Avis juridique important

Council Directive 93/39/EEC of 14 June 1993 amending Directives 65/65/EEC, 75/318/EEC and 75/319/EEC in respect of medicinal products Official Journal L 214 , 24/08/1993 P. 0022 - 0030 Finnish special edition: Chapter 13 Volume 24 P. 0178 Swedish special edition: Chapter 13 Volume 24 P. 0178

COUNCIL DIRECTIVE 93/39/EEC of 14 June 1993 amending Directives 65/65/EEC, 75/318/EEC and 75/319/EEC in respect of medicinal products THE COUNCIL OF THE EUROPEAN COMMUNITIES, Having regard to the Treaty establishing the European Economic Community, and in particular Article 100a thereof, Having regard to the proposal from the Commission (1), In cooperation with the European Parliament (2), Having regard to the opinion of the Economic and Social Committee (3), Whereas it is important to adopt measures with the aim of progressively establishing the internal market over a period expiring on 31 December 1992; whereas the internal market shall comprise an area without internal frontiers in which the free movement of goods, persons, services and capital is ensured; Whereas Article 15 (2) of Second Council Directive 75/319/EEC of 20 May 1975 on the approximation of provisions laid down by law, regulation or administrative action relating to proprietary medicinal products (4) provides that the Commission shall submit to the Council a proposal containing appropriate measures leading towards the abolition of any remaining barriers to the free movement of proprietary medicinal products; Whereas, in the interest of public health and of the consumer of medicinal products, it is necessary that decisions on the authorization to place medicinal products on the market be exclusively based on the criteria of quality, safety and efficacy; whereas these criteria have been extensively harmonized by Council Directive 65/65/EEC of 26 January 1965 on the approximation of provisions laid down by law, regulation or administration action relating to medicinal products (5), by Council Directive 75/319/EEC, and by Council Directive 75/318/EEC of 20 May 1975 on the approximation of the laws of the Member States relating to analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products (6); whereas, however, Member States should exceptionally be able to prohibit the use on their territory of medicinal products which infringe objectively defined concepts of public order or public morality; Whereas, with the exception of those medicinal products which are subject to the centralized Community authorization procedure established by Council Regulation (EEC) No 2309/93 of 22 July 1993 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Agency for the Evaluation of Medicinal Products (7), an authorization to place a medicinal product on the market in one Member State ought in principle to be recognized by the competent authorities of the other Member States unless there are serious grounds for supposing that the authorization of the medicinal product concerned may present a risk to public health; whereas, in the event of a disagreement between Member States about the quality, the safety or the efficacy of a medicinal product, a scientific evaluation of the matter should be undertaken by the Committee for Proprietary Medicinal Products attached to the European Agency for the Evaluation of Medicinal Products, leading to a single decision on the area of disagreement binding on the Member States concerned; whereas this decision should be adopted by a rapid procedure ensuring close cooperation between the Commission and the Member States; Whereas in order better to protect public health and avoid any unnecessary duplication of effort during the examination of application for authorization to place medicinal products on the market, Member States should systematically prepare assessment reports in respect of each medicinal product which is authorized by them, and exchange the reports upon request; whereas, furthermore, a Member State should be able to suspend the examination of an application for authorization to place a medicinal product on the market which is currently under active consideration in another Member State with a view to recognizing the decision reached by the latter Member State; Whereas following the establishment of the internal market, specific controls to guarantee the quality of medicinal products imported from third countries can be waived only if appropriate arrangements have been made by the Community to ensure that the necessary controls are carried out in the exporting country; Whereas it is desirable to codify and improve the cooperation and exchange of information between Member States relating to the supervision of medicinal products and in particular the monitoring of adverse reactions under practical conditions of use through the national pharmacovigilance systems, HAS ADOPTED THIS DIRECTIVE: Article 1 Directive 65/65/EEC is hereby amended as follows: 1. Article 3 is replaced by the following: 'Article 3 No medicinal product may be placed on the market of a Member State unless a marketing authorization has been issued by the competent authorities of that Member State in accordance with this Directive or an authorization has been granted in accordance with Regulation (EEC) No 2309/93 of 22 July 1993 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Agency for the Evaluation of Medicinal Products (*). The provisions of this Directive shall not affect the powers of the Member States' authorities either as regards the setting of prices for medicinal products or their inclusion in the scope of national health insurance schemes, on the basis of health, economic and social conditions. (*) OJ No L 214, 24. 8. 1993, p. 1'; 2. the following subparagraph is added between the first and second subparagraphs of Article 4: 'The person responsible for placing medicinal products on the market shall be established in the Community. In respect of medicinal products authorized on the date of implementation of this Directive, the Member State shall if necessary apply this provision at the time of the five-yearly renewal of the marketing authorization provided for in Article 10.'; 3. in the second paragraph of Article 4, points 6 and 11 are replaced by the following: ' 6. Posology, pharmaceutical form, method and route of administration and expected shelf life. If applicable, reasons for any precautionary and safety measures to be taken for the storage of the medicinal product, its administration to patients and for the disposal of waste products, together with an indication of any potential risks presented by the medicinal product for the environment.'; '11. Copies of any authorization obtained in another Member State or in a third country to place the relevant medicinal product on the market, together with a list of those Member States in which an application for authorization submitted in accordance with this Directive is under examination. Copies of the summary of the product characteristics proposed by the applicant in accordance with Article 4a or approved by the competent authorities of the Member State in accordance with Article 4b. Copies of the package leaflet proposed in accordance with Article 6 of Directive 92/27/EEC or approved by the competent authorities of the Member State in accordance with Article 10 of the same Directive. Details of any decision to refuse authorization, whether in the Community or in a third country, and the reasons for such decision. This information shall be updated on a regular basis'; 4. Article 4b is replaced by the following: 'Article 4b When the marketing authorization referred to in Article 3 is issued, the person responsible for placing that product on the market shall be informed, by the competent authorities of the Member State concerned, of the summary of the product characteristics as approved by it. The competent authorities shall take all necessary measures to ensure that the information given in the summary is in conformity with that accepted