02001L0083 — EN — 28.01.2019 — 012.001

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►B 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 (OJ L 311 28.11.2001, p. 67)

Amended by:





Corrected by:









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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







TITLE I

DEFINITIONS

Article 1

For the purposes of this Directive, the following terms shall bear the following meanings:

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2. Medicinal product : (a) Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or (b) Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.

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3. Substance : Any matter irrespective of origin which may be: — human, e.g. — human blood and human blood products; — animal, e.g. — micro-organisms, whole animals, parts of organs, animal secretions, toxins, extracts, blood products; — vegetable, e.g. — micro-organisms, plants, parts of plants, vegetable secretions, extracts; — chemical, e.g. — elements, naturally occurring chemical materials and chemical products obtained by chemical change or synthesis.

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3a. Active substance : Any substance or mixture of substances intended to be used in the manufacture of a medicinal product and that, when used in its production, becomes an active ingredient of that product intended to exert a pharmacological, immunological or metabolic action with a view to restoring, correcting or modifying physiological functions or to make a medical diagnosis.

3b. Excipient : Any constituent of a medicinal product other than the active substance and the packaging material.

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4. Immunological medicinal product : Any medicinal product consisting of vaccines, toxins, serums or allergen products: (a) vaccines, toxins and serums shall cover in particular: (i) agents used to produce active immunity, such as cholera vaccine, BCG, polio vaccines, smallpox vaccine; (ii) agents used to diagnose the state of immunity, including in particular tuberculin and tuberculin PPD, toxins for the Schick and Dick Tests, brucellin; (iii) agents used to produce passive immunity, such as diphtheria antitoxin, anti-smallpox globulin, antilymphocytic globulin; (b) ‘allergen product’ shall mean any medicinal product which is intended to identify or induce a specific acquired alteration in the immunological response to an allergizing agent.

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4a. Advanced therapy medicinal product : A product as defined in Article 2 of Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products ( 1 ).

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5. Homeopathic medicinal product : Any medicinal product prepared from substances called homeopathic stocks in accordance with a homeopathic manufacturing procedure described by the European Pharmacopoeia or, in the absence thereof, by the pharmacopoeias currently used officially in the Member States. A homeopathic medicinal product may contain a number of principles.

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6. Radiopharmaceutical : Any medicinal product which, when ready for use, contains one or more radionuclides (radioactive isotopes) included for a medicinal purpose.

7. Radionuclide generator : Any system incorporating a fixed parent radionuclide from which is produced a daughter radionuclide which is to be obtained by elution or by any other method and used in a radiopharmaceutical.

8. ►M4 Kit ◄ : Any preparation to be reconsitituted or combined with radionuclides in the final radiopharmaceutical, usually prior to its administration.

9. Radionuclide precursor : Any other radionuclide produced for the radio-labelling of another substance prior to administration.

10. Medicinal products derived from human blood or human plasma : Medicinal products based on blood constitutents which are prepared industrially by public or private establishments, such medicinal products including, in particular, albumin, coagulating factors and immunoglobulins of human origin.

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11. Adverse reaction : A response to a medicinal product which is noxious and unintended.

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12. Serious adverse reaction : An adverse reaction which results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly/birth defect.

13. Unexpected adverse reaction : An adverse reaction, the nature, severity or outcome of which is not consistent with the summary of product characteristics.

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15. Post-authorisation safety study : Any study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures.

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16. Abuse of medicinal products : Persistent or sporadic, intentional excessive use of medicinal products which is accompanied by harmful physical or psychological effets.

17. Wholesale distribution of medicinal products : All activities consisting of procuring, holding, supplying or exporting medicinal products, apart from supplying medicinal products to the public. Such activities are carried out with manufacturers or their depositories, importers, other wholesale distributors or with pharmacists and persons authorized or entitled to supply medicinal products to the public in the Member State concerned.

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17a. Brokering of medicinal products : All activities in relation to the sale or purchase of medicinal products, except for wholesale distribution, that do not include physical handling and that consist of negotiating independently and on behalf of another legal or natural person.

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18. Public service obligation : The obligation placed on wholesalers to guarantee permanently an adequate range of medicinal products to meet the requirements of a specific geographical area and to deliver the supplies requested within a very short time over the whole of the area in question.

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18a Representative of the marketing authorisation holder : The person, commonly known as local representative, designated by the marketing authorisation holder to represent him in the Member State concerned.

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19. Medicinal Prescription : Any medicinal prescription issued by a professional person qualified to do so.

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20. Name of the medicinal product : The name, which may be either an invented name not liable to confusion with the common name, or a common or scientific name accompanied by a trade mark or the name of the marketing authorisation holder.

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21. Common name : The international non-proprietary name recommended by the World Health Organization, or, if one does not exist, the usual common name.

22. Strength of the medicinal product : The content of the active substances expressed quantitatively per dosage unit, per unit of volume or weight according to the dosage form.

23. Immediate packaging : The container or other form of packaging immediately in contact with the medicinal product.

24. Outer packaging : The packaging into which is placed the immediate packaging.

25. Labelling : Information on the immediate or outer packaging.

26. Package leaflet : A leaflet containing information for the user which accompanies the medicinal product.

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26a. Variation or variation to the terms of a marketing authorisation : An amendment to the contents of the particulars and documents referred to in: (a) Article 8(3) and Articles 9 to 11 of this Directive and Annex I thereto, Article 6(2) of Regulation (EC) No 726/2004 and in Article 7 of Regulation (EC) No 1394/2007; and (b) the terms of the decision granting the marketing authorisation for a medicinal product for human use, including the summary of the product characteristics and any conditions, obligations, or restrictions affecting the marketing authorisation, or changes to the labelling or the package leaflet related to changes to the summary of the product characteristics.

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27. Agency : The European Medicines Agency established by Regulation (EC) No 726/2004 ( 2 ).

28. Risks related to use of the medicinal product : — any risk relating to the quality, safety or efficacy of the medicinal product as regards patients' health or public health; — any risk of undesirable effects on the environment.

28a. Risk-benefit balance : An evaluation of the positive therapeutic effects of the medicinal product in relation to the risks as defined in point 28, first indent.

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28b. Risk management system : a set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to a medicinal product, including the assessment of the effectiveness of those activities and interventions.

28c. Risk management plan : a detailed description of the risk management system.

28d. Pharmacovigilance system : a system used by the marketing authorisation holder and by Member States to fulfil the tasks and responsibilities listed in Title IX and designed to monitor the safety of authorised medicinal products and detect any change to their risk-benefit balance.

28e. Pharmacovigilance system master file : A detailed description of the pharmacovigilance system used by the marketing authorisation holder with respect to one or more authorised medicinal products.

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29. Traditional herbal medicinal product : A herbal medicinal product that fulfils the conditions laid down in Article 16a(1).

30. Herbal medicinal product : Any medicinal product, exclusively containing as active ingredients one or more herbal substances or one or more herbal preparations, or one or more such herbal substances in combination with one or more such herbal preparations.

31. Herbal substances : All mainly whole, fragmented or cut plants, plant parts, algae, fungi, lichen in an unprocessed, usually dried, form, but sometimes fresh. Certain exudates that have not been subjected to a specific treatment are also considered to be herbal substances. Herbal substances are precisely defined by the plant part used and the botanical name according to the binomial system (genus, species, variety and author).

32. Herbal preparations : Preparations obtained by subjecting herbal substances to treatments such as extraction, distillation, expression, fractionation, purification, concentration or fermentation. These include comminuted or powdered herbal substances, tinctures, extracts, essential oils, expressed juices and processed exudates.

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33. Falsified medicinal product : Any medicinal product with a false representation of: (a) its identity, including its packaging and labelling, its name or its composition as regards any of the ingredients including excipients and the strength of those ingredients; (b) its source, including its manufacturer, its country of manufacturing, its country of origin or its marketing authorisation holder; or (c) its history, including the records and documents relating to the distribution channels used. This definition does not include unintentional quality defects and is without prejudice to infringements of intellectual property rights.

