TITLE IIIPLACING ON THE MARKET

CHAPTER 1Marketing authorization

Article 6

F31

No medicinal product may be placed on the market of a Member State unless a marketing authorisation has been issued by the competent authorities of that Member State in accordance with this Directive or unless an authorisation has been granted in accordance with Regulation (EC) No 726/2004, read in conjunction with Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use24.

F2When a medicinal product has been granted an initial marketing authorisation in accordance with the first subparagraph, any additional strengths, pharmaceutical forms, administration routes, presentations, as well as any variations and extensions shall also be granted an authorisation in accordance with the first subparagraph or be included in the initial marketing authorisation. All these marketing authorisations shall be considered as belonging to the same global marketing authorisation, in particular for the purpose of the application of Article 10(1).

F21a

The marketing authorisation holder shall be responsible for marketing the medicinal product. The designation of a representative shall not relieve the marketing authorisation holder of his legal responsibility.

2

The authorisation referred to in paragraph 1 shall also be required for radionuclide generators, F1kits, radionuclide precursor radiopharmaceuticals and industrially prepared radiopharmaceuticals.

Article 7

A marketing authorization shall not be required for a radiopharmaceutical prepared at the time of use by a person or by an establishment authorized, according to national legislation, to use such medicinal products in an approved health care establishment exclusively from authorized radionuclide generators, F1kits or radionuclide precursors in accordance with the manufacturer's instructions.

Article 8

1

In order to obtain an authorization to place a medicinal product on the market regardless of the procedure established by Regulation (EEC) No 2309/93, an application shall be made to the competent authority of the Member State concerned.

2

A marketing authorization may only be granted to an applicant established in the Community.

3

The application shall be accompanied by the following particulars and documents, submitted in accordance with Annex I:

a

Name or corporate name and permanent address of the applicant and, where applicable, of the manufacturer.

F1b

Name of the medicinal product.

c

Qualitative and quantitative particulars of all the constituents of the medicinal product, including the reference to its international non-proprietary name (INN) recommended by the WHO, where an INN for the medicinal product exists, or a reference to the relevant chemical name.

F2ca

Evaluation of the potential environmental risks posed by the medicinal product. This impact shall be assessed and, on a case-by-case basis, specific arrangements to limit it shall be envisaged.

d

Description of the manufacturing method.

e

Therapeutic indications, contra-indications and adverse reactions.

f

Posology, pharmaceutical form, method and route of administration and expected shelf life.

F1g

Reasons for any precautionary and safety measures to be taken for the storage of the medicinal product, its administration to patients and for the disposal of waste products, together with an indication of potential risks presented by the medicinal product for the environment.

h

Description of the control methods employed by the manufacturer.

i

Results of:

  • pharmaceutical (physico-chemical, biological or microbiological) tests,

  • pre-clinical (toxicological and pharmacological) tests,

  • clinical trials.

ia

A detailed description of the pharmacovigilance and, where appropriate, of the risk-management system which the applicant will introduce.

ib

A statement to the effect that clinical trials carried out outside the European Union meet the ethical requirements of Directive 2001/20/EC.

j

A summary, in accordance with Article 11, of the product characteristics, a mock-up of the outer packaging, containing the details provided for in Article 54, and of the immediate packaging of the medicinal product, containing the details provided for in Article 55, together with a package leaflet in accordance with Article 59.

k

A document showing that the manufacturer is authorised in his own country to produce medicinal products.

l

Copies of any authorisation obtained in another Member State or in a third country to place the medicinal product on the market, together with a list of those Member States in which an application for authorisation submitted in accordance with this Directive is under examination. Copies of the summary of the product characteristics proposed by the applicant in accordance with Article 11 or approved by the competent authorities of the Member State in accordance with Article 21. Copies of the package leaflet proposed in accordance with Article 59 or approved by the competent authorities of the Member State in accordance with Article 61. Details of any decision to refuse authorization, whether in the Community or in a third country, and the reasons for such a decision.