when the marketing authorization is issued or subsequently. The competent authorities shall forward to the European Agency for the Evaluation of Medicinal Products a copy of the authorization together with the summary of the product characteristics referred to in Article 4a. Furthermore, the competent authorities shall draw up an assessment report and comments on the dossier as regards the results of the analytical and pharmacotoxicological tests and the clinical trials of the medicinal product concerned. The assessment report shall be udapted whenever new information becomes available which is of importance for the evaluation of the quality, safety or efficacy of the medicinal product concerned.'; 5. Article 6 is replaced by the following: 'Article 6 This Directive shall not affect the application of national legislation prohibiting or restricting the sale, supply or use of medicinal products as contraceptives or abortifacients. The Member States shall communicate the national legislation concerned to the Commission'; 6. Article 7 is replaced by the following: 'Article 7 1. Member States shall take all appropriate measures to ensure that the procedure for granting an authorization to place a medicinal product on the market is completed within 210 days of the submission of a valid application. 2. Where a Member State notes that an application for authorization submitted after 1 January 1995 is already under active examination in another Member State in respect of that medicinal product, the Member State concerned may decide to suspend the detailed examination of the application in order to await the assessment report prepared by the other Member State in accordance with Article 4b. The Member State concerned shall inform the other Member State and the applicant of its decision to suspend detailed examination of the application in question. As soon as it has completed the examination of the application and reached a decision, the other Member State shall forward a copy of its assessment report to the Member State concerned. Within 90 days of the receipt of the assessment report, the Member State concerned shall either recognize the decision of the other Member State and the summary of the product characteristics as approved by it, or, if it considers that there are grounds for supposing that the authorization of the medicinal product concerned may present a risk to public health (*), it shall apply the procedures set out in Articles 10 to 14 of Directive 75/319/EEC. (*) The expression "risk to public health " refers to the quality, safety and efficacy of the medicinal product.'; 7. insert the following Article 7a: 'Article 7a With effect from 1 January 1998, where a Member State is informed in accordance with point 11 of the second paragraph of Article 4 that another Member State has authorized a medicinal product which is the subject of an application for authorization in the Member State concerned, that Member State shall forthwith request the authorities of the Member State which has granted the authorization to forward to it the assessment report referred to in the second paragraph of Article 4b. Within 90 days of the receipt of the assessment report, the Member State concerned shall either recognize the decision of the first Member State and the summary of the product characteristics as approved by it or, if it considers that there are grounds for supposing that the authorization of the medicinal product concerned may present a risk to public health (*), it shall apply the procedures set out in Articles 10 to 14 of Directive 75/319/EEC. (*) The expression "risk to public health " refers to the quality, safety and efficacy of the medicinal product'; 8. Article 9a is replaced by the following: 'Article 9a After an authorization has been issued, the person responsible for placing the product on the market must, in respect of the methods of preparation and control provided for in points 4 and 7 of the second paragraph of Article 4, take account of technical and scientific progress and introduce any changes that may be required to enable that medicinal product to be manufactured and checked by means of generally accepted scientific methods. These changes shall be subject to the approval of the competent authority of the Member State concerned'; 9. Article 10 is replaced by the following: 'Article 10 1. Authorization shall be valid for five years and shall be renewable for five-year periods, on application by the holder at least three months before the expiry date and after consideration by the competent authority of a dossier containing in particular details of the data on pharmacovigilance and other information relevant to the monitoring of the medicinial product. 2. In exceptional circumstances, and following consultation with the applicant, an authorization may be granted subject to certain specific obligations, including: - the carrying out of further studies following the granting of authorization, - the notification of adverse reactions to the medicinal product. These exceptional decisions may be adopted only for objective and verifiable reasons and shall be based on one of the causes referred to in Part 4 (G) of the Annex to Directive 75/318/EEC.' Article 2 In Directive 75/318/EEC, the Committee referred to in Article 2b shall be called 'the Standing Committee on Medicinal Products for Human Use'. Article 3 Directive 75/319/EEC is hereby amended as follows: 1. Chapter III is replaced by the following: 'CHAPTER III Committee for Proprietary Medicinal Products Article 8 1. In order to facilitate the adoption of common decisions by Member States on the authorization of medicinal products for human use on the basis of the scientific criteria of quality, safety and efficacy, and to achieve thereby the free movement of medicinal products within the Community, a Committee for Proprietary Medicinal Products, hereinafter referred to as "the Committee ", is hereby set up. The Committee shall be part of the European Agency for the Evaluation of Medicinal Products established by Council Regulation (EEC) No 2309/93 of 22 July 1993 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Agency for the Evaluation of Medicinal Products (*), hereinafter referred to as "the Agency ". 2. In addition to the other responsibilities conferred upon it by Community law, the Committee shall examine any question relating to the granting, variation, suspension or withdrawal of marketing authorization for a medicinal product which is submitted to it in accordance with this Directive. (*) OJ No L 214, 24. 8. 1993, p. 1. Article 9 1. In order to obtain the recognition according to the procedures laid down in this Chapter in one or more of the Member States of an authorization issued by a Member State in accordance with Article 3 of Directive 65/65/EEC, the holder of the authorization shall submit an application to the competent authorities of the Member State or Member States concerned, together with the information and particulars referred to in Articles 4, 4a and 4b of Directive 65/65/EEC. He shall testify that the dossier is identical to that accepted by the first Member State, or shall identify any additions or amendments it may contain. In the latter case, he shall certify that the summary of the product characteristics proposed by him in accordance with Article 4a of Directive 65/65/EEC is identical to that accepted by the first Member State in accordance with Article 4b of Directive 65/65/EEC. Moreover he shall certify that all the dossiers filed as part of the procedure are identical. 2. The holder of the marketing authorization shall notify the Committee of this application, inform it of the Member States concerned and of the dates of submission of the application and send it a copy of the authorization granted by the first Member State. He shall also send the Committee copies of any such authorization which may have been granted by the other Member States in respect of the medicinal product concerned, and shall indicate whether any application for authorization is currently under consideration in any Member State. 