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TITLE II

SCOPE

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Article 2

1. This Directive shall apply to medicinal products for human use intended to be placed on the market in Member States and either prepared industrially or manufactured by a method involving an industrial process.

2. In cases of doubt, where, taking into account all its characteristics, a product may fall within the definition of a ‘medicinal product’ and within the definition of a product covered by other Community legislation the provisions of this Directive shall apply.

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3. Notwithstanding paragraph 1 of this Article and Article 3(4), Title IV of this Directive shall apply to the manufacture of medicinal products intended only for export and to intermediate products, active substances and excipients.

4. Paragraph 1 shall be without prejudice to Articles 52b and 85a.

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Article 3

This Directive shall not apply to:

1. Any medicinal product prepared in a pharmacy in accordance with a medical prescription for an individual patient (commonly known as the magistral formula).

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2. Any medicinal product which is prepared in a pharmacy in accordance with the prescriptions of a pharmacopoeia and is intended to be supplied directly to the patients served by the pharmacy in question (commonly known as the officinal formula).

3. Medicinal products intended for research and development trials, but without prejudice to the provisions of Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use ( 3 ).

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4. Intermediate products intended for further processing by an authorized manufacturer.

5. Any radionuclides in the form of sealed sources.

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6. Whole blood, plasma or blood cells of human origin, except for plasma which is prepared by a method involving an industrial process.

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7. Any advanced therapy medicinal product, as defined in Regulation (EC) No 1394/2007, which is prepared on a non-routine basis according to specific quality standards, and used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient.

Manufacturing of these products shall be authorised by the competent authority of the Member State. Member States shall ensure that national traceability and pharmacovigilance requirements as well as the specific quality standards referred to in this paragraph are equivalent to those provided for at Community level in respect of advanced therapy medicinal products for which authorisation is required pursuant to Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency ( 4 ).

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Article 4

1. Nothing in this Directive shall in any way derogate from the Community rules for the radiation protection of persons undergoing medical examination or treatment, or from the Community rules laying down the basic safety standards for the health protection of the general public and workers against the dangers of ionizing radiation.

2. This Directive shall be without prejudice to Council Decision 86/346/EEC of 25 June 1986 accepting on behalf of the Community the European Agreement on the Exchange of Therapeutic Substances of Human Origin ( 5 ).

3. The provisions of this Directive shall not affect the powers of the Member States' authorities either as regards the setting of prices for medicinal products or their inclusion in the scope of national health insurance schemes, on the basis of health, economic and social conditions.

4. This Directive shall not affect the application of national legislation prohibiting or restricting the sale, supply or use of medicinal products as contraceptives or abortifacients. The Member States shall communicate the national legislation concerned to the Commission.

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5. This Directive and all Regulations referred to therein shall not affect the application of national legislation prohibiting or restricting the use of any specific type of human or animal cells, or the sale, supply or use of medicinal products containing, consisting of or derived from these cells, on grounds not dealt with in the aforementioned Community legislation. The Member States shall communicate the national legislation concerned to the Commission. The Commission shall make this information publicly available in a register.

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Article 5

1. A Member State may, in accordance with legislation in force and to fulfil special needs, exclude from the provisions of this Directive medicinal products supplied in response to a bona fide unsolicited order, formulated in accordance with the specifications of an authorised health-care professional and for use by an individual patient under his direct personal responsibility.

2. Member States may temporarily authorise the distribution of an unauthorised medicinal product in response to the suspected or confirmed spread of pathogenic agents, toxins, chemical agents or nuclear radiation any of which could cause harm.

3. Without prejudice to paragraph 1, Member States shall lay down provisions in order to ensure that marketing authorisation holders, manufacturers and health professionals are not subject to civil or administrative liability for any consequences resulting from the use of a medicinal product otherwise than for the authorised indications or from the use of an unauthorised medicinal product, when such use is recommended or required by a competent authority in response to the suspected or confirmed spread of pathogenic agents, toxins, chemical agents or nuclear radiation any of which could cause harm. Such provisions shall apply whether or not national or Community authorisation has been granted.

4. Liability for defective products, as provided for by Council Directive 85/374/EEC of 25 July 1985 on the approximation of the laws, regulations and administrative provisions of the Member States, concerning liability for defective products ( 6 ), shall not be affected by paragraph 3.

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TITLE III

PLACING ON THE MARKET







CHAPTER 1

Marketing authorization

Article 6

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1. ►M6 ►C1 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 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 use ( 7 ) and Regulation (EC) No 1394/2007. ◄ ◄

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When 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).

1a. 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.

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2. The authorisation referred to in paragraph 1 shall also be required for radionuclide generators, ►M4 kits ◄ , 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, ►M4 kits ◄ 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.

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(b) 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.

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(ca) 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.

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(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.

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(g) 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.

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(ha) A written confirmation that the manufacturer of the medicinal product has verified compliance of the manufacturer of the active substance with principles and guidelines of good manufacturing practice by conducting audits, in accordance with point (f) of Article 46. The written confirmation shall contain a reference to the date of the audit and a declaration that the outcome of the audit confirms that the manufacturing complies with the principles and guidelines of good manufacturing practice.

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(i) Results of:

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

— pre-clinical (toxicological and pharmacological) tests,

— clinical trials.

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(ia) A summary of the applicant’s pharmacovigilance system which shall include the following elements:

— proof that the applicant has at his disposal a qualified person responsible for pharmacovigilance,

— the Member States in which the qualified person resides and carries out his/her tasks,

— the contact details of the qualified person,

— a statement signed by the applicant to the effect that the applicant has the necessary means to fulfil the tasks and responsibilities listed in Title IX,

— a reference to the location where the pharmacovigilance system master file for the medicinal product is kept.

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(iaa) The risk management plan describing the risk management system which the applicant will introduce for the medicinal product concerned, together with a summary thereof.

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(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.

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

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(l) Copies of the following:

— any authorisation, obtained in another Member State or in a third country, to place the medicinal product on the market, a summary of the safety data including the data contained in the periodic safety update reports, where available, and suspected adverse reactions reports, together with a list of those Member States in which an application for authorisation submitted in accordance with this Directive is under examination;

— 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 and 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 authorisation, whether in the Union or in a third country, and the reasons for such a decision.

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(m) 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 products ( 8 ), accompanied by a copy of the relevant Agency opinion.

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The 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.

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The risk management system referred to in point (iaa) of the first subparagraph shall be proportionate to the identified risks and the potential risks of the medicinal product, and the need for post-authorisation safety data.

The information referred to in the first subparagraph shall be updated where and when appropriate.

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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.

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Article 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.

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Article 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.

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Article 11

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

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

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. pharmaceutical form.

4. clinical particulars:

4.1. therapeutic indications,

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

4.3. contra-indications,

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,

4.5. interaction with other medicinal products and other forms of interactions,

4.6. use during pregnancy and lactation,

4.7. effects on ability to drive and to use machines,

4.8. undesirable effects,

4.9. overdose (symptoms, emergency procedures, antidotes).

5. pharmacological properties:

5.1. pharmacodynamic properties,

5.2. pharmacokinetic properties,

5.3. preclinical safety data.

6. pharmaceutical particulars:

6.1. list of excipients,

6.2. major incompatibilities,

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

6.4. special precautions for storage,

6.5. nature and contents of container,

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

7. marketing authorisation holder.

8. marketing authorisation number(s).

9. date of the first authorisation or renewal of the authorisation.

10. date of revision of the text.

11. for radiopharmaceuticals, full details of internal radiation dosimetry.

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.

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For medicinal products included on the list referred to in Article 23 of Regulation (EC) No 726/2004, the summary of product characteristics shall include the statement: ‘This medicinal product is subject to additional monitoring’. This statement shall be preceded by the black symbol referred to in Article 23 of Regulation (EC) No 726/2004 and followed by an appropriate standardised explanatory sentence.