This information shall be updated on a regular basis.

F2m

A copy of any designation of the medicinal product as an orphan medicinal product under Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products25, accompanied by a copy of the relevant Agency opinion.

n

Proof that the applicant has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country.

F2The documents and information concerning the results of the pharmaceutical and pre-clinical tests and the clinical trials referred to in point (i) of the first subparagraph shall be accompanied by detailed summaries in accordance with Article 12.

Article 9

In addition to the requirements set out in Articles 8 and 10(1), an application for authorization to market a radionuclide generator shall also contain the following information and particulars:

  • a general description of the system together with a detailed description of the components of the system which may affect the composition or quality of the daughter nucleid preparation,

  • qualitative and quantitative particulars of the eluate or the sublimate.

F1Article 10

1

By way of derogation from Article 8(3)(i), and without prejudice to the law relating to the protection of industrial and commercial property, the applicant shall not be required to provide the results of pre-clinical tests and of clinical trials if he can demonstrate that the medicinal product is a generic of a reference medicinal product which is or has been authorised under Article 6 for not less than eight years in a Member State or in the Community.

A generic medicinal product authorised pursuant to this provision shall not be placed on the market until ten years have elapsed from the initial authorisation of the reference product.

The first subparagraph shall also apply if the reference medicinal product was not authorised in the Member State in which the application for the generic medicinal product is submitted. In this case, the applicant shall indicate in the application form the name of the Member State in which the reference medicinal product is or has been authorised. At the request of the competent authority of the Member State in which the application is submitted, the competent authority of the other Member State shall transmit within a period of one month, a confirmation that the reference medicinal product is or has been authorised together with the full composition of the reference product and if necessary other relevant documentation.

The ten-year period referred to in the second subparagraph shall be extended to a maximum of eleven years if, during the first eight years of those ten years, the marketing authorisation holder obtains an authorisation for one or more new therapeutic indications which, during the scientific evaluation prior to their authorisation, are held to bring a significant clinical benefit in comparison with existing therapies.

2

For the purposes of this Article:

a

‘reference medicinal product’ shall mean a medicinal product authorised under Article 6, in accordance with the provisions of Article 8;

b

‘generic medicinal product’ shall mean a medicinal product which 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. The different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy. In such cases, additional information providing proof of the safety and/or efficacy of the various salts, esters or derivatives of an authorised active substance must be supplied by the applicant. The various immediate-release oral pharmaceutical forms shall be considered to be one and the same pharmaceutical form. Bioavailability studies need not be required of the applicant if he can demonstrate that the generic medicinal product meets the relevant criteria as defined in the appropriate detailed guidelines.

3

In cases where the medicinal product does not fall within the definition of a generic medicinal product as provided in paragraph 2(b) or where the bioequivalence cannot be demonstrated through bioavailability studies or in case of changes in the active substance(s), therapeutic indications, strength, pharmaceutical form or route of administration, vis-à-vis the reference medicinal product, the results of the appropriate pre-clinical tests or clinical trials shall be provided.

4

Where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or differences in manufacturing processes of the biological medicinal product and the reference biological medicinal product, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided. The type and quantity of supplementary data to be provided must comply with the relevant criteria stated in Annex I and the related detailed guidelines. The results of other tests and trials from the reference medicinal product's dossier shall not be provided.

5

In addition to the provisions laid down in paragraph 1, where an application is made for a new indication for a well-established substance, a non-cumulative period of one year of data exclusivity shall be granted, provided that significant pre-clinical or clinical studies were carried out in relation to the new indication.

6

Conducting the necessary studies and trials with a view to the application of paragraphs 1, 2, 3 and 4 and the consequential practical requirements shall not be regarded as contrary to patent rights or to supplementary protection certificates for medicinal products.