3. Except in cases referred to in Article 7a of Directive 65/65/EEC, before submitting the application, the holder of the authorization shall inform the Member State which granted the authorization on which the application is based that an application is to be made in accordance with this Directive and shall notify it of any additions to the original dossier; that Member State may require the applicant to provide it with all the particulars and documents necessary to enable it to check that the dossiers filed are identical. In addition the holder of the authorization shall request the Member State which granted the initial authorization to prepare an assessment report in respect of the medicinal product concerned, or, if necessary, to update any existing assessment report. That Member State shall prepare the assessment report, or update it, within 90 days of the receipt of the request. At the same time as the application is submitted in accordance with paragraph 1 the Member State which granted the initial authorization shall forward the assessment report to the Member State or Member States concerned by the application. 4. Save in the exceptional case provided for in Article 10 (1), each Member State shall recognize the marketing authorization granted by the first Member State within 90 days of receipt of the application and the assessment report. It shall inform the Member State which granted the initial authorization, the other Member States concerned by the application, the Committee, and the person responsible for placing the medicinal product on the market. Article 10 1. Notwithstanding Article 9 (4), where a Member State considers that there are grounds for supposing that the authorization of the medicinal product concerned may present a risk to public health (*), it shall forthwith inform the applicant, the Member State which granted the initial authorization, any other Member States concerned by the application and the Committee. The Member State shall state its reasons in detail and shall indicate what action may be necessary to correct any defect in the application. 2. All the Member States concerned shall use their best endeavours to reach agreement on the action to be taken in respect of the application. They shall provide the applicant with the opportunity to make his point of view known orally or in writing. However, if the Member States have not reached agreement within the time limit referred to in Article 9 (4) they shall forthwith refer the matter to the Committee for the application of the procedure laid down in Article 13. 3. Within the time limit referred to in paragraph 2, the Member States concerned shall provide the Committee with a detailed statement of the matters on which they have been unable to reach agreement and the reasons for their disagreement. The applicant shall be provided with a copy of this information. 4. As soon as he is informed that the matter has been referred to the Committee, the applicant shall forthwith forward to the Committee a copy of the information and particulars referred to in Article 9 (1). (*) The expression "risk to public health " refers to the quality, safety and efficacy of the medicinal product. Article 11 If several applications submitted in accordance with Article 4 and 4a of Directive 65/65/EEC have been made for marketing authorization for a particular medicinal product, and Member States have adopted divergent decisions concerning the authorization of the medicinal product or its suspension or withdrawal from the market, a Member State, or the Commission, or the person responsible for placing the medicinal product on the market may refer the matter to the Committee for application of the procedure laid down in Article 13. The Member State concerned, the person responsible for placing the medicinal product on the market or the Commission shall clearly identify the question which is referred to the Committee for consideration and, where appropriate, shall inform the aforementioned person thereof. The Member State and the person responsible for placing the medicinal product on the market shall forward to the Committee all available information relating to the matter in question. Article 12 The Member States or the Commission or the applicant or holder of the marketing authorization may, in specific cases where the interests of the Community are involved, refer the matter to the Committee for the application of the procedure laid down in Article 13 before reaching a decision on a request for a marketing authorization or on the suspension or withdrawal of an authorization, or on any other variation to the terms of a marketing authorization which appears necessary, in particular to take account of the information collected in accordance with Chapter Va. The Member State concerned or the Commission shall clearly identify the question which is referred to the Committee for consideration and shall inform the person responsible for placing the medicinal product on the market. The Member States and the aforementioned person shall forward to the Committee all available information relating to the matter in question. Article 13 1. When reference is made to the procedure described in this Article, the Committee shall consider the matter concerned and issue a reasoned opinion within 90 days of the date on which the matter was referred to it. However, in cases submitted to the Committee in accordance with Articles 11 and 12, this period may be extended by 90 days. In case of urgency, on a proposal from its Chairman, the Committee may agree to impose a shorter deadline. 2. In order to consider the matter, the Committee may appoint one of its members to act as rapporteur. The Committee may also appoint individual experts to advise it on specific questions. When appointing experts, the Committee shall define their tasks and specify the time limit for the completion of these tasks. 3. In the cases referred to in Articles 10 and 11, before issuing its opinion, the Committee shall provide the person responsible for placing the medicinal product on the market with an opportunity to present written or oral explanations. In the case referred to in Article 12, the person responsible for placing the medicinal product on the market may be asked to explain himself orally or in writing. If it considers it appropriate, the Committee may invite any other person to provide information relating to the matter before it. The Committee may suspend the time limit referred to in paragraph 1 in order to allow the person responsible for placing the medicinal product on the market to prepare explanations. 4. Where the opinion of the Committee is that: - the application does not satisfy the criteria for authorization, or - the summary of the product characteristics proposed by the applicant in accordance with Article 4a of Directive 65/65/EEC should be amended, or - the authorization should be granted subject to conditions, with regard to conditions considered essential for the safe and effective use of the medicinal product including pharmacovigilance, or - a marketing authorization should be suspended, varied or withdrawn, the Agency shall forthwith inform the person responsible for placing the medicinal product on the market. Within 15 days of the receipt of the opinion, the aforementioned person may notify the Agency in writing of his intention to appeal. In that case, he shall forward the detailed grounds for appeal to the Agency within 60 days of receipt of the opinion. Within 60 days of receipt of the grounds for appeal, the Committee shall consider whether its opinion should be revised, and the conclusions reached on the appeal shall be annexed to the assessment report referred to in paragraph 5. 