For all medicinal products, a standard text shall be included expressly asking healthcare professionals to report any suspected adverse reaction in accordance with the national spontaneous reporting system referred to in Article 107a(1). Different ways of reporting, including electronic reporting, shall be available in compliance with the second subparagraph of Article 107a(1).

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Article 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.

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CHAPTER 2

Specific provisions applicable to homeopathic medicinal products

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Article 13

1. Member States shall ensure that homeopathic medicinal products manufactured and placed on the market within the Community are registered or authorised in accordance with Articles 14, 15 and 16, except where such medicinal products are covered by a registration or authorisation granted in accordance with national legislation on or before 31 December 1993. In case of registrations, Article 28 and Article 29(1) to (3) shall apply.

2. Member States shall establish a special simplified registration procedure for the homeopathic medicinal products referred to in Article 14.

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Article 14

1. Only homeopathic medicinal products which satisfy all of the following conditions may be subject to a special, simplified registration procedure:

— they are administered orally or externally,

— no specific therapeutic indication appears on the labelling of the medicinal product or in any information relating thereto,

— there is a sufficient degree of dilution to guarantee the safety of the medicinal product; in particular, the medicinal product may not contain either more than one part per 10 000 of the mother tincture or more than 1/100th of the smallest dose used in allopathy with regard to active substances whose presence in an allopathic medicinal product results in the obligation to submit a doctor's prescription.

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If new scientific evidence so warrants, the Commission may amend the third indent of the first subparagraph. That measure, designed to amend non-essential elements of this Directive, shall be adopted in accordance with the regulatory procedure with scrutiny referred to in Article 121(2a).

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At the time of registration, Member States shall determine the classification for the dispensing of the medicinal product.

2. The criteria and rules of procedure provided for in Article 4(4), Article 17(1) and Articles 22 to 26, 112, 116 and 125 shall apply by analogy to the special, simplified registration procedure for homeopathic medicinal products, with the exception of the proof of therapeutic efficacy.

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Article 15

An application for special, simplified registration may cover a series of medicinal products derived from the same homeopathic stock or stocks. The following documents shall be included with the application in order to demonstrate, in particular, the pharmaceutical quality and the batch-to-batch homogeneity of the products concerned:

— scientific name or other name given in a pharmacopoeia of the homeopathic stock or stocks, together with a statement of the various routes of administration, pharmaceutical forms and degree of dilution to be registered,

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— dossier describing how the homeopathic stock or stocks is/are obtained and controlled, and justifying its/their homeopathic use, on the basis of an adequate bibliography,

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— manufacturing and control file for each pharmaceutical form and a description of the method of dilution and potentization,

— manufacturing authorization for the medicinal product concerned,

— copies of any registrations or authorizations obtained for the same medicinal product in other Member States,

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— one or more mock-ups of the outer packaging and the immediate packaging of the medicinal products to be registered,

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— data concerning the stability of the medicinal product.

Article 16

1. Homeopathic medicinal products other than those referred to in Article 14(1) shall be authorized and labelled in accordance with ►M4 Articles 8, 10, 10a, 10b, 10c and 11 ◄ .

2. A Member State may introduce or retain in its territory specific rules for the ►M4 preclinical tests ◄ and clinical trials of homeopathic medicinal products other than those referred to in Article 14(1) in accordance with the principles and characteristics of homeopathy as practised in that Member State.

In this case, the Member State concerned shall notify the Commission of the specific rules in force.

3. Title IX shall apply to homeopathic medicinal products, with the exception of those referred to in Article 14(1).

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CHAPTER 2a

Specific provisions applicable to traditional herbal medicinal products

Article 16a

1. A simplified registration procedure (hereinafter ‘traditional-use registration’) is hereby established for herbal medicinal products which fulfil all of the following criteria:

(a) they have indications exclusively appropriate to traditional herbal medicinal products which, by virtue of their composition and purpose, are intended and designed for use without the supervision of a medical practitioner for diagnostic purposes or for prescription or monitoring of treatment;

(b) they are exclusively for administration in accordance with a specified strength and posology;

(c) they are an oral, external and/or inhalation preparation;

(d) the period of traditional use as laid down in Article 16c(1)(c) has elapsed;

(e) the data on the traditional use of the medicinal product are sufficient; in particular the product proves not to be harmful in the specified conditions of use and the pharmacological effects or efficacy of the medicinal product are plausible on the basis of long-standing use and experience.

2. Notwithstanding Article 1(30), the presence in the herbal medicinal product of vitamins or minerals for the safety of which there is well-documented evidence shall not prevent the product from being eligible for registration in accordance with paragraph 1, provided that the action of the vitamins or minerals is ancillary to that of the herbal active ingredients regarding the specified claimed indication(s).

3. However, in cases where the competent authorities judge that a traditional herbal medicinal product fulfils the criteria for authorisation in accordance with Article 6 or registration pursuant to Article 14, the provisions of this chapter shall not apply.

Article 16b

1. The applicant and registration holder shall be established in the Community.

2. In order to obtain traditional-use registration, the applicant shall submit an application to the competent authority of the Member State concerned.

Article 16c

1. The application shall be accompanied by:

(a) the particulars and documents:

(i) referred to in Article 8(3)(a) to (h), (j) and (k);

(ii) the results of the pharmaceutical tests referred to in the second indent of Article 8(3)(i);

(iii) the summary of product characteristics, without the data specified in Article 11(4);

(iv) in case of combinations, as referred to in Article 1(30) or Article 16a(2), the information referred to in Article 16a(1)(e) relating to the combination as such; if the individual active ingredients are not sufficiently known, the data shall also relate to the individual active ingredients;

(b) any authorisation or registration obtained by the applicant in another Member State, or in a third country, to place the medicinal product on the market, and details of any decision to refuse to grant an authorisation or registration, whether in the Community or a third country, and the reasons for any such decision;

(c) bibliographical or expert evidence to the effect that the medicinal product in question, or a corresponding product has been in medicinal use throughout a period of at least 30 years preceding the date of the application, including at least 15 years within the Community. At the request of the Member State where the application for traditional-use registration has been submitted, the Committee for Herbal Medicinal Products shall draw up an opinion on the adequacy of the evidence of the long-standing use of the product, or of the corresponding product. The Member State shall submit relevant documentation supporting the referral;

(d) a bibliographic review of safety data together with an expert report, and where required by the competent authority, upon additional request, data necessary for assessing the safety of the medicinal product.

Annex I shall apply by analogy to the particulars and documents specified in point (a).

2. A corresponding product, as referred to in paragraph 1(c), is characterised by having the same active ingredients, irrespective of the excipients used, the same or similar intended purpose, equivalent strength and posology and the same or similar route of administration as the medicinal product applied for.

3. The requirement to show medicinal use throughout the period of 30 years, referred to in paragraph 1(c), is satisfied even where the marketing of the product has not been based on a specific authorisation. It is likewise satisfied if the number or quantity of ingredients of the medicinal product has been reduced during that period.

4. Where the product has been used in the Community for less than 15 years, but is otherwise eligible for simplified registration, the Member State where the application for traditional-use registration has been submitted shall refer the product to the Committee for Herbal Medicinal Products. The Member State shall submit relevant documentation supporting the referral.

The Committee shall consider whether the other criteria for a simplified registration as referred to in Article 16a are fully complied with. If the Committee considers it possible, it shall establish a Community herbal monograph as referred to in Article 16h(3) which shall be taken into account by the Member State when taking its final decision.

Article 16d

1. Without prejudice to Article 16h(1), Chapter 4 of Title III shall apply by analogy to registrations granted in accordance with Article 16a, provided that:

(a) a Community herbal monograph has been established in accordance with Article 16h(3), or

(b) the herbal medicinal product consists of herbal substances, preparations or combinations thereof contained in the list referred to in Article 16f.

2. For other herbal medicinal products as referred to in Article 16a, each Member State shall, when evaluating an application for traditional-use registration, take due account of registrations granted by another Member State in accordance with this chapter.

