European Union: Review of EU Legislation From Directive 2001/83/EC To Date

Since the enactment of Directive 2001/83/EC ("Community Code Directive") the European Community has conducted a comprehensive review of its legislation on medicinal products. It is not only that the Community since then has adopted Directive 2004/27/EC amending the Community Code.¹ In fact, several other acts of legislation have been issued. As far as these acts have to be implemented, the Member States are currently working on the transposition. In particular, the implementation of the "EU Pharmaceutical Reform 2004" is under way in most Member States. Other directly applicable EU legislation has come into force or will come into force this year.

This article aims to help the reader to keep track of the miscellaneous European legislation issued since Directive 2001/83/EC and gives an overview on the most important changes to the European law on medicinal products for human use.

Beginning with Directive 65/65/EEC the European Community adopted a highly sophisticated system of legal provisions dealing with medicinal products. The system mainly was formed by a conglomeration of Directives, each dealing with aspects of the law on medicinal products. For example, in addition to Directive 65/65/EEC there co-existed directives specifically dealing with radiopharmaceuticals, homeopathic medicinal products, immunological medicinal products and so forth. Moreover, different legal aspects of medicinal products like classification, labelling and promotion were subject to separate directives. Finally, each of these different directives – due to scientific, technical and judicial progress – underwent several revisions and amendments. As a result the complexity and diversity of the implementation and application of EU legislation within the Member States was high.

With two steps, the European Community has pursued its policy to reform the application of European law on medicinal products as well as to further harmonise legal provisions.

In November 2001, European Parliament and the Council adopted Directive 2001/83/EC on the Community Code relating to medicinal products for human use. The so-called "Community Code Directive" combined in one legal act nearly all aspects of European law on medicinal products. This was an act of codification as the contents of all previous directives were fully preserved and amendments were only made as far as required by the merger. The Community Code Directive superseded former directives.

As a result, there remained two main pieces of legislation regulating medicinal products: the Community Code Directive and Regulation 2309/93/EEC of 22 July 1993 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Agency for the Evaluation of Medicinal Products ("Community Procedures Regulation"). The former applies to all medicinal products which are to be authorised by national authorisation or mutual recognition procedure, whereas the latter deals with products subject to the centralised authorisation procedure.²

In a second step, the European Community revised two legislative acts: Directive 2001/83/EC on products subject to national authorisation and mutual recognition was amended by new Directive 2004/27/EC ("Revised Community Code Directive")³ and the former Regulation 2309/93/EEC of 22 July 1993 on centrally authorised product was replaced by Regulation 726/2004/EC ("Revised Community Procedures Regulation")⁴.

In addition several other laws were issued, such as Directive 2002/98/EC (re human blood) and Directive 2003/63/EC (re dossier harmonisation) as well as Commission Regulations (EC) 1084/2004 and (EC) 1085/2003 (re variations) and directives dealing with human tissues and herbal medicinal products.

The following gives an overview of some of this European legislation on medicinal products for human use. The changes in legislation on human tissues, herbal medicinal products and medicinal products for veterinary use will not be discussed.

Proprietary medicinal products derived from human blood or plasma are subject to the Community Code. For blood and blood components as a starting material of such products the Code provides specific provisions on the safety and traceability. However, Article 3 no. 6 of the Community Code Directive excludes whole blood, plasma⁵ and blood cells of human origin from the Code.

As far as they are intended for transfusion and not processed as such, the quality and safety of blood products have not previously been subject to any binding Community legislation. This gap is to be filled by Directive 2002/98/EC ("Human Blood Directive")⁶. It contains provisions to ensure that blood and its components are of comparable quality and safety throughout the blood transfusion chain in all Member States. The Directive applies to the collection and testing of human blood and blood components, whatever their intended purpose, and to their processing, storage, and distribution when intended for transfusion and not as a starting material for proprietary medicinal products.

The Human Blood Directive calls for the establishment of specific technical requirements which have been set under Commission Directive 2004/33/EC. It establishes detailed rules on traceability requirements, donor information rights, suitability of donors and adverse events reporting. Moreover requirements for screening, storage, transport and distribution of donated blood and blood components, are specifically stipulated as well as specifications for blood establishments. The date for transposition into national law of both Directives is 8 February, 2005.