5. Within 30 days of its adoption, the Agency shall forward the final opinion of the Committee to the Member States, the Commission and the person responsible for placing the medicinal product on the market together with a report describing the assessment of the medicinal product and stating the reasons for its conclusions. In the event of an opinion in favour of granting or maintaining an authorization 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 4a of Directive 65/65/EEC; (b) any conditions affecting the authorization within the meaning of paragraph 4. Article 14 1. Within 30 days of the receipt of the opinion, the Commission shall prepare a draft of the decision to be taken in respect of the application, taking into account Community law. In the event of a draft decision which envisages the granting of marketing authorization, the documents referred to in Article 13 (5) (a) and (b) shall be annexed. Where, exceptionally, the draft decision is not in accordance with the opinion of the Agency, the Commission shall also annex a detailed explanation of the reasons for the differences. The draft decision shall be forwarded to the Member States and the applicant. 2. A final decision on the application shall be adopted in accordance with the procedure laid down in Article 37b. 3. The rules of procedure of the Committee referred to in Article 37b shall be adjusted to take account of the tasks incumbent upon it in accordance with this Directive. These adjustments shall involve the following: - except in cases referred to in the third subparagraph of paragraph 1, the opinion of the Standing Committee shall be obtained in writing, - each Member State is allowed at least 28 days to forward written observations on the draft decision to the Commission, - each Member State is able to require in writing that the draft decision be discussed by the Standing Committee, giving its reasons in detail. 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 of the Agency, the Chairman shall suspend the procedure and refer the application back to the Agency for further consideration. The provisions necessary for the implementation of this paragraph shall be adopted by the Commission in accordance with the procedure laid down in Article 37a. 4. A decision adopted in accordance with this Article shall be addressed to the Member States concerned by the matter and to the person responsible for placing the medicinal product on the market. The Member States shall either grant or withdraw marketing authorization, or vary the terms of a marketing authorization as necessary to comply with the decision within 30 days of its notification. They shall inform the Commission and the Committee thereof. 5. The procedure referred to in Articles 8 to 14 shall not apply in the cases provided for in Article 9 (2) of Council Directive 92/73/EEC of 22 September 1992 widening the scope of Directive 65/65/EEC and 75/319/EEC on the approximation of the laws of the Member States on medicinal products and laying down additional provisions on homeopathic medicinal products (*). (*) OJ No L 297, 13. 10. 1992, p. 8. Article 15 Any application by the person responsible for placing the medicinal product on the market to vary a marketing authorization which has been granted in accordance with the provisions of this Chapter shall be submitted to all the Member States which have previously authorized the medicinal product concerned. The Commission shall, in consultation with the Agency, adopt appropriate arrangements for the examination of variations to the terms of a marketing authorization. These arrangements shall include a notification system or administration procedures concerning minor variations and define precisely the concept of "a minor variation ". These arrangements shall be adopted by the Commission in the form of an implementing Regulation in accordance with the procedure laid down in Article 37a. The procedure laid down in Articles 13 and 14 shall apply by analogy to variations made to marketing authorizations for products subject to the Commission's arbitration. Article 15a 1. Where a Member State considers that the variation of the terms of a marketing authorization which has been granted in accordance with the provisions of this Chapter or its suspension or withdrawal is necessary for the protection of public health, the Member State concerned shall forthwith refer the matter to the Committee for the application of the products laid down in Articles 13 and 14. 2. Without prejudice to the provisions of Article 12, in exceptional cases, where urgent action is essential to protect public health, until a definitive decision is adopted a Member State may suspend the marketing and the use of the medicinal product concerned on its territory. It shall inform the Commission and the other Member States no later than the following working day of the reasons for its action. Article 15b Articles 15 and 15a shall apply by analogy to medicinal products authorized by Member States following an opinion of the Committee given in accordance with Article 4 of Directive 87/22/EEC before 1 January 1995. Article 15c 1. The Agency shall publish an annual report on the operation of the procedures laid down in this chapter and shall forward that report to the European Parliament and the Council for information. 2. By 1 January 2001, the Commission shall publish a detailed review of the operation of the procedures laid down in this chapter and shall propose any amendments which may be necessary to improve these procedures. The Council shall decide, under the conditions provided for in the Treaty, on the Commission proposal within one year of its submission.'; 2. the third subparagraph of Article 22 (1) is replaced by the following: 'In the case of medicinal products imported from a third country, where appropriate arrangements have been made by the Community with the exporting country to ensure that the manufacturer of the medicinal product applies standards of good manufacturing practice at least equivalent to those laid down by the Community and to ensure that the controls referred to under (b) have been carried out in the exporting country, the qualified person may be relieved of responsibility for carrying out those controls.'; 3. the following Chapter Va is inserted after Article 29: 'CHAPTER Va Pharmacovigilance Article 29a In order to ensure the adoption of appropriate regulatory decisions concerning the medicinal products authorized within the Community, having regard to information obtained about adverse reactions to medicinal products under normal conditions of use, the Member States shall establish a pharmacovigilance system. This system shall be used to collect information useful in the surveillance of medicinal products, with particular reference to adverse reactions in human beings, and to evaluate such information scientifically. Such information shall be collated with data on consumption of medicinal products. This system shall also collate information on frequently observed misuse and serious abuse of medicinal products. Article 29b For the purpose of this Directive, the following definitions shall apply: - "adverse reaction " means a reaction which is harmful and unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis or treatment of disease or the modification of physiological function, - "serious adverse reaction " means an adverse reaction which is fatal, life-threatening, disabling, incapacitating, or which results in or prolongs hospitalization, - "unexpected adverse reaction " means an adverse reaction which is not mentioned in the summary of product characteristics, - "serious unexpected adverse reaction " means an adverse reaction which is both serious and unexpected. Article 29c The person responsible for placing the medicinal product on the market shall have permanently and continuously at his disposal an appropriately qualified person responsible for pharmacovigilance. That qualified person shall be responsible for the following: (a) the establishment and maintenance of 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 and collated at a single point within the Community; (b) the preparation for the competent authorities of the reports referred to in Article 29d, in such form as may be laid down by those authorities, in accordance with the relevant national or Community guidelines; (c) ensuring that any request from the competent authorities for the provision of additional information necessary for the evaluation of the benefits and risks afforded by a medicinal product is answered fully and promptly, including the provision of information about the volume of sales or prescriptions of the medicinal product concerned. Article 29d 1. The person responsible for placing the medicinal product on the market shall be required to record and to report all suspected serious adverse reactions which are brought to his attention by a health care professional to the competent authorities immediately, and in any case within 15 days of their receipt at the latest. 