Article 16e

1. Traditional-use registration shall be refused if the application does not comply with Articles 16a, 16b or 16c or if at least one of the following conditions is fulfilled:

(a) the qualitative and/or quantitative composition is not as declared;

(b) the indications do not comply with the conditions laid down in Article 16a;

(c) the product could be harmful under normal conditions of use;

(d) the data on traditional use are insufficient, especially if pharmacological effects or efficacy are not plausible on the basis of long-standing use and experience;

(e) the pharmaceutical quality is not satisfactorily demonstrated.

2. The competent authorities of the Member States shall notify the applicant, the Commission and any competent authority that requests it, of any decision they take to refuse traditional-use registration and the reasons for the refusal.

Article 16f

1. A list of herbal substances, preparations and combinations thereof for use in traditional herbal medicinal products shall be established in accordance with the procedure referred to in Article 121(2). The list shall contain, with regard to each herbal substance, the indication, the specified strength and the posology, the route of administration and any other information necessary for the safe use of the herbal substance as a traditional medicinal product.

2. If an application for traditional-use registration relates to a herbal substance, preparation or a combination thereof contained in the list referred to in paragraph 1, the data specified in Article 16c(1)(b)(c) and (d) do not need to be provided. Article 16e(1)(c) and (d) shall not apply.

3. If a herbal substance, preparation or a combination thereof ceases to be included in the list referred to in paragraph 1, registrations pursuant to paragraph 2 for herbal medicinal products containing this substance shall be revoked unless the particulars and documents referred to in Article 16c(1) are submitted within three months.

Article 16g

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1. Article 3(1) and (2), Article 4(4), Article 6(1), Article 12, Article 17(1), Articles 19, 20, 23, 24, 25, 40 to 52, 70 to 85, 101 to 108b, Article 111(1) and (3), Articles 112, 116, 117, 118, 122, 123, 125, the second paragraph of Article 126, and Article 127 of this Directive as well as Commission Directive 2003/94/EC of 8 October 2003 laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use ( 9 ) shall apply, by analogy, to traditional-use registration granted under this Chapter.

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2. In addition to the requirements of Articles 54 to 65, any labelling and user package leaflet shall contain a statement to the effect that:

(a) the product is a traditional herbal medicinal product for use in specified indication(s) exclusively based upon long-standing use; and

(b) the user should consult a doctor or a qualified health care practitioner if the symptoms persist during the use of the medicinal product or if adverse effects not mentioned in the package leaflet occur.

A Member State may require that the labelling and the user package leaflet shall also state the nature of the tradition in question.

3. In addition to the requirements of Articles 86 to 99, any advertisement for a medicinal product registered under this chapter shall contain the following statement: Traditional herbal medicinal product for use in specified indication(s) exclusively based upon long-standing use.

Article 16h

1. A Committee for Herbal Medicinal Products is hereby established. That Committee shall be part of the Agency and shall have the following competence:

(a) as regards simplified registrations, to:

— perform the tasks arising from Article 16c(1) and (4),

— perform the tasks arising from Article 16d,

— prepare a draft list of herbal substances, preparations and combinations thereof, as referred to in Article 16f(1), and

— establish Community monographs for traditional herbal medicinal products, as referred to in paragraph 3 of this Article;

(b) as regards authorisations of herbal medicinal products, to establish Community herbal monographs for herbal medicinal products, as referred to in paragraph 3 of this Article;

(c) as regards referrals to the Agency under Chapter 4 of Title III, in relation to herbal medicinal products as referred to in Article 16a, to perform the tasks set out in Article 32;

(d) where other medicinal products containing herbal substances are referred to the Agency under Chapter 4 of Title III, to give an opinion on the herbal substance where appropriate.

Finally, the Committee for Herbal Medicinal Products shall perform any other task conferred upon it by Community law.

The appropriate coordination with the Committee for Human Medicinal Products shall be ensured by a procedure to be determined by the Executive Director of the Agency in accordance with Article 57(2) of Regulation (EEC) No 2309/93.

2. Each Member State shall appoint, for a three-year term which may be renewed, one member and one alternate to the Committee for Herbal Medicinal Products.

The alternates shall represent and vote for the members in their absence. Members and alternates shall be chosen for their role and experience in the evaluation of herbal medicinal products and shall represent the competent national authorities.

The said Committee may coopt a maximum of five additional members chosen on the basis of their specific scientific competence. These members shall be appointed for a term of three years, which may be renewed, and shall not have alternates.

With a view to the coopting of such members, the said Committee shall identify the specific complementary scientific competence of the additional member(s). Coopted members shall be chosen among experts nominated by Member States or the Agency.

The members of the said Committee may be accompanied by experts in specific scientific or technical fields.

3. The Committee for Herbal Medicinal Products shall establish Community herbal monographs for herbal medicinal products with regard to the application of Article 10(1)(a)(ii) as well as traditional herbal medicinal products. The said Committee shall fulfil further responsibilities conferred upon it by provisions of this chapter and other Community law.

When Community herbal monographs within the meaning of this paragraph have been established, they shall be taken into account by the Member States when examining an application. Where no such Community herbal monograph has yet been established, other appropriate monographs, publications or data may be referred to.

When new Community herbal monographs are established, the registration holder shall consider whether it is necessary to modify the registration dossier accordingly. The registration holder shall notify any such modification to the competent authority of the Member State concerned.

The herbal monographs shall be published.

4. The general provisions of Regulation (EEC) No 2309/93 relating to the Committee for Human Medicinal Products shall apply by analogy to the Committee for Herbal Medicinal Products.

Article 16i

Before 30 April 2007, the Commission shall submit a report to the European Parliament and to the Council concerning the application of the provisions of this chapter.

The report shall include an assessment on the possible extension of traditional-use registration to other categories of medicinal products.

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CHAPTER 3

Procedures relevant to the marketing authorization

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Article 17

1. Member States shall take all appropriate measures to ensure that the procedure for granting a marketing authorisation for medicinal products is completed within a maximum of 210 days after the submission of a valid application.

Applications for marketing authorisations in two or more Member States in respect of the same medicinal product shall be submitted in accordance with ►M10 Articles 28 ◄ to 39.

2. Where a Member State notes that another marketing authorisation application for the same medicinal product is being examined in another Member State, the Member State concerned shall decline to assess the application and shall advise the applicant that ►M10 Articles 28 ◄ to 39 apply.

Article 18

Where a Member State is informed in accordance with Article 8(3)(1) that another Member State has authorised a medicinal product which is the subject of a marketing authorisation application in the Member State concerned, it shall reject the application unless it was submitted in compliance with ►M10 Articles 28 ◄ to 39.

▼B

Article 19

In order to examine the application submitted in accordance with ►M4 Articles 8, 10, 10a, 10b and 10c ◄ , the competent authority of the Member State:

1. must verify whether the particulars submitted in support of the application comply with the said ►M4 Articles 8, 10, 10a, 10b and 10c ◄ and examine whether the conditions for issuing an authorization to place medicinal products on the market (marketing authorization) are complied with.

2. may submit the medicinal product, its starting materials and, if need be, its intermediate products or other constituent materials, for testing by ►M4 an Official Medicines Control Laboratory or a laboratory that a Member State has designated for that purpose ◄ in order to ensure that the control methods employed by the manufacturer and described in the particulars accompanying the application in accordance with Article 8(3)(h) are satisfactory.

3. may, where appropriate, require the applicant to supplement the particulars accompanying the application in respect of the items listed in the ►M4 Articles 8(3), 10, 10a, 10b and 10c ◄ . Where the competent authority avails itself of this option, the time limits laid down in Article 17 shall be suspended until such time as the supplementary information required has been provided. Likewise, these time limits shall be suspended for the time allowed the applicant, where appropriate, for giving oral or written explanation.

