognition of a traditional herbal medicine, labelling and advertising requirements, the role of the new HMPC and the transitional arrangements. 1. Concerning the composition of a traditional herbal medicine:

a. There is no legal barrier at the EU level to the combination of herbal plants with vitamin or mineral food supplements; national laws might restrict such combinations, however, unless and until there is EU harmonising legislation.

b. Similarly, there is no legal barrier at the EU level to the combination of herbal plants with

medicines; again, national laws might restrict such combinations unless and until there is EU harmonising legislation.

c. By July 2007, the European Commission will present a report on the advisability of

including additional categories of substances in the existing legal provisions for food supplements. This will possibly be combined with a proposal for broader legislation that might include categories such as herbals, amino acids and fatty acids. Until that time, the national legal provisions continue to prevail. Provided that the relevant legal provisions are respected, this will allow the use of plants in medicines as well as in food and, respectively, food supplements.

2. A particularly sensitive topic was the acceptance of non-European tradition when deciding

on the status of traditional herbal medicinal products. It was decided that, ordinarily, products would be expected to have at least 15 years of traditional use outside the European Community, with the possibility of considering, on an exception basis, an application for a product with less than 15 years of use in the Community. After an application for a traditional use registration has been submitted, Member States may refer such an application to the HMPC. The HMPC would consider the relevant documentation and decide whether to establish a community herbal monograph, which then would allow acceptance in national markets. This was the compromise following a difficult debate and will ensure an open attitude toward tradition from outside the EU while applying the general EU quality, safety and efficacy standards established for this kind of medicine.

3. The European Commission originally proposed that applications for traditional herbal

medicines look primarily for national authorisations only. However, the European Parliament insisted on the possibility of mutual recognition by other Member States for this kind of product and gave EMEA a significant harmonisation role in developing community monographs. The final legislation foresees mutual recognition for all products that are covered by a community monograph and by an official list of herbal substances.

4. Contrary to the European Commission’s original proposal advocating a quite negative

disclaimer, the final legislation now requires a statement on the labelling and in advertising that the product is for use for the specified indication, based exclusively upon long-standing use. This was viewed as an appropriate reflection of the reality and as a means to allow consumers to have the necessary background information on the product concerned.


5. Compared to the European Commission’s original proposal, which gave the HMPC very

limited responsibilities, the final legislation assigned this committee an important role in evaluating and assessing herbal medicinal products and gave it more independence. One important task of the HMPC is to make the final judgment in any arbitration process in cases where a mutual recognition procedure between EU Member States could not be finalised successfully.

6. The Directive provides for a seven-year transition period, to allow manufacturers to take

steps toward compliance. 2. Homeopathic medicines Homeopathic medicines are generally subject to many of the same controls as other medicinal products, under the Community Code Directive, as amended by the Code Amendment Directive.85 An exception is that a simplified marketing authorisation approach is prescribed for homeopathic medicines under Articles 14 and 15 of this legislation.86 On 12 May 2005, the European Court of Justice issued a preliminary ruling, in a case referred by Germany, concerning these provisions of the Community Code Directive.87 German regulators had dismissed an application to register a homeopathic medicinal product submitted by Meta Fackler KG. German law included provisions barring use of the special simplified registration procedure for a medicinal product composed of several known homeopathic substances, where its use as a homeopathic medicinal product is not generally known. The Court ruled that Articles 14 and 15 of Directive 2001/83/EC on the Community Code must be interpreted as precluding such national provisions. Another recent case barring Member States from imposing additional controls on imported homeopathic medicines as well as other imported medicinal products is Commission v. France, discussed below in Chapter XIV. I. Radiopharmaceuticals and related products The Community Code Directive, as amended by the Code Amendment Directive, applies special controls to radiopharmaceuticals. In some cases the controls are more stringent, while in others these products are exempted from requirements that apply to medicines in general.88 J. Provisions giving marketing authorisation holders additional flexibility Co-marketing is permissible.89 Some Member States had, in the past, restricted this

practice.

85 See, e.g., Articles 53, 68, 69, 85 and 119 of the Community Code Directive, 2001/83, as amended by the Code Amendment Directive 2004/27.

86 Articles 13-16, 39 of the Community Code Directive, 2001/83, as amended by the Code Amendment Directive 2004/27.

87 C-444/03: Reference for a preliminary ruling from the Verwaltungsgericht Berlin Meta Fackler KG v Bundesrepublik Deutschland, May 12,

2005 (Medicinal products for human use — Homeopathic medicinal products — National provision excluding from the special, simplified

registration procedure a medicinal product composed of known homeopathic substances if its use as a homeopathic medicinal product is not

generally known) (OJ, C 182, July 25, 2005, p. 11).

88 See, e.g., Articles 6.2, 7, 9, 66, and 67.

89 Article 2, EMEA Regulation 726/2004; Article 6.1a, Community Code Directive 2001/83, as amended by Code Amendment Directive

2004/27.


EMEA had allowed only one brand name, for use throughout the EU, for the same centrally authorised product. This policy has been controversial and, in some cases, has deterred use of the centralised procedure. Although the new EMEA Regulation continues the single trade name policy for centrally-authorised medicinal products as a general rule, it also specifically allows for exceptions related to trademark law.90

The EMEA Regulation authorises several measures to assist Small or Medium-Sized

Enterprises (SMEs):91

o fee reduction or deferment92 o document translation o other administrative assistance

K. Patient information The new legislation includes important additions to existing labelling and packaging requirements:

o An obligation for marketing authorisation applicants to conduct “user testing” of patient information leaflets93

o A requirement that certain information be in Braille in the labelling on the outer packs of

medicines94 When the pharmaceutical review legislation was under consideration, the issue of information for patients was controversial. The European Commission proposed opening channels of communication, to some degree, between pharmaceutical companies and patients. The proposal was endorsed by industry but opposed by consumer groups and key European parliamentarians. The notion that the Commission’s proposal might lead to arrival in Europe of US-style direct-to-consumer advertising was disturbing to opponents of the Commission’s proposal. The European Commission insisted that its proposal should not be objectionable. It wanted a way for manufacturers to respond to requests from patients for information about products for chronic diseases like AIDS, asthma and diabetes and pointed out that the process would be supervised by EMEA. The Parliament was unpersuaded, and the European

90 Article 6.1, EMEA Regulation 726/2004.

91 Article 70(2), EMEA Regulation 726/2004. 92 See also European Commission, Provisions for Micro, Small and Medium-Sized Enterprises (SMEs), Establishing the Circumstances in Which SMEs May Pay Reduced Fees, Defer Payment of the Fee, or Receive Administrative Assistance. October 2004. 93 Articles 59 (3) and 61(1) of Community Code Directive 2001/83/EC as amended by Code Amendment Directive 2004/27/EC. In August 2005,

the European Commission published draft “Guidance concerning consultations with target patient groups for the package leaflet.” On 20 October

2005, EMEA published an Operational Procedure, EMEA/277378/2005, on Handling of “Consultations with target patient groups” on Package

Leaflets (PL) for Centrally Authorised Products for Human Use.

94 Article 56a of the Community Code Directive, 2001/83 as amended by the Code Amendment Directive 2004/27. On 13 April 2005, the

European Commission issued guidance on this subject that will be integrated into an existing Guideline on the readability of the label and

package leaflet of medicinal product for human use. http://pharmacos.eudra.org/F2/pharmacos/new.htm


Commission’s proposed broadening of what information could be provided to the general public was rejected—for now. In a compromise, the revised Community Code directs the Commission to report within three years concerning information practices including those relating to the Internet—a phenomenon that makes somewhat academic the parliamentary rejection of the Commission’s proposal. In this report, the European Commission can propose information strategies. Commission officials and industry continue to argue for more information, although not US-style direct-to-consumer advertising. L. EMEA transparency and guidelines procedure 1. Access to information The EU has a general law on access to information, under which the European Commission makes decisions on access to documents.95 The pharmaceuticals legislation also has provisions to increase transparency and improve access to information on the results of the pharmaceutical decision-making process, including assessment reports and Summaries of Product Characteristics.96 The Community Code, as revised, contains new provisions97 on the publication of: Reasons for a drug’s withdrawal Reasons for refusals to recommend a drug’s authorisation European Product Evaluation Reports (EPARs) Rules of Procedure Clinical trials database (for now, access to it would be granted to Member States only) CHMP pharmacovigilance opinions Other transparency initiatives Under Article 125 of the Community Code Directive, every decision referred to in the Directive that is taken by a Member State Competent Authority shall state in detail the reasons upon which it is based. The concerned party shall be notified of such a decision and provided with information as to the redress available to it under the laws in force and the time limit allowed for access to such redress. Also, decisions to grant or revoke a marketing authorisation shall be made publicly available. Under Article 126, an authorisation to market a medicinal product shall not be refused, suspended or revoked except on the grounds set out in this Directive. No decision concerning suspension of manufacture or of importation of medicinal products coming from third countries, prohibition of supply or withdrawal from the market of a medicinal product may be taken except on the grounds specified for such decisions as to EU companies.

95 Regulation 1049/2001, OJ L 145, 31 May 2001, p. 43.

96 Articles 8.3 (j), 11, 21, Community Code on Medicinal Products 2001/83.

97 Article 21, 123, 125, Community Code on Medicinal Products 2001/83.


2. Guidance on guidance In June 2005, EMEA adopted a new procedure for EU pharmaceutical guidelines. The document helps address two key questions facing regulatory affairs professionals, i.e., the legal effect on pharmaceutical companies of the various EU guidelines and related documents and how to influence EU policies affecting companies. Except for Regulations such as the EMEA Regulation 726/2004, decisions such as centralised product authorisations and a few guidelines having binding legal status, the only EU-level medicine laws that are mandatory for pharmaceutical companies in the Community are Member State laws, e.g., those implementing the Community Code on Medicinal Products, not the code itself. Nevertheless, the code itself is frequently cited as if it were directly applicable to companies and certain provisions sound as though they are meant to have direct relevance. In essence, most companies believe they must adhere to both the EU-level and national-level laws. Published by EMEA on 30 June 2005, the Procedure for European Union guidelines and related documents within the pharmaceutical legislative framework (EMEA Guidelines Procedure)98 both provided greater clarity on the legal status of guidelines and established a procedure for involving stakeholders in guideline development. The EMEA Guidelines Procedure covers the drafting, consultation, adoption and implementation of pharmaceutical guidelines. Importantly, the public is given an earlier chance to offer opinions on whether guidelines are needed and their impact on industry and others. EMEA and the European Commission also announced their intent to update and consolidate the Notice to Applicants (NtA) rules governing medicinal products in the EU described as “the vehicle for publication of guidelines and legislation within the pharmaceutical legislative framework.” The new procedure responds, in part, to requests from stakeholders for a more transparent process. The European Federation of Pharmaceutical Industries and Associations (EFPIA) issued a position paper in April 2004 calling for greater openness in the EU pharmaceutical policy formulation process. A draft of the EMEA Guidelines Procedure was published for consultation by EMEA in September 2004.99 The new procedure replaces current guidance on the subject, in particular, a European Commission paper on a Procedure for European Union Guidelines. Guidelines are documents that help to explain EU pharmaceutical laws. An EU guideline typically elaborates on an obligation contained in an EU Directive, Regulation or decision or provides advice to companies and public authorities on the best way to comply with requirements in EU pharmaceutical laws. With some exceptions,100 guidelines do not have legal status and are not legally binding. Alternative approaches may be taken, but only if justified to the authorities. This approach sounds similar to an FDA “guidance document,” but many believe it may be more difficult to justify deviation from an EU guideline. Guidelines are highly influential because they reflect the Commission’s position on implementing EU legislation. Guidelines are, thus, an indispensable

98 The procedure is available on the EMEA web site at http://www.emea.eu.int/pdfs/human/regaffair/2414304en.pdf.

99 Overview of Comments Received on Draft Guideline is available on the EMEA web site at

http://www.emea.eu.int/pdfs/general/direct/pr/21683205en.pdf. Many comments made useful suggestions to improve EMEA processes outside

the scope of the new procedure.

100 An example of a binding guidance is the Note for Guidance on minimising the risk of transmitting animal spongiform encephalopathy agents

via human and veterinary medicinal products, OJ C 24, 28.01.2004, p. 3. This guidance is binding because it was required by Directive 2001/83,

the Community Code on Medicinal Products.


tool for interested persons who need to understand the rather complex EU pharmaceutical legislative framework and adjust their conduct to the law’s requirements and obligations. Guidelines provide legal certainty to affected industry concerning the authorities’ interpretation of the relevant laws. If followed, guidelines can facilitate the approval, control and assessment of medicinal products by the relevant authorities. Given guidelines’ significance, it is essential that the procedure for their adoption is open and transparent, allowing interested parties to express their views and participate in the decision-making process. After all, guidelines can have a significant impact on the research and commercialisation practices and policies of pharmaceutical companies. Some guidelines are followed by the industry as if they were requirements. Guidelines have different sources, e.g., EMEA or the European Commission, and are sometimes the result of efforts among the EU, US, Japan and other international partners through an activity known as International Conference for the Harmonisation of the Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH). ICH guidelines are now expressly given the same status as Commission and EMEA guidelines. ICH guidelines can play a role in reducing global product development costs and, thus, in facilitating availability of medicines. The EMEA Guidelines Procedure proposes the term “guideline” for all pharmaceutical guidance documents. Other names are used, such as note for guidance, guideline, position paper, etc. The choice of a unique name is intended to avoid confusion concerning the nature and legal status of the various forms of guidance. The EMEA Guidelines Procedure lists and describes the different types of pharmaceutical guidelines, with 13 examples, including: Regulatory Guidelines, such as those contained in the Commission’s Notice to Applicants; Scientific Guidelines related to Quality, Safety and Efficacy; Good Manufacturing Practice Guidelines; Good Clinical Practice Guidelines; and Orphan Medicinal Products Designation Guidelines. The procedure also lists documents not considered guidelines, e.g., reflection papers and question and answer (Q&A) documents. In addition, EMEA has stated that a procedure is in place so that issues arising from scientific advice or reviews of individual applications can be progressed to guidelines or Q&A documents. The EMEA Guidelines Procedure spells out a series of 12 steps to be followed when adopting guidelines and largely codifies the Commission and EMEA’s standard practice. Some steps can be omitted under special circumstances, e.g., when changes in previous documents are minor or adoption of the guideline is urgent. 1. Selection of topics and inclusion in EMEA work program. The selection of topics occurs

mainly within EMEA, including its scientific committees and other groups comprised of EU experts. Input on guideline topics can also be received from Member States and interested parties. The procedure does not specify a single mechanism for suggesting new initiatives. Suggestions may be made spontaneously to EMEA or Member State officials on EMEA committees. Input can be given spontaneously or in response to an EMEA request.

2. Appointment of a rapporteur to reflect the views of the relevant committee. Once a

topic has been selected, a rapporteur is appointed who is in charge of drafting the concept paper and the subsequent guideline, with the support of others in EMEA and its committees. There is no barrier to interested persons contacting “guideline rapporteurs” directly but this is “generally considered not appropriate.”101

101 Overview of Comments Received on Draft Guideline, at 12.


3. Development of a concept paper. A concept paper is meant to communicate the need for a specific guideline. It is short, e.g., two pages, and outlines the issues to be covered and possibly some options, without elaborating on solutions. Importantly, the concept paper stage gives the public a chance to comment before EMEA or Commission positions are firmly established.

4. Adoption and release for consultation of a concept paper. Following adoption, concept

papers are published on EMEA's website and open to comments for two to three months. EMEA says it is developing improved mechanisms “for hearing views from groups representing patients or healthcare professionals.”

5. Preparation of initial draft guideline. The draft should include references to existing EU

directives and guidelines, as well as related documents from other regions, e.g., Food and Drug Administration (FDA) guidance. It should take into account comments received during the concept paper consultation period. Before publication, the draft will be discussed internally within EMEA and its relevant committees.

6. Release for consultation of draft guideline. Draft guidelines are published on the website

of EMEA, the European Commission or the European Pharmacopoeia, as appropriate, and normally will be open for consultation for three to six months.

7. Collection and handling of comments. Comments received from Member States, other

regulatory authorities, European industry associations, scientific societies, patient groups and others will be carefully considered by the rapporteur and/or the drafting group in charge of the guideline. All comments will be published on the relevant website unless they contain commercially confidential information or the author has objected to their publication. In response to “specific justified concerns,” EMEA may convene a meeting with interested persons on a concept paper. Many stakeholders wished for more details on the criteria for a meeting.

8. Preparation of final version. Comments received will be considered. (However, there

generally is no document responding to comments received, a source of frustration to industry.)

9. Adoption of final guideline. Depending upon the guideline type, the relevant EMEA

Committee and/or the European Commission adopts the final guideline and publishes it on the pertinent website.

10. Implementation. Generally, a guideline will become effective six months after its adoption.

Guidelines are rarely retroactive; when they apply to medicines already on the market, this coverage will be explained and justified.

11. Training. EMEA will provide training to Member State officials to ensure uniform application.

In some cases, other interested parties could be allowed to participate in the training. 12. Maintenance and revision of adopted guidelines. As a general rule, guidelines will be

reviewed after five years—in some cases, earlier—depending upon available experience and knowledge. EMEA is interested in suggestions on this issue.

Adoption of the EMEA Guidelines Procedure is part of an effort by the agency to increase transparency in its procedures. With the adoption of the procedure, EMEA acknowledges the


indispensability of pharmaceutical sector involvement in its decision-making processes. For these reasons, the pharmaceutical industry has welcomed the adoption of the EMEA Guidelines Procedure, but would like to see an increase in face-to-face meetings as part of the improved transparency. Industry also would often like to know the identity of the authors of EMEA guidelines. The EMEA Guidelines Procedure applies to all draft and final guidelines published after 1 September 2005. 3. Database on medicines EMEA is developing an extensive database of all approved products that will include information on ongoing clinical trials and adverse events for each drug. When completed, the database will be available in varying degrees to regulators, healthcare professionals, industry and the public. M. Scientific advice to sponsors EMEA has provided scientific advice to sponsors since 1996 and has a Scientific Advice Working Party. Since 2000, EMEA has been providing protocol assistance to sponsors of orphan medicines (see Chapter XII) and joined the US FDA in announcing a joint advice procedure in certain cases. Under the new EMEA Regulation, the agency has a specific mandate to “advis[e] companies on the conduct of the various tests and trials necessary to demonstrate the quality, safety and efficacy of medicinal products.”102 EMEA is raising the priority of its scientific advice function, seeing it as a way to facilitate the development of new medicines and cut review times. EMEA’s Road Map (see section O. of this Chapter) identified it as a key priority, and in September 2005, EMEA launched a public consultation on a new framework for scientific advice and protocol assistance.103 2. EMEA cooperation with the US Food and Drug Administration (FDA) Under a pilot program announced in 2004, EMEA and FDA proposed joint scientific advice meetings with sponsors starting in 2005. This is the most significant component of a broader plan to promote exchange of information among the EU and US agencies and pharmaceutical product sponsors. Specifically, the parallel scientific advice program provides a mechanism for sharing advice on specific scientific questions, “to optimise product development and avoid unnecessary testing replication or unnecessary diverse testing methodologies.” Although this program’s scope remains limited, it represents a unique opportunity for sponsors to gain valuable time before both regulatory bodies and, potentially, to benefit from a more harmonised review and approval standard. According to a “General Principles” document and the implementation plan, a few key points deserve emphasis:

The pilot program focuses only on “important” or “breakthrough” products, including products for orphan indications or paediatric populations and compounds for indications for which there is little or contradictory guidance.

102 Article 57(1)(n), EMEA Regulation 726/2004.

103 EMEA Press Release, European Medicines Agency proposes new, faster scientific advice procedure, EMEA/311762/2005, 23 September

2005; EMEA, New Framework for Scientific Advice & Protocol Assistance, EMEA/267187/2005.


Thus, the program’s primary focus will be products that have been granted “fast track” status.

Each parallel scientific advice meeting should replace a milestone meeting (e.g., end of

Phase II or pre-IND meeting) or address specific scientific issues. The agencies emphasise that there will be one meeting per product.

The pilot program “should not be viewed as a possibility of a continuing series of parallel

scientific advice meetings on the same specific product.”

Importantly, these parallel advice meetings usually will occur at the sponsor’s request.

o To request such a meeting, a sponsor should send a single letter to identified contacts at EMEA and FDA, explaining why a joint advice meeting would be beneficial and identifying specific questions it would like clarified.

o Sponsors must explicitly authorise the two agencies to exchange information,

including trade secret material. o Both agencies have committed, pursuant to “Confidentiality Arrangements”

concluded in 2003 and renewed in 2005, to protect all such proprietary information. By the end of 2005, several parallel scientific advice sessions had occurred, and industry observers were cautiously optimistic about the value of the program. Agency representatives participate by teleconference or videoconference. In addition to the parallel scientific advice program, the implementation plan provides for the ad hoc exchange between EMEA and FDA of several kinds of information, including pharmacovigilance data, internal discussion papers and advance notice regarding “significant regulatory sanctions of mutual interest.” The agencies also will exchange, on a quarterly basis, specified information regarding products that are approved or under review, inspection reports and draft guidance documents. Despite these formalised efforts at increased cooperation between European and US regulators, EMEA and FDA caution sponsors not to expect to receive similar recommendations from the two agencies. Nonetheless, the joint advice program and information-sharing plan signify an important step toward a global approach to drug development and regulation. On 21 June 2005, EU and US leaders endorsed a concrete joint program to improve regulatory cooperation. The “2005 Roadmap for Regulatory Cooperation” set the agenda for a number of specific regulatory cooperation activities between the European Commission and the US government for the coming year. Cooperation concerning efforts to ensure the safety, quality and efficacy of pharmaceutical products was among the topics listed as areas of cooperation. N. EU initiatives on pharmaceutical access in developing countries 1. Anti-diversion regulation Council Regulation (EC) No. 953/2003 of 26 May 2003 was enacted to avoid trade diversion into the EU of certain key medicines that were intended, by pharmaceutical companies that choose to participate in the program, to go to specified developing countries confronted with public health emergencies such as HIV/AIDS, malaria or tuberculosis. The Regulation sets


criteria for a “tiered priced product,” the conditions under which EU Member State customs authorities shall take action and other measures which must be taken by Member States. A “tiered price product” is a pharmaceutical used in the prevention, diagnosis, or treatment HIV/AIDS, malaria, tuberculosis and related opportunistic diseases. As to any products for such uses that are destined to any country on the Regulation’s list of developing countries, it is illegal to import for re-export any tiered price products other than to a country on the list. Unique coding and labelling are prescribed to discourage diversion of these cut-price drugs. On 23 June 2005, the Trade Directorate-General of the European Commission issued a report to the European Parliament and Council on the functioning of this Regulation. Entitled the European Commission’s First Annual Report (2003-2004) on access to medicines, the European Commission concluded that the Regulation helps to encourage access to newer second-line AIDS treatments and to make these available in poor countries in the future. Only one company, GlaxoSmithKline (GSK) is participating in the program. The Commission considers it an achievement that GSK is prepared to supply poor and developing countries with nine products at prices that will help make continued supply sustainable. The Commission observes that other producers also sell key medicines at reduced prices or make drug donations, but expresses concern about the sustainability of certain of these efforts. (Most companies producing anti-retrovirals, including Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GSK, Merck and Roche, have reduced pricing schemes for developing countries.) Council Regulation 953/2003 is part of a package of measures adopted by the EU to facilitate affordable access to medicine in developing countries, particularly products to treat HIV/AIDS, malaria and tuberculosis. The World Trade Organisation (WTO) General Council has stated that the Agreement on Trade-Related Intellectual Property Protections (TRIPS Agreement) permits compulsory licenses on patented drugs for export purposes. As discussed in the next section, a draft EU Regulation provides for implementation of this decision at Community level.

2. Draft Compulsory Licensing Regulation. In October 2004, the European Commission proposed a Regulation to implement the WTO General Council decision on TRIPS and compulsory licensing.104 The WTO decision interprets the TRIPS agreement as allowing national authorities to grant compulsory licenses for the production of patented medicines for a country in need, if that country lacks the capacity to produce the medicines itself. Importantly, the destination country must first have notified the WTO that it is seeking the medicine covered by the license. Under the European Commission’s proposal, companies would apply to national authorities for a grant of a compulsory license from a patent holder. As with Council Regulation 953/2003, discussed in the preceding section, the proposal would prohibit the reimportation into the EU of medicines destined for the developing-country market, and Member State customs authorities would be empowered to take actions to prevent reimportation. Also, the patent holder could use existing national procedures to enforce its rights against reimported products re-entering the EU. In such cases, the license permitting the export could be terminated. In July 2005, the European Parliament's trade committee broadened the scope of the proposed EU regulation on compulsory licensing. Under the Commission's draft Regulation allowing generic pharmaceutical companies to export patented medicines to developing countries, only countries that are members of the WTO can apply to import such medicines. In

104 Draft Regulation on compulsory licensing of patents relating to the manufacture of pharmaceutical products for export to countries with

public health problems, 2004/0258 (COD).


its report, the European Parliament proposed that all countries, not just WTO members, should be able to benefit from the proposed regulation. Furthermore, the European Parliament's trade committee took the position that the ability to request imports of pharmaceutical products should be extended to nongovernmental organisations. The European Parliament was expected to consider the legislation in the latter part of 2005.

3. Evaluation of medicines for use outside the EU The new EMEA Regulation contains a provision105 for the evaluation of products intended exclusively for use outside the EU. Accordingly, in 2005, the EMEA CHMP issued an implementing Guideline on Procedural Aspects Regarding a CHMP Centralised Opinion in the Context of Cooperation with the World Health Organisation (WHO) for the Evaluation of Medicinal Products Intended Exclusively for Markets Outside the Community.106 The applicant follows the regular procedure in putting together an application as if it were an application for marketing authorisation. However, these scientific opinions would not result in EU marketing authorisations, as marketing in the EU is expressly not contemplated by this program. The guideline states that a marketing authorisation application could be submitted in the future. The idea behind this program is that a favourable EMEA CHMP assessment—like a favourable US FDA opinion in that agency’s similar program—would give a measure of confidence about the assessed products both to the WHO and to developing-country drug regulatory authorities that might choose to rely on the assessment. This program could allow low-price generic versions of on-patent drugs to be supplied to needy developing-country markets, but with some assurance that these countries do not become dumping grounds for poor-quality drugs. The guideline states that the operation of the procedure is without prejudice to another entity’s intellectual property rights. The draft guideline states that products subject to compulsory licensing under the final Regulation, to be based upon the proposal described in the preceding section,107 would automatically qualify for the use of this procedure. Also, the draft guideline is meant to be for diseases of “major public interest,” such as vaccines, products for HIV/AIDS, malaria or tuberculosis, lymphatic filariasis (elephantitis), trachoma, leishmaniasis, schistosomiasis, African trypanosomiasis (sleeping sickness), onchoserciasis (river blindness), dengue fever, Chagas disease and leprosy. Applicants need to make advance requests for use of the CHMP review procedure, under a procedure set forth in the draft guideline. O. EMEA “Road Map to 2010” initiative On 15 April 2004, the EMEA issued an ambitious document on its vision for itself by the year 2010.108 The following year, EMEA issued The European Medicines Agency Road Map to 2010: Preparing the Ground for the Future,109 which covers such topics as scientific advice, postauthorisation oversight, transparency, communication, patient information and oversight of good manufacturing practices (GMPs) and good clinical practices (GCPs).

105 Article 58, Regulation 726/2004.

106 EMEA/CHMP/5579/04, 23 May 2005.

107 Draft Regulation on compulsory licensing of patents relating to the manufacture of pharmaceutical products for export to countries with

public health problems, 2004/0258 (COD).

108 EMEA/D/936/04/Final; EMEA/H/34163/03/Rev 2.0.

109 EMEA/H/34 163/03/Final, 4 March 2005.


P. EU competitiveness and the G10 The “High Level Group on Innovation and Provision of Medicines”—nicknamed the “G10” group—was set up in 2001 by the two European Commissioners then in charge of the Directorate General for Enterprise and the Directorate General for Health and Consumer Protection. The group included Member State health and industry members, as well as representatives of the pharmaceutical industry, health insurance industry and patient groups. The G10 was influential in developing what became the 2004 pharmaceutical review regulation. The final G10 report was issued 7 May 2002 and was the subject of a Commission Communication dated 1 July 2003; the European Council issued its own report on 22 September 2003. Concerns continue to be raised about the competitiveness of the European pharmaceutical industry and whether EU regulation, price controls and parallel trade stifle innovation. Q. Pricing controls, third-party reimbursements, health technology assessments and patient mobility The EMEA Regulation “shall not affect the powers of Member States’ authorities as regards setting the prices of medicinal products or their inclusion in the scope of the national health system or social security schemes on the basis of health, economic or social conditions.”110 Member States may decide which of the authorised indications and pack sizes will be covered by their social security bodies.111 A virtually identical provision is found in the Community Code on Medicinal Products Directive.112 Before a pharmaceutical product may be marketed and sold in certain countries, its proposed pricing must be approved. The requirements governing product pricing vary widely from country to country and can be implemented disparately at national level. At the EU level, the only control is the Transparency Directive, which sets forth certain requirements for Member State agencies regarding timeframes and responsiveness to industry requests. Two recent European Court of Justice cases113 held that the deadline in Article 6 of the Transparency Directive for a Member State to adopt a decision on an application to include a medicinal product in the list of products covered by the health insurance system is a mandatory time limit that Member States are not entitled to exceed. However, it is up to the Member States to decide the effects of exceeding the time limit, as the Directive does not provide for a product to be included automatically on the list of covered products in cases where a Member State exceeds the time limit. In the EU and elsewhere, sales of pharmaceutical products are dependent in part upon the availability of consumer reimbursement from third-party payers, such as government and private insurance plans. Third-party payers increasingly challenge the prices charged for medical products and services. Due to the limited authority at EU-level in this area, Member States have considerable latitude to restrict the range of medicinal products for which their national health insurance systems provide reimbursement. Some Member States have a “positive list” while others have a “negative list.” A positive list sets forth all medicinal products covered under the national health insurance system, while a negative list designates medicinal products excluded from coverage. While the UK and Spain use a negative list mechanism, France employs a positive list approach. Some countries have

110 EMEA Regulation, Article I.

111 Id.

112 Article 4.3, Community Code on Medicinal Products Directive 2001/83.

113 Merck, Sharp & Dohme BV v. Belgium, C 245-03, 20 January 2005; GlaxoSmithKline SA v. Belgium, C 296-03, 20 January 2005.


not only positive and negative lists, but also a process for a clinical and cost effectiveness review by a health technology assessment body. A negative determination by such a body regarding a product could affect that product’s prescribing. For example, in the UK, the National Institute for Clinical Excellence (NICE) provides guidance to the National Health Service on whether it regards a particular drug as clinically effective and cost-effective. Doctors are expected to consider the NICE’s advice, although it is presented as mere guidance when choosing a drug to prescribe. In addition, health authorities may decide not to make funding available for drugs that have not received a favourable recommendation by NICE. Thus, a negative determination by NICE means fewer prescriptions. Although NICE will consider drugs with orphan status, there is some tension on the application of the standard cost assessment for those products, which often are more highly priced to compensate for the limited market. At the time a product sponsor is expending funds for research and development of new products, it is difficult to ascertain whether various EU countries will consider them to be cost-effective, whether reimbursement will be available or whether a price can be charged that will be sufficient to allow a product’s sale on a competitive and profitable basis. Increasingly, cases are being litigated in the European Court of Justice that have a bearing on the ability of citizens of an EU Member State to seek out pharmaceuticals, medical devices or medical services in another Member State or even in a non-EU country. A detailed discussion of these “patient mobility” cases is beyond the scope of this publication but will take on increasing importance in the future. Among noteworthy cases are the Doc Morris114 and Keller115 judgments.

114 In Deutscher Apothekerverband e.V. v. DocMorris NV, Jacques Waterval, C-322/01, 2003, the ECJ dealt with cross-border practice of

pharmacy.

115 Annette Keller’s heirs v. the Spanish National Institute of Public Health Care (INSS), C-145/03), 12 April 2005.


Chapter IV. Medical Devices Regulation A. EU medical device regulation summarised For more than a decade, the Medical Devices Directive (MDD),116 supplemented by an older directive on active implantable medical devices and a newer one on in vitro diagnostic devices,117 has served as the sector’s principal governing legislation. Where the legislative instrument is a Directive (rather than an EU Regulation), each EU Member State must enact a law to implement (transpose) it. The EU legislative framework thus is comprised of literally dozens of medical device laws. The European medical device regulatory system emerged at a time when there was keen interest in a “New Approach” that would replace the difficult and frustrating harmonisation process that then applied to food and pharmaceuticals. Backed by European court cases holding that Member States had limited power to exceed the essential requirements specified in Directives, the Commission began proposing New Approach Directives aimed at creating a single market and eliminating barriers and inconsistencies among Member States. The New Approach was seen as a way to avoid both detailed regulations prescribing technical requirements and excessive use of government approvals, especially duplicative approvals, as a regulatory tool. Product categories handled under New Approach legislation include pressure vessels, toys and personal protective equipment, as well as medical devices. A New Approach Directive contains a legislative statement of “essential requirements” that are further defined by technical standards. It is the responsibility of manufacturers to meet, and document how they meet, essential requirements. For some products, self-declaration of conformity is sufficient. For others, including medium- to high-risk medical devices, there must be a third-party assessment of a manufacturer’s conformity, with the manufacturer given a degree of choice among methods for “conformity assessment” of the product or production system. The endpoint is issuance of a certificate of conformity. A manufacturer applies a European conformity (CE) mark to the product to symbolise conformity with essential requirements. For medical devices in the EU, the third-party conformity assessment is carried out not by the Member States’ Competent Authorities—the drug and device regulatory agencies—but rather by conformity assessment bodies that Member States believe possess the necessary technical competency to review specified types of medical devices. Each Member State must notify the European Commission of the “bodies” it believes capable of reviewing the various medical device categories under the different Directives. The Commission publishes periodic listings in its Official Journal of these so-called notified bodies, but there is not yet a database of medical devices that have been authorised for marketing in the EU. Although not involved in the premarket authorisation stage, Member State regulatory agencies have important responsibilities to approve and oversee notified bodies, regulate medical device clinical trials, oversee postmarket surveillance, including adverse event reporting (medicovigilance), and bring enforcement actions where needed. They also participate in various EU committees.

116 See Consolidated text of Council Directive 93/42/EEC of 14 June 1993 concerning medical devices, OJ L 169, 12.7.1993, p. 1) at

http://europa.eu.int/eurlex/en/consleg/pdf/1993/en_1993L0042_do_001.pdf&e=9707

117 Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of the Member States relating to active implantable medical

equipment; Council Directive 98/79/EC of 27 October 1998 on in vitro diagnostic medical devices.


B. Recent legislative changes Recent changes in medical device regulation in Europe have been less far reaching than those affecting medicinal products. On 11 August 2005, the European Commission published a Directive that reclassified hip, knee and shoulder implants from class II to class III, the most restrictive category.118 C. Draft proposed directive to amend the Medical Devices Directive On 11 May 2005, the European Commission published a draft proposal119 to amend the 1993 Medical Devices Directive, 93/42/EEC (MDD).120 This action launched an important European initiative affecting the global medical devices industry. As this volume went to press, the period for comments had closed, and the Commission was considering comments and preparing to publish a formal proposal in the Official Journal of the European Communities. This begins a legislative process that will also involve the European Council and Parliament and is unlikely to be completed prior to 2007 at the earliest. The recently published draft is not only an important milestone but also is the product of a review mandated by the MDD itself.121 In 2003, the Commission issued a report122 concluding that the regulatory framework works well overall but its implementation could be improved. Concerns included the adequacy of product testing for some devices, premarket assessment mechanisms, transparency and trust, market surveillance and cooperation among authorities. At the same time, stakeholders generally agreed that any tightening of regulations to enhance safety should neither undermine patient access to new therapies nor impose unjustified regulatory burdens on industry. In late 2004, the Commission circulated a draft amended MDD to stakeholders and solicited their comments. The Commission’s May 2005 draft continued the consultative process. The Commission apparently aims to clarify and tighten clinical data requirements for medical devices, strengthen classification and conformity assessment procedures and enhance current provisions for a central database of medical device information. Overall, the amendments are relatively modest and, much to industry’s relief, do not embark on the radical overhaul that only a few regulators and stakeholders had hoped might occur. The current system would remain intact, with no call for an EU medical device agency. Nor is there a proposal to broaden EMEA’s jurisdiction to encompass certain medical devices, a move that would be emphatically opposed by medical device industry groups. It remains to be seen whether the European Parliament seeks more ambitious changes than those contemplated by the European Commission.

118 Commission Directive 2005/50/EC.

119 European Commission, Public Consultation Text, 5 April 2005-Draft Commission Proposal, COUNCIL DIRECTIVE 93/42/EEC of 14 June

1993 concerning medical devices. The draft and related documents are posted at

http://europa.eu.int/comm/enterprise/medical_devices/consult.htm

120 See Consolidated text of Council Directive 93/42/EEC of 14 June 1993 concerning medical devices (Official Journal L 169, 12.7.1993, p. 1)

at http://europa.eu.int/eur-lex/en/consleg/pdf/1993/en_1993L0042_do_001.pdf&e=9707

121 Article 11.4 of the MDD requires the Commission to submit a report within five years of the entry into force of the MDD with a view to

updating and improving the framework and its overall implementation.

122 Communication from the Commission to the Council and the European Parliament on medical devices, 2 July 2003, COM (2003) 386 final

http://europa.eu.int/comm/enterprise/medical_devices/consult.htm


However, the draft MDD needs to be read with the broadened definition of “medicinal product” in the 2004 Code Amendment Directive (see Chapter I.C.1 above) as well as the draft proposed Regulation on human tissue engineered products (hTEPs) and other advanced therapies (see chapter XI). While, for most medical devices, the status quo would continue, hTEPs are slated under the hTEP draft regulation for handling as a special type of medicinal product. Those hTEPs that entered the EU market as medical devices would also come under EMEA’s authority and would need medicinal product marketing authorisations, after a transition period. Notably, many reforms of medical device regulation are being achieved, not through proposed amendments to the MDD, but through use of tools already available under the current MDD legislation. Among these are reclassification of selected implants, additional guidance and standards, pressure on notified bodies to strengthen oversight and enhanced regulatory cooperation. Based upon the draft, the following topics seem likely to be covered in a future proposed directive to amend the Medical Devices Directive: 1. Clinical Data Requirements: Clinical data requirements would be more clearly defined, although literature-supported dossiers would still be permitted. Ethics committees would be required to review clinical investigation plans (presumably, not just informed consent documents). Clinical evaluation would be required for all devices, even those in Class I, the lowest risk category. 2. Classifications: There would be a clear mechanism for Member States to raise issues about medical device classification. Also, several definitions that drive Annex IX classification rules would be changed. For example, an amendment to the definition of “central circulatory system,” to encompass the aorta descendens to the bifurcatio aortae, moves any devices contacting these vessels into Class III, the most stringent regulatory category. Devices for use in direct contact with the central nervous system would also be in Class III. 3. Conformity Assessments: Notified bodies would be required to sample technical documentation across the range of devices carrying CE marks, when they conduct quality systems audits under the “conformity assessment modules” in MDD annexes that are based upon a quality systems approach. Notified bodies would be required to evaluate the design documentation for a representative sample of the product line. 4. Member State Measures: Member States would be allowed to take “health protection measures” and the current reference to safeguard measures as “transitional” would be deleted. This deletion implies that permanent health protection measures, more stringent at national than EU level, might be tolerated. As before, a national safeguard found to be justified might be considered for EU-wide adoption. However, where “the national measures are unjustified,” the draft’s only remedy is for the Commission to inform all Member States and interested parties. 5. Medical Device Database, Transparency and Cooperation: The draft seeks to address a major shortcoming of the current EU medical device system, i.e., the lack of a database containing information on products, manufacturers, authorised representatives and conformity assessment certificates. Member States are ordered to “take all necessary measures” to ensure that the required information is registered “immediately” in the database. The confidentiality requirements would be relaxed, to facilitate both creation of the database and sharing information among regulators (e.g., on refusals to allow clinical trials) and with the public (e.g., final vigilance reports). A “Cooperation” article would facilitate EU adoption of Global Harmonisation Task Force guidance.


6. Borderline and Combination Products: To more clearly draw the line between medical devices and medicinal products, the regulatory classification of a borderline product would depend upon the product’s “principal mode of action” rather than its “intended purpose.” Furthermore, the regulatory pathway for medical devices that incorporate a medicinal product would be clarified. A notified body must first verify the substance’s usefulness as part of a medical device, taking its intended purpose into account. Then, it must seek a scientific opinion on the medicinal product’s quality and safety from EMEA (where the medicinal component is a human blood derivative, has been the subject of an EMEA authorisation or is under mandatory EMEA jurisdiction) or from a Member State authority. 7. Software: The definition of “medical device” would be broadened to include software, whether standalone or incorporated into another device. Software would be treated as an “active medical device.” These proposals reflect positions now contained in guidance documents. A software validation requirement also would be imposed. 8. Elabelling: The amended Directive opens the way for instructions in electronic, rather than paper format, via electronic labelling. The mention of "leaflet" in the current MDD has impeded use of elabelling, despite its obvious practical benefits, i.e., dealing with 20 official languages, limited space and reduction of paper waste. The draft does not explicitly permit elabelling but it permits the Commission, where justified, to “adopt measures allowing instructions for use to be provided by other means.” Minimising the risks of inadequate regulation, while retaining the benefits of a relatively flexible regulatory system, has been seen as a key objective throughout this entire MDD review process. All involved want the EU to continue to be seen as a place where high quality medical devices can be investigated, manufactured, imported, used in patient care and exported. The hope is that the EU medical device framework, however it might be revised in the upcoming process, will maintain Europe’s reputation as a hospitable region for medical device development and marketing. D. Current issues in medical devices compliance A. Device Information Bulletins The European Commission has warned the medical device industry to comply with its “voluntary” program for Device Information Bulletins (DIBs); otherwise, it will propose new requirements in this area. The Commission reportedly regards issuance of such Bulletins as part of a medical device manufacturer’s transparency responsibilities. Since EU authorities have embraced DIBs as the primary way in which companies are expected to inform the public about medical devices and issues concerning their assessment, they view manufacturer participation in this program as critical. To participate, the manufacturer posts any DIB to its own website and the Commission features a link to the DIB on its website. To date, few companies have participated in the program, although its official status might allow companies to circumvent national advertising laws restricting Internet posting of any device information that could be linked to the manufacturer. Germany recently changed its law in this area but similar laws remain in place in Switzerland and Austria.


The type of information that Competent Authorities would like to see featured in DIBs, to improve understanding of CE marking is:

Manufacturer name and address Device name, principal intended purpose and description

Notified body name, conformity assessment route and date of conformity certificate

Clinical data held to demonstrate performance, safety, etc.

Benefit-risk analysis

Standards, MED DEVs (European Commission guidance) or other guidance notes

against which conformity is claimed

Details of device accuracy and sensitivity

Limitations to the device's use

Where the device contains a pharmaceutical or blood component, information on consultation with other relevant regulatory authorities

Information on the source or traceability, etc., where devices contain animal tissue

Postmarket surveillance details

Device biocompatibility information

The manufacturer is responsible for ensuring DIBs are accurate and up-to-date and that commercially-sensitive information is safeguarded. The manufacturer is permitted to choose the language of the DIB. B. Vigilance for “suspicious” devices In January 2005, the European Commission set up a new mechanism to share information about devices that may be unsafe, going beyond the vigilance system, which covers reports of actual device incidents. For these so-called "suspicious" devices, EU regulators are looking for better ways to prevent problems before they happen and to alert and consult with Member States via electronic means. The Commission has a system that is serving as the basis for the “suspicious” device cooperation scheme. This system, known as CIRCA is an online tool, developed by the Commission and intended to facilitate information exchange among the authorities and the Commission.


C. In-house manufacture issues (“home brews”) One of the most vexing problems to emerge in the implementation of the In Vitro Diagnostics Directive (IVDD)123 is the issue of “in-house manufacture.” Article 1.5 of the IVD Directive provides that:

This Directive shall not apply to devices manufactured and used only within the same health institution and on the premises of their manufacture or used on premises in the immediate vicinity without having been transferred to another legal entity. This does not affect the right of Member State to subject such activities to appropriate protection requirement.

The underlying legislative intent is expressed in Recital 10:

Whereas, having regard to the principle of subsidiarity, reagents which are produced within health-institution laboratories for use in that environment and are not subject to commercial transactions are not covered by this Directive…

Questions have arisen concerning the interpretation of the IVDD for devices manufactured in-house and used to test samples from external patients, i.e., from the offices of general practitioners or other health institutions. As a result, in December 2004, the European Commission issued a document containing a draft definition of “in-house products,” a term that generally applies to products manufactured by hospitals for their own use. The term “medical institution” is another term that the European Commission hopes to define. The Commission described its objective as helping to improve understanding of how EU medical device legislation affects these products and trying to end current confusion. The Commission explained:

Since the In-vitro Diagnostic (IVD) Directive 98/79/EC became mandatory in December 2003, there has been much debate regarding whether IVDs manufactured in-house and used for diagnostic purposes are excluded from the IVD legislation. These IVDs are referred to as in-house or “home-brew” assays. It is clear from the Directive that IVDs manufactured and used to test patient samples from within the same health institution fall outside the scope of the legislation.

This debate stems from Article 9.13 of the IVDD:

The provisions of this Article shall apply accordingly to any natural or legal person who manufactures devices covered by this Directive and, without placing them on the market, puts them into service and uses them in the context of his professional activity.

123 Directive 98/79/EC.


Recital 11 of the IVDD explains: Whereas, however, devices that are manufactured and intended to be used in a professional and commercial context for purposes of medical analysis without being marketed are subject to this Directive;

Several Member States and the Medical Device Expert Group sought advice from the European Commission in the interest of an agreed European position. The Commission announced its legal interpretation of the IVDD for IVDs manufactured in-house, at a December 2004 meeting of the Expert Group:

IVDs that are manufactured in-house and used to test patient samples for the same health institution are excluded from the IVDD.

IVDs that are manufactured in-house and used to test samples from external patients,

i.e., from a GP practice or another hospital are excluded from the IVDD.

IVDs that are manufactured in-house and then transferred to another hospital laboratory, which is outside its own legal entity, for diagnostic use are considered to fall within the scope of the IVDD.

Some Member States, e.g., Ireland, are encouraging hospital laboratories, even for IVDs manufactured and used in-house that fall outside the scope of the IVDD, to consider reviewing the principles of CE marking for them and adopting the Directive’s approach, wherever possible, in developing new in-house assays or re-assessing existing in-house assays. Further discussion concerning the definition of a “health institution” will take place at Medical Device Expert Group meetings. A pan-European definition may be an elusive goal, considering that healthcare services differ in each country. Pending a harmonised definition, each Member State is responsible for defining “health institution” at the national level.


