Germany: Reform of European Pharmaceutical Legislation
An Overview of Recent Changes in the Licensing Procedure for Medicinal Products

It was only recently that the process of reforming European pharmaceutical legislation within the framework of European Commission proposal ‘Pharma Review 2001’ was finally completed, with the adoption of a pharmaceutical legislation package comprising a new Regulation (EC) No. 726/2004 and two amending Directives 2004/27/EC and 2004/28/EC by the European Parliament and the Council of the European Union on 17 December 2003 and 11 March 2004, respectively.

The main objective of this reform is to improve the current authorisation procedure in a way that strengthens the availability of innovative medicinal products and, at the same time, ensures the right balance between the competitiveness of the pharmaceutical industry, the completion of the single market, and a high level of public health within the enlarged European Union. We will look at the individual pieces of legislation ultimately agreed upon to reach this goal in practice in the course of this article. At the beginning, however, we will briefly introduce the different marketing authorisation procedures for medicinal products available in Europe to provide the reader with a better understanding of the regulatory framework in which the recent changes took place.

Within the European Union there are three different forms of marketing authorisation procedures —the Centralised Procedure, the Mutual Recognition Procedure and the independent National Procedures. The latter two are also referred to as the Decentralised Procedures.

The Centralised Procedure is currently compulsory for all medicinal products that satisfy the criteria listed in Part A of the Annex to Regulation (EEC) No. 2309/93, i.e., products developed by certain biotechnological processes, and optional for all medicinal products that come under one of the criteria referred to in Part B of that Annex, i.e., certain other innovative products. In both cases, applications for marketing authorisation must be submitted to the European Agency for the Evaluation of Medicinal Products (EMEA). Following the Agency’s scientific evaluation and positive opinion, marketing authorisations will generally be granted by the European Commission after further consultation with the Member States through the relevant standing committee. Marketing authorisations granted under the Centralised Procedure are valid throughout the Community and confer the same rights and obligations in each of the Member States as a national marketing authorisation granted in a particular Member State.

All medicinal products for which the Centralised Procedure is not mandatory may be eligible for national marketing authorisations in one or more of the Member States. If medicinal products are to be authorised in more than one Member State, the marketing authorisations will generally be granted in the Mutual Recognition Procedure. This means that one Member State acts as Reference Member State which—after carrying out a complete assessment of the application—will issue the national marketing authorisation for that Member State. All other Member States in which the medicinal product are to be marketed are referred to as Concerned Member States, all of which will base their respective national marketing authorisation on the mutual recognition of the national marketing authorisation granted by the Reference Member State. That said, the independent National Procedures are generally limited to cases where either a complete review is being undertaken by the Reference Member State in the initial phase of the Mutual Recognition Procedure, or marketing authorisations are sought for one particular Member State only.

Under Article 71 of Regulation (EEC) No. 2309/93, which set up the Centralised Procedure for certain medicinal products for human and veterinary use and established the EMEA, the European Commission was asked to report within 6 years after the Regulation’s entry into force in 1995 on the experience of using this new form of centralised marketing authorisation procedure. In its report, the Commission concluded that, whilst the general principle and basic structure of the Centralised and Decentralised Procedure should be maintained, there was nevertheless a need to improve and fine-tune certain details regarding the operation of these authorisation procedures in practice, such as:

• access to the Centralised Procedure;
• availability of a fast track procedure;
• regulatory data protection; and 
• compassionate use.

The new Regulation and the two amending Directives reflect these initial recommendations by the European Commission, as this article explains.

The new legislation extends the current scope of the compulsory Centralised Procedure. Effective 20 November 2005, the Centralised Procedure will become mandatory for all medicinal products for human use containing a new active substance and indicated for the treatment of AIDS, cancer, neurodegenerative disorders and diabetes. It will also apply to medicinal products designated as orphan medicinal products pursuant to Regulation (EC) No. 141/2000. Following an initiative of the European Parliament, with effect from 20 May 2008, the compulsory Centralised Procedure will also cover medicinal products for the treatment of auto-immune diseases and other immune dysfunctions as well as viral diseases.

Marketing authorisations in the optional Centralised Procedure may be granted:

1. for medicinal products containing new active substances not authorised in the EU on the date of entry into force of the new Regulation;
2. for medicinal products which the applicants show constitute a significant therapeutic, scientific or technical innovation or that the granting of authorisation in accordance with the new Regulation is in the interests of patients or animal health at the EU level; or
3. for immunological veterinary medicinal products for the treatment of animal diseases that are subject to EU prophylactic measures.

