2004R0726 — EN — 06.07.2009 — 004.001

This document is meant purely as a documentation tool and the institutions do not assume any liability for its contents

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

Amended by:









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

of 31 March 2004

laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency

(Text with EEA relevance)







THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE EUROPEAN UNION, Having regard to the Treaty establishing the European Community, and in particular Article 95 and Article 152(4)(b) thereof, Having regard to the proposal from the Commission ( 1 ), Having regard to the Opinion of the European Economic and Social Committee ( 2 ), After consulting the Committee of the Regions, In accordance with the procedure laid down in Article 251 of the Treaty ( 3 ), Whereas: (1) Article 71 of Council Regulation (EEC) No 2309/93 of 22 July 1993 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Agency for the Evaluation of Medicinal Products ( 4 ) provides that, within six years of the entry into force of the Regulation, the Commission is to publish a general report on the experience acquired as a result of the operation of the procedures laid down in the Regulation. (2) In the light of the Commission's report on the experience gained, it has proved necessary to improve the operation of the authorisation procedures for the placing of medicinal products on the market in the Community and to amend certain administrative aspects of the European Agency for the Evaluation of Medicinal Products. In addition, the name of that Agency should be simplified and changed to the European Medicines Agency, (hereinafter referred to as the ‘Agency’). (3) It emerges from the conclusions of that report that the amendments to be made to the centralised procedure set up by Regulation (EEC) No 2309/93 consist of corrections to some of the operating procedures and adaptations to take account of the probable development of science and technology and the future enlargement of the European Union. It also emerges from the report that the general principles previously established which govern the centralised procedure should be maintained. (4) Moreover, since the European Parliament and the Council have adopted Directive 2001/83/EC of 6 November 2001 on the Community code relating to medicinal products for human use ( 5 ) and Directive 2001/82/EC of 6 November 2001 on the Community code relating to veterinary medicinal products ( 6 ), all the references to the codified Directives in Regulation (EEC) No 2309/93 should be updated. (5) For the sake of clarity, it is necessary to replace the said Regulation with a new Regulation. (6) It is appropriate to preserve the Community mechanism set up by the repealed Community legislation for concertation prior to any national decision relating to a high-technology medicinal product. (7) Experience gained since the adoption of Council Directive 87/22/EEC of 22 December 1986 on the approximation of national measures relating to the placing on the market of high-technology medicinal products, particularly those derived from biotechnology ( 7 ) has shown that it is necessary to create a centralised authorisation procedure that is compulsory for high-technology medicinal products, particularly those resulting from biotechnical processes, in order to maintain the high level of scientific evaluation of these medicinal products in the European Union and thus to preserve the confidence of patients and the medical professions in the evaluation. This is particularly important in the context of the emergence of new therapies, such as gene therapy and associated cell therapies, and xenogenic somatic therapy. This approach should be maintained, particularly with a view to ensuring the effective operation of the internal market in the pharmaceutical sector. (8) With a view to harmonising the internal market for new medicinal products, this procedure should also be made compulsory for orphan medicinal products and any medicinal product for human use containing an entirely new active substance, i.e. one that has not yet been authorised in the Community, and for which the therapeutic indication is the treatment of acquired immune deficiency syndrome, cancer, neurodegenerative disorder or diabetes. Four years after the date of entry into force of this Regulation, the procedure should also become compulsory for medicinal products for human use containing a new active substance, and for which the therapeutic indication is for the treatment of auto-immune diseases and other immune dysfunctions and viral diseases. It should be possible to review the provisions in point 3 of the Annex via a simplified decision-making procedure not earlier than four years after the entry into force of this Regulation. (9) As regards medicinal products for human use, optional access to the centralised procedure should also be provided for in cases where use of a single procedure