Article 20

Member States shall take all appropriate measures to ensure that:

(a) the competent authorities verify that manufacturers and importers of medicinal products coming from third countries are able to carry out manufacture in compliance with the particulars supplied pursuant to Article 8(3)(d), and/or to carry out controls according to the methods described in the particulars accompanying the application in accordance with Article 8(3)(h);

(b) the competent authorities may allow manufacturers and importers of medicinal products coming from third countries, ►M4 in justifiable cases ◄ , to have certain stages of manufacture and/or certain of the controls referred to in (a) carried out by third parties; in such cases, the verifications by the competent authorities shall also be made in the establishment designated.

Article 21

1. When the marketing authorization is issued, the holder shall be informed, by the competent authorities of the Member State concerned, of the summary of the product characteristics as approved by it.

2. The competent authorities shall take all necessary measures to ensure that the information given in the summary is in conformity with that accepted when the marketing authorization is issued or subsequently.

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3. The national competent authorities shall, without delay, make publicly available the marketing authorisation together with the package leaflet, the summary of the product characteristics and any conditions established in accordance with Articles 21a, 22 and 22a, together with any deadlines for the fulfilment of those conditions for each medicinal product which they have authorised.

4. The national competent authorities shall draw up an assessment report and make comments on the file as regards the results of the pharmaceutical and pre-clinical tests, the clinical trials, the risk management system and the pharmacovigilance system of the medicinal product concerned. The assessment report shall be updated whenever new information becomes available which is important for the evaluation of the quality, safety or efficacy of the medicinal product concerned.

The national competent authorities shall make the assessment report publicly accessible without delay, together with the reasons for their opinion, after deletion of any information of a commercially confidential nature. The justification shall be provided separately for each indication applied for.

The public assessment report shall include a summary written in a manner that is understandable to the public. The summary shall contain, in particular, a section relating to the conditions of use of the medicinal product.

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Article 21a

In addition to the provisions laid down in Article 19, a marketing authorisation for a medicinal product may be granted subject to one or more of the following conditions:

(a) to take certain measures for ensuring the safe use of the medicinal product to be included in the risk management system;

(b) to conduct post-authorisation safety studies;

(c) to comply with obligations on the recording or reporting of suspected adverse reactions which are stricter than those referred to in Title IX;

(d) any other conditions or restrictions with regard to the safe and effective use of the medicinal product;

(e) the existence of an adequate pharmacovigilance system;

(f) to conduct post-authorisation efficacy studies where concerns relating to some aspects of the efficacy of the medicinal product are identified and can be resolved only after the medicinal product has been marketed. Such an obligation to conduct such studies shall be based on the delegated acts adopted pursuant to Article 22b while taking into account the scientific guidance referred to in Article 108a.

The marketing authorisation shall lay down deadlines for the fulfilment of these conditions where necessary.

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Article 22

In exceptional circumstances and following consultation with the applicant, the marketing authorisation may be granted subject to certain conditions, in particular relating to the safety of the medicinal product, notification to the national competent authorities of any incident relating to its use, and action to be taken.

The marketing authorisation may be granted only when the applicant can show that he is unable to provide comprehensive data on the efficacy and safety of the medicinal product under normal conditions of use, for objective, verifiable reasons and must be based on one of the grounds set out in Annex I.

Continuation of the marketing authorisation shall be linked to the annual reassessment of these conditions.

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Article 22a

1. After the granting of a marketing authorisation, the national competent authority may impose an obligation on the marketing authorisation holder:

(a) to conduct a post-authorisation safety study if there are concerns about the risks of an authorised medicinal product. If the same concerns apply to more than one medicinal product, the national competent authority shall, following consultation with the Pharmacovigilance Risk Assessment Committee, encourage the marketing authorisation holders concerned to conduct a joint post-authorisation safety study;

(b) to conduct a post-authorisation efficacy study when the understanding of the disease or the clinical methodology indicate that previous efficacy evaluations might have to be revised significantly. The obligation to conduct the post-authorisation efficacy study shall be based on the delegated acts adopted pursuant to Article 22b while taking into account the scientific guidance referred to in Article 108a.

The imposition of such an obligation shall be duly justified, notified in writing, and shall include the objectives and timeframe for submission and conduct of the study.

2. The national competent authority shall provide the marketing authorisation holder with an opportunity to present written observations in response to the imposition of the obligation within a time limit which it shall specify, if the marketing authorisation holder so requests within 30 days of receipt of the written notification of the obligation.

3. On the basis of the written observations submitted by the marketing authorisation holder, the national competent authority shall withdraw or confirm the obligation. Where the national competent authority confirms the obligation, the marketing authorisation shall be varied to include the obligation as a condition of the marketing authorisation and the risk management system shall be updated accordingly.

Article 22b

1. In order to determine the situations in which post-authorisation efficacy studies may be required under Articles 21a and 22a of this Directive, the Commission may adopt, by means of delegated acts in accordance with Article 121a, and subject to the conditions of Articles 121b and 121c, measures supplementing the provisions in Articles 21a and 22a.

2. When adopting such delegated acts, the Commission shall act in accordance with the provisions of this Directive.

Article 22c

1. The marketing authorisation holder shall incorporate any conditions referred to in Articles 21a, 22 or 22a in his risk management system.

2. The Member States shall inform the Agency of the marketing authorisations that they have granted subject to conditions pursuant to Articles 21a, 22 or 22a.

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Article 23

1. After a marketing authorisation has been granted, the marketing authorisation holder shall, in respect of the methods of manufacture and control provided for in Article 8(3)(d) and (h), take account of scientific and technical progress and introduce any changes that may be required to enable the medicinal product to be manufactured and checked by means of generally accepted scientific methods.

Those changes shall be subject to the approval of the competent authority of the Member State concerned.

2. The marketing authorisation holder shall forthwith provide the national competent authority with any new information which might entail the amendment of the particulars or documents referred to in Article 8(3), Articles 10, 10a, 10b and 11, or Article 32(5), or Annex I.

In particular, the marketing authorisation holder shall forthwith inform the national competent authority of any prohibition or restriction imposed by the competent authorities of any country in which the medicinal product is marketed and of any other new information which might influence the evaluation of the benefits and risks of the medicinal product concerned. The information shall include both positive and negative results of clinical trials or other studies in all indications and populations, whether or not included in the marketing authorisation, as well as data on the use of the medicinal product where such use is outside the terms of the marketing authorisation.

3. The marketing authorisation holder shall ensure that the product information is kept up to date with the current scientific knowledge, including the conclusions of the assessment and recommendations made public by means of the European medicines web-portal established in accordance with Article 26 of Regulation (EC) No 726/2004.

4. In order to be able to continuously assess the risk-benefit balance, the national competent authority may at any time ask the marketing authorisation holder to forward data demonstrating that the risk-benefit balance remains favourable. The marketing authorisation holder shall answer fully and promptly any such request.

The national competent authority may at any time ask the marketing authorisation holder to submit a copy of the pharmacovigilance system master file. The marketing authorisation holder shall submit the copy at the latest 7 days after receipt of the request.

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Article 23a

After a marketing authorisation has been granted, the holder of the authorisation shall inform the competent authority of the authorising Member State of the date of actual marketing of the medicinal product for human use in that Member State, taking into account the various presentations authorised.

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If the product ceases to be placed on the market of a Member State, either temporarily or permanently, the marketing authorisation holder shall notify the competent authority of that Member State. Such notification shall, other than in exceptional circumstances, be made no less than two months before the interruption in the placing on the market of the product. The marketing authorisation holder shall inform the competent authority of the reasons for such action in accordance with Article 123(2).

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Upon request by the competent authority, particularly in the context of pharmacovigilance, the marketing authorisation holder shall provide the competent authority with all data relating to the volume of sales of the medicinal product, and any data in his possession relating to the volume of prescriptions.