To make certain human and veterinary medicinal products which are of major interest from the viewpoint of public or animal health and in particular because of their therapeutic innovation, available within the shortest possible time, the new Regulation provides for an "Accelerated Assessment Procedure". Once the Committee of the EMEA reviewing the application has accepted the applicant’s request for such a procedure, the time limit for the Committee to deliver its opinion is reduced from 210 days after receipt of a valid application to just 150 days.

Furthermore, the new Regulation enables Member States to make certain medicinal products available on a compassionate use basis before a marketing authorisation has been granted for them, as long as they qualify for the Centralised Procedure and, if no application for marketing authorisation has already been submitted, as long as they are at least undergoing clinical trials. Availability is limited to patients with a chronically or seriously debilitating or life-threatening disease for which satisfactory treatment with an authorised medicinal product is unavailable.

One of the most debated issues of the reform was the protection of the pharmacological, toxicological and clinical data contained in the dossier of an original medicinal product against references by generic competitors.

Under the current regime, all medicinal products authorised under the Centralised Procedure benefit from a 10-year period of exclusivity. The same protection period is conferred upon medicinal products authorised in Belgium, Germany, France, Italy, the Netherlands, Sweden, the United Kingdom and Luxembourg, whereas Austria, Denmark, Finland, Greece, Ireland, Iceland, Norway, Portugal and Spain only grant data exclusivity for a period of 6 years.

Despite strong concerns being voiced from the 10 new Member States, who expect a huge negative impact on their national healthcare budgets due to the later availability of generic medicinal products, the new legislation implements a uniform extended period of regulatory data protection in all EU countries. Medicinal products authorised under the Centralised Procedure (both in compulsory and optional) as well as the Decentralised Procedure will now enjoy a period of data protection of 8 years and an additional 2 years of marketing protection. This means that generic manufacturers can submit an application for marketing authorisation 8 years after an originator product is first put on the market, but that the generic product cannot be marketed for a further 2 years after the end of that period. If one or more new therapeutic indications of significant clinical benefit are authorised within the first 8 years of data protection then the protection may be extended by one additional year, up to total of 11 years. For certain veterinary medicinal products, this protection can even add up to an overall period of 13 years.

At present, the initial term of validity of a marketing authorisation granted under the Centralised Procedure and in the Decentralised Procedure is 5 years. Whilst this situation will basically not change under the new legislation, a new regime will come into operation for renewals of initial authorisations.

In future, upon expiry of the initial five-year term, the marketing authorisation may be renewed upon request of the marketing authorisation holder, for an generally unlimited period of time. Requests for renewals have to be accompanied by supporting data such as a consolidated version of the file in respect of quality, safety and efficacy, and have to be submitted to the competent authority at least 6 months before the initial marketing authorisation ceases to be valid.

Once a marketing authorisation has been granted, the holder will now have to make use of it because any authorisation not followed by the actual placing on the market of the authorised product within 3 years of its granting will cease to be valid. This will equally apply to authorised products were previously marketed in the authorising Member State but which have not been present on the market for three consecutive years. To this end, the marketing authorisation holder must inform the competent authority of the dates of actual marketing of the medicinal product in the Member States, taking into account the various presentations authorised. Further notification has to be made if the product ceases to be placed on the market, either temporarily or permanently.

As a result of Regulation (EC) No 726/2004 entering into force, the name of the European Agency for the Evaluation of Medicinal Products will be changed to the European Medicines Agency. In addition, the tasks of the EMEA Scientific Committees have been redefined and now reflect to a greater extent a modern, service-oriented approach. In particular, future applicants for marketing authorisations will be able to obtain scientific advice from the Scientific Committees more generally and in greater depth. Further measures have been put in place to allow the development of advice, particularly for small and medium-sized companies.

As mentioned above, major parts of the new Regulation will come into force on 20 November 2005. By 30 October 2005, Member States must have implemented Directives 2004/27/EC and 2004/28/EC into their national laws.

Given the particularly crucial issue of regulatory data protection, this time schedule may make it advisable for some manufacturers of innovative medicinal products to reconsider their timing strategies and so delay application for a new medicinal product to enjoy greater protection. This is because the new standards only apply to those medicinal products for which application for marketing authorisation is submitted after the date of entry into force of the new legislation. 

Copyright © 2007, Mayer, Brown, Rowe & Maw LLP. and/or Mayer Brown International LLP. This Mayer Brown article provides information and comments on legal issues and developments of interest. The foregoing is not a comprehensive treatment of the subject matter covered and is not intended to provide legal advice. Readers should seek specific legal advice before taking any action with respect to the matters discussed herein.

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