produces added value for the patient. This procedure should remain optional for medicinal products which, although not belonging to the abovementioned categories, are nevertheless therapeutically innovative. It is also appropriate to allow access to this procedure for medicinal products which, although not innovative, may be of benefit to society or to patients if they are authorised from the outset at Community level, such as certain medicinal products which can be supplied without a medical prescription. This option may be extended to generic medicinal products authorised by the Community, provided that this in no way undermines either the harmonisation achieved when the reference medicinal product was evaluated or the results of that evaluation. (10) In the field of veterinary medicinal products, administrative measures should be laid down in order to take account of the specific features of this field, particularly those due to the regional distribution of certain diseases. It should be possible to use the centralised procedure for the authorisation of veterinary medicinal products used within the framework of Community provisions regarding prophylactic measures for epizootic diseases. Optional access to the centralised procedure should be maintained for veterinary medicinal products containing a new active substance. (11) For medicinal products for human use, the period for protection of data relating to pre-clinical tests and clinical trials should be the same as that provided for in Directive 2001/83/EC. For medicinal products for veterinary use, the period for protection of data relating to pre-clinical tests and clinical trials as well as safety and residue tests should be the same as that provided for in Directive 2001/82/EC. (12) In order to reduce the cost for small and medium-sized enterprises of marketing medicinal products authorised via the centralised procedure, provisions should be adopted to allow for a reduction of fees, deferring the payment of fees, taking over responsibility for translations and offering administrative assistance in respect of these enterprises. (13) In the interest of public health, authorisation decisions under the centralised procedure should be taken on the basis of the objective scientific criteria of quality, safety and efficacy of the medicinal product concerned, to the exclusion of economic and other considerations. However, Member States should be able exceptionally to prohibit the use in their territory of medicinal products for human use which infringe objectively defined concepts of public policy and public morality. Moreover, a veterinary medicinal product is not to be authorised by the Community if its use would contravene the rules laid down within the framework of the Common Agricultural Policy or if presented for a use prohibited under other Community provisions, inter alia Directive 96/22/EC ( 8 ). (14) Provision should be made for the quality, safety and efficacy criteria in Directives 2001/83/EC and 2001/82/EC to apply to medicinal products authorised by the Community and it should be possible to assess the risk-benefit balance of all medicinal products when they are placed on the market, at the time of the renewal of the authorisation and at any other time the competent authority deems appropriate. (15) The Community is required, pursuant to Article 178 of the Treaty, to take account of the development policy aspects of any measure and to promote the creation of conditions fit for human beings worldwide. Pharmaceutical law should continue to ensure that only efficacious, safe and top-quality medicinal products are exported, and the Commission should consider creating further incentives to carry out research into medicinal products against widespread tropical diseases. (16) There is also a need to provide for the ethical requirements of Directive 2001/20/EC of 4 April 2001 of the European Parliament and of the Council on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use ( 9 ) to apply to medicinal products authorised by the Community. In particular, with respect to clinical trials conducted outside the Community on medicinal products destined to be authorised within the Community, at the time of the evaluation of the application for authorisation, it should be verified that these trials were conducted in accordance with the principles of good clinical practice and the ethical requirements equivalent to the provisions of the said Directive. (17) The Community should have the means to carry out a scientific assessment of the medicinal products presented in accordance with the decentralised Community authorisation procedures. Moreover, with a view to ensuring the effective harmonisation of administrative decisions taken by Member States with regard to medicinal products presented in accordance with decentralised authorisation procedures, it is necessary to endow the Community with the means to resolve disagreements between Member States concerning the quality, safety and efficacy