The Human Blood Directive has implications for companies which run blood establishments to satisfy their requirements for blood and blood components: blood establishments have to be authorised by competent authorities and have to abide by requirements addressing personnel, safety and quality system, documentation, traceability, and adverse events reporting in connection with the collection and the testing of blood and its components. The companies must comply with specific documentation requirements as well as a 30-year document retention period.

In order to take account of scientific and technical progress and changes to European legislation the Commission, by Art. 120 Community Code Directive, is entitled to improve the requirements relating to the marketing authorisation application dossier as laid down in Annex I of the Community Code Directive. The Commission did so by issuing Directive 2003/63/EC ("Dossier Harmonisation Directive")⁷ on 25 June 2003.

The Directive implements the decisions of the Fifth International Conference on Harmonisation (ICH) of 2000 on a harmonised format and technology for regulatory submissions (Common Technical Document – CTD) into European law.

It aims to facilitate the assessment and the better use of parts of the dossier which are common for some groups of medicinal products. Some groups of medicinal products are produced by using the same basic material. As a result, a substantial part of the marketing authorisation dossier may be common to a great number of other dossiers. For example, this applies to plasma-derived medicinal products which may contain the same plasma component. In the light of the Human Blood Directive, a separate document called a plasma master file has to be submitted for the regulatory assessment of blood plasma as a component of the plasma product. Independently of the product-related application dossiers, the plasma master file (PMF) is to be assessed at EU level and EU compliance is confirmed through granting of a certificate of compliance. In a second step, the common assessment of the finished plasma-derived medicinal product containing a modified part of the certified PMF has to be conducted by the competent authority to grant the market authorisation. The certified compliance with Community legislation for each PMF, must be taken into account by any national competent authority, preventing them from carrying out any subsequent reassessment.

Similar provisions are issued for vaccines where a vaccine antigen master file (VAMF) for each antigen component is required to be included in the application dossier for a vaccine product. The Dossier Harmonisation Directive also makes special provision for gene therapy and cell therapy.

The new format is applicable since 31 October 2003 to all market authorisation applications for medicinal products, irrespective of the procedure being fulfilled.⁸

Due to the abovementioned changes of the dossier requirements in the Community Code Directive and in order to simplify the procedure for varying the terms of a marketing authorisation the Commission on 3 June 2003 issued the Regulations (EC) 1084/2003⁹ and (EC) 1085/2003 (Revised Variation Regulation(s)¹⁰.

Regulation (EC) 1084/2003 is applicable to medicinal products subject to national authorisation procedures, whereas (EC) 1085/2003 covers centrally authorised products. The Revised Variation Regulations supersede the previous regulations dealing with variations of market authorisations (former Regulations (EC) No 541/95 and (EC) No 542/95).

The main difference between the former and new regulations is the introduction of notifications: certain minor changes which do not affect the quality, safety or efficacy of the product, may be introduced by the market authorisation holder only by notification. They will not need to be evaluated by the competent authority of the Reference Member State or the European Medicines Agency ("EMEA"). The competent authority is only required to acknowledge the validity of the notification within 14 days of the receipt of the notification. However, the submitted documentation of other minor variations are still to be evaluated.

Variations to the abovementioned plasma/vaccines antigen master files will also be subject to Regulation (EC) 1085/2003.

The Regulations were applicable from 1 October 2003.

In March 2004, the European Council adopted a package of Community legislation, updating the existing rules on medicinal products.11 The package contains the Revised Community Code Directive (Directive (EC) 2004/27) and Revised Community Procedures Regulation (Regulation 726/2004/EC). The revised provisions should have effect – directly or through implementation by the Member States – from October and November 2004, respectively.

The main changes in the revised provisions are:

The Revised Community Code Directive provides a new definition of medicinal product, stating that a medicinal product is a substance 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 alternative requirement of a pharmacological, immunological or metabolic action covers several novel medicinal products as well as distinguishes between pharmaceuticals and medical devices and foodstuffs.

In addition, the new Art. 2 para. 2 Community Code Directive declares borderline products, in respect of which there has previously been doubt as to their classification, to be subject to the strict pharmaceutical legislation.

