Generics medicines: a tradition of quality, safety & efficacy.

About Generics

The Science of Generic Medicines

Biosimilar Medicines

Affordability & Sustainable Health

Intellectual Property

Further Resources

Authorisation

The Marketing Authorisation Process for Generic Medicines

All medicinal products must be evaluated by the relevant competent authorities and approved before they may be marketed. The same levels of quality, safety and efficacy must be demonstrated by all medicinal products and in all Member States.

The Authorisation of Generic Medicines

Generic medicinal products submit abridged applications, but are not required to repeat pre-clinical and clinical trials – indeed it would be unethical to do so. Even so, the documentation and data required is extensive and very specific. Generic medicines applications typically include chemical-pharmaceutical data and the results of bioequivalence studies, which demonstrate the quality and the “essential similarity” of the product (see the article on Quality, Safety & Efficacy). For information concerning the safety and efficacy of the molecule, the regulatory agencies are referred to the data that was established in the originator product’s application for authorisation. This is only possible once the data exclusivity period has expired on that dossier (see Article 10 of Directive 2001/83/EC, as amended by Directive 2004/27/EC).

Three Authorisation Procedures

Marketing authorisation for a pharmaceutical product in more than one country in the European Union must currently be applied for through one of two procedures: either the “Centralised Procedure” or the “Mutual Recognition Procedure” (MRP). A third, the “Decentralised Procedure,” came into force with the newly revised EU pharmaceutical Directive in November 2005.

The Centralised Procedure

The Centralised Procedure is administered by the European Medicines Agency (EMEA) in London. It consists of a single application which, when approved, grants marketing authorisation for all markets within the European Union. This procedure is obligatory for high-tech and biotechnology-derived products, for products used for the rare diseases (so called: orphan products), and for products used for treating AIDS, cancer, neurodegenerative disorders and diabetes, as well as for auto-immune and viral diseases since May 2008. This procedure may be also used for authorisation of products with new active substances and for all other products bringing therapeutic or scientific progress and which are important for patients and animals at the Community level. This procedure may also be used for generic medicines applications once the data exclusivity periods granted to originator products authorised through this procedure begin to expire.

The detailed guidelines on how to apply for Marketing Authorisation of medicinal product via the Centralised Procedure is available on the EMEA website, particularly in the document outlining Pre-submission Guidance.

The Mutual Recognition Procedure (MRP)

The majority of authorisations for generic medicines are granted through the Mutual Recognition Procedure and the Decentralised Procedure. Under MRP, the assessment and marketing authorisation of one Member State, (the “Reference Member State”) should be “mutually recognised” by other “Concerned Member States”.

Since the introduction of the DCP, the MRP is mainly used for extending the existing marketing authorisation to other countries in what is known as the “repeat use” procedure.

The New Decentralised Procedure

The Decentralised came into operation in late 2005. It is applicable in cases where an authorisation does not yet exist in any of the EU Member States. Identical dossiers are submitted in all Member States where a marketing authorisation is sought. A Reference Member State, selected by the applicant, will prepare draft assessment documents and send them to the Concerned Member States. They, in turn, will either approve the assessment or the application will continue into arbitration procedures. The new Decentralised Procedure involves Concerned Member States at an earlier stage of the evaluation than under the MRP in an effort to minimise disagreements and to facilitate the application for marketing authorisation in as many markets as possible.

The Mutual Recognition Procedure and the new Decentralised Procedure are set out in Directive 2001/83/EC, as amended by Directive 2004/27/EC, and further guidance is given in the Notice to Applicants, which forms Chapter 2 of the Rules Governing Medicinal Products in the EU. See: EudraLex: The Rules Governing Medicinal Products in the European Union.

The detailed guidelines on how to apply for Marketing Authorisation for a medicinal product via the Mutual Recognition Procedure and the new Decentralised Procedure are also available on the Heads of the Medicines Agencies website, particularly under the CMD(h) (Coordination Group for the Mutual Recognition and the Decentralised Procedure) section.

SmPCs: a Major Hurdle

The Summary of Product Characterstics - or SmPC - constitutes one of the major hurdles facing a generic medicine’s application for authorisation. The SmPC is the information which accompanies the product. This is a more detailed version of the patient information leaflet included in the box with medicines dispensed.

Until 1998, originator companies submitted applications for marketing authorisation on a national basis, which gave rise to differing assessments of the same data from one country to another due to differences in local medical practices. This also explains why originators made differing applications for a product in the various countries. As a result, the dosage, uses and warnings, etc often vary between Member States. The generic medicines applicant, however, must introduce the same application file with the same SmPC in all Concerned Member States, forcing a harmonisation where none existed previously.

In some cases, Member States are unwilling to accept any difference between the SmPC of the originator and the generic medicine on their national market, and the generic medicines applicant is forced either to withdraw the application from one or more countries in order to save the others, or is forced into costly and time-consuming arbitration proceedings. In other cases, harmonised generic medicines authorisations may be achieved by establishing what is known as “horizontal harmony”. But the resulting SmPC differences between generic and originator SmPCs, known as “vertical disharmony”, is often considered unacceptable to national authorities. As a result, the generic medicine will not be included in lists allowing substitution or reimbursement in those countries, which in turn limits, or even blocks, sales of the lower-priced product, denying the potential savings to patients.

Contested Applications

If disagreements between the Concerned Member States over the acceptability of an application remain unresolved at a certain point, the issue is automatically referred to the relevant Committee at the EMEA (CHMP) for arbitration. The opinion of the CHMP is then communicated to the European Commission for a final decision.

In practice, however, this recourse has not proven very effective and has received only limited use due largely to its cost to the generic medicines company in terms of finance, human resources and, most importantly, the delay to market in other Member States.

Recent Position of the Competent Authorities

The CMD(h) published in November 2006 their position regarding approval of generic medicines products in case of differences in the indications as compared to the reference product.

A deviation in indications (more or fewer) in the generic medicine, not in line with the SmPC of the national reference product is not considered per se to be an appropriate reason to refuse licensing to the generic medicine applicant. More detailed argumentation is available on the CMD(h) website.

In accordance with the art.30.2 of the revised Directive 83/2001, in order to promote harmonisation of medicinal products containing the same active substance, but having disharmonised product information among EU countries, the CMD(h) should propose an annual list of products to be revised.

Taking into consideration these two initiatives of the CMD(h), the issue of the SmPC disharmony should progressively improve. This will still, however, be a long term project.