EU PHARMACEUTICAL REVIEW
2005 heralded a number of significant changes for the European pharmaceutical industry, thanks in large part to three new pieces of European Union legislation that completely overhauled the existing pharmaceutical regulatory framework. As a result, 2006 promises to be an interesting – albeit challenging – year for many pharmaceutical companies as they come to terms with the changes and their impact on the industry.

The deadline for Member States to implement the new legislation was 30 October 2005 for EU Directive 2004/27/EC¹, and 20 November 2005 for Regulation (EC) No 726/2004². As such, the end of 2005 prompted a flurry of activity both at national level and EU level, with Member States introducing new or amending legislation, and the European Commission (EC) and the European Medicines Agency (EMEA) releasing a number of guidance documents.

MAJOR CHANGES
Key changes introduced by the legislation include the following:

1. Harmonisation of the period of data and marketing protection afforded to medicinal products across the EU to a period of between eight and 11 years (the so-called “8+2+1” provision).
2. The introduction of a “Bolar” type provision that enables generic companies to conduct, without liability for infringement, certain studies and trials to support abridged marketing authorisation applications before the expiry of any relevant patent or supplementary protection certificates (SPCs).
3. The introduction of a European reference product for abridged marketing authorisations for generic medicines.
4. The introduction of a “sunset clause” invalidating the marketing authorisation of a product if it is not placed on the market within three years of grant of authorisation, or for a continuous three-year period.
5. New and improved patient information on packaging.

1. THE 8+2+1 DATA PROTECTION PERIOD
The 8 + 2 protection period
Under the old legislation, medicinal products were afforded either a six or 10-year data exclusivity and marketing protection period, depending on which EU country the application was made in. Directive 2004/27/EC (the “Directive”) harmonises the protection period, and introduces a new marketing and data exclusivity period for medicinal products that are granted a marketing authorisation in the EU after 30 October 2005.

Under the new legislation, generic applicants can apply using the “abridged” application procedure for a generic version of a new medicinal product once the original product has been authorised for eight years, and may rely on the dossier of clinical trials and pre-clinical tests submitted with the original application. In addition, for the purposes of generic applications, the original product will be deemed to be the very first marketing authorisation of an active substance. Thus “line extension” products, where the active substance has subsequently been authorised in a form that differs from the original product, will not be afforded the same protection.

Regardless of when the abridged application is granted under the new procedure, a generic version of a medicinal product may not be placed on the market until 10 years after the reference product was first authorised.

The + 1 protection period
Additionally, holders of original marketing authorisations can extend the period of marketing protection for an further year
if, during the first eight years of authorisation of the original product, the marketing authorisation holder obtains an authorisation for one or more new therapeutic indications that are deemed to be of “significant clinical benefit” when compared to existing therapies. “Significant clinical benefit” means that no product containing the same active substance has ever previously been authorised in the relevant indication and/or is extended to new categories of patients.
It is important to note that the 8+2+1 protection period will only apply to applicants using the abridged application procedure. It is still open to generic manufacturers to obtain an authorisation using the full marketing authorisation procedure as has, until now, been required for generic versions of biological products. The Directive, supported by guidelines, now provides a mechanism for applications for so called “biosimilar” products.

2. THE “BOLAR” PROVISION
Except where, as in the US following Roche Products Inc v Bolar Pharmaceutical Co (1984), specific legislative exception exists, generic pharmaceutical companies were not allowed to conduct tests on a patented substance prior to patent expiry. This prevented generic pharmaceutical companies from making a generic application until after patent expiry. The Directive introduces a new provision that effectively mirrors the US position and allows generic applicants to conduct certain necessary studies and trials with a view to submitting an abridged application.

Although the Directive states that such tests and studies “shall not be regarded as contrary to patent rights of to supplementary protection certifications”, implementing this change into national law will require many Member States to also amend their patent laws. This presents a risk in that each Member State may interpret and implement the provision differently, and it is likely that the scope of the Bolar provision will be defined by rulings of the European Court of Justice in years to come.
The UK is proposing an amendment that refers expressly to the provision in the Directive, and it is hoped that this will avoid confusion by referring expressly to the requirements of the Directive.

3. A EUROPEAN REFERENCE PRODUCT FOR ABRIDGED APPLICATIONS
One further amendment aimed at facilitating abridged applications is the introduction of the concept of a European-wide reference product for abridged applications. The Directive introduces a definition of a “reference medicinal product” that encompasses any product authorised in accordance with the Directive. As a result of this change, generic applications will now be able to rely on the dossiers of original or reference medicinal products that have been submitted in any Member State and not just the State that had granted the original authorisation.

4. THE “SUNSET” CLAUSE
The Directive and Regulation 726/2004 also introduces a so-called “sunset” clause. This means that marketing authorisations of products that have not been placed on the market within three years of grant or have not been marketed for three consecutive years following authorisation will automatically expire. Previously, medicinal products were initially authorised for five years, with an additional five-year renewable period.

6. NEW AND IMPROVED PATIENT INFORMATION ON PACKAGING
The Directive also introduces a number of measures aimed at protecting patients and providing them with better access to information about medicinal products. Changes include requiring the majority of products to be labelled with their name in Braille, large-print patient information leaflets (PILs), or PILs available on the internet, on audio tapes or on CD-rom. Additionally, patients are to be given direct input into the design and content of PILs by the introduction of user testing requirements. In the UK, the MHRA has indicated that these requirements will apply to all products authorised after 30 October 2005.

CONCLUSION
The above-mentioned points highlight some, but by no means all, of the changes introduced by the legislation. However, as these changes illustrate, the new legislation is bound to have a far-reaching impact on the pharmaceutical industry, both from the perspective of pharmaceutical companies and patients.
It is still too early to gauge whether or not all the amendments will transition smoothly into easy-to-follow practices and procedures, but the issue of a growing volume of guidance by the EC and the EMEA will assist both the national regulatory agencies and pharmaceutical companies to come to grips with the changes.

1 EU Directive 2004/27/EC on the Community Code relating to medicinal products for human use, amending the Community Code on Medicines for Human Use, Directive 2001/83/EC.

2 EU Regulation (EC) No 726/2004 laying down Community procedures for the authorisation and supervision of medicinal products for human use and veterinary use and establishing a European Medicines Agency.