02004R0726 — EN — 30.03.2019 — 009.001

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►B REGULATION (EC) No 726/2004 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 31 March 2004 laying down Union procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency (Text with EEA relevance) (OJ L 136 30.4.2004, p. 1)

Amended by:





Corrected by:









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REGULATION (EC) No 726/2004 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL

of 31 March 2004

laying down ►M8 Union ◄ procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency

(Text with EEA relevance)







TITLE I

DEFINITIONS AND SCOPE

Article 1

The purpose of this Regulation is to lay down ►M8 Union ◄ procedures for the authorisation, supervision and pharmacovigilance of medicinal products for human and veterinary use, and to establish a European Medicines Agency (hereinafter referred to as ‘the Agency’).

The provisions of this Regulation shall not affect the powers of Member States' authorities as regards setting the prices of medicinal products or their inclusion in the scope of the national health system or social security schemes on the basis of health, economic and social conditions. In particular, Member States shall be free to choose from the particulars shown in the marketing authorisation those therapeutic indications and pack sizes which will be covered by their social security bodies.

Article 2

The definitions laid down in Article 1 of Directive 2001/83/EC and those laid down in Article 1 of Directive 2001/82/EC shall apply for the purposes of this Regulation.

The holder of a marketing authorisation for medicinal products covered by this Regulation must be established in the ►M8 Union ◄ . The holder shall be responsible for the placing on the market of those medicinal products, whether he does it himself or via one or more persons designated to that effect.

Article 3

1. No medicinal product appearing in the Annex may be placed on the market within the ►M8 Union ◄ unless a marketing authorisation has been granted by the ►M8 Union ◄ in accordance with the provisions of this Regulation.

2. Any medicinal product not appearing in the Annex may be granted a marketing authorisation by the ►M8 Union ◄ in accordance with the provisions of this Regulation, if:

(a) the medicinal product contains a new active substance which, on the date of entry into force of this Regulation, was not authorised in the ►M8 Union ◄ ; or

(b) the applicant shows that the medicinal product constitutes a significant therapeutic, scientific or technical innovation or that the granting of authorisation in accordance with this Regulation is in the interests of patients or animal health at ►M8 Union ◄ level.

Immunological veterinary medicinal products for the treatment of animal diseases that are subject to ►M8 Union ◄ prophylactic measures may also be granted such authorisation.

3. A generic medicinal product of a reference medicinal product authorised by the ►M8 Union ◄ may be authorised by the competent authorities of the Member States in accordance with Directive 2001/83/EC and Directive 2001/82/EC under the following conditions:

(a) the application for authorisation is submitted in accordance with Article 10 of Directive 2001/83/EC or Article 13 of Directive 2001/82/EC;

(b) the summary of the product characteristics is in all relevant respects consistent with that of the medicinal product authorised by the ►M8 Union ◄ except for those parts of the summary of product characteristics referring to indications or dosage forms which were still covered by patent law at the time when the generic medicine was marketed; and

(c) the generic medicinal product is authorised under the same name in all the Member States where the application has been made. For the purposes of this provision, all the linguistic versions of the INN (international non-proprietary name) shall be considered to be the same name.

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4. After the competent committee of the Agency has been consulted, the Commission may adapt the Annex to technical and scientific progress and may adopt any necessary amendments without extending the scope of the centralised procedure.

Those measures, designed to amend non-essential elements of this Regulation, shall be adopted in accordance with the regulatory procedure with scrutiny referred to in Article 87(2a).

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Article 4

1. Applications for the marketing authorisations referred to in Article 3 shall be submitted to the Agency.

2. The ►M8 Union ◄ shall grant and supervise marketing authorisations for medicinal products for human use in accordance with Title II.

3. The ►M8 Union ◄ shall grant and supervise marketing authorisations for veterinary medicinal products in accordance with Title III.







TITLE II

AUTHORISATION AND SUPERVISION OF MEDICINAL PRODUCTS FOR HUMAN USE







Chapter 1

Submission and examination of applications — Authorisations

Article 5

1. A Committee for Medicinal Products for Human Use is hereby established. The Committee shall be part of the Agency.

2. Without prejudice to Article 56 or to other tasks which ►M8 Union ◄ law may confer on it, the Committee for Medicinal Products for Human Use shall be responsible for drawing up the opinion of the Agency on any matter concerning the admissibility of the files submitted in accordance with the centralised procedure, the granting, variation, suspension or revocation of an authorisation to place a medicinal product for human use on the market in accordance with the provisions of this Title, and pharmacovigilance. ►M5 For the fulfilment of its pharmacovigilance tasks, including the approval of risk management systems and monitoring their effectiveness provided for under this Regulation, the Committee for Medicinal Products for Human Use shall rely on the scientific assessment and recommendations of the Pharmacovigilance Risk Assessment Committee referred to in Article 56(1)(aa). ◄

3. At the request of the Executive Director of the Agency or the Commission representative, the Committee for Medicinal Products for Human Use shall also draw up an opinion on any scientific matter concerning the evaluation of medicinal products for human use. The Committee shall take due account of any requests by Member States for an opinion. The Committee shall also formulate an opinion whenever there is disagreement in the evaluation of medicinal products through the mutual recognition procedure. The opinion of the Committee shall be made publicly accessible.

Article 6

1. Each application for the authorisation of a medicinal product for human use shall specifically and completely include the particulars and documents as referred to in Articles 8(3), 10, 10a, 10b or 11 of, and Annex I to, Directive 2001/83/EC. The documents must include a statement to the effect that clinical trials carried out outside the European Union meet the ethical requirements of Directive 2001/20/EC. These particulars and documents shall take account of the unique, ►M8 Union ◄ nature of the authorisation requested and, otherwise than in exceptional cases relating to the application of the law on trade marks, shall include the use of a single name for the medicinal product.

The application shall be accompanied by the fee payable to the Agency for the examination of the application.

2. In the case of a medicinal product for human use containing or consisting of genetically modified organisms within the meaning of Article 2 of Directive 2001/18/EC, the application shall be accompanied by:

(a) a copy of the competent authorities' written consent to the deliberate release into the environment of the genetically modified organisms for research and development purposes where provided for in Part B of Directive 2001/18/EC or in Part B of Council Directive 90/220/EEC of 23 April 1990 on the deliberate release into the environment of genetically modified organisms ( 1 );

(b) the complete technical dossier supplying the information required by Annexes III and IV to Directive 2001/18/EC;

(c) the environmental risk assessment in accordance with the principles set out in Annex II to Directive 2001/18/EC; and

(d) the results of any investigations performed for the purposes of research or development.

Articles 13 to 24 of Directive 2001/18/EC shall not apply to medicinal products for human use containing or consisting of genetically modified organisms.

3. The Agency shall ensure that the opinion of the Committee for Medicinal Products for Human Use is given within 210 days after receipt of a valid application.

The duration of the analysis of the scientific data in the file concerning the application for marketing authorisation must be at least 80 days, except in cases where the rapporteur and co-rapporteur declare that they have completed their assessment before that time.

On the basis of a duly reasoned request, the said Committee may call for the duration of the analysis of the scientific data in the file concerning the application for marketing authorisation to be extended.

In the case of a medicinal product for human use containing or consisting of genetically modified organisms, the opinion of the said Committee shall respect the environmental safety requirements laid down by Directive 2001/18/EC. During the process of evaluating applications for marketing authorisations for medicinal products for human use containing or consisting of genetically modified organisms, the rapporteur shall carry out necessary consultations of bodies that the ►M8 Union ◄ or Member States have set up in accordance with Directive 2001/18/EC.

4. The Commission shall, in consultation with the Agency, Member States and interested parties, draw up a detailed guide regarding the form in which applications for authorisation are to be presented.

Article 7

In order to prepare its opinion, the Committee for Medicinal Products for Human Use:

(a) shall verify that the particulars and documents submitted in accordance with Article 6 comply with the requirements of Directive 2001/83/EC, and shall examine whether the conditions specified in this Regulation for granting a marketing authorisation are satisfied;

(b) may request that an Official Medicines Control Laboratory or a laboratory that a Member State has designated for that purpose test the medicinal product for human use, its starting materials and, if need be, its intermediate products or other constituent materials in order to ensure that the control methods employed by the manufacturer and described in the application documents are satisfactory;

(c) may request that the applicant supplement the particulars accompanying the application within a specific time period. Where the said Committee avails itself of this option, the time-limit laid down in Article 6(3), first subparagraph, shall be suspended until such time as the supplementary information requested has been provided. Likewise, this time-limit shall be suspended for the time allowed for the applicant to prepare oral or written explanations.