Chapter V. Preclinical Testing and Clinical Trials Regulation Clinical trials regulation is one of the areas in which the EU regulatory landscape has most changed in the last several years. Clinical trials are overseen by Member State drug and medical device regulatory agencies, such as the UK’s Medicines and Healthcare products Regulatory Agency (MHRA). However, the norms under which Member States oversee clinical trials are set increasingly at EU level. Also, the level of cooperation and information sharing has intensified, led in part by EMEA in the case of pharmaceuticals and by the European Commission in the case of medical devices. A. Good Laboratory Practices As part of the general overhaul of EU pharmaceutical legislation, the Good Laboratory Practices Directive was revised and replaced with GLP Directive, 2004/10.124 As was the case with its predecessor, it applies only to nonclinical testing of pharmaceuticals, not medical devices. B. Medical device clinical trials Legislation governing medical device clinical trials has been in place for several years. At the EU level, the key documents are the Medical Devices Directive (MDD), principally Article 15 and Annex VIII, and ISO 14155 on clinical investigations of medical devices. The May 2005 draft proposed Directive amending the MDD would strengthen clinical data

requirements, although it does not expressly call for new legislation along the lines of the EU Clinical Trials Directive. It should be noted that some Member States, including France, regulate medical device clinical trials in a manner similar to regulation of pharmaceutical clinical trials. There is confusion as to what controls apply to clinical trials of CE-marked medical devices. ISO 14155 applies to all clinical investigations for which a device’s performance and safety are being studied, i.e., totally new devices or modifications to existing devices. However, its applicability to marketing studies is not clear, and the EU Member State authorities do not have a consistent approach. The implementation of the Clinical Trials Directive, 2001/20, is having other effects upon the regulation of clinical trials of medical devices in some Member States. For example, in several countries (including Belgium, The Netherlands and the UK), the “lead ethics committee” approach required by the Clinical Trials Directive is being applied not only to medicines investigations but also to medical device investigations. The result is that medical device companies are expected to appoint a lead ethics committee to fully review the clinical trial application. Other clinical trial sites also give an approval, but that approval relates only to whether their sites will participate. Some ethics committees are confused about the scope of the EU legislation and ask sponsors or investigators of medical device clinical trials to provide the EUDRACT number, an EMEA numbering system that supports a pharmaceutical clinical trials database but that has no applicability to medical device trials. There are some key differences in the way that devices under investigation are regulated compared to CE-marked devices, for example, the reporting of adverse events. While the Commission's medical device vigilance guidance document (MEDDEV) for CE-marked devices makes a distinction between the reporting times for incidents and near incidents (10 days

124 European Parliament and Council Directive 2004/10/EC of 11 Feb. 2004, OJ, 20 Feb. 2004; L050/44. See also 2004/9/EC of 11 Feb. 2004,

OJ 20 Feb. 2004; L050/28.


versus 30 days), ISO 14155 states that all events are considered serious in clinical investigations and, therefore, all should be reported "immediately" (within 10 days). Some Member States have an even stricter reporting standard. Spanish and French authorities must receive adverse event notifications within seven days, and Spain wants to be notified of all incidents that have occurred in any country where the investigations are being carried out. Under ISO 14155, the investigator also must report all serious adverse device events to the ethics committees and all adverse events (serious and non-serious) to the sponsor. It is the role of the sponsor to report adverse events to the Competent Authority in accordance with the relevant reporting criteria. Those involved in clinical investigations need to be aware of national or local requirements, as well as the possibility that an ethics committee might require investigators to inform it of all serious adverse events, whether or not device-related. Some national authorities, i.e., Spain and the UK, require the same information. EU national requirements for clinical trials differ dramatically on such issues as insurance, decision timeframes and translations. C. Medicinal product clinical trials As discussed above, the 2001 Clinical Trials Directive125 applies only to medicinal products, i.e., pharmaceuticals. It must be borne in mind, however, that the expanded definition of medicinal products brings various therapeutic classes such as gene and somatic cell therapy under medicinal products controls, including Member State laws implementing the Clinical Trials Directive. Control of clinical trials is at the Member State level. EMEA has only limited responsibilities in this area, such as managing the EU-wide clinical trials database, EUDRACT; hosting conferences and training; and coordinating conduct of Good Clinical Practice (GCP) audits, especially for products subject to the central authorisation procedure through EMEA. 1. Entry into Force of the EU Clinical Trials Directive Since 1 May 2004, EU Member States have been required to have national legislation in effect, implementing the EU Clinical Trials Directive. The Directive aims to make clinical trials regulation across the EU more uniform, while enhancing patient safety. It mandated that Member States adopt and publish the necessary laws, regulations and administrative provisions to comply with the directive before 1 May 2003 and that such legislation be fully operational one year later. With few exceptions, Member States were late publishing the necessary legislation and guidance. The delays were understandable, due to the complexity of the changes, but created widespread confusion as manufacturers and other clinical sponsors attempted to comply with the new requirements. By the end of 2004, most Member States had completed the necessary steps. At the time of this writing, only The Netherlands had not completed legislative action, but the French government had not yet issued the decrees necessary for its implementing legislation to take effect. The 1 May 2004 deadline applied equally to the 10 new Member States, as none had sought an exception to obtain extra time for compliance with the Directive. Indeed, most had new laws in place before the deadline. Countries like Germany, France and

125 Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of laws, regulation and

administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on

medicinal products for human use, OJ 121, 1.5.2001, p. 34. The implementation deadlines are set forth in Article 22 of the Directive.


The Netherlands needed more time to transpose the Clinical Trials Directive because they had to integrate the new requirements into complex, pre-existing laws on clinical trials. 2. Overview of the Clinical Trials Directive The Directive, through national implementing legislation, regulates clinical trials conduct, including multi-centre trials, on human subjects involving medicinal products (i.e., pharmaceuticals).126 It does not apply to noninterventional trials,127 also known as observational studies, although some Member States regulate such trials at national level. The Directive applies without prejudice to national requirements for protection of clinical trial subjects and obliges Member States to adopt, if they have not done so already, detailed rules to protect individuals unable to give consent. Key features of the Directive are:

common time limits and harmonised format for applying for opinions and approval from ethics committees and Competent Authorities128

adoption of a single opinion by each Member State’s lead ethics committee standard procedure for all Member States on content of applications and on start and

completion of clinical trials

creation of an EU-wide clinical trials data base (“EUDRACT”)

formal notification procedure for adverse reactions, with reports to be collected in an EU database129

inspection procedures to ensure compliance with good clinical practice and good

manufacturing practice in production of investigational medicines The original aim of the Directive was to harmonise existing national regulations for clinical trials. This goal has not been fully achieved. The Directive does not go so far as introducing mutual recognition of clinical trial approval among EU Member States. Therefore, in the case of a multi-centre trial in more than one EU country, applications still must be submitted in all countries involved. Also, while the Directive set uniform general standards, many details and practical aspects of implementation were left to Member States to determine.

126 This term was defined in the Community Code Directive 2001/83/EC as amended by the Code Amendment Directive 2004/27/EC.

127 This term is defined in Article 2(c) of the Clinical Trials Directive as “a study where the medicinal product(s) is (are) prescribed in the usual

manner in accordance with the terms of the marketing authorisation.”

128 To aid sponsors, the European Commission has published Guidelines entitled, “Detailed guidance on the application format and

documentation to be submitted in an application for an Ethics Committee opinion on the clinical trial on medicinal products for human use;

Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the Competent Authorities,

notification of substantial amendments and declaration of the end of the trial.”

129 The European Commission has published Guidelines entitled, “Detailed guidance on the collection, verification and presentation of adverse

reaction reports arising from clinical trials on medicinal products for human use” and “Detailed guidance on the European database of Suspected

Unexpected Serious Adverse Reactions.”


3. Summary of major changes resulting from the Directive a. Protection of Clinical Trial Subjects The Directive requires that certain conditions be fulfilled before a clinical trial may be undertaken. First, the ethics committee and/or Competent Authority must conclude that anticipated benefits for the subject and other patients justify any risks and inconveniences the trial entails. Second, prior to intake, the subject, or the subject’s legal representative if the subject is not able to give informed consent, must understand the trial’s objectives, risks and inconveniences and the conditions under which it is to be conducted, and must be informed of the right to withdraw at any time. The subject’s rights to physical and mental integrity must be safeguarded, together with the protection of any personal data.130 Consent must be given in writing; where the patient is unable to write, oral consent must be obtained in the presence of at least one witness. Further, provision must be made for insurance or indemnity to cover investigator and sponsor liability. The Directive does not require a specific compensation scheme for non-negligent harm to a subject. In this area, Member State national requirements vary widely. b. Clinical trials involving children and incapacitated adults The Directive addresses the ethical conduct of clinical trials involving children and incapacitated adults. For a child to participate, informed consent must be obtained from a parent or legal representative. Incentives or financial inducements, other than expense compensation, are prohibited. The trial must offer a direct benefit for minor subjects, must be essential to validate data obtained from trials on other subjects able to give informed consent and must relate to a condition from which the minor suffers, or be of such a nature that the trial may be carried out only on minors. In all circumstances, steps must be taken to minimise pain, discomfort, fear and risks, and the interests of the patient must prevail over the interests of science and society. Similar protection is provided for incapacitated adults unable to give informed consent. Again, the trial must relate directly to a life-threatening or debilitating clinical condition from which the incapacitated adult involved suffers. The ethics committee must approve the trial, and there must be grounds for expecting that the trial will produce a benefit to the patient that outweighs any risks. c. Ethics Committees Each Member State is required to establish one or more ethics committees, responsible for giving an opinion before a clinical trial commences on any issue requested of it, including considering whether the trial is justified given risks/benefits evaluation. Member States must delegate specific responsibilities to ethics committees, including a 60-day time limit for decisions. It is expected that ethics committee review and Competent Authority authorisation take place in parallel. Clinical trials of gene or somatic cell therapy and of any medicinal product containing genetically-modified organisms are permitted certain extensions of the 60-day time limit for ethical and Competent Authority approvals; no time limit is imposed on ethics committees for consideration of xenogenic cell therapy trials.

130 In accordance with the Personal Data Protection Directive, 95/46/EC, and pertinent Member State implementing legislation.


d. Commencement and conduct of a clinical trial The Directive requires the submission of an application for authorisation to the Competent Authority and a favourable ethics committee opinion before a trial—including one in healthy volunteers—may commence. Each clinical trial must have a sponsor. The term “sponsor” is defined as “an individual, company, institution or organisation, which takes responsibility for the initiation, management and/or financing of a clinical trial,”131 and thus is not limited to drug companies. It includes “non-commercial” sponsors that conduct clinical trials within the Directive’s scope. The sponsor must submit a valid authorisation request to the Competent Authority of any Member State in which it is planning to conduct the trial.132 The Competent Authority must consider a valid request as soon as possible (not to exceed 60 days). A 90-day extension may be allowed for trials of certain product types: gene therapy, somatic cell therapy (including xenogenic cell therapy) and all types of genetically modified organisms. A report must be submitted to the Competent Authority and ethics committee within 90 days of the trial’s conclusion.133 The Directive includes provisions for a clinical trial’s suspension or prohibition by a Competent Authority and for reporting serious adverse events and serious unexpected adverse reactions.134 The application to the ethics committee and Competent Authority must include a trial reference number for the clinical trials database, EUDRACT. e. Good Manufacturing Practice (GMP) GMP and Qualified Person (QP) requirements have been extended to investigational medicinal products (IMPs). IMPs include placebos and active comparator products. Authorisation must be granted by the Competent Authority before an IMP may be manufactured or imported, and IMP preparation within the EU must occur only at licensed manufacturing sites. EU and non-EU IMP manufacturers whose products are to be used in the EU must follow GMP requirements. Manufacturers and importers must have a QP, as defined in Article 49 of Directive 2001/83/EC, available in the EU who is responsible for ensuring that the products meet the specifications approved for the trial and have been made in accordance with existing EU GMP guidance. Member States may send investigators to visit sites involved in a clinical trial conducted to verify compliance with GCPs and GMPs.135 f. Impact of Clinical Trials Directive Implementation of this Directive has had wide-ranging implications for clinical trials in the EU. Those undertaking research will need to take new requirements into account when planning work programs involving clinical trials. These new requirements have been associated with significant costs, in terms of administrative burdens, the requirement to purchase liability insurance, and the “legal representative” requirement discussed in section E.2.d below. The impact of the Directive on clinical trial costs is still being debated. One issue is the proliferation of legislation engendered by the use of a Directive rather than a Regulation as a legal instrument. If EU authorities were to issue a single Regulation on Clinical Trials, the quantity of legislation at Member State level would be reduced. Certainly, it can be argued that there is no need for 25 different national laws to implement directives. Under the treaties

131 Article 2(e), Clinical Trials Directive.

132 Article 9, Clinical Trials Directive.


134 Articles 12, 16 and 17, Clinical Trials Directive.



governing the European Community, Regulations are “direct-acting” and do not depend upon Member State action for the requirements to be effective. D. Good Clinical Practices Directive In April 2005, the European Commission adopted Directive 2005/28/EC (the GCP Directive), establishing GCP principles and guidelines for medicinal product (pharmaceutical) investigations for human use.136 It supplements and strengthens the Clinical Trials Directive.137 Like the Clinical Trials Directive, the Commission’s GCP Directive aims to protect clinical trial subjects. Additionally, it seeks to ensure that, at all stages of clinical trial organisation, involved professionals throughout the EU apply the same GCP standards. A key purpose of the GCP Directive is to solidify the legal basis for requiring compliance by Member States, sponsors, investigators and other trial participants with global GCP norms established by ICH and already adopted by EMEA’s CHMP.138 The Directive likewise provides a firmer legal basis for any other guidelines on investigational medicines issued by EMEA or the European Commission. A second purpose of the GCP Directive is to allow Member States to adopt more lenient rules for noncommercial clinical trials conducted by researchers without pharmaceutical industry participation. EU and Member State officials had heard complaints from academic researchers about the Directive’s applicability to them regarding trials conducted on their own initiative, without pharmaceutical company sponsorship. The GCP Directive refers to the benefit to patients of noncommercial studies and enables Member States to relax certain requirements, particularly regarding manufacturing controls, importation and documentation.139 Member States must still ensure that patients’ rights are protected and GCP principles are achieved. Also, where authorised medicinal product trials are conducted for the patient population covered by an authorised indication, Member States are to take into consideration the fact that manufacturers have already met EU GMP and importation requirements. Noncommercial researchers, like commercial researchers, must continue to meet applicable human subject protection requirements. 1. Major features of the GCP Directive a. Ethics committees Ethics committees must adopt rules of procedure as defined in the EU Clinical Trials Directive. They must retain essential documents relating to each clinical trial for at least three years after its completion. The GCP Directive also emphasises that communication between ethics committees and Member State drug regulatory agencies must be ensured through appropriate and efficient systems. 136 Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards

investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such

products, OJ L 91, 09.04.2005, page 13 (GCP Directive).

137 Directive 2001/20/EC, the Clinical Trials Directive, is a fundamental piece of legislation whose adoption required action not only by the

European Commission but also by the European Council and Parliament and which authorised the Commission to issue the GCP Directive.

138 EMEA, Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95), January 1997 [2002 version].

139 Recital (11), pp. 2-3, GCP Directive.


b. Sponsors Sponsors are permitted to delegate any or all of their trial-related functions to an individual, company, institution or organisation. This is a useful clarification, given the key roles of consultants and contract research organisations in conducting clinical trials. Of course, the sponsor remains responsible for ensuring that the trial and its final data comply with applicable requirements. c. Investigator’s brochure The GCP Directive mandates that the investigator’s brochure, already required by the EU Clinical Trials Directive, be in a concise, simple, objective, balanced and nonpromotional form that provides clinicians or potential investigators a clear understanding of the trial. Also, a sponsor must validate and update the investigator’s brochure at least once per year. However, if the IMP has a marketing authorisation, the Summary of Product Characteristics may be used in lieu of an investigator’s brochure, a useful clarification for trials of marketed products. d. Manufacturing or import authorisations The GCP Directive elaborates on the requirements of the Clinical Trials Directive that authorisation—in effect, establishment licensure—is required for IMP manufacture (finished dosage forms) and for the various processes of dividing up, packaging or presenting products. Authorisations are required for export-only products, as well as for imports from non-EU countries. The GCP Directive lists requirements that the applicant must meet in order to be granted authorisation. The applicant must specify the medicinal product types and pharmaceutical forms to be manufactured or imported. “Types of medicinal products” refers to such categories as “blood products, immunological products, cell therapy products, gene therapy products, biotechnology products, human or animal extracted products, herbal products, homeopathic products, radiopharmaceutical products and products containing chemical active ingredients.” Member State regulators are supposed to make inquiries before granting authorisations, to ensure the accuracy of the applicant’s information. Manufacturing authorisation is not compelled by the GCP Directive for reconstitution of product prior to use or packaging, in a hospital or health centre, by a pharmacist or other person legally authorised by a Member State to carry out such processes, if the IMP is intended for use exclusively in that institution. The GCP Directive specifies that the relevant EU Member State drug regulatory agency may require further information from the applicant, including information concerning the QP used by the applicant. A QP ensures that medicinal products (in this case, investigational products) released into the EU have been produced under GMPs and meet other quality requirements. Also, to ensure compliance with requirements, the EU Member State drug regulatory agency can make any clinical trial authorisation conditional upon the applicant’s carrying out certain obligations imposed either when authorisation is granted or at a later date. e. Trial Master File and Archiving The so-called Trial Master File, a requirement imposed by the EU Clinical Trials Directive, includes documents that are supposed to show whether the investigator and sponsor have complied with GCP principles and guidelines. The GCP Directive specifies that the European Commission will provide additional guidance on the Trial Master File content. As for archiving, the GCP Directive requires sponsors and investigators to retain essential documents relating to a trial for at least five years after its completion. Documents must be


readily available to the relevant EU Member State drug regulatory authority. Each sponsor must designate who, within its organisation, is responsible for trial archives. Also, any alteration to records must be traceable. f. Inspectors and Inspection Procedures The GCP Directive requires that inspectors appointed by EU Member States be subject to a duty of confidentiality regarding information to which they gain access. Training requirements also are specified. Completion of relevant academic education or the acquisition of equivalent experience in the field is a prerequisite to appointment as an inspector. Each EU Member State must ensure that inspectors receive appropriate training, that they have knowledge of the principles and processes applicable to clinical research and medicinal product development, and that they are familiar both with procedures for recording clinical data and the organisation and regulation of health systems in that Member State. The GCP Directive states that clinical trial inspections may take place at various times: before, during or after the conduct of a clinical trial; as part of the verification of an application for marketing authorisation; or as follow-up to an authorisation. Also, EMEA may request inspections. Each Member State must make publicly available, within its territory, the documents relating to the adoption of GCP principles, establish a legal and administrative framework within which its GCP inspections operate and define the powers of inspectors for entry into a clinical trial site and accessing trial data. Member States are expected to appoint an adequate number of inspectors to ensure verification of GCP compliance and to establish procedures for verifying compliance. Each Member State also will have to establish procedures for appointing experts to accompany inspectors, where needed, requesting inspections or assistance from other Member States and arranging inspections in non-EU countries. In addition, Member States must maintain records of national and, if applicable, international inspections including GCP compliance status of sites visited and any follow-up. Finally, the European Commission is required to publish guidance documents on the conduct of inspections, with the aim of harmonising EU Member State agencies’ inspections. h. Implementation The GCP Directive entered into force 29 April 2005. Member State implementation was required by 29 January 2006. E. Guidelines on Clinical Trials The European Commission has published guidelines and draft guidelines implementing the Clinical Trials Directive, to assist Member States and clinical trial sponsors while encouraging uniform implementation of the Directive.140 This is important because each EU Member State has been required to enact its own legislation to implement the Clinical Trials Directive and now

140 To aid sponsors, the European Commission has published such Guidelines as:

Detailed guidance on the application format and documentation to be submitted in an application for an Ethics Committee opinion on the clinical

trial on medicinal products for human use

Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the Competent Authorities,

notification of substantial amendments and declaration of the end of the trial” (Rev. 2 October 2005)

Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for

human use

Detailed guidance on the European database of Suspected Unexpected Serious Adverse Reactions.


the GCP Directive. For example, guidelines set forth the suggested format for clinical trial applications.141 1. ICH GCPs EMEA has long recognised the International Conference on Harmonisation’s Guideline on Good Clinical Practice (ICH GCP).142 However, guidelines are not legally enforceable, and there were doubts about whether an EMEA guideline on clinical trials would properly apply to trials of medicines authorised by EU Member States, especially products whose entry into the EU marketplace would be controlled by Member States rather than EMEA’s review process. The GCP Directive seeks to remedy these problems. 2. Clinical Trials Directive GCP Guidance In January 2005, the European Commission issued the Clinical Trials Directive GCP Guidance, which addressed several key issues: a. Effect of delayed implementation on sponsors. As noted above, not all Member States had fully implemented the Clinical Trials Directive by the 1 May 2004 deadline. However, for purposes of assessing a marketing authorisation application, a clinical trial conducted in a Member State that has not implemented the Directive will be accepted if it was conducted in accordance with local regulations and principles of GCP and ethical principles, at least equivalent to those prescribed in the Community guideline Note for Guidance on Good Clinical Practice.143 The Commission takes a pragmatic approach in its interpretation due to many Member States’ delayed implementation of the Clinical Trials Directive. A different approach would have unfairly penalised sponsors in many EU Member States where the governments failed to implement the Clinical Trials Directive in a timely manner. b. Outsourcing tasks; ultimate responsibility of sponsor. A trial sponsor, may delegate, in writing, any or all trial-related tasks to a third party. However, in all such cases the trial must have an overall sponsor that remains ultimately responsible for the trial’s compliance with applicable law. Prior to commencing the trial, the sponsor must define, establish and allocate all trial-related responsibilities. An organisation such as a Contract Research Organisation (CRO) can also fulfil the sponsor’s role. The distribution of the sponsor’s tasks must be established in writing (i.e., by contract). c. Sponsor’s ability to supply free or reduced-price product to noncommercial trial investigators. The Clinical Trials Directive acknowledges that, “Noncommercial clinical trials conducted by researchers without the participation of the pharmaceuticals industry may be of great benefit to the patients concerned.” According to the January 2005 GCP Guidance, industry support in providing investigator-initiated studies with medicinal products free or at reduced cost, or in providing financial, material or scientific support, does not disqualify the trial from being considered noncommercial.

141 Detailed guidelines on the principles of good clinical practice in the conduct in the EU of clinical trials of medical products for human use,

ENTR6416/01, July 2002. This document complements the ICH GCP guideline referenced in the next footnote.

142 EMEA, Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95), January 1997 [2002 version].

143 Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95).


d. Legal representative. A trial’s sponsor that is not established in the EU must have an established legal representative in the EU (Article 19 of the Clinical Trials Directive). There are several ways in which a sponsor can be “established in the EU” and, in where establishment in the EU has been achieved, there is no requirement to name a legal representative:

First, the sponsor could be an EU-headquartered company.

Second, the sponsor could be an already-existing EU affiliate or subsidiary of (for example) an American, Canadian or Japanese company that assumes the duties of a sponsor under the Clinical Trials Directive and Member State implementing legislation.

Third, a non-EU company could partner with an established EU company, with the latter

assuming the sponsor’s responsibilities.

Fourth, a non-EU company could establish a subsidiary or affiliate corporation or other legal entity within an EU Member State. That new EU legal entity would be named as, and would serve as, the clinical trial’s sponsor.

Fifth, considering the Commission’s lenient position on outsourcing (so long as the

sponsor maintains ultimate responsibility), the already-existing or newly-established EU legal entity ought to be able to hire a CRO or consultants to carry out some or all responsibilities of a clinical trial, including those expected of a legal representative, so long as the responsibilities are clearly defined by contract, and nothing is overlooked.

In any case, the necessary insurance, indemnification and other arrangements must be in place so that no authority can accuse either the EU-based entity or its non-EU parent of trying to evade legal responsibility under the contract. Obviously, legal advice is needed on this issue, but the above possibilities are discussed as an introduction to the subject for regulatory affairs professionals and their legal counsel. Turning now to cases where a non-EU sponsor elects to name a legal representative instead of taking advantage of one of the “EU presence” options discussed above, the GCP Guidance takes the position that the legal representative is responsible for any civil and/or criminal liability. This much seems clear from Article 19 of the Clinical Trials Directive itself, but the GCP Guidance goes the additional step of interpreting Article 19 as limiting the ability of EU-based legal representatives’ and sponsors to include in their contracts provisions that assign civil and criminal liability arising from the clinical trial to non-EU sponsors. While many in the clinical research community had viewed the legal representative as someone to serve a local post box function, the GCP Guidance seems to say that, notwithstanding a clinical trial sponsor’s acceptance of ultimate legal responsibility, the European legal representative needs to have insurance (or other financial arrangements with the sponsor) sufficient to provide coverage in the event of civil or criminal liability. Contracts between legal representatives and non-EU sponsors that lack an EU presence will no doubt continue to have provisions allocating to sponsors the legal responsibility and liability in the event of an occurrence not involving negligence or other malfeasance on the part of the legal representative. However, the Commission guideline places the sponsor’s liability squarely on the legal representative’s shoulders and is discouraging EU-based CROs and consultants from serving in this capacity.


e. Multinational trials. In multinational trials, the GCP Guidance states that a trial can commence once it has been authorised by the local and lead ethics committees and the Competent Authority of a Member State, without having to wait until the trial has been authorised in other Member States where it is planned to be conducted. f. New sites. The addition of a new clinical trial site must be communicated to the relevant drug regulatory authority as well as the local and lead ethics committees. A positive opinion is required by the local and lead ethics committees on the new site’s participation. 3. ENGAGE GCP Audit Guideline To assist in implementing the GCP audit provisions mandated by the Clinical Trials Directive, a group known as the European Network of GCP Auditors and other GCP Experts (ENGAGE) has prepared a draft Optional Guideline for Good Clinical Practice Compliance and Quality Systems Auditing dated January 2005. Its objective is to harmonise and promote common GCP audit methodology. The document is based upon internationally accepted quality standards including ISO 19011:2002, based upon the view that, “Whether auditing trials, systems or processes, the basic audit methodology remains similar and this document can therefore be considered as a guideline for the conduct of all types of Good Clinical Practice compliance and quality systems audits.” F. Privacy data protection legislation Although the Data Protection Directive144 and Member State implementing laws have been in place for more than a decade, pharmaceutical and medical device companies continue to find compliance with these laws challenging. It is important that adequate safeguards be put into place to safeguard the confidentiality of sensitive health and other personal data. Also, the informed consent forms provided clinical trial subjects should unambiguously request permission for the personal data from their participation in the study to be transferred outside the EU for analysis and regulatory assessments. Anonymisation of personal data is an option in some cases. It should be emphasised that each Member State has its own laws on the subject of data privacy protection and there is wide variation in what they require.

144 Directive 95/46/EC.


Chapter VI. Good Manufacturing Practices and Inspections: Medicines The area of EU pharmaceutical GMPs has quietly been undergoing radical change. Legislative reforms that affected GMPs included the Clinical Trials Directive, the two 2001 Community Codes on Medicinal Products for human and for veterinary use, the 2004 Code Amendment Directives, and the expansion of the “medicinal product” category (first by the 2003 Dossier Harmonisation Directive and now by the Community Code’s broader “medicinal product” definition). Also, the ICH has stepped up harmonisation efforts in the GMP area, starting with the landmark Q7A document on GMPs for Active Pharmaceutical Ingredients, and more recently branching into broader initiatives to revamp GMPs to apply concepts from quality systems management and risk analysis principles. A. 2003 GMP Directive and related legislation On 8 October 2003, the European Commission published Commission Directive 2003/94/EC on “the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use”145 (2003 GMP Directive). This legislation has close linkages to several other laws: the two Community Codes on Medicinal Products which authorised it, the one for human use products (Article 47) and for veterinary use products (Article 51); Article 47 of the Dossier Harmonisation Directive; and the Article 13(3) of the Clinical Trials Directive. All medicinal products for human use manufactured in or imported into the EU, including medicinal products intended for export, are required to have been manufactured in accordance with GMP principles and guidelines. Since 1991, this has been a requirement at the European Community level for marketed, finished dosage form medicinal products.146 This requirement was carried over in the Community Code Directive147as well as the 2003 GMP Directive. While the 1991 Directive applied GMPs to finished dosage form marketed drugs, the Clinical Trials Directive and GMP Directive extended the application of GMPs to investigational drugs. The Trials Directive required that detailed guidance be drawn up, in accordance with the guidelines on GMP, on elements to be taken into account when evaluating IMPs for human use with the object of releasing batches within the Community. It, therefore, was necessary to extend and adapt the provisions of the 1991 Directive to cover good manufacturing practice of IMPs, which was a major purpose of the 2003 GMP Directive. Also, GMPs now are required for production of active substances used as starting materials.148 Because most of the 1991 Directive’s provisions had to be modified, the Commission decided, for the sake of clarity, to issue the 2003 GMP Directive as a consolidation of the expanded requirements. The 2003 GMP Directive also detailed provisions on Competent Authority inspections and certain manufacturer obligations. Thus, the 2003 GMP Directive sets forth good manufacturing practice principles and guidelines for production of medicinal products for human use whose manufacture requires GMP compliance and, for finished dosage forms, manufacturing authorisation under the Community Code Directive,149 for production of investigational medicines for human use. 145 Official Journal L 262 , 14/10/2003 P. 0022 – 0026.

146 Commission Directive 91/356/EEC of 13 June 1991 laying down the principles and guidelines of good manufacturing practice for medicinal

products for human use.

147 Article 40, Community Code Directive 2001/83.

148 Article 46a; 47 111.1; Annex I (Part I, point 3.2.1.1(b).

149 Article 40, Community Code Directive 2001/83.


Member States shall ensure that manufacturers respect the good manufacturing practice principles and guidelines set forth in the 2003 GMP Directive by conducting inspections (Article 3). Member States shall also take into account the compilation, published by the Commission, of Community procedures on inspections and exchange of information. Also, in interpreting GMP principles and guidelines, manufacturers and the Member State Competent Authorities shall take into account the detailed guidelines published by the Commission in the Guide to good manufacturing practice for medicinal products and for investigational medicinal products in the Notice to Applicants (NtA), currently undergoing revision. The manufacturer shall ensure that manufacturing operations are carried out in accordance with GMPs and with the manufacturing authorisation (Article 4). This provision also applies to medicinal products intended only for export. For medicinal products and IMPs imported from non-EU countries, the importer shall ensure that products have been manufactured in accordance with standards at least equivalent to EU GMP standards. The manufacturer shall ensure that all manufacturing operations for medicinal products subject to an authorisation are carried out in accordance with the information in the application for marketing authorisation as accepted by the Competent Authorities (Article 5). For IMPs, the manufacturer shall ensure that all operations are carried out in accordance with sponsor information provided in the relevant clinical trial application as accepted by the Competent Authorities. Manufacturers shall regularly review production methods in the light of scientific progress and investigational product development. If a variation to the marketing authorisation dossier or an amendment to the clinical trial application is necessary, the application for modification shall be submitted to the Competent Authorities. The manufacturer shall establish and implement an effective pharmaceutical quality assurance system, involving active participation by management and personnel from different departments (Article 6). At each production site, the manufacturer shall have a sufficient number of competent and appropriately qualified personnel available to achieve the pharmaceutical quality assurance objective. Managerial and supervisory staff, including the qualified persons responsible for GMP, shall have duties defined in job descriptions and an organisation chart (Article 7). Personnel shall receive initial and ongoing training, the effectiveness of which shall be verified, covering in particular the theory and application of quality assurance concepts and good manufacturing practice and, where appropriate, the particular requirements for the IMP’s manufacture. Training and hygiene programs are required. There also are requirements for premises and equipment (Article 8), documentation (Article 9), validation (Article 10) and quality control (Article 11). For an IMP, batch documentation shall be retained for at least five years after the completion or formal discontinuation of the last clinical trial in which the batch was used (Article 9). The sponsor or marketing authorisation holder, if different, shall be responsible for ensuring that records are retained as required for authorisation, in accordance with the Annex I to the Community Code Directive 2001/83/EC, if required for a subsequent marketing authorisation. When electronic, photographic or other data processing systems are used instead of written documents, the manufacturer shall first validate the systems by showing that the data will be appropriately stored during the anticipated storage period. Data stored by those systems shall be made readily available in legible form and provided to the Competent Authorities at their request. Electronically-stored data shall be protected, by methods such as duplication or back-up and transfer onto another storage system, against data loss or damage and audit trails shall be maintained. For IMPs, the manufacturing process shall be validated in its entirety, as appropriate, taking into account the product development stage. At the least, critical process steps such as


sterilisation shall be validated. All steps in manufacturing process design and development shall be fully documented (Article 10). Concerning quality control, the manufacturer shall establish and maintain a system placed under the authority of one person—the Qualified Person (QP)—who has the requisite qualifications and is independent of production (Article 11). That person shall have, or have access to, one or more quality control laboratories, appropriately staffed and equipped to carry out necessary starting and packaging materials examination and testing, as well as the testing of intermediate and finished products. Contract laboratories may be used if authorised. However, under the Article 51.2 of the Community Code Directive 2001/83, there is the possibility that controls within the country where the medicinal product is manufactured can relieve the QP of certain responsibilities for recheck. For IMPs, the sponsor shall ensure that the contract laboratory complies with the clinical trial application’s content, as accepted by the Competent Authority. When IMPs are imported from non-EU countries, analytical control shall not be mandatory. During final finished product control before a product’s release for sale or distribution or use in clinical trials, the quality control system shall take into account, in addition to analytical results, such essential information as production conditions, results of in-process controls, examination of manufacturing documents and product conformity, including the final finished pack, to its specifications. Samples of each batch of finished medicinal product shall be retained for at least one year after the expiry date. For an investigational product, sufficient samples of each batch of bulk formulated product and of key packaging components used for each finished product batch shall be retained for at least two years after completion or formal discontinuation of the last clinical trial in which the batch was used, whichever period is the longer. Samples of starting materials, other than solvents, gases or water, used in the manufacturing process generally shall be retained for at least two years after product release. Contract manufacturing is covered under Article 12, and any manufacturing operation or operation linked thereto that is carried out under contract shall be the subject of a written contract that clearly defines each party’s responsibilities and specifies, in particular, that GMPs must be followed. Provisions also were included on complaints, product recall and emergency unblinding (Article 13). The manufacturer shall implement a system for recording and reviewing complaints, together with an effective system for recalling, promptly and at any time, medicinal products in the distribution network. Any complaint concerning a defect shall be recorded and investigated by the manufacturer. The manufacturer shall inform the Competent Authority of any defect that could result in a recall or abnormal restriction on supply and, in so far as is possible, indicate the countries of destination. The Community Code also has provisions relevant to recalls (Article 123). Similar provisions are now included for investigational medicinal products (system for recording and reviewing complaints, recalls, investigations of defects, and reporting certain defects to Competent Authorities). The manufacturer shall conduct repeated self-inspections as part of the quality assurance system in order to monitor good manufacturing practice implementation and respect and to propose any necessary corrective measures (Article 14). In the case of an IMP, labelling shall be such as to ensure subject protection and traceability and enable identification of the product and trial (Article 15). Member States were required by 30 April 2004, to bring into force the laws, regulations and administrative provisions necessary to comply with the 2003 GCP Directive.


B. Inspections In October 2005, EMEA published, on behalf of the European Commission, a Compilation of Community Procedures on Inspections and Exchange of Information, updated to include new EU formats and procedures. The updated Compilation includes a revised EU format for manufacturing authorisations. In addition, the EU inspection report format has been updated and the guideline on the preparation of reports under the centralised system revised. A new format for GMP certificates was issued. A new procedure on inspection triggers for inspections of the premises of active substance starting material manufacturers, developed with the Member States’ authorities, was published. This document stemmed from a need to update the existing manufacturing authorisation and inspection report formats, based upon practical experience and the new provisions of the two Community Code Directives, 2001/83/EC and 2001/82/EC, as amended by Directives 2004/28/EC and 2004/27/EC respectively. In addition, the Commission was required to publish guidance on the form and content of the GMP Certificate (Articles 47 and 51 respectively). The new Guidance on occasions when it is appropriate for competent authorities to conduct inspections at the premises of manufacturers of active substances used as starting materials was developed in the light of the new manufacturer obligations to ensure the application of GMP for active substances and corresponding inspection provisions for Member States. The Compilation of Community Procedures was prepared by EMEA, using Member States’ expertise through the Ad Hoc Working Group of GMP inspectors Generally, EU Member States are expected to accept the results of inspections performed by other Member States. Article 122 of the Community Code Directive governs disagreements in this area. C. Revision of Notice to Applicants and related documents In October 2005, the European Commission published the basic requirements for the manufacture of active substances used as starting materials as GMP Part II, replacing the former GMP Annex 18. Part II applies to active substances used in the manufacture of both human and veterinary medicinal products. The technical requirements are substantively the same as in the former Annex 18. The legal basis for the GMP Part II document is Article 47 of the Community Code on Medicinal Products for Human Use, Directive 2001/83/EC, and its counterpart, Article 51, in the Veterinary Medicinal Products Code, 2001/82/EC. Member States were required to bring the requirements into force by 30 October 2005. With the implementation of GMP provisions for active substances the GMP Guide has been restructured. The previous basic requirements for GMP have become Part I and the existing annexes remain, other than Annex 18, which has now been withdrawn. In early 2005, the European Commission and EMEA began issuing a number of documents relating to revision of EU GMPs. Among these were a new Part II: The Principles of Good Manufacturing Practice for Active Substances used as Starting Materials;150 Detailed GMP guidelines for active substances used as starting materials-public consultation;151 and the EMEA’s ad hoc inspection services’ Concept paper on the revision of some annexes to the European GMP guide in the context of GMP for active substances.152 The latter document described the plan by EMEA and Member State representatives to review and rewrite several Annexes to the NtA, including the new Part II of the GMP Guide based upon the text of Annex

150 EMEA/INS/GMP/15202/2005, 8 March 2005.

151 http://pharmacos.eudra.org/F2/pharmacos/new.htm, 3 March 2005.

152 EMEA/INS/GMP/147444/2005, 25 April 2005.


18 to the NtA. Both the old Annex 18 and the new Part II are based upon the ICH Q7A document on GMPs for active pharmaceutical ingredients. There also is a plan to review and revise documents that may contain duplications and overlaps with Annex 18. Among the Annexes to be reviewed and revised are: Annex 2, Manufacture of Biological Medicinal Products for Human Use Annex 6, Manufacture of Medicinal Gases Annex 7, Manufacture of Herbal Medicinal Products Because there is no specific guidance yet on GMP aspects of radionuclides, the active ingredients in radiopharmaceuticals, GMPs for these substances will be included in the upcoming revision. Also in March 2005, the EU institutions published Concept papers for revision of the GMP Guide on medicinal products derived from human blood or plasma; 153 a Community basic format for manufacturers/importers authorisation; and revised guidance on the format and content of a Certificate of GMP Compliance.154 EMEA and the Commission have recently published various documents on inspection issues, among them: A revised Compilation of Community procedures on inspections and exchange of

information155 Inspections at Manufacturers of Active Substances; Guidance on Grounds (Triggers) for

Inspection156 Guidance on the occasions when it is appropriate for Competent Authorities to conduct

inspections at the premises of manufacturers of active substances used as starting materials.157

Also in the works is a new Guideline on monitoring and inspection of compliance with Pharmacovigilance obligations.158 On its website, the European Commission emphasises that most of these documents will be equally applicable in the veterinary sector. D. Requirements for wholesalers and distributors The Community Code on Medicinal Products requires Member States to license wholesalers and distributors of medicinal products and to require observance by them of Good Distribution

153 http://pharmacos.eudra.org/F2/pharmacos/new.htm, 3 March 2005.

154 EMEA/INS/GMP/3351/2005.

155 EMEA/INS/GMP/82801/2005 8 March 2005; EMEA/INS/GMP/3351/03/Rev 3 corr, 8 March 2005.

156 Issued for public comment 8 March 2005.

157 EMEA/INS/GMP/50288/2005.

158 EMEA/INS/PhV/71267/2005.


Practices.159 To this end, the European Commission has published a Guideline on “GDPs,”160 with provisions resembling GMPs but focusing on responsibilities of the middlemen in the supply chain to maintain product quality. Among those subject to these requirements are parallel traders, discussed further in Chapter XIV.

159 Articles 76-85 of the Community Code on Medicinal Products set forth responsibilities of wholesalers and distributors, including parallel

traders. 160 Guidelines on Good Distribution Practice for Medicinal Products for Human Use, 94/C 63/03. The Guidelines were issued in conjunction

with Council Directive 92/25/EEC of 31 March 1992 on wholesale distribution of pharmaceuticals for human use, the substantive provisions of

which are now found in the Community Code on Medicinal Products, Directive 2001/83.


Chapter VII. Medicinal Products: Postauthorisation A. Variations 1. Purpose of legislation on variations In 2003, the EU published two regulations aimed at reducing workload by facilitating and accelerating the authorisation procedure in regard to variations, in order to: encourage simplified and faster alterations and improvements of medicinal products meet the challenges presented by EU enlargement differentiate minor variations from major variations, and differentiate both from extensions create a notification procedure for minor variations establish distinct timescales for validation of variation notifications The Decentralised Variation Regulation covers variations in marketing authorisations by Member States161 while the Centralised Variation Regulation covers variations in EMEA marketing authorisations.162 Both Variation Regulations took effect 1 October 2003. The approval procedures for variations under the two Regulations are intended to be as congruent as possible. The Community Code also contains provisions on variations.163 2. Key elements of variations regulations An important reform was the introduction of an approval procedure for major variations that is simpler than that required for a new marketing authorisation. There is an arbitration procedure in certain cases where a variation to a national marketing authorisation has been refused. The fundamental premise behind the legislation is that small alterations and improvements to medicinal products do not need a new marketing authorisation, due to their limited impact on the product.

161 Commission Regulation (EC) No 1084/2003 of 3 June 2003 concerning the examination of variations to the terms of a marketing

authorisation for medicinal products for human use and veterinary medicinal products granted by a Competent Authority of a Member State

(Official Journal L 159, 27/6/2003 p. 1 - 23) (Decentralised Variation Regulation).

162 Commission Regulation (EC) No 1085/2003 of 3 June 2003 concerning the examination of variations to the terms of a marketing

authorisation for medicinal products for human use and veterinary medicinal products falling within the scope of Council Regulation (EEC) No

2309/93 (Official Journal L 159, 27/6/2003 p. 24 - 45) (Centralised Variation Regulation).

163 Article 35 and 36, Community Code Directive 2001/83, as amended by Code Amendment Directive 2004/27.


Variations are divided into three types: Types IA and IB are minor variations listed in Annex I to the two Variation Regulations Type II consists of major variations that cannot be deemed to be either minor variations or

an extension of the marketing authorisation 3. Type IA variations The Type IA variation is a new category, intended for changes that do not affect the quality, safety or efficacy of the approved medicinal product and, thus, are suitable for a rapid notification procedure. Examples include: change in the name or address of the marketing authorisation holder (MAH) change in the active substance name change in the Anatomical Therapeutic Chemical (ATC) classification code used to classify

drugs deletion of any manufacturing site For a Type IA variation, the MAH submits a notification to either EMEA or the affected Member State drug regulatory authority. The Competent Authority issues a document acknowledging receipt of the notification. If the notification fulfils the requirements of a Type IA Variation, the Competent Authority informs the MAH of its validity within 14 days following receipt and does not assess the variation. If necessary, the Competent Authority shall inform other concerned Member State authorities. 4. Type IB variations Like Type IA variations, Type IB variations are a subcategory of minor changes listed in Annex I to the two Variation Regulations. In contrast to Type IA Variations, the Competent Authority must evaluate documentation submitted for Type IB Variations due to the nature of the change. Examples are: change in medical product name minor change in the active substance manufacturing process minor change in finished product manufacture change in container shape or dimensions or the closure of sterile pharmaceutical forms and

biological medicinal products For a Type IB variation, the MAH submits a notification to EMEA or the affected Member State drug regulatory authority. If, within 30 days following the receipt of a valid notification, the Competent Authority has not sent a nonacquiescence notice to the MAH, the variation is deemed to have been accepted. If necessary, other Member State authorities concerned shall be informed.


If the Competent Authority issues a nonacquiescence notice, the MAH may amend the notification within another 30 days following receipt of the opinion. However, if the MAH does not amend the notification, the notification shall be deemed rejected. 5. Contents of Type IA and IB submissions All Type IA and IB submissions should include the following: all necessary documents, including those amended as a result of the variation relevant fees in the case of a Member State authorisation: an indication as to which country is the

Reference Member State and which are the Concerned Member States, for the medicinal product affected by the proposed variation under consideration

6. Type II major variation Major or Type II variations are a category of intermediate significance, lying between the truly minor changes categorised as Type I variations and the more significant changes known as extensions, which are listed in Annex II to the Variation Regulations. For Type II variations, the MAH shall submit to EMEA a major variation application. Then, within 60 days of receipt of a valid application, the relevant EMEA committee (e.g., CHMP) shall give its opinion. This period can be reduced for urgent safety issues or can be extended to 90 days for therapeutic indication changes (or non-food-producing target species for veterinary medicines). The MAH can be asked for further information and the procedure shall be suspended until that information is provided. When the competent Committee delivers an opinion, the EMEA shall inform the MAH and the European Commission. When necessary, the European Commission makes necessary amendments in the marketing authorisation. The Centralised Variation Regulation 1085/2003 contains provisions for the MAH to request review (re-examination) in cases where the relevant EMEA committee is of the opinion that the application does not satisfy the requirements for a favourable response. Within 15 days of receipt of the opinion, the MAH may give written notice of a request for re-

examination. Within 60 days, the MAH shall forward the detailed grounds. Within 60 days of receipt of the grounds, the Committee shall re-examine its opinion. Within 15 days of adopting a final opinion, the Committee shall communicate that opinion to

the Commission, the Member States and the MAH. For a Type II Major Variation under the Decentralised Regulation 1084/2003, the MAH shall submit an application to the Competent Authorities of the Member States where the product has been authorised. The Competent Authorities notify the Reference Member State’s Competent Authority of their receipt of a valid application, and the Reference Member State then informs the other authorities and the MAH about the procedure’s starting date. Within 60 days of the starting date, the reference authority shall issue a draft decision and an assessment report to the other Competent Authorities. This period can be reduced for urgent safety issues or


extended to 90 days in some cases. The MAH can be asked for further information and the procedure shall be suspended until that information is provided. The next step for a Type II Major Variation that has received favourable action under the Decentralised Variation Regulation 1084/2003 is Mutual Recognition. Within 30 days of receipt of the draft decision, the other Competent Authorities shall recognise the decision. Each Competent Authority shall amend the market authorisation, if necessary. If Mutual Recognition of the draft opinion by one or more Competent Authorities fails, the matter shall be referred to EMEA for a re-examination of the decision, following the procedure in the relevant Community Code Directive (for human use products or veterinary products). If the variation application is rejected, the MAH may refer the matter to EMEA for re-examination. The following documents must be submitted with a Type II Major Variation, under either of the Variations Regulations: relevant particulars and supporting documents supporting data relating for the variation all documents amended as a result of the application an addendum to or update of existing expert reports/overviews/summaries relating to the

variation relevant fees for a decentralised authorisation, a list of the Concerned Member States and an indication of

the Reference Member State for the medicinal product For “urgent safety restrictions,” there is a special procedure designed to permit expeditious action. An urgent safety restriction is an interim change to product information concerning one or more product characteristics needed as a result of new information having a bearing on the medicinal product’s safe use. Following is the procedure for urgent safety restrictions: Where the restriction is initiated by the MAH, the MAH is required “forthwith” to inform the

Competent Authorities of the restriction.

o If no objections are raised within 24 hours of that information’s receipt, the urgent safety restriction shall be deemed accepted.

o A corresponding application for a variation shall be submitted without delay.

