New legislation on pharmaceuticals that was published in April includes many important changes in the EU legislative framework for regulation of product quality, safety and efficacy, write Linda Horton, Jacqueline Mailly and Klaus Goecke

New EU rules on pharmaceuticals were published on 30 April 2004.

The legislation covers the authorisation and regulation of human and veterinary medicines, provides for an increased role for the re-named European Medicines Agency (EMA), and aims to speed product approvals.

The rules also simplify authorisation procedures and improve transparency without changing the basic principles of the existing system in which a centralised authorisation procedure exists alongside a decentralised procedure based on mutual recognition.

The package consists of:

* Regulation No.

726/2004 on authorisation and supervision of medicinal products for human and veterinary use and on the EMA (replacing regulation 2309/93 that set up the European Agency for the Evaluation of Medicinal Products, or EMEA);

* Directive 2004/27/EC on the community code relating to medicinal products for human use (amending Directive 2001/83/EC);

* Directive 2004/28/EC on the community code relating to medicinal products for veterinary use (amending Directive 2001/82/EC);

* Directive 2004/24/EC on traditional herbal medicinal products (amending the community code Directive 2001/83/EC).

The three directives entered into force on 30 April 2004 (the date of official publication).

Member states have until 30 October 2005 to implement these measures in national law.

Under the new regulation, assessment of new medicines by the EMA will be quicker, and that will enable new medicinal products to be placed on the community market faster.

The authorisation procedure will be changed so that more categories of medicine will be obliged to use the centralised procedure instead of seeking authorisation in first a 'reference member state' then in other member states through the decentralised mutual recognition system.

Currently, the centralised procedure must be used for the authorisation of biotechnology products.

Under the new rules, the centralised procedure becomes mandatory for medicines to treat AIDS, cancer, diabetes, neurodegenerative disorders and orphan diseases and, after four years, this procedure will be further extended to cover medicines for auto-immune diseases and viral diseases.

A general review clause will enable further extension of the EMA exclusive jurisdiction to medicines for other diseases.

A fast-track registration procedure for products of significant therapeutic interest has been introduced, allowing these products to be assessed and authorised in an expedited way.

In addition, the possibility of a conditional marketing authorisation has been introduced, which allows for a one-year authorisation to be granted.

This will be reliant on there being an important expected health benefit for the patients concerned and on the company agreeing to carry out additional monitoring and clinical studies, which will be reviewed at the end of this period.

Subject to additional provisions, a European-wide system to make medicinal products available in advance of authorisation for a 'compassionate use' will also be possible.

One of the biggest changes brought by the new legislation is in the area of regulatory data exclusivity, which will now be harmonised across the 25 members of the expanded EU in a compromise policy called '8+2+I'.

Data submitted by companies for the approval of medicines will be protected for 10 years across the EU from the time of first authorisation.

Therefore, it will not be possible to market generics until ten years have elapsed.

This can be extended by another year if a further innovative indication for the medicine is authorised.

However, it is possible for a generic company to submit an abridged application, seeking to rely on the innovator's data, eight years after the date of the marketing authorisation of the innovative product.

This improves the current situation in many countries in the expanded EU that currently only offer six (and in some cases three) years' protection.

The aim of this change is to allow pharmaceutical companies more time to recoup investments made in research, before a generic product may be authorised, and thereby encourage innovation.

The new 8+2+1 formula applies only to medicines approved after the legislation's effective date.

Regarding the generic pharmaceutical sector, the new 'Bolar' rule introduces for the first time the possibility for companies to start development work on a product while the innovator's product is still under patent protection.

'Generic medicinal product is defined as a medicinal product that 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...' (see article 1(8) of regulation 726/2004 and article 10.2(b) of Directive 2004/27/EC).

This should provide greater legal certainty and better application of the regulatory procedures for generic medicines.

There are some biological medicinal products that are similar to a reference bioloical product, but do not meet the definition of a 'generic'.

For these 'biosimilar' products, the results of 'appropriate' pre-clinical tests or clinical trials must be provided, the type and quantity of supplementary data must comply with the 'relevant criteria' for full application, and 'the results of other tests and trials from the reference medicinal product's dossier shall not be provided' (see article 1(8) of regulation 726/2004 and article 10.4 of Directive 2004/27/EC).

The new directives clarify key definitions and the scope of directives 2001/83/EC and 2001/82/EC.

The definition of 'medicinal product' in article 1 of regulation 726/2004 and article 1.2 of the community code for medicinal products for human use now clearly includes new therapies and the growing number of so-called 'borderline' products between the medicinal product sector and other sectors.

It specifies the type of action that the medicinal product may exert on physiological functions.

It covers medicinal products such as gene therapy, radiopharmaceutical products as well as certain medicinal products for topical use.

The new directive provides for a simplified registration procedure for traditional medicinal products, requiring fulfilment of European standards of quality, safety and efficacy.

Although most changes will not become effective until sometime in 2005, in part because of the accession of the ten states, certain changes will take place soon after publication of the new laws and those who deal with EU pharmaceutical issues are already modifying their vocabulary.

The EMEA will soon become the EMA.

Its committee on proprietary medicinal products becomes the committee on human medicinal products (CHMP).

The composition of the CHMP will be revamped to make room for the ten new countries.

The legislation includes many important changes in the EU legislative framework for both regulation of product quality, safety and efficacy and also for innovator and generic rights.

These developments have potentially significant implications for pharmaceutical companies selling their products in the EU, particularly those exporting products from the US to the EU.

Linda Horton, Jacqueline Mailly and Klaus Goecke are based in the Washington, Brussels and Berlin offices respectively of international law firm Hogan & Hartson