of medicinal products. (18) The structure and operation of the various bodies making up the Agency should be designed in such a way as to take into account the need constantly to renew scientific expertise, the need for cooperation between Community and national bodies, the need for adequate involvement of civil society, and the future enlargement of the European Union. The various bodies of the Agency should establish and develop appropriate contacts with the parties concerned, in particular representatives of patients and health-care professionals. (19) The chief task of the Agency should be to provide Community institutions and Member States with the best possible scientific opinions so as to enable them to exercise the powers regarding the authorisation and supervision of medicinal products conferred on them by Community legislation in the field of medicinal products. Only after a single scientific evaluation procedure addressing the quality, safety and efficacy of high-technology medicinal products has been conducted by the Agency, applying the highest possible standards, should marketing authorisation be granted by the Community, and this should be done by means of a rapid procedure ensuring close cooperation between the Commission and Member States. (20) In order to ensure close cooperation between the Agency and scientists operating in Member States, the composition of the Management Board should be such as to guarantee that the competent authorities of the Member States are closely involved in the overall management of the Community system for authorising medicinal products. (21) The Agency's budget should be composed of fees paid by the private sector and contributions paid out of the Community budget to implement Community policies. (22) Paragraph 25 of the Interinstitutional Agreement of 6 May 1999 between the European Parliament, the Council and the Commission on budgetary discipline and improvement of budgetary procedure ( 10 ) provides for the Financial Perspective to be adjusted in order to cover the new needs resulting from enlargement. (23) Exclusive responsibility for preparing the Agency's opinions on all questions concerning medicinal products for human use should be vested in a Committee for Medicinal Products for Human Use. As far as veterinary medicinal products are concerned, such responsibility should be vested in a Committee for Medicinal Products for Veterinary Use. As regards orphan medicinal products, the task should fall to the Committee on Orphan Medicinal Products set up under Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products ( 11 ). Lastly, as regards herbal medicinal products, this responsibility should be vested in the Committee on Herbal Medicinal Products set up under Directive 2001/83/EC. (24) The creation of the Agency will make it possible to reinforce the scientific role and independence of the committees, particularly through the setting-up of a permanent technical and administrative secretariat. (25) The field of activity of the Scientific Committees should be enlarged and their operating methods and composition modernised. Scientific advice for future applicants seeking marketing authorisation should be provided more generally and in greater depth. Similarly, structures allowing the development of advice for companies, in particular small and medium-sized enterprises, should be put in place. The committees should be able to delegate some of their evaluation duties to standing working parties open to experts from the scientific world appointed for this purpose, whilst retaining total responsibility for the scientific opinions issued. The re-examination procedures should be amended to provide a better guarantee for applicants' rights. (26) The number of members of the Scientific Committees participating in the centralised procedure should be established with a view to ensuring that the committees remain of an efficient size after the enlargement of the European Union. (27) It is also necessary to reinforce the role of the Scientific Committees in such a way as to enable the Agency to participate actively in international scientific dialogue and to develop certain activities that will be necessary, in particular regarding international scientific harmonisation and technical cooperation with the World Health Organisation. (28) Furthermore, in order to create greater legal certainty it is necessary to define the responsibilities regarding the transparency rules for the Agency's work, to set certain conditions for the marketing of medicinal products authorised by the Community, to confer on the Agency powers to monitor the distribution of medicinal products authorised by the Community and to specify the sanctions and the procedures for implementing them in the event of failure to observe the provisions of this Regulation and the conditions contained in the authorisations granted under the procedures it establishes. (29) It is also necessary to take measures for the supervision of medicinal