Where a Competent Authority imposes an urgent safety restriction on the MAH, the MAH is

obliged to submit an application for a variation, not later than 15 days after the initiation of the urgent safety restriction.

B. Extensions Extensions, as defined in Annex II to the Variation Regulations, are major alterations that change: the medicinal product’s active substance(s)


the strength, pharmaceutical form and route of administration in regard to veterinary medicinal products to be administered to food-producing animals, the

target species The application for a marketing authorisation extension follows the same procedures as the first marketing authorisation of the medicinal product in question. Thus, if the product is subject to EMEA’s centralised authorisation, the procedure in the EMEA Regulation 726/2004 applies. Otherwise, the decentralised authorisation procedure applies, where approval is given by the Reference Member State’s Competent Authority. In the extension application procedure, the same type of data must be submitted as is submitted when an applicant applies for a first marketing authorisation. Thus, in regard to extensions, the Variation Regulations do nothing to lighten the workload of the MAH or regulators. To aid MAHs and regulators in distinguishing extensions from variations, the European Commission has issued a Guideline on the Categorisation of Extension Applications versus Variations Applications.164 The Guideline gives several examples: A change from multi-dose to single-dose (or vice versa) always requires an extension

application. A pharmaceutical form change or addition always requires an extension application, except

where a solvent is deleted, in which case a Type II variation application should be submitted.

The addition or replacement of spacer devices for metered dose inhalers is a Type II

variation, unless the device is an integral part of the medicinal product, and the change results in a change of strength, pharmaceutical form or route of administration, in which case an extension application should be submitted.

Initial assessments by Member State authorities are favourable to the new system for variations; most difficulties are technical issues. Several authorities or associations have published detailed guidelines on how to submit notifications or applications, for example: European Commission Mutual Recognition Facilitation Group (MRFG) EMEA Danish Medicines Agency (DKMA) Dutch Medicines Evaluation Board (DBG/MEB)

164 F2/AW D2002, Final-Revision 3, October 2003.


UK Medicines and Healthcare products Regulatory Agency (MHRA) http://medicines.mhra.gov.uk/ourwork/licensingmeds/maintaining/variations.htm

C. Special approach for pandemic influenza vaccine There is one important exception to the rule that changes in active substances are defined as new products or at least extensions. In the case of the annual renewal procedure for human influenza vaccines, and possibly other human diseases in which a pandemic situation might occur, only a Type II Variation is necessary. The procedure is based upon two EMEA guidelines that came into force in April 2004, as well as more recent guidelines. A marketing authorisation applicant first submits a “core pandemic dossier” (actually a “mock dossier”) for a pandemic flu vaccine, based upon a vaccine of the type that the manufacturer might make in the future. This somewhat hypothetical procedure is necessary because, at the time of the submission, the vaccine’s precise composition for the next season is unknown. The applicant may be granted a marketing authorisation on the basis of this “core pandemic dossier.” If a pandemic is declared later and WHO and/or EMEA CHMP publishes a viral strain recommendation, the MAH can quickly prepare vaccine samples against that strain. The MAH then would be able to take advantage of the fast-track process, through a Type II variation procedure in which the CHMP might issue its opinion within a few days. The variation would then be published by the European Commission and the manufacturer would be required to collect immunogenicity, efficacy and safety data, which would be shared among all EU authorities. As part of this initiative, in July 2005, EMEA’s Vaccine Working Party (VWP) issued two guidelines on pandemic influenza vaccines on: dossier structure and content for pandemic influenza vaccine marketing authorisations

pandemic influenza vaccine marketing authorisation applications under the centralised

procedure In addition, a harmonised Summary of Product Characteristics has been developed by the VWP to facilitate submission of the core pandemic dossier and authorisation of the variation. Manufacturers are urged to consult with EMEA at the earliest possible time to discuss both the core dossier and the clinical trial plan. Since trials cannot be done on a future season’s precise viral strain, the applicant needs to show immunological response to a “mock-up vaccine.” D. Renewals Under long-standing EU law, a marketing authorisation for a medicinal product was valid for five years, after which it had to be renewed. This has all changed. Under the revision to the Community Code on Medicinal Products that Member States were required to implement by 30 October 2005, a medicine’s initial marketing authorisation is five years. After that initial period, the authorisation may be renewed for an unlimited period, unless the European Commission decides to require one additional five-year renewal. This change is a result of the 2004 amendments to the Community Code on Medicinal Products for Human Use and the Community Code on Veterinary Medicinal Products. In exchange, the frequency of certain pharmacovigilance reporting was increased. After marketing authorisation renewal, periodic safety update reports (PSURs) must be submitted every three years instead of every five years, as is discussed in the next section. The renewal procedure is:


The MAH shall provide a consolidated version of the file reflecting all quality, safety and efficacy variations introduced since the marketing authorisation was granted.

The file shall be submitted at least six months before the marketing authorisation expires.

This is a key timeframe for regulatory affairs professionals. The Competent Authority will re-assess the complete data. One controversial issue in implementing the Community Code revisions is the position taken by Member State authorities and the Commission that every medicinal product now on the market will require re-assessment to qualify for indefinite marketing authorisation. Industry suspects that some authorities want the additional fee income from renewals. There also is concern that Member State authorities, fearing the loss of the leverage that five-year renewals provided, may use the last renewal as an opportunity to make unreasonable data requests. EMEA has issued guidance on renewals of centrally authorised products.165 E. Pharmacovigilance and risk management The 2004 pharmaceutical review legislation introduced a number of key changes in this area. Deadlines for filing Periodic Safety Update Reports (PSURs) have been tightened:166 Old PSUR deadlines New PSUR deadlines Initial Every six months during the first

two years of authorisation Every six months after authorisation until they are placed on the EU market

Every six months during the first two years after EU market introduction

Intermediate Annually for the next three years Annually for next two years Regular At five-year intervals At three-year intervals

thereafter; also, PSURs can be requested at any time

The marketing authorisation application must now include a product risk management plan along with information on how the applicant will meet certain pharmacovigilance responsibilities. As indicated in the table below in block K, the EMEA has issued a draft guideline on risk management systems. A risk management system is a set of pharmacovigilance activities and interventions designed to proactively identify, characterise and prevent or minimise risks relating to medicinal products, including risk communication and the assessment of the effectiveness of risk minimisation interventions.167 EMEA can impose conditions and/or restrictions that reinforce an ongoing risk/benefit assessment. At any time, the agency may ask a marketing authorisation holder to submit data demonstrating favourable benefit-risk ratio.

165 EMEA CHMP, Guideline on the Processing of Renewals in the Centralised Procedure, EMEA/CHMP/2990/00 Rev 3, 20 October 2005.

166 The timetable for transition to the new reporting timeframes for centrally authorised products is set out in an EMEA guidance document

entitled Practical Considerations on the Impact of the New Pharmaceutical Legislation on Marketing Authorisation Applications via the

Centralised Procedure and Centrally Authorised Medicinal Products for Human Use EMEA/243280/2005, 8 September 2005. A similar

document for veterinary medicines, EMEA/31976/2005, was published 17 October 2005.

167 EMEA/CHMP/96268/2005, 6 September 2005, at page 4.


Marketing authorisation holders may not communicate pharmacovigilance information to the general public without giving prior or simultaneous notification to EMEA for centrally authorised products, or the relevant Member State agencies under a national or mutual recognition procedure.168 The information shall be objective and not misleading.

Key European Union Drug Safety Requirements

Type of action Description Legal authority (Community Code cites include 2004 revisions)

A. Adverse event reports

Marketing authorisation holder (MAH) shall maintain detailed records of all suspected unexpected adverse reactions occurring anywhere (in the EU or a “third country”). All suspected serious adverse events (SUSARs) shall be reported promptly (within 15 days) to the Competent Authority in the EU Member State where the incident occurs

Community Code Directive Article 104.

B. Conditional authorisations

EMEA can grant conditional authorisation for life-saving medicines, if a manufacturer agrees to follow-up studies when the product is on the market. In exceptional circumstances, marketing authorisation may be granted subject to specific procedures on safety and notification of adverse events. Continuing authorisation is linked to the annual assessment of the conditions to the authorisation.

EMEA Regulation Art. 14.8; Community Code Art. 22 EMEA Guideline on procedures for the granting of a marketing authorisation under exceptional circumstances pursuant to Article 14.8 of EMEA Regulation, EMEA/ CHMP/7350/2005

C. Eudravigilance The European electronic reporting system for transmission and management of safety reports on pharmacovigilance (Eudravigilance) will now include premarket as well as postmarket data, giving a more comprehensive profile on a product.

Community Code 88a, 105

D. Expert consultation

CHMP rapporteurs (while application is pending or postauthorisation) can solicit expert consultation on safety, quality or efficacy issues.

CPMP Procedure for Handling Special Safety Concerns (EMEA/CPMP /4285/2004)

168 Community Code, Article 104.9.


E. Inspection The EU authorities expect to conduct

more inspections of manufacturers focused upon compliance with pharmacovigilance requirements.

EMEA Guideline on monitoring and inspection of compliance with Pharmacovigilance obligations. EMEA/INS/PhV/ 71267/2005.

F. MedDRA The Medical Dictionary for Drug Regulatory Agencies (MedDRA) will be used for reporting.

ICH documents

G. Penalties for non-compliance

EMEA may impose financial penalties.Member States are required to take the necessary measures to ensure that marketing authorisation holders that fail to comply with their obligations are subject to effective, proportionate and dissuasive penalties.

EMEA Regulation Art. 84(3) Community Code, Art. 116-118

H. Periodic Safety Update Reports (PSURs)

PSURs are required more frequently to allow closer monitoring of new products. After marketing authorisation renewal, PSURs will be submitted six months after authorisation, then every six months in the first two years following authorisation and once a year for the following two years. Thereafter PSURs are every three years (instead of every five years as was the case under the prior law), reflecting the inauguration of the indefinite renewal following an initial five-year renewal (in some cases with a second five-year term). CMSs as well as RMS will receive relevant pharmacovigilance information

Community Code, Art. 104.6

I. Pharmacovigilance data from specific populations

For five years after a product is placed on the market, EMEA may request specific pharmacovigilance data on specific patient populations

EMEA Regulation Art. 26; Dossier Harmonisation Directive; Article 8.3(ia) Community Code Directive 2001/83/EC, as amended by the Code Amendment Directive


J. Pharmacovigilance plan in application for marketing authorisation

The applicant must include in the application for marketing authorisation, “where appropriate,” a description of a “risk-management system” and information on how the pharmacovigilance responsibilities will be fulfilled.

Community Code Art. 8.3 (ia), (n)

K. Pharmacovigilance and risk management plan

Detailed, long-standing requirements have recently been updated under the new legislation. EMEA may, at any time, request a marketing authorisation holder to send data demonstrating that the favourable benefit-risk ratio continues. Also, the recent ICH guideline on pharmacovigilance planning is being used by both FDA and EMEA in their drug safety programs. The document is widely read because it provides a toolkit of measures, in addition to collection of spontaneous reports of adverse events that might be imposed or recommended for the product. A marketing authorisation holder can suggest the application of these tools to address concerns about a product. An EU Risk Management Plan (EU-RMP) consists of: Part I A safety specification A pharmacovigilance plan Part II Evaluation of need for risk

minimisation, if needed Risk minimisation plan Provision of information Specifying legal status of medicine

(e.g., prescription-only) Control at pharmacy level Control of prescription size or

validity Informed consent Restricted access programmes Patient registries

Community Code Art. 101-108 Volume 9, Notice to Applicants ICH E2 guidelines EMEA Draft Guideline on Risk Management Systems for Medicinal Products for Human Use, EMEA/CHMP/ 96268/2005, 6 September 2005 (to become Chapter I.3 of Volume 9, Notice to Applicants)


L. Postmarket studies

EMEA can order postmarket studies if concerns about safety or efficacy arise after authorisation.

EMEA Regulation Art. 16(2), Art. 84(3) Community Code Art. 22

M. Qualified Person (PvQP)

The Pharmacovigilance Qualified Person (PvQP) must be named and is responsible for establishing and maintaining a system that ensures that information about all suspected adverse reactions reported to the company and to medical representatives. Information must be collected, collated and accessible at a point within the EU.

Community Code Art. 8.3(n), 103

N. Renewal procedures

Since 30 October 2005, the norm has been just one renewal after an initial marketing authorisation period of five years. Thereafter the marketing authorisation is valid for an unlimited period. However, the European Commission, based upon advice of EMEA’s CHMP, can decide that safety concerns warrant one additional five-year renewal. Such a decision is based upon the evaluation of the benefit-risk balance at the time of the initial renewal. At least six months before the initial authorisation’s expiry, marketing authorisation holders must submit requests for renewal along with a “consolidated version of the file” on all quality, safety and efficacy aspects and any variations.

Community Code, Art. 24


O. Removal of product from market

The European Commission, acting upon the opinion of EMEA’s CHMP, may order the withdrawal of a medicine from the market if the clinical evidence shows it is harmful under normal conditions of use, lacks therapeutic efficacy or the benefit-risk analysis is not positive under normal conditions of use. A modified definition for the withdrawal of a product from the market enables the additional basis for product withdrawal that it is “concluded” (previous law said “established”) that a product lacks therapeutic efficacy, is harmful or the “risk-benefit balance is not positive.”

Community Code Art. 116

P. Suspensions by Member States

Member States may suspend authorisations due to safety concerns and refer the matter to the CHMP for consideration and for decision at Community level.


Q. Third-country restrictions and information on benefit-risk

After a product’s authorisation, an MAH shall forthwith inform the Competent Authority of any prohibition or restriction in any country in which the medicinal product is marketed and of any other new information which may influence the evaluation of benefits and risks.


R. Unauthorised product may be permitted by a Member State

Member States are allowed to permit an unauthorised product on the market for “justified public health reasons.” This provision was included in response to concerns from small EU Member States that applicants for marketing authorisations might not bother with their small markets. Other provisions afford a means to address the need for rapid product availability in the case of emerging infectious diseases or other public health threats.

Community Code Art. 126a Article 5.1, Community Code on Medicinal Products Directive 2001/83, as amended.


S. Volume of sales Upon a pharmacovigilance-related request from EMEA or a Member State regulatory agency, the marketing authorisation holder shall provide data on sales volume or number of prescriptions for medicinal products.

Community Code Art. 23a


Chapter VIII. Generic Products Striking the balance between innovator rights and generic opportunities was one of the most contentious issues in the recently enacted EU medicines laws:

The new EMEA Regulation169

The Code Amendment Directive170 Importantly, the old and the new Community Code sections on abridged applications for generic products stipulate that these provisions are “without prejudice to the law relating to the protection of industrial and commercial property.”171 A. 2004 legislative changes The new EMEA Regulation contains provisions on generic medicinal products, aimed principally at describing the circumstances under which generic companies may use the:

centralised procedure under the optional route

decentralised procedure, for Member State authorisations of generic versions of reference products that were authorised via EMEA’s centralised procedure

The Code Amendment Directive has brought in a statutory definition of “generic medicinal product” that codifies case law, revises content and procedure provisions for various abridged application categories slightly and creates the opportunity for a generic company to submit its abridged application to a Member State regulatory agency other than the one that authorised the reference product. It also has inaugurated a “Bolar” amendment to allow generic manufacturers to do testing during the reference product’s patent life and has added a definition of “global marketing authorisation” to try to prevent innovators from “evergreening” exclusivities through product changes. In addition, there is a new definition of “similar biological medicinal product,” i.e., “biosimilar,” as discussed in Chapter IX.C. The EMEA Regulation and the Code Amendment Directive both contain provisions that will eventually revolutionise and, to some degree, harmonise the EU regulatory data protection period, described as “8+2+1.” This formula refers to the period during which an innovator’s reference product is shielded from generic competition. The new legislation sought to resolve issues that have, in the past, resulted in a large volume of litigation on generic regulation and innovator exclusivity. Lawmakers made a conscious effort to codify and rationalise a number of the European Court of Justice’s judgments in this area. Many issues have been resolved, but just as many new ones can be expected to emerge from the new laws, and litigation involving those laws will soon arise. The innovator industry believes the new legislation favours generic manufacturers, due to the inclusion of Bolar, the enshrinement of a broad reading of “essential similarity” from the case

169 Regulation on authorisation and supervision of medicinal products for human and veterinary use and on the European Medicines Agency, OJ

L 136, 30.04.2004, p. 1, replacing Regulation 2309/93, which set up the European Agency for the Evaluation of Medicinal Products.

170 Directive on the Community Code relating to medicinal products for human use, OJ L 136, 30.04.2004, p. 34, amending the Community

Code on Medicinal Products directive, 2001/83/EC.

171 Article 10.1, Community Code.


law,172 and an erosion of the pure 10-years’ exclusivity formerly in place for centralised authorisations and in many Member States. Many Member State healthcare reimbursement authorities wish to encourage generic use. Still, it was not all good news for the generic industry, as is discussed in this Chapter. In particular, the provision for a one-year extension of regulatory exclusivity for a new indication creates the opportunity for an 11-year exclusivity period. B. The EMEA Regulation The new legislation provides the industry with some choices regarding use of the centralised or decentralised process for generic versions of reference products that entered the market through the centralised EMEA route. In the next few years, EMEA will begin to grapple on a large scale with generic versions of products that have gone through the centralised procedure or are variants of other companies’ products, in instances where the applicant has justified the use of the centralised procedure under the optional jurisdiction provisions of Article 3 (discussed above at III.C. above). The new EMEA Regulation specifically mentions the possibility of extending the centralised authorisation option to generics “provided that this in no way undermines either the harmonisation achievement when the reference medicinal product was evaluated or the results of that evaluation.”173 This phrase appears to indicate that, in opening EMEA’s doors to generics, the European Community does not wish to disrupt whatever success may have been achieved through the Mutual Recognition process in multi-State marketing of the same product and, particularly, harmonisation of Summaries of Product Characteristics. Conversely, a generic version of a reference product that had been authorised under the centralised EMEA procedure may be authorised by the Competent Authorities of the Member States in accordance with the relevant Community Code (for human or veterinary products) under three conditions:174 the application is in accordance with the relevant Community Code abridged application

provisions175 the Summary of Product Characteristics is “in all relevant respects consistent with that of the

medicinal product authorised by the Community except for those parts of the summary referring to indications or dosage forms which were still covered by patent law at the time when the generic medicine was marketed”

the generic medicinal product is authorised under the same name in all the Member States

where the application has been made176 C. Definition of generic The Code Amendment Directive 2004/27 aimed to provide greater legal certainty in the use of abridged application procedures for generic medicines. The new legislation indicates that, generally speaking, entities that are salts, esters, etc., of authorised products no longer under

172 Generics, European Court of Justice, C 368/96, of 3 December 1998, and its progeny.

173 Preamble at (9).

174 Article 3.3, New EMEA Regulation, OJ L136, 30 April 2004, p. 6.

175 Article 10 of Directive 2001/83/EC or Article 13 of Directive 2001/82/EC.

176 For purposes of this provision, all linguistic versions of the International non-proprietary name shall be considered the same name. Article

3.3(c).


patent or exclusivity periods might qualify for handling under abridged applications. It clarifies what information the generic applicant must supply to justify such handling and strengthens the generic authorisation process at the Member State level. It is hoped that the new legislation will eliminate some of the previous ambiguities that have surrounded the issue of when the abridged-application pathway is open to generic companies. Two key definitions involve the “reference medicinal product” and the “generic medicinal product.” Article 10.2 (a) of the Community Code defines the “reference medicinal product” as one authorised under the procedures applicable to full applications177 while Article 10.2 states that a:

‘generic medicinal product’ shall mean a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies. The different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy. In such cases, additional information providing proof of the safety and/or efficacy of the various salts, esters or derivatives of an authorised active substance must be supplied by the applicant. The various immediate-release oral pharmaceutical forms shall be considered to be one and the same pharmaceutical form. Bioavailability studies need not be required of the applicant if he can demonstrate that the generic medicinal product meets the relevant criteria as defined in the appropriate detailed guidelines.

This definition largely codifies the approach taken by the European Court of Justice in the Generics case178 and others, in the context of challenges by innovators to decisions by EU Member State Competent Authorities granting marketing authorisations for generic versions of their products. D. Types of applications To be approved in the EU, a generic drug must go through what is called an abridged product application process. There are several types of abridged applications. In most cases, generic companies must prove bioequivalence to the innovator’s reference product and, of course, meet such general requirements as GMPs and labelling and advertising controls. However, they do not need to conduct preclinical and clinical trials to prove product safety and efficacy, because the innovator’s submitted and approved dossier for the reference product is treated as demonstrating safety and efficacy. The generic company does not have a right to obtain a copy of the reference product’s dossier but is allowed to refer the regulatory reviewer to that dossier, so long as the reference product is no longer under pertinent patents or regulatory data exclusivity. As a practical matter, the regulator may not even need to refer to the reference product’s dossier, as the safety and efficacy of the active substance are treated as having been established by the innovator’s efforts. It should be noted that, generally, an applicant has the option to “test its way to market,” even during the data exclusivity period, unless the reference product has orphan drug marketing exclusivity or a patent bars the ultimate approval. This testing option is not appealing to generic

177 Articles 6 and 8 of the Community Code.

178 European Court of Justice, C 368/96, of 3 December 1998.


companies because their business models seek to minimise the need for preclinical or clinical tests. Several types of marketing authorisation applications (MAAs) were described in Article 10 of the 2001 Community Code Directive (carryovers from the legacy Directive 65/65, as amended).179 Today these MAA categories are carried over to, and largely defined by Article 10 of the Community Code as amended and the Annex to the Community Code, added by the Dossier Harmonisation Directive. 1. Full (or Complete) Application. As a frame of reference for what the generic applicant

avoids by filing an abridged application, we refer here to a Full Application. It consists of the results of physicochemical, biological or microbiological tests; pharmacological and toxicological tests; and clinical trials. The data requirements are described in great detail in the Community Code Directive,180 particularly its Annex as amended by the Dossier Harmonisation Directive.181 See Chapter III.A. For products going through the EMEA centralised process, the EMEA Regulation specifies certain additional requirements.182

2. “Mixed Data” Applications. These are applications in which published scientific literature is

presented together with original test and trial results. Such applications must be submitted and processed following the complete, full and independent marketing authorisation dossier requirements. This applies to the use of bibliographic references in mixed dossiers both as supportive data of a manufacturer’s own tests or trials or in order to replace any tests or trials in certain modules (sections) of the Annex to the Community Code Directive. All other modules are comparable to those found in a full application. According to an EMEA guidance document, the reviewing agency accepts the proposed format on a case-by-case basis.183

3. Bibliographical Application. According to long-standing provisions of EU medicinal

products law,184 it is possible to replace results of pharmacological and toxicological tests or clinical trials with detailed references to published scientific literature (information available in the public domain) if it can be demonstrated that the constituents of a medicinal product have a “well-established medicinal use,” with recognised efficacy and an acceptable level of safety. Bibliographical applications have been treated as a type of full and independent application. The term “well-established medicinal use” has been much debated in the years since the term entered EU pharmaceutical parlance, but some guidance is now available in

179 Much of this section is drawn from the EMEA Pre-Submission Guidance for Users of the Centralised Procedure, February 2005, pp. 8-9,

with updating to reflect the 2004 legislation. The accompanying text does not, however, adopt a viewpoint expressed in the guidance citing to

Article 10(1)(a)(iii) of the Community Code Directive as providing a biosimilar pathway. The citation to 10(1)(a)(iii) as authority for biosimilars

is controversial with innovative manufacturers, which point to the Dossier Harmonisation Directive and Article 10.4 of the Code as revised by the

Code Amendment Directive as the only proper sources of authority for biosimilars.

180 Article 8.3 of the Community Code Directive as amended by the Code Amendment Directive.

181 Annex to Community Code Directive as amended by the Dossier Harmonisation Directive, Commission Directive 2003/63/EC, 25 June

2003, L 159/46.

182 Article 6 of new EMEA Regulation, 726/2004.

183 EMEA Pre-Submission Guidance for Users of the Centralised Procedure, February 2005.

184 Until 30 October 2005, the citation is to Article 10(a)(1)(ii) of the Community Code. However, this provision no longer appears in the

Community Code after the effective date of the Code Amendment Directive. Its subject matter is now handled in the Annex to the Community

Code, following the law described in the next footnote.


the Dossier Harmonisation Directive,185 adding the Annex to the Community Code. It contains sections concerning demonstration of the safety and efficacy of these well-established uses. This approach applies to any medicinal product to which essential similarity can be claimed. For example, there are old medicinal products that have long been marketed, but for which there is no original or reference product to which sameness or similarity could—in an abridged application—be claimed. Typically, these old medicinal products are well-established and have known indications, strengths and pharmaceutical forms. Over the years in which they have been marketed and used, there generally is public information available about their safety and efficacy.

4. Abridged Applications. These are applications in which, subject to certain conditions, the

applicant is not required to provide the results of pharmacological and toxicological tests or clinical trials, as they refer to information contained in the dossier of a reference product’s authorisation. Among the possible types of abridged applications are:

Informed consent application The owner of certain privileged information gives or sells a right of reference to such

data, which can be a right of reference to a full application, similar to the common use of master files covering substances contained in a medicine. 186

Generic application An application for a medicinal product claimed to be “essentially similar” to a reference

medicinal product if the generic applicant demonstrates that its medicinal product is essentially similar to a reference product that has been authorised within the Community for the time period set in the relevant legislation on regulatory data exclusivity, as discussed below.187

Hybrid abridged procedure “…where the medicinal product is intended for a different therapeutic use from that of the

other medicinal products marketed or is to be administered by different routes or in different doses, the results of appropriate pharmacological and toxicological texts and/or of appropriate clinical trials must be provided.” There are two possible hybrid abridged procedure scenarios:

o “Where the active substance of an essentially similar medicinal product contains

the same therapeutic moiety as the original authorised product [reference product] associated with a different salt/ester-complex/derivative evidence that

185 Commission Directive 2003/63 of 25 June 2003, Annex I, Part II.1.

186 Commission Directive 2003/63 of June 25 2003, Annex I, Part II.2 a); also, until 30 October 2005, article 10(1)(a)(i) of the Community Code

Directive. EMEA Pre-Submission Guidance for Users of the Centralised Procedure (Feb. 2005) available at

www.emea.eu.int/htms/human/presub/PSG%20Compilation.pdf

says the Active Substance Master File (ASMF) concept is not acceptable for biological medicinal products because “the characterisation and

determination of biologically active substances’ quality requires not only a combination of physicochemical and biological testing, but also an

extensive knowledge of the production process and its controls.”

187 Commission Directive 2003/63 of June 25 2003, Annex I, Part II.2 b); until 30 October 2005, article 10(1)(a)(iii) of the Community Code

Directive.


there is no change in the pharmacokinetics of the moiety, pharmacodynamics and/or in toxicity which could change the safety/efficacy profile shall be demonstrated [with the admonition that, “should this not be the case, this association shall be considered a new active substance].” 188

o “Where a medicinal product is intended for a different therapeutic use or to be

administered by different routes or in different doses or with a different posology, the results of appropriate toxicological and pharmacological tests and/or of clinical trials shall be provided.”189

In addition to the changes noted above, it should be mentioned that a generic company may seek to avoid breaching patents by omitting patented indications and dosage forms from Summaries of Product Characteristics. E. Contents of an abridged application based on essential similarity

complete quality information (or documentation of consent to refer the regulator to the reference product’s file)190 together with data showing bioavailability and bioequivalence with the reference product, provided that the latter is not a biological medicinal product (particular requirements for biosimilars are specified separately)

grounds for claiming essential similarity

summary and evaluation of impurities present in batches of the active substance(s) as

well as those of the finished medicinal product (and, where relevant, decomposition products arising during storage)

evaluation of bioequivalence studies or justification why studies were not performed in

accordance with the European Commission Note for Guidance on the Investigation of Bioavailability and Bioequivalence

update of published literature relevant to the substance and the present application

(articles in peer-reviewed journals may be annotated)

discussion and substantiation (by published literature and/or additional studies) of every claim in the Summary of Product Characteristics not known or inferred from the properties of the medicinal product and/or its therapeutic group

if applicable, additional data to demonstrate evidence of the equivalence of safety and

efficacy properties of different salts, esters or derivatives of an authorised active substance

188 Commission Directive 2003/63 of June 25 2003, Annex I, Part II.3.

189 Id.

190 EMEA Pre-Submission Guidance for Users of the Centralised Procedure (Feb. 2005) available at

www.emea.eu.int/htms/human/presub/PSG%20Compilation.pdf states that the Active Substance Master File (ASMF) concept is not acceptable

for biological medicinal products because “the characterisation and determination of biologically active substances’ quality requires not only a

combination of physicochemical and biological testing, but also an extensive knowledge of the production process and its controls.”


F. Generic submissions to Member States other than Reference Member State A generic medicinal product application may be submitted to a Member State drug regulatory authority other than the Reference Member State/Member State agency that originally reviewed and approved the innovator’s full application.191 At the request of the agency with which the generic application is filed, the Competent Authority with the reference product dossier must, within one month, confirm that the reference product is or has been authorised, together with the full composition of the product and “if necessary other relevant documentation.” The latter change has caused some consternation in the innovator industry about creating a situation where the entire Reference Product dossier might be requested by the agency reviewing the generic application and where the Reference Product’s sponsor might then be subjected to burdensome inquiries. This amendment reverses the long-standing principle of permitting abridged application submission only to an authority fully in charge of the reference product’s original full marketing authorisation. In providing that the reference product need no longer be authorised at the time of the generic product application, the legislation is consistent with the holding of the ECJ in AstraZeneca v. Laegemiddelstyrensen192 involving the originator product Losec (omeprazole). G. Impact of new legislation on patent law 1. Patents Fundamental EU patent law remains intact; European drug patents run for 20 years from the time of filing. 2. Supplementary Protection Certificates (SPCs)193 Created by a 1992 Regulation, the SPC for a medicine provides up to five years additional patent protection to compensate for the lost patent life between the time of patent filing and EU marketing authorisation. (The US counterpart provision, in the Hatch Waxman Act, also adds five years.) SPCs help make up for the significant portion of that 20 years spent developing a drug product and obtaining regulatory approval. SPCs were unaffected by the 2004 legislation, are discussed in further detail in section VIII.H. below. 3. US Bolar Provision

In Roche Products, Inc. v. Bolar Pharmaceutical Co. 733 F. 2nd 858, certiorari denied 469 U.S.

856 (1984), the court of appeals held that US patent law was violated when a generic company (Bolar) tested its product against that of the pioneer (Roche) during the patent life of the latter’s pioneer product. Subsequently, as part of the 1984 Hatch-Waxman Drug Price Competition and Patent Term Restoration Act,194 the holding of the Bolar case was reversed in a clause dubbed the “Bolar” provision that reads in part:195

191 Article 10.1 of the Community Code as revised by the Code Amendment Directive, 2004/27.

192 ECJ judgment of 16 October 2003 in C 223/01.

193 The acronym “SPC” (or sometimes “SmPC”) is used also for the Summary of Product Characteristics. In this book “SPC” is reserved for the

Supplementary Protection Certificate.

194 Pub.L.98-417 (1984).

195 35 USC 271 (e)(1).


It shall not be an act of infringement to make, use, offer to sell, or sell within the United States or import into the United States a patented invention . . . solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products.

4. WTO “Bolar” Case Guidance on the outer limits of a permissible Bolar provision is provided by a World Trade Organisation (WTO) panel report issued in 2000, in an EU challenge to Canada, Canada-Patent Protection of Pharmaceutical Products.196 Testing and development of generic copies of patented drugs would not infringe patent rights, so long as the steps taken are “confined to conduct needed to comply with the requirements of the regulatory approval process” including “substantial amounts of test production to demonstrate reliable manufacturing,” but only if “such production runs are solely for regulatory purposes and no commercial use is made of the resulting final products.”197 The Canadian law at issue was acceptable in permitting generic testing during the pioneer’s patent life, but went too far in allowing the generic company to manufacture product and stockpile it for launch immediately upon patent expiry. The manufacture and stockpiling of commercial quantities of the generic drug during the patent term of the pioneer for future sale purposes, rather than regulatory approval purposes, is not allowed: this conduct “constitutes substantial impairment of the exclusionary rights required to be granted to patent owners under Article 28.1 of TRIPS.”198 Canada was required to amend its law to align with the WTO ruling. US law is consistent with the WTO ruling. And, when the European Commission decided in 2001 to propose a Bolar provision in the pharmaceutical review legislation, it had the benefit of the WTO panel’s thinking in a case the EU had half-lost and half-won the year before. 5. EU Bolar Provision A harmonised EU-wide Bolar provision allows the use of patented drugs for generic testing and development work, in any EU country, without such “early working” being considered patent infringement. Prior to the enactment of this provision, part of the 2004 Community Code Amendment Directive, testing a generic drug during the innovator product’s patent life—to develop copies and test them for bioequivalence with the patented drug—was regarded by many EU countries (and by the European Commission) as patent infringement. Although some EU countries allowed very limited generic experimentation, the laws varied by country and were much stricter than those of the US and other countries with Bolar laws. Several of the 10 new EU Member States had Bolar laws and, as a result, had become popular European locations for generic testing. This EU Bolar provision is intended to keep both the technical expertise and the investment money involved in such work within the expanded EU and to allow generics to reach the market more quickly. Previously, companies could conduct generic testing and trials outside the EU and use the results to submit an EU marketing authorisation application following the expiration of any patents and exclusivity periods. Thus, the new EU Bolar rule introduces the possibility for generic companies to start development work on a generic while the innovator’s product is still under patent protection. The

196 WTO WT/DS 114/R, 18 August 2000.

197 Id.at 203.

198 Id.at 200.


Community Code as amended now provides that, “Conducting the necessary studies and trials with a view to the application of [provisions on abridged applications] and the consequential practical requirements shall not be regarded as contrary to patent rights or to supplementary protection certificates for medicinal products.”199 Providing samples is considered a permissible activity. H. Supplementary Protection Certificates (SPCs) The EU Regulation on Supplementary Protection Certificates200 is otherwise unaffected by the new legislation. In 1992, European authorities had created the SPC as a means of extending certain medicinal product patents, in order to compensate a patent holder for the elapsed time between filing the patent application and the product’s first EU marketing authorisation. An SPC may be granted once, at the expiry of patent protection. In Europe, when an innovator company has a SPC for its product, a very long patent term is possible. These terms, extending as much as 25 years after patent filing, generally exceed the applicable data exclusivity time periods. However, in some cases, the data exclusivity provisions discussed below can be a vitally important incentive for innovators by shielding products from generic competition long enough for some or all development investments to be recouped. Data exclusivity periods are particularly useful when: a product is, for one reason or another, not patentable; an innovator is unable to get a SPC; or product development and regulatory review take so long that the effective remaining patent life is short. Importantly, many biotechnology products could not be patented in the EU until a 1998 Directive201 was enacted on this subject. Without this data exclusivity period, certain innovative drugs might never reach the market.

The patent and data exclusivity systems complement one another to protect innovation. It is important to look not only at patent expiry (including any SPC) but also exclusivity period expiry.

Complicating efforts to keep on top of a company’s intellectual property portfolio is the fact that there is no EU registry of products subject to unexpired data exclusivity periods. For SPCs, there is a register at the European Patent Office of all SPCs filed and granted in any EU Member State. An SPC is unavailable for a first authorisation of a product for human use,

if it was already marketed for veterinary purposes. In October 2004, a European Court of Justice (ECJ)202 decided a case of importance to the pharmaceutical industry relating to SPCs.

According to the ECJ judgment, the protection provided by the SPC applies to any use of the medicinal product, without any distinction between human or veterinary use. Consequently, a medicinal product cannot be granted a SPC for the first authorisation for human use if it had earlier been marketed for veterinary purposes.

The ECJ case was a referral from a German Federal Court following Pharmacia’s appeal of a ruling by the German Patent Office. The agency had refused to issue a SPC to Pharmacia, which Pharmacia had requested in 1994 for the active ingredient cabergoline, an ingredient first authorised as a medicinal

199 Article 10.6, Community Code, as amended by the Code Amendment Directive.

200 Council Regulation (EEC) No 1768/92 of 18 June 1992 concerning the creation of a supplementary protection certificate for medicinal

products (OJ 1992 L 182, p. 1).

201 Biotechnology Patent Directive, 98/44/EC.

202 ECJ Judgment of October 19, 2004 in C-31/03, Pharmacia Italia.


product for human use in 1992 in The Netherlands. Under the Regulation as applied in Germany, only those products for which the first marketing authorisation in the European Community was obtained after 1 January 1988 were eligible for a SPC in Germany, and Galastop, a veterinary medicinal product that also contains cabergoline, had been authorised in Italy in 1987. The German Patent Office, therefore, took the position that the first marketing authorisation for the purposes of Article 19 of the EU SPC Regulation was the one granted in 1987 in Italy and rejected Pharmacia’s application for a SPC for the human-use cabergoline product.

In its appeal to the German Court, Pharmacia argued that the first marketing authorisation was the one The Netherlands granted for the medicinal product for human use. Under procedures in the European Community treaty, the German court stayed its proceedings and requested the ECJ to decide an EU law question: whether an authorisation for a veterinary medicinal product granted in an EU Member State should be regarded as the “first marketing authorisation” that would prevent granting of a SPC for the same product for human use.

Pharmacia also argued that, based upon an examination of the Regulation as a whole, as well as its “broad logic and purpose,” a distinction was intended between medicinal products for human use and those for veterinary use.

In its judgment, the ECJ noted that, while the Regulation mentions human use products and veterinary use products separately, it makes no distinction between these categories in the definition of “product” or the relevant authorisation procedures, the provisions the court considered most pertinent. The ECJ held that “neither the purpose of Article 19 nor the broad logic of the [Regulation]” supported Pharmacia’s interpretation. The ECJ therefore backed the decision by the German Patent office.

Although situations affected by this ruling will be rare, it is clear that patent owners must take care to reserve first entry into the EU marketplace to human medicinal products rather than veterinary use products, if the interest is in patent term restoration, through a SPC, for the human uses of the product. I. Regulatory data protection: “8+2+1” and “global marketing authorisation” One of the biggest changes effected by the 2004 pharmaceutical review legislation was in the area of regulatory data exclusivity, which will be harmonised across the “EU25” in a compromise policy called 8+2+1. 1. Background Data exclusivity laws prevent regulators from reviewing or processing a generic manufacturer’s abridged marketing application that references the innovator’s clinical safety and effectiveness data, for a set period of time after the reference product’s marketing authorisation is granted. During this time period, a competitor may conduct its own original testing and clinical trials. However, a generic company that does not want to conduct trials of its own, but needs to prove that its product meets the legal standard, may be barred from referring the regulator to the innovator’s data until the relevant data exclusivity period expires.

As discussed above, patent protection continues to be the primary mechanism to reward innovation and protect innovators’ R&D investments from early generic competition that would erode incentives. An additional safeguard, known as regulatory data protection or exclusivity, given to first-time innovators of new chemical entities is also an important protection for


undisclosed proprietary information. Providing such protection is a requirement of the World Trade Organization Agreement on Trade-Related Intellectual Property Rights (TRIPS).203 Under EU law, data exclusivity provisions have been in place since 1987 but have eroded through judicial interpretations. The exclusivity period is only for the new chemical entity for which the first authorisation was obtained. Consequently, any new indications, dosage strengths or dosage forms will not be treated as initiating additional or new data exclusivity periods. This was made clear in the European Court of Justice’s 1998 judgment in the "Generics case"7 and other judgments. The new pharmaceutical review legislation codifies or rationalises the judicial interpretations in the Community Code’s new “generic” definition and in the related definition of “global marketing authorisation.” 2. Overview of changes Key elements of the new 8+2+1 regulatory data exclusivity system are: eight years’ data exclusivity: during this period no generic applications may be filed (unless

the follow-on application is based upon its own data or has the consent of the innovator) two years’ marketing protection: generic applications may be submitted on the eighth

anniversary of the reference product’s marketing authorisation’s publication in the Official Journal of the European Communities but, postauthorisation, they may not be marketed until the 10th anniversary of the innovator’s authorisation

one additional year possible: for a new indication (or indications) that offers significant

clinical benefit and is authorised during the first eight years; if an innovator qualifies for the extra year, generic versions are barred from the market as to all indications until the 11th year has ended

The new legislation creates a harmonised exclusivity period in all Member States for all approvals (centralised and decentralised). The new 8 + 2+ 1 system applies to all products for which applications were submitted after the new Code Amendment Directive became operational, 30 October 2005, or to the EMEA after 20 November 2005. A generic company may submit its abridged application that references the innovator’s data to EMEA or a Member State drug regulatory authority as early as the eighth anniversary of innovator authorisation. However, neither EMEA nor a Member State regulatory authority may approve and allow marketing of a generic product for two more years—or until the 10th anniversary of the reference product’s authorisation. Again, the “+1” would come into play if the innovator sought and obtained approval for a new indication during the first eight years of its product’s exclusivity and was granted approval of the new indication. The result would be a total of 11 years of exclusivity. Also, there is a separate “+1” for a new use for a well-established product or for an Rx-to-OTC switch, as discussed below.

The 8+2+1 formula is a grand-scale legislative compromise that pleases no one completely but also is not as bad as it might have been, in the eyes of the interested parties. Innovators suffer some erosion of research incentives compared to the previous 10-year data exclusivity period they enjoyed in centralised EMEA approvals and in most key Member States. This was a full 10 years, with Bolar testing generally disallowed and generic firms unable to submit abridged applications in the eighth year. At the same time, generic companies in the EU 15 and

203 Article 39.3.


the 10 accession countries would have strongly preferred either harmonisation to a six-year data exclusivity period or retention of the “6 versus 10” option allowed under previous law. (New Member States are not being given additional time to adjust to the new 8+2+1 formulation, as discussed in section L. of this chapter.)

As a result of the new legislation, EU data protection laws are now, in many respects, markedly more innovation-friendly than those of the US. The US exclusivity period is five years after approval of a new chemical entity and innovators may receive an additional three years for approval of a new indication, creating a “5+ 3” scheme. 3. The system that is being replaced As noted, the system preceding enactment of the new legislation will continue to be significant for a long time, until at least 2012. The old “10/6” system continues to govern all applications submitted prior to 30 October 2005, under the decentralised system, or prior to 20 November 2005, under the centralised system. Key elements of the old 10/6 regulatory data exclusivity system were:

centrally-approved products had a full 10 years, starting with authorisation (publication by the European Commission of a decision granting the marketing authorisation)

nationally-approved products had either 10 or six years, based upon the Member State’s

choice:

o 10 years: Belgium, France, Germany, Italy, Luxembourg, The Netherlands, Sweden and the UK

o six years: Austria, Denmark, Finland, Greece, Ireland, Portugal, Spain and all the

new Member States (Cyprus, the Czech Republic, Estonia, Hungary, Latvia, Lithuania, Malta, Poland, Slovakia, and Slovenia)

o six years: Norway and Iceland (linked to the EU through the European Economic

Area treaty) 4. Possibility of exclusivity periods for new indications or switches Under 8+2+1, data submitted by companies for product approval will be protected for 10 years across the EU from the time of first authorisation, making it impossible to market generics until after that period has elapsed. This can be extended by another year if an additional innovative indication for the product is authorised. There are two ways products already marketed can, after the effective dates of the new Community Code revisions (30 October 2005) and EMEA Regulation (20 November 2005), achieve regulatory exclusivity periods:

a one-time, one-year data exclusivity period for a new indication for a well-established substance (Art. 10.5)

a one-year data exclusivity for change of classification (prescription to OTC) (Art. 74a) The generic industry had opposed these provisions, citing concerns about their impact on efforts to harmonise Summaries of Product Characteristics as well as other product information. The industry also argued that the impact on Member State generic substitution laws is unclear.