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Article 23b

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1. Variations shall be classified in different categories depending on the level of risk to public health and the potential impact on the quality, safety and efficacy of the medicinal product concerned. Those categories shall range from changes to terms of the marketing authorisation that have the highest potential impact on the quality, safety or efficacy of the medicinal product, to changes that have no or minimal impact thereon.

2. The procedures for examination of applications for variations shall be proportionate to the risk and impact involved. Those procedures shall range from procedures that allow implementation only after approval based on a complete scientific assessment to procedures that allow immediate implementation and subsequent notification by the marketing authorisation holder to the competent authority.

2a. The Commission is empowered to adopt delegated acts in accordance with Article 121a in order to supplement this Directive by:

(a) specifying the categories in which variations shall be classified; and

(b) establishing procedures for the examination of applications for variations to the terms of marketing authorisations.

3. When adopting the delegated acts referred to in this Article, the Commission shall endeavour to make possible the submission of a single application for one or more identical changes made to the terms of different marketing authorisations.

4. A Member State may continue to apply national provisions on variations applicable at the time of entry into force of Commission Regulation (EC) No 1234/2008 ( 10 ) to marketing authorisations granted before 1 January 1998 to medicinal products authorised only in that Member State. Where a medicinal product subject to national provisions in accordance with this Article is subsequently granted a marketing authorisation in another Member State, Regulation (EC) No 1234/2008 shall apply to that medicinal product from that date.

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5. Where a Member State decides to continue to apply national provisions pursuant to paragraph 4, it shall notify the Commission thereof. If a notification has not been made by 20 January 2011, ►M13 Regulation (EC) No 1234/2008 ◄ shall apply.

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Article 24

1. Without prejudice to paragraphs 4 and 5, a marketing authorisation shall be valid for five years.

2. The marketing authorisation may be renewed after five years on the basis of a re-evaluation of the risk-benefit balance by the competent authority of the authorising Member State.

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To this end, the marketing authorisation holder shall provide the national competent authority with a consolidated version of the file in respect of quality, safety and efficacy, including the evaluation of data contained in suspected adverse reactions reports and periodic safety update reports submitted in accordance with Title IX, and information on all variations introduced since the marketing authorisation was granted, at least 9 months before the marketing authorisation ceases to be valid in accordance with paragraph 1.

3. Once renewed, the marketing authorisation shall be valid for an unlimited period, unless the national competent authority decides, on justified grounds relating to pharmacovigilance, including exposure of an insufficient number of patients to the medicinal product concerned, to proceed with one additional five-year renewal in accordance with paragraph 2.

▼M4

4. Any authorisation which within three years of its granting is not followed by the actual placing on the market of the authorised product in the authorising Member State shall cease to be valid.

5. When an authorised product previously placed on the market in the authorising Member State is no longer actually present on the market for a period of three consecutive years, the authorisation for that product shall cease to be valid.

6. The competent authority may, in exceptional circumstances and on public health grounds grant exemptions from paragraphs 4 and 5. Such exemptions must be duly justified.

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Article 25

Authorization shall not affect the civil and criminal liability of the manufacturer and, where applicable, of the marketing authorization holder.

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Article 26

1. The marketing authorisation shall be refused if, after verification of the particulars and documents listed in Articles 8, 10, 10a, 10b and 10c, it is clear that:

(a) the risk-benefit balance is not considered to be favourable; or

(b) its therapeutic efficacy is insufficiently substantiated by the applicant; or

(c) its qualitative and quantitative composition is not as declared.

2. Authorisation shall likewise be refused if any particulars or documents submitted in support of the application do not comply with Articles 8, 10, 10a, 10b and 10c.

3. The applicant or the holder of a marketing authorisation shall be responsible for the accuracy of the documents and the data submitted.







▼M10 —————

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Article 27

▼M10

1. A coordination group shall be set up for the following purposes:

(a) the examination of any question relating to a marketing authorisation of a medicinal product in two or more Member States in accordance with the procedures laid down in Chapter 4;

(b) the examination of questions related to the pharmacovigilance of medicinal products authorised by the Member States, in accordance with Articles 107c, 107e, 107g, 107k and 107q;

(c) the examination of questions relating to variations of marketing authorisations granted by the Member States, in accordance with Article 35(1).

The Agency shall provide the secretariat of this coordination group.

For the fulfilment of its pharmacovigilance tasks, including approving risk management systems and monitoring their effectiveness, the coordination group shall rely on the scientific assessment and the recommendations of the Pharmacovigilance Risk Assessment Committee provided for in Article 56(1)(aa) of Regulation (EC) No 726/2004.

2. The coordination group shall be composed of one representative per Member State appointed for a renewable period of 3 years. Member States may appoint an alternate for a renewable period of 3 years. Members of the coordination group may arrange to be accompanied by experts.

Members of the coordination group and experts shall, for the fulfilment of their tasks, rely on the scientific and regulatory resources available to national competent authorities. Each national competent authority shall monitor the level of expertise of the evaluations carried out and facilitate the activities of nominated coordination group members and experts.

Article 63 of Regulation (EC) No 726/2004 shall apply to the coordination group as regards transparency and the independence of its members.

▼M4

3. The coordination group shall draw up its own Rules of Procedure, which shall enter into force after a favourable opinion has been given by the Commission. These Rules of Procedure shall be made public.

▼M10

4. The Executive Director of the Agency or his representative and representatives of the Commission shall be entitled to attend all meetings of the coordination group.

5. The members of the coordination group shall ensure that there is appropriate coordination between the tasks of that group and the work of national competent authorities, including the consultative bodies concerned with the marketing authorisation.

6. Save where otherwise provided for in this Directive, the Member States represented within the coordination group shall use their best endeavours to reach a position by consensus on the action to be taken. If such a consensus cannot be reached, the position of the majority of the Member States represented within the coordination group shall prevail.

7. Members of the coordination group shall be required, even after their duties have ceased, not to disclose information of the kind covered by the obligation of professional secrecy.







CHAPTER 4

Mutual recognition and decentralised procedure

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Article 28

1. With a view to the granting of a marketing authorisation for a medicinal product in more than one Member State, an applicant shall submit an application based on an identical dossier in these Member States. The dossier shall contain the information and documents referred to in Articles 8, 10, 10a, 10b, 10c and 11. The documents submitted shall include a list of Member States concerned by the application.

The applicant shall request one Member State to act as ‘reference Member State’ and to prepare an assessment report on the medicinal product in accordance with paragraphs 2 or 3.

2. Where the medicinal product has already received a marketing authorisation at the time of application, the concerned Member States shall recognise the marketing authorisation granted by the reference Member State. To this end, the marketing authorisation holder shall request the reference Member State either to prepare an assessment report on the medicinal product or, if necessary, to update any existing assessment report. The reference Member State shall prepare or update the assessment report within 90 days of receipt of a valid application. The assessment report together with the approved summary of product characteristics, labelling and package leaflet shall be sent to the concerned Member States and to the applicant.

3. In cases where the medicinal product has not received a marketing authorisation at the time of application, the applicant shall request the reference Member State to prepare a draft assessment report, a draft summary of product characteristics and a draft of the labelling and package leaflet. The reference Member State shall prepare these draft documents within 120 days after receipt of a valid application and shall send them to the concerned Member States and to the applicant.

4. Within 90 days of receipt of the documents referred to in paragraphs 2 and 3, the Member States concerned shall approve the assessment report, the summary of product characteristics and the labelling and package leaflet and shall inform the reference Member State accordingly. The reference Member State shall record the agreement of all parties, close the procedure and inform the applicant accordingly.

5. Each Member State in which an application has been submitted in accordance with paragraph 1 shall adopt a decision in conformity with the approved assessment report, the summary of product characteristics and the labelling and package leaflet as approved, within 30 days after acknowledgement of the agreement.

Article 29

1. If, within the period laid down in Article 28(4), a Member State cannot approve the assessment report, the summary of product characteristics, the labelling and the package leaflet on the grounds of potential serious risk to public health, it shall give a detailed exposition of the reasons for its position to the reference Member State, to the other Member States concerned and to the applicant. The points of disagreement shall be forthwith referred to the coordination group.