F2Article 10a

By way of derogation from Article 8(3)(i), and without prejudice to the law relating to the protection of industrial and commercial property, the applicant shall not be required to provide the results of pre-clinical tests or clinical trials if he can demonstrate that the active substances of the medicinal product have been in well-established medicinal use within the Community for at least ten years, with recognised efficacy and an acceptable level of safety in terms of the conditions set out in Annex I. In that event, the test and trial results shall be replaced by appropriate scientific literature.

Article 10b

In the case of medicinal products containing active substances used in the composition of authorised medicinal products but not hitherto used in combination for therapeutic purposes, the results of new pre-clinical tests or new clinical trials relating to that combination shall be provided in accordance with Article 8(3)(i), but it shall not be necessary to provide scientific references relating to each individual active substance.

Article 10c

Following the granting of a marketing authorisation, the authorisation holder may allow use to be made of the pharmaceutical, pre-clinical and clinical documentation contained in the file on the medicinal product, with a view to examining subsequent applications relating to other medicinal products possessing the same qualitative and quantitative composition in terms of active substances and the same pharmaceutical form.

F1Article 11

The summary of the product characteristics shall contain, in the order indicated below, the following information:

  1. 1.

    name of the medicinal product followed by the strength and the pharmaceutical form.

  2. 2.

    qualitative and quantitative composition in terms of the active substances and constituents of the excipient, knowledge of which is essential for proper administration of the medicinal product. The usual common name or chemical description shall be used.

  3. 3.

    pharmaceutical form.

  4. 4.

    clinical particulars:

    1. 4.1.

      therapeutic indications,

    2. 4.2.

      posology and method of administration for adults and, where necessary for children,

    3. 4.3.

      contra-indications,

    4. 4.4.

      special warnings and precautions for use and, in the case of immunological medicinal products, any special precautions to be taken by persons handling such products and administering them to patients, together with any precautions to be taken by the patient,

    5. 4.5.

      interaction with other medicinal products and other forms of interactions,

    6. 4.6.

      use during pregnancy and lactation,

    7. 4.7.

      effects on ability to drive and to use machines,

    8. 4.8.

      undesirable effects,

    9. 4.9.

      overdose (symptoms, emergency procedures, antidotes).

  5. 5.

    pharmacological properties:

    1. 5.1.

      pharmacodynamic properties,

    2. 5.2.

      pharmacokinetic properties,

    3. 5.3.

      preclinical safety data.

  6. 6.

    pharmaceutical particulars:

    1. 6.1.

      list of excipients,

    2. 6.2.

      major incompatibilities,

    3. 6.3.

      shelf life, when necessary after reconstitution of the medicinal product or when the immediate packaging is opened for the first time,

    4. 6.4.

      special precautions for storage,

    5. 6.5.

      nature and contents of container,

    6. 6.6.

      special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product, if appropriate.

  7. 7.

    marketing authorisation holder.

  8. 8.

    marketing authorisation number(s).

  9. 9.

    date of the first authorisation or renewal of the authorisation.

  10. 10.

    date of revision of the text.

  11. 11.

    for radiopharmaceuticals, full details of internal radiation dosimetry.

  12. 12.

    for radiopharmaceuticals, additional detailed instructions for extemporaneous preparation and quality control of such preparation and, where appropriate, maximum storage time during which any intermediate preparation such as an eluate or the ready-to-use pharmaceutical will conform with its specifications.

For authorisations under Article 10, those parts of the summary of product characteristics of the reference medicinal product referring to indications or dosage forms which were still covered by patent law at the time when a generic medicine was marketed need not be included.

F1Article 12

1

The applicant shall ensure that, before the detailed summaries referred to in the last subparagraph of Article 8(3) are submitted to the competent authorities, they have been drawn up and signed by experts with the necessary technical or professional qualifications, which shall be set out in a brief curriculum vitae.

2

Persons having the technical and professional qualifications referred to in paragraph 1 shall justify any use made of scientific literature under Article 10a in accordance with the conditions set out in Annex I.

3

The detailed summaries shall form part of the file which the applicant submits to the competent authorities.