Article 8

1. Upon receipt of a written request from the Committee for Medicinal Products for Human Use, a Member State shall forward the information showing that the manufacturer of a medicinal product or the importer from a third country is able to manufacture the medicinal product concerned and/or carry out the necessary control tests in accordance with the particulars and documents supplied pursuant to Article 6.

2. Where it considers it necessary in order to complete its examination of an application, the said Committee may require the applicant to undergo a specific inspection of the manufacturing site of the medicinal product concerned. Such inspections may be made unannounced.

The inspection shall be carried out within the time-limit laid down in the first subparagraph of Article 6(3) by inspectors from the Member State holding the appropriate qualifications; they may be accompanied by a rapporteur or an expert appointed by the Committee.

Article 9

1. The Agency shall forthwith inform the applicant if the opinion of the Committee for Medicinal Products for Human Use is that:

(a) the application does not satisfy the criteria for authorisation set out in this Regulation;

(b) the summary of the product characteristics proposed by the applicant needs to be amended;

(c) the labelling or package leaflet of the product is not in compliance with Title V of Directive 2001/83/EC;

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(d) the authorisation needs to be granted subject to the conditions provided for in Article 14(8) and Article 14-a.

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2. Within 15 days after receipt of the opinion referred to in paragraph 1, the applicant may give written notice to the Agency that he wishes to request a re-examination of the opinion. In that case, the applicant 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 said Committee shall re-examine its opinion in accordance with the conditions laid down in the fourth subparagraph of Article 62(1). The reasons for the conclusion reached shall be annexed to the final opinion.

3. Within 15 days after its adoption, the Agency shall send the final opinion of the said Committee to the Commission, to the Member States and to the applicant, together with a report describing the assessment of the medicinal product by the Committee and stating the reasons for its conclusions.

4. If an opinion is favourable to the granting of the relevant 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 of Directive 2001/83/EC;

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(aa) a recommendation on the frequency of submission of periodic safety update reports;

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(b) details of any conditions or restrictions which should be imposed on the supply or use of the medicinal product concerned, including the conditions under which the medicinal product may be made available to patients, in accordance with the criteria laid down in Title VI of Directive 2001/83/EC;

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

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(ca) details of any recommended measures for ensuring the safe use of the medicinal product to be included in the risk management system;

(cb) if appropriate, details of any recommended obligation to conduct post-authorisation safety studies or to comply with obligations on the recording or reporting of suspected adverse reactions which are stricter than those referred to in Chapter 3;

(cc) if appropriate, details of any recommended obligation 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 10b while taking into account the scientific guidance referred to in Article 108a of Directive 2001/83/EC;

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(d) the draft text of the labelling and package leaflet proposed by the applicant, presented in accordance with Title V of Directive 2001/83/EC;

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(e) the assessment report as regards the results of the pharmaceutical and pre-clinical tests and of the clinical trials, and as regards the risk management system and the pharmacovigilance system for the medicinal product concerned.

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Article 10

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1. Within 15 days after receipt of the opinion referred to in Article 5(2), the Commission shall prepare a draft of the decision to be taken in respect of the application.

Where a draft decision envisages the granting of a marketing authorisation, it shall include or make reference to the documents mentioned in points (a) to (d) of Article 9(4).

Where a draft decision envisages the granting of a marketing authorisation subject to the conditions referred to in points (c), (ca), (cb), or (cc) of Article 9(4), it shall lay down deadlines for the fulfilment of the conditions, where necessary.

Where the draft decision differs from the opinion of the Agency, the Commission shall attach a detailed explanation of the reasons for the differences.

The draft decision shall be forwarded to Member States and the applicant.

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2. The Commission shall take a final decision in accordance with, and within 15 days after the end of, the procedure referred to in Article 87(3).

3. The Standing Committee on Medicinal Products for Human Use referred to in Article 87(1) shall adjust its rules of procedure so as to take account of the tasks incumbent upon it under this Regulation.

The adjustments shall provide that:

(a) the opinion of the said Standing Committee is to 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 may request in writing that the draft decision referred to in paragraph 1 be discussed by a plenary meeting of the said Standing Committee, stating their reasons in detail.

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

5. The Commission shall adopt the provisions necessary for the implementation of paragraph 4 in accordance with the procedure referred to in Article 87(2).

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6. The Agency shall disseminate the documents referred to in points (a) to (d) of Article 9(4), together with any deadlines laid down pursuant to the third subparagraph of paragraph 1 of this Article.

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Article 10a

1. After the granting of a marketing authorisation, the Agency 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 Agency 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 10b while taking into account the scientific guidance referred to in Article 108a of Directive 2001/83/EC.

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 Agency 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, and of the opinion of the Agency, the Commission shall withdraw or confirm the obligation. Where the Commission 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 10b

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1. The Commission is empowered to adopt delegated acts in accordance with Article 87b, in order to supplement this Regulation by determining the situations in which post-authorisation efficacy studies may be required under point (cc) of Article 9(4) and point (b) of Article 10a(1).

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

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Article 11

If an applicant withdraws an application for a marketing authorisation submitted to the Agency before an opinion has been given on the application, the applicant shall communicate its reasons for doing so to the Agency. The Agency shall make this information publicly accessible and shall publish the assessment report, if available, after deletion of all information of a commercially confidential nature.

Article 12

1. The marketing authorisation shall be refused if, after verification of the particulars and documents submitted in accordance with Article 6, it appears that the applicant has not properly or sufficiently demonstrated the quality, safety or efficacy of the medicinal product.

Authorisation shall likewise be refused if particulars or documents provided by the applicant in accordance with Article 6 are incorrect or if the labelling and package leaflet proposed by the applicant are not in accordance with Title V of Directive 2001/83/EC.

2. The refusal of a ►M8 Union ◄ marketing authorisation shall constitute a prohibition on the placing on the market of the medicinal product concerned throughout the ►M8 Union ◄ .

3. Information about all refusals and the reasons for them shall be made publicly accessible.

Article 13

1. ►M2 Without prejudice to Article 4(4) and (5) of Directive 2001/83/EC, a marketing authorisation which has been granted in accordance with this Regulation shall be valid throughout the ►M8 Union ◄ . ◄ It shall confer the same rights and obligations in each of the Member States as a marketing authorisation granted by that Member State in accordance with Article 6 of Directive 2001/83/EC.

Authorised medicinal products for human use shall be entered in the ►M8 Union Register ◄ of Medicinal Products and shall be given a number, which shall appear on the packaging.

2. Notification of marketing authorisation shall be published in the Official Journal of the European Union, quoting in particular the date of authorisation and the registration number in the ►M8 Union Register ◄ , any International Non-proprietary Name (INN) of the active substance of the medicinal product, its pharmaceutical form, and any Anatomical Therapeutic Chemical Code (ATC).

3. The Agency shall immediately publish the assessment report on the medicinal product for human use drawn up by the Committee for Medicinal Products for Human Use and the reasons for its opinion in favour of granting authorisation, after deletion of any information of a commercially confidential nature.

The European Public Assessment Report (EPAR) 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.

4. After a marketing authorisation has been granted, the holder of the authorisation shall inform the Agency of the dates of actual marketing of the medicinal product for human use in the Member States, taking into account the various presentations authorised.

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The marketing authorisation holder shall notify the Agency if the product ceases to be placed on the market of a Member State, either temporarily or permanently. 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 Agency of the reasons for such action in accordance with Article 14b.

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Upon request by the Agency, particularly in the context of pharmacovigilance, the marketing authorisation holder shall provide the Agency with all data relating to the volume of sales of the medicinal product at ►M8 Union ◄ level, broken down by Member State, and any data in the holder's possession relating to the volume of prescriptions.

Article 14

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1. Without prejudice to paragraphs 4 and 5 of this Article and to Article 14-a, a marketing authorisation shall be valid for five years.

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2. The marketing authorisation may be renewed after five years on the basis of a re-evaluation by the Agency of the risk-benefit balance.

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To this end, the marketing authorisation holder shall provide the Agency 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 Chapter 3, 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 Commission 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.

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4. Any authorisation which is not followed by the actual placing of the medicinal product for human use on the ►M8 Union ◄ market within three years after authorisation shall cease to be valid.

5. When an authorised medicinal product previously placed on the market is no longer actually present on the market for three consecutive years, the authorisation shall cease to be valid.

6. In exceptional circumstances and on public health grounds the Commission may grant exemptions from paragraphs 4 and 5. Such exemptions must be duly justified.

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8. 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 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 to Directive 2001/83/EC. Continuation of the marketing authorisation shall be linked to the annual reassessment of these conditions.

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9. When an application is submitted for a marketing authorisation in respect of medicinal products for human use which are of major interest from the point of view of public health and in particular from the viewpoint of therapeutic innovation, the applicant may request an accelerated assessment procedure. The request shall be duly substantiated.