A European Commission guidance provides details on what information must be submitted by companies seeking a one-year data exclusivity for change of classification. This document, issued in October 2005, is entitled A Guideline on Changing the Classification for the Supply of a Medicinal Product for Human Use. 5. Other product improvements Other product improvements do not earn the innovator the opportunity to request data exclusivity. The controversial Novartis/Sangstat judgment of the European Court of Justice—decided under laws recodified in the Community Code in 2001—continues to attract interest and debate. Novartis/Sangstat is summarised in a box at the end of this Chapter. 6. Global marketing authorisation The new legislation introduces the term “global marketing authorisation.” This term has absolutely nothing to do with the Common Technical Document developed by the International Conference for the Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Rather, it is a legal construct seeking to reduce innovators’ ability to claim that an innovation in its product warrants a new regulatory exclusivity period and is in many respects a companion to the new definition of “generic medical product” discussed at the beginning of this chapter. Article 6.1 of the Community Code, as amended, provides as follows:

When a medicinal product has been granted an initial marketing authorisation in accordance with the first subparagraph, any additional strengths, pharmaceutical forms, administration routes, presentations, as well as any variations and extensions shall also be granted an authorisation in accordance with the first subparagraph or be included in the initial marketing authorisation …

It remains to be seen whether one global marketing authorisation can restrict a later applicant, unconnected to the original marketing authorisation holder, who wants a period of protection for a product improvement investment. As discussed below, there is a chance that the different wording in the EMEA Regulation, compared to the Community Code, might create a way for such second-comer innovations to have an exclusivity period of their own under the centralised procedure. Decentralised authorisations certainly will be governed by the Novartis/Sangstat judgment that an innovator who makes improvements in his product—such that the new improved product is not essentially similar to the reference product—does not get an additional period of exclusivity. 7. Differences between the Community Code and EMEA Regulation The preamble to the new EMEA Regulation states that, “For medicinal products for human use, the period for protection of data relating to pre-clinical tests and clinical trials should be the same as that provided in Directive 2001/83/EC.”204 However, the provisions on regulatory data exclusivity in the Community Code Amendment Directive and the EMEA Regulation are not entirely congruent. On first reading, there appears to be harmonisation between the regulatory data exclusivity period prescribed for Member State



authorisations under the Community Code Amendment Directive and the similar-sounding exclusivity period provision for centralised authorisations through EMEA. In reality, however, some key differences between the two laws might result in advantages to innovators that use the centralised authorisation procedure (whether required to do so or through exercise of the optional review provisions in Article 3 of the EMEA Regulation). The question is whether the regulatory exclusivity provision in Article 10.1 of the Community Code for decentralised authorisations, and the regulatory exclusivity period in Article 14.11 of the EMEA Regulation for centralised authorisations, should be interpreted in the same way. Their wording is similar, but there is no direct legal link between these provisions (i.e., neither cross-references the other). There appears to be the possibility of claiming a full 8 + 2 regulatory exclusivity period under the EMEA Regulation, in the case of a second company having bought from the innovator all of an existing product’s development rights for a new indication. It can be argued that, when the second company submits an original marketing authorisation application for a second indication, it should obtain not the meagre, one-year exclusivity period but rather the 8 + 2 regulatory exclusivity period for its centrally authorised, new product. This may be true even though the same chemical is already authorised, because the new indication is through the centralised process and another company had the original indication. This possibility stems from the fact that the regulatory exclusivity provision in Article 14.11 of the new EMEA Regulation—unlike its 1993 predecessor—contains no reference to the Community Code’s similar regulatory exclusivity provision. Article 14.11 can be read as allowing the second company to have the full 8 + 2 exclusivity period even though the first company, if it were to seek a second indication for its product, would receive only a one-year extension. J. Other exclusivity laws Orphan product marketing exclusivity was unchanged by the pharmaceutical review legislation. Since 2000, under the EU Orphan Drug Regulation,205 a company whose product had been designated as an orphan drug could, upon approval, receive 10 years of exclusivity. During that 10-year period, applications for the same therapeutic indication could not be accepted or approved. Marketing exclusivity is intended to allow the innovator to recoup its investment in a product that, because it is for rare diseases and conditions, would not otherwise attract the necessary interest among investors and manufacturers. EU orphan medicinal product law is discussed below in Chapter XII. At the time of publication of this book, in October 2005, legislation providing a proposed six-month extension for paediatric indications had been passed by the EU Parliament, on 8 September 2005 and seemed headed for adoption in 2006. The proposal is discussed below in Chapter XII.H. K. EU initiative to punish innovators for alleged violation of competition rules In July 2005, the European Commission ordered AstraZeneca to pay a fine for its alleged infringement of EU competition rules. The Commission concluded that, from 1993 to 2000, AstraZeneca kept Losec’s EU market share and prices artificially high by blocking or delaying market access for generic versions and preventing parallel imports. The EU Commissioner for Competition was quoted as saying that, while she fully supports strong intellectual property protection for companies to recoup their R&D costs, “misleading regulators to gain longer protection acts as a disincentive to innovate and is a serious infringement of EU competition

205 Regulation (EC) no. 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products.


rules.” This is the first antitrust case in which the Commission has used competition law remedies to tackle alleged patent abuse in the EU pharmaceutical sector. AstraZeneca has announced its intent to appeal the Commission’s decision in EU court. L. Controversial issues associated with the new legislation Many issues concern the balance between innovators and generics and involve the New Member States, as discussed in Chapter XXII below. Will new Member States automatically recognise the exclusivity periods of centrally

authorised products? What activities may be undertaken during years eight and 10? What are the eligibility criteria for the +1? What is a “significant clinical benefit” in comparison to existing therapies and who will decide

if the criterion is met?206 What will the sponsor have to do to show superiority? Will the decision on the +1 be made soon enough for a sponsor to decide whether doing the

research to support the new indication is worthwhile? Have the new definitions of generics and global marketing authorisation put an end to efforts

by innovators to have a period of exclusivity to reward and recoup efforts at product improvements?

Will the EMEA 8+2+1 be different from decentralised 8+2+1? Seven new Member States—Malta, Hungary, Slovenia, Slovakia and Poland—requested exemptions from data exclusivity provisions. In April 2004, the first of these, Poland, stated its intention to apply for a 15-year transitional period before implementing the provisions. In October 2005, the EU Commission began informing inquirers that it has no intention of proposing any transition period for new Member States.207 This decision was based upon the results of an external study commissioned to look into new Member States’ pharmaceutical

206 EMEA is developing a Guideline on elements required to support the significant clinical benefit in comparison with existing therapies of a

new therapeutic indication in order to benefit from an extended marketing protection period (1 year) pursuant to article 14(11) of Regulation (EC)

No 726/2004 (EMEA/CHMP/63980/2005).

207 For example, an e-mail dated 12 October 2005 from Stefaan VanDerSpiegel of the European Commission, Enterprise Directorate-General to

Malgorzata Lesiak of the Warsaw office of Hogan & Hartson LLP (with a copy sent to Nils Behrndt, Acting Head of Unit for Pharmaceuticals)

stated that:

…Alcimed, the contracted expert has concluded its study and the report will be published soon. In it's findings the expert indicated that impact of

a potential derogation would be limited by (1) the fact that most innovative drugs are anyhow protected from generic entry through a patent and

(2) the fact that the marketing authorisation for most innovative drugs will go through the Central Community Procedure which will give them an

exclusivity for 10 years in the entire EU.

As a consequence, the Commission has not found sufficient ground to propose postponing the implementation of the new pharmaceutical

legislation in any of the requesting Member States. The requesting Member States have been informed of this.


industries, to assess the economic impact of the new provisions. Consequently, all Member States—including the new Members—were under a legal obligation to adopt legislative measures to harmonise with the Community Code Amendment, including its new 8+2+1 regulatory data protection time period, as of the 30 October 2005 implementation deadline. Obviously, many Member States missed this deadline, and pharmaceutical companies should be prepared to argue that they should not be disadvantaged due to the failure or inability of a Member State to conform its law to Community law by 30 October 2005. Therefore, their applications to Member States for decentralised applications after that date must be eligible for the new 8+2+1 exclusivity formula, whether or not that Member State has enacted legislation to replace previous six-year exclusivity laws with this new formula. ECJ allows a hybrid abridged application relying on <10-year-old data on a

second generation product. The issue in this case was whether the UK Medicines Control Agency acted properly when considering certain Novartis data for its second-generation cyclosporine, Neoral, in the agency’s 1999 approval of a hybrid, abridged application submitted by SangStat for its product SangCya. A provision of the EU directive then in effect,208 allowed a hybrid abridged application in certain cases (Hybrid Abridged Procedure).

The UK court had referred certain European Community legal questions to the ECJ. The ECJ upheld the Medicines Control Agency’s action.

In a judgment209 rendered in early 2004, the ECJ ruled that: 1. Products cannot be regarded as essentially similar for the purposes of the

EU abridged procedure, where they are not bioequivalent.210 2. However, the three medicinal products at issue211 may be treated as

having the same “pharmaceutical form”212—a factor supporting eligibility for the two later products, Neoral and SangCya, for the Hybrid Abridged Procedure—a solution to be mixed in a drink for patient administration and which, after mixing, forms, respectively, a macroemulsion (Sandimmun), a microemulsion (Neoral) and a nanodispersion (SangCya).

3. For the Hybrid Abridged Procedure, the later medicinal product must be

essentially similar to the authorised product, unless differences necessitate filing the results of appropriate preclinical and/or clinical trials.

208 Article 4.8 of Council Directive 65/65/EEC of 26 January 1965, as amended by Council Directives 87/21/EEC of 22 December 1986,

89/341/EEC of 3 May 1989, and 93/39/EEC of 14 June 1993. These laws were superseded and repealed by the Community Code on Medicinal

Products, Directive 2001/83/EC, which recodified into Article 10. The former Article 4.8 “essential similarity” provisions as interpreted in ECJ

Case C-368/96, Generics.

209 Novartis SangStat, C-106/01. 210 This holding is confusing. Apparently the Court believed that the bioavailability differences among the three products do not preclude the

UK agency from regarding them as bioequivalent and, upon that basis, as essentially similar.

211 Sandimmun, Neoral, and SangCya are all immuno-suppressants containing the active ingredient cyclosporine, used to prevent rejection of

organs or tissues in transplantation surgery and in treatment of certain autoimmune diseases

212 “Pharmaceutical form” was discussed in ECJ Case C-368/96 Generics.


4. A Member State agency considering a new product marketing authorisation application for product C (SangCya) under the EU Abridged Procedure Law, with reference to product A (Sandimmun), authorised for 6 to 10 years,213 is entitled to refer—without the consent of the person responsible for marketing—to data submitted in support of product B (Neoral). Product B had been authorised within the previous 6 or 10 years under the Hybrid Abridged Procedure through reference to product A, with data from clinical trials demonstrating that product B, though “suprabioavailable” to product A214 when administered in the same dose, is safe. The ECJ “added that the Court of Appeal rightly points out in the order for reference that the competent authority of a Member State, in making a decision on an application for marketing authorisation, must examine the safety and efficacy of the medicinal product and that it is, therefore, permissible for that authority to take account of all data in its possession, from whatever source, to the extent that such data demonstrate that the product is harmful or that it lacks efficacy.”215

The ECJ decision has disturbing implications for innovator companies.

Innovators whose new products are sufficiently distinctive from their old ones as to be separate products will not enjoy a restart of the 10-year data exclusivity period.

Although the decision purports to limit use of the Hybrid Abridged

Procedure to products that are “essentially similar,” it adopts an extremely broad interpretation of this term, facilitating approval of products that are not the same as those of the innovator. The decision also discusses the adoption in the 2004 Community Code Amendment Directive of references to “sameness” as the statutory standard but then proceeds to treat this language as continuing the old “essentially similar” standard.

For biosimilars, where the follow-on applicant may not provide “the results

of other tests and trials from the reference medicinal product’s dossier,”216 the impact of Novartis is unclear.

The case also involves several complex and unusual facts that may limit its significance as a broad precedent:

An earlier Novartis product, Sandimmun, had been approved in 1983. Its 10-year exclusivity period, as well as its patents, had expired prior to the SangCya submission.

213 Of course, the new pharma review legislation prescribes a harmonised “8+2+1” period for all approvals of medicines whose applications are

submitted after the effective date of the legislation.

214 Neoral is absorbed into the bloodstream of patients more quickly and consistently than Sandimmun and has approximately 29% higher

bioavailability.

215 Paragraph 29, pp. 8-9.

216 New Art. 10.4., Community Code as amended.


Both Novartis’ Neoral and SangStat’s SangCya were submitted as abridged applications in which Sandimmun was the cited reference product, although neither was essentially similar to the original.

Neoral, a patented product developed to overcome Sandimmun’s

absorption and administration, now dominates Novartis’ sales. Regulators required Novartis to conduct substantial clinical trials of

Neoral; SangCya was not required to repeat these trials.

SangCya was not developed as a copy of Sandimmun or Neoral, is not identical to either and is covered by its own US patents.

SangStat submitted data to demonstrate SangCya’s “suprabioavailability”

compared to Sandimmun and the essential similarity of the two products. It also submitted US studies showing bioequivalence between SangCya and Neoral.


Chapter IX. Marketing Authorisations for Products Derived From Biotechnology A. Genetically modified organisms General requirements relating to the release of genetically modified organisms affect the marketing authorisations of medicinal products that contain such organisms.217 These provisions are not detailed in this book, except to note the need to comply with them in regulatory submissons as well as the longer timeframes permitted for decisions on clinical trial applications for medicinal products containing genetically modified organisms. Fortunately, the intense opposition that has surrounded the marketing in Europe of genetically modified foods has not impeded the introduction of medicines with genetically modified components. It is believed that European consumers can more readily appreciate the value of biotech medicines—often safer and cleaner replacements of older biologicals derived from animals or cadavers—as compared with biotech foods. B. Biological medicinal products A biological medicinal product is “a product, the active substance of which is a biological substance…[that] is produced by or extracted from a biological source and that needs for its characterisation and the determination of its quality a combination of physicochemical-biological testing, together with the production process and its control.”218 Examples of biologicals are immunological medicines, medicinal products derived from human blood and human plasma, biotech-derived medicinal products falling within the scope of mandatory jurisdiction under the EMEA Regulation, and advanced therapy medicinal products. Any other substances used for manufacturing or extracting the active substances but from which the active substance is not directly derived, e.g. reagents, culture media or fetal calf serum, are treated as raw materials. Under the Dossier Harmonisation Directive, 2003/63/EC, applications for marketing authorisations for biological medicinal products must contain all the information required for full applications of other medicines and, in addition, must contain extensive additional information about the products and processes. C. Biosimilars The question is whether the extensive testing and documentation requirements for biological medicinal products can be reduced for similar versions of off-patent reference products. Many EU authorities seem interested in this possibility and, in June 2003, the EU launched a regulatory pathway for biosimilars by including in the Dossier Harmonisation Directive, 2003/63/EC, amending the Community Code on Medicinal Products provisions that contemplate some data reduction for biosimilars. Annex I of the Dossier Harmonisation Directive spells out the required contents of an application for marketing authorisation and, in Article 4, sets forth the specific marketing authorisation dossier requirements for “similar biological medicinal products.” The new EU pharmaceutical review legislation, published 30 April 2004, amended the Community Code Directive, 2001/83, to provide a definition of “similar biological medicinal 217 New EMEA Regulation, Article 6.2, citing Directive 2001/18/EC and Council Directive 90/220/EEC of 23 April 1990 on the deliberate

release into the environment of genetically modified organisms (GMO), but also applying these “horizontal” laws in a special way to medicinal

products. The rapporteur handling a marketing authorisation application for a GMO-containing medicinal product must carry out consultations

with Community or Member State bodies set up under Directive 2001/18/EC.

218 Dossier harmonisation Directive 2003/63/EC, Annex 3.2.1.1. (L 159/62).


product” to accompany the Annex’s streamlined regulatory pathway. Various guidelines, discussed below, have been issued to supplement the statutes. 1. Background In the EU, the term “biosimilars” refers to products that cannot meet “generic” criteria, generally because they are large-molecule proteins that cannot be proven to be sufficiently close to innovator products. The term “biogenerics” is also used, but is a misnomer because the copy cannot be identical to the reference product. The EU legislation provides a legal framework for biosimilars under which it is understood that such products will need less supporting data than had been required for the original reference product. This is not a “clear legal framework,” however, as the statute is just a starting point for many difficult and unresolved issues. Heading the list is the question of how much data follow-on applicants will be required to provide. In other words, what data requirements might biosimilar applicants be allowed to skip and will the hoped-for savings provide assurance in terms of added public risk, given the many unknowns about assuring that biosimilars are safe, despite regulatory short-cuts? As regulators are well aware, even experienced manufacturers have encountered serious immunogenecity problems as biologics production processes evolve. The European Commission has stated that, within the EU, only EMEA has authority to assess applications for biotechnology-derived biosimilar applications. This flows from EMEA’s exclusive authority over biotechnology-derived medicines in general.

2. “Similar biological medicinal products” Article 10.4 of the amended Community Code Directive states, in its entirety:

Where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or differences in manufacturing processes of the biological medicinal product and the reference biological medicinal product, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided. The type and quantity of supplementary data to be provided must comply with the relevant criteria stated in the Annex and the related detailed guidelines. The results of other tests and trials from the reference medicinal product’s dossier shall not be provided.

3. Annex to Community Code per Dossier Harmonisation Directive 2003/63 The first EU regulatory pathway for biosimilars was the June 2003 Dossier Harmonisation Directive (2003/63/EC), amending the Community Code on Medicinal Products by establishing a new Annex on the required contents of a marketing authorisation application. Although the principal purpose of this Directive was to implement the ICH Common Technical Document, the Commission also included provisions intended to clarify the regulatory pathway for biotechnology-derived biological medicinal products that are similar to previously authorised products. 4. Guidelines EMEA has issued a series of guidelines to detail biosimilar requirements, but many questions still need to be resolved. Only partial answers are found in these EMEA guidelines:


two comparability guidelines, December 2003 draft guideline describing general biosimilar approval principles and four “concept

papers” outlining areas in which EMEA intended to provide more targeted guidance (requirements for four human recombinant product classes containing erythropoietin, human growth hormone, granulocyte-colony stimulating factor and insulin), November 2004

Guideline on similar biological medicinal products containing biotechnology-derived

proteins as active substance: quality issues, March 2005

Guideline describing the general principles for clinical/nonclinical issues and four proposed annexes on the four product classes that had been the subject of earlier concept papers, May/June 2005.

5. EMEA guidelines: more questions than answers? On 16 May 2005, EMEA issued a final guideline describing general principles for clinical and nonclinical issues involved in the approval of biosimilars. The guideline establishes general principles for the development and assessment of biosimilar marketing authorisation applications. Four annexes accompany the guideline, providing more targeted guidance on approval requirements for four product classes containing recombinant proteins as active substances:

Erythropoietin

Granulocyte-colony stimulating factor

Insulin

Somatropin (human growth hormone) The guideline clarifies nonclinical and clinical requirements:

Each application will be handled on a case-by-case basis. Each biosimilar applicant must justify its approach and is encouraged to seek early

discussions with EMEA.

The same reference product should be used for all application aspects (quality, safety and efficacy).

A full quality dossier is required, as a biosimilar’s safety/efficacy profile is highly

dependent upon quality aspects.

EMEA recommends the use, in required clinical trials, of the test product from the final manufacturing process.

Certain clinical and nonclinical data are required:


o Extensive nonclinical studies (in vitro and in vivo) and clinical trials of the biosimilar itself, and

o Immunogenicity data.

In addition, the biosimilar applicant must carry out an "extensive" comparability exercise to demonstrate that the product has a profile similar to the identified reference product, in terms of quality, safety and efficacy. Comparative pharmacokinetic studies to demonstrate equivalence are an essential part of this exercise. In specifying clinical safety and pharmacovigilance requirements, the guideline distinguishes the preapproval phase, which consists of safety data collected in preauthorisation clinical studies, from the postapproval phase, which consists of close product monitoring. The biosimilar application should include a “risk specification” (describing possible safety issues arising from the fact that the manufacturing process differs from the innovator’s) as well as a risk management plan, in accordance with EU legislation and guidelines.219 The guideline advises the applicant to have ready and in place, prior to approval, the pharmacovigilance systems and procedures (including traceability) needed to meet requirements. EMEA warns that compliance will be strictly monitored. Each of the four annexes relates to one product class and provides proposed guidance on specific preclinical and clinical requirements for biosimilar applications, taking into account the special concerns of each class. For example, the erythropoietin annex states that efficacy trial safety data from at least 300 patients treated with a biosimilar are considered adequate for a premarket safety database (a number that many observers found shockingly small). Postmarket reporting will add to this database. The applicant also should provide at least 12 months of immunogenicity data in patients treated with the biosimilar. Retaining samples for both titration and maintenance studies is recommended. A validated, highly sensitive assay should be used to detect anti-epoetin antibodies. EMEA has proposed excusing erythropoietin biosimilars from many safety studies that were carried out by the innovator companies. The final guideline and proposed annexes are a step toward creating a more robust legal framework for the approved and control of biosimilars. However, many thorny issues remain.

• The final guideline stipulates that, “in case the reference product has more than one indication the efficacy and safety of the biosimilar must be justified or demonstrated separately for each of the claimed indications”

• The biosimilar applicant must consider the risk of immunogenicity separately for each

indication.

Nevertheless, the draft annex on somatropin and the draft annex on erythropoietin each had a section entitled, “extension of indication,” under which a demonstration of efficacy and safety in the most sensitive clinical model (renal failure, for erythropoietin) would allow the biosimilar to be labelled with all the reference product’s other indications, given the same mode of action and justification by current scientific knowledge. Whether biosimilar applicants for other product classes will be allowed the same latitude remains to be seen. In other words, would biosimilar sponsors be permitted to carry out tests for one indication and obtain authorisation for other reference product indications without conducting clinical studies for each? This “multiple-indication” issue illustrates a primary question about the relation of the annexes to the general guideline. Are the annexes lex specialis (specific laws) that overrule the

219 See section VII.E.


general guideline? Or, is an annex to be viewed as merely complementary to, and to be read in conjunction with, the general guideline? Innovator companies have asked EMEA to provide assurance that no biosimilars will be approved until the agency and affected stakeholders have fully vetted the issues and all relevant guidelines are in place. 6. Innovator data issue A key issue is the extent to which regulators can rely upon innovators’ data in agency files to reduce generic data requirements; clearly EMEA should refrain from any reliance upon data in the reference medicinal product’s dossier. The generally accepted interpretation of the last sentence in the biosimilars definition—“The results of other tests and trials from the reference medicinal product’s dossier shall not be provided”—is that no reference may be made to the reference product’s dossier. Yet the EMEA guidelines that excuse biosimilars from certain safety tests or from efficacy tests for additional indications implicitly rely upon results from innovators’ data. Such reliance is extremely risky in the case of biologicals where there are always differences among various manufacturers’ products and “the process is the product, and the product is the process.” It needs to be recognised that the biosimilar situation is very different from the typical generic drug, a chemical that can be copied exactly, where the product is not so process-dependent and consistent copies can be produced through reverse engineering, good chemistry, tight specifications and GMPs. 7. Omnitrop Sandoz, a generic subsidiary of Novartis, has brought a suit in the European Court of First Instance (CFI), challenging the European Commission’s refusal to publish a marketing authorisation for a biosimilar human growth hormone product, Omnitrop®. The European Commission found flaws in the legal reasoning underlying EMEA’s June 2003 favourable opinion supporting Omnitrop’s approval under the 2001 Community Code on Medicinal Products (this was an opinion rendered prior to the 2003 Dossier Harmonisation Directive and 2004 Code Amendment Directive). In essence, the Commission took the position that the 2001 Community Code provided no legal basis for authorising a biosimilar based upon less than a full complement of data. Interestingly, at the time of writing this book, the same issue was pending in US courts due to the apparent decision of FDA to not approve a new drug application for Omnitrop. 8. Unanswered questions How will EMEA and the EU legislation handle the naming of biosimilar products? How will they prevent confusion between the original product and the biosimilar? Biosimilars need to have unique names, to avoid mix-ups and, thus, to help ensure patient safety. Are biosimilars and reference products meant to be interchangeable? If so, to what extent is product substitution allowed? Healthcare reimbursement authorities, physicians, pharmacists and patients need to be aware of safety issues that arise when patients are switched from one biological to another. In this respect, biosimilars are very different from small molecule chemical generic drugs because they are not, per se, interchangeable. Whether, and under which conditions, a physician can prescribe a biosimilar in lieu of the reference product remains a conspicuously open question. EU authorities, unlike ICH and FDA, do not limit use of the term “comparability” to situations where a manufacturer's own processes (and products) have been changed. Regulatory affairs


professionals need to be aware of this unharmonised terminology. For comparisons between unrelated manufacturers, use by the EMEA of a term such as “similarity exercise” would be more accurate and would promote understanding. How will “traceability” work, in terms of the records and, in some cases, serum samples that need to be retained to determine what specific product each patient receives? Will EU privacy legislation complicate the needed traceability? How will EMEA treat innovator data in this biosimilar approval process? What principles and safety rules will govern use of innovator’s data by regulators? May EMEA rapporteurs take into account results from innovator tests and trials in their review of a biosimilar application? These efforts to clarify biosimilar requirements have become more urgent, as several biosimilar product applications were reportedly pending before EMEA as of October 2005. Also, EMEA is striving to have its biosimilar guidelines in place in 2006.


Chapter X. Medicinal Products Manufactured from Blood or Plasma Medicinal products manufactured from blood or plasma are regulated under the Community Code on Medicinal Products. Where blood or plasma is a starting material for a medicinal product, the Community Code contains specific requirements on safety and traceability. The Community Code, however, exempts whole blood and blood cells of human origin. Plasma has been exempt from the Code but, upon the effective date of the 2004 Code Revision Directive, plasma is excluded only insofar as it is prepared by a method that does not involve a medicinal product. Until recently, there was no mandatory EU legislation covering blood donations and related product handling steps. Neither was there legislation covering whole blood for transfusion that is not processed. The Human Blood Directive220 addressed these gaps and requires establishment of specific technical requirements, which have now been put in place by a related Directive on Blood Technical Requirements.221 Together, these laws establish detailed rules on donor information rights, suitability of donors and adverse event reporting. There also are requirements for screening, storage, transport and distribution of donated blood and blood components, along with specific requirements for blood establishments. The deadline for Member States to implement requirements from both Directives into national law was 8 February 2005. Companies using blood and blood components in their products must maintain certain documents, including ones to ensure traceability as to what blood lots were used in which products. The Human Blood Directive also affects companies that maintain blood establishments in order to obtain needed supplies of blood and blood product components for their products. Blood establishments must be authorised by the responsible national authorities and must obey requirements concerning their personnel, safety, quality system, documentation, traceability and adverse event reporting in connection with blood collection and testing. Because many medicinal products contain plasma, the 2003 Dossier Harmonisation Directive222 referred to a special category of master file, known as a plasma master file (PMF), which may be assessed at EU level and granted a certificate of compliance. Then, when a proposed medicinal product is to incorporate the plasma covered by a PMF into a finished medicinal product, the review authority for the application for marketing authorisation (the Member State agency or EMEA) need not reassess the safety of the plasma, except insofar as there are any changes from the PMF that would affect the product’s quality and safety. This procedure applies to both centralised and decentralised applications. Other laws of interest regarding blood products are:

1. Directive 2000/70/EC of the European Parliament and of the Council of 16 November 2000 amending Council Directive 93/42/EEC as regards medical devices incorporating stable derivatives of human blood or human plasma (OJ L 313, 13.12.2000, p. 22)

2. Council Recommendation of 29 June 1998 on the suitability of blood and plasma donors

and the screening of donated blood in the European Community (OJ L 203, 21.7.1998, p. 14).

220 Directive 2002/98/EC of the European Parliament and of the Council of 27 January 2003 setting standards of quality and safety for the

collection, testing, processing, storage and distribution of human blood and blood components (OJ L 33, 8.2.2003, p. 30).

221 Commission Directive 2004/33/EC.

222 Directive 2003/63/EC 25 June 2003, Part III.1, OJ L 159/80.


Chapter XI. Regulation of Human Tissue and Other Advanced Therapy A. Tissue Handling Directive Directive 2004/23/EC (31 March 2004) (the Tissue Handling Directive) deals with the standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells.223 The Tissue Handling Directive entered into force on the day of its publication in the Official Journal of the European Communities and must be implemented by Member States by 7 April 2006. The Directive responded to a need for a unified framework in order to ensure high standards of quality and safety of tissues and cells across the EU, and to facilitate distribution of tissues and cells needed for patients receiving this type of therapy. The legislation was intended to ensure that human tissues and cells, whatever their intended use, are of comparable quality and safety. The establishment of such standards is also seen as a way to help reassure the public that human tissue and cells procured in another Member State carry the same guarantees as those in their own country. This Directive establishes standards of quality and safety for human tissues and cells intended for human applications, to ensure a high level of protection of human health. It applies to the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells intended for human applications and of manufactured products derived from human tissues and cells intended for human applications. However, where such manufactured products are covered by other directives, the Tissue Handling Directive applies only to donation, procurement and testing. Thus, tissues and cells intended to be used for industrially manufactured products, including medicines and medical devices, are covered by the Tissue Handling Directive only as to donation, procurement and testing, as these are instances in which the tissue’s processing, preservation, storage and distribution are unregulated by other EU legislation. Thus, for tissues used in medicine, further manufacturing steps beyond what is covered in the Tissue Handling Directive are covered by the Community Code on Medicinal Products for Human Use. The Tissue Handling Directive does not apply to:

tissues and cells used as an autologous graft within the same surgical procedure224 blood and blood components as defined by Directive 2002/98/EC (as discussed below;

see also Chapter X)

organs or parts of organs if it is their function to be used for the same purpose as the entire organ in the human body

organs, tissues or cells of animal origin

223 Directive 2004/23/EC of the European Parliament and of the Council of 31 March 2004 on setting standards of quality and safety for the

donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells, Official Journal L 102 , 07/04/2004

P. 0048 – 0058.

224 Paragraph (3) of the preamble explains further that tissues and cells used as an autologous graft (tissues removed and transplanted back to the

same individual), within the same surgical procedure and without being subjected to any banking process, are excluded because the quality and

safety considerations associated with this process are completely different.


However, the Tissue Handling Directive does apply to tissues and cells, including hematopoietic peripheral blood, umbilical-cord (blood) and bone-marrow stem cells, reproductive cells (eggs, sperm), foetal tissues and cells and adult and embryonic stem cells. Except for its coverage of haematopoietic progenitor cells, the Tissue Handling Directive excludes blood and blood products. This is because blood and blood products are regulated by Directives 2001/83/EC and 2000/70/EC (5), Recommendation 98/463/EC (6) and Directive 2002/98/EC (7). The Tissue Handling Directive covers tissues and cells intended for human applications, including human tissues and cells used for the preparation of cosmetic products. However, in view of the risk of transmission of communicable diseases, the use of human cells, tissues and products in cosmetic products is prohibited by Commission Directive 95/34/EC of 10 July 1995 relating to cosmetic products. The Tissue Handling Directive does not cover research using human tissues and cells, when used for purposes other than application to the human body, e.g., in vitro research or in animal models. Addressing the controversial issue of stem cell research, the Tissue Handling Directive states that there should not be interference with decisions made by Member States concerning the use or non-use of any specific type of human cells, including germ cells and embryonic stem cells. If, however, any particular use of stem cells is authorised in a Member State, then the Tissue Handling Directive must be implemented in that Member State, to apply to stem cell research all provisions necessary to protect public health, given the specific risks of these cells based on the scientific knowledge and their particular nature. The Member State also must guarantee respect for fundamental rights. Moreover, this Directive does not interfere with provisions of Member State laws defining the legal term "person" or "individual." As part of an effort to secure the best scientific advice on issues that might arise under this legislation, the opinions of the Scientific Committee for Medicinal Products and Medical Devices and that of the European Group on Ethics in Science and New Technologies have been taken into account, as well as international experience in this field, and further advice will be sought in the future as necessary. The Directive defines a number of key terms:225

"Cells" is individual human cells or a collection of human cells when not bound by any form of connective tissue.

"Tissue" is all constituent parts of the human body formed by cells.

"Organ" is a differentiated and vital part of the human body, formed by different tissues,

that maintains its structure, vascularisation and capacity to develop physiological functions with an important level of autonomy.

A "tissue establishment" is a tissue bank or unit of a hospital or other institution where activities of processing, preservation, storage or distribution of human tissues and cells are undertaken. It may also be responsible for procuring or testing tissues and cells. A “donor” is every human source, whether living or deceased, of human cells or tissues, while “procurement” is the process by which tissue or cells are collected. The term “processing” covers all operations involved in preparing, manipulating, preserving and packaging of tissues or cells intended for human applications, while “distribution” is transporting and delivering tissues or cells intended for human applications. “Human application" is the use of tissues or cells on or in a human recipient and extracorporeal applications, whether for “allogeneic use”—

225 Article 3, Tissue Handling Directive.


cells or tissues removed from one person and applied to another—or “autologous use”—cells or tissues removed from and applied in the same person. Member States shall designate the competent authority or authorities responsible for implementing the requirements of this Directive.226 Each Member State is expressly allowed to maintain or introduce more stringent protective measures, provided that they comply with the provisions of the EU Treaty. In particular, a Member State may introduce requirements for voluntary unpaid donation, including prohibiting or restricting imports of human tissues and cells, to ensure a high level of health protection, provided that the conditions of the Treaty are met. Also, the Directive does not affect Member States’ decisions prohibiting the donation, procurement, testing, processing, preservation, storage, distribution or use of any specific type of human tissues or cells or cells from any specified source (e.g., stem cells), including cases where such restrictions also concern imports of the same type of human tissues or cells. Supervision of human tissue and cell procurement is required, so that procurement and testing are carried out only by persons with appropriate training, experience and credentials and so the procurement complies with requirements.227 Member State authorities must:

Regulate tissue establishments and tissue and cell preparation processes to ensure compliance with the requirements under the Directive, including the tissue and cell preparation processes which the tissue establishments carry out,228 as well as agreements between tissue establishments and third parties.

Organise inspections and ensure that tissue establishments carry out appropriate control

measures in order to ensure compliance with the requirements of this Directive, particularly whenever there is any serious adverse reaction or serious adverse event or when the Member State authority has received a duly justified request of a competent authority in another Member State in such a case.229

Ensure traceability, so that all tissues and cells procured, processed, stored or

distributed on their territory can be traced from the donor to the recipient and vice versa.

Implement a donor identification and tissue and cell labelling system with a unique code for each donation and the products associated with it.230

Take all necessary measures to ensure that all imports and exports of tissues and cells

from third countries are undertaken by appropriately regulated tissue establishments; that imported tissues and cells can be traced from the donor to the recipient and vice versa; and, that imports and exports of tissues and cells meet quality and safety standards.231




229 Article 7, A "serious adverse event" means any untoward occurrence associated with the procurement, testing, processing, storage and

distribution of tissues and cells that might lead to the transmission of a communicable disease, to death or life-threatening, disabling or

incapacitating conditions for patients or which might result in, or prolong, hospitalisation or morbidity. A "serious adverse reaction" means an

unintended response, including a communicable disease, in the donor or in the recipient associated with the procurement or human application of

tissues and cells that is fatal, life-threatening, disabling, incapacitating or which results in, or prolongs, hospitalisation or morbidity.




The European Commission may establish procedures for assessing whether non-EU countries meet equivalent standards for regulating cells and tissues.232 Each Member State’s competent authority or authorities shall establish and maintain a publicly accessible register of tissue establishments, specifying the activities for which they have been accredited, designated, authorised or licensed, and the Member States and the Commission shall establish a network linking the national tissue establishment registers.233

Member States shall ensure that there is a system in place to report, investigate, register and transmit information about serious adverse events and reactions that may influence the quality and safety of tissues and cells and that may be attributed to the procurement, testing, processing, storage and distribution of tissues and cells, as well as any serious adverse reaction observed during or after a clinical application that may be linked to the quality and safety of tissues and cells.234 All persons or establishments using human tissues and cells regulated by the Tissues Handling Directive shall report relevant information to tissue establishments to facilitate traceability and ensure quality and safety control.235 Each tissue establishment must have a responsible person to ensure that the competent authorities are notified of any serious adverse events and reactions and are provided with a report analysing the cause and the outcome.236 Each tissue establishment shall ensure that an accurate, rapid and verifiable procedure is in place to enable it to recall from distribution any product that may be related to an adverse event or reaction.237 The Tissue Handling Directive also requires Member States to implement measures on donor selection and compensation (aimed at ensuring that donations are voluntary and non-profit),238 informed consent239 and data protection and confidentiality.240 The Directive mandates documented standards for donor evaluation and selection and for proper handling of donated tissues, overseen by Member State authorities.241 Member States are required to ensure that each tissue establishment puts in place and updates a quality system based upon the principles of good practice in accordance with Community standards and specifications for such quality systems, including traceability, as set by the European Commission. Every tissue establishment shall designate a responsible person who shall fulfil certain academic and experience requirements, be responsible for ensuring that human tissues and cells intended for human applications in the establishment meet requirements of the Directive and Member State laws and provide information to the Competent Authority or authorities as required.242 There also are requirements that personnel directly involved in activities relating to tissue and cell procurement, processing, preservation, storage and distribution in a tissue establishment be qualified and trained to perform such tasks.243 Establishments must ensure that tissues and cells received from donors are tested, identified and quarantined and meet

232 Article 9.4, Tissue Handling Directive.




236 Article 17, 11.3, Tissue Handling Directive.






242 Article 17.

243 Article 18.


specified requirements; they also must keep records of acceptance or rejection of received tissues and cells.244 Tissue establishments’ standard operating procedures must cover all processes that affect quality and safety (including process modifications and processes for discarding noncompliant tissues and cells) and ensure that the equipment used, working environment, process design and validation and control conditions all meet applicable requirements.245 All procedures associated with the storage of tissues and cells must be documented in standard operating procedures, packaging and storage areas must meet requirements, and no processed tissues or cells may be distributed until all the requirements laid down in the Directive have been met.246 Member States shall ensure that tissue establishments have agreements and procedures in place that guarantee that, in the event of termination of activities, stored tissues and cells shall be transferred to another authorised tissue establishment and the Member State’s law on disposal of donated tissues or cells, according to the applicable donor consents, be obeyed.247 Tissue establishments shall ensure that labelling, documentation and packaging conform to requirements,248 that tissues and cells maintain quality during distribution249 and that they execute written agreements with a third party each time they engage in an activity with that party that influences tissue and cell quality and safety.250 Member States must establish an identification system for human tissues and cells, to ensure their traceability, aided by a coding system to be designed by the European Commission.251 The Tissue Handling Directive also establishes various reporting requirements involving the Member States and European institutions,252 requires Member States to establish penalties applicable to infringements of their implementing legislation,253 empowers the Commission to establish technical requirements by Commission Directives,254 sets up a Committee255 and calls for consultation with relevant scientific committees when defining or adapting technical requirements referred to scientific and technical progress.256 The Tissue Handling Directive includes an Annex on information to be provided on the donation of cells and/or tissues that is, basically, an informed consent procedure. For deceased donors, all information must be provided and all necessary consents and authorisations must be obtained in accordance with the legislation in force in the Member State and the confirmed

244 Article 19.

245 Article 20.

246 Article 21.

247 Article 21.5.

248 Article 22.

249 Article 23.

250 Article 24.

251 Article 25.

252 Article 26.

253 Article 27.

254 Article 28. Topics to be covered include:(a) requirements for the accreditation, designation, authorisation or licensing of tissue

establishments; (b) requirements for the procurement of human tissues and cells; (c) quality system, including training; (d) selection criteria for

the donor of tissues and/or cells; (e) laboratory tests required for donors; (f) cell and/or tissue procurement procedures and reception at the tissue

establishment; (g) requirements for the tissue and cell preparation process; (h) tissue and cell processing, storage and distribution; (i)

requirements for the direct distribution to the recipient of specific tissues and cells.

255 Article 29.

256 Article 30.


results of the donor's evaluation must be communicated and clearly explained to the relevant persons in accordance with that legislation. B. Advanced Therapies Two key documents extended the definition of medicinal products to include gene therapy and somatic cell therapy:

June 2003 Commission Dossier Harmonisation Directive 2003/63 April 2004 revisions to the Community Code on Medicinal Products, in which the revised

definition of “medicinal product” encompasses these forms of advanced therapies EMEA published a concept paper on GMPs for gene therapy and somatic cell therapy in December 2003. On 24 April 2005, EMEA announced that the guidance on this subject will be covered in a new Annex on GMPs (see Chapter VI). In early 2005, the Directorate General of the European Commission restructured its internal assignment of responsibilities for advanced therapies. At the same time, it created a focal point on its website for information on advanced therapies. The following discussion was posted on that website, as part of this realignment and in anticipation of the Commission’s announcement of a Proposed Regulation on Human Tissue-Engineered Products (hTEPs), discussed below.

Advancements in the fields of biology, biotechnology and medicine have fuelled the development of promising gene- and cell-based approaches, such as gene or somatic cell therapy, for preventing and treating human diseases or dysfunctions.

In addition, the new biotechnology area, human tissue engineering, has emerged, which combines various aspects of medicine, cell and molecular biology, materials science and engineering, to regenerate, repair or replace diseased tissues. Current applications of this nascent “regenerative medicine” field include treatment for skin, cartilage and bone diseases or injuries. More complex products are already in development and could reach the Community market in the near future.

These advanced gene and cell therapies and tissue engineering represent a fast-growing sector that holds great promise for improved treatment opportunities and enhanced quality of life across Europe. To develop this potential, the European Commission is preparing legislation to:

o Guarantee a high level of health protection for European patients treated with

advanced therapies o Facilitate market access for advanced therapies by establishing a

harmonised regulatory framework for their authorisation, supervision and post-authorisation vigilance

o Foster the competitiveness of European undertakings

o Provide overall legal certainty, while allowing for sufficient flexibility at the

technical level, to keep the pace with the evolution of science and technology


C. Draft proposed human tissue-engineered product regulation On 10 May 2005, the European Commission published a draft proposed Regulation on “advanced therapies,” as well as a framework for future requirements for one such therapy, human tissue-engineered products (hTEPs).257 The Draft proposal for a Regulation of the European Parliament and of the Council on Advanced Therapies and amending Regulation (EC) No 726/2004258 aims to create legal certainty and, thus, foster innovation, by clarifying the authorisation and postmarketing regulation rules for advanced therapy products—especially hTEPs—as medicinal products (i.e., pharmaceuticals). The new draft proposal also is intended to clarify EU’s regulatory pathway for combinations of advanced therapies and medical devices. The three advanced therapy types covered are gene therapy, somatic cell therapy and hTEPs. EMEA, already responsible for gene and somatic cell therapies as medicinal products, would also be assigned responsibilility for hTEPs. EU authorities are already implementing uniform tissue collection and handling requirements, as discussed in the first part of this chapter,259 but there had not previously been any decision at the EU level about whether hTEPs were medicinal products, medical devices or a new third category. Under the proposal, hTEPs would be a special medicinal product category. Any currently marketed products that were placed on the EU market as medical devices or through other pathways would need EMEA authorisations within three years of the future Regulation’s entry into force. 1. What exactly is tissue engineering and why is this new Regulation important? According to the Commission, tissue engineering is “a new biotechnology area…which combines various aspects of medicine, cell and molecular biology, materials science and engineering, for the purpose of regenerating, repairing or replacing diseased tissues.” Examples are treatments for skin, cartilage and bone diseases or injuries. Also, more complex versions of heart valves and blood vessel replacements, all employing tissue engineering, are being developed. In the absence of harmonisation, various regulatory frameworks have been employed across Europe, resulting in the uncertainty that has impeded innovation. Therefore, a key draft proposal objective is harmonising regulatory categorisation and procedures, thus fostering innovation, new product development and early patient access to new therapies. 2. How would advanced therapies be regulated? The draft proposal’s central objective is to address all advanced therapies within “a single, integrated and tailored framework.” The EMEA Regulation, as well as a June 2003 amendment to the Community Code on Medicinal Products,260 designated gene and somatic cell therapies as medicinal products. The European Commission believes that hTEPs present similar issues 257 See http://pharmacos.eudra.org/F2/advtherapies/docs/DraftRegulation-Advanced%20Therapies-2005-May-04.pdf and

http://pharmacos.eudra.org/F2/advtherapies/docs/ConsultationPaper-AdvancedTherapies-2005-May-04.pdf. 258 Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004.

259 Directive 2004/23/EC of the European Parliament and of the Council of 31 March 2004 (Official Journal L 102, 07/04/2004 pp. 0048 –

0058).

260 168 Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community Code relating to

medicinal products for human use (Official Journal L 311, 28/11/2001 pp. 67 - 128), as amended by Directive 2002/98/EC (Official Journal L 33,

8/2/2003

pp. 30 - 40), Directive 2003/63/EC (Official Journal L 159, 27/6/2003 pp. 46 - 94), Directive 2004/24/EC (Official Journal L 136, 30/4/2004,

pp. 85 - 90) and Directive 2004/27/EC (Official Journal L 136, 30/4/2004 pp. 34 - 57).


and that advanced therapy products share unique scientific, technical and ethical features that distinguish them from medical devices and conventional medicines. The Commission background paper speaks of bridging a regulatory gap and sees centralised approval, following EMEA assessment, as a way to make sound decisions through pooled expert resources. Assigning hTEPs to EMEA sends a clear message that EU authorities regard these products as needing centralised handling and stringent, yet flexible regulation. The Commission emphasises benefits to innovators of the medicinal product category, e.g., eligibility of hTEPs for the “8+2+1”exclusivity provisions (eight years’ data exclusivity and two more years of marketing exclusivity, plus the possibility of a one-year new-use extension). Medical device trade groups had pressed for a legislative framework that would resemble the one now in use, fearing that EMEA jurisdiction over hTEPs might be the beginning of the end of the “Notified Body” approach to medical device regulation (see Chapter IV). 261 No doubt, simultaneous publication of the Draft Revised Medical Devices Directive was intended to allay that concern by showing that, aside from medicinal products or designated advanced therapies, the current EU approach to medical device regulation is meant to remain unchanged. 3. What would the proposed Regulation cover? The proposed Regulation would govern authorisation and postauthorisation surveillance for advanced therapies (tissue engineering, cell therapy and gene therapy). Within its scope are advanced therapy products produced in mass quantities and patient-specific products manufactured with a standardised industrial process. Single-patient treatments are exempt. Therapies using xenogenic techniques or animal tissues are not included but could be added at a later date. 4. What are the draft proposal’s main elements? A compulsory centralised authorisation procedure would be established.

A Committee for Advanced Therapies (CAT) would be created within EMEA to initially assess advanced therapy products with the Committee for Medicinal Products for Human Use (CHMP) offering final opinions.

Advanced therapy products, including hTEPs, would be categorised legally as medicinal

products, without implying that they are subject to precisely the same technical requirements as conventional medicines.

Technical requirements specific to hTEPs would be adopted as complementary EMEA

or European Commission guidelines.

Ad hoc guidelines on the application of advanced therapy product good manufacturing practices and good clinical practices would be adopted.

261 EU regulation of medical devices is a “New Approach” directive in which premarket review is carried out by conformity assessment bodies

(“notified bodies”) that generally are private sector entities. Also, clinical testing requirements for medical devices have generally been less

extensive than for medicines, although the European Commission’s recent draft proposed amendment to the Medical Devices Directive is likely

to result in more extensive testing than in the past.


Advanced therapy medicinal product clinical trials must be conducted under the Clinical Trials Directive262 and the Directive’s extra time periods for ethics committee and regulatory reviews of certain trials apply not only to gene and cell therapy products, but also to hTEPs.

Any medical device that is part of an advanced therapy product would be required to

meet essential requirements under the Medical Devices Directive263 (but without CE marking) and the CAT would consult with notified bodies.

Stringent requirements for risk management and postauthorisation traceability would

require marketing authorisation holders to maintain product and patient traceability data for at least 30 years.

Obtaining advice from EMEA might be possible at a 90% discounted fee.