As the centralised procedure has shown its effectiveness in recent years it will be opened to more types of new medicines. In addition to biotechnological products which already qualified under the Community Procedures Regulation for the centralised procedure it will also be mandatory for all new active substances for the treatment of AIDS, cancer, diabetes, neurodegenerative disorders as well as all orphan diseases subject to Regulation (EC) 141/2000. This will come into effect in November 2005. With effect from 20 May 2008 there will be a further expansion to cover medicines for autoimmune diseases and viral diseases.

Moreover the centralised procedure can be used on an optional basis where the applicant basically shows that the product contains a new active substance or is a significant innovation and a single procedure adds value for patients.

Generic medicinal products of which the reference product is subject to the centralised procedure may – under certain conditions – be authorised either under the centralised or the national procedure at the applicant’s choice.

According to the legislator, the Revision 2004 aims to facilitate faster patients’ access to new medicinal products. Therefore, the time period to obtain market authorisation is shortened by cutting some deadlines in the various steps in both the centralised procedure and the national procedure. Products may also be granted a conditional (centralised or national) market authorisation, provided that there is an expected important health benefit for patients and the company commits to carrying out additional monitoring and clinical studies.

Moreover, the new provisions for the first time codify "compassionate use". Compassionate use shall mean making a medicinal product available for compassionate reasons to a group of patients with a chronically or seriously debilitating or life-threatening disease if no other satisfactory treatment by an authorised medicinal product is available.

The former time limits of the market authorisation’s validity have been abolished. Once a market authorisation is granted for the first time, it is valid for five years. Then it has to be renewed on the basis of a re-evaluation. Once renewed, the marketing authorisation shall be valid for an unlimited period, unless the competent authority decides, on justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal.

On the other hand, an authorisation ceases to be valid if it is not followed by the actual placing on the market of the authorised product within three years of its granting or – once properly placed on the market – is withdrawn from the market for a period of three consecutive years.

As regards the new "8+2+1" formula for the Generics harmonised data exclusivity rules see Our forthcoming article,"The Syfait Case - observations on Advocate General Jacob's opinion"..

In order to safeguard public health in light of the abovementioned increased market access for medicinal products pharmacovigilance has been reinforced by the reform. From now on an applicant has to ensure within his application documents that he will be able to meet certain pharmacovigilance obligations and, where appropriate, will introduce a risk-management system for the product.

Moreover, the European Community enables the patient to evaluate risks and benefits of authorised products by improving access to the results of the pharmaceutical decision making process, assessment reports and the summaries of product characteristics.

In addition to these amendments the "EU Pharmaceutical Reform 2004" also brought comprehensive changes to the EMEA including changing its name to the European Medicines Agency. In addition the form and composition of its Management Board and its scientific committees have been revised and its role as a scientific adviser has been strengthened. Moreover, the EMEA is empowered to request the Commission to impose financial penalties on the holders of central marketing authorisations if they fail to observe certain obligations laid down in connection with the authorisations.

As far as the abovementioned European legislation requires implementation in the national jurisdictions, several Member States have issued draft bills. The German Ministry of Health for example very recently issued its first tentative draft bill on the 14th Amendment of the German Drug Act.

1. See our February 2004 Newsletter - http://www.lovells.com/control/PDFLoader/pubIssueId/2514

2. Besides these main legislative acts there were a few other directives directly or indirectly dealing with medicinal products, for example, Directive 2001/20/EC 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 ("Clinical Trials Directive").

3. Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use, Official Journal L 136 , 30/04/2004 P. 34 – 57.

4. 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, Official Journal L 136 , 30/04/2004 P. 1 – 33. 5. With the enforcement of the Revised Community Code Directive (Directive 2004/27/EC) plasma will only be excluded from the scope of the Code as far as it is not prepared by a method involving a medicinal process. 6. 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 and amending Directive 2001/83/EC, Official Journal L 33, 08/02/2003 P. 30 – 40.

7. Commission Directive 2003/63/EC of 25 June 2003 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use, Official Journal L 159 , 27/06/2003 P. 46 – 94.

8. As regards medicinal products subject to the centralised procedure see Art. 6 Revised Community Procedures Regulation.

9. 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, 27/06/2003 P. 1 – 23.

10. 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, 27/06/2003 P. 24 – 45.

11. See our February 2004 Newsletter - - http://www.lovells.com/control/PDFLoader/pubIssueId/2514

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.