2. In addition, the person responsible for placing the medicinal product on the market shall be required to maintain detailed records of all other suspected adverse reactions which are reported to him by a health care professional. Unless other requirements have been laid down as a condition of the granting of authorization, these records shall be submitted to the competent authorities immediately upon request or at least every six months during the first two years following authorization, and once a year for the following three years. Thereafter, the records shall be submitted at five-yearly intervals together with the application for renewal of the authorization, or immediately upon request. These records shall be accompanied by a scientific evaluation. Article 29e The Member States shall take all appropriate measures to encourage doctors and other health care professionals to report suspected adverse reactions to the competent authorities. The Member States may impose specific requirements on medical practitioners, in respect of the reporting of suspected serious or unexpected adverse reactions, in particular where such reporting is a condition of the authorization. Article 29f The Member States shall ensure that reports of suspected serious adverse reactions are immediately brought to the attention of the Agency and the person responsible for placing the medicinal product on the market, and in any case within 15 days of their notification, at the latest. Article 29g In order to facilitate the exchange of information about pharmacovigilance within the Community, the Commission, in consultation with the Agency, Member States and interested parties, shall draw up guidance on the collection, verification and presentation of adverse reaction reports. This guidance shall take account of international harmonization work carried out with regard to terminology and classification in the field of pharmacovigilance. Article 29h Where as a result of the evaluation of adverse reaction reports a Member State considers that a marketing authorization should be varied, suspended or withdrawn, it shall forthwith inform the Agency and the person responsible for placing the medicinal product on the market. In case of urgency, the Member State concerned may suspend the marketing of a medicinal product, provided the Agency is informed at the latest on the following working day. Article 29i Any amendments which may be necessary to update provisions of this Chapter to take account of scientific and technical progress shall be adopted in accordance with the procedure laid down in Article 37a.'; 4. the following Chapter VIa is inserted after Article 37: 'CHAPTER VIa Standing Committee procedures Article 37a Where the procedure laid down in this Article is to be followed the Commission shall be assisted by the Standing Committee on Medicinal Products for Human Use. The representative of the Commission shall submit to the Committee a draft of the measures to be taken. The Committee shall deliver its opinion on the draft within a time limit which the Chairman may lay down according to the urgency of the matter. The opinion shall be delivered by the majority laid down in Article 148 (2) of the Treaty in the case of decisions which the Council is required to adopt on a proposal from the Commission. The votes of the representatives of the Member States within the Committee shall be weighted in the manner set out in that Article. The Chairman shall not vote. The Commission shall adopt the measures envisaged if they are in accordance with the opinion of the Committee. If the measures envisaged are not in accordance with the opinion of the Committee, or if no opinion is delivered, the Commission shall, without delay, submit to the Council a proposal relating to the measures to be taken. The Council shall act by a qualified majority. If on the expiry of a period of three months from the date of referral to the Council, the Council has not acted, the proposed measures shall be adopted by the Commission. Article 37b Where the procedure laid down in this Article is to be followed the Commission shall be assisted by the Standing Committee on Medicinal Products for Human Use. The representative of the Commission shall submit to the Committee a draft of the measures to be taken. The Committee shall deliver its opinion on the draft within a time limit which the Chairman may lay down according to the urgency of the matter. The opinion shall be delivered by the majority laid down in Article 148 (2) of the Treaty in the case of decisions which the Council is required to adopt on a proposal from the Commission. The votes of the representatives of the Member States within the Committee shall be weighted in the manner set out in that Article. The Chairman shall not vote. The Commission shall adopt the measures envisaged if they are in accordance with the opinion of the Committee. If the measures envisaged are not in accordance with the opinion of the Committee, or if no opinion is delivered, the Commission shall, without delay, submit to the Council a proposal relating to the measures to be taken. The Council shall act by a qualified majority. If on the expiry of a period of three months from the date of referral to the Council, the Council has not acted, the proposed measures shall be adopted by the Commission, save where the Council has decided against the said measures by a simple majority.'; 5. in Article 19a of Directive 75/319/EEC the reference to Article 2c of Directive 75/318/EEC shall be replaced by a reference to Article 37a. Article 4 Member States shall take all appropriate measures to comply with this Directive, with the exception of Article 1 (7), before 1 January 1995. They shall forthwith inform the Commission thereof. Member States shall take all appropriate measures to comply with Article 1 (7) of this Directive before 1 January 1998. They shall forthwith inform the Commission thereof. When Member States adopt these provisions, they shall contain a reference to this Directive or shall be accompanied by such reference at the time of their official publication. The methods of making such a reference shall be laid down by Member States. Member States shall communicate to the Commission the text of the provisions of national law which they adopt in the field governed by this Directive. Article 5 This Directive is addressed to the Member States. Done at Luxembourg, 14 June 1993. For the Council The President J. TROEJBORG (1) OJ No C 330, 31. 12. 1970, p. 18, and OJ No C 310, 30. 11. 1991, p. 22.(2) OJ No C 183, 15. 7. 1991, p. 187, and OJ No C 150, 31. 5. 1993.(3) OJ No C 269, 14. 10. 1991, p. 84.(4) OJ No L 147, 9. 6. 1975, p. 13. Directive last amended by Directive 92/27/EEC (OJ No L 113, 30. 4. 1992, p. 8).(5) OJ No 22, 9. 2. 1965, p. 369/65. Directive last amended by Directive 92/27/EEC (OJ No L 113, 30. 4. 1992, p. 8).(6) OJ No L 147, 9. 6. 1975, p. 1. Directive last amended by Commission Directive 91/507/EEC (OJ No L 270, 26. 9. 1991, p. 32).(7) See page 1 of this Official Journal.