If the Committee for Medicinal Products for Human Use accepts the request, the time-limit laid down in Article 6(3), first subparagraph, shall be reduced to 150 days.

10. When adopting its opinion, the Committee for Medicinal Products for Human Use shall include a proposal concerning the criteria for the prescription or use of the medicinal products in accordance with Article 70(1) of Directive 2001/83/EC.

11. Without prejudice to the law on the protection of industrial and commercial property, medicinal products for human use which have been authorised in accordance with the provisions of this Regulation shall benefit from an eight-year period of data protection and a ten-year period of marketing protection, in which connection the latter period shall be extended to a maximum of 11 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.

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Article 14-a

1. In duly justified cases, to meet unmet medical needs of patients, a marketing authorisation may, for medicinal products intended for the treatment, prevention or medical diagnosis of seriously debilitating or life-threatening diseases, be granted prior to the submission of comprehensive clinical data provided that the benefit of the immediate availability on the market of the medicinal product concerned outweighs the risk inherent in the fact that additional data are still required. In emergency situations, a marketing authorisation for such medicinal products may be granted also where comprehensive pre-clinical or pharmaceutical data have not been supplied.

2. For the purposes of this Article, ‘unmet medical needs’ means a condition for which there exists no satisfactory method of diagnosis, prevention or treatment authorised in the Union or, even if such a method exists, in relation to which the medicinal product concerned will be of major therapeutic advantage to those affected.

3. Marketing authorisations may be granted pursuant to this Article only if the risk-benefit balance of the medicinal product is favourable and the applicant is likely to be able to provide comprehensive data.

4. Marketing authorisations granted pursuant to this Article shall be subject to specific obligations. Those specific obligations and, where appropriate, the time limit for compliance shall be specified in the conditions to the marketing authorisation. Those specific obligations shall be reviewed annually by the Agency.

5. As part of the specific obligations referred to in paragraph 4, the holder of a marketing authorisation granted pursuant to this Article shall be required to complete ongoing studies, or to conduct new studies, with a view to confirming that the risk-benefit balance is favourable.

6. The summary of product characteristics and the package leaflet shall clearly mention that the marketing authorisation for the medicinal product has been granted subject to specific obligations as referred to in paragraph 4.

7. By way of derogation from Article 14(1), a marketing authorisation granted pursuant to this Article shall be valid for one year, on a renewable basis.

8. When the specific obligations referred to in paragraph 4 of this Article have been fulfilled, the Commission may, following an application by the marketing authorisation holder, and after receiving a favourable opinion from the Agency, grant a marketing authorisation valid for five years and renewable pursuant to Article 14(2) and (3).

9. The Commission is empowered to adopt delegated acts in accordance with Article 87b in order to supplement this Regulation by specifying:

(a) the categories of medicinal products to which paragraph 1 of this Article applies; and

(b) the procedures and requirements for granting a marketing authorisation pursuant to this Article and for its renewal.

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Article 14a

The marketing authorisation holder shall incorporate any conditions referred to in points (c), (ca), (cb) and (cc) of Article 9(4) or in Article 10a, or in Article 14(7) and (8) in his risk management system.

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Article 14b

1. The marketing authorisation holder shall notify the Agency forthwith of any action the holder takes to suspend the marketing of a medicinal product, to withdraw a medicinal product from the market, to request the withdrawal of a marketing authorisation or not to apply for the renewal of a marketing authorisation, together with the reasons for such action. The marketing authorisation holder shall in particular declare if such action is based on any of the grounds set out in Article 116 or Article 117(1) of Directive 2001/83/EC.

2. The marketing authorisation holder shall also make the notification pursuant to paragraph 1 of this Article if the action is taken in a third country and such action is based on any of the grounds set out in Article 116 or Article 117(1) of Directive 2001/83/EC.

3. In the cases referred to in paragraphs 1 and 2, the Agency shall forward the information to the competent authorities of the Member States without undue delay.

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Article 15

The granting of authorisation shall not affect the civil or criminal liability of the manufacturer or of the holder of the marketing authorisation pursuant to the applicable national law in Member States.







Chapter 2

Supervision and penalties

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Article 16

1. After a marketing authorisation has been granted in accordance with this Regulation, the marketing authorisation holder shall, in respect of the methods of manufacture and control provided for in points (d) and (h) of Article 8(3) of Directive 2001/83/EC, 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. He shall apply for approval of corresponding variations in accordance with this Regulation.

2. The marketing authorisation holder shall forthwith provide the Agency, the Commission and the Member States with any new information which might entail the amendment of the particulars or documents referred to in Article 8(3), Article 10, 10a, 10b and 11, or Article 32(5) of Directive 2001/83/EC, in Annex I thereto, or in Article 9(4) of this Regulation.

In particular, the marketing authorisation holder shall forthwith inform the Agency and the Commission 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.

3a. In order to be able to continuously assess the risk-benefit balance, the Agency 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 Agency 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 seven days after receipt of the request.

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Article 16a

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 the 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 Agency.

3. The Commission is empowered to adopt delegated acts in accordance with Article 87b in order to supplement this Regulation 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.

Article 16b

A marketing authorisation may be transferred to a new marketing authorisation holder. Such a transfer shall not be considered to be a variation. The transfer shall be subject to prior approval by the Commission, following the submission of an application for the transfer to the Agency.

The Commission is empowered to adopt delegated acts in accordance with Article 87b in order to supplement this Regulation by establishing procedures for the examination of applications to the Agency for the transfer of marketing authorisations.

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Article 17

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

Article 18

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1. In the case of medicinal products manufactured within the Union, the supervisory authorities for manufacturing shall be the competent authorities of the Member State or Member States which granted the manufacturing authorisation provided for in Article 40(1) of Directive 2001/83/EC in respect of the medicinal product concerned.

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2. ►M5 In the case of medicinal products imported from third countries, the supervisory authorities for imports shall be the competent authorities of the Member State or Member States that granted the authorisation provided for in Article 40(3) of Directive 2001/83/EC to the importer, unless appropriate agreements have been made between the Union and the exporting country to ensure that those controls are carried out in the exporting country and that the manufacturer applies standards of good manufacturing practice at least equivalent to those laid down by the Union. ◄

A Member State may request assistance from another Member State or from the Agency.

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3. The supervisory authority for pharmacovigilance shall be the competent authority of the Member State in which the pharmacovigilance system master file is located.

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Article 19

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1. The supervisory authorities for manufacturing and imports shall be responsible for verifying on behalf of the Union that the marketing authorisation holder for the medicinal product or the manufacturer or importer established within the Union satisfies the requirements concerning manufacturing and imports laid down in Titles IV and XI of Directive 2001/83/EC.

The supervisory authorities for pharmacovigilance shall be responsible for verifying on behalf of the Union that the marketing authorisation holder for the medicinal product satisfies the pharmacovigilance requirements laid down in Titles IX and XI of Directive 2001/83/EC. They may, if this is considered necessary, conduct pre-authorisation inspections to verify the accuracy and successful implementation of the pharmacovigilance system as it has been described by the applicant in support of his application.

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2. Where, in accordance with Article 122 of Directive 2001/83/EC, the Commission is informed of serious differences of opinion between Member States as to whether the holder of the marketing authorisation for the medicinal product for human use or a manufacturer or importer established within the ►M8 Union ◄ satisfies the requirements referred to in paragraph 1, the Commission may, after consultation with the Member States concerned, request an inspector from the supervisory authority to undertake a new inspection of the marketing authorisation holder, the manufacturer or the importer; the inspector in question shall be accompanied by two inspectors from Member States which are not party to the dispute or by two experts nominated by the Committee for Medicinal Products for Human Use.

3. Subject to any agreements which may have been concluded between the ►M8 Union ◄ and third countries in accordance with Article 18(2), the Commission may, following a reasoned request from a Member State or from the said Committee, or on its own initiative, require a manufacturer established in a third country to submit to an inspection.

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The inspection shall be undertaken by inspectors from the Member States who possess the appropriate qualifications. They may be accompanied by a rapporteur or expert appointed by the Committee referred to in paragraph 2. The report of the inspectors shall be made available electronically to the Commission, the Member States and the Agency.

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Article 20

1. Where the supervisory authorities or the competent authorities of any other Member State are of the opinion that the manufacturer or importer established within the ►M8 Union ◄ territory is no longer fulfilling the obligations laid down in Title IV of Directive 2001/83/EC, they shall forthwith inform the Committee for Medicinal Products for Human Use and the Commission, stating their reasons in detail and indicating the course of action proposed.

The same shall apply where a Member State or the Commission considers that one of the measures envisaged in Titles IX and XI of Directive 2001/83/EC should be applied in respect of the medicinal product concerned or where the said Committee has delivered an opinion to that effect in accordance with Article 5 of this Regulation.

2. The Commission shall request the opinion of the Agency within a time-limit which it shall determine in the light of the urgency of the matter, in order to examine the reasons advanced. Whenever practicable, the holder of the authorisation for placing the medicinal product for human use on the market shall be invited to provide oral or written explanations.

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3. Following an opinion by the Agency, the Commission shall adopt the necessary provisional measures, which shall be applied immediately.

A final decision in respect of the medicinal product concerned shall be adopted within 6 months, in accordance with the regulatory procedure referred to in Article 87(2).

The Commission may also adopt a decision addressed to the Member States pursuant to Article 127a of Directive 2001/83/EC.

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4. Where urgent action is essential to protect human health or the environment, a Member State may, on its own initiative or at the Commission's request, suspend the use in its territory of a medicinal product for human use which has been authorised in accordance with this Regulation.

When it does so on its own initiative, it shall inform the Commission and the Agency of the reasons for its action at the latest on the next working day following the suspension. The Agency shall inform the other Member States without delay. The Commission shall immediately initiate the procedure provided for in paragraphs 2 and 3.

5. In this case, the Member State shall ensure that health-care professionals are rapidly informed of its action and the reasons for the action. Networks set up by professional associations may be used to this effect. The Member States shall inform the Commission and the Agency of actions taken for this purpose.

6. The suspensive measures referred to in paragraph 4 may be maintained in force until such time as a definitive decision has been reached in accordance with the procedure referred to in Article 87(3).

7. The Agency shall, upon request, inform any person concerned of the final decision and make the decision publicly accessible immediately after it has been taken.

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8. Where the procedure is initiated as a result of the evaluation of data relating to pharmacovigilance, the opinion of the Agency, in accordance with paragraph 2 of this Article, shall be adopted by the Committee for Medicinal Products for Human Use on the basis of a recommendation from the Pharmacovigilance Risk Assessment Committee and Article 107j(2) of Directive 2001/83/EC shall apply.

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9. By way of derogation from paragraphs 1 to 7 of this Article, where a procedure under Article 31 or Articles 107i to 107k of Directive 2001/83/EC concerns a range of medicinal products or a therapeutic class, medicinal products that are authorised in accordance with this Regulation and that belong to that range or class shall only be included in the procedure under Article 31, or Articles 107i to 107k of that Directive.

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Article 20a

Where the Agency concludes that a holder of a marketing authorisation granted pursuant to Article 14-a failed to comply with the obligations laid down in the marketing authorisation, the Agency shall inform the Commission accordingly. The Commission shall adopt a decision to vary, suspend or revoke that marketing authorisation in accordance with the procedure set out in Article 10.

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Chapter 3

Pharmacovigilance

Article 21

1. The obligations of marketing authorisation holders laid down in Article 104 of Directive 2001/83/EC shall apply to marketing authorisation holders for medicinal products for human use authorised in accordance with this Regulation.

Without prejudice to paragraphs 2, 3 and 4 of this Article, holders of marketing authorisations granted before 2 July 2012 shall, by way of derogation from Article 104(3)(c) of Directive 2001/83/EC not be required to operate a risk management system for each medicinal product.

2. The Agency may impose an obligation on a marketing authorisation holder to operate a risk management system, as referred to in point (c) of Article 104(3) of Directive 2001/83/EC, if there are concerns about the risks affecting the risk-benefit balance of an authorised medicinal product. In that context, the Agency shall also oblige the marketing authorisation holder to submit a detailed description of the risk-management system which he intends to introduce for the medicinal product concerned.

The imposition of such obligations shall be duly justified, notified in writing, and shall include the timeframe for submission of the detailed description of the risk-management system.

3. The Agency 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.

4. On the basis of the written observations submitted by the marketing authorisation holder, and of the opinion of the Agency, the Commission shall withdraw or confirm the obligation. Where the Commission confirms the obligation, the marketing authorisation shall be varied accordingly, to include the measures to be taken as part of the risk management system as conditions of the marketing authorisation referred to in point (ca) of Article 9(4).

Article 22

The obligations of marketing authorisation holders laid down in Article 106a(1) of Directive 2001/83/EC, and the obligations of the Member States, the Agency and the Commission laid down in paragraphs 2, 3 and 4 of that Article shall apply to the safety announcements referred to in point (e) of Article 57(1) of this Regulation concerning medicinal products for human use authorised in accordance with this Regulation.

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Article 23

1. The Agency shall, in collaboration with the Member States, set up, maintain and make public a list of medicinal products that are subject to additional monitoring.

That list shall include the names and active substances of:

(a) medicinal products authorised in the Union that contain a new active substance which, on 1 January 2011, was not contained in any medicinal product authorised in the Union;

(b) any biological medicinal product not covered by point (a) that was authorised after 1 January 2011;

(c) medicinal products that are authorised pursuant to this Regulation, subject to the conditions referred to in point (cb) of Article 9(4), point (a) of the first subparagraph of Article 10a(1) or Article 14(7) or (8);

(d) medicinal products that are authorised pursuant to Directive 2001/83/EC, subject to the conditions referred to in points (b) and (c) of the first paragraph of Article 21a, Article 22, or point (a) of the first subparagraph of Article 22a(1) thereof.

1a. At the request of the Commission, following consultation with the Pharmacovigilance Risk Assessment Committee, medicinal products that are authorised pursuant to this Regulation, subject to the conditions referred to in points (c), (ca) or (cc) of Article 9(4), point (b) of the first subparagraph of Article 10a(1) or Article 21(2), may also be included in the list referred to in paragraph 1 of this Article.

At the request of a national competent authority, following consultation with the Pharmacovigilance Risk Assessment Committee, medicinal products that are authorised pursuant to Directive 2001/83/EC, subject to the conditions referred to in points (a), (d), (e) or (f) of the first paragraph of Article 21a, point (b) of the first subparagraph of Article 22a(1) or Article 104a(2) thereof, may also be included in the list referred to in paragraph 1 of this Article.

2. The list referred to in paragraph 1 shall include an electronic link to the product information and to the summary of the risk management plan.

3. In the cases referred to in points (a) and (b) of paragraph 1 of this Article, the Agency shall remove a medicinal product from the list five years after the Union reference date referred to in Article 107c(5) of Directive 2001/83/EC.

In the cases referred to in points (c) and (d) of paragraph 1 and in paragraph 1a of this Article, the Agency shall remove a medicinal product from the list once the conditions have been fulfilled.

4. For medicinal products included in the list referred to in paragraph 1, the summary of product characteristics and the package leaflet shall include the statement ‘This medicinal product is subject to additional monitoring’. That statement shall be preceded by a black symbol which shall be selected by the Commission by 2 July 2013, following a recommendation of the Pharmacovigilance Risk Assessment Committee, and shall be followed by an appropriate standardised explanatory sentence.

4a. By 5 June 2018, the Commission shall present to the European Parliament and the Council a report on the use of the list referred to in paragraph 1 based on the experience and data provided by the Member States and the Agency.

The Commission shall, if appropriate, on the basis of that report, and after consultation with the Member States and other appropriate stakeholders, present a proposal in order to adjust the provisions relating to the list referred to in paragraph 1.

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Article 24

1. The Agency shall, in collaboration with the Member States and the Commission, set up and maintain a database and data processing network (hereinafter the ‘Eudravigilance database’) to collate pharmacovigilance information regarding medicinal products authorised in the Union and to allow competent authorities to access that information simultaneously and to share it.

The Eudravigilance database shall contain information on suspected adverse reactions in human beings arising from use of the medicinal product within the terms of the marketing authorisation as well as from uses outside the terms of the marketing authorisation, and on those occurring in the course of post-authorisation studies with the medicinal product or associated with occupational exposure.

2. The Agency shall, in collaboration with the Member States and the Commission, draw up the functional specifications for the Eudravigilance database, together with a timeframe for their implementation.

The Agency shall prepare an annual report on the Eudravigilance database and send it to the European Parliament, the Council and the Commission. The first annual report shall be prepared by 2 January 2013.

The Management Board of the Agency shall on the basis of an independent audit report that takes into account the recommendation of the Pharmacovigilance Risk Assessment Committee confirm and announce when the Eudravigilance database has achieved full functionality and the system meets the functional specifications drawn up pursuant to the first subparagraph.

Any substantial change to the Eudravigilance database and the functional specifications shall take into account the recommendations of the Pharmacovigilance Risk Assessment Committee.

The Eudravigilance database shall be fully accessible to the competent authorities of the Member States and to the Agency and the Commission. It shall also be accessible to marketing authorisation holders to the extent necessary for them to comply with their pharmacovigilance obligations.

The Agency shall ensure that healthcare professionals and the public have appropriate levels of access to the Eudravigilance database, while guaranteeing personal data protection. The Agency shall work together with all stakeholders, including research institutions, healthcare professionals, and patient and consumer organisations, in order to define the ‘appropriate level of access’ for healthcare professionals and the public to the Eudravigilance database.

The data held on the Eudravigilance database shall be made publicly accessible in an aggregated format together with an explanation of how to interpret the data.

3. The Agency shall, in collaboration either with the marketing authorisation holder or with the Member State that submitted an individual suspected adverse reaction report to the Eudravigilance database, be responsible for operating procedures that ensure the quality and integrity of the information collected in the Eudravigilance database.

4. Individual suspected adverse reaction reports and follow-ups submitted to the Eudravigilance database by marketing authorisation holders shall be transmitted electronically upon receipt to the competent authority of the Member State where the reaction occurred.

Article 25

The Agency shall, in collaboration with the Member States, develop standard web-based structured forms for the reporting of suspected adverse reactions by healthcare professionals and patients in accordance with the provisions referred to in Article 107a of Directive 2001/83/EC.

Article 25a

The Agency shall, in collaboration with the national competent authorities and the Commission, set up and maintain a repository for periodic safety update reports (hereinafter the ‘repository’) and the corresponding assessment reports so that they are fully and permanently accessible to the Commission, the national competent authorities, the Pharmacovigilance Risk Assessment Committee, the Committee for Medicinal Products for Human Use and the coordination group referred to in Article 27 of Directive 2001/83/EC (hereinafter the ‘coordination group’).

The Agency shall, in collaboration with the national competent authorities and the Commission, and after consultation with the Pharmacovigilance Risk Assessment Committee, draw up the functional specifications for the repository.

The Management Board of the Agency shall, on the basis of an independent audit report that takes into account the recommendations of the Pharmacovigilance Risk Assessment Committee, confirm and announce when the repository has achieved full functionality and meets the functional specifications drawn up pursuant to the second paragraph.

Any substantial change to the repository and the functional specifications shall always take into account the recommendations of the Pharmacovigilance Risk Assessment Committee.

Article 26

1. The Agency shall, in collaboration with the Member States and the Commission, set up and maintain a European medicines web-portal for the dissemination of information on medicinal products authorised in the Union. By means of that portal, the Agency shall make public at least the following:

(a) the names of members of the Committees referred to in points (a) and (aa) of Article 56(1) of this Regulation and the members of the coordination group, together with their professional qualifications and with the declarations referred to in Article 63(2) of this Regulation;

(b) agendas and minutes from each meeting of the Committees referred to in points (a) and (aa) of Article 56(1) of this Regulation and of the coordination group as regards pharmacovigilance activities;

(c) a summary of the risk management plans for medicinal products authorised in accordance with this Regulation;

(d) the list of medicinal products referred to in Article 23 of this Regulation;

(e) a list of the locations in the Union where pharmacovigilance system master files are kept and contact information for pharmacovigilance enquiries, for all medicinal products authorised in the Union;

(f) information about how to report to national competent authorities suspected adverse reactions to medicinal products and the standard structured forms referred to in Article 25 for their web-based reporting by patients and healthcare professionals, including links to national websites;

(g) Union reference dates and frequency of submission of periodic safety update reports established in accordance with Article 107c of Directive 2001/83/EC;

(h) protocols and public abstracts of results of the post-authorisation safety studies referred to in Articles 107n and 107p of Directive 2001/83/EC;

(i) the initiation of the procedure provided for in Articles 107i to 107k of Directive 2001/83/EC, the active substances or medicinal products concerned and the issue being addressed, any public hearings pursuant to that procedure and information on how to submit information and to participate in public hearings;

(j) conclusions of assessments, recommendations, opinions, approvals and decisions taken by the Committees referred to in points (a) and (aa) of Article 56(1) of this Regulation and by the coordination group, the national competent authorities and the Commission in the framework of the procedures of Articles 28, 28a and 28b of this Regulation and of sections 2 and 3 of Chapter 3 and Chapter 4 of Title IX of Directive 2001/83/EC.

2. Before the launch of this portal, and during subsequent reviews, the Agency shall consult relevant stakeholders, including patient and consumer groups, healthcare professionals and industry representatives.

Article 27

1. The Agency shall monitor selected medical literature for reports of suspected adverse reactions to medicinal products containing certain active substances. It shall publish the list of active substances being monitored and the medical literature subject to this monitoring.

2. The Agency shall enter into the Eudravigilance database relevant information from the selected medical literature.

3. The Agency shall, in consultation with the Commission, Member States and interested parties, draw up a detailed guide regarding the monitoring of medical literature and the entry of relevant information into the Eudravigilance database.

Article 28

1. The obligations of marketing authorisation holders and of Member States laid down in Articles 107 and 107a of Directive 2001/83/EC shall apply to the recording and reporting of suspected adverse reactions for medicinal products for human use authorised in accordance with this Regulation.

2. The obligations of marketing authorisation holders laid down in Article 107b of Directive 2001/83/EC and the procedures under Article 107b and Article 107c of that Directive shall apply to the submission of periodic safety update reports, the establishment of Union reference dates and changes to the frequency of submission of periodic safety update reports for medicinal products for human use authorised in accordance with this Regulation.

The provisions applicable to the submission of periodic safety update reports laid down in the second subparagraph of Article 107c(2) of that Directive shall apply to holders of marketing authorisations which were granted before 2 July 2012 and for which the frequency and dates of submission of the periodic safety update reports are not laid down as a condition to the marketing authorisation until such time as another frequency or other dates of submission of the reports are laid down in the marketing authorisation or are determined in accordance with Article 107c of that Directive.

3. The assessment of the periodic safety update reports shall be conducted by a rapporteur appointed by the Pharmacovigilance Risk Assessment Committee. The rapporteur shall closely collaborate with the rapporteur appointed by the Committee for Medicinal Products for Human Use or the Reference Member State for the medicinal products concerned.

The rapporteur shall prepare an assessment report within 60 days of receipt of the periodic safety update report and send it to the Agency and to the members of the Pharmacovigilance Risk Assessment Committee. The Agency shall send the report to the marketing authorisation holder.

Within 30 days of receipt of the assessment report, the marketing authorisation holder and the members of the Pharmacovigilance Risk Assessment Committee may submit comments to the Agency and to the rapporteur.

Following the receipt of the comments referred to in the third subparagraph, the rapporteur shall within 15 days update the assessment report taking into account any comments submitted, and forward it to the Pharmacovigilance Risk Assessment Committee. The Pharmacovigilance Risk Assessment Committee shall adopt the assessment report with or without further changes at its next meeting and issue a recommendation. The recommendation shall mention the divergent positions with the grounds on which they are based. The Agency shall include the adopted assessment report and the recommendation in the repository set up under Article 25a, and forward both to the marketing authorisation holder.

4. In the case of an assessment report that recommends any action concerning the marketing authorisation, the Committee for Medicinal Products for Human Use shall, within 30 days of receipt of the report by the Pharmacovigilance Risk Assessment Committee, consider the report and adopt an opinion on the maintenance, variation, suspension or revocation of the marketing authorisation concerned, including a timetable for the implementation of the opinion. Where this opinion of the Committee for Medicinal Products for Human Use differs from the recommendation of the Pharmacovigilance Risk Assessment Committee, the Committee for Medicinal Products for Human Use shall attach to its opinion a detailed explanation of the scientific grounds for the differences together with the recommendation.

Where the opinion states that regulatory action concerning the marketing authorisation is necessary, the Commission shall adopt a decision to vary, suspend or revoke the marketing authorisation. Article 10 of this Regulation shall apply to the adoption of that decision. Where the Commission adopts such a decision, it may also adopt a decision addressed to the Member States pursuant to Article 127a of Directive 2001/83/EC.

5. In the case of a single assessment of periodic safety update reports concerning more than one marketing authorisation in accordance with Article 107e(1) of Directive 2001/83/EC which includes at least one marketing authorisation granted in accordance with this Regulation, the procedure laid down in Articles 107e and 107g of that Directive shall apply.

6. The final recommendations, opinions and decisions referred to in paragraphs 3 to 5 of this Article shall be made public by means of the European medicines web-portal referred to in Article 26.

Article 28a

1. Regarding medicinal products for human use authorised in accordance with this Regulation, the Agency shall, in collaboration with the Member States, take the following measures:

(a) monitor the outcome of risk minimisation measures contained in risk management plans and of conditions referred to in points (c), (ca), (cb) and (cc) of Article 9(4) or in points (a) and (b) of Article 10a(1), and in Article 14(7) and (8);

(b) assess updates to the risk management system;

(c) monitor the data in the Eudravigilance database to determine whether there are new risks or whether risks have changed and whether those risks impact on the risk-benefit balance.

2. The Pharmacovigilance Risk Assessment Committee shall perform the initial analysis and prioritisation of signals of new risks or risks that have changed or changes to the risk-benefit balance. Where it considers that follow-up action may be necessary, the assessment of those signals and agreement on any subsequent action concerning the marketing authorisation shall be conducted in a timescale commensurate with the extent and seriousness of the issue.

3. The Agency and national competent authorities and the marketing authorisation holder shall inform each other in the event of new risks or risks that have changed or changes to the risk-benefit balance being detected.

Article 28b

1. For non-interventional post-authorisation safety studies concerning medicinal products for human use authorised in accordance with this Regulation which fulfil one of the requirements referred to in Articles 10 and 10a of this Regulation, the procedure provided for in paragraphs 3 to 7 of Article 107m, Articles 107n to 107p and Article 107q(1) of Directive 2001/83/EC shall apply.

2. Where, in accordance with the procedure referred to in paragraph 1 of this Article, the Pharmacovigilance Risk Assessment Committee issues recommendations for the variation, suspension or revocation of the marketing authorisation, the Committee on Medicinal Products for Human Use shall adopt an opinion taking into account the recommendation, and the Commission shall adopt a decision in accordance with Article 10.

Where the opinion of the Committee on Medicinal Products for Human Use differs from the recommendation of the Pharmacovigilance Risk Assessment Committee, the Committee on Medicinal Products for Human Use shall attach to its opinion a detailed explanation of the scientific grounds for the differences, together with the recommendation.

Article 28c

1. The Agency shall collaborate with the World Health Organisation in matters of pharmacovigilance and shall take the necessary steps to submit to it, promptly, appropriate and adequate information regarding the measures taken in the Union which may have a bearing on public health protection in third countries.

The Agency shall make available promptly all suspected adverse reaction reports occurring in the Union to the World Health Organisation.

2. The Agency and the European Monitoring Centre for Drugs and Drug Addiction shall exchange information that they receive on the abuse of medicinal products including information related to illicit drugs.

Article 28d

At the request of the Commission, the Agency shall participate in collaboration with the Member States in international harmonisation and standardisation of technical measures in relation to pharmacovigilance.

Article 28e

The Agency and the Member States shall cooperate to continuously develop pharmacovigilance systems capable of achieving high standards of public health protection for all medicinal products, regardless of the routes of marketing authorisation, including the use of collaborative approaches, to maximise use of resources available within the Union.

Article 28f

The Agency shall perform regular independent audits of its pharmacovigilance tasks and report the results to its Management Board on a 2-yearly basis.

Article 29

The Commission shall make public a report on the performance of pharmacovigilance tasks by the Agency on 2 January 2014 at the latest and subsequently every 3 years thereafter.

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TITLE III

AUTHORISATION AND SUPERVISION OF VETERINARY MEDICINAL PRODUCTS







Chapter 1

Submission and examination of applications — Authorisations

Article 30

1. A Committee for Medicinal Products for Veterinary Use is hereby established. The Committee shall be part of the Agency.

2. Without prejudice to Article 56 and other tasks which ►M8 Union ◄ law may confer on it, in particular under Regulation (EEC) No 2377/90 ( 2 ), the Committee for Medicinal Products for Veterinary Use shall be responsible for drawing up the opinion of the Agency on any question concerning the admissibility of files submitted in accordance with the centralised procedure, the granting, variation, suspension or revocation of an authorisation to place a veterinary medicinal product on the market arising in accordance with the provisions of this Title, and pharmacovigilance.

3. At the request of the Executive Director of the Agency or the Commission representative, the Committee for Medicinal Products for Veterinary Use shall also draw up opinions on any scientific matters concerning the evaluation of veterinary medicinal products. The Committee shall take due account of any requests from Member States for an opinion. The Committee shall also formulate an opinion whenever there is disagreement in the assessment of a veterinary medicinal product through the mutual recognition procedure. The opinion of the Committee shall be made publicly accessible.

Article 31

1. Each application for the authorisation of a medicinal product for veterinary use shall specifically and exhaustively include the particulars and documents as referred to in Articles 12(3), 13, 13a, 13b and 14 of, and Annex I to, Directive 2001/82/EC. These particulars and documents shall take account of the unique, ►M8 Union ◄ nature of the authorisation requested and, otherwise than in exceptional cases relating to the application of the law on trade marks, shall include the use of a single name for the medicinal product.

The application shall be accompanied by the fee payable to the Agency for the examination of the application.

2. In the case of a veterinary medicinal product containing or consisting of genetically modified organisms within the meaning of Article 2 of Directive 2001/18/EC, the application shall also be accompanied by:

(a) a copy of the written consent of the competent authorities to the deliberate release into the environment of the genetically modified organisms for research and development purposes, as provided for in Part B of Directive 2001/18/EC or in Part B of Directive 90/220/EEC;

(b) the complete technical file supplying the information required under Annexes III and IV to Directive 2001/18/EC;

(c) the environmental risk assessment in accordance with the principles set out in Annex II to Directive 2001/18/EC; and

(d) the results of any investigations performed for the purposes of research or development.

Articles 13 to 24 of Directive 2001/18/EC shall not apply to veterinary medicinal products containing or consisting of genetically modified organisms.

3. The Agency shall ensure that the opinion of the Committee for Medicinal Products for Veterinary Use is given within 210 days after the receipt of a valid application.

In the case of a veterinary medicinal product containing or consisting of genetically modified organisms, the opinion of the said Committee must respect the environmental safety requirements laid down by Directive 2001/18/EC. During the process of evaluating applications for marketing authorisations for veterinary medicinal products containing or consisting of genetically modified organisms, necessary consultations shall be held by the rapporteur with the bodies set up by the ►M8 Union ◄ or the Member States in accordance with Directive 2001/18/EC.

4. The Commission shall, in consultation with the Agency, Member States and interested parties, draw up a detailed guide regarding the form in which applications for authorisation are to be presented.

Article 32

1. In order to prepare its opinion, the Committee for Medicinal Products for Veterinary Use:

(a) shall verify that the particulars and documents submitted in accordance with Article 31 comply with the requirements of Directive 2001/82/EC and examine whether the conditions specified in this Regulation for granting a marketing authorisation are satisfied;

(b) may request that an Official Medicines Control Laboratory or a laboratory that a Member State has designated for that purpose test the veterinary medicinal product, its starting materials and, where appropriate, its intermediate products or other constituent materials in order to ensure that the control methods employed by the manufacturer and described in the application are satisfactory;

(c) may request a ►M8 Union ◄ reference laboratory, Official Medicines Control Laboratory or laboratory that a Member State has designated for that purpose to verify, using samples provided by the applicant, that the analytical detection method proposed by the applicant for the purposes of Article 12(3)(j), second indent, of Directive 2001/82/EC is satisfactory and is suitable for use to reveal the presence of residue levels, particularly those above the maximum residue level accepted by the ►M8 Union ◄ in accordance with the provisions of Regulation (EEC) No 2377/90;

(d) may request the applicant to supplement the particulars accompanying the application within a specific time-limit. Where the said Committee avails itself of this option, the time-limit laid down in Article 31(3), first subparagraph shall be suspended until such time as the supplementary information requested has been provided. Likewise, the time-limit shall be suspended for the time allowed to the applicant to prepare oral or written explanations.

2. In those cases where the analytical method has not been subject to verification by one of the abovementioned laboratories under the procedures established by Regulation (EEC) No 2377/90, the verification shall be carried out within the framework of this Article.

Article 33

1. Upon receipt of a written request from the Committee for Medicinal Products for Veterinary Use, a Member State shall forward the information establishing that the manufacturer of a veterinary medicinal product or the importer from a third country is able to manufacture the veterinary medicinal product concerned and/or carry out the necessary control tests in accordance with the particulars and documents supplied pursuant to Article 31.

2. Where it considers it necessary in order to complete its examination of the application, the said Committee may require the applicant to undergo a specific inspection of the manufacturing site of the veterinary medicinal product concerned. Such inspections may be made unannounced.

The inspection, which shall be completed within the time-limit referred to in Article 31(3), first subparagraph, shall be undertaken by inspectors from the Member State who possess the appropriate qualifications; they may be accompanied by a rapporteur or expert appointed by the said Committee.

Article 34

1. The Agency shall forthwith inform the applicant if the opinion of the Committee for Medicinal Products for Veterinary Use is that:

(a) the application does not satisfy the criteria for authorisation set out in this Regulation;

(b) the summary of the product characteristics should be amended;

(c) the labelling or package leaflet of the product is not in compliance with Title V of Directive 2001/82/EC;

(d) the authorisation should be granted subject to the conditions provided for in Article 39(7).

2. Within 15 days after receipt of the opinion referred to in paragraph 1, the applicant may provide written notice to the Agency that he wishes to request a re-examination of the opinion. In that case the applicant shall forward to the Agency the detailed grounds for the request within 60 days after receipt of the opinion.

Within 60 days after receipt of the grounds for the request, the said Committee shall re-examine its opinion in accordance with the conditions laid down in Article 62(1), fourth subparagraph. The reasons for the conclusion reached shall be annexed to the final opinion.

3. Within 15 days after its adoption, the Agency shall forward the final opinion of the said Committee to the Commission, to Member States and to the applicant, together with a report describing the assessment of the veterinary medicinal product by the Committee and stating the reasons for its conclusions.

4. If an opinion is favourable to the granting of the relevant authorisation to place the relevant veterinary medicinal product 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 14 of Directive 2001/82/EC; where appropriate, this draft shall reflect differences in the veterinary conditions in the Member States;

(b) in the case of a veterinary medicinal product intended for administration to food-producing animals, a statement of the maximum residue level which may be accepted by the ►M8 Union ◄ in accordance with Regulation (EEC) No 2377/90;

(c) details of any conditions or restrictions which should be imposed on the supply or use of the veterinary medicinal product concerned, including the conditions under which the veterinary medicinal product may be made available to users, in conformity with the criteria laid down in Directive 2001/82/EC;

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

(e) the draft text of the labelling and package leaflet proposed by the applicant, presented in accordance with Title V of Directive 2001/82/EC;

(f) the assessment report.

Article 35

1. Within 15 days after receipt of the opinion referred to in Article 30(2), the Commission shall prepare a draft of the decision to be taken in respect of the application.

Where a draft decision envisages the granting of marketing authorisation, it shall include or make reference to the documents mentioned in Article 34(4)(a) to (e).

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

The draft decision shall be forwarded to Member States and the applicant.

2. The Commission shall take a final decision in accordance with, and within 15 days after the end of, the procedure referred to in Article 87(3).

3. The Standing Committee for Veterinary Medicinal Products referred to in Article 87(1) shall adjust its rules of procedure so as to take account of the tasks assigned to it by this Regulation.

The adjustments shall provide that:

(a) the opinion of the said Standing Committee is to 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 may request in writing that the draft decision referred to in paragraph 1 be discussed at a plenary meeting of the said Standing Committee, stating their reasons in detail.

4. 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.

5. The provisions necessary for the implementation of paragraph 4 shall be adopted by the Commission in accordance with the procedure referred to in Article 87(2).

6. The Agency shall disseminate the documents referred to in Article 34(4) (a) to (e).

Article 36

If an applicant withdraws an application for a marketing authorisation submitted to the Agency before an opinion has been given on the application, the applicant shall communicate its reasons for doing so to the Agency. The Agency shall make this information publicly accessible and shall publish the assessment report, if available, after deletion of all information of a commercially confidential nature.

Article 37

1. The marketing authorisation shall be refused if, after verification of the particulars and documents submitted in accordance with Article 31, it appears that:

(a) the applicant has not properly or sufficiently demonstrated the quality, safety or efficacy of the veterinary medicinal product;

(b) in the case of zootechnical veterinary medicinal products and performance enhancers, when the safety and welfare of the animals and/or consumer safety have not been sufficiently taken into account;

(c) the withdrawal period recommended by the applicant is not long enough to ensure that foodstuffs obtained from treated animals do not contain residues which might constitute a health hazard for the consumer or is insufficiently substantiated;

(d) the veterinary medicinal product is presented for a use prohibited under other ►M8 Union ◄ provisions.

Authorisation shall likewise be refused if particulars or documents provided by the applicant in accordance with Article 31 are incorrect or if the labelling and package leaflets proposed by the applicant are not in accordance with Title V of Directive 2001/82/EC.

2. The refusal of a ►M8 Union ◄ marketing authorisation shall constitute a prohibition on the placing on the market of the veterinary medicinal product concerned throughout the ►M8 Union ◄ .

3. Information about all refusals and the reasons for them shall be made publicly accessible.

Article 38

1. Without prejudice to Article 71 of Directive 2001/82/EC, a marketing authorisation which has been granted in accordance with this Regulation shall be valid throughout the ►M8 Union ◄ . It shall confer the same rights and obligations in each of the Member States as a marketing authorisation granted by that Member State in accordance with Article 5 of Directive 2001/82/EC.

Authorised veterinary medicinal products shall be entered in the ►M8 Union ◄ Register of Medicinal Products and shall be given a number which shall appear on the packaging.

2. Notification of marketing authorisation shall be published in the Official Journal of the European Union, quoting in particular the date of authorisation and the number in the ►M8 Union ◄ Register, any International Non-proprietary Name (INN) of the active substance of the medicinal product, its pharmaceutical form, and any Anatomical Therapeutic Chemical Veterinary Code (ATC Vet Code).

3. The Agency shall immediately publish the assessment report on the veterinary medicinal product drawn up by the Committee for Medicinal Products for Veterinary Use and the reasons for its opinion in favour of granting authorisation, after deletion of any information of a commercially confidential nature.

The European Public Assessment Report (EPAR) 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.

4. After a marketing authorisation has been granted, the holder of the authorisation shall inform the Agency of the dates of actual placing on the market of the veterinary medicinal product in Member States, taking into account the various presentations authorised.

The holder shall also notify the Agency if the product ceases to be placed on the market, either temporarily or permanently. Such notification shall, other than in exceptional circumstances, be made no less than 2 months before the interruption in the placing of the product on the market.

Upon request by the Agency, particularly in the context of pharmacovigilance, the marketing authorisation holder shall provide the Agency with all data relating to the volume of sales of the medicinal product at ►M8 Union ◄ level, broken down by Member State, and any data in the holder's possession relating to the volume of prescriptions.

Article 39

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 by the Agency of the risk-benefit balance.

To this end, the marketing authorisation holder shall submit a consolidated list of all documents submitted in respect of quality, safety and efficacy, including all variations introduced since the marketing authorisation was granted, at least six months before the marketing authorisation ceases to be valid in accordance with paragraph 1. The Agency may require the applicant to submit the listed documents at any time.

3. Once renewed, the marketing authorisation shall be valid for an unlimited period, unless the Commission decides, on justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal in accordance with paragraph 2.

4. Any authorisation which is not followed by the actual placing of the medicinal product for veterinary use on the ►M8 Union ◄ market within three years after authorisation shall cease to be valid.

5. When an authorised medicinal product previously placed on the market is no longer actually present on the market for three consecutive years, the authorisation shall cease to be valid.

6. In exceptional circumstances and on public and/or animal health grounds the Commission may grant exemptions from the provisions of paragraphs 4 and 5. Such exemptions must be duly justified.

7. In exceptional circumstances and following consultation with the applicant, authorisation may be granted subject to a requirement for the applicant to introduce specific procedures, in particular concerning product safety, notification to the relevant authorities of any incident relating to its use, and action to be taken. This authorisation may be granted only for objective, verifiable reasons. Continuation of the authorisation shall be linked to the annual reassessment of these conditions.

8. When an application is submitted for a marketing authorisation in respect of veterinary medicinal products of major interest, particularly from the point of view of animal health and from the viewpoint of therapeutic innovation, the applicant may request an accelerated assessment procedure. The request shall be duly substantiated.

If the Committee for Medicinal Products for Veterinary Use accepts the request, the time-limit laid down in Article 31(3), first subparagraph, shall be reduced to 150 days.

9. When adopting its opinion, the said Committee shall include a proposal concerning the conditions for the prescription or use of the veterinary medicinal products.

10. Veterinary medicinal products which have been authorised in accordance with the provisions of this Regulation shall benefit from the provisions on protection in Articles 13 and 13a of Directive 2001/82/EC.

Article 40

The granting of authorisation shall not affect the civil or criminal liability of the manufacturer or the holder of the marketing authorisation pursuant to the applicable national law in Member States.







Chapter 2

Supervision and sanctions

Article 41

1. After an authorisation has been granted in accordance with this Regulation, the holder of the marketing authorisation shall, in respect of the methods of manufacture and control provided for in Article 12(3)(d) and (i) of Directive 2001/82/EC, take account of technical and scientific progress and make any variations that may be required to enable the medicinal products to be manufactured and checked by means of generally accepted scientific methods. He shall apply for approval of these variations in accordance with this Regulation.

2. The competent authority of a Member State or the Agency may require the holder of the marketing authorisation to provide substances in sufficient quantities for the performance of tests to detect the presence of residues of the veterinary medicinal products concerned in foodstuffs of animal origin.

3. At the request of the competent authority of a Member State or the Agency, the holder of the marketing authorisation shall provide technical expertise to facilitate the implementation of the analytical method for detecting residues of veterinary medicinal products by the ►M8 Union ◄ reference laboratory or, where appropriate, national reference laboratories designated in accordance with Council Directive 96/23/EC of 29 April 1996 on measures to monitor certain substances and residues thereof in live animals and animal products ( 3 ).

4. The holder of the marketing authorisation shall forthwith supply to the Agency, the Commission and the Member States any new information which might entail the variation of the particulars or documents referred to in Articles 12(3), 13, 13a, 13b and 14 of Directive 2001/82/EC, in Annex I thereto, or in Article 34(4) of this Regulation.

He shall forthwith inform the Agency, the Commission and the Member States of any prohibition or restriction imposed by the competent authorities of any country in which the veterinary medicinal product is marketed and of any other new information which might influence the evaluation of the benefits and risks of the veterinary medicinal product concerned.

In order that the risk-benefit balance may be continuously assessed, the Agency may at any time ask the holder of the marketing authorisation to forward data justifying that the risk-benefit balance remains favourable.

5. If the holder of the marketing authorisation for the veterinary medicinal product proposes to make any variation of the particulars and documents referred to in paragraph 4, he shall submit the relevant application to the Agency.

▼M3

6. The Commission shall, after consulting the Agency, adopt appropriate provisions for the examination of variations to marketing authorisations in the form of a regulation. Those measures, designed to amend non-essential elements of this regulation by supplementing it, shall be adopted in accordance with the regulatory procedure with scrutiny referred to in Article 87(2a).

▼B

Article 42

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

Article 43

1. In the case of veterinary medicinal products manufactured within the ►M8 Union ◄ , the supervisory authorities shall be the competent authorities of the Member State or Member States which granted the manufacturing authorisation provided for in Article 44(1) of Directive 2001/82/EC in respect of the manufacture of the medicinal product concerned.

2. In the case of veterinary medicinal products imported from third countries, the supervisory authorities shall be the competent authorities of the Member State or Member States that granted the authorisation provided for in Article 44(3) of Directive 2001/82/EC to the importer, unless appropriate agreements have been made between the ►M8 Union ◄ and the exporting country to ensure that those controls are carried out in the exporting country and that the manufacturer applies standards of good manufacturing practice at least equivalent to those laid down by the ►M8 Union ◄ .

A Member State may request assistance from another Member State or the Agency.

Article 44

1. The supervisory authorities shall be responsible for verifying on behalf of the ►M8 Union ◄ that the holder of the marketing authorisation for the veterinary medicinal product or the manufacturer or importer established within the ►M8 Union ◄ satisfies the requirements laid down in Titles IV, VII and VIII of Directive 2001/82/EC.

2. Where, in accordance with Article 90 of Directive 2001/82/EC, the Commission is informed of serious differences of opinion between Member States as to whether the holder of the marketing authorisation for the veterinary medicinal product or a manufacturer or importer established within the ►M8 Union ◄ satisfies the requirements referred to in paragraph 1, the Commission may, after consultation with the Member States concerned, request an inspector from the supervisory authority to undertake a new inspection of the holder of the marketing authorisation, the manufacturer or the importer; the inspector in question shall be accompanied by two inspectors from Member States which are not party to the dispute and/or by two experts nominated by the Committee for Medicinal Products for Veterinary Use.

3. Subject to any agreements which may have been concluded between the ►M8 Union ◄ and third countries in accordance with Article 43(2), the Commission may, upon receipt of a reasoned request from a Member State or from the said Committee, or on its own initiative, require a manufacturer established in a third country to submit to an inspection.

The inspection shall be undertaken by inspectors from the Member State who possess the appropriate qualifications; they may be accompanied by a rapporteur or expert appointed by the said Committee. The report of the inspectors shall be made available to the Commission, the Member States and the said Committee.

Article 45

1. Where the supervisory authorities or the competent authorities of any other Member State are of the opinion that the manufacturer or importer established within the ►M8 Union ◄ is no longer fulfilling the obligations laid down in Title VII of Directive 2001/82/EC, they shall forthwith inform the Committee for Medicinal Products for Veterinary Use and the Commission, stating their reasons in detail and indicating the course of action proposed.

The same shall apply where a Member State or the Commission considers that one of the measures envisaged in Title VIII of Directive 2001/82/EC should be applied in respect of the veterinary medicinal product concerned or where the said Committee has delivered an opinion to that effect in accordance with Article 30 of this Regulation.

2. The Commission shall request the opinion of the Agency within a time-limit which it shall determine in the light of the urgency of the matter, in order to examine the reasons advanced. Whenever practicable, the holder of the marketing authorisation for the medicinal product shall be invited to provide oral or written explanations.

3. Following an opinion by the Agency, the Commission shall adopt the necessary provisional measures, which shall be applied immediately.

A final decision shall be adopted within six months, in accordance with the procedure referred to in Article 87(3).

4. Where urgent action is essential to protect human or animal health or the environment, a Member State may, on its own initiative or at the Commission's request, suspend the use on its territory of a veterinary medicinal product which has been authorised in accordance with this Regulation.

When it does so on its own initiative, the Member State shall inform the Commission and the Agency of the reasons for its action at the latest on the next working day following the suspension. The Agency shall inform the other Member States without delay. The Commission shall immediately initiate the procedure provided for in paragraphs 2 and 3.

5. In this case, the Member State shall ensure that health-care professionals are rapidly informed of its action and the reasons for the action. Networks set up by professional associations may be used to this effect. Member States shall inform the Commission and the Agency of actions taken for this purpose.

6. The suspensive measures referred to in paragraph 4 may be maintained until such time as a definitive decision has been reached in accordance with the procedure referred to in Article 87(3).

7. The Agency shall, upon request, inform any person concerned of the final decision and make the decision publicly accessible, immediately after it has been taken.







Chapter 3

Pharmacovigilance

Article 46

For the purpose of this Chapter, Article 77(2) of Directive 2001/82/EEC shall apply.

Article 47

The Agency, acting in close cooperation with the national pharmacovigilance systems established in accordance with Article 73 of Directive 2001/82/EC, shall receive all relevant information about suspected adverse reactions to veterinary medicinal products which have been authorised by the ►M8 Union ◄ in accordance with this Regulation. Where appropriate the Committee for Medicinal Products for Veterinary Use shall, in accordance with Article 30 of this Regulation, draw up opinions on the measures necessary. These opinions shall be made publicly accessible.

These measures may include amendments to the marketing authorisation granted in accordance with Article 35. They shall be adopted in accordance with the procedure referred to in Article 87(3).

The holder of the marketing authorisation and the competent authorities of the Member States shall ensure all relevant information about suspected adverse reactions to the veterinary medicinal products authorised under this Regulation is brought to the attention of the Agency in accordance with the provisions of this Regulation. Animal owners and breeders shall be encouraged to communicate any adverse reaction to health-care professionals or to the competent national authorities responsible for pharmacovigilance.

Article 48

The holder of the marketing authorisation for a veterinary medicinal product granted in accordance with the provisions of this Regulation shall have permanently and continuously at his disposal an appropriately qualified person responsible for pharmacovigilance.

That qualified person shall reside in the ►M8 Union ◄ and shall be responsible for the following:

(a) establishing and managing a system which ensures that information about all suspected adverse reactions which are reported to the personnel of the company and to medical representatives is collected, evaluated and collated so that it may be accessed at a single point within the ►M8 Union ◄ ;

(b) preparing the reports referred to in Article 49(3) for the competent authorities of the Member States and the Agency in accordance with the requirements of this Regulation;

(c) ensuring that any request from the competent authorities for the provision of additional information necessary for the evaluation of the risks and benefits of a veterinary medicinal product is answered fully and promptly, including the provision of information about the volume of sales or prescriptions for the veterinary medicinal product concerned;

(d) providing the competent authorities with any other information relevant to the evaluation of the risks and benefits of a veterinary medicinal product, particularly information concerning post-authorisation safety studies, including information regarding the validity of the withdrawal period or lack of expected efficacy or potential environmental problems.

Article 49

1. The holder of the marketing authorisation for a veterinary medicinal product shall ensure that all suspected serious adverse reactions, and adverse human reactions to a veterinary medicinal product authorised in accordance with the provisions of this Regulation occurring within the ►M8 Union ◄ which a health-care professional brings to his attention are recorded and reported promptly to the Member States in the territory of which the incident occurred no later than 15 days following receipt of the information.

The holder of the marketing authorisation shall record any other suspected serious adverse reactions and human adverse reactions occurring within the ►M8 Union ◄ , in accordance with the guidelines r