Community Code Directive Safeguards Public Health
February 20, 2003
The Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community Code Relating to Medicinal Products for Human Use is of great relevance to pharmaceutical companies worldwide.
The directive codifies and harmonises a number of directives relating to medicinal products and aims to safeguard public health while encouraging the development of the pharmaceutical industry and trade in medicinal products within the European Union (EU). It aims to eliminate disparities between national provisions, particularly those relating to medicinal products affecting the functioning of the internal market.
Application of the Directive
The directive applies to industrially produced medicinal products for human use intended to be placed on the market in member states. A medicinal product includes any substance or combination presented for treating or preventing disease in human beings. It includes any substance or combination which may be administered to humans with a view to making a medical diagnosis or restoring, correcting or modifying physiological functions in humans.
"Substances" include any matter irrespective of origin which may be human. This includes human blood and blood products; animal (micro-organisms, whole animals, parts of organs, animal secretions, toxins, extracts and blood products); vegetable (micro-organisms, plants, parts of plants, vegetable secretions and extracts); and chemical (elements, naturally occurring chemical materials and chemical products obtained by chemical change or synthesis). The directive does not apply in all circumstances. For example, it does not apply to medicinal products intended for research and development trials.
Placing Medicinal Products on the Market
Medicinal products may only be placed on the market of a member state if a marketing authorisation has been issued by that member state’s competent authorities in accordance with the directive or if an authorisation has been granted in accordance with Regulation (EEC) No 2309/93, otherwise known as the centralised procedure.
Marketing authorisations may only be granted to applicants established in the European Union. To obtain a marketing authorisation, other than by the centralised procedure, an application must be submitted to the relevant member state’s competent authority. There is a choice, except in respect to biotech products and medical devices, whether to apply for approval in one member state and obtain EU-wide approval through the mutual recognition procedure or to apply to the European Medicines Evaluation Agency (EMEA) through the centralised procedure.
Applications must be accompanied by certain particulars and documents, submitted in accordance with Annex I of the directive, including, among others, the results of physicochemical, biological or microbiological tests, toxicological and pharmacological tests and clinical trials. Pursuant to Article 8, this requires a full dossier.
The Abridged Procedure: Article 10
Article 10 provides broadly that, notwithstanding certain factors, including relevant industrial and commercial property law, marketing authorisation applicants need not provide toxicological and pharmacological tests or clinical trials results if they can demonstrate consent, bibliographic application and read across/essential similarity.
First, consent or essential similarity must be shown of the relevant product to an already authorised medicinal product. Also, the holder of the marketing authorisation for the original medicinal product has to consent to the file being used for this purpose.
Bibliographic application is when the constituents of the medicinal product have a "well established medicinal use" (i.e., at least 10 years use in the EU), with recognised efficacy and an acceptable safety level, by means of a detailed scientific bibliography. Read-across/essential similarity shows that the medicinal product is essentially similar to a medicinal product authorised within the European Community on the basis of read-across from the original data. The data protection period in most member states is 10 years, and this period also applies to all applications through the EMEA and to all high-tech medicinal products. A minority of member states apply a period of six years from the date of first marketing. Where the medicinal product is intended for a different therapeutic use from that of the other medicinal products marketed or is to be administered by different routes or different doses, appropriate test results must also be provided.
These exceptions benefit manufacturers of generic "me, too" medicinal products. For new medicinal products containing known constituents not previously combined for therapeutic purposes, toxicological and pharmacological tests and clinical trials results must be provided but a reference to each individual constituent is unnecessary.
Annex I of the directive applies by analogy where bibliographic references to published data are submitted. Mixed applications are treated as full applications.
Procedures Relevant to the Marketing Authorisation
Procedures for granting authorisations to place medicinal products on the market must be completed within 210 days of the submission of a valid application. Where queries are raised regarding the application, the clock is stopped until they have been satisfactorily resolved. If an application is already under active examination in another member state for the same medicinal product, the member state concerned may suspend detailed examination of the application and await the other member state’s assessment report. As soon as it has reached a decision, the other member state forwards a copy of its assessment report to the member state concerned.
Where another member state has authorised a medicinal product which is the subject of an application for authorisation in a second member state, that member state is required to request a copy of the first member state’s assessment report and, within 90 days of receipt, either recognise the first member state’s decision and the summary of the product characteristics as approved by it or apply certain procedures if it considers there are grounds the authorisation may present a risk to public health. This is called mutual recognition. In practice, the mutual recognition procedure is not as automatic as it may seem, due to significant variations between regulatory authorities within the EU.
To examine applications, the competent authority of the member state must comply with various procedures, including (among others) verification of the particulars submitted in support of the application.
Issue of Marketing Authorisations
When a marketing authorisation is issued, the holder must be informed by the member state concerned of the summary of the product characteristics as approved by it. The competent authorities forward to the agency a copy of the authorisation EMEA together with the summary of the product characteristics. The competent authorities draw up an assessment report and comments on the dossier in respect of the analytical and pharmacotoxicological tests and the clinical trials results of the medicinal product concerned, which must be updated whenever new information becomes available.
In exceptional circumstances, authorisations may be granted subject to certain specific obligations. Authorisations are valid for five years and are renewable for five-year periods, subject to certain conditions. Marketing authorisations will be refused in certain circumstances, for example if, subject to certain conditions, it is proved that the medicinal product is harmful in the normal conditions of use.
Mutual Recognition of Authorisations
The directive provides for mutual recognition of marketing authorisations between member states in certain circumstances. Except in exceptional cases, member states must recognise marketing authorisations granted by the reference member states within 90 days of receipt of the application and assessment report. In practice, some authorities, such as the United Kingdom and Germany, are slow to recognise marketing authorisations from some other EU countries.
Manufacture and Importation
Generally, member states must ensure that the manufacture of the medicinal products within their territory is subject to a manufacturing authorisation, even if the relevant medicinal products are intended for export. To obtain such an authorisation, an applicant must comply with certain requirements. Manufacturing authorisations must be granted within 90 days from the day that the competent authority receives the application. Manufacturing authorisation holders are obliged to comply with certain legal obligations, such as having available the services of staff who comply with the legal requirements existing in the member state concerned. The directive also establishes various provisions concerning qualified persons and their responsibilities regarding manufacturing authorisations for medicinal products.
Other Relevant Provisions
The directive also contains provisions in respect to a number of other relevant matters. This includes the labelling and packaging of medicinal products, classification of medicinal products, wholesale distribution of medicinal products, advertising of medicinal products, pharmaco-vigilance within and between member states, medicinal products derived from human blood and plasma, homeopathic products, standing committees and supervision and sanctions in respect of marketing authorisations.
It is a criminal offence to make for commercial purposes or market a medicinal product without a marketing authorisation. Finally, marketing authorisation holders must exercise pharmaco-vigilance and report any contraindications or side effects.