2. Guidelines to be adopted by the Commission shall define a potential serious risk to public health.

3. Within the coordination group, all Member States referred to in paragraph 1 shall use their best endeavours to reach agreement on the action to be taken. They shall allow the applicant the opportunity to make his point of view known orally or in writing. If, within 60 days of the communication of the points of disagreement, the Member States reach an agreement, the reference Member State shall record the agreement, close the procedure and inform the applicant accordingly. Article 28(5) shall apply.

4. If the Member States fail to reach an agreement within the 60-day period laid down in paragraph 3, the Agency shall be immediately informed, with a view to the application of the procedure under Articles 32, 33 and 34. The Agency shall be provided with a detailed statement of the matters on which the Member States have been unable to reach agreement and the reasons for their disagreement. A copy shall be forwarded to the applicant.

5. As soon as the applicant is informed that the matter has been referred to the Agency, he shall forthwith forward to the Agency a copy of the information and documents referred to in the first subparagraph of Article 28(1).

6. In the circumstances referred to in paragraph 4, Member States that have approved the assessment report, the draft summary of product characteristics and the labelling and package leaflet of the reference Member State may, at the request of the applicant, authorise the medicinal product without waiting for the outcome of the procedure laid down in Article 32. In that event, the authorisation granted shall be without prejudice to the outcome of that procedure.

Article 30

1. If two or more applications submitted in accordance with Articles 8, 10, 10a, 10b, 10c and 11 have been made for marketing authorisation for a particular medicinal product, and if Member States have adopted divergent decisions concerning the authorisation of the medicinal product or its suspension or revocation, a Member State, the Commission or the applicant or the marketing authorisation holder may refer the matter to the Committee for Medicinal Products for Human Use, hereinafter referred to as ‘the Committee’, for the application of the procedure laid down in Articles 32, 33 and 34.

2. In order to promote harmonisation of authorisations for medicinal products authorised in the Community, Member States shall, each year, forward to the coordination group a list of medicinal products for which a harmonised summary of product characteristics should be drawn up.

The coordination group shall lay down a list taking into account the proposals from all Member States and shall forward this list to the Commission.

The Commission or a Member State, in agreement with the Agency and taking into account the views of interested parties, may refer these products to the Committee in accordance with paragraph 1.

Article 31

1. ►M10 The Member States, the Commission, the applicant or the marketing authorisation holder shall, in specific cases where the interests of the Union are involved, refer the matter to the Committee for application of the procedure laid down in Articles 32, 33 and 34 before any decision is reached on an application for a marketing authorisation or on the suspension or revocation of a marketing authorisation, or on any other variation of the marketing authorisation which appears necessary. ◄

▼M10

Where the referral results from the evaluation of data relating to pharmacovigilance of an authorised medicinal product, the matter shall be referred to the Pharmacovigilance Risk Assessment Committee and Article 107j(2) may be applied. The Pharmacovigilance Risk Assessment Committee shall issue a recommendation according to the procedure laid down in Article 32. The final recommendation shall be forwarded to the Committee for Medicinal Products for Human Use or to the coordination group, as appropriate, and the procedure laid down in Article 107k shall apply.

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However, where one of the criteria listed in Article 107i(1) is met, the procedure laid down in Articles 107i to 107k shall apply.

▼M4

The Member State concerned or the Commission shall clearly identify the question which is referred to the Committee for consideration and shall inform the applicant or the marketing authorisation holder.

The Member States and the applicant or the marketing authorisation holder shall supply the Committee with all available information relating to the matter in question.

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2. Where the referral to the Committee concerns a range of medicinal products or a therapeutic class, the Agency may limit the procedure to certain specific parts of the authorisation.

In that event, Article 35 shall apply to those medicinal products only if they were covered by the authorisation procedures referred to in this Chapter.

Where the scope of the procedure initiated under this Article concerns a range of medicinal products or a therapeutic class, medicinal products authorised in accordance with Regulation (EC) No 726/2004 which belong to that range or class shall also be included in the procedure.

3. Without prejudice to paragraph 1, a Member State may, where urgent action is necessary to protect public health at any stage of the procedure, suspend the marketing authorisation and prohibit the use of the medicinal product concerned on its territory until a definitive decision is adopted. It shall inform the Commission, the Agency and the other Member States, no later than the following working day, of the reasons for its action.

4. Where the scope of the procedure initiated under this Article, as determined in accordance with paragraph 2, includes medicinal products authorised in accordance with Regulation (EC) No 726/2004, the Commission may, where urgent action is necessary to protect public health, at any stage of the procedure, suspend the marketing authorisations and prohibit the use of the medicinal products concerned until a definitive decision is adopted. The Commission shall inform the Agency and the Member States no later than the following working day of the reasons for its action.

▼M4

Article 32

1. When reference is made to the procedure laid down in this Article, the Committee shall consider the matter concerned and shall issue a reasoned opinion within 60 days of the date on which the matter was referred to it.

However, in cases submitted to the Committee in accordance with Articles 30 and 31, this period may be extended by the Committee for a further period of up to 90 days, taking into account the views of the applicants or the marketing authorisation holders concerned.

In an emergency, and on a proposal from its Chairman, the Committee may agree to a shorter deadline.

2. In order to consider the matter, the Committee shall appoint one of its members to act as rapporteur. The Committee may also appoint individual experts to advise it on specific questions. When appointing experts, the Committee shall define their tasks and specify the time-limit for the completion of these tasks.

3. Before issuing its opinion, the Committee shall provide the applicant or the marketing authorisation holder with an opportunity to present written or oral explanations within a time limit which it shall specify.

The opinion of the Committee shall be accompanied by a draft summary of product characteristics for the product and a draft text of the labelling and package leaflet.

If necessary, the Committee may call upon any other person to provide information relating to the matter before it.

The Committee may suspend the time-limits referred to in paragraph 1 in order to allow the applicant or the marketing authorisation holder to prepare explanations.

4. The Agency shall forthwith inform the applicant or the marketing authorisation holder where the opinion of the Committee is that:

(a) the application does not satisfy the criteria for authorisation; or

(b) the summary of the product characteristics proposed by the applicant or the marketing authorisation holder in accordance with Article 11 should be amended; or

(c) the authorisation should be granted subject to certain conditions, in view of conditions considered essential for the safe and effective use of the medicinal product including pharmacovigilance; or

(d) a marketing authorisation should be suspended, varied or revoked.

Within 15 days after receipt of the opinion, the applicant or the marketing authorisation holder may notify the Agency in writing of his intention to request a re-examination of the opinion. In that case, he shall forward to the Agency the detailed grounds for the request within 60 days after receipt of the opinion.

Within 60 days following receipt of the grounds for the request, the Committee shall re-examine its opinion in accordance with the fourth subparagraph of Article 62(1) of Regulation (EC) No 726/2004. The reasons for the conclusion reached shall be annexed to the assessment report referred to in paragraph 5 of this Article.

5. Within 15 days after its adoption, the Agency shall forward the final opinion of the Committee to the Member States, to the Commission and to the applicant or the marketing authorisation holder, together with a report describing the assessment of the medicinal product and stating the reasons for its conclusions.

In the event of an opinion in favour of granting or maintaining an authorisation to place the medicinal product concerned on the market, the following documents shall be annexed to the opinion:

(a) a draft summary of the product characteristics, as referred to in Article 11;

(b) any conditions affecting the authorisation within the meaning of paragraph 4(c);

(c) details of any recommended conditions or restrictions with regard to the safe and effective use of the medicinal product;

(d) the proposed text of the labelling and leaflet.

▼B

Article 33

Within ►M4 15 days ◄ of the receipt of the opinion, the Commission shall prepare a draft of the decision to be taken in respect of the application, taking into account Community law.

In the event of a draft decision which envisages the granting of marketing authorization, the documents referred to in ►M4 Article 32(5), second subparagraph ◄ shall be annexed.