COUNCIL DIRECTIVE 93/39/EEC of 14 June 1993 amending Directives 65/65/EEC, 75/318/EEC and 75/319/EEC in respect of medicinal products

THE COUNCIL OF THE EUROPEAN COMMUNITIES,

Having regard to the Treaty establishing the European Economic Community, and in particular Article 100a thereof,

Having regard to the proposal from the Commission (1),

In cooperation with the European Parliament (2),

Having regard to the opinion of the Economic and Social Committee (3),

Whereas it is important to adopt measures with the aim of progressively establishing the internal market over a period expiring on 31 December 1992; whereas the internal market shall comprise an area without internal frontiers in which the free movement of goods, persons, services and capital is ensured;

Whereas Article 15 (2) of Second Council Directive 75/319/EEC of 20 May 1975 on the approximation of provisions laid down by law, regulation or administrative action relating to proprietary medicinal products (4) provides that the Commission shall submit to the Council a proposal containing appropriate measures leading towards the abolition of any remaining barriers to the free movement of proprietary medicinal products;

Whereas, in the interest of public health and of the consumer of medicinal products, it is necessary that decisions on the authorization to place medicinal products on the market be exclusively based on the criteria of quality, safety and efficacy; whereas these criteria have been extensively harmonized by Council Directive 65/65/EEC of 26 January 1965 on the approximation of provisions laid down by law, regulation or administration action relating to medicinal products (5), by Council Directive 75/319/EEC, and by Council Directive 75/318/EEC of 20 May 1975 on the approximation of the laws of the Member States relating to analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products (6); whereas, however, Member States should exceptionally be able to prohibit the use on their territory of medicinal products which infringe objectively defined concepts of public order or public morality;

Whereas, with the exception of those medicinal products which are subject to the centralized Community authorization procedure established by Council Regulation (EEC) No 2309/93 of 22 July 1993 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Agency for the Evaluation of Medicinal Products (7), an authorization to place a medicinal product on the market in one Member State ought in principle to be recognized by the competent authorities of the other Member States unless there are serious grounds for supposing that the authorization of the medicinal product concerned may present a risk to public health; whereas, in the event of a disagreement between Member States about the quality, the safety or the efficacy of a medicinal product, a scientific evaluation of the matter should be undertaken by the Committee for Proprietary Medicinal Products attached to the European Agency for the Evaluation of Medicinal Products, leading to a single decision on the area of disagreement binding on the Member States concerned; whereas this decision should be adopted by a rapid procedure ensuring close cooperation between the Commission and the Member States;

Whereas in order better to protect public health and avoid any unnecessary duplication of effort during the examination of application for authorization to place medicinal products on the market, Member States should systematically prepare assessment reports in respect of each medicinal product which is authorized by them, and exchange the reports upon request; whereas, furthermore, a Member State should be able to suspend the examination of an application for authorization to place a medicinal product on the market which is currently under active consideration in another Member State with a view to recognizing the decision reached by the latter Member State;

Whereas following the establishment of the internal market, specific controls to guarantee the quality of medicinal products imported from third countries can be waived only if appropriate arrangements have been made by the Community to ensure that the necessary controls are carried out in the exporting country;

Whereas it is desirable to codify and improve the cooperation and exchange of information between Member States relating to the supervision of medicinal products and in particular the monitoring of adverse reactions under practical conditions of use through the national pharmacovigilance systems,

HAS ADOPTED THIS DIRECTIVE:

Directive 65/65/EEC is hereby amended as follows:

1. Article 3 is replaced by the following:

'Article 3

No medicinal product may be placed on the market of a Member State unless a marketing authorization has been issued by the competent authorities of that Member State in accordance with this Directive or an authorization has been granted in accordance with Regulation (EEC) No 2309/93 of 22 July 1993 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Agency for the Evaluation of Medicinal Products (*).

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

(*) OJ No L 214, 24. 8. 1993, p. 1';

2. the following subparagraph is added between the first and second subparagraphs of Article 4:

'The person responsible for placing medicinal products on the market shall be established in the Community. In respect of medicinal products authorized on the date of implementation of this Directive, the Member State shall if necessary apply this provision at the time of the five-yearly renewal of the marketing authorization provided for in Article 10.';

3. in the second paragraph of Article 4, points 6 and 11 are replaced by the following:

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

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

'11. Copies of any authorization obtained in another Member State or in a third country to place the relevant medicinal product on the market, together with a list of those Member States in which an application for authorization submitted in accordance with this Directive is under examination. Copies of the summary of the product characteristics proposed by the applicant in accordance with Article 4a or approved by the competent authorities of the Member State in accordance with Article 4b. Copies of the package leaflet proposed in accordance with Article 6 of Directive 92/27/EEC or approved by the competent authorities of the Member State in accordance with Article 10 of the same Directive. Details of any decision to refuse authorization, whether in the Community or in a third country, and the reasons for such decision.

This information shall be updated on a regular basis';

4. Article 4b is replaced by the following:

'Article 4b

When the marketing authorization referred to in Article 3 is issued, the person responsible for placing that product on the market shall be informed, by the competent authorities of the Member State concerned, of the summary of the product characteristics as approved by it. The competent authorities shall take all necessary measures to ensure that the information given in the summary is in conformity with that accepted when the marketing authorization is issued or subsequently. The competent authorities shall forward to the European Agency for the Evaluation of Medicinal Products a copy of the authorization together with the summary of the product characteristics referred to in Article 4a.

Furthermore, the competent authorities shall draw up an assessment report and comments on the dossier as regards the results of the analytical and pharmacotoxicological tests and the clinical trials of the medicinal product concerned. The assessment report shall be udapted whenever new information becomes available which is of importance for the evaluation of the quality, safety or efficacy of the medicinal product concerned.';

5. Article 6 is replaced by the following:

'Article 6

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

6. Article 7 is replaced by the following:

'Article 7

1. Member States shall take all appropriate measures to ensure that the procedure for granting an authorization to place a medicinal product on the market is completed within 210 days of the submission of a valid application.

2. Where a Member State notes that an application for authorization submitted after 1 January 1995 is already under active examination in another Member State in respect of that medicinal product, the Member State concerned may decide to suspend the detailed examination of the application in order to await the assessment report prepared by the other Member State in accordance with Article 4b.

The Member State concerned shall inform the other Member State and the applicant of its decision to suspend detailed examination of the application in question. As soon as it has completed the examination of the application and reached a decision, the other Member State shall forward a copy of its assessment report to the Member State concerned.

Within 90 days of the receipt of the assessment report, the Member State concerned shall either recognize the decision of the other Member State and the summary of the product characteristics as approved by it, or, if it considers that there are grounds for supposing that the authorization of the medicinal product concerned may present a risk to public health (*), it shall apply the procedures set out in Articles 10 to 14 of Directive 75/319/EEC.