products authorised by the Community, and in particular for the intensive supervision of undesirable effects of these medicinal products within the framework of Community pharmacovigilance activities, so as to ensure the rapid withdrawal from the market of any medicinal product presenting a negative risk-benefit balance under normal conditions of use. (30) In order to enhance the efficiency of market surveillance, the Agency should be responsible for coordinating Member States' pharmacovigilance activities. A number of provisions need to be introduced to put in place stringent and efficient pharmacovigilance procedures, to allow the competent authority to take provisional emergency measures, including the introduction of amendments to the marketing authorisation and, finally, to permit a reassessment to be made at any time of the risk-benefit balance of a medicinal product. (31) It is also appropriate to entrust the Commission, in close cooperation with the Agency and after consultations with the Member States, with the task of coordinating the execution of the various supervisory responsibilities vested in the Member States, and in particular with the tasks of providing information on medicinal products and of checking the observance of good manufacturing, laboratory and clinical practices. (32) It is necessary to provide for the coordinated implementation of Community procedures for the authorisation of medicinal products, and of the national procedures of Member States which have already been harmonised to a considerable degree by Directives 2001/83/EC and 2001/82/EC. It is appropriate that the operation of the procedures laid down by this Regulation be re-examined by the Commission every ten years on the basis of experience gained. (33) In order to meet, in particular, the legitimate expectations of patients and to take account of the increasingly rapid progress of science and therapies, accelerated assessment procedures should be set up, reserved for medicinal products of major therapeutic interest, and procedures for obtaining temporary authorisations subject to certain annually reviewable conditions. In the field of medicinal products for human use, a common approach should also be followed, whenever possible, regarding the criteria and conditions for the compassionate use of new medicinal products under Member States' legislation. (34) Member States have developed an evaluation of the comparative efficacy of medicinal products aimed at positioning a new medicinal product with respect to those that already exist in the same therapeutic class. Similarly, the Council, in its Conclusions on medicinal products and public health ( 12 ), adopted on 29 June 2000, emphasised the importance of identifying medicinal products that presented an added therapeutic value. However this evaluation should not be conducted in the context of the marketing authorisation, for which it is agreed that the fundamental criteria should be retained. It is useful in this respect to allow for the possibility of gathering information on the methods used by the Member States to determine the therapeutic benefit obtained by each new medicinal product. (35) In line with the current provisions of Directives 2001/83/EC and 2001/82/EC, the term of validity of a Community marketing authorisation should be limited initially to a period of five years, upon the expiry of which it should be renewed. Thereafter the marketing authorisation should normally be of unlimited validity. Furthermore, any authorisation not used for three consecutive years, that is to say, one which has not led to the placing on the market of a medicinal product in the Community during that period, should be considered invalid, in order, in particular, to avoid the administrative burden of maintaining such authorisations. However, this rule should be subject to exemptions when these are justified on public health grounds. (36) Environmental risks may arise from medicinal products containing or consisting of genetically modified organisms. It is thus necessary to subject such products to an environmental risk-assessment procedure similar to the procedure under Directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001 on the deliberate release into the environment of genetically modified organisms ( 13 ), to be conducted in parallel with the evaluation, under a single Community procedure, of the quality, safety and efficacy of the product concerned. (37) The measures necessary for the implementation of this Regulation should be adopted in accordance with Council Decision 1999/468/EC of 28 June 1999 laying down the procedures for the exercise of implementing powers conferred on the Commission ( 14 ). (38) The provisions of Regulation (EC) No 1647/2003 ( 15 ) amending Regulation (EC) No 2309/93 as regards the budgetary and financial rules applicable to the Agency and access to the Agency's documents should be fully incorporated into this Regulation, Whereas: HAVE ADOPTED THIS REGULATION:







TITLE I

DEFINITIONS AND SCOPE

Article 1

The purpose of this Regulation is to lay down Community 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 Community. 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 Community unless a marketing authorisation has been granted by the Community 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 Community 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 Community; 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 Community level.

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

3. A generic medicinal product of a reference medicinal product authorised by the Community 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 Community 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 Community shall grant and supervise marketing authorisations for medicinal products for human use in accordance with Title II.

3. The Community 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 Community 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.

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, Community 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 ( 16 );

(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 Community 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;

(d) the authorisation needs to be granted subject to the conditions provided for in Article 14(7) and (8).

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;

(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;

(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;

(e) the assessment report.

Article 10

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 Article 9(4)(a), (b), (c) and (d).

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 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).

6. The Agency shall disseminate the documents referred to in Article 9(4)(a), (b), (c) and (d).

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 Community marketing authorisation shall constitute a prohibition on the placing on the market of the medicinal product concerned throughout the Community.

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 Community. ◄ 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 Community 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 Community 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.

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

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 Community level, broken down by Member State, and any data in the holder's possession relating to the volume of prescriptions.

Article 14

1. Without prejudice to paragraphs 4, 5 and 7 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 provide the Agency with a consolidated version of the file 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.

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 human use on the Community 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.

7. Following consultation with the applicant, an authorisation may be granted subject to certain specific obligations, to be reviewed annually by the Agency. The list of these obligations shall be made publicly accessible.

By way of derogation from paragraph 1, such authorisation shall be valid for one year, on a renewable basis.

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The Commission shall adopt a Regulation laying down provisions for granting such authorisation. That measure, 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).

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

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.

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

Article 16

1. After an authorisation has been granted in accordance with this Regulation, the holder of the marketing authorisation for a medicinal product for human use shall, in respect of the methods of manufacture and control provided for in Article 8(3)(d) and (h) of Directive 2001/83/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 such variations in accordance with this Regulation.

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

In particular, 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 medicinal product for human use is marketed and of any other new information which might influence the evaluation of the benefits and risks of the medicinal product for human use 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 demonstrating that the risk-benefit balance remains favourable.

3. If the holder of the authorisation for a medicinal product for human use proposes to make any variation of the particulars and documents referred to in paragraph 2, he shall submit the relevant application to the Agency.

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4. 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).

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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

1. In the case of medicinal products for human use manufactured within the Community, the supervisory authorities 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.

2. In the case of 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 40(3) of Directive 2001/83/EC to the importer, unless appropriate agreements have been made between the Community 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 Community.

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

Article 19

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

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 Community 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 Community 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.

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 said Committee. The report of the inspectors shall be made available to the Commission, the Member States and the said Committee.

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 Community 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.

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 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.







Chapter 3

Pharmacovigilance

Article 21

For the purposes of this Chapter, Article 106(2) of Directive 2001/83/EC shall apply.

Article 22

The Agency, acting in close cooperation with the national pharmacovigilance systems established in accordance with Article 102 of Directive 2001/83/EC, shall receive all relevant information concerning suspected adverse reactions to medicinal products for human use which have been authorised by the Community in accordance with this Regulation. Where appropriate, the Committee for Medicinal Products for Human Use shall, in accordance with Article 5 of this Regulation, draw up opinions on the measures necessary. These opinions shall be made publicly accessible.

The measures referred to in the first paragraph may include amendments to the marketing authorisation granted in accordance with Article 10. 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 Member States shall ensure that all relevant information concerning suspected adverse reactions to the medicinal products authorised under this Regulation are brought to the attention of the Agency in accordance with the provisions of this Regulation. Patients shall be encouraged to communicate any adverse reaction to health-care professionals.

Article 23

The holder of an authorisation for a medicinal product for human use 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 Community and shall be responsible for the following:

(a) establishing and managing a system which ensures that information concerning 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 Community;

(b) preparing the reports referred to in Article 24(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 medicinal product is answered fully and promptly, including the provision of information regarding the volume of sales or prescriptions for the medicinal product concerned;

(d) providing the competent authorities with any other information relevant to the evaluation of the risks and benefits of a medicinal product, particularly information concerning post-authorisation safety studies.

Article 24

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

The holder of the marketing authorisation shall record any other suspected serious adverse reactions occurring within the Community, in accordance with the guide referred to in Article 26, of which he may reasonably be expected to be aware, and promptly notify the competent authority of Member States in the territory of which the incident occurred and the Agency, and no later than 15 days following receipt of the information.

2. ►M3 The holder of the marketing authorisation for a medicinal product for human use shall ensure that all suspected serious unexpected adverse reactions and any suspected transmission via a medicinal product of any infectious agent occurring in the territory of a third country are reported promptly to Member States and the Agency, and no later than 15 days following receipt of the information. The Commission shall adopt provisions for the reporting of suspected unexpected adverse reactions which are not serious, whether occurring in the Community or in a third country. 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). ◄

Save in exceptional circumstances, these reactions shall be transmitted electronically in the form of a report and in accordance with the guide referred to in Article 26.

3. The holder of the marketing authorisation for a medicinal product for human use shall maintain detailed records of all suspected adverse reactions within or outside the Community which are reported to him by a health-care professional.

Unless other requirements have been laid down as a condition for the granting of the marketing authorisation by the Community, these records shall be submitted, in the form of a periodic safety update report, to the Agency and Member States immediately upon request or at least every six months after authorisation until the placing on the market. Periodic safety update reports shall also be submitted immediately upon request or at least every six months during the first two years following the initial placing on the Community market and once a year for the following two years. Thereafter, the reports shall be submitted at three-yearly intervals, or immediately upon request.

These reports shall be accompanied by a scientific evaluation, particularly of the risk-benefit balance of the medicinal product.

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4. The Commission may lay down provisions to amend paragraph 3 in view of experience gained with its operation. 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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5. The holder of a marketing authorisation may not communicate information relating to pharmacovigilance concerns to the general public in relation to its authorised medicinal product without giving prior or simultaneous notification to the Agency.

In any case, the marketing authorisation holder shall ensure that such information is presented objectively and is not misleading.

Member States shall take the necessary measures to ensure that a marketing authorisation holder who fails to discharge these obligations is subject to effective, proportionate and dissuasive penalties.

Article 25

Each Member State shall ensure that all suspected serious adverse reactions occurring within their territory to a medicinal product for human use authorised in accordance with this Regulation which are brought to their attention are recorded and reported promptly to the Agency and the marketing authorisation holder, and no later than 15 days following receipt of the information.

The Agency shall forward the information to the national pharmacovigilance systems set up in accordance with Article 102 of Directive 2001/83/EC.

Article 26

The Commission, in consultation with the Agency, Member States and interested parties, shall draw up a guide on the collection, verification and presentation of adverse-reaction reports. This guide shall contain, in particular, for the benefit of health-care professionals, recommendations concerning the communication of information on adverse reactions.

In accordance with this guide, holders of marketing authorisations shall use the medical terminology accepted at international level for the transmission of adverse-reaction reports.

The Agency, in consultation with Member States and the Commission, shall set up a data-processing network for the rapid transmission of information to the competent Community authorities in the event of an alert relating to faulty manufacture, serious adverse reactions and other pharmacovigilance data regarding medicinal products authorised in accordance with Article 6 of Directive 2001/83/EC. Such data shall be made publicly accessible, if relevant, after evaluation.

For a period of five years following the initial placing on the market in the Community, the Agency may request that the marketing authorisation holder arrange for specific pharmacovigilance data to be collected from targeted groups of patients. The Agency shall state the reasons for the request. The marketing authorisation holder shall collate and assess the data collected and submit it to the Agency for evaluation.

Article 27

The Agency shall collaborate with the World Health Organisation in matters of international pharmacovigilance and shall take the necessary steps to submit to it, promptly, appropriate and adequate information regarding the measures taken in the Community which may have a bearing on public health protection in third countries; it shall send a copy thereof to the Commission and the Member States.

Article 28

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

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Article 29

The Commission may adopt any amendment which may be necessary to update the provisions of this Chapter in order to take account of scientific and technical progress. 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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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 Community law may confer on it, in particular under Regulation (EEC) No 2377/90 ( 17 ), 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, Community 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 Community 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 Community 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 Community 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 Community 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 Community 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 Community marketing authorisation shall constitute a prohibition on the placing on the market of the veterinary medicinal product concerned throughout the Community.

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 Community. 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 Community 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 Community 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 Community 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 Community 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 Community 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 ( 18 ).

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.

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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).

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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 Community, 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 Community 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 Community.

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 Community that the holder of the marketing authorisation for the veterinary medicinal product or the manufacturer or importer established within the Community 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 Community 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 Community 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 Community 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 Community 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 Community 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 Community;

(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 Community 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 Community, in accordance with the guidelines referred to in Article 51, of which he may reasonably be expected to be aware, and promptly notify Member States in the territory of which the incident occurred and the Agency, and no later than 15 days following receipt of the information.