Where, exceptionally, the draft decision is not in accordance with the opinion of the Agency, the Commission shall also annex a detailed explanation of the reasons for the differences.

The draft decision shall be forwarded to the Member States and the applicant ►M4 or the marketing authorisation holder ◄ .

▼M4

Article 34

1. The Commission shall take a final decision in accordance with, and within 15 days after the end of, the procedure referred to in Article 121(3).

2. The rules of procedure of the Standing Committee established by Article 121(1) shall be adjusted to take account of the tasks incumbent upon it under this Chapter.

Those adjustments shall entail the following provisions:

(a) except in cases referred to in the third paragraph of Article 33, the opinion of the Standing Committee shall be given in writing;

(b) Member States shall have 22 days to forward their written observations on the draft decision to the Commission. However, if a decision has to be taken urgently, a shorter time-limit may be set by the Chairman according to the degree of urgency involved. This time-limit shall not, otherwise than in exceptional circumstances, be shorter than 5 days;

(c) Member States shall have the option of submitting a written request that the draft Decision be discussed in a plenary meeting of the Standing Committee.

Where, in the opinion of the Commission, the written observations of a Member State raise important new questions of a scientific or technical nature which have not been addressed in the opinion delivered by the Agency, the Chairman shall suspend the procedure and refer the application back to the Agency for further consideration.

The provisions necessary for the implementation of this paragraph shall be adopted by the Commission in accordance with the procedure referred to in Article 121(2).

3. The decision as referred to in paragraph 1 shall be addressed to all Member States and reported for information to the marketing authorisation holder or applicant. The concerned Member States and the reference Member State shall either grant or revoke the marketing authorisation, or vary its terms as necessary to comply with the decision within 30 days following its notification, and they shall refer to it. They shall inform the Commission and the Agency accordingly.

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Where the scope of the procedure initiated under Article 31 includes medicinal products authorised in accordance with Regulation (EC) No 726/2004 pursuant to the third subparagraph of Article 31(2) of this Directive, the Commission shall, where necessary, adopt decisions to vary, suspend or revoke the marketing authorisations or to refuse the renewal of the marketing authorisations concerned.

▼B

Article 35

1. Any application by the marketing authorization holder to vary a marketing authorization which has been granted in accordance with the provisions of this Chapter shall be submitted to all the Member States which have previously authorized the medicinal product concerned.

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▼M4 —————

▼M8 —————

▼B

2. In case of arbitration submitted to the Commission, the procedure laid down in Articles 32, 33 and 34 shall apply by analogy to variations made to marketing authorizations.

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▼B

Article 37

►M12 Article 35 shall apply ◄ by analogy to medicinal products authorized by Member States following an opinion of the Committee given in accordance with Article 4 of Directive 87/22/EEC before 1 January 1995.

Article 38

1. The Agency shall publish an annual report on the operation of the procedures laid down in this Chapter and shall forward that report to the European Parliament and the Council for information.

▼M4

2. At least every ten years the Commission shall publish a report on the experience acquired on the basis of the procedures described in this Chapter and shall propose any amendments which may be necessary to improve those procedures. The Commission shall submit this report to the European Parliament and to the Council.

Article 39

Article 29(4), (5) and (6) and Articles 30 to 34 shall not apply to the homeopathic medicinal products referred to in Article 14.

Articles 28 to 34 shall not apply to the homeopathic medicinal products referred to in Article 16(2).

▼B







TITLE IV

MANUFACTURE AND IMPORTATION

Article 40

1. Member States shall take all appropriate measures to ensure that the manufacture of the medicinal products within their territory is subject to the holding of an authorization. This manufacturing authorization shall be required nothwithstanding that the medicinal products manufactured are intended for export.

2. The authorization referred to in paragraph 1 shall be required for both total and partial manufacture, and for the various processes of dividing up, packaging or presentation.

However, such authorization shall not be required for preparation, dividing up, changes in packaging or presentation where these processes are carried out, solely for retail supply, by pharmacists in dispensing pharmacies or by persons legally authorized in the Member States to carry out such processes.

3. Authorization referred to in paragraph 1 shall also be required for imports coming from third countries into a Member State; this Title and Article 118 shall have corresponding application to such imports as they have to manufacture.

▼M11

4. Member States shall enter the information relating to the authorisation referred to in paragraph 1 of this Article in the Union database referred to in Article 111(6).

▼B

Article 41

In order to obtain the manufacturing authorization, the applicant shall meet at least the following requirements:

(a) specify the medicinal products and pharmaceutical forms which are to be manufactured or imported and also the place where they are to be manufactured and/or controlled;

(b) have at his disposal, for the manufacture or import of the above, suitable and sufficient premises, technical equipment and control facilities complying with the legal requirements which the Member State concerned lays down as regards both manufacture and control and the storage of medicinal products, in accordance with Article 20;

(c) have at his disposal the services of at least one qualified person within the meaning of Article 48.

The applicant shall provide particulars in support of the above in his application.

Article 42

1. The competent authority of the Member State shall issue the manufacturing authorization only after having made sure of the accuracy of the particulars supplied pursuant to Article 41, by means of an inquiry carried out by its agents.

2. In order to ensure that the requirements referred to in Article 41 are complied with, authorization may be made conditional on the carrying out of certain obligations imposed either when authorization is granted or at a later date.

3. The authorization shall apply only to the premises specified in the application and to the medicinal products and pharmaceutical forms specified in that same application.

Article 43

The Member States shall take all appropriate measures to ensure that the time taken for the procedure for granting the manufacturing authorization does not exceed 90 days from the day on which the competent authority receives the application.

Article 44

If the holder of the manufacturing authorization requests a change in any of the particulars referred to in points (a) and (b) of the first paragraph of Article 41, the time taken for the procedure relating to this request shall not exceed 30 days. In exceptional cases this period of time may be extended to 90 days.

Article 45

The competent authority of the Member State may require from the applicant further information concerning the particulars supplied pursuant to Article 41 and concerning the qualified person referred to in Article 48; where the competent authority concerned exercises this right, application of the time-limits referred to in Article 43 and 44 shall be suspended until the additional data required have been supplied.

Article 46

The holder of a manufacturing authorization shall at least be obliged:

(a) to have at his disposal the services of staff who comply with the legal requirements existing in the Member State concerned both as regards manufacture and controls;

(b) to dispose of the authorized medicinal products only in accordance with the legislation of the Member States concerned;

(c) to give prior notice to the competent authority of any changes he may wish to make to any of the particulars supplied pursuant to Article 41; the competent authority shall, in any event, be immediately informed if the qualified person referred to in Article 48 is replaced unexpectedly;

(d) to allow the agents of the competent authority of the Member State concerned access to his premises at any time;

(e) to enable the qualified person referred to in Article 48 to carry out his duties, for example by placing at his disposal all the necessary facilities;

▼M11

(f) to comply with the principles and guidelines of good manufacturing practice for medicinal products and to use only active substances, which have been manufactured in accordance with good manufacturing practice for active substances and distributed in accordance with good distribution practices for active substances. To this end, the holder of the manufacturing authorisation shall verify compliance by the manufacturer and distributors of active substances with good manufacturing practice and good distribution practices by conducting audits at the manufacturing and distribution sites of the manufacturer and distributors of active substances. The holder of the manufacturing authorisation shall verify such compliance either by himself or, without prejudice to his responsibility as provided for in this Directive, through an entity acting on his behalf under a contract.

The holder of the manufacturing authorisation shall ensure that the excipients are suitable for use in medicinal products by ascertaining what the appropriate good manufacturing practice is. This shall be ascertained on the basis of a formalised risk assessment in accordance with the applicable guidelines referred to in the fifth paragraph of Article 47. Such risk assessment shall take into account requirements under other appropriate quality systems as well as the source and intended use of the excipients and previous instances of quality defects. The holder of the manufacturing authorisation shall ensure that the appropriate good ma