(*) The expression "risk to public health " refers to the quality, safety and efficacy of the medicinal product.';

7. insert the following Article 7a:

'Article 7a

With effect from 1 January 1998, where a Member State is informed in accordance with point 11 of the second paragraph of Article 4 that another Member State has authorized a medicinal product which is the subject of an application for authorization in the Member State concerned, that Member State shall forthwith request the authorities of the Member State which has granted the authorization to forward to it the assessment report referred to in the second paragraph of Article 4b.

Within 90 days of the receipt of the assessment report, the Member State concerned shall either recognize the decision of the first Member State and the summary of the product characteristics as approved by it or, if it considers that there are grounds for supposing that the authorization of the medicinal product concerned may present a risk to public health (*), it shall apply the procedures set out in Articles 10 to 14 of Directive 75/319/EEC.

(*) The expression "risk to public health " refers to the quality, safety and efficacy of the medicinal product';

8. Article 9a is replaced by the following:

'Article 9a

After an authorization has been issued, the person responsible for placing the product on the market must, in respect of the methods of preparation and control provided for in points 4 and 7 of the second paragraph of Article 4, take account of technical and scientific progress and introduce any changes that may be required to enable that medicinal product to be manufactured and checked by means of generally accepted scientific methods. These changes shall be subject to the approval of the competent authority of the Member State concerned';

9. Article 10 is replaced by the following:

'Article 10

1. Authorization shall be valid for five years and shall be renewable for five-year periods, on application by the holder at least three months before the expiry date and after consideration by the competent authority of a dossier containing in particular details of the data on pharmacovigilance and other information relevant to the monitoring of the medicinial product.

2. In exceptional circumstances, and following consultation with the applicant, an authorization may be granted subject to certain specific obligations, including:

- the carrying out of further studies following the granting of authorization,

- the notification of adverse reactions to the medicinal product.

These exceptional decisions may be adopted only for objective and verifiable reasons and shall be based on one of the causes referred to in Part 4 (G) of the Annex to Directive 75/318/EEC.'

Article 2

In Directive 75/318/EEC, the Committee referred to in Article 2b shall be called 'the Standing Committee on Medicinal Products for Human Use'.

Directive 75/319/EEC is hereby amended as follows:

1. Chapter III is replaced by the following:

'CHAPTER III

Committee for Proprietary Medicinal Products

Article 8

1. In order to facilitate the adoption of common decisions by Member States on the authorization of medicinal products for human use on the basis of the scientific criteria of quality, safety and efficacy, and to achieve thereby the free movement of medicinal products within the Community, a Committee for Proprietary Medicinal Products, hereinafter referred to as "the Committee ", is hereby set up. The Committee shall be part of the European Agency for the Evaluation of Medicinal Products established by Council Regulation (EEC) No 2309/93 of 22 July 1993 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Agency for the Evaluation of Medicinal Products (*), hereinafter referred to as "the Agency ".

2. In addition to the other responsibilities conferred upon it by Community law, the Committee shall examine any question relating to the granting, variation, suspension or withdrawal of marketing authorization for a medicinal product which is submitted to it in accordance with this Directive.

(*) OJ No L 214, 24. 8. 1993, p. 1.

Article 9

1. In order to obtain the recognition according to the procedures laid down in this Chapter in one or more of the Member States of an authorization issued by a Member State in accordance with Article 3 of Directive 65/65/EEC, the holder of the authorization shall submit an application to the competent authorities of the Member State or Member States concerned, together with the information and particulars referred to in Articles 4, 4a and 4b of Directive 65/65/EEC. He shall testify that the dossier is identical to that accepted by the first Member State, or shall identify any additions or amendments it may contain. In the latter case, he shall certify that the summary of the product characteristics proposed by him in accordance with

Article 4a of Directive 65/65/EEC is identical to that accepted by the first Member State in accordance with Article 4b of Directive 65/65/EEC. Moreover he shall certify that all the dossiers filed as part of the procedure are identical.

2. The holder of the marketing authorization shall notify the Committee of this application, inform it of the Member States concerned and of the dates of submission of the application and send it a copy of the authorization granted by the first Member State. He shall also send the Committee copies of any such authorization which may have been granted by the other Member States in respect of the medicinal product concerned, and shall indicate whether any application for authorization is currently under consideration in any Member State.

3. Except in cases referred to in Article 7a of Directive 65/65/EEC, before submitting the application, the holder of the authorization shall inform the Member State which granted the authorization on which the application is based that an application is to be made in accordance with this Directive and shall notify it of any additions to the original dossier; that Member State may require the applicant to provide it with all the particulars and documents necessary to enable it to check that the dossiers filed are identical.

In addition the holder of the authorization shall request the Member State which granted the initial authorization to prepare an assessment report in respect of the medicinal product concerned, or, if necessary, to update any existing assessment report. That Member State shall prepare the assessment report, or update it, within 90 days of the receipt of the request.

At the same time as the application is submitted in accordance with paragraph 1 the Member State which granted the initial authorization shall forward the assessment report to the Member State or Member States concerned by the application.

4. Save in the exceptional case provided for in Article 10 (1), each Member State shall recognize the marketing authorization granted by the first Member State within 90 days of receipt of the application and the assessment report. It shall inform the Member State which granted the initial authorization, the other Member States concerned by the application, the Committee, and the person responsible for placing the medicinal product on the market.

Article 10

1. Notwithstanding Article 9 (4), where a Member State considers that there are grounds for supposing that the authorization of the medicinal product concerned may present a risk to public health (*), it shall forthwith inform the applicant, the Member State which granted the initial authorization, any other Member States concerned by the application and the Committee. The Member State shall state its reasons in detail and shall indicate what action may be necessary to correct any defect in the application.

2. All the Member States concerned shall use their best endeavours to reach agreement on the action to be taken in respect of the application. They shall provide the applicant with the opportunity to make his point of view known orally or in writing. However, if the Member States have not reached agreement within the time limit referred to in Article 9 (4) they shall forthwith refer the matter to the Committee for the application of the procedure laid down in Article 13.

3. Within the time limit referred to in paragraph 2, the Member States concerned shall provide the Committee with a detailed statement of the matters on which they have been unable to reach agreement and the reasons for their disagreement. The applicant shall be provided with a copy of this information.