2. ►M3 The holder of the marketing authorisation for a veterinary medicinal product shall ensure that all suspected serious unexpected adverse reactions, and adverse human reactions, and any suspected transmission via a medicinal product of any infectious agent occurring in the territory of a third country are reported promptly to the Member States and the Agency, and no later than 15 days following receipt of the information. The Commission shall adopt provisions for the reporting of suspected unexpected adverse reactions which are not serious, whether occurring in the Community or in a third country. 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). ◄

Save in exceptional circumstances, these reactions shall be transmitted electronically in the form of a report and in accordance with the guide referred to in Article 51.

3. The holder of the marketing authorisation for a veterinary medicinal product shall maintain detailed records of all suspected adverse reactions occurring within or outside the Community which are reported to him.

Unless other requirements have been laid down as a condition for the granting of the marketing authorisation by the Community, these records shall be submitted, in the form of a periodic safety update report, to the Agency and Member States immediately upon request or at least every six months after authorisation until the placing on the market. Periodic safety update reports shall also be submitted immediately upon request or at least every six months during the first two years following the initial placing on the Community market and once a year for the following two years. Thereafter, the reports shall be submitted at three-yearly intervals, or immediately upon request.

These reports shall be accompanied by a scientific evaluation, particularly of the risk-benefit balance of the medicinal product.

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4. The Commission may lay down provisions to amend paragraph 3 in view of experience gained with its operation. Those measures, designed to amend non-essential elements of this regulation, shall be adopted in accordance with the procedure referred to in Article 87(2a).

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5. The holder of a marketing authorisation may not communicate information relating to pharmacovigilance concerns to the general public in relation to its authorised medicinal product without giving prior or simultaneous notification to the Agency.

In any case, the marketing authorisation holder shall ensure that such information is presented objectively and is not misleading.

Member States shall take the necessary measures to ensure that a marketing authorisation holder who fails to discharge these obligations is subject to effective, proportionate and dissuasive penalties.

Article 50

Each Member State shall ensure that all suspected serious adverse reactions, and adverse human reactions, occurring within its territory to a veterinary medicinal product authorised in accordance with the provisions of this Regulation which are brought to its attention are recorded and reported promptly to the Agency and the holder of the marketing authorisation for the veterinary medicinal product, and no later than 15 days following receipt of the information.

The Agency shall forward the information to the national pharmacovigilance systems set up in accordance with Article 73 of Directive 2001/82/EC.

Article 51

The Commission, in consultation with the Agency, Member States and interested parties, shall draw up a guide on the collection, verification and presentation of adverse-reaction reports. This guide shall contain, in particular, for the benefit of health-care professionals, recommendations concerning the communication of information on adverse reactions.

In accordance with this guide, holders of marketing authorisations shall use the medical terminology accepted at international level for the transmission of adverse-reaction reports.

The Agency, in consultation with the Member States and the Commission, shall set up a data-processing network for the rapid transmission of data between the competent Community authorities in the event of an alert relating to faulty manufacture, serious adverse reactions and other pharmacovigilance data regarding veterinary medicinal products authorised in accordance with Article 5 of Directive 2001/82/EC.

For a period of five years following the initial placing on the market in the Community, the Agency may request that the marketing authorisation holder arrange for specific pharmacovigilance data to be collected from targeted groups of animals. The Agency shall state the reasons for the request. The marketing authorisation holder shall collate and assess the data collected and submit it to the Agency for evaluation.

Article 52

The Agency shall cooperate with international organisations concerned with veterinary pharmacovigilance.

Article 53

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

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Article 54

The Commission may adopt any amendment which may be necessary to update the provisions of this Chapter in order to take account of scientific and technical progress. 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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TITLE IV

THE EUROPEAN MEDICINES AGENCY — RESPONSIBILITIES AND ADMINISTRATIVE STRUCTURE







Chapter 1

Tasks of the Agency

Article 55

A European Medicines Agency is hereby established.

The Agency shall be responsible for coordinating the existing scientific resources put at its disposal b