5. What ethical requirements apply? The draft proposed regulation will fully observe the Charter of Fundamental Rights of the EU as well as the Convention for the protection of human rights and dignity of the human being with regard to the application of biology and medicine. Decisions on whether to allow use of any specific human cell types, e.g., germ cells or embryonic stem cells, are left entirely to Member States. Present policies on tissue donations, founded upon voluntary and upaid donation principles, continue. 6. What is the status of the draft proposed Regulation on hTEPs? The public had until 20 June 2005 to comment on the draft proposal and the European Commission has indicated its plans to issue a formal proposal in the Official Journal of the European Communities in late 2005 or early 2006. This would begin a complex process (“co-decision”) that also will include the European Council and Parliament.

262 Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and

administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on

medicinal products for human use (Official Journal L 121, 1/5/2001 pp. 34 - 44).

263 Council Directive 93/42/EEC of 14 June 1993 concerning medical devices (Official Journal L 169 of 12.07.1993) as amended by Directive

98/79/EC (Official Journal L 331 of 07.12.1998), Directive 2000/70/EC (Official Journal L 313 of 13.12.2000), Directive 2001/104/EC (Official

Journal L 6 of 10.01.2002) and Regulation (EC) No 1882/2003 (Official Journal L 284 of 31.10.2003).


Chapter XII. Orphan Medicines and Paediatric Testing A. Orphan Medicinal Product Regulation The EU Orphan Product Regulation264 established a procedure for the designation of orphan medicinal products, along with incentives for the research, development and marketing of designated products. Member States are encouraged to adopt similar or complementary measures at the national level. The most significant incentive provided by the legislation is a 10-year period of marketing exclusivity for new orphan products. This compares to seven years of exclusivity under the US system. This advantage may be offset, however, by a significant difference between the European and American approaches. Under the EU law, a medicinal product may lose its orphan drug exclusivity if the European Commission determines that the product is sufficiently profitable that it no longer warrants market exclusivity. This provision has injected uncertainty and risk into an otherwise rewarding incentive scheme. Drug sponsors must consider whether the potential benefits of orphan drug status and marketing exclusivity are outweighed by the prospect of both continual monitoring of their drug pricing and other financial practices and even potential loss of marketing exclusivity. B. Applications for orphan designation Sponsors may apply to EMEA for orphan drug designation at any time during the product’s development, but the application for designation must be submitted before submission of the marketing authorisation application (MAA).265 The application is reviewed by EMEA’s Committee for Orphan Medicinal Products (COMP), which also advises the European Commission on orphan drug policy and acts as a liaison with patient groups and regulated industry.266 Based upon the criteria discussed below, COMP issues an opinion on whether the European Commission should grant or deny the application for orphan designation within 90 days of its receipt.267 The COMP forwards its recommendation to the Commission, which must adopt a decision to grant or deny orphan designation within 30 days (or, in “exceptional circumstances,” it may give reasons for deviation from COMP’s opinion).268 If the application for orphan designation is approved, the product is entered into the Community Register of Orphan Medicinal Products.269 Each year thereafter, the sponsor reports to EMEA on the state of the product’s development.270 C. Definition of orphan product Orphan medicinal products are used to treat rare diseases. Specifically, a medicinal product may be designated as an orphan product if it is intended for: the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting not more than five in

264 Regulation 141/2000.

265 Regulation (EC) no. 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products at Article

5(1); EMEA, General Information for Sponsors of Orphan Medicinal Products (Oct. 25, 2002).

266 Regulation 141/2000 at Article 4(2).

267 Id. at Article 5(5).





10,000 persons in the EU;271 or the diagnosis, prevention or treatment of a life-threatening, seriously debilitating, or serious and chronic condition, and whose marketing in the EU, without incentives, is unlikely to generate sufficient return to justify the necessary investment.272 In either case, the sponsor also must demonstrate that no satisfactory method of diagnosis, prevention or treatment of the condition has been authorised in the EU or, if such a method exists, that the medicinal product will be of “significant benefit” to those affected by the condition. “Significant benefit” is defined as “a clinically relevant advantage or a major contribution to patient care.”273 For example, a demonstration of significant benefit may be based upon:

expected benefit to a particular subset of the disease population (including patients resistant to the existing method)

the expectation of an improved safety profile

a more convenient product formulation or route of administration, if there are serious

difficulties with the current formulation or route of administration

more favourable and clinically relevant pharmacokinetic properties

insufficient quantity or limitation in availability of the authorised product274 Any claim of significant benefit “must be justified by the applicant through the provision of evidence/data, which must be considered in the light of the particular characteristics of the condition and the existing methods.”275 Because there may be little or no clinical experience with the medicinal product in question, the justification for significant benefit is “likely to be made on assumptions of benefit.”276 For some sponsors, this may prove a substantial hurdle, because clinical trials may be necessary to show preliminary efficacy. In any case, COMP will assess whether the applicant has supported the assumptions of benefit with sufficient data and evidentiary support, in light of the characteristics of the condition and existing treatments. D. Incentives The EU Orphan Products Regulation created a number of community-wide incentives for designated and approved orphan products. For example, sponsors developing orphan medicinal products may be eligible for grants from EU and Member State programs designed to support such research and development.277 Sponsors who have received orphan drug designations may also receive fee waivers (for MAAs, inspections, variations, etc.); protocol assistance; and direct

271 For purposes of orphan designation, the relevant population is the population within the EU at the time of the request for orphan designation.

Communication from the Commission on Regulation (EC) no. 141/2000 on orphan medicinal products (July 28, 2003) [hereinafter

“Communication”] at A(2). Establishing Community-wide prevalence can be difficult, as there is no centralised EU epidemiology database.

272 Regulation 141/2000 at Article 3.1(b). 273 Regulation (EC) no. 847/2000 of 27 April 2000 laying down the provisions for implementation of the criteria for designation of a medicinal

product as an orphan medicinal product and definitions of the concepts ‘similar medicinal product’ and ‘clinical superiority’ at Article 3(2).

274 Communication at A(4).

275 Id.

276 Id.

277 Regulation 141/2000 at Article 9; EMEA, Orphan Medicinal Product Designation in the European Union.


access to the EMEA centralised procedure for submitting MAAs.278 The new EMEA Regulation advances this access to the EMEA centralised procedure one step further: starting 20 November 2005, orphan medicinal products may be authorised only under the EMEA centralised procedure. By far, the most significant incentive is the 10-year period of market exclusivity awarded to eligible products. Although multiple products in a class of “similar medicinal product[s]” with the “same therapeutic indication” may be designated as orphan products, it is the product (or products) that achieve marketing authorisation in the EU that will be granted a 10-year period of marketing exclusivity. During this period, neither EMEA nor Member States’ drug regulators may accept or approve another application for marketing authorisation for a “similar medicinal product” for the “same therapeutic indication.”279 Obviously, the terms “similar medicinal product” and “same therapeutic indication” are key legal standards in defining the availability of orphan drug status. 1. “Similar medicinal product.” A similar medicinal product is one containing a similar active substance (or substances) as contained in a currently authorised orphan medicinal product.280 A “similar active substance” is an active substance—a substance with physiological or pharmacological activity—that is identical to, or has the same principal molecular structural features as, another active substance, and which acts via the same mechanism.281 The mechanism of action is the functional description of the interaction of the active substance with a pharmacological target that elicits the primary pharmacodynamic effect that drives the therapeutic indication.282 Examples of similar products include:

isomers, mixture of isomers, complexes, esters, salts and noncovalent derivatives of the original active substance, or an active substance that differs from the original active substance only with respect to minor changes in the molecular structure, such as a structural analogue

macromolecules within specified margins of variability, such as polysaccharide

substances having identical saccharide repeating units, even if the number of units varies and even if there are postpolymerization modifications (including conjugation)283



280 Regulation 847/2000 at Article 3(b).

281 Id. at Article 3(a) and (c).

282 European Commission guideline on aspects of the application of Article 8 of Regulation (EC) No. 141/2000: Assessment of similarity and/or

clinical superiority of orphan medicinal products when assessing marketing authorisation applications and variations (draft for public

consultation) (Dec. 2004) [hereinafter “Draft guideline”] at II.2.

283 This group includes proteinaceous substances where: the difference is due to infidelity of transcription or translation; the difference in

structure between them is due to post-translational events (such as different glycosylation patterns) or different tertiary structures; the monoclonal

antibodies bind to the same target epitope; or the difference in the amino acid sequence is not major. Regulation 847/2000 at Article 3.3(c)(2.1).

“Therefore, two pharmacologically related protein substances of the same group (for example two biological compounds having the same

International Non-proprietary name (INN) sub-stem) would normally be considered similar.” Id. The group also includes certain polynucleotide

substances and other “closely related complex partly definable substances.” Id. at Article 3.3(c)(2.3), (2.4).


the same radiopharmaceutical active substance, or one differing from the original radionuclide, ligand, site of labelling or molecule-radionuclide coupling mechanism linking the molecule and radionuclide, provided that it acts via the same mechanism284

For further illustration, the draft guideline on similarity provides that interferon beta products would be considered similar to other interferon beta products and interferon alfa products would be considered similar to other interferon alpha products; interferon betas, however, would not be considered similar to interferon alfas.285 Moreover, pegylated and nonpegylated versions of the same protein would be considered similar, as would different products containing the same protein, whether produced by biotechnology or synthesis.286 Two monoclonal antibodies targeting the same antigen normally would be considered similar.287 An applicant claiming that its product is not similar to another orphan product being considered for authorisation or already authorised should provide a “reasoned argument” to that effect in its MAA.288 In general terms, this argument should include information regarding the proposed structure of the molecule, with two- and three-dimensional graphs, if possible.289 The active substance should be described “precisely” with “systematic terminology.”290 For purposes of determining similarity, consideration will also be given to International Nonproprietary Names and World Health Organization reports, if applicable.291 Recognising, however, that “the conceptual basis of similarity is constantly being refined,” the European Commission welcomes the submission of other evidence that may be used to demonstrate similarity.292 Based upon all of this information, the EMEA’s Committee for Medicinal Products for Human Use (CHMP) will give an opinion, in the first instance, regarding the similarity of two orphan products.293 Often, this opinion will be given during the CHMP’s routine evaluation of a product’s MAA and in parallel with its evaluation of the product’s quality, safety and efficacy.294 CHMP’s opinion on this point is reviewed by COMP and the European Commission, which will verify whether the criteria for orphan medicinal product designation and exclusivity have been met.295 2. “Same therapeutic indication.” The marketing authorisation for an orphan medicinal product covers only those therapeutic indications that meet the orphan designation requirements, as discussed above.296 The “same therapeutic indication” means “the same subset of the designated condition.”297 Thus, if one orphan medicinal product has been granted exclusivity for an indication in a subset of the designated condition, a second applicant for a product to treat a subset of the same condition

284 Id. at Article 3(c)(1)-(3).

285 Draft guideline at Appendix 1.

286 Id.

287 Id.

288 Draft guideline at II.1.

289 Id.

290 Id.

291 Id. at II.

292 Id. at II.1.

293 Id. at Introduction, 1.1; Communication at D(1.1).

294 Id.

295 Id.




will need to show that its subset is distinct and clinically meaningful.298 The two products will be considered to have the same therapeutic indication if there is “significant overlap” between the target populations.299 On the other hand, different sponsors of similar orphan products could each be granted marketing authorisations if their orphan indications are sufficiently different. In such a case, each product would be granted market exclusivity for the authorised orphan indication, only.300 Similarly, a sponsor of a non-orphan product could receive orphan designation and market exclusivity for a new (orphan) indication.301 E. Review of market exclusivity The Orphan Product Regulation provides for the regular review of an orphan product’s eligibility for orphan status. An authorised orphan medicinal product that no longer meets the established requirements for that status will be removed from the orphan drug register and stripped of its market exclusivity.302 For example, the 10-year marketing exclusivity period may be reduced to six if, at the end of the fifth year, it is established that the product is “sufficiently profitable” that the maintenance of market exclusivity is no longer justified.303 The European lawmakers’ view is that “an orphan medicinal product should not benefit from market exclusivity if it enjoys raised profit levels from the time of marketing.”304 To facilitate regular monitoring of the non-profitability criterion, the orphan drug sponsor is asked to submit information to the Commission and the COMP on “the marketing, prices and reimbursement, distribution costs, annual estimate of number of patients treated or prescriptions, and all other necessary economic data related to” the product.305 The Commission is responsible for establishing, through guidelines, other procedures and systems to monitor the prices of orphan products.306 It is recommended that, by the end of the fifth year of market exclusivity, the Member States “systematically check” whether the orphan drug criteria are still met and report to the Commission cases in which they are not.307 Although this sort of review is normally to occur at the end of five years, an evaluation of the orphan designation criteria—including an assessment of profitability—may be conducted at any time.308 The non-profitability criterion obviously presents serious issues for companies developing new products with hopes that the products will be successful in the marketplace. There may not be the opportunity in the EU that has been available in the US for a product originally designated as an orphan to surpass expectations and achieve marketplace success, without the loss of the orphan exclusivity that was in some measure responsible for this success.


299 Id.

300 Communication at D(3).

301 Draft guideline at C(2).

302 Regulation 141/2000 at Article 5(12); 8(2).



305 Id.

306 Id.

307 Id.

308 Id.


F. Breaking exclusivity The 10-year market exclusivity may be broken, without prejudice to any intellectual property rights of the original applicant, if:

The orphan drug marketing authorisation holder has given consent to a second applicant.

The orphan drug marketing authorisation holder is unable to supply sufficient quantities

of the product.

The second applicant can establish that its drug, although similar to the already authorised orphan drug, is safer, more effective or otherwise clinically superior.309

In any of these situations, the holders of the first and second approved marketing applications would share the remainder of the 10-year marketing exclusivity period that had been granted to the first product.310 To demonstrate “clinical superiority,” the second product must be shown to provide “a significant therapeutic or diagnostic advantage” over that provided by any authorised orphan medicinal product.311 Typically, evidence similar to that necessary to support a comparative efficacy claim for two different medicinal products will be needed—i.e., direct comparative clinical trials—but other evidence can be used, provided the methodology can be justified. Specifically, clinical superiority may be shown by a demonstration of:

greater efficacy (as assessed by effect on a clinically meaningful endpoint in adequate and well-controlled clinical trials)

greater safety in a substantial portion of the target population (in some cases direct

comparative clinical trials will be necessary)

in exceptional cases, where neither greater safety nor efficacy has been shown, a demonstration that the medicinal product otherwise makes a major contribution to diagnosis or to patient care312

The sponsor seeking to demonstrate clinical superiority should submit the appropriate data in a “critical report,” including a comparison of the two products, with particular reference to clinical studies and support from the scientific literature.313 The December 2004 draft guideline on the assessment of similarity and clinical superiority does not expand on these instructions, but suggests that further guidance could be proposed following additional regulatory experience with orphan products.314



311 Regulation 847/2000 at Article 3(d).

312 Id.

313 Draft guideline at I.2.

314 Id. at IV.


G. Advice and translations An orphan medicinal product sponsor may seek EMEA’s advice on the data necessary to demonstrate product quality, safety and efficacy.315 The Community Code, as amended, creates the possibility that an orphan medicine might not need to be labelled in all 20 Community languages.316 H. Paediatric legislation 1. Current status of legislation. On 8 September 2005, the European Parliament passed legislation providing a six-month extension of the Supplementary Protection Certificate (SPC) as proposed by the European Commission. Earlier in the year, Parliament’s Committee on Environment, Public Health and Food Safety had voted in favour of the legislation. An SPC already provides five years on top of the patent term and is intended to grant innovators time to recover a portion of R&D costs. The six-month SPC extension is aimed at allowing companies conducting additional paediatric trials of a given drug to recover certain investigation costs. An application for an extension of a certificate’s duration must be lodged not later than six months before the certificate’s expiry. Although some members of the European Parliament proposed alternative extensions, such as a three-month period that could be extended an additional three months for products with sales below a certain threshold, a fixed term of six months was favored by the overwhelming majority of European parliamentarians. A review clause states that this point should be reassessed six years after the Regulation enters into force. Final adoption is not expected before the end of 2006. 2. New Paediatrics Use Regulation. The new Regulation on medicinal products for paediatric use was proposed on 29 September 2004. The area of medicines for paediatric population—newborn through 18 years of age—is viewed as a serious legislative vacuum in the EU. While any medicine must be authorised for use in adults, there were no legislative requirements concerning medicines for children. To stimulate paediatric research and testing by pharmaceutical firms, the new Regulation approved by the European Parliament on 8 September 2005 combines obligations and incentives, covering:

medicinal products not yet authorised for marketing authorised medicinal products covered by a patent or SPC extending patent protection

authorised medicinal products no longer covered by a patent or SPC.

The proposed Regulation’s main features are:

an advisory expert committee, the Paediatric Board (PB), consisting of ethicists and representatives of Member States, associations of professional and patient

315 Regulation 141/2000 at Article 6.

316 Article 63.1 of the Community Code on Medicinal Products Directive 2001/83, as amended by the Code Amendment Directive 2004/27.


representative organisations and EMEA’s CHMP, which will give opinions on paediatric investigation plans and requests for waivers or variations from data requirements

assessment results of tests performed under the legislation by EMEA’s CHMP for

centrally authorised products, or by national Competent Authorities for products under the decentralised marketing authorisation procedure, possibly following input from the PB

a requirement that new medicinal product marketing authorisation applications, as well

as any authorisation application for a new indication, new pharmaceutical form or new route of administration, include paediatric study results according to an agreed investigation plan and describe how long-term efficacy and possible adverse reactions will be ascertained

a requirement that the results of all completed studies conducted in accordance with the

agreed paediatric investigation plan, whether terminated prematurely or not, as well as details of the results of all relevant studies funded by the Community and the Member States will be published by EMEA with all relevant conclusions for medicinal products in the same therapeutic class that cover the same proposed paediatric use

only paediatric studies that offer potential benefit to children may be conducted

paediatric data requirement waivers or deferrals, in some cases

a six-month patent extension may be granted if the marketing authorisation application is

for a product covered by a patent or supplementary protection certificate (SPC) and is accompanied by paediatric investigation plan results

10 years’ regulatory exclusivity for off-patent products with a paediatric use marketing

authorisation

funding for paediatric off-patent medicine use research or for paediatrics that do not have SPCs, under Community research programmes (Medicines Investigation for the Children of Europe [MICE])

a PB inventory (to be published by EMEA within two years of the entry into force of the

proposed Regulation and updated regularly) to identify unmet paediatric medical needs, the extent to which medicines corresponding to these needs are available, the availability of relevant data from trials including ones done outside the EU and research priorities to assess paediatric investigation plans

Member State surveys and reports to EMEA of all existing healthcare professionals’

uses of medicinal products for paediatric indications

a network of researchers and research centres to avoid duplication of research and or tests on children, to be put in place by the EMEA Management Board starting with the publication of an implementing strategy within one year of the entry into force of the Regulation


a European register of clinical trials of medicinal products for paediatric use, with these caveats:

o Studies should also be entered into current Member State databases of

paediatric clinical investigations.

o Repetition of studies already performed in non-EU countries should be avoided.

o If unavoidable, controlled studies should be carried out. The proposed legislation creates the possibility for a third party to use the pharmaceutical, preclinical and clinical documentation contained in the file on the medicinal product, if the marketing authorisation holder discontinues placing the medicinal product on the market. In such cases, the holder must allow a third party to make such use, provided that the medicinal product is authorised for a paediatric indication, and the marketing authorisation holder has benefited from the incentive provisions in the new Regulation. The Commission must carry out an analysis of the incentive and reward provisions, including a financial assessment relating to the research costs and profits resulting from such incentives, within six years of the regulation entering into force. Should the analysis show the mechanism to be ill-suited to the results sought or achieved—notably, the stimulation of research on paediatric uses—the Commission can propose an amendment to the legislation. 3. EMEA working group’s list of paediatric needs. EMEA’s paediatric expert group (PEG) is compiling a list of medicines categories in which paediatric formulations are needed as part of an effort to promote the development of new paediatric drugs. In creating this list, the PEG is relying in part upon information on paediatric needs already compiled by Member States. The PEG also is consulting closely with experts, national authorities and European associations and inviting comments from interested persons. As part of this initiative, the following documents appear on EMEA’s website:

EMEA/PEG Procedure for Identifying Paediatric Needs Assessment of the Paediatric Needs in the Area of Pain Relief (closed for consultation

31 December 2005)

Reflection Paper on Formulations of Choice for the Paediatric Population (closed for consultation 31 December 2005)

Note of Explanation to accompany the Reflection Paper.

For centrally authorised products, the EMEA’s CHMP is specifically directed to attach to its opinion on a product’s authorisation the details of any conditions or restrictions which should be imposed on the supply or use of medicinal product317

317 Article 9(4) b) and c) of the new EMEA Regulation 726/2004.


Chapter XIII. Prescription versus Over-the-Counter Classification of Products Like other medicinal products, nonprescription products (also called Over-the-Counter or OTC products) must have a marketing authorisation to be lawfully marketed in the EU. According to Article 70 of the Community Code on Medicinal Products, at the time the EMEA/European Commission or a Member State authority grants a marketing authorisation, the approving authority is required to specify the classification of the medicinal product as either: a medicinal product subject to medical prescription; or a medicinal product not subject to medical prescription. The criteria for limiting a product to medical prescription are spelled out in Article 71(1) and the products that do not meet these criteria are non-prescription (OTC) (Article 72 of the Community Code on Medicinal Products). According to Article 71(1), medicinal products shall be subject to medical prescription where they:

are likely to present a danger either directly or indirectly, even when used correctly, if utilised without medical supervision

are frequently and to a very wide extent used incorrectly, and as a result are likely to

present a direct or indirect danger to human health

contain substances or preparations thereof, the activity and/or adverse reactions of which require further investigation

are normally prescribed by a doctor to be administered parentally

Under Article 73, the Competent Authorities shall draw up a list of the medicinal products subject, on their territory, to medical prescription, specifying, if necessary, the category of classification. They shall update this list annually. According to Article 75, Member States must update the European Commission and to other Member States, annually about any changes that have been made to this list. Article 74 requires re-examination of a medicine’s classification at the time its authorisation is renewed or when new facts are brought to the notice of Competent Authorities. The Competent Authorities are authorised by Article 70 to fix subcategories for prescription-only medicinal products, as follows:

medicinal products on renewable or non-renewable medical prescription

medicinal products subject to special medical prescription

medicinal products on restricted medical prescription, reserved for use in certain specialised areas

Under Article 71(2), any Member State that provides for subcategories of medicinal products subject to special medical prescriptions must consider these factors:

the medicinal product contains, in a nonexempt quantity, a substance classified as a narcotic or a psychotropic substance within the meaning of the international conventions in force, such as the United Nations Conventions of 1961 and 1971


the medicinal product is likely, if incorrectly used, to present a substantial risk of medicinal abuse, to lead to addiction or be misused for illegal purposes

the medicinal product contains a substance which, by reason of its novelty or properties,

could be considered as belonging to the group envisaged in the second indent as a precautionary measure

Additionally, under Article 71(3), any Member State that provides for a subcategory of medicinal products subject to restricted prescription shall consider:

the medicinal product, because of its pharmaceutical characteristics or novelty or in the interests of public health, is reserved for treatments which can only be followed in a hospital environment

the medicinal product is used in the treatment of conditions which must be diagnosed in

a hospital environment or in institutions with adequate diagnostic facilities, although administration and follow-up may be carried out elsewhere

the medicinal product is intended for outpatients but its use may produce very serious

adverse reactions requiring a prescription drawn up as required by a specialist and special supervision throughout the treatment

EMEA and Member States may waive both the regular and the specialised controls for prescription-only products for: the maximum single dose, the maximum daily dose, the strength, the pharmaceutical form, certain types of packaging; and/or other circumstances of use which it has specified. Under Article 71(5), if a Competent Authority does not designate medicinal products into subcategories referred to above (Article 70(2)), it shall nevertheless take into account the statutory criteria in determining whether any medicinal product is a prescription-only medicine. Under Article 127a of the Community Code as amended by the Code Amendment Directive, when a medicinal product is to be authorised in accordance with the EMEA Regulation, and the CHMP in its opinion refers to recommended conditions or restrictions with regard to the safe and effective use of the medicinal product, the Commission is required to adopt a decision addressed to the Member States, under the procedure described in Articles 33 and 34 of the Community Code, for the implementation of those conditions or restrictions. It also is possible for such processes as the arbitration procedure to be used to effectuate Community-wide classifications of products on the market by a decentralised procedure. In October 2005, the European Commission published A Guideline on Changing the Classification for the Supply of a Medicinal Product for Human Use. It describes the information to be submitted to the relevant authority by a marketing authorisation holder seeking to switch the classification of a product. It also sets forth information needed to request a one-year period of exclusivity in connection with the switch (as discussed below) and is meant to aid EU Member States in achieving greater harmonisation as to the supply classification of products. As is discussed in greater detail elsewhere in this document, the new pharmaceutical review legislation contains several provisions of interest to the self-medication industry:

The Code Amendment Directive revises the Community Code on Medicinal Products to create a possible one-year exclusivity period to a company that conducts investigations to support switching a product from prescription to OTC.


The new EMEA Regulation expands the opportunity for OTC product manufacturers to use the centralised procedure for OTC medicines under the new Article 3 optional jurisdiction provisions.

On this point, the new EMEA Regulation specifically mentions the appropriateness of

allowing access to the centralised procedure for medicinal products which, although not innovative, may be of benefit to society or to patients if they are authorised from the outset at the Community level [i.e., through the EMEA procedure], such as certain medicinal products that can be supplied without a medicinal prescription.318

The new Herbal Medicinal Products Directive is of great interest to the self-medication

industry, as these products often are OTC products.



Chapter XIV. Parallel Trade A. Background One of the most contentious issues in the EU is parallel trade. European governments generally control the prices of and/or reimbursement for pharmaceutical products, an area in which there is no harmonisation. Price disparities among the Member States have led to the development of an industry that purchases medicines in markets with lower fixed prices and resells them in markets where prices are higher, pocketing the difference. Those who know about pharmaceuticals and their vulnerability to quality concerns cannot help but worry about a practice in which pharmaceutical products are moved around Europe, repacked, relabelled and resold, without the permission or technical compliance support of the marketing authorisation holder (MAH). Also, parallel trade can open the way to counterfeits and non-interchangeable substitutes for the product prescribed.

Parallel trade also has an adverse impact on innovation, as margins that otherwise would have gone to pharmaceutical research and development are instead eroded as lower-priced products move into markets where the governments have set higher prices.

Much to the chagrin of pharmaceutical manufacturers, parallel trade is tolerated, even encouraged, in the EU due to a long-standing interpretation of the fundamental EU treaty’s competition provisions.

B. Recent developments Recently, the EU parallel trade battle has taken on some new twists. While it is unnecessary for regulatory affairs professionals to be completely versed in the case law and other technicalities involving parallel trade, several points should be kept in mind:

Articles 76-85 of the Community Code on Medicinal Products set forth responsibilities of wholesalers and distributors, including parallel traders.

The European Commission has issued Guidance on Good Distribution Practices

intended to reduce the risk that parallel trade activity might undermine product quality (see Chapter VI.).

Article 57 of the EMEA Regulation 726/2004 made notification of parallel trade in

centrally-authorised products mandatory as of 20 May 2004.

A provision of the Community Code, as amended, requires marketing authorisation holders and distributors to ensure appropriate and continued supplies of a medicinal product to pharmacies and other persons authorised to supply medicinal products, to meet the needs of patients in the Member State concerned.319 Backed by parallel traders, this provision has limited effect. It applies only when the product is actually placed on the market in the relevant Member State.

EU legislators did not adopt a proposal by parallel traders to require marketing

authorisation holders, in general, to provide an uninterrupted supply of medicinal products to wholesale distributors.

319 Article 81, Community Code Directive as amended by the Code Amendment Directive.


Wholesalers importing medicines into a Member State must inform the marketing authorisation holder.320

Certain regulatory filings with Member State regulatory authorities are required of

parallel traders, including possession of a manufacturing authorisation that includes authorisation to distribute at wholesale the medicinal products covered by the authorisation.321

Authorised wholesalers must supply a pedigree with products that will make it possible

to ascertain the date, the name and pharmaceutical form of the medicinal product, the quantity supplied and the name and address of the supplier and consignor, and Member States must take measures to ensure traceability of medicines.322

Member States may apply more stringent requirements to the wholesale distribution of

narcotics, psychotropic substances, medicinal products derived from blood, immunological medicinal products and radiopharmaceuticals.323

The European Commission is authorised to publish guidelines on good distribution

practice324 (and, as noted earlier, has done so).

Companies concerned about parallel trade of their products must establish a system that monitors both notices received from wholesalers and information made public about parallel traders’ filings with regulatory authorities. Such steps should be part of an effort to establish and maintain effective postmarket product surveillance. A company has a very limited opportunity to object to authorities about parallel trade of its product, although it is difficult to predict whether lodging such an objection might result in a Member State refusing a parallel import permit. Certainly, the procedure could be tried in cases presenting a compelling public health concern, e.g., parallel traders handling biologicals or other products requiring careful storage and handling.

As is discussed in greater detail in Chapter XXI.D, the accession treaties325 for eight326 of

the 10 new EU Member States prescribed certain filings.327 A specific mechanism was included requiring parallel importers to notify patent holders of their intention to import a product 30 days prior to their making an application. This means patent holders will not have to wait until a parallel import is marketed before they can take legal action. Also, provisions were included to circumscribe parallel trade between the old and new

320 Article 76.3, Community Code Directive as amended by the Code Amendment Directive.

321 Article 77-81, Community Code Directive as amended by the Code Amendment Directive.

322 Article 82, Community Code Directive as amended by the Code Amendment Directive.

323 Article 83 Community Code Directive as amended by the Code Amendment Directive.

324 Article 84 Community Code Directive as amended by the Code Amendment Directive. This requirement has been implemented by

Guidelines on Good Distribution Practice of Medicinal Products for Human Use (94/C63/03) pharmacos.eudra.org/F2/pharmacos/

docs/Doc2001/may/GDPGuidelines1.pdf.

325 Annex IV (2) of the Treaty of Accession.

326 The Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Slovakia, and Slovenia.

327 The Association of the British Pharmaceutical Industry was one of the import notice's principal sponsors. Its campaign won the support of the

UK government, but only limited support from other member states and, at some stages, direct opposition from the Commission.


Member States. Otherwise, such trade would almost certainly have occurred in large volume due to the generally lower product prices in the new Member States (which tend to have less affluent populations). For the eight countries involved, the accession derogation amounts to an exception from the general rule under Community law on exhaustion of trademark rights, a doctrine that is one of the legal underpinnings to parallel trade.

Parallel trade relates only to the movement of goods within the EU/European Economic

Area.

Also, efforts by pharmaceutical companies and authorities to have two-tier price schemes for pharmaceuticals for developing countries are undermined when—as has happened—products meant for HIV/AIDS patients in southern Africa turn up in EU ports of entry. As discussed above in Chapter III.N., to discourage such diversion, the EU has issued a regulation requiring special marking of products destined for developing countries under tiered price schemes.

Further litigation will be required to resolve certain issues, like supply quotas.

Pharmaceutical officials were heartened by two recent developments: the December 2003 decision of the European Court of Justice in the Bayer Adalat case and the opinion of Advocate General Jacobs in the Glaxo case (even though the ECJ ultimately dismissed the latter case as “inadmissible” due to the fact that it was an appeal from a Member State administrative body that does not possess the status of a court entitled to refer cases to the ECJ). Bayer Adalat and Glaxo are summarised below.

Regulatory affairs professionals need to keep in mind that the ECJ appears willing to

move at a faster pace than both the EU Member States and EU lawmakers in striking down Member State laws that bar entry into their markets of pharmaceuticals permitted elsewhere in the EU. The Kohlpharma judgment is a disturbing example of this trend and might reflect, in part, judicial misunderstanding of the distinction between parallel-trade import permits and marketing authorisations.

In the Commission v. France case, the ECJ recently struck down French laws aimed at

maintaining controls over importation of pharmaceuticals for personal use.

Kohlpharma and Commission v. France are summarised below. C. Recent case law 1. Bayer Adalat. On 6 January 2004, the European Court of Justice issued a decision in the Bayer Adalat case, dealing with parallel trade in pharmaceutical products in the EU. This trade is protected by competition rules and their enforcement by the European Commission. The Commission has frequently imposed significant fines for parallel trade restrictions, which it considers a serious antitrust infringement. This case concerned European distribution of the cardiovascular drug, Adalat, which was priced some 40% lower in France and Spain than in the UK. Bayer’s French and Spanish wholesalers sought to exploit that difference by purchasing additional quantities of Adalat for export to the UK. Bayer reacted by adapting its supply policy, to the extent that it ceased fulfilling the increasingly large Adalat orders placed by French and Spanish wholesalers.


Following a complaint from certain wholesalers, the European Commission concluded that, by imposing an export ban as part of its commercial relations with Adalat wholesalers, Bayer had infringed the European Community Treaty.328 In Bayer Adalat, the Court of Justice found that the European Commission had failed to establish that the wholesalers acquiesced in a ban imposed by Bayer to prevent parallel imports of Adalat into the UK. On the contrary, the Court took the position that Bayer’s unilateral supply policy did not depend upon the cooperation of the wholesalers, who attempted to make Bayer believe—by switching their ordering patterns—that the needs of their national markets had grown. The mere fact that the wholesalers continued to distribute Adalat despite Bayer’s altered supply policy did not prove the wholesalers’ (tacit) acceptance of the alleged export ban. Therefore, the Court of Justice upheld the initial decision of the Court of First Instance by ruling that the European Commission erred in their legal assessment of the facts and wrongfully fined Bayer for breach of EU competition rules. The decision allows at least those manufacturers who are not dominant in the market some limited manoeuvring room to manage supplies in a way that could reduce parallel trade. However, the Commission has promised continued scrutiny of supply quota schemes, and manufacturers will need to carefully review measures taken to stem flow of products to low-price EU countries. 2. Glaxo Syfait In May 2005, the ECJ decided not to rule on this Greek parallel export case, Glaxo Syfait, saying it lacked jurisdiction to answer the questions referred to it by the Greek competition commission, as this agency is not a “court” possessing authority to refer cases to the EU courts.329 This development was a disappointment to the pharmaceutical industry, especially since Advocate General Jacobs had delivered a nonbinding opinion in favour of the GlaxoSmithKline position in October 2004. In that opinion, he declared that a pharmaceutical company holding a dominant position may, in some cases, be justified in refusing to meet orders from wholesalers, even if this leads to a limitation on parallel trade. Many in the industry had hoped for a definitive ECJ ruling supporting this view. 3. Kohlpharma In Kohlpharma GmbH v Bundesrepublik Deutschland,330 the ECJ issued a confusing opinion that could be read as radically changing the rules for marketing authorisations in the context of parallel pharmaceutical product imports. As a result of this judgment, parallel importers will no longer have to show “common origin” to obtain parallel import authorisation. Prior to this case, Court jurisprudence in this area had been widely interpreted to mean that a parallel importer had to establish that a link existed between the imported product’s 328 Art. 81(1) of the European Community Treaty prohibits anticompetitive agreements that appreciably affect trade between EU Member States. (Genuinely unilateral conduct falls outside the scope of this prohibition Article 82 of the Treaty regulates unilateral conduct to the extent that it

amounts to abuse of a dominant position). Nevertheless, the prohibition in Article 81 (1) applies to anticompetitive distribution practices, which,

though apparently adopted unilaterally by a manufacturer in the context of its contractual relationship with its dealers, receive at least the tacit

acquiescence of those dealers. For a distribution agreement by tacit acceptance to be within the ambit of Article 81(1), the supplier must require

from its dealers, as a condition of their future contractual relationship, that they comply with the supplier’s new commercial policy aimed at

achieving an anticompetitive goal.

329 C-53/03, Reference for a preliminary ruling from the Epitropi Antagonismou in Synetairismos Farmakopoin Aitolias & Akarnanias (Syfait

and Others v GlaxoSmithKline plc and Others, 31 May 2005.)

330 Case C-112/02.


manufacturer and the locally authorised product, either because the manufacturers were part of the same group or were common licensees. Applying the European Community Treaty’s free movement of goods principles, the ECJ in Kohlpharma ruled that a refusal to grant authorisation for a pharmaceutical product’s parallel import cannot be justified on the grounds of protecting public health solely because the local product and the imported product do not have a “common origin.” The Court asserted that the prime consideration is protection of public health.331 The importer must demonstrate by means of “accessible or readily available information” that the medicinal product to be imported does not differ significantly from the locally authorised product. Where the importer does not have access to sufficient information but provides data which show it is “at least plausible” that the two products do not differ significantly, the Competent Authority is obliged to verify this, including contacting the health authority in the Member State of exportation.332 This ruling raises a number of questions. Of immediate concern to pharmaceutical companies is the effect it may have on importing generic medicinal products. As discussed elsewhere in this publication, generic medicinal products are subject to the authorisation procedure set out in Directive 2001/83, as amended. Generics can apply for authorisation under an abridged procedure, due to the fact that the supporting clinical safety and efficacy data were already submitted under the innovator’s application. A parallel import is different insofar as the product in question is already on the market in one Member State and, thus, has already been issued a market authorisation. Under Kohlpharma, however, the Court treats as a parallel import a product different from a manufacturer’s own product, but possessing a common active ingredient and possessing an authorisation in another Member State. The result can be read as a means to avoid the need to have a marketing authorisation in a destination EU Member State notwithstanding the plain requirement of Directive 2001/83333 and EU Member States’ implementing laws. Because the parallel importer does not have access to all the information available to a manufacturer, it cannot fully comply with the requirements of these laws. Rather than obligating the parallel importer to justify the acceptability of its wares to Member State authorities, the Kohlpharma court has placed that burden on the Competent Authorities, to verify the safety and efficacy of a parallel-trade product within their borders that lacks a marketing authorisation. Pharmaceutical manufacturers also were concerned that this ruling could undermine data exclusivity protection if parallel traders could take advantage of shorter exclusivity periods in some Member States as compared to others. A generic copy of a product no longer under protection in a Member State observing the six-year data exclusivity period could be approved there and then shipped as a parallel import to another Member State where the innovator product is under 10-year protection. Previously, such an occurrence was precluded by the “common origin” principle. Now that “common origin” is no longer a prerequisite to qualify for market authorisation of a parallel import, it could be argued that a generic company fulfils the conditions of a parallel import insofar as the generic product has been issued a market authorisation in the Member State of export, so long as the product is “essentially similar.”334

331 Paragraph 14, case C-112/02, Kohlpharma GmbH v Bundesrepublik Deutschland.

332 Paragraphs 19 and 20, case C-112/02, Kohlpharma GmbH v Bundesrepublik Deutschland.

333 Article 6 sets forth a general requirement that a medicinal product have a Marketing authorisation in each Member State, and Article 76

compels Member States to enforce this requirement. There are a few exceptions, e.g. permitting unauthorised products on a named-patient basis.

334 The new definition of “generic medicinal product” in Directive 2001/83 as amended by Directive 2004/27 published April 30, 2004

resembles the test set out by Advocate General Tizzano in his Opinion on “essentially identical” in Kohlpharma. Directive 2004/27 defines

“generic medicinal product” as “a medicinal product which has the same qualitative and quantitative composition in active substances and the

same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been


Over time, the eventual harmonisation of regulatory data exclusivity periods to the new 8+2+1 formula will reduce concerns about this potential interpretation of Kohlpharma. The Code Amendment Directive to the Community Code on Medicinal Products contains provisions that enable a generic company to apply for authorisation in a different Member State from the one that issued the innovator drug’s authorisation.335 Previously, application had to be made in the same Member State where the innovator’s product was authorised. However, there is nothing in the new legislation that explains the relationship, if any, between this new legislative provision and the ruling in Kohlpharma. It remains to be seen whether the parallel trade cases, and particularly Kohlpharma, have enabled an alternative route to market other than that outlined in the Community Code, as amended, and the EMEA Regulation. The ruling in Kohlpharma states that, in a situation where “the assessment of safety and efficacy carried out for the medicinal product which is already authorised can be used in the application for a marketing authorisation for the second product without risk to the public health,” the lack of “common origin” may not be the sole reason to reject an application for a parallel import’s authorisation. Lurking in this case and others—as well as in the operational problems of the decentralised mutual recognition system—is the reality of regulatory inequivalence and lack of trust among the 25 Member States. In the context of the mutual recognition procedure, the Code Amendment Directive enacted 30 April 2004 provides for a coordination group that will examine any questions arising that relate to the marketing authorisation of a medicinal product in two or more Member States. This group also might serve as a forum for the discussion of parallel trade concerns. With Kohlpharma throwing the relationship between the amended Community Code’s generics provisions and the rules on parallel imports into question, the European Commission, the 25 Member States and this new “coordination” group could find themselves with no shortage of questions to be examined. 4. Commission v. France On 26 May 2005 the European Court of Justice ruled that the French Republic had failed to fulfil its European Community Treaty obligations due to its national legislation demanding a prior authorisation procedure for personal imports of medicinal products and homeopathic medicinal products lawfully prescribed in France and authorised under relevant Community Directives.336 The ECJ ruled that the French requirements were disproportionate and therefore incompatible with the EU rules on free movement of goods. The French public health code requires prior authorisation for the import of medicinal products for personal use not carried out by personal transport. The European Commission brought the proceedings in response to a complaint. In its case, the Commission referred to three situations involving personal imports, not effected by personal transport, of lawfully prescribed medicinal products:

demonstrated by appropriate bioavailability studies.…” The Advocate General’s definition of “essentially identical” is “when proprietary

medicinal products contain qualitatively and quantitatively the same active ingredients, have the same pharmaceutical form, are bio-equivalents,

and do not appear to differ as to their safety and efficacy.” Paragraph 51: Opinion of Advocate General Tizzano of 11 September 2003, case C-

112/02.

335 Article 1 (8) of Directive 2004/27/EC, which replaces Article 10 of Directive 2001/83.

336 Case C-212/03.


medicinal products which, in accordance with Community law, are authorised both in France and in the Member State where they are purchased

homeopathic medicinal products which, in accordance with Community law, are

registered in another Member State

medicinal products not authorised in France but which are authorised in the Member State where they are purchased

The Commission argued that, in requiring a prior authorisation, French law is per se contrary to Article 28 of the European Community Treaty in the first two situations outlined. The authorisation procedure, as applied by the authorities concerned in the third situation, is disproportionate and, therefore, also contrary to that article. The Commission took the view that a prior authorisation procedure imposed on the importation of medicinal products authorised both in the Member State into which they are imported, and in the Member State from which they are exported constitutes a restriction on the free movement of goods between Member States contrary to Article 28. The French authorities argued that the controls introduced by the French regulations on importation of medicinal products by individuals were justified by Article 30 of the European Community Treaty, since they were intended solely to guarantee the protection of health and life of humans through measures that are not disproportionate. The ECJ agreed with the Commission. The Court held that the French Republic has failed to fulfil its obligations under Article 28 EC, by applying:

a prior authorisation procedure to personal imports, not effected by personal transport, of medicinal products lawfully prescribed in France and authorised under the precursor to the Community Code Directive, both in France and in the Member State where they are purchased

a prior authorisation procedure to personal imports, not effected by personal transport, of

homeopathic medicinal products lawfully prescribed in France and registered in a Member State under a precursor to the Community Code Directive337

a disproportionate prior authorisation procedure to personal imports, not effected by

personal transport, of medicinal products lawfully prescribed in France and not authorised in that Member State but both authorised by the French regulatory agency (or EMEA) but only in the Member State where they are purchased

In the third situation, the ECJ found that the French agency’s practice of checking that the medicinal product imported contains active ingredients already evaluated in France thus precluding, de facto, the possibility of obtaining an authorisation for a medicinal product is not justified insofar as it restricts importation into France of medicinal products not approved by the French agency but approved in the Member State where they were purchased, which are lawfully prescribed and which are intended for personal use. The Court was unpersuaded by the French Government’s argument that the procedure was meant to combat fraud or abuse of its

337 Because the part of the case concerning homeopathic medicinal products dealt only with homeopathic products which have been

manufactured, controlled and inspected in accordance with the harmonised rules and which have a sufficient degree of dilution to guarantee their

safety, the ECJ held that the French Government has not shown, on grounds of health protection, that a prior authorisation procedure is necessary

for personal imports, not effected by personal transport, of these products.


marketing authorisation system. The ECJ agreed with the Commission that a Member State is free to require an authorisation for personal imports, but that it is disproportionate to apply the same authorisation procedure to personal imports that is applied to commercial imports, particularly when such burdensome procedures are not required for personal imports effected by personal transport. The Court explained that, although grounds of health protection may justify restrictions on the free movement of goods between Member States, such measures must comply with the principle of proportionality. They must be confined to what is actually necessary to ensure safeguarding public health; they must be proportionate to the objective pursued, which could not have been attained by measures which are less restrictive of intra-Community trade.338 The Court went on to say that French authorities may adopt an authorisation procedure adapted to the specific nature of those imports that does not exceed what is necessary to attain the objective pursued. This procedure must be easily accessible and capable of being completed within a reasonable period.

338 The ECJ cited Case C-192/01 Commission v Denmark [2003] ECR I-9693, paragraph 45


Chapter XV. Veterinary Medicinal Products A. Veterinary Code Amendment Directive and New EMEA Regulation On 30 April 2004, a directive amending the Community Code on veterinary medicinal products (Veterinary Code Amendment Directive)339 was published in the Official Journal of the European Communities, along with a new EMEA Regulation340 that affects veterinary medicinal products in a manner similar to its impact on medicinal products for human use. The EU framework for veterinary medicinal products (like the one for human medicinal products) is based upon two separate procedures: a centralised procedure and the decentralised mutual recognition procedure. Recent amendments to both procedures are still being implemented. B. Overview For veterinary medicines used in food-producing animals (for production of meat, dairy or eggs), the manufacturer must not only obtain authorisation of the medicinal product, but also set Maximum Residue Levels (MRLs) before the food may be marketed in the EU.341 It is essential to seek an EMEA MRL assessment prior to starting the medicinal product authorisation procedure. This is a specific requirement under the mutual recognition procedure. Although prior establishment of a MRL is not specifically referred to or required under the centralised procedure, there is reference to the fact that EMEA needs to establish these levels. Furthermore, the Notice to Applicants and Note for Guidance on the establishment of MRLs for veterinary medicinal products recommends that MRL applications be submitted at least six months before filing an application for marketing authorisation. In October 2005, the European Commission published a revision of Volume 8 of the Notice to Applicants and guidelines and rules governing veterinary medicinal products in the EU. The revision takes into account the harmonised data requirements agreed at the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Products (VICH) and other guidance and makes it available in a single, comprehensive document. The revision provides information on the operational procedure for applications for the establishment of MRLs and provides guidance on the presentation and content of the application dossier. It also provides information on how the safety and residue data are evaluated and describes the assessment process. At the same time, the Commission published a consolidated, unofficial version of Annexes I to IV on the Council Regulation dealing with MRLs. C. Centralised procedure Under the centralised procedure, a veterinary medicinal product obtains a single marketing authorisation which is valid throughout the EU. An authorisation is granted by the European Commission in the form of a Decision and is based upon a scientific evaluation by the EMEA’s Committee for Medicinal Products for Veterinary Use (CVMP). 339 Directive 2004/28/EC.

340 EMEA Regulation 726/2004.

341 Article 1(1)(b) of Regulation 2377/90 laying down a Community procedure for the establishment of maximum residue limits of veterinary

medicinal products in food of animal origin, (OJ No L 67 of 7.3 1997, p.1). A maximum residue limit (MRL) is defined in EU legislation as “the

maximum concentration of residue resulting from the use of a veterinary medicinal product (expressed in mg/kg or g/kg on a fresh weight basis)

which may be accepted by the Union to be legally permitted or recognised as acceptable in or on a food.


The centralised procedure is mandatory for certain biotechnology products and for “medicinal products for veterinary use intended primarily for use as performance enhancers in order to promote the growth of treated animals or to increase yields from treated animals.”342 Also, the centralised procedure is available on an optional basis for:

a veterinary product containing a new active substance343

any other product for which the applicant shows that the product constitutes a significant innovation

any other product for which the applicant shows that authorisation is in the interest of

animal health at Community level

immunological veterinary products subject to community prophylactic measures

generic medicinal versions of centrally-authorised medicinal products344 Immunological veterinary medicinal products for the prevention or control of animal diseases that are the subject of EU prophylactic measures are granted access to the centralised EMEA procedure.345 The new EMEA Regulation states that there is the option of using the centralised procedure “for medicinal products which, although not innovative, may be of benefit to society or to patients if they are authorised from the outset at Community level” (i.e., through the EMEA centralised procedure). If an animal health product company wishes to avail itself of the centralised procedure, it would likely be required to show that “the granting of authorisation (for a veterinary medicine product, through the centralised procedure) is in the interests of patients or animal health at Community level.”346 EMEA recently issued a guidance document to assist applicants and marketing authorisation holders in adapting to the requirements of the new EMEA Regulation. The guidance is entitled Practical Considerations on the Impact of the New Pharmaceutical Legislation on Marketing Authorisation Applications via the Centralised Procedure and Centrally Authorised Medicinal Products for Veterinary Use.347 The document is essential reading for regulatory affairs officials in companies with applications and/or marketing authorisations involving the centralised procedure or interested in submitted an application in this procedure. When a company wishes to place a medicinal product eligible for the centralised procedure on the EU market, it must send an application directly to EMEA. Authorisation decisions under the centralised procedure are based upon objective scientific criteria of quality, safety and efficacy. Two distinct phases constitute the authorisation procedure.

342 Annex to Regulation (EC) No 726/2004. The provision likely reflects EU lawmakers’ skepticism about animal medicines (hormones or

antimicrobials) used for growth promotion. Because companies are therefore more likely to seek approvals of a veterinary medicine product for

therapeutic use, rather than growth-promotion use, this section focuses on therapeutic use.

343 Regulation 726/2004, Paragraph 10 of the Preamble and Article 3.2(a).

344 Article 3 of Regulation (EC) No 726/2004.

345 New EMEA Regulation, Article 3(2); preamble at (10).

346 Article 3.2(b) EMEA Regulation.

347 EMEA/31976/2005, published 17 October 2005.


1. First phase: the application process. A company wishing to place a medicinal product on the market must first send a complete application directly to EMEA to be assessed by the CVMP. Each application for authorisation shall include the requested documents and information set out in Directive 2001/82/EC on the Community Code on veterinary medicinal products. This Directive sets forth a detailed list of requirements, including analytical protocols, safety tests and clinical tests, which applicants must submit:348

a detailed description of the veterinary product, product characteristics, manufacturing method, therapeutic indications and adverse reactions, dosage for the various species of animals and explanations of the precautionary and safety measures

a thorough description of the control testing methods employed by the manufacturer and

the result of the safety and residues testing (physicochemical, biological and microbiological tests, toxicological and pharmacological test, clinical trials), applicant must also demonstrate the specific measures taken concerning the prevention of the transmission of animal spongiform encephalopathies

documents showing that the manufacturer is authorised in his own country to produce

veterinary medical products and copies of any marketing authorisation obtained in another Member State or in a “third country” (here, non-European Economic Area country) for the relevant veterinary medicinal product

Once the evaluation is completed, the CVMP will give an opinion within 210 days of receipt of a valid application.349 However, a recent decision by the European Court of Justice ruled in favour of the European Commission indicates that an applicant has little recourse if a decision takes longer, even much longer, than this. The case was a challenge by CEVA Santé Animale SA and Pfizer to the Commission’s 10-year timeframe in making a decision in response to the companies’ request to classify progesterone (a naturally occurring steroid hormone used in animal reproduction) in the list of substances for which an MRL need not be set.350 The ECJ reversed a decision in favour of the companies that had been rendered by the Court of First Instance and ordered the companies to bear the cost of the litigation. The desired endpoint of this procedure is a Commission Decision, binding on all 25 EU Member States, to authorise the product. Centrally-authorised products may be marketed in all Member States. 2. The decision-making process. Upon receipt of the CVMP opinion, EMEA has 15 days to forward its opinion to the Commission, the Member States and the applicant, together with a report describing the veterinary product’s assessment by the Committee.351 This is the start of the second phase of the procedure, the decision-making process. If the CVMP opinion is favourable, the opinion must include:

348 Articles 12, 13, 14 and Annex I, Directive 2001/82/EC.

349 Article 31(3) Directive 2001/82.

350 Case C-198/03. The case is interesting reading because it documents a disagreement between the EMEA CVMP, which persisted in its view

of the safety of the substances in question, and the European Commission, which wished a more restrictive approach to hormones generally.

351 Article 33(3) EMEA Regulation.


summary of product characteristics details of any conditions or restrictions which should be imposed on the veterinary

product’s supply or use (in the case of a veterinary product intended for administration to food-producing animals, a statement of the accepted maximum residue level)

copy of the proposed labelling and the package leaflet

The Commission has 15 days to prepare a draft decision that will be forwarded to Member States and the applicant. The product is assigned a Community registration number that will be placed on the packaging if the marketing authorisation is granted. The draft decision is then sent to the Standing Committee for Veterinary Medicinal Products, composed of Member States, for its opinion. The Member States have 22 days352 to forward their written observations on the draft decision. This procedure is conducted in writing but, if a duly justified objection is raised by one or more Member States, the Committee holds a plenary session to discuss it. When the decision is favourable, the Commission makes a final decision within 15 days after the procedure concludes. However, an application for a marketing authorisation may be refused if it appears that:

the applicant has not demonstrated the product’s quality, safety or efficacy animal safety and welfare and/or consumer safety have not been taken into account

the applicant’s recommended period recommended for ensuring that food from treated

animals does not contain residues is not sufficiently long and that residues might constitute a consumer health hazard the veterinary product is presented for a use prohibited under other Community provisions353

If an application for a Community marketing authorisation is refused, the product is prohibited from entering the market throughout the European Community. After a marketing authorisation has been granted, the authorisation holder (MAH) shall inform EMEA of the date on which the product was placed on the market. Marketing authorisations via this centralised procedure are valid for five years. This marketing authorisation may be renewed after five years on the basis of an EMEA re-evaluation of the risk-benefit balance. Once renewed, this authorisation shall be valid for an unlimited period. However, if the product is not marketed within three years, the authorisation ceases to be valid. Finally, once the authorisation has been granted, EMEA or a Member State Competent Authority may require the holder to provide substances in sufficient quantities to perform tests to detect the presence of residues of the veterinary products concerned in food of animal origin. 3. Reference to Maximum Residue Levels (MRLs) for veterinary medicinal products The CVMP may request a Community reference laboratory, Official Medicines Control laboratory or a laboratory designated by a Member State to assure that the applicant’s proposed MRL analytical detection method is adequate to determine residue levels.354

352 Article 35(3)(a) & (b) EMEA Regulation.

353 Article 37 of the EMEA Regulation. 354 Article 32, EMEA Regulation.


Also, after an authorisation has been granted, EMEA or a Member State’s Competent Authority may require the MAH to provide sufficient quantities of substances to perform tests to detect the presence of veterinary medicinal product residues in food of animal origin. The MAH shall provide technical expertise to facilitate the implementation of the analytical method for detecting veterinary product residues.355 EMEA shall advise on the maximum limits for veterinary medicinal product residues.356 This issue is discussed further below. D. Mutual Recognition Procedure The Mutual Recognition Procedure (MRP) is used for veterinary medicinal products not eligible for the centralised procedure or for which the applicant has a choice but elects not to follow the centralised procedure. The MRP would be followed where a particular marketing authorisation application concerns two or more Member States. The specific steps involved are described in Directive 2001/82/EC on the Community Code on veterinary medicinal products, as last amended by Directive 2004/28/EC. The MRP generally applies to the majority of medicinal veterinary products. An applicant submits an application to the Competent Authority of the selected Member State. After that authority grants authorisation, the applicant seeks recognition by some or all other national agencies. Since 1 January 2004, the MRP has been compulsory for all medicinal products to be marketed in a Member State other than that in which they were first authorised. Any national marketing authorisation granted by an EU Member State’s Competent Authority could be used to support an application for its mutual recognition by another Member State. 1. The application process An applicant seeking a veterinary medical product marketing authorisation under the MRP is required to submit an application based upon an identical dossier in the Member States in which marketing authorisation is sought.357 The dossier shall contain all the required administrative information and scientific and technical documentation delineated in the legislation.358 As with the centralised procedure described above, this Directive establishes a detailed list of requirements and analytical protocols and safety and clinical tests. Among the information applicants must submit are:

a detailed description of the veterinary product, product characteristics, manufacturing method, therapeutic indications and adverse reactions, dosage for various animal species and explanations of any precautionary and safety measures

a thorough description of the manufacturer’s control testing methods and the results of

safety and residue testing (physicochemical, biological and microbiological tests, toxicological and pharmacological test, clinical trials), where relevant, the applicant must also demonstrate the specific measures it took to prevent transmission of animal spongiform encephalopathies

355 Article 41, EMEA Regulation.

356 Article 57, EMEA Regulation.

357 See Directive 2004/28/EC amending Directive 2001/82/EC on the Community Code relating to veterinary medicinal products.

358 Articles 12(3), 13,13a, 13b, 14 and Annex I of Directive 2004/28/EC list the requested documents. http://europa.eu.int/eur-

lex/pri/en/oj/dat/2001/l_311/l_31120011128en00010066.pdf Annex I indicates in great detail the requirements, tests needed and the way to

present the dossier.


documents showing that the manufacturer is authorised in its own country to produce veterinary medical products, plus any marketing authorisations obtained in another Member State or a third country for the product

Member States shall take all appropriate measures to ensure that the procedure for granting a veterinary medical product marketing authorisation is completed within 210 days after the submission of a valid application. 2. The decision-making process As with the procedures for decentralised authorisation of medicines for human use, the first Member State that decides to accept an application to evaluate the relevant veterinary medicinal product becomes the Reference Member State for the relevant application and it will notify all other Member States (Concerned Member States) to whom applications have also been submitted of its decision. Concerned Member States may then suspend their own evaluations, and await the Reference Member State’s detailed product assessment report. The Directive provides that the Reference Member State shall prepare or update the assessment report within 120 days (90 days if the veterinary medical product has already received a marketing authorisation in another Member State at the time of application) of receipt of a valid application. As soon as the assessment is completed, copies of this report shall be sent to all Member States, as well as to the applicant, and each Member State will then have 90 days to recognise the decision of the Reference Member State. If a Member State disagrees with the assessment report, a detailed statement of the reasons should be provided to the Reference Member State, the Concerned Member States and the applicant. A coordination group representing all Member States should meet to reach an agreement on the action to be taken. The applicant has the opportunity to make its point of view orally or in writing. If, within 60 days of a Member State’s communication to the coordination group of its reasons for disagreement, the Member States reach an agreement, then the Reference Member State shall record the agreement and close the procedure. Thereafter, the Concerned Member States shall adopt a decision in conformity with the approved assessment report, summary of product characteristics, labelling and package leaflet, within 30 days after the agreement. If, within an additional 60 days, the Member States fail to reach an agreement, EMEA shall be immediately informed and shall be provided with the reasons for the disagreement. The applicant shall then forward to EMEA a copy of the application. The CVMP will consider the matter and issue a reasoned opinion within 60 days of the date on which the matter was referred to it. EMEA will then forward the Committee’s opinion to the Member States, the Commission and the applicant. Ultimately, the European Commission may take a decision on the matter. Such a decision would, under these circumstances, be binding on all Member States. A marketing authorisation obtained under the MRP is valid for five years. The Competent Authority may renew the authorisation after five years on the basis of a re-evaluation of the risk-benefit balance. Once renewed, the marketing authorisation shall be valid for an unlimited period. However, if the product is not marketed within three years, the authorisation ceases to be valid.359

359 Article 28 of Directive 2001/82, as last amended by Directive 2004/28.


3. Reference to Maximum Residue Levels (MRLs) for veterinary medicinal products Council Regulation (EEC) No 2377/90 of 26 June 1990 (the MRL Regulation) established a Community procedure for the establishment of MRLs for veterinary medicinal products in food of animal origin.360 For veterinary medicinal products intended for one or more food-producing species, but whose pharmacologically active substances have not yet been included for the species in question in Annexes I, II or III of the MRL Regulation, the sponsor may not apply for a marketing authorisation until after a valid application to establish that substance’s MRL has been submitted.361 At least six months must elapse between the submission of a valid application for establishing a MRL and an application for a marketing authorisation. E. EU framework for MRLs for veterinary medicinal products in food The MRL Regulation has been amended several times since its adoption. In June 2003, the European Commission published a Notice to applicants and Note for Guidance (the MRL Notice) that incorporates the amendments the MRL Regulation has undergone and provides information on the operational procedure for MRL establishment applications. 362The MRL Notice provides guidance on the application dossier presentation and content. It also provides information on how safety and residue data are evaluated and describes the CVMP assessment process. The information provided in the MRL Notice is summarised below. 1. Background The EU framework for setting MRLs was established to help ensure that food obtained from animals treated with veterinary medicinal products does not contain residues or metabolites of those products that might constitute a consumer health hazard. In addition, the MRL Regulation is intended to facilitate uniform application of the MRL regime throughout the EU and to ensure that differences in assessment of residue effects by Member States do not create barriers to the free movement of food. The periodic amendments to the MRL Regulation Annexes reference newly established MRL values for various substances used in veterinary medicinal products. Also, the MRL Regulation has been amended to reflect technical progress and to make conforming amendments to related regulatory procedures. The entry into force of the MRL Regulation on 1 January 1992 coincided with the entry into force of the veterinary medicinal product legislation (predecessor to Directive 2001/82/EC). This convergence of requirements has had legal consequences for veterinary medicinal product marketing authorisation holders in the EU. The MRL Regulation had granted a transition period to permit marketing, on a provisional basis, of the so-called “old substances.”363 From 1 January 2000 forward, it has not been possible to use any active substance in a veterinary medicinal

360 Council Regulation (EEC) No 2377/90 of 26 June 1990 laying down a Community procedure for the establishment of maximum residue

limits of veterinary medicinal products in food of animal origin, OJ No L 67, p.1, 7. 3 1997.

361 Article 12 of Directive 2004/28, the Community code on veterinary medicinal products. 362 Notice to applicants and note for Guidance -Establishment of maximum residue limits (MRLs) for residues of veterinary medicinal products

in food of animal origin, June 2003 ( http://pharmacos.eudra.org/F2/eudralex/vol-8/home.htm).

363 For these substances, the European Commission needed to evaluate the substances, upon receipt of an MRL application. This transition

period was originally set to expire on January 1, 1997 but was ultimately extended until December 31, 1999 for all “defended” old substances

(ones for which a submission had been made), with the exception of some old substances specified in the legislation (for these substances, the

transition period ended January 1, 1998). See Regulation (EEC) No 434/974.


product for food-producing animals that is not included in Annex I, II or III of the MRL Regulation. 2. Applications for the establishment of MRLs—EMEA EMEA is responsible for processing MRL establishment applications.364 EMEA also coordinates the existing scientific resources put at its disposal by Member State Competent Authorities for evaluating and supervising medicinal products. The Agency delivers scientific opinions on applications for centralised marketing authorisation for both human and veterinary use. As discussed above, the CVMP is responsible for preparing the Agency’s opinion on any question relating to veterinary medicinal product evaluation. EMEA’s Secretariat provides technical administrative support and ensures appropriate coordination. Since MRLs have already been established for existing substances, the MRL Regulation as well as the MRL Notice describe the procedure in relation to applications for new pharmacologically active substances, i.e., substances which are not contained in any veterinary medicinal products marketed for food producing animals in the European Union, or new uses of substances included in the Annexes to the MRL Regulation. The procedure is also applicable to applications for MRL extensions or modifications. 3. General principles applicable to residue safety evaluations A MRL is defined in EU legislation as “the maximum concentration of residue resulting from the use of a veterinary medicinal product (expressed in mg/kg or g/kg on a fresh weight basis) which may be accepted by the [EU] to be legally permitted or recognised as acceptable in or on a food.”365 This definition is virtually identical to that adopted by the Codex Alimentarius Committee for Residues of Veterinary Drugs in Foods. The EU MRL Notice states that the approach used by the CVMP for evaluating residue safety is similar to the approach used by other committees and international scientific bodies charged with the safety evaluation of food additives and contaminants. The MRLs are based upon the establishment of a no-effect-level and the use of safety factors to determine an acceptable daily intake (ADI). Nevertheless, there are certain specific differences between evaluating the safety of veterinary medicine residues and food additives or contaminants. Because of the properties of active veterinary medicine substances, their toxicological properties (such as teratogenic, mutagenic or carcinogenic effects) as well as their pharmacological properties and possible immunotoxic potential must be taken into account. Moreover, in the case of antibiotics and similar substances, possible microbiological risks, including the development of resistant bacteria in the human gut flora, may also need to be considered. Additionally, it is necessary to consider the fact that the residues to which the consumer of food of animal origin are exposed may not necessarily be the same as the parent drug substance, since the treated animal may metabolize the original substance. Following the completion of the various pharmacological, toxicological and other tests undertaken to demonstrate the safety of the substance and, where relevant, its metabolites, the first major stage in safety evaluation is establishing the ADI. The ADI is an estimate of the

364 Council Regulation (EC) No 1308/1999 of 15 June 1999 amending Regulation (EC) No 2377/90 laying down a Community procedure for

the establishment of maximum residue limits of veterinary medicinal products in food of animal origin, Official Journal L 156, p. 1, 23.06.1999.

365 Article 1(1)(b) of Regulation 2377/90 laying down a Community procedure for the establishment of maximum residue limits of veterinary

medicinal products in food of animal origin, (OJ No L 67 of 7.3 1997, p.1).


residues, expressed in terms of µg or mg per kg of body weight, that can be ingested daily over a lifetime without any appreciable health risk to exposed individuals.366 The MRL Notice states that:367

The basis for the calculation of the ADI is the no-observed-(adverse)-effect-level (NO(A)EL) with respect to the most sensitive parameter in the most sensitive appropriate test species, or in some cases, in humans. A safety factor (SF) is then applied to provide a margin of safety, taking into account the inherent uncertainties in extrapolating animal toxicity data to human beings and to take account of variations within the human species. In selecting a safety factor, it is usually assumed that human beings are ten times more sensitive than the test animal, and that there is a ten-fold range of sensitivity within the human species. Thus, where good quality data are available, a safety factor of l00 is usually applied, although this may be increased or reduced depending on the nature and quality of the data available and of the effects observed in animals or humans. Where the available data are sufficient to demonstrate that exposure to residues over several years will not present a risk to health, but there are insufficient data to guarantee safety over a life-time, a temporary ADI may be accepted using a higher safety factor. The ADI concept is not applicable to substances for which it is not possible to determine a NO(A)EL because they demonstrate non-threshold effects. In such cases, an alternative approach to safety evaluation is applied on a case-by-case basis, having regard to all the data available. Once the ADI has been agreed, it is then necessary to determine MRLs for the individual food commodities concerned. Since the ADI is related to body weight, an arbitrary average human bodyweight is defined at 60 kg. The ADI expressed on a µg or mg per kg body weight basis is therefore multiplied by 60 to give the total amount of residue, which can be ingested by an individual. Moreover, consideration also has to be given to the actual levels of consumption of foods of animal origin. Since accurate consumption figures are difficult to obtain, and there are in any case substantial variations between individual consumers, arbitrarily high fixed values are used to ensure the protection of the majority of consumers. Thus, for example, in order to derive MRLs from the ADI it is assumed that the average person consumes, on a daily basis, 500 g of meat (made up of 300 g of muscle, 100 g of liver, 50 g of kidney and 50 g of fat) together with 1.5 litres of milk and 100 g of eggs or egg products. Allowance is also made for the consumption of poultry, fish and honey. The total amount of residues present in this daily food basket is not allowed to exceed the ADI. MRLs are then allocated to the individual food commodities concerned: muscle tissue, liver, kidney, skin and fat, eggs, milk and honey. At this stage, account is also taken of the pattern of residue depletion of the substance through the target animal, and the possible persistence of residues in specific organs such as the liver or kidneys, or at the injection site. The MRLs allocated to animal tissues apply to the species indicated in the annexes of Regulation No (EEC) 2377/90, unless otherwise

366 Notice to applicants and note for Guidance -Establishment of maximum residue limits (MRLs) for residues of veterinary medicinal products

in food of animal origin, June 2003, p.9 (MRL Notice) http://pharmacos.eudra.org/F2/eudralex/vol-8/home.htm) .

266 MRL Notice at 9-10.

367 MRL Notice at 9-10.


stated. Once the safety evaluation is completed and MRLs have been derived for a particular substance, consideration is given to the likely level of residue which may be expected to remain after the use of the substance in accordance with good veterinary practice, and to the availability of analytical detection methods suitable for use for routine monitoring purposes. The MRLs may be further reduced, but never increased, to take account of these factors.

The MRL Regulation368 recognises that, in certain instances, it may not be necessary, with respect to public health, to establish MRLs for a particular substance. Such substances are to be included in Annex II of the Regulation. However, it should be noted that substances may be listed in Annex II only after a comprehensive safety and residue evaluation. Once MRLs have been allocated, it is necessary, in the context of granting veterinary medicinal product marketing authorisations, to determine withdrawal periods after the last product administration. During this period, the animal must neither be slaughtered nor may milk, eggs or honey be taken for human consumption, ensuring that residues will not exceed the MRLs. Because the withdrawal period depends upon the individual pharmaceutical formulation concerned, specific withdrawal periods will be determined as part of the evaluation process of marketing authorisation application. Thus, depending upon the applicant’s chosen procedure to obtain a marketing authorisation, withdrawal periods will either continue to be determined by Member States, where the product is authorised via the mutual recognition or national procedure or, for the centralised marketing authorisation procedure, it will be proposed by the CVMP. To ensure a uniform approach to withdrawal period establishment throughout the EU, the CVMP has drawn up a Note for Guidance regarding withdrawal periods for animal tissues and milk and will be doing the same for eggs. 4. Procedure to apply for new pharmacological active substances369 To apply for new pharmacological active substances, the Community Code on Veterinary Medicinal Products Directive370 provides that:

In order that a veterinary medicinal product may be the subject of a marketing authorisation for the purpose of administering it to food producing animals, the active substances which it contains must be shown in Annex I, II or III of Regulation (EEC) No 2377/90.

Veterinary Code Amendment Directive 2004/28 amends the Community Code on Veterinary Medicinal Products Directive to establish a specific requirement371 that an applicant apply for the establishment of a MRL in accordance with the MRL Regulation, before applying for marketing authorisation to a Member State. Prior to the amendment, the legislation left it to the applicant’s discretion whether to apply for the establishment of MRLs in accordance with the MRL Regulation before applying for marketing authorisation or to submit the two simultaneously. However, the European Commission, to avoid potential delays that may arise from doubts about residue safety, strongly

368 (EEC) No 2377/90.


in food of animal origin, June 2003, p.16 ( http://pharmacos.eudra.org/F2/eudralex/vol-8/home.htm)

370 Article 6, Directive 2001/82/EC.

371 Article 12, Directive 2001/82/EC.


advises applicants that it is in their interest to submit a MRL application to EMEA as soon as the necessary documentation is complete and before submitting a medicinal product marketing authorisation application to EMEA or individual Member States. The Commission suggests that it is highly advisable to submit an application for establishing MRLs at least six months before the submission of a centralised marketing authorisation application for a veterinary medicinal product containing the substance in question. 5. Steps to take before the submitting an application The European Commission suggests that the applicant contact EMEA approximately three to four months before the anticipated date of submission of the MRL establishment application for a particular substance, indicating that the application is to be submitted to EMEA’s Unit for the Evaluation of Veterinary Medicines, in accordance with the MRL Regulation (EC), as amended. The information to be submitted includes:

substance name chemical group to which it belongs

therapeutic category

proposed target species and indications

food commodities for which MRLs will be required

anticipated submission date

contact name, address, fax and phone numbers within the company who will be

responsible for all application-related correspondence with EMEA The CVMP uses a system of rapporteurs and co-rapporteurs drawn from among its members to evaluate MRL applications. EMEA notifies the applicant of the number assigned to the application, which must be quoted in all subsequent correspondence. 6. Presentation of the dossier372 The information required by the European Community to establish MRLs is set out in Annex V of the MRL Regulation (EEC) No. 2377/90 as amended.373 To facilitate dossier review, the European Commission suggests that this information be presented in two distinct parts of the dossier: a safety file and a residue file. These expert reports are fundamental in facilitating the evaluation of the detailed documentation submitted to support the application. The Commission stresses that applications not accompanied by expert reports, and those with manifestly unsatisfactory expert reports, will not be accepted. Further details on these files are provided in Part III of the MRL Notice. 372 Notice to applicants and note for Guidance -Establishment of maximum residue limits (MRLs) for residues of veterinary medicinal products


373 Commission Regulation (EEC) No 762/92 of 27 March 1992 modifying Annex V to Council Regulation (EEC) No 2377/90 laying down a

Community procedure for the establishment of maximum residue limits of veterinary medicinal products in food of animal origin, Official

Journal L 083, 28/03/1992 P. 0014 – 0016.


The application form set out in Annex I of the MRL Regulation No 2377/90 must be completed and enclosed with each copy of the application. Ideally, the correct number of application copies should be transmitted directly to EMEA and the rapporteur and co-rapporteur simultaneously. The application must be accompanied by the fee payable to the EMEA. An up-to-date address list is provided by EMEA prior to the submission. Alternatively, an applicant may choose to submit the application to the rapporteur and co-rapporteur and the required information to the other CVMP members, once EMEA has validated the application. Applicants are advised to use registered mail with acknowledgement of receipt or a similar transmission method. Applications are considered as having been submitted to EMEA only when both the dossier and fee have been received; the validation time period then begins. The evaluation time limit begins only after EMEA has validated the application and the rapporteur and co-rapporteur have confirmed receipt of the validated application. Following validation, applicants should send the required information to the remaining CVMP members. 7. Validation of the application. Validation is by the EMEA Secretariat, which must complete the administrative validation within 10 working days of the application's receipt. Applicants will be contacted by EMEA if it views the application as unacceptable for evaluation. If deficiencies can be resolved within a short period of time, the applicant will be advised of steps that must be taken to remedy application defects. EMEA will inform the applicant in writing once the application has been validated. 8. Evaluation of the application.374 The MRL Regulation (EEC) No. 2377/90 provides a period of 120 days for the CVMP’s evaluation of the application. To ensure optimal use of the 120-day period for initial assessment and consideration of any subsequently requested additional information, the CVMP has endorsed the following time lines: Initial evaluation: within 90 days of receipt of a valid

application Evaluation of additional information: within 30 days of receipt of the

consolidated response After the initial evaluation and CVMP recommendations, the EMEA Secretariat will transmit to the applicant either:

a draft of the CVMP Opinion, including a Summary Report regarding the application a List of Questions included in a Status Report of the CVMP assessment to which the

applicant is invited to reply If questions arise after the initial application evaluation, the 120-day time limit for completing the evaluation specified in the legislation is suspended until a reply is received from the applicant. The timeframe given for the reply is normally six months. A single consolidated response should




be presented to all the questions. This response should follow the same structure as the initial application and the same guidelines apply for its presentation and submission. An updated expert report will be required if:

significant additional safety or residue information is submitted

as a result of the questions asked and comments received, the applicant decides to amend the proposals for MRLs for the substance concerned

As appropriate, the updated expert report may be presented as a supplement to the original report, or may be consolidated into the original report. However, in the latter case, changes made to the original report must be clearly identifiable, through underlining, sidelining, etc. The consolidated response must be submitted to the rapporteur, co-rapporteur and EMEA. When an updated expert report accompanies the consolidated response (or an addendum to the expert report) it is sufficient to submit only the revision of or addendum to the expert report(s) to the remaining CVMP members. In the absence of a revision or addendum to the export report(s), the complete consolidated response must be sent to all CVMP members. Applicants are strongly advised to coordinate the submission of the consolidated response with the EMEA Secretariat. Furthermore, applicants are advised to submit the consolidated response to the List of Questions first to the rapporteur, co-rapporteur and the remaining CVMP members, allowing a period of at least 30 days before the consolidated response is submitted to the EMEA Secretariat. The procedure, i.e., the period of 30 days remaining for the evaluation of the additional information, will re-start on the first working day following the receipt of the response by the EMEA Secretariat. The time between the submission of the response to the rapporteur and co-rapporteur and the submission to EMEA will be used to evaluate the data. The 30 days remaining of the 120-day period are used for the necessary consultation of the CVMP members and for the Committee to reach its final opinion. In principle, the evaluation has three possible conclusions:

The CVMP recommends the establishment of MRLs (either final or, in exceptional cases, provisional) or the inclusion in Annex II of the MRL Regulation No 2377/90.

Because of the public health risks presented by the substance, the CVMP recommends

that its use in food-producing animals be prohibited through inclusion in Annex IV of the MRL Regulation.

The CVMP, after evaluating the additional information received as a consolidated

response to a List of Questions issued after the initial evaluation or the recommendation of provisional MRLs, concludes that there is still insufficient information available for a recommendation for the inclusion of the substance in any of the annexes of the MRL Regulation, or into Annex I, respectively.

A CVMP Opinion including a Summary Report in such cases will be transmitted to the applicant following CVMP consideration. Furthermore, in all cases, in accordance with Article 7 of the MRL Regulation, as amended, the applicant has the right to appeal the Opinion. Where no notice of appeal is given EMEA within 15 days after receipt of the Opinion, the Opinion becomes final and will be submitted together with the Summary Report and analytical method, where appropriate, to the European Commission within 30 days after adoption by the CVMP. The Commission will then prepare a draft Regulation to amend Annex I, II, III or IV, as appropriate,


and submit it to the Standing Committee on Veterinary Medicinal Products for adoption in accordance with the procedure laid down in Article 8 of Regulation (EEC) No 2377/90. a. Appeals Where a CVMP Opinion is appealed, the final decision of the CVMP is forwarded to the European Commission only after consideration of the appeal.375 Where an applicant wishes to appeal an adverse opinion of the CVMP, written notice of this intention must be provided to the EMEA Secretariat within 15 days of receipt of the Opinion. The day of receipt is the day when the Applicant receives by fax the Opinion and Summary Report. Written detailed grounds for the appeal must be submitted within 60 days of receipt of the CVMP Opinion. Appeals and supporting grounds for appeals should contain argumentation and clarification of data previously submitted in the original application. An appeal is not an opportunity for the submission of new data. The CVMP will, in cases of appeal, appoint a new rapporteur (and, where appropriate, a new co-rapporteur). The detailed grounds for appeal shall be presented in one of the following ways: attached to the applicant’s written notice to the EMEA Secretariat of its intention to appeal

the CVMP Opinion (to be sent within 15 days after receipt of the CVMP Opinion); a copy should be sent to the rapporteur for the assessment of the appeal (and, where appropriate, to the co-rapporteur)

submitted separately to the EMEA Secretariat within 60 days of receipt of the CVMP Opinion and to the rapporteur for the assessment of the appeal and, where appropriate, to the co-rapporteur (if not more than approximately 20 pages)

submitted to the EMEA Secretariat and directly to all CVMP Members within 60 days of receipt of the CVMP Opinion (if more than approximately 20 pages)

Applicants are advised to contact the EMEA Secretariat before submitting the grounds for appeal to clarify which option is most suitable. A copy of the grounds for appeal should be submitted to the rapporteur for assessment of the appeal, (and, where appropriate, the co-rapporteur) at the same time as submission to EMEA. If, in addition to providing written detailed grounds for the appeal, the applicant wishes to request an opportunity for an oral presentation of the case, this is submitted in writing to EMEA. The EMEA Secretariat will then inform the CVMP of receipt of the written notice of an intention to appeal, at the next CVMP meeting. At that meeting, the CVMP will appoint the new rapporteur for assessing the appeal. The CVMP will consider the appeal and agree on the final Opinion within 60 days (i.e., normally by the second CVMP meeting) following EMEA’s receipt of the applicant’s detailed grounds for appeal. Where the applicant requests a hearing, the CVMP will decide whether to grant this request at the very next CVMP meeting after receipt of the request for hearing. b. Hearings376 The CVMP may grant a request for an oral presentation of the case. It is at the discretion of the CVMP whether to grant applicants the opportunity to present their case orally, i.e., such hearings are not a matter of right. Time and resource restrictions could limit the number of oral explanations that can take place. Therefore, appearances before the CVMP are reserved to cases where the committee believes a hearing would contribute to the resolution of an


in food of animal origin, June 2003, p.21 ( http://pharmacos.eudra.org/F2/eudralex/vol-8/home.htm) .




applicant’s objections. The written detailed grounds for the appeal and reason for the request of an oral explanation must always be submitted first, so that time at the hearing is well-spent. F. Recent EU initiatives on veterinary medicinal products 1. Commission Reflection Paper on residues of veterinary medicinal products In December 2003, the Commission published a Reflection Paper requesting comments on the various points raised for reconsideration and possible modification of the Community legislation concerning veterinary medicinal product residues.377 The main aim of any future amendments to the existing laws or the development of new laws is to have a more consistent approach to risk analysis and the control of residues of pharmacologically active substances used in veterinary medicinal products in food producing animals, where these residues may be present in food produced in or imported into the EU. The Reflection Paper analyses the reasons for the difficulties encountered in applying the existing legislation. It also seeks to propose alternative ways to achieve a high level of consumer protection coupled with continued availability and development of veterinary medicinal products for the EU market and good functioning of the intra- and extra-Community trade in food of animal origin. Comments on the Reflection Paper were received from more than 40 sources, including 12 Member States, EMEA, a veterinary profession association, the animal health industry, trade associations for primary producers of foods of animal origin, umbrella organisations of the European food industry, organisations for particular types of food production, two countries outside the EU and a few individuals. Most comments concerned residue monitoring and enforcement, food imported from third countries, minimum requirement performance limits/zero tolerances, the structure and performance of the Community reference and control laboratories and risk analysis, including differentiation of risk assessment and risk management options and the scientific risk assessment process. In addition, the issue of availability of veterinary medicinal products was the subject of several trade association comments, although this issue relates more to the legislation on medicines authorisation than to the legislation on residues. The Commission might propose changes in various laws, including the MRL Regulation, echoing the policy considerations in the Reflection Paper and considering the comments received. Several Member States and consumer organisations considered it important that third countries provide additional guarantees, beyond the monitoring plans assessed and agreed by the Commission to show an equivalent regulatory system. According to these comments, non-EU countries should be evaluated against certain criteria (authorisation schemes, control of production and use, identification of prohibited substances and monitoring plans). This evaluation should be updated regularly. It was also suggested that developing countries that do not fulfil the criteria should receive technical assistance. Concerning import evaluation at points of entry, several Member States called for a harmonised sampling plan for Border Inspection Posts. Member States and a food industry group suggested that the sampling procedure follow the risk assessment principles as those for Community products, including (according to one Member State) use of the same methods/detection limits. Certain food importers requested that consignments presented for import, and containing residues above EU MRLs, not be automatically destroyed.

377 http://pharmacos.eudra.org/F2/mrl/reflpaper.htm


2. EFSA working document on updating criteria for resistance to antibiotics for

assessing feed additives378 The European Food Safety Authority (EFSA) has established a working group to update the criteria used in assessing bacteria for resistance to antibiotics of human or veterinary importance. When finalised, this document will be used as a guidance document. The Scientific Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) aims to:

revise the Opinion of Directorate General on Health and Consumer Protection’s (DG SANCO) former Scientific Committee on Animal Nutrition (SCAN) on assessing bacteria for resistance to antibiotics of human clinical or veterinary importance, taking into consideration data published after the Opinion’s adoption

define appropriate breakpoint values that indicate the need for a more extensive

assessment of the basis for the resistance

consider whether the distinction between “intrinsic” and “acquired” resistance, used as indicative of the probability of resistance transfer, is still valid for the safety assessment of microbial feed additives

378 The full text of the Working Document on Updating Criteria for Resistance to Antibiotics for the Assessment of Feed Additives can be found

on http://www.efsa.eu.int/science/feedap/feedap_consultation/748_en.html


XVI. Food Supplements A. Background Food supplements are:

…foodstuffs the purpose of which is to supplement the normal diet and which are concentrated sources of nutrients or other substances with a nutritional or physiological effect, alone or in combination, marketed in dose form, namely forms such as capsules, pastilles, tablets, pills and other similar forms, sachets of powder, ampoules of liquids, drop dispensing bottles, and other similar forms of liquids and powders designed to be taken in measured small unit quantities.

Medicinal products are excluded from the scope of the 2002 EU Food Supplements Directive.379 It establishes positive lists of vitamins and minerals approved for use in food supplements as well as labelling rules to better inform consumers. The Directive permits food supplements to be marketed freely across the EU while ensuring the safety of consumers. It required the Member States, from 1 August 2003, to allow trade in products containing substances included on the “positive list” annexed to the Directive and, from 1 August 2005, to prohibit trade in products that do not comply with the Directive. In a ruling issued on 12 July 2005, the European Court of Justice (ECJ) upheld the legality of the EU Food Supplements Directive, which became effective 1 August 2005.380 The case had been referred to the ECJ after a preliminary ruling from the High Court of Justice of England and Wales. A coalition of consumers, manufacturers, distributors and retailer associations in the United Kingdom (UK) had challenged the validity of the legislation of England and Wales that had implemented the EU Food Supplements Directive, arguing that the legislation constituted an unnecessary burden on British business. The coalition argued further that the Directive constitutes an unlawful restriction under Community law, particularly concerning legal principles favouring free movement of goods, proportionality and subsidiarity. According to the EU proportionality principle, regulation should not be more restrictive than necessary to fulfil a legitimate objective. Under the EU subsidiarity principle, EU institutions should perform only those tasks which cannot be performed at the Member State level. The UK court referred the case to the ECJ.

379 Directive 2002/46 of the European Parliament and of the Council on the approximation of the laws of the Member States relating to food

supplements, 10 June 2002, OJ 12.7.2002 L 183.51.

380 2002/46/EC. , Joined Cases C-154/04 The Queen Alliance for Natural Health Nutri-Link Ltd v Secretary of State for Health and C-155/04

The Queen, National Association of Health Stores Health Food Manufacturers Ltd v Secretary of State for Health and National Assembly for

Wales.


B. Advocate General’s opinion In his Opinion,381 Advocate General Geelhoed took the position that the Directive should be declared invalid due to defects relating to transparency and legal certainty. He found the Directive deficient in three respects:

It lacks a standard for assessing whether the European Commission, in making decisions concerning modifications of the positive lists, remains within its legal powers.

It is unclear whether private persons may propose that specific substances be evaluated

for inclusion in the positive lists.

If private persons are indeed authorised to propose substances for evaluation and possible inclusion in the positive lists, there is no clear procedure for this purpose that provides minimum guarantees for protecting those persons’ interests.

Advocate General Geelhoed did not, however, question the “positive list” which, in his view, could not be regarded as contrary to the principle of proportionality. C. The ECJ judgment On 12 July 2005, the ECJ decided not to follow Advocate General Geelhoed’s Opinion and proclaimed the EU Food Supplements Directive valid. In its judgment, the ECJ ruled that, by prohibiting the marketing of food supplements containing vitamins and minerals, or vitamin and mineral substances, not included on the positive lists, the provisions indeed are capable of restricting the free movement of food supplements in the EU. However, Article 30 of the European Community Treaty (EC Treaty) provides that such restrictions are justified on the grounds of, among other things, human health. Also, Article 95 of the EC Treaty, upon which the measure is based, states that, in achieving harmonisation, a high level of protection of human health should be guaranteed. Indeed, harmonisation was the intent of this measure as, prior to the adoption of Directive 2002/46/EC, food supplements were regulated by widely differing national rules that were liable to impede the products’ free movement. As to proportionality, the claimants complained that the Directive’s positive list was compiled on the basis of ingredients authorised in the manufacture of food for particular nutritional purposes. Therefore, the Directive’s prohibitions affected many nutrients which were, nonetheless, suitable for the normal diet and had not been shown to represent a risk to human health. The Court, however, stated that the Directive concerns, specifically, food supplements containing vitamins and/or minerals derived from a manufacturing process using “chemical substances,” and not food supplements whose ingredients include “amino acids, essential fatty acids, fibre and various plant and herbal extracts,” whose conditions for use were to be handled by national rules until specific Community rules are adopted. The ECJ also upheld the system’s reliance upon a positive list of vitamins and minerals and their sources. Its view was that a negative list, as requested by the applicants, would not go far

381 Opinion of Advocate General Geelhoed, delivered on 5 April 2005 In the EU legal system, Advocates General are not judges, but have a

quasi-judicial role. After parties have concluded written submissions and oral arguments, and before the ECJ judges begin deliberation, the

Advocate General presents in open court his independent, impartial, and fully reasoned opinion on the case. The opinion sets out relevant facts

and legislation, discusses the issues in terms of the Court's case law, and recommends a decision to the Judges. A persuasive opinion will

strongly influence the subsequent deliberation and the ultimate judgment. Usually, the judgment and its rationale follow the opinion of the

Advocate General closely.


enough to achieve the desired level of public health protection, since a substance could be used in the manufacture of a food supplement even though it had not been subjected to any scientific review. The ECJ emphasised, however, that a positive list should be accompanied by a procedure that allows a substance to be added to the list, according to principles of sound administration and legal certainty. Applications for inclusion in a positive list should be refused only on the basis of a full risk assessment, based upon “the most reliable scientific data available and the most recent results of international research.” The latter statement places the burden of coming forward with information on the regulator rather than on industry. Also, refusals are open to legal challenge. On subsidiarity, the ECJ ruled that Member States should not be left with the task of regulating trade in food supplements that do not comply with Directive 2002/46, as this would perpetuate the uncoordinated development of national rules and risk continued obstacles to trade and distortion of competition among Member States. Action in this area is, therefore, best taken at EU level. D. Effect of judgment Since 1 August 2003, Member States have been required to permit trade in food supplements containing vitamins and minerals on the positive lists. With the ECJ judgment, from 1 August 2005, Member States must prohibit the trade of products not on the “positive list” and that, therefore, do not comply with the Directive. For unlisted vitamins and minerals, however, the Directive contains a temporary derogation (exception) from this requirement until 31 December 2009, provided that:

the unlisted vitamin or mineral was already marketed in the Community on 12 July 2002 a dossier supporting the substance’s use had been submitted to the European

Commission by 12 July 2005

the European Food Safety Authority (EFSA) has not issued an unfavourable opinion concerning that substance’s use

The ECJ, in its ruling, expressed the view that the Directive should have included specific provisions on transparency and deadlines to be respected, particularly at the stage between filing a dossier seeking a modification of a positive list and the time when the matter is brought before the relevant committee, a step that involves consultation with EFSA. The European Commission has taken note of this judicial request that the EFSA consultation stage be carried out in a transparent and efficient manner. It has already adopted procedures to be followed by EFSA for scientific opinion requests and the Commission will, in consultation with EFSA, examine whether there is a need for further measures or procedures.


Chapter XVII. Borderline and Combination Products A report issued in mid-2005 estimated that the global market for drug-device combinations was valued at US $5.4 billion and is estimated to rise, at an annual growth rate of of 13.6%, to US $11.5 billion in the year 2010.382 The product categories covered by these estimates included drug-eluting stents, antimicrobial catheters, antimicrobial wound-care products, bone graft substitutes and antibiotic bone cements and photodynamic therapy. Except for the bone graft substitutes and antibiotic bone cements, all categories will show double-digit growth. Topping the list for market size is the drug-eluting stent category, which has doubled in less than two years. from US $2 billion in 2003, when it was first introduced, to US $4 billion at the end of 2004. In 2004, the US had approximately 65% of the drug-device product market while Europe held 24% and Japan 7%. A. Recent legislative changes and proposals Unlike the US, the EU does not have a separate regulatory category for combination products. Neither is there an Office of Combination Products to sort out regulatory classification and assignment issues. Rather, as previously discussed in Chapter IV concerning the draft proposal to amend the Medical Devices Directive (MDD), the EU is contemplating modest legislative changes in this area. Already, the 2004 pharmaceutical review legislation changed the definition of “medicinal product” to move some devices from the “medical device” to the “medicinal product” category, as discussed in Chapter I.C. To more clearly draw the line between medical devices and medicinal products, the regulatory classification of a borderline product would depend upon the product’s “principal mode of action” rather than its “intended purpose.” Furthermore, the regulatory pathway for medical devices that incorporate a medicinal product substance would be clarified. A Notified Body (NB) must first verify the substance’s usefulness as part of a medical device, taking its intended purpose into account. It must then seek a scientific opinion on the medicinal substance’s quality and safety from EMEA (where the medicinal component is a human blood derivative, has been subject to an EMEA authorisation or is under mandatory EMEA jurisdiction) or from a Member State authority. Chapter I.C. includes a discussion of changes in the definition of medicinal products that broadens that category at the expense of medical devices. The general trend in the EU, in many borderline cases, is toward handling products under medicines law rather than medical devices law. Evidence of this trend is found in the broadened definition of medicinal products in Directive 2004/27’s revisions to Directive 2001/83, the 2003 Commission Directive “clarifying” the medicinal product categorisation of certain cell therapy, and the May 2005 proposed regulation on human tissue-engineered products. B. Medical Devices Directive Directive 93/42/EEC, the Medical Devices Directive, defines a medical device as “any instrument, apparatus, appliance, material or other article, whether used alone or in combination, including the software necessary for its proper application intended by the manufacturer to be used for human beings for the purpose of:

diagnosis, prevention, monitoring, treatment or alleviation of disease,

382 Drug-Device Combination Market: $11.5B in 2010, in Pharmaceutical Quality (discussing a report to be issued by Business Communications

Company, Inc.); June-July 2005, www.pharmaquality.com


diagnosis, monitoring, treatment, alleviation of or compensation for an injury or

handicap,

investigation, replacement or modification of the anatomy of a physiological process,

control of contraception and which does not achieve its principal intended action in or on the body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means.”383

Further, an “accessory” under the Directive is, “an article which whilst not being a device is intended specifically by its manufacturer to be used together with a device to enable it to be used in accordance with the use of the device intended by the manufacturer of the device.” Accessories are to be treated as medical devices in their own right, but must be intended to enable a device to be used in accordance with its intended use. The Medical Devices Directive excludes from its scope blood products384, transplants, tissues and cells of human origin and products incorporating or derived from tissues and cells of human origin, as well as transplants, tissues or cells of animal origin, unless the tissue or cells have been rendered nonviable.385 A device’s intended purpose is determined according to “the data supplied by the manufacturer in the labelling, in the instructions and/or in promotional materials.”386 In addition, the medical device definition includes products intended to be used for medical purposes, not those products intended as toiletries or cosmetics, e.g., toothbrushes, dental floss or baby diapers.387 The Medical Devices Directive addresses some combination product issues and describes the regulatory handling of three categories:

drug-delivery or administration devices, e.g., empty syringe, nebuliser

single-use medicinal product-device combinations designed exclusively for use in combination, e.g., pre-filled syringes

devices incorporating medicinal substances with ancillary action, e.g., antibiotic-coated

catheters Article 1(3) of Directive 93/42/EEC mandates that drug-delivery devices, or “a device that is intended to administer a medicinal product,” shall be governed by the MDD. Any medicinal product that a device is intended to administer must be independently authorised and approved by prescribed medicinal products procedures. If, however, “such a [drug-delivery] device is placed on the market in such a way that the device and the medicinal product form a single integral product which is intended exclusively for use in the given combination and which is not reusable,” that single product shall be governed by the Medicinal Products Directive. EU medicinal product regulators must assess these combinations, but the device component must 383 Medical Devices Directive 93/42/EEC, article 1(a). 384 Another directive covers medical devices containing blood. See Chapter X.

385 Id. at article 1(5)(e) – (g).

386 Id. at article 1(g).

387 Guidelines Relating to the Demarcation Between Directive 90/385/EEC on Active Implantable Medical Devices, Directive 93/42/EEC on

Medical Devices, and Directive 65/65/EEC Relating to Medicinal Products and Related Directives, MED DEV2.1/3 (March 1998)

(“Demarcation Guidelines”).


also meet the essential device safety and performance-related requirements under the MDD. Article 1(4) covers the last category and provides:

…where a device incorporates, as an integral part, a substance which, if used separately, may be considered to be a medicinal product . . . and which is liable to act upon the body with action ancillary to that of the device, that device must be assessed and authorised in accordance with [the medical devices] directive. A Notified Body must approve the device component and verify through a consultation process with the proper Competent Authority regulating the medicinal product component, the safety, quality, and usefulness of the ancillary medicinal part.

C. Demarcation guidelines EU guidelines published in 1998 further explain application of the devices and medicinal product Directives to certain borderline products.388 The Demarcation Guidelines—which are still used to some degree despite the need for an update in light of recent legislation—explain that, as a general rule, a product is regulated as either a device or a medicinal product under the relevant EU directive.389 Normally, a product will not be dually regulated under both directives. The Demarcation Guidelines offer two criteria to determine which regulatory regime will apply to a combination product:

(Step 1) The intended purpose of the product, taking into account the way the product is presented, and (Step 2) the method by which the principal intended action is achieved.”390 Determining a product’s “principal intended action” is crucial for classification. Medical devices typically function by physical means, while medicinal products generally function by pharmacological, immunological or metabolic action. The EU authorities consider manufacturer’s labelling and claims, as well as scientific data, regarding mechanisms of action to determine a product’s “principal intended action.391

Manufacturers’ intended claims are usually the basis of an intended action determination, unless they contradict current scientific data. For borderline products, manufacturers “may be required to justify scientifically their rationale for classification.”392 For the ancillary medicinal combination product consultation process, the device Notified Body (NB) should review manufacturer safety, usefulness and medicinal quality data and reach a preliminary decision on the device’s suitability with the ancillary medicinal substance. The NB should then request a Competent Authority’s opinion on the medicinal substance and its application.393 Generally, the NB has the discretion to choose the Competent Authority with whom to consult (EMEA or individual Member State drug regulatory authorities) but it may be useful to consult the previously responsible Competent Authority that granted the medicinal

388 Guidelines Relating to the Demarcation Between Directive 90/385/EEC on Active Implantable Medical Devices, Directive 93/42/EEC on

Medical Devices, and Directive 65/65/EEC Relating to Medicinal Products and Related Directives, MED DEV2.1/3 (March 1998)

(“Demarcation Guidelines”).

389 Id. at 3.

390 Id. at 4.

391 Id.

392 Id.

393 Id. at 15.


substance’s marketing authorisation. Also, if the medicinal product is derived from blood or plasma, or involves biotech or cells or an EMEA-authorised substance, the consultation should ordinarily be with EMEA. (However, Member State agencies have been willing in some cases to provide NBs with medicinal product consultations on combination products primarily regulated as medical devices, even when it would appear that a strong case could be made for exclusive EMEA jurisdiction over such consultations.) Data review requirements are flexible, depending upon whether the medicinal substance is well-known for established purposes, a new active substance or one for a non-established purpose. Well-known substances and medicinal products with established purposes may not require all safety and usefulness aspects, and literature references rather than original data may be sufficient. New active substances and non-established purposes, conversely, will require comprehensive data submission data including manufacturing descriptions, control tests, stability, pharmacokinetics, clinical documentation, toxicity and labelling information.394 All devices, regardless of classification, must be supported by adequate clinical data concerning their performance and characteristics under normal use.395 The adequacy of the data (i.e., scientific literature or full clinical trial findings or results) will depend upon the device’s class and potential. Gaining EU authorisation, or a CE mark, for a device-containing combination product means that it can be sold and marketed anywhere in the European Economic Area (all EU countries plus Iceland, Liechtenstein and Norway). D. Steps toward greater clarity In October 2004, the European Commission held a workshop on pharmaceutical/device borderline issues as well as other overlap issues between the medicinal products legislation and other Directives. At the workshop, medical device industry representatives argued that the new definition of medicinal products in the Directive amending the Community Code on Medicinal Products creates legal uncertainty for producers of drug/device hybrid products, such as heparin-coated vascular devices, antibiotic-treated urinary catheters and bone cement. These products have, for many years, fallen under the Medical Devices Directive, because they do not achieve their "principal intended purpose" by pharmacological, immunological or metabolic action. However, the clause in the Code Amendment Directive adding a provision to the Community Code assigning products to the medicinal products category "in cases of doubt" concerns the medical device, cosmetics, food and food supplements industries. Following the workshop, the European Commission device and drug units agreed to set up a joint working group on drug/device borderline issues to revise an existing European Commission guideline (MEDDEV) on the demarcation between medicinal products and medical devices. As of November 2005, however, the working group had still not been established.

394 Id. at 14-15.

395 Article 15, Medical Devices Directive.


XVIII. Cosmetics A “cosmetic product” is any substance or preparation intended to be placed in contact with the various external parts of the human body (epidermis, hair system, nails, lips and external genital organs) or with the teeth and the mucous membranes of the oral cavity with a view exclusively to mainly cleaning them, perfuming them, changing their appearance and/or correcting body odours and/or protecting them or keeping them in good condition.396 Compared with other areas, there has been relatively little recent change in EU cosmetic regulation. One area of difficulty involves testing cosmetics on animals. After much delay, the EU put legislation restricting such testing into effect. An effort by France to maintain certain requirements for public health reasons was struck down by the European Court of Justice.397

396 Article 1.1 of Council Directive of 27 July 1976 (7668EEC) as amended.

397 French Republic v European Parliament and European Council, C-244/03, 24 May 2005.


Chapter XIX. Enforcement: Medicinal Products A. Community Code provisions EU Directives commonly include provisions requiring EU Member States to enact legislation that not only transposes (implements) the Directive but also provides for Member State surveillance and enforcement. For example, the Community Code on Medicinal Products Directive provides that Member States have an obligation to enforce Community requirements. Under Article 111.1, the Member State authority shall ensure that the legal requirements governing medicinal products are complied with, by means of repeated inspections and, if necessary, unannounced inspections and, where appropriate, by asking an Official Medicines Control Laboratory or a laboratory designated for that purpose to carry out tests on samples. The Competent Authority may also carry out unannounced inspections at the premises of manufacturers of active substances used as starting materials or at the premises of marketing authorisation holders whenever it considers that there are grounds for suspecting noncompliance with GMPs. These inspections may also be carried out at the request of a Member State, the Commission or the Agency. The European Pharmacopoeia has a unit, the European Directorate for the Quality of Medicinal Products (EDQM), which supplies conformity certificates for starting materials. There are times when the EDQM wishes to have an inspection performed in order to verify whether data submitted to it, with a request for a conformity certificate that a substance complies with EP monographs. In these cases, EDQM may ask the Commission or the EMEA to arrange for an inspection when the starting material is the subject of an EP monograph. In addition, the Competent Authority of a Member State may carry out inspections of starting material manufacturers at the specific request of the manufacturer. Inspections shall be carried out by officials representing the Competent Authority that shall be empowered to:

inspect the manufacturing or commercial establishments of manufacturers of medicinal products or of active substances used as starting materials, and any laboratories employed by the manufacturing authorisation holder

take samples and have independent tests carried out by an Official Medicines Control

Laboratory or a laboratory designated for that purpose by a Member State

examine documents

inspect the premises, records and documents of marketing authorisation holders or any firms employed by the marketing authorisation holder to perform certain activities

Under Article 111.2, Member States shall take all appropriate steps to ensure that the manufacturing processes used in the manufacture of immunological products are properly validated and attain batch-to-batch consistency. Under Article 111.3, after every inspection, the officials representing the Competent Authority shall report on whether the manufacturer complies with GMPs or special GMP requirements for blood and plasma in Articles 101 to 108. The content of such reports shall be communicated to the manufacturer or marketing authorisation holder who has undergone the inspection. It is expected that non-EU manufacturers will submit to an inspection except as otherwise provided in any arrangements between the Community and third countries, i.e., non-EU


countries (Article 111.4). Such inspections may be requested by a Member State, the Commission or EMEA. Within 90 days of an inspection, a certificate of GMP shall be issued to a manufacturer if the outcome of the inspection shows that the manufacturer complies with GMP principles and guidelines, as provided for by Community legislation (Article 111.5). If inspections are performed as part of the certification procedure for the monographs of the European Pharmacopoeia, a certificate shall be drawn up. Member States shall enter the certificates of GMP which they issue into a Community database managed by EMEA on behalf of the Community (Article 111.6). If the outcome of the inspection, as referred to in paragraph 1, is that the manufacturer does not comply with GMP principles and guidelines, as provided for by Community legislation, the information shall be entered into the same database (Article 111.7). Member States shall take all appropriate measures to ensure that the holder of the marketing authorisation for a medicinal product and, where appropriate, the manufacturing authorisation holder, furnish proof of the controls carried out on the medicinal product and/or the ingredients and of the controls carried out at an intermediate stage of the manufacturing process (Article 112). To implement this requirement, Member States may require manufacturers of immunological products to submit to a Competent Authority copies of all the control reports signed by the Qualified Person (Article 113). Where it considers it necessary in the interests of public health, a Member State may require the holder of an authorisation for marketing certain products to submit samples from each batch of the bulk and/or the medicinal product for examination by an Official Medicines Control Laboratory or a laboratory that a Member State has designated for that purpose before release onto the market unless, in the case of a batch manufactured in another Member State, the Competent Authority of that Member State has previously examined the batch in question and declared it to be in conformity with the approved specifications (Article 114.1). Member States shall ensure that any such examination is completed within 60 days of the receipt of the samples. Products that may be subjected to this procedure are:

live vaccines—immunological medicinal products used in the primary immunization of infants or of other groups at risk

immunological medicinal products used in public health immunization programmes

new immunological medicinal products or immunological medicinal products

manufactured using new or altered kinds of technology or new for a particular manufacturer, during a transitional period normally specified in the marketing authorisation

The Competent Authorities shall suspend, revoke, withdraw or vary a marketing authorisation if the view is taken that the product is harmful under normal conditions of use, lacks therapeutic efficacy, the risk-benefit balance is not positive under the normal conditions of use or its qualitative and quantitative composition is not as declared (Article 116). Therapeutic efficacy is lacking when it is concluded that therapeutic results cannot be obtained from the medicinal product. An authorisation shall also be suspended, revoked, withdrawn or varied where the particulars supporting the application are incorrect or have not been amended as required, or where the required controls under in Article 112, as discussed above, have not been carried out. Member States are required by Article 117 to take all appropriate steps to ensure that the supply of the medicinal product is prohibited and the medicinal product withdrawn from the market, if the view is taken that:


the medicinal product is harmful under normal conditions of use it lacks therapeutic efficacy

the risk-benefit balance is not favourable under the authorised conditions of use

its qualitative and quantitative composition is not as declared

the controls on the medicinal product and/or on the ingredients and the controls at an

intermediate stage of the manufacturing process have not been carried out or if some other requirement or obligation relating to the grant of the manufacturing authorisation has not been fulfilled

In addition, a Competent Authority may limit the prohibition to supply the product, or its withdrawal from the market, to those batches which are the subject of dispute. Under Article 118, the Competent Authority shall suspend or revoke the marketing authorisation for a category of preparations or all preparations where any one of the requirements relating to a Manufacturing Authorisation (Article 41) is no longer met. In addition to the powers described already, a Competent Authority may suspend the manufacture or imports of medicinal products coming from third countries, or suspend or revoke the manufacturing authorisation for a category of preparations or all preparations where various manufacturing-related requirements are not met. B. EMEA Regulation and Draft Penalties Regulation The new EMEA Regulation not only entrusts EMEA with the task of coordinating Member State execution of the various supervisory responsibilities and particularly GMPs, GLPs and GCPs,398 it also empowers EMEA to initiate inquiries and other actions concerning products authorised by the Community, i.e., through the centralised EMEA procedure. For example, the preamble provides that:

…in order to create greater legal certainty it is necessary to…confer on the Agency powers to monitor the distribution of medicinal products authorised by the Community and to specify the sanctions and the procedures for implementing them in the event of failure to observe the provisions of this Regulation and the conditions contained in the authorisations granted under the procedure it establishes.399

In early 2005, EU authorities launched a stakeholder consultation on a Draft Penalties Regulation to establish a procedure to penalise drug companies that fail to carry out EMEA-imposed obligations under the new EMEA Regulation.400 The Draft Penalties Regulation would set upper limits for penalties and their collection procedures and methods. 398 Preamble at (31), OJ 30 April 2004, L 136/4.

399 Preamble at (28), OJ 30 April 2004, L 136/4.

400 Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the

authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency O J L 136,

30/04/2004 p. 1. This Regulation replaced a 1993 Regulation establishing the European Agency for the Evaluation of Medicinal Products

(EMEA). The same acronym (EMEA) is used for the renamed European Medicines Agency.


1. Aim and scope of the Draft Penalties Regulation. The Draft Penalties Regulation would establish EU-level enforcement of medicine approval (authorisation) obligations under the new EMEA Regulation. The otherwise broad powers given to EMEA since its inception in 1995 included neither provisions for regulatory investigations nor power to act upon violations. Issued in the wake of recent EU and US drug safety issue publicity, the Draft Penalties Regulation is broad in scope, covering failures to submit information required in marketing authorisation applications as well as various postmarketing requirement violations. For example, marketing authorisation holders could be fined for not executing pharmacovigilance responsibilities (including adverse event reporting) or conducting an EMEA-required Phase IV study. Fines also could be imposed for violating requirements concerning manufacturing, importing, labeling, advertising and promotion. The Draft Penalties Regulation applies to medicines approved under EMEA’s centralised procedure, not those under EU Member States’ mutual recognition system. EMEA Regulation Article 84(3), which enables the European Commission to impose financial penalties for marketing authorisation violations at EMEA’s request, is the basis of the draft. 2. Cooperation between EMEA, European Commission and Member States. The EMEA Regulation grants concurrent supervision and enforcement powers to the EU and its Member States for medicines authorisations. Thus, Member States are already able to act under their own laws when marketing authorisation holders (MAHs)—including EMEA authorisations—violate requirements. To facilitate cooperation in investigating alleged violations, the Draft Penalties Regulation allows Member States’ drug regulatory agencies to submit relevant information to EMEA and the European Commission. 3. Two penalty types. The European Commission could impose two types of financial penalties:

fines (lump sums) for violating marketing authorisation obligations periodic penalty payments for enforcing “measures of inquiry” (such as written or oral

explanations, submissions of documents, product testing or inspections) during EMEA investigation of possible violations as well as enforcing decisions finding a violation and, where imposed, fines

a. Fines.

The Draft Penalties Regulation proposes granting the Commission the power to impose fines not exceeding 10% of the previous business year’s total turnover on the MAH due to certain infringements of the EMEA Regulation.

b. Periodic penalty payments. The Draft Penalties Regulation would allow the European Commission to impose periodic penalty payments where the MAH: o has not complied with an EMEA measure of inquiry; in this case, the European

Commission may impose periodic penalty payments not exceeding 1% of the preceding year’s average daily turnover


o has not complied with a European Commission decision ordering a violation to cease; the European Commission may impose periodic penalty payments not exceeding 5% of the average daily turnover in the preceding business year

4. The “infringement procedure.” Violations would be adjudicated by EMEA and the European Commission under a two-stage infringement procedure. EMEA would be responsible for the enquiry stage, while the European Commission would carry out the decision stage.

a. Role of EMEA.

It would be EMEA’s decision whether to initiate an infringement procedure. EMEA first would carry out an enquiry and, to this end, would have the power to require all the information necessary to spot violations.

b. Role of the European Commission.

The European Commission would decide whether an infringement had occurred and whether to impose penalties. The decision would be based upon EMEA’s opinion following its enquiry. Additionally, the European Commission would consider observations submitted by the affected MAH, who also could be ordered by the Commission to submit further information on the matter.

5. The simplified infringement procedure. The Draft Penalties Regulation would create a simplified infringement procedure for enforcing European Commission decisions that a MAH must cease infringing the EMEA Regulation. In this case, imposing periodic penalty payments on the MAH can occur without an EMEA enquiry. 6. Timeframe and dates. At the time of writing, the European Commission had not advanced the draft Penalties Regulation. Comments were due by 8 April 2005. Although the European Commission had originally stated that it wished to adopt this Commission Regulation quickly, so that it could be applied effective November 2005 to coincide with the entry into force of the new EMEA Regulation 726/2004, in late September 2005, Commission staff acknowledged that this intent would not be realised. C. Proposed anti-counterfeiting directive On 12 July 2005, the European Commission issued a Proposal for a European Parliament and Council Directive on Criminal Measures aimed at ensuring the enforcement of intellectual property rights along with a Proposal for a Council Framework Decision to strengthen the criminal law framework to combat intellectual property offences (Proposed Counterfeit Directive).401 In an accompanying memorandum, the European Commission said that counterfeit medicine is a danger and that penalties are too lenient: Criminal law in some EU countries "has not kept pace sufficiently with the development of counterfeiting and piracy over recent years and, in particular, with the increasing involvement of networks of organised crime", says the European Commission in a memorandum on this problem. The Commission cited 2003

401 COM(2005)276 final; 2005/0127(COD); 2005/0128(CNS), 12 July 2005.


statistics showing a 77% increase in seizures of food products and medicines at its external borders. To illustrate the danger of counterfeit medicines to public health, the memo draws attention to several episodes:

Before April 1999, the World Health Organisation found more than 771 cases of counterfeit medicines. Some had no active ingredients; others had very small quantities; in the worst cases, the active ingredients had been replaced with lethal poisons.

More than a ton of pirated antimalarials and antibiotics were intercepted in Belgium in

2000, en route from Asia to Africa.

Seizures of counterfeit Viagra in 2003 included 41,040 tablets in Germany; 299,388 in Belgium; 10,000 in Spain; and 147,662 in the UK.

D. European Healthcare Fraud and Corruption Office The EU plans to launch a new institution, the European Healthcare Fraud and Corruption Office (EHFCO) that will help EU Member States coordinate enforcement activities.


Chapter XX. Advertising and Promotion A. Community code provisions The basic EU-level legislative framework governing pharmaceutical marketing practices and manufacturers’ relationships with physicians and other healthcare professionals has changed little for 13 years. The rules were recodified in EU’s 2001 Community Code on Medicinal Products for human use and were tightened, slightly, in the April 2004 pharmaceutical review legislation. Due to the importance of these provisions, and the recent increase in enforcement as described below, set forth below is the entire text of the Community Code Directive’s provisions in this area, as amended by the Code Amendment Directive 2004/27.

ADVERTISING PROVISIONS: COMMUNITY CODE ON MEDICINAL PRODUCTS

Article 86 1. For the purposes of this Title, "advertising of medicinal products" shall include any form of door-to-door information, canvassing activity or inducement designed to promote the prescription, supply, sale or consumption of medicinal products; it shall include in particular: - the advertising of medicinal products to the general public, - advertising of medicinal products to persons qualified to prescribe or supply them, - visits by medical sales representatives to persons qualified to prescribe medicinal products, - the supply of samples, - the provision of inducements to prescribe or supply medicinal products by the gift, offer or promise of any benefit or bonus, whether in money or in kind, except when their intrinsic value is minimal, - sponsorship of promotional meetings attended by persons qualified to prescribe or supply medicinal products, - sponsorship of scientific congresses attended by persons qualified to prescribe or supply medicinal products and in particular payment of their travelling and accommodation expenses in connection therewith. 2. The following are not covered by this Title: - the labelling and the accompanying package leaflets, which are subject to the provisions of Title V, - correspondence, possibly accompanied by material of a non-promotional nature, needed to answer a specific question about a particular medicinal product,


- factual, informative announcements and reference material relating, for example, to pack changes, adverse-reaction warnings as part of general drug precautions, trade catalogues and price lists, provided they include no product claims,. - information relating to human health or diseases, provided that there is no reference, even indirect, to medicinal products. Article 87 1. Member States shall prohibit any advertising of a medicinal product in respect of which a marketing authorisation has not been granted in accordance with Community law. 2. All parts of the advertising of a medicinal product must comply with the particulars listed in the summary of product characteristics. 3. The advertising of a medicinal product: - shall encourage the rational use of the medicinal product, by presenting it objectively and without exaggerating its properties, - shall not be misleading. Article 88 1. Member States shall prohibit the advertising to the general public of medicinal products which: a) are available on medical prescription only, in accordance with Title VI, b) contain substances defined as psychotropic or by international convention such as the United Nations Conventions of 1961 and 1971, 2. Medicinal products may be advertised to the general public which, by virtue of their composition and purpose, are intended and designed for use without the intervention of a medical practitioner for diagnostic purposes or for the prescription or monitoring of treatment, with the advice of the pharmacist, if necessary. 3. Member States shall be entitled to ban, on their territory, advertising to the general public of medicinal products the cost of which may be reimbursed. 4. The prohibition contained in paragraph 1 shall not apply to vaccination campaigns carried out by the industry and approved by the Competent Authorities of the Member States. 5. The prohibition referred to in paragraph 1 shall apply without prejudice to Article 14 of Directive 89/552/EEC. 6. Member States shall prohibit the direct distribution of medicinal products to the public by the industry for promotional purposes.


TITLE VIIIa INFORMATION AND ADVERTISING Article 88a Within three years of the entry into force of Directive 2004/726/EC, the Commission shall, following consultations with patients’ and consumers’ organisations, doctors and pharmacists’ organisations, Member States and other interested parties, present to the European Parliament and the Council a report on current practice with regard to information provision – particularly on the Internet – and its risks and benefits for patients. Following analysis of the above data, the Commission shall, if appropriate, put forward proposals setting out an information strategy to ensure good-quality, objective, reliable and non-promotional information on medicinal products and other treatments and shall address the question of the information source’s liability. Article 89 1. Without prejudice to Article 88, all advertising to the general public of a medicinal product shall: (a) be set out in such a way that it is clear that the message is an advertisement and that the product is clearly identified as a medicinal product; (b) include the following minimum information: - the name of the medicinal product, as well as the common name if the medicinal product contains only one active substance, - the information necessary for correct use of the medicinal product, - an express, legible invitation to read carefully the instructions on the package leaflet or on the outer packaging, as the case may be. 2. Member States may decide that the advertising of a medicinal product to the general public may, notwithstanding paragraph 1, include only the name of the medicinal product or its international non-proprietary name, where this exists, or the trademark if it is intended solely as a reminder. Article 90 The advertising of a medicinal product to the general public shall not contain any material which: (a) gives the impression that a medical consultation or surgical operation is unnecessary, in particular by offering a diagnosis or by suggesting treatment by mail; (b) suggests that the effects of taking the medicine are guaranteed, are unaccompanied by adverse reactions or are better than, or equivalent to, those of another treatment or medicinal product;


(c) suggests that the health of the subject can be enhanced by taking the medicine; (d) suggests that the health of the subject could be affected by not taking the medicine; this prohibition shall not apply to the vaccination campaigns referred to in Article 88(4); (e) is directed exclusively or principally at children; (f) refers to a recommendation by scientists, health professionals or persons who are neither of the foregoing but who, because of their celebrity, could encourage the consumption of medicinal products; (g) suggests that the medicinal product is a foodstuff, cosmetic or other consumer product; (h) suggests that the safety or efficacy of the medicinal product is due to the fact that it is natural; (i) could, by a description or detailed representation of a case history, lead to erroneous self-diagnosis; (j) refers, in improper, alarming or misleading terms, to claims of recovery; (k) uses, in improper, alarming or misleading terms, pictorial representations of changes in the human body caused by disease or injury, or of the action of a medicinal product on the human body or parts thereof. Article 91 1. Any advertising of a medicinal product to persons qualified to prescribe or supply such products shall include: - essential information compatible with the summary of product characteristics; - the supply classification of the medicinal product. Member States may also require such advertising to include the selling price or indicative price of the various presentations and the conditions for reimbursement by social security bodies. 2. Member States may decide that the advertising of a medicinal product to persons qualified to prescribe or supply such products may, notwithstanding paragraph 1, include only the name of the medicinal product, or its international non-proprietary name, where this exists, or the trademark, if it is intended solely as a reminder. Article 92 1. Any documentation relating to a medicinal product which is transmitted as part of the promotion of that product to persons qualified to prescribe or supply it shall


include, as a minimum, the particulars listed in Article 91(1) and shall state the date on which it was drawn up or last revised. 2. All the information contained in the documentation referred to in paragraph 1 shall be accurate, up-to-date, verifiable and sufficiently complete to enable the recipient to form his or her own opinion of the therapeutic value of the medicinal product concerned. 3. Quotations as well as tables and other illustrative matter taken from medical journals or other scientific works for use in the documentation referred to in paragraph 1 shall be faithfully reproduced and the precise sources indicated. Article 93 1. Medical sales representatives shall be given adequate training by the firm which employs them and shall have sufficient scientific knowledge to be able to provide information which is precise and as complete as possible about the medicinal products which they promote. 2. During each visit, medical sales representatives shall give the persons visited, or have available for them, summaries of the product characteristics of each medicinal product they present together, if the legislation of the Member State so permits, with details of the price and conditions for reimbursement referred to in Article 91(1). 3. Medical sales representatives shall transmit to the scientific service referred to in Article 98(1) any information about the use of the medicinal products they advertise, with particular reference to any adverse reactions reported to them by the persons they visit. Article 94 1. Where medicinal products are being promoted to persons qualified to prescribe or supply them, no gifts, pecuniary advantages or benefits in kind may be supplied, offered or promised to such persons unless they are inexpensive and relevant to the practice of medicine or pharmacy. 2. Hospitality at sales promotion events shall always be strictly limited to their main purpose and must not be extended to persons other than health-care professionals. 3. Persons qualified to prescribe or supply medicinal products shall not solicit or accept any inducement prohibited under paragraph 1 or contrary to paragraph 2. 4. Existing measures or trade practices in Member States relating to prices, margins and discounts shall not be affected by paragraphs 1, 2 and 3. Article 95 The provisions of Article 94(1) shall not prevent hospitality being offered, directly or indirectly, at events for purely professional and scientific purposes; such


hospitality shall always be strictly limited to the main scientific objective of the event; it must not be extended to persons other than health-care professionals. Article 96 1. Free samples shall be provided on an exceptional basis only to persons qualified to prescribe them and on the following conditions: (a) the number of samples for each medicinal product each year on prescription shall be limited; (b) any supply of samples shall be in response to a written request, signed and dated, from the prescribing agent; (c) those supplying samples shall maintain an adequate system of control and accountability; (d) each sample shall be identical with the smallest presentation on the market; (e) each sample shall be marked "free medical sample - not for sale" or shall show some other wording having the same meaning; (f) each sample shall be accompanied by a copy of the summary of product characteristics; (g) no samples of medicinal products containing psychotropic or narcotic substances within the meaning of international conventions, such as the United Nations Conventions of 1961 and 1971, may be supplied. 2. Member States may also place further restrictions on the distribution of samples of certain medicinal products. Article 97 1. Member States shall ensure that there are adequate and effective methods to monitor the advertising of medicinal products. Such methods, which may be based on a system of prior vetting, shall in any event include legal provisions under which persons or organisations regarded under national law as having a legitimate interest in prohibiting any advertisement inconsistent with this Title, may take legal action against such advertisement, or bring such advertisement before an administrative authority competent either to decide on complaints or to initiate appropriate legal proceedings. 2. Under the legal provisions referred to in paragraph 1, Member States shall confer upon the courts or administrative authorities powers enabling them, in cases where they deem such measures to be necessary, taking into account all the interests involved, and in particular the public interest: - to order the cessation of, or to institute appropriate legal proceedings for an order for the cessation of, misleading advertising, or


- if misleading advertising has not yet been published but publication is imminent, to order the prohibition of, or to institute appropriate legal proceedings for an order for the prohibition of, such publication, even without proof of actual loss or damage or of intention or negligence on the part of the advertiser. 3. Member States shall make provision for the measures referred to in the second subparagraph to be taken under an accelerated procedure, either with interim effect or with definitive effect. It shall be for each Member State to decide which of the two options set out in the first subparagraph to select. 4. Member States may confer upon the courts or administrative authorities powers enabling them, with a view to eliminating the continuing effects of misleading advertising the cessation of which has been ordered by a final decision: - to require publication of that decision in full or in part and in such form as they deem adequate, - to require in addition the publication of a corrective statement. 5. Paragraphs 1 to 4 shall not exclude the voluntary control of advertising of medicinal products by self-regulatory bodies and recourse to such bodies, if proceedings before such bodies are possible in addition to the judicial or administrative proceedings referred to in paragraph 1. Article 98 1. The marketing authorisation holder shall establish, within his undertaking, a scientific service in charge of information about the medicinal products which he places on the market. 2. The marketing authorisation holder shall: - keep available for, or communicate to, the authorities or bodies responsible for monitoring advertising of medicinal products, a sample of all advertisements emanating from his undertaking together with a statement indicating the persons to whom it is addressed, the method of dissemination and the date of first dissemination, - ensure that advertising of medicinal products by his undertaking conforms to the requirements of this Title, - verify that medical sales representatives employed by his undertaking have been adequately trained and fulfil the obligations imposed upon them by Article 93(2) and (3), - supply the authorities or bodies responsible for monitoring advertising of medicinal products with the information and assistance they require to carry out their responsibilities,


- ensure that the decisions taken by the authorities or bodies responsible for monitoring advertising of medicinal products are immediately and fully complied with. Article 99 Member States shall take the appropriate measures to ensure that the provisions of this Title are applied and shall determine in particular what penalties shall be imposed should the provisions adopted in the execution of Title be infringed. Article 100 Advertising of the homeopathic medicinal products referred to in Article 14(1) shall be subject to the provisions of this Title with the exception of Article 87(1). However, only the information specified in Article 69(1) may be used in the advertising of such medicinal products. ________ Preamble: (46) Furthermore, distribution of samples free of charge to the general public for promotional ends must be prohibited. (47) The advertising of medicinal products to persons qualified to prescribe or supply them contributes to the information available to such persons. Nevertheless, this advertising should be subject to strict conditions and effective monitoring, referring in particular to the work carried out within the framework of the Council of Europe. (48) Advertising of medicinal products should be subject to effective, adequate monitoring. Reference in this regard should be made to the monitoring mechanisms set up by Directive 84/450/EEC. (49) Medical sales representatives have an important role in the promotion of medicinal products. Therefore, certain obligations should be imposed upon them, in particular the obligation to supply the person visited with a summary of product characteristics. (50) Persons qualified to prescribe medicinal products must be able to carry out these functions objectively without being influenced by direct or indirect financial inducements. (51) It should be possible within certain restrictive conditions to provide samples of medicinal products free of charge to persons qualified to prescribe or supply them so that they can familiarise themselves with new products and acquire experience in dealing with them. (52) Persons qualified to prescribe or supply medicinal products must have access to a neutral, objective source of information about products available on the market. Whereas it is nevertheless for the Member States to take all measures necessary to this end, in the light of their own particular situation.


(53) Each undertaking which manufactures or imports medicinal products should set up a mechanism to ensure that all information supplied about a medicinal product conforms to the approved conditions of use. B. Increased enforcement During the last several years, enforcement activities have increased significantly in both level and intensity regarding various pharmaceutical marketing practices in many European countries. 1. Enforcement agencies Increased enforcement is the major area of change, accompanied by more stringent industry codes and a large number of governmental investigations. Notably, enforcement is not being initiated only—or even principally—by traditional drug regulatory authorities. Rather, from the north to the south of Europe, the challenges are being brought by prosecutors, tax police, competition authorities and anticorruption officials. Targeted activities include pharmaceutical companies’ sales representatives’ practices, social activity sponsorships in connection with medical congresses and various company financial arrangements with medical experts. 2. Non-governmental actions Industry code bodies, like the European Federation of Pharmaceutical Industry Associations, have recently tightened their rules, while national-level associations are handling increasing numbers of trade complaints. 3. International activities Some multinational healthcare product manufacturers are seeking to establish global corporate compliance policies for several reasons.

Drug manufacturers have to decide what standards will govern international affiliate operations when establishing compliance programs to satisfy US Attorneys’ and the DHHS Inspector General.

The precise source of a governmental enforcement action, or the country in which an

issue might arise, can be difficult to predict. The case may come from a prosecutor’s office or government body with which the company has had little or no prior involvement. Or, it may be a competitor’s complaint to one or more trade groups.

Therefore, companies need to have solid, defensible compliance programs in place before an enforcement action or trade complaint occurs, including internal marketing practice controls. In some jurisidictions, diligent compliance efforts can result in case dismissal or mitigate any penalty.

Companies cannot easily establish global product development and marketing strategies—or global Standard Operating Procedures (SOPs)—when marketing practices are being determined at the local level.


Efforts by a CEO to boost the company’s image, emphasize its role in new product development and maintain a high corporate integrity level can be undermined by employees’ improper activities in any country.

o CEOs find it difficult to understand, and even more difficult to explain, why a rule

applies to dealings with doctors in one country but not in another.

o In today’s world of instantaneous communication, word spreads fast if a company encounters trouble anywhere in the world. Such bad news lowers stock value and may stimulate lawsuites or investigations by prosecutors and politicians in other countries.

In many countries, medicine prescribers and purchasers are government officials.

Governments everywhere are trying to manage social security program spending,

including outlays for medicines. Company marketing practices are a prime target for actions under criminal codes and anticorruption, regulatory or competition laws.

Drug manufacturers are trying to better manage the spending associated with current

marketing practices. Recent news reports indicate that several large companies are contemplating possible sales force reductions.

C. Situation in various countries 1.The United Kingdom In 2004 and 2005, the UK Parliament’s Select Health Committee held a much-publicized inquiry into the pharmaceutical industry’s influence on prescribing practices, patient groups and regulators. The Committee report criticized the industry and the Medicines and Healthcare products Regulatory Agency (MHRA). Singled out for particular attention were spending on marketing rather than research and development; selective publication of clinical trial data, particularly suppression of negative results; drug company representatives’ “ghost-writing” articles published with an expert shown as author; and companies sponsoring physicians’ attendance at lavish conferences in exotic locations. Even a seemingly benign activity—industry support of disease awareness campaigns and sponsoring patient organisations—came under attack, characterised by some Members of Parliament as “disease mongering.” The MHRA was accused of excessive closeness to industry, a pro-approval bias and undue secrecy. Although it is too soon to tell what legislative or other recommendations might emerge from the Health Committee’s report, industry is already tackling these issues. At the parliamentary inquiry, the Association of the British Pharmaceutical Industry (ABPI) defended its Prescription Medicines Code of Practice Authority (PMCPA) in enforcing the requirements of EU and UK law. Certainly, of all the drug industry trade associations around the world, none has issued as much guidance on marketing practices as ABPI and no code enforcement body has handled as many adjudications as PMCPA. Many rulings go against the company whose marketing practices are being attacked. Still, further tightening is on the UK horizon. ABPI is preparing to revise its Code of Practice rules regarding controls on prescription medicine promotion. Also, member companies have stepped up training and compliance activities, voluntarily refrained from certain marketing programs for products under safety reviews and posting clinical trial data.


The PMCPA caseload is on the rise, and counterpart bodies in other countries are likewise seeing an increase in trade complaints. One successful challenge involved a competitor that offered an ophthalmic lamp (valued at £175) or an educational grant (£250) to any clinician who started 20 patients on a ophthalmic drug product. This was seen as an inducement to prescribe the drug. Insofar as government marketing enforcement action, MHRA possesses strong authority but has not, in the past, brought many cases, preferring to rely upon ABPI and its PMCPA. This recently changed and now the MHRA website routinely documents MHRA actions against both established drug manufacturers and Fly-by-night operations Some observers believe that this change stems from the parliamentary inquiry described above. 2. Sweden Enforcement is on the rise in Sweden, with several prosecutions announced in 2005. New agreements have been reached—between the Swedish Association of the Pharmaceutical Industry and organisations representing local governments, doctors and the national drug purchasing authority—on forms of cooperation between pharmaceutical companies and public-sector medical professionals. Drug companies’ ability to offer lavish marketing events and conferences to professionals has been severely limited. Restrictions include a cap on travel expense reimbursment, including accommodation and food (50%); a requirement that invitations to scientific conferences be sent to hospital management only, who then decide which healthcare professionals may attend; a ban on social activities (e.g., golf, theatre) in connection with conferences; and a ban on sponsoring events organised by healthcare professionals themselves, such as hospital staff parties. 3. Italy Developments in Italy include cases brought by tax authorities and new industry code requirements. In 2005, Italian police responsible for investigating economic crimes completed a two-year investigation into drug industry marketing practices. More recently, a number of cases have been in the news. In 2004, a small US company and its CEO became the subjects of a criminal investigation in Milan. The company is alleged to have paid a physician and hospital administrator the sum of €13,500 in exchange for hospital contracts. In a second case, Verona’s public prosecutor is investigating 4,000 doctors and 300 officials from a global manufacturer. It is alleged that company sales representatives sought to influence doctors’ prescribing preferences by offering cash, cameras, computer equipment and holidays. In a third case, in Florence, a major company is charged with illegal payments to doctors. As a result, the pharmaceutical trade association, Farmindustria, now requires each member company to hire a third-party body annually to audit and certify that the company is in compliance with laws and the industry marketing practice code. April 2005 was the deadline for the first certification. 4. Croatia Transitional economies present special challenges to companies. In 2004, a major pharmaceutical company announced an internal probe of its Croatian sales operations. Croatia will launch accession negotiations with the EU in a few years.


D. EFPIA’s new Marketing Code of Practice A new code of practice on the promotion of medicines was ratified by the members of the European Federation of Pharmaceutical Industries and Associations (EFPIA) at its annual meeting in June 2005. A copy of the revised EFPIA Code can be found at the end of this publication. The new code bans exotic venues for industry-sponsored conferences for healthcare professionals, tightens rules to ensure that scientific aspects predominate at meetings and draws a distinction between industry marketing practices and scientific information activities. The new code is markedly longer than previous versions and includes a recommendation that, where possible, fines and “naming and shaming” should be used against companies that violate the code. Sanctions should be proportionate to the nature of the infringement, have a deterrent effect and take account of repeated offences of a similar nature or patterns of different offenses, according to the code. EFPIA comprises 29 national pharmaceutical industry associations and 43 leading pharmaceutical companies involved in European research, development and manufacturing of medicinal products for human use. E. Eucomed Code The leading European medical device trade association, EUCOMED, has an ethical code which provides as follows:

2.2 Interactions with Health Care Professionals

Compliance with applicable laws and adherence to ethical standards are important to the medical technology/device industry’s ability to continue to collaborate effectively with health care professionals. Such collaboration can take the form of a) developing medical technologies; b) providing training, education, service and support to enable the safe and effective use of medical technologies; and c) supporting medical research, education, and enhancement of professional skills. These activities are necessary to advance medical science, improve patient care. To ensure ethical interactions with individuals or entities that purchase, lease, recommend or use members’ products, members should duly consider the Eucomed Guidelines on Interactions with Health Care Professionals.

2.3 Advertising and Promotion Members should ensure that all promotional presentations, including product claims and comparisons, are accurate, balanced, fair, objective and unambiguous. They should be justified by appropriate evidence. Statements should not mislead the intended audience.

2.4 Unlawful Payments and Practices Members should not directly or indirectly offer, make, or authorise payment of money or anything of material value, to unlawfully (a) influence the judgment or conduct of any individual, customer, or company; (b) win or retain business; (c) influence any act or decision of any governmental official; or (d) gain an advantage. This requirement extends not only to direct inducements, but also to indirect inducements made by a member in any form through agents, consultants or other third parties. Members should have particular regard to laws and regulations prohibiting or restricting inducements aimed at influencing clinicians or customers.


Chapter XXI. National Authorities A. EU Member State responsibilities under new legislation The impact of the new EU Laws on Member States’ drug regulatory authorities includes:

heavy load of Eurocentric legislation to implement

increased informatics requirements (clinical trial database, pharmacovigilance, website updates, etc.)

increased interaction with patients and industry

resource shortfalls due to:

o new responsibilities at Member State level

o committee responsibilities at EU level

o fewer fees when more products are approved centrally and national authorisations

do not need renewal every five years Key Member State Responsibilities Include:

clinical trial approvals and oversight national authorisations and maintenance

licensing of establishments within Member State’s territory

importation licenses, including parallel imports

licensing of wholesalers and distributors

surveillance and enforcement

sales and promotional activities (relations with doctors and hospitals)—much recent

enforcement activity Member State experts also serve on EMEA and European Commission committees:

rapporteurs and co-rapporteurs of centralised applications through the CHMP

Reference Member State for decentralised applications

reviewers in Concerned Member States after favourable decision by the Reference Member State

experts participating in Mutual Recognition Facilitation Group and other groups


Notice to Applicants Working Group (these guidelines apply to both centralised and

decentralised procedures) B. New Member States’ implementation steps as of the 1 May 2005, date of accession 1. Cyprus The Medicine Council controls medicinal product marketing and the committee to control medicine prices have yet to be established. Since the 2000 report, progress has been made in implementing the acquis concerning pharmaceuticals. Further transposition was achieved with the adoption of the Veterinary Medicinal Products Regulations in 2002. In the course of the accession negotiations, Cyprus was granted a transitional period relating to the renewal of marketing authorisations for pharmaceutical products until the end of 2005 (europa.eu.int/scadplus/leg/en/lvb/e07111.htm).

a. The Medicinal Products for Human Use (Control of Quality, Supply and Prices) Law of 200119/04/2001 Entry into force: 04 May 2001 amended by The Medicinal Products for Human Use (Control of Quality, Supply and Prices) (Amendment) Law of 2002 (Law No.83 (I)/2002)06/06/2002 Entry into force: 21 June 2002

b. Regulations:

1. The Medicinal Products for Human Use (Presentation and Content of the Application

for a Marketing Licence) Regulations of 2001. 19/04/2001 Entry into force: 04 May 2001

2. The Medicinal Products for Human Use (Fees) Regulations of 2001 19/04/2001 Entry into force: 04 May 2001

2. The Czech Republic In 2003, the Czech Parliament passed Act No.129/2003 Sb. (the "Act"), which has substantially amended Act No. 79/1997 Sb. on medicinal products. The main purpose of the act was to bring the previous Czech medicinal products regulation in broad conformity with Directive 2001/83/EC. The Acts 129/2003 and 79/1997 cover, in full, the subject matter of Directive 2001/83/EC.

a. Act on Medicinal Products: Zakon o lecivech a o zmenach a doplneni nekterych souvisejicich zakonu (Act on Medicinal Products and on Amendments to Certain Related Laws) Passed 19 March 1997 Entry into force: 01 January 1998 Reference No: 79/1997 Sb.—published 15 April 1997 in the official Collection of Laws (Sbirka zakonu)

Amending Act:


Zakon, kterym se meni zakon c. 79/1997 Sb., o lecivech a o zmenach a doplneni nekterych souvisejicich zakonu, ve zneni pozdejsich predpisu (Act Amending Act No. 79/1997 Sb. on Medicinal Products and on Amendments to Certain Related Laws) Passed 02 April 2003 Entry into force: 05 June 2003 (certain provisions) and 1 May 2004 (EU provisions) Reference No: 129/2003 Sb.—published 06 May 2003 in the official Collection of Laws (Sbirka zakonu)

b. Regulations:

To implement Act No. 79/1997 Sb., the Czech Ministry of Health (in cooperation with the Ministry of Agriculture) issued Decree (Vyhlaska) No. 473/2000 Sb., as amended by Decree No. 302/2003 Sb. Decree No. 473/2000 Sb. was, as of 11 May 2004, repealed by Decree No. 288/2004 Sb (New Decree). Entry into force: 11 May 2004 Published in the official Collection of Laws, 11 May 2004

3. Estonia The Estonian Ministry of Health has stated that Directive 2001/83/EC is currently fully implemented in Estonia through a large number of legal acts (not in a structured way). Ministerial Regulation has been published on mutual recognition and pharmacovigilance. A proposal in the Parliament of Estonia will reorganise and restructure Estonian pharmaceutical legislation. 4. Hungary

a. Hungarian Regulations to implement the Community Code on Medicinal Products

(2001/83) include: 1. Act XXV of 1998, medicinal products for human use, amended by Act XXVI of

2004, incorporating regulations compatible with the EU Directive on Medicinal Products (2001/83) Entry into force: 01 May 2004 Published in the official Hungarian Gazette (Magyar Kozlony), Issue No. 56/2004, 26 April 2004

2. Decree No. 37/2000 (III. 23.) of the Hungarian Government, personal and material

conditions for the production of medicinal products for human use, amended by Decree No. 86/2004 (IV. 20.) Entry into force: 01 May 2004 Published in the official Hungarian Gazette (Magyar Kozlony), Issue No. 50/2004, 20 April 2004

3. Decree No 64/2003 (X. 31.) of the Ministry of Health, advertisement and promotion of

medicinal products for human use, stipulates regulations compatible with Sections 86 to 100 of the Directive Entry into force: 15 November 2003 Published in the official Hungarian Gazette (Magyar Kozlony), Issue No. 125/2003, 31 October 2003


4. Decree No. 39/2004 (IV. 26.) of the Ministry of Health, qualifying conditions of the persons authorised for quality assurance of medicinal products Entry into force: 01 May 2004 Published in the official Hungarian Gazette (Magyar Kozlony), Issue No. 56/2004, 26 April 2004

5. Decree No 44/2004 (IV. 28.) of the Ministry of Health, prescription and distribution of

medicinal products\for human use, contains regulations compatible with Directive Sections 70 to 75

Entry into force: 01 August 2004 Published in the official Hungarian Gazette, Issue No. 58/2004, 28 April 2004

5. Latvia The process of Directive approximation has been carried out according to the schedule established by the National Integration Program into the European Union. The structural reorganisation in the area of pharmaceuticals has been completed. All necessary institutions are established and operating in Latvia: State Pharmaceutical Inspection and State Agency of Medicines and the State Medicines Price Agency.

a. The main requirements of EU Directive 2001/83 (formerly: Directives 65/65/EEC; 75/319/EEC; 89/105/EEC; 92/27/EEC; 92/26/EEC; 91/356/EEC; 92/25/EEC; 92/28/EEC) in the area of pharmaceuticals are introduced to the Latvian legislation by the Law On Pharmaceuticals. Entry into force: 08 May 1997 Published in Latvian Gazette (Latvijas Vēstnesis), No: 103, 24 April 1997 Amendments: Amended 19 March 1998

Entry into force: 22 April 1998

Amended 17 December 1998 Entry into force: 01 January 1999

Amended 01 June 2000 Entry into force: 28 June 2000

Amended 14 June 2001 Entry into force: 01 July 2001

b. Regulations:

1. Regulations of Cabinet of Ministers No 88 27/02/2001, Regulations on Import, Export and Distribution of Medicinal Products, Entry into force: 03 March 2001 Published in Latvian Gazette (Latvijas Vēstnesis), No: 35, 02 March 2001

2. Order of the Ministry of Welfare Nr.155, Order of Issuing and Renewal of Marketing

Authorisations Adopted: 21 May 1999


3. Regulations of the Cabinet of Ministers No 381 31/10/2000, On Registration of Medicinal Products Entry into force: 04 November 2000 Published in Latvian Gazette (Latvijas Vēstnesis), No: 391/393, 03 November 2000 Amended by Regulations of the Cabinet of Ministers No 418 22/04/2004, Amendments on regulations of the Cabinet of Ministers On Registration of Medicinal Products Entry into force: 01 May 2004 Published in Latvian Gazette (Latvijas Vēstnesis), No: 69, 01 May 2004

4. Regulations of Cabinet of Ministers No 348 07/10/1997, On Licencing Entrepreneurial Activities Entry into force: 01 January 1998 Published in Latvian Gazette (Latvijas Vēstnesis), No: 260/262, 09 October 1997

6. Lithuania

a Laws

Law No I-1025 on Pharmaceutical Activities Adopted 31 January 1991 Entry into force: 28 February 1991

Law No I-1633 on Pharmaceuticals Adopted 19 November 1996 Entry into force: 01 January 1997

Amendments:

Law No VIII-258 on Amending the Law on Pharmaceutical Activities Entry into force: 20 June 1997 Published in Farmacines veiklos istatymo 10, 14 straipsniu pakeitimo ir papildymo istatymas, Nr. VIII-258, 12 June 1997

Law No I-1442 on Amending the Law on Pharmaceutical Activities No.1025 Entry into force: 04 July 1996 Published in Farmacines veiklos istatymo 1, 5, 7, 10, 12, 14, 16, 17, 19, 21, 22, 23, 24 straipsniu pakeitimo ir papildymo 25 straipsniu istatymas, Nr. I-1442, 04 July 1996

Law No VIII-1802 on Amending the Law on Pharmaceutical Activities Entry into force; 04 July 2000 Published in Farmacines veiklos istatymo 17, 21, 22, 23, 24, straipsniu pakeitimo ir papildymo Nr. VIII-1802, 04 July 2000

Law No I-1633 on Amending the Articles 1, 4, 5, 10, 11, 15, 17, 19, 20 and Supplementing with Articles 10(1), 17(1) of the Law on Pharmaceutical Activities Entry into force: 14 June 2002 Published in Farmacines veiklos istatymo 1, 4, 5, 10, 11, 15, 17, 19, 20 straipsniu pakeitimo ir istatymo papildymo 10(1), 17(1) straipsniais istatymas Nr. IX-922, 14 June 2002


Law No. I-552 on Health System

Adopted 19 July 1994 Entry into force: 17 August 1994

b. Regulations:

1. Governmental Resolution No 802 on Adoption of Rules of Licencing Pharmaceutical Activities Adopted 30 June 1998 Entry into force: 09 July 1998 Amended by Governmental Resolution No 1194 on Amendment of the Governmental Resolution No 802 on Rules of Licencing of Pharmaceutical Activities Adopted 30 September 2003 Entry into force: 02 October 2003

2. Order No 796 On Rules on the Classification for the Supply of Medicines for Human Use, Adopted by the Ministry of Health Adopted 31 December 1998 Entry into force: 06 January 1999

3. Order No 669 on Requirements for the Registration of the Pharmaceuticals, adopted by the Minister of Health Amended by Order No V-169 on Amendment of the Order No 669 on Requirements for the Registration of the Pharmaceuticals, adopted by the Minister of Health Adopted 24 March 2003 Entry into Force: 01 April 2003 Amended by Order No V-377 on Amendment of the Order No 669 on Requirements for the Registration of Pharmaceuticals, adopted by the Minister of Health Adopted 24 June 2003 Entry into force: 01 July 2003

4. Order No V-658 on Regulation on imports of pharmaceuticals from third countries, adopted by the Minister of Health Adopted 10 November 2003 Entry into force: 01 May 2004

7. Malta

a. The Medicines Act, 21/11/2003, (Chapter 458 of the Laws of Malta) Entered into force: 21 November 2003

b. Regulations:

1. Medicines (Marketing Authorisation) Regulations, 2003 under the Medicines Act, 2003 (Chap 458) Entry into force: 26 December 2003


8. Poland a. Most of the relevant pharmaceutical legislation covered by the Community Code on

Medicinal Products Directive 2001/83 is contained in the Act Ustawa prawo farmaceutyczne (Pharmaceutical Law) Date of enactment: 06 September 2001 Entry into force: 01 October 2002, with exceptions Consolidated text published in Journal of Laws 2004, No. 53, Item 533, h

Amendments

Subsequent amendments published in: JoL 2004, No. 92, Item 882, JoL 2004, No.69, Item 625, JoL 2004, No. 91, Item 877, JoL 2004, No. 93, Item 896. All the amendments to the Pharmaceutical Law entered into force on 01 May 2004. Also, some of the provisions of the original text of the Pharmaceutical Law entered into force on that date.

b. Some detailed matters are further developed by secondary law; approximately 75

Ordinances implement various provisions of the Pharmaceutical Law. Many of them develop issues covered by Directive 2001/83, including:

1. Ordinance of the Minister of Health of 3 December 2002, on the Requirements of the

Good Manufacture Practice (Rozporzadzenie Ministra Zdrowia z 3 grudnia 2002 r. w sprawie wymagan Dobrej Praktyki Wytwarzania), Journal of Laws of 2002, No. 224, Item 1882

2. Ordinance of the Minister of Health of 20 December 2002, on the rules of the control

procedure carried out by the pharmaceutical inspector (Rozporzadzenie Ministra Zdrowia z 20 grudnia 2002 r. w sprawie trybu przeprowadzania kontroli przez inspektora farmaceutycznego), Journal of Laws of 2003, No. 21, Item 185

3. Ordinance of the Minister of Health of 17 February 2003, on the monitoring of safety

of medicinal products (Rozporzadzenie Ministra Zdrowia z 17 lutego 2003 r. w sprawie monitorowania bezpieczenstwa produktow leczniczych), Journal of Laws of 2003, No. 47, Item 405

4. Ordinance of the Minister of Health of 16 January 2003, on the documentation of the

trial results of medicinal product, including veterinary products, and expert reports (Rozporzadzenie Ministra Zdrowia z 16 stycznia 2003 r. w sprawie dokumentacji wyników badan produktu leczniczego, w tym produktu leczniczego weterynaryjnego, oraz raportow eksperta), Journal of Laws of 2003, No. 19, Item 168

5. Ordinance of the Minister of Health of 30 April 2004, on the detailed rules of the

mutual recognition procedure (Rozporzadzenie Ministra Zdrowia z 30 kwietnia 2004 r. w sprawie szczegolowego trybu postepowania dotyczacego procedury wzajemnego uznania), Journal of Laws 2004, No. 104, Item 1106)

9. Slovakia Slovak Parliament has enacted Act No. 9/2004 Z.z, the purpose of which was to align Act No. 140/1998 Z.z., on medicinal products, with the EC Directive.


a. Act on Medicinal Products: Zakon o liekoch a zdravotnickych pomockach (Act on Medical Drugs and Devices) Passed: 03 April 1998 Entry into force: 06 June 1998 Reference No. 140/1998 Z.z., published 21 May 1998 in the Official Collection of Laws (Zbierka zakonov)

b. Amending Act:

Zakon ktorym sa meni a doplna zakon c. 140/1998 Z.z. o liekoch a zdravotnickych pomockach (Act Amending Act No. 140/1998 Z.z. on Medical Drugs and Devices) Passed: 03 December 2003 Entry into force: 02 February 2004 (certain provisions), 01 May 2004 (EU provisions) Reference No. 9/2004 Z.z., published 13 January 2004 in the Official Collection of Laws (Zbierka zakonov)

10. Slovenia

a. Medicinal Products and Medicinal Devices Act (Ur.l. RS, št. 101/1999, 70/2000, 7/2002, 13/2002, 67/2002) Adopted: 16 December 1999 Entry into force: 31 December 1999

Amendments:

o Act Amending the Medicinal Products and Medical Devices Act, (Ur.l. RS, št. 70/2000) Adopted: 08 August 2000 Entry into force: 09 August 2000

o Act Amending the Medicinal Products and Medical Devices Act, (Ur.l. RS, št. 7/2002) Adopted: 30 January 2002 Entry into force: 31 March 2002

o Act Amending the Medicinal Products and Medical Devices Act, (Ur.l. RS, št. 67/2002) Adopted: 26 July 2002 Entry into force: 10 August 2002

b. Regulations:

1. Rules on registration methods for medicinal products, 04/07/2000 (Ur.l. RS, št. 67/2000, 59/2003) Adopted: 28 July 2000 Entry into force: 05 August 2000 Amended by Rules amending the Rules on registration methods for medicinal products, (Ur.l. RS, št. 59/2003) Adopted: 20 June 2003 Entry into force: 28 June 2003

2. Rules on the classification, prescribing and dispensing of medicinal products for

human use (Ur.l. RS, št. 59/2003, 114/2003)


Adopted: 20 June 2003 Entry into force: 05 July 2003 Amended by Rules amending the Rules on the classification, prescribing and dispensing of medicinal products for human use Adopted: 07 October 2003

3. Decision on the implementation of the sixth, seventh and eighth supplements to the

European Pharmacopoeia Fourth Edition, (Ur.l. RS, št. 114/2003) Adopted: 21 November 2003

Entry into force: 22 November 2003 C. Provisions in accession treaties on parallel trade The Treaty of Accession402 for eight403 of the 10 new EU Member States prescribed certain filings404 and also, at the request of the pharmaceutical industry, included provisions to circumscribe parallel trade between the old Member States and the new ones.405 Under these provisions, the holder or beneficiary of a patent or supplementary protection certificate (SPC) for a pharmaceutical product filed in a Member State at a time when such protection could not be obtained for that product in the Czech Republic, Estonia, Latvia, Lithuania, Hungary, Poland, Slovenia or Slovakia, had to rely upon the rights granted by that patent or SPC to prevent the import and marketing of that product in the Member State or States where the product in question enjoys patent and/or SPC protection, even if the product was put on the market in that new Member State for the first time by him or with his consent. Furthermore, in order to enable the Community rightholders to exercise effective control over potential parallel imports which may nevertheless take place, the Treaty of Accession provides that:

any person intending to import or market a pharmaceutical product covered by the above paragraph in a Member State where the product enjoys patent or supplementary protection shall demonstrate to the Competent Authorities in the application regarding that import that one month’s prior notification has been given to the holder or beneficiary of such protection.

402 Annex IV (2) of the Treaty of Accession.

403 The Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Slovakia, and Slovenia.

404 A specific mechanism requires parallel importers to notify patent holders of their intention to import a product 30 days prior to their making

an application. Patent holders will not have to wait until a parallel import is marketed before they can take legal action if the terms of the

derogation are infringed. The Association of the British Pharmaceutical Industry was one of the import notice's principal sponsors. Its campaign

won the support of the UK government, but only limited support from other member states and, at some stages, direct opposition from the

Commission.

405 A derogation was also inserted into the Treaty of Accession signed by the 10 new accession countries in Athens in April 2003 to limit

parallel trade for an indefinite period between accession countries and existing member states in situations where IP rights were not equal at the

time of a product’s launch. Under the derogation, patent or Supplementary Protection Certificate (SPC) holders of products patented or awarded

an SPC in existing member states before product patents were available in accession countries can prevent exports from new member states. The

effect of the derogation will erode over time as more and more products reach the end of their patent or SPC term in existing member states. The

derogation does not protect against the possibility of parallel trade from Western to Eastern Europe. Parallel importation is therefore a regulatory

issue for new Member States. The Pan-European Regulatory Forum produced a working paper in July 2002 informally discussing the regulatory

systems needed.


This safeguard measure clearly reflects the EU’s intent to provide full protection to 15 “old” Member States’ pharmaceutical industries. However, there is one circumstance which may amount to legal uncertainty and thus give rise to potential disputes, namely the diversity of conditions under which the Central and Eastern European states allowed retroactive pipeline-protection of already patented Community pharmaceuticals to be introduced. Although the candidate countries suggested during the negotiations that “the provisions in question are not applicable where the holder, or his beneficiary, of a patent or supplementary protection certificate in a present Member State could have filed for a product patent under the transitional provisions, but did not use this opportunity,” any reference to the pipeline protections has been omitted in the final wording of the Accession Treaty. Consequently, it will be entirely up to the Member States and the European Court of Justice to interpret the meaning of the words “at a time when such protection could not be obtained.” There were disparities as to the level of protection for pharmaceuticals within the acceding states which could not be remedied at the time of the accession negotiations. This is said to be why the European Commission insisted that candidate countries enact laws on SPCs and was unwilling to grant individual derogations on this minimum level of intellectual property protection. Without the special provisions in the accession treaties, parallel trade would almost certainly have occurred in large volume, due in large part to the generally lower prices for products in the new Member States (which, generally, have less affluent populations).406 As to the eight countries involved, the accession derogation amounts to an exception to the general rule under Community law on exhaustion of trademark rights, a doctrine that is one of the legal underpinnings of parallel trade. D. New Member States: contact information for drug regulatory authorities www.cadreac.org/agencies.htm Bulgaria Bulgarian Drug Agency

26 Yanko Sakazov blvd., 1504 Sofia, Bulgaria phone: +359 2 943 40 46 fax: +359 2 943 44 87 email: [email protected] www.bda.bg email director: [email protected]

Cyprus Pharmaceutical Services, Ministry of Health 1475 Lefkosia, Cyprus phone: +357 2 309601 fax: +357 2 305802 email: [email protected]

406 Disparities between the level of IP protection in accession countries and existing member states have long been a concern in EU enlargement.

Where these differences have been acute, derogations have given candidate countries time to bring IP protection into line with EU requirements.

Spain joined the EU and signed up to the European Patent Convention in 1986. In 1992, effective product patent protection was introduced,

following the expiry of a transitional period negotiated at the time of entry. A derogation was then brought in, effectively banning parallel exports

from Spain for three years (the research-based industry had campaigned for ten). Predictably, the expiry of the derogation coincided with a surge

in parallel exports from Spain to other member states with higher pharmaceutical prices. A similar situation also applied in Portugal, which joined

the EU at the same time as Spain.


Czech Republic

State Institute for Drug Control Srobarova 48, 100 41 Prague 10, Czech Republicphone: +420 2 6731 1153 fax: +420 2 7173 2377, +420 2 72739995 email: [email protected] www.sukl.cz email director: [email protected]

Estonia State Agency of Medicines 19 Ravila Str., 50411 Tartu, Estonia phone: +372 7 374 140 fax: +372 7 374 142 email: [email protected] www.sam.ee

Hungary National Institute of Pharmacy Zrinyi u.3, P.O.B. 450, Budapest V.H-1372, Hungary phone: +361 317 4044 fax: +361 317 1462 email: [email protected] www.ogyi.hu

Latvia State Agency of Medicines 15 Jersikas Str, Riga LV1003, Latvia phone: +371 7078400 fax: +371 7078428 email: [email protected] www.vza.gov.lv

Lithuania State Medicines Control Agency Traku 14, 2001 Vilnius, Lithuania phone:+370 5 2 61 40 40 fax:+370 5 2 63 92 64 email: [email protected] www.vvkt.lt

Poland Office of Medical Products, Medical Devices and Biocides 30/34 Chelmska Str, 00 725 Warsaw, Poland phone: +48 22 851 43 81 fax: +48 22 851 52 43 email: [email protected] www.il.waw.pl

Romania National Medicines Agency 48 Aviator Sanatescu Str, 71324 Bucharest, Romania phone: +401 224 1079 fax: +401 230 50 83 email: [email protected] email president: [email protected]


Slovak Republic

State Institute for Drug Control Kvetna 11, 82508 Bratislava, Slovak Republic phone/fax: +421 7 5556 4217 email director: [email protected] www.sukl.sk

Slovenia Agency for Medicinal Products Kersnikova 2, SI-1000 Ljubljana, Slovenia phone: +386 61 478 6240 fax: +386 61 478 6260 phone-director: +386 61 478 6243 email: [email protected] www.gov.si/mz/ur-zdrav/english/index_en.htm

Turkey General Directorate of Pharmaceuticals and Pharmacy Ilkiz Sok. ą 4, 06434 Sihhiye, Ankara, Turkey phone: +90 312 230 2794, +90 312 231 9120 fax: +90 312 230 1610 email: [email protected] www.iegm.gov.tr email director: [email protected]


APPENDIX EUROPEAN FEDERATION

OF PHARMACEUTICAL INDUSTRIES AND ASSOCIATIONS ________________________________

EFPIA CODE OF PRACTICE ON THE

PROMOTION OF MEDICINES

Adopted by EFPIA (2005; effective 31 December 2005) _________________________________

INTRODUCTION The European Federation of Pharmaceutical Industries and Associations (“EFPIA”) is

the representative body of the pharmaceutical industry in Europe. Its members are the national industry associations of over twenty pharmaceutical producing countries in Europe and over forty leading pharmaceutical companies. EFPIA’s primary mission is to promote the technological and economic development of the pharmaceutical industry in Europe and to assist in bringing to market medicinal products which improve human health worldwide.

EFPIA and its members are conscious of the importance of providing accurate, fair and objective information about medicinal products so that rational decisions can be made as to their use. With this in mind, EFPIA has adopted the EFPIA Code of Practice on the Promotion of Medicines (the “EFPIA Code”).407 The EFPIA Code reflects the requirements of Council Directive 2001/83/EC, as amended, relating to medicinal products for human use (the “Directive”). The EFPIA Code fits into the general framework established by the Directive, which recognises the role of voluntary control of advertising of medicinal products by self-regulatory bodies and recourse to such bodies when complaints arise.

EFPIA encourages competition among pharmaceutical companies. The EFPIA Code is not intended to restrain the promotion of medicinal products in a manner that is detrimental to fair competition. Instead, it seeks to ensure that pharmaceutical companies conduct such promotion in a truthful manner, avoiding deceptive practices and potential conflicts of interest with healthcare professionals, and in compliance with applicable laws and regulations. The EFPIA Code thereby aims to foster an environment where the general public can be confident that choices regarding their medicines are being made on the basis of the merits of each product and the healthcare needs of patients.

SCOPE OF THE EFPIA CODE OF PRACTICE The EFPIA Code covers the promotion to healthcare professionals of prescription-only

medicinal products. “Promotion”, as used in the EFPIA Code, includes any activity undertaken, organised or sponsored by a pharmaceutical company, or with its authority, which promotes the prescription, supply, sale, administration or consumption of its medicinal product(s). “Medicinal products”, as used in the EFPIA Code has the meaning set forth in Article 1 of the Directive. The EFPIA Code covers promotional activity and communication directed not only to doctors but Adopted in 1991 at the initiative of the European pharmaceutical industry, the EFPIA Code took effect on 1 January 1992. On 31 March 1992,

the Council of the European Communities adopted Council Directive 92/28/EEC to govern the advertising of medicinal products for human use

in European Community Member States. The EFPIA Code was therefore adapted in 1992 to make it fully consistent with Directive 92/28/EEC.

The revised version of the EFPIA Code took effect on 1 January 1993. In November 2001, Council Directive 2001/83/EC superseded Council

Directive 92/28/EEC. Council Directive 2001/83/EC was amended in 2004 by Council Directive 2004/27/EC. The EFPIA Code was further

revised in 2004 to adopt various improvements and to make it fully consistent with Directive 2001/83/EC, as amended. This revised version of

the EFPIA Code was adopted by EFPIA on 19 November 2004 and will take effect as early as possible but no later than 31 December 2005.


also those directed towards any member of the medical, dental, pharmacy or nursing professions or any other person who in the course of his or her professional activities may prescribe, purchase, supply or administer a medicine (each, a “healthcare professional”).

The EFPIA Code covers all methods of promotion including, but not limited to, oral and written promotional activities and communications, journal and direct mail advertising, the activities of medical sales representatives, internet and other electronic communications, the use of audio-visual systems such as films, video recordings, data storage services and the like, and the provision of samples, gifts and hospitality.

The EFPIA Code is not intended to restrain or regulate the provision of non-promotional medical, scientific and factual information; nor is it intended to restrain or regulate activities directed towards the general public which relate solely to non-prescription only medicines. EFPIA, however, acknowledges that some member associations address these activities in their respective national codes, and encourages other member associations to do so, where appropriate.

The EFPIA Code does not cover the following: - the labelling of medicinal products and accompanying package leaflets, which are subject to the provisions of Title V of the Directive; - correspondence, possibly accompanied by material of a non-promotional nature, needed to answer a specific question about a particular medicinal product; - factual, informative announcements and reference material relating, for example, to pack changes, adverse-reaction warnings as part of general precautions, trade catalogues and price lists, provided they include no product claims; - nonpromotional information relating to human health or diseases; - activities which relate solely to non-prescription only medicinal products; - nonpromotional, general information about companies (such as information directed to investors or to current/prospective employees), including financial data, descriptions of research and development programmes, and discussion of regulatory developments affecting the company and its products.

Attached to the EFPIA Code are: Annex A, the “Implementation and Procedure Rules” which set forth the framework for the implementation of the EFPIA Code, the processing of complaints and the initiation or administration of sanctions by member associations; and Annex B, the “Guidelines for Internet Websites Available to Healthcare Professionals, Patients and the Public in the EU” which provide guidance to member associations and companies with respect to the content of websites containing information on medicinal products subject to prescription.

APPLICABILITY OF CODES

The EFPIA Code sets out the minimum standards which EFPIA considers must apply. In a manner compatible with their respective national laws and regulations, member associations must, at a minimum, adopt in their national codes provisions no less rigorous than the provisions contained in the EFPIA Code. Member associations are encouraged to tailor their national codes to adapt to national conditions and to adopt additional provisions which extend further than the minimum standards included in the EFPIA Code.

EFPIA member companies must comply, and must ensure that their respective subsidiaries comply, with applicable codes (as defined below) and any laws and regulations to which they are subject. Member associations must establish adequate procedures for ensuring that their respective member companies comply with applicable codes.

Promotion which takes place within Europe must comply with applicable laws and regulations. In addition, promotion which takes place within Europe must also comply with each of the following “applicable codes”:

(a) (i) in the case of promotion that is undertaken, sponsored or organised by a company located within Europe, the member association national code of the country in which such


company is located; or (ii) in the case of promotion that is undertaken, sponsored or organised by a company located outside of Europe, the EFPIA Code; and

(b) the member association national code of the country in which the promotion takes place.

In the event of a conflict between the provisions of the applicable codes set forth above, the more restrictive of the conflicting provisions shall apply. For the avoidance of doubt, the term “company” as used in this EFPIA Code, shall mean any legal entity that organises or sponsors promotion which takes place within Europe, whether such entity be a parent company (e.g., the headquarters, principal office, or controlling company of a commercial enterprise), subsidiary company or any other form of enterprise or organisation.

To facilitate compliance with applicable codes, each member association must establish adequate procedures for ensuring that each of its member companies complies with the requirements of such member association’s national code and any other member association’s national code which may be applicable to its conduct, even if the member company does not belong to the other member association. Additionally, all international events (as defined in the EFPIA Code) must be notified to any relevant local subsidiary or, alternatively, local advice taken.

The spirit, as well as the letter of the provisions of the EFPIA Code must be complied with. For example, companies should apply consistent standards to their relationships with healthcare professionals, particularly with respect to gifts and hospitality. EFPIA also encourages compliance with the letter and spirit of the provisions of the International Federation of Pharmaceutical Manufacturers Associations (“IFPMA”) Code of Pharmaceutical Marketing Practices where applicable.

PROVISIONS OF THE EFPIA CODE OF PRACTICE

ARTICLE 1 MARKETING AUTHORISATION

Section 1.01. A medicinal product must not be promoted prior to the grant of the marketing authorisation allowing its sale or supply or outside of its approved indications.

Section 1.02. Promotion must be consistent with the particulars listed in the summary of product characteristics of the relevant medicinal product.

ARTICLE 2 INFORMATION TO BE MADE AVAILABLE

Section 2.01. Subject to applicable national laws and regulations, all promotional material must include the following information clearly and legibly:

(a) essential information consistent with the summary of product characteristics, specifying the date on which such essential information was generated or last revised;

(b) the supply classification of the product; and (c) when appropriate, the selling price or indicative price of the various presentations

and the conditions for reimbursement by social security bodies. Section 2.02. Subject to applicable national laws and regulations, where an

advertisement is intended only as a reminder, the requirements of Section 2.01 above need not be complied with, provided that the advertisement includes no more than the name of the medicinal product or its international non-proprietary name, where this exists, or the trademark.

ARTICLE 3 PROMOTION AND ITS SUBSTANTIATION

Section 3.01. Promotion must be accurate, balanced, fair, objective and sufficiently complete to enable the recipient to form his or her own opinion of the therapeutic value of the medicinal product concerned. It should be based on an up-to-date evaluation of all relevant evidence and reflect that evidence clearly. It must not mislead by distortion, exaggeration, undue emphasis, omission or in any other way.


Section 3.02. Promotion must be capable of substantiation which must be promptly provided in response to reasonable requests from healthcare professionals. In particular, promotional claims about side-effects must reflect available evidence or be capable of substantiation by clinical experience. Substantiation need not be provided, however, in relation to the validity of elements approved in the marketing authorisation.

Section 3.03. Promotion must encourage the rational use of medicinal products by presenting them objectively and without exaggerating their properties. Claims must not imply that a medicinal product, or an active ingredient, has some special merit, quality or property unless this can be substantiated.

Section 3.04. When promotion refers to published studies, clear references should be given.

Section 3.05. Any comparison made between different medicinal products must be based on relevant and comparable aspects of the products. Comparative advertising must not be misleading or disparaging.

Section 3.06. All artwork, including graphs, illustrations, photographs and tables taken from published studies included in promotional material should:

(a) clearly indicate the precise source(s) of the artwork; (b) be faithfully reproduced; except where adaptation or modification is required in order

to comply with any applicable code(s), in which case it must be clearly stated that the artwork has been adapted and/or modified.

Particular care must be taken to ensure that artwork included in promotion does not mislead about the nature of a medicine (for example whether it is appropriate for use in children) or mislead about a claim or comparison (for example by using incomplete or statistically irrelevant information or unusual scales).

Section 3.07. The word “safe” must never be used to describe a medicinal product without proper qualification.

Section 3.08. The word “new” must not be used to describe any product or presentation which has been generally available, or any therapeutic indication which has been generally promoted, for more than one year.

Section 3.09. It must not be stated that a product has no side-effects, toxic hazards or risks of addiction or dependency.

ARTICLE 4 USE OF QUOTATIONS IN PROMOTION

Section 4.01. Quotations from medical and scientific literature or from personal communications must be faithfully reproduced (except where adaptation or modification is required in order to comply with any applicable code(s), in which case it must be clearly stated that the quotation has been adapted and/or modified) and the precise sources identified.

ARTICLE 5 ACCEPTABILITY OF PROMOTION

Section 5.01. Companies must maintain high ethical standards at all times. Promotion must: (a) never be such as to bring discredit upon, or reduce confidence in, the pharmaceutical industry; (b) be of a nature which recognises the special nature of medicines and the professional standing of the recipient(s); and (c) not be likely to cause offence.

ARTICLE 6 DISTRIBUTION OF PROMOTION

Section 6.01. Promotion should only be directed at those whose need for, or interest in, the particular information can reasonably be assumed.

Section 6.02. Mailing lists must be kept up-to-date. Requests by healthcare professionals to be removed from promotional mailing lists must be complied with.


Section 6.03. Subject to applicable national laws and regulations, the use of faxes, e-mails, automated calling systems, text messages and other electronic data communications for promotion is prohibited except with the prior permission, or upon the request, of the recipient.

ARTICLE 7 TRANSPARENCY OF PROMOTION

Section 7.01. Promotion must not be disguised. Section 7.02. Clinical assessments, post-marketing surveillance and experience

programmes and post-authorisation studies must not be disguised promotion. Such assessments, programmes and studies must be conducted with a primarily scientific or educational purpose.

Section 7.03. Where a company pays for or otherwise secures or arranges the publication of promotional material in journals, such promotional material must not resemble independent editorial matter.

Section 7.04. Material relating to medicines and their uses, whether promotional in nature or not, which is sponsored by a company must clearly indicate that it has been sponsored by that company.

ARTICLE 8 NO ADVICE ON PERSONAL MEDICAL MATTERS

Section 8.01. In the case of requests from individual members of the general public for advice on personal medical matters, the enquirer should be advised to consult a healthcare professional.

ARTICLE 9 EVENTS AND HOSPITALITY

Section 9.01. All promotional, scientific or professional meetings, congresses, conferences, symposia, and other similar events (each, an “event”) organised or sponsored by a company must be held in an appropriate venue that is conducive to the main purpose of the event and may only offer hospitality when such hospitality is appropriate and otherwise complies with the provisions of any applicable code(s).

Section 9.02. No company may organise or sponsor an event that takes place outside its home country (an “international event”) unless:

(a) most of the invitees are from outside of its home country and, given the countries of origin of most of the invitees, it makes greater logistical sense to hold the event in another country; or

(b) given the location of the relevant resource or expertise that is the object or subject matter of the event, it makes greater logistical sense to hold the event in another country.

Section 9.03. Hospitality extended in connection with promotional, professional or scientific events shall be limited to travel, meals, accommodation and genuine registration fees.

Section 9.04. Hospitality may only be extended to persons who qualify as participants in their own right.

Section 9.05. All forms of hospitality offered to healthcare professionals shall be reasonable in level and strictly limited to the main purpose of the event. As a general rule, the hospitality provided must not exceed what healthcare professional recipients would normally be prepared to pay for themselves.

Section 9.06. Hospitality shall not include sponsoring or organising entertainment (e.g., sporting or leisure) events. Companies should avoid using venues that are renowned for their entertainment facilities.

Section 9.07. Companies must comply with guidance concerning the meaning of the term “reasonable”, as used in this Article 9, as provided in, or in connection with, any applicable code(s).


ARTICLE 10 GIFTS AND INDUCEMENTS

Section 10.01. No gift, pecuniary advantage or benefit in kind may be supplied, offered or promised to a healthcare professional as an inducement to prescribe, supply, sell or administer a medicinal product.

Section 10.02. Subject to Section 10.01 above, where medicinal products are being promoted to healthcare professionals, gifts, pecuniary advantages or benefits in kind may be supplied, offered or promised to such persons only if they are inexpensive and relevant to the practice of medicine or pharmacy.

Section 10.03. Except where they carry all the information stipulated in Section 2.01 above, gifts may bear no more than the name and logo of the company and the name of the medicinal product, or its international non-proprietary name, where this exists, or the trademark.

Section 10.04. Gifts for the personal benefit of healthcare professionals (such as tickets to entertainment events) should not be offered or provided.

Section 10.05. Companies must comply with guidance concerning the meaning of the term “inexpensive”, as used in this Article 10, as provided in, or in connection with, any applicable code(s).

ARTICLE 11 SPONSORSHIP OF HEALTHCARE PROFESSIONALS

Section 11.01. Companies must comply with criteria governing the selection and sponsorship of healthcare professionals to attend events as provided in, or in connection with, any applicable code(s). Funding must not be offered to compensate merely for the time spent by healthcare professionals in attending events. For the avoidance of doubt, this Section 11.01 is not intended to prohibit the extension of hospitality to healthcare professionals in accordance with Article 9 hereof.

ARTICLE 12 SAMPLES

Section 12.01. In accordance with national and/or Community laws and regulations, a limited number of free samples of a particular medicinal product may be supplied to healthcare professionals who are qualified to prescribe that medicinal product in order to familiarise them with the product; but only in response to a written request, signed and dated, from the recipient.

Section 12.02. Companies must have adequate systems of control and accountability for samples which they distribute and for all medicines handled by its representatives.

Section 12.03. Each sample shall be no larger than the smallest presentation on the market.

Section 12.04. Each sample must be marked ‘free medical sample– not for resale’ or words to that effect and must be accompanied by a copy of the summary of product characteristics.

Section 12.05. No samples of the following medicinal products may be supplied: (a) medicinal products which contain substances defined as psychotropic or narcotic by international convention, such as the United Nations Conventions of 1961 and 1971; and (b) any other medicinal products for which the supply of samples is inappropriate, as determined by Competent Authorities, from time to time.

ARTICLE 13 PHARMACEUTICAL COMPANY STAFF

Section 13.01. (a) Each company shall ensure that its sales representatives, including personnel retained by way of contract with third parties, and any other company representatives who call on healthcare professionals, pharmacies, hospitals or other healthcare facilities in connection with the promotion of medicinal products (each, a “medical sales representative”) are familiar with the relevant requirements of the applicable code(s), and all applicable laws and


regulations, and are adequately trained and have sufficient scientific knowledge to be able to provide precise and complete information about the medicinal products they promote.

(b) Medical sales representatives must comply with all relevant requirements of the applicable code(s), and all applicable laws and regulations, and companies are responsible for ensuring their compliance.

(c) Medical sales representatives must approach their duties responsibly and ethically. (d) During each visit, and subject to applicable laws and regulations, medical sales

representatives must give the persons visited, or have available for them, a summary of the product characteristics for each medicinal product they present.

(e) Medical sales representatives must transmit to the scientific service of their companies forthwith any information they receive in relation to the use of their company’s medicinal products, particularly reports of side effects.

(f) Medical sales representatives must ensure that the frequency, timing and duration of visits to healthcare professionals, pharmacies, hospitals or other healthcare facilities, together with the manner in which they are made, do not cause inconvenience.

(g) Medical sales representatives must not use any inducement or subterfuge to gain an interview. In an interview, or when seeking an appointment for an interview, medical sales representatives must, from the outset, take reasonable steps to ensure that they do not mislead as to their identity or that of the company they represent.

Section 13.02. (a) All company staff, and any personnel retained by way of contract with third parties, who are concerned with the preparation or approval of promotional material or activities must be fully conversant with the requirements of the applicable code(s) and relevant laws and regulations.

(b) Every company must establish a scientific service in charge of information about its medicinal products. This scientific service must include a doctor or, where appropriate, a pharmacist who will be responsible for approving any promotional material before release. Such person must certify that he or she has examined the final form of the promotional material and that in his or her belief it is in accordance with the requirements of the applicable code(s) and any applicable advertising laws and regulations, is consistent with the summary of product characteristics and is a fair and truthful presentation of the facts about the medicine.

(c) Each company must appoint at least one senior employee who shall be responsible for supervising the company and its subsidiaries to ensure that the standards of the applicable code(s) are met.

ARTICLE 14 SANCTIONS

Section 14.01. In the event that a breach is established pursuant to the procedures of its national code, each member association shall require from the offending company an immediate cessation of the offending activity and a signed undertaking by the company to prevent recurrence. Each member association shall also include in its national code provisions governing the imposition of sanctions for breaches of its national code. Sanctions should be proportionate to the nature of the infringement, have a deterrent effect and take account of repeated offences of a similar nature or patterns of different offences. A combination of publication and fines is generally considered to be the most effective sanction; however, each member association may use any other effective sanction to enforce its national code. Each member association should consider any applicable legal, regulatory or fiscal requirements which would affect the nature of sanctions which may be imposed. Where publication or fines are not permitted due to applicable legal, regulatory or fiscal requirements, member associations should impose the best alternative effective sanction.


ANNEX A IMPLEMENTATION AND PROCEDURE RULES

The Implementation and Procedure Rules set forth herein establish the framework for the implementation of the European Federation of Pharmaceutical Industries and Associations (“EFPIA”) Code of Practice on the Promotion of Medicines (the “EFPIA Code”), the processing of complaints and the initiation or administration of sanctions by member associations.

SECTION 1. Member Association Implementation. Each member association is required to:

(a) establish national procedures and structures to receive and process complaints, to determine sanctions and to publish appropriate details regarding the same including, at a minimum, a national body of the member association that is designated to handle complaints and consists of a non-industry chairman and, besides any industry members, membership from other stakeholders;

(b) ensure that its national code, together with its administrative procedures and other relevant information, are easily accessible through, at a minimum, publication of its national code on its website; and

(c) prepare, and provide to the EFPIA Code Committee (defined below), an annual report summarising the work undertaken by it in connection with the implementation, development and enforcement of its national code during the year.

SECTION 2. EFPIA Code of Practice Committee Implementation and Key Tasks. (a) The EFPIA Code of Practice Committee (the “EFPIA Code Committee”) shall assist

member associations to comply with their obligations under Section 1 above. (b) The EFPIA Code Committee will be composed of all the national code secretaries,

and chaired by the EFPIA Director General, assisted by one person from the EFPIA staff. (c) As a key part of its role of assisting member associations in their national code

compliance activities, the EFPIA Code Committee shall monitor the adoption of compliant national codes. The EFPIA Code Committee will not participate in the adjudication of any individual complaint under any national code.

(d) The EFPIA Code Committee shall publish an annual code report (the “EFPIA Code Report”) which summarises the work and operations which have taken place in connection with the implementation, development and enforcement of the various national codes during the applicable year, based on the country reports provided by the member associations pursuant to Section 1(c) above.

(e) On an annual basis, the EFPIA Code Committee shall (i) advise the EFPIA Board of its work and operations and the work and operations of the member associations, as summarised in the member association annual reports and (ii) review with the EFPIA Board any additional recommendations to improve the EFPIA Code with a view towards increasing transparency and openness within the pharmaceutical industry and among member associations and companies.

SECTION 3. Reception of Complaints. (a) Complaints may be lodged either with a member association or with EFPIA.

Adjudication of complaints shall be a matter solely for the national associations. (b) Complaints received by EFPIA shall be processed as follows:

(i)EFPIA will forward any complaints it receives (without considering their admissibility or commenting upon them) to the relevant member association(s).

(ii)EFPIA will send an acknowledgement of receipt to the complainant, indicating the relevant national association(s) to which the complaint has been sent for processing and decision. In addition, upon receipt by EFPIA of multiple external complaints (i.e. several complaints on the same or similar subjects lodged from outside the industry against several subsidiaries of a


single company), EFPIA will communicate these complaints to the national association either of the parent company or of the EU subsidiary designated by the parent company.

SECTION 4. Processing of Complaints and Sanctions by Member Associations. (a) Member associations shall ensure that industry and non-industry complaints are

processed in the same manner, without regard to who has made the complaint. (b) Complaints will be processed at the national level through the procedures and

structures established by the member associations pursuant to Section 1(a) above. Each member association’s national body shall take decisions and pronounce any sanctions on the basis of the national code in force in its country.

(c) Where a complaint fails to establish a prima facie case for a violation of an applicable code, such complaint shall be dismissed with respect to that national code. Member associations may also provide that any complaint which pursues an entirely or predominantly commercial interest shall be dismissed.

(d) Each member association should establish effective procedures for appeals against the initial decisions made by its national body. Such procedures and appeals should also take place at the national level.

(e) National committees shall ensure that any final decision taken in an individual case shall be published in its entirety or, where only selected details are published, in a level of detail that is linked to the seriousness and/or persistence of the breach as follows:

(i)in cases of a serious/repeated breach, the company name should be published together with details of the case;

(ii)in cases of a minor breach, publication of the details of the may exclude the company name; and

(iii)in cases where the relevant national body concludes that there is no breach, no publication of the case is necessary.

ANNEX B GUIDELINES FOR INTERNET WEBSITES AVAILABLE TO

HEALTHCARE PROFESSIONALS, PATIENTS AND THE PUBLIC IN THE EU The Guidelines for Internet Websites Available to Healthcare Professionals, Patients and

the Public in the EU set forth herein are intended as a supplement to the provisions of the European Federation of Pharmaceutical Industries and Associations Code of Practice on the Promotion of Medicines (the “EFPIA Code”). Member associations and companies may find it necessary to adapt these guidelines to meet their particular requirements or needs and are encouraged to adopt additional measures which extend further than the provisions included in these guidelines.

SECTION 5. Transparency Of Website Origin, Content And Purpose. Each website shall clearly identify:

(a) the identity and physical and electronic addresses of the sponsor(s) of the website; (b) the source(s) of all information included on the website, the date of publication of the

source(s) and the identity and credentials (including the date credentials were received) of all individual/institutional providers of information included on the website;

(c) the procedure followed in selecting the content included on the website; (d) the target audience of the website (e.g., healthcare professionals, patients and the

general public, or a combination thereof); and (e) the purpose or objective of the website. SECTION 6. Content Of Websites. (a) Information included in the website shall be regularly updated and shall clearly

display, for each page and/or item, as applicable, the most recent date as of which such information was up-dated.

(b) Examples of the information that may be included in a single website or in multiple websites are: (i) general information on the company; (ii) health education information; (iii)


information intended for healthcare professionals (as defined in the EFPIA Code), including any promotion; and (iv) non-promotional information intended for patients and the general public about specific medicinal products marketed by the company.

(i)General information on the company. Websites may contain information that would be of interest to investors, the news media and the general public, including financial data, descriptions of research and development programmes, discussion of regulatory developments affecting the company and its products, information for prospective employees, etc. The content of this information is not regulated by these guidelines or provisions of medicines advertising law.

(ii)Health education information. Websites may contain non-promotional health education information about the characteristics of diseases, methods of prevention and screening and treatments, as well as other information intended to promote public health. They may refer to medicinal products, provided that the discussion is balanced and accurate. Relevant information may be given about alternative treatments, including, where appropriate, surgery, diet, behavioural change and other interventions that do not require use of medicinal products. Websites containing health education information must always advise persons to consult a healthcare professional for further information.

(iii)Information for healthcare professionals. Any information on websites directed to healthcare professionals that constitutes promotion (as defined in the EFPIA Code) must comply with applicable code(s) (as defined in the EFPIA Code) and any other industry codes of practice governing the content and format of advertisement and promotion of medicinal products. Such information must be clearly identified as information for healthcare professionals, but need not be encrypted or otherwise restricted.

(iv)Non-promotional information for patients and the general public. Subject to any applicable national laws and regulations, websites may include non-promotional information for patients and the general public on products distributed by the company (including information on their indications, side-effects, interactions with other medicines, proper use, reports of clinical research, etc.), provided that such information is balanced, accurate and consistent with the approved summary of product characteristics. For each product that is discussed, the website must contain full, unedited copies of the current summary of product characteristics and patient leaflet. These documents should be posted in conjunction with other information about the products or be connected with that discussion by a prominent link advising the reader to consult them. In addition, the website may provide a link to the full, unedited copy of any public assessment report issued by the Committee for Medicinal Products for Human Use or a relevant national Competent Authority. Brand names should be accompanied by international non-proprietary names. The website may include links to other websites containing reliable information on medicinal products, including websites maintained by government authorities, medical research bodies, patient organisations, etc. The website must always advise persons to consult a healthcare professional for further information.

SECTION 7. E-mail Enquiries. A website may invite electronic mail communications from healthcare professionals and patients or the general public seeking further information regarding the company’s products or other matters (e.g., feedback regarding the website). The company may reply to such communications in the same manner as it would reply to enquiries received by post, telephone or other media. In communications with patients or members of the general public, discussion of personal medical matters must be avoided. If personal medical information is revealed, it must be held in confidence. Where appropriate, replies shall recommend that a healthcare professional be consulted for further information.

SECTION 8. Links From Other Websites. Links may be established to a company-sponsored website from websites sponsored by other persons, but companies should not establish links from websites designed for the general public to company-sponsored websites that are designed for healthcare professionals. In the same manner, links may be established to


separate websites, including websites sponsored by the company or by other persons. Links should ordinarily be made to the home page of a website or otherwise managed so that the reader is aware of the identity of the website.

SECTION 9. Website Addresses In Packaging. Subject to any applicable national laws and regulations, uniform resource locators (URLs) of company-sponsored websites that comply with these guidelines may be included in packaging of medicinal products.

SECTION 10. Scientific Review. Companies should ensure that scientific and medical information prepared by them for inclusion in their websites is reviewed for accuracy and compliance with the applicable code(s). The scientific service established within the company pursuant to those provisions of the applicable code that adopt Section 13.02 of the EFPIA Code may perform this function, or it may be entrusted to other appropriately qualified persons.