4. As soon as he is informed that the matter has been referred to the Committee, the applicant shall forthwith forward to the Committee a copy of the information and particulars referred to in Article 9 (1).

(*) The expression "risk to public health " refers to the quality, safety and efficacy of the medicinal product.

Article 11

If several applications submitted in accordance with Article 4 and 4a of Directive 65/65/EEC have been made for marketing authorization for a particular medicinal product, and Member States have adopted divergent decisions concerning the authorization of the medicinal product or its suspension or withdrawal from the market, a Member State, or the Commission, or the person responsible for placing the medicinal product on the market may refer the matter to the Committee for application of the procedure laid down in Article 13.

The Member State concerned, the person responsible for placing the medicinal product on the market or the Commission shall clearly identify the question which is referred to the Committee for consideration and, where appropriate, shall inform the aforementioned person thereof.

The Member State and the person responsible for placing the medicinal product on the market shall forward to the Committee all available information relating to the matter in question.

Article 12

The Member States or the Commission or the applicant or holder of the marketing authorization may, in specific cases where the interests of the Community are involved, refer the matter to the Committee for the application of the procedure laid down in

Article 13

before reaching a decision on a request for a marketing authorization or on the suspension or withdrawal of an authorization, or on any other variation to the terms of a marketing authorization which appears necessary, in particular to take account of the information collected in accordance with Chapter Va.

The Member State concerned or the Commission shall clearly identify the question which is referred to the Committee for consideration and shall inform the person responsible for placing the medicinal product on the market.

The Member States and the aforementioned person shall forward to the Committee all available information relating to the matter in question.

Article 13

1. When reference is made to the procedure described in this Article, the Committee shall consider the matter concerned and issue a reasoned opinion within 90 days of the date on which the matter was referred to it.

However, in cases submitted to the Committee in accordance with Articles 11 and 12, this period may be extended by 90 days.

In case of urgency, on a proposal from its Chairman, the Committee may agree to impose a shorter deadline.

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

3. In the cases referred to in Articles 10 and 11, before issuing its opinion, the Committee shall provide the person responsible for placing the medicinal product on the market with an opportunity to present written or oral explanations.

In the case referred to in Article 12, the person responsible for placing the medicinal product on the market may be asked to explain himself orally or in writing.

If it considers it appropriate, the Committee may invite any other person to provide information relating to the matter before it.

The Committee may suspend the time limit referred to in paragraph 1 in order to allow the person responsible for placing the medicinal product on the market to prepare explanations.

4. Where the opinion of the Committee is that:

- the application does not satisfy the criteria for authorization, or

- the summary of the product characteristics proposed by the applicant in accordance with Article 4a of Directive 65/65/EEC should be amended, or

- the authorization should be granted subject to conditions, with regard to conditions considered essential for the safe and effective use of the medicinal product including pharmacovigilance, or

- a marketing authorization should be suspended, varied or withdrawn,

the Agency shall forthwith inform the person responsible for placing the medicinal product on the market. Within 15 days of the receipt of the opinion, the aforementioned person may notify the Agency in writing of his intention to appeal. In that case, he shall forward the detailed grounds for appeal to the Agency within 60 days of receipt of the opinion. Within 60 days of receipt of the grounds for appeal, the Committee shall consider whether its opinion should be revised, and the conclusions reached on the appeal shall be annexed to the assessment report referred to in paragraph 5.

5. Within 30 days of its adoption, the Agency shall forward the final opinion of the Committee to the Member States, the Commission and the person responsible for placing the medicinal product on the market together with a report describing the assessment of the medicinal product and stating the reasons for its conclusions.

In the event of an opinion in favour of granting or maintaining an authorization 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 4a of Directive 65/65/EEC;

(b) any conditions affecting the authorization within the meaning of paragraph 4.

Article 14

1. Within 30 days of the receipt of the opinion, the Commission shall prepare a draft of the decision to be taken in respect of the application, taking into account Community law.

In the event of a draft decision which envisages the granting of marketing authorization, the documents referred to in Article 13 (5) (a) and (b) shall be annexed.

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

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

2. A final decision on the application shall be adopted in accordance with the procedure laid down in Article 37b.

3. The rules of procedure of the Committee referred to in Article 37b shall be adjusted to take account of the tasks incumbent upon it in accordance with this Directive.

These adjustments shall involve the following:

- except in cases referred to in the third subparagraph of paragraph 1, the opinion of the Standing Committee shall be obtained in writing,

- each Member State is allowed at least 28 days to forward written observations on the draft decision to the Commission,

- each Member State is able to require in writing that the draft decision be discussed by the Standing Committee, giving its reasons in detail.

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 of the Agency, the Chairman shall suspend the procedure and refer the application back to the Agency for further consideration.

The provisions necessary for the implementation of this paragraph shall be adopted by the Commission in accordance with the procedure laid down in Article 37a.

4. A decision adopted in accordance with this Article shall be addressed to the Member States concerned by the matter and to the person responsible for placing the medicinal product on the market. The Member States shall either grant or withdraw marketing authorization, or vary the terms of a marketing authorization as necessary to comply with the decision within 30 days of its notification. They shall inform the Commission and the Committee thereof.

5. The procedure referred to in Articles 8 to 14 shall not apply in the cases provided for in Article 9 (2) of Council Directive 92/73/EEC of 22 September 1992 widening the scope of Directive 65/65/EEC and 75/319/EEC on the approximation of the laws of the Member States on medicinal products and laying down additional provisions on homeopathic medicinal products (*).

(*) OJ No L 297, 13. 10. 1992, p. 8.

Article 15

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

The Commission shall, in consultation with the Agency, adopt appropriate arrangements for the examination of variations to the terms of a marketing authorization.

These arrangements shall include a notification system or administration procedures concerning minor variations and define precisely the concept of "a minor variation ".

These arrangements shall be adopted by the Commission in the form of an implementing Regulation in accordance with the procedure laid down in Article 37a.

The procedure laid down in Articles 13 and 14 shall apply by analogy to variations made to marketing authorizations for products subject to the Commission's arbitration.

Article 15a

1. Where a Member State considers that the variation of the terms of a marketing authorization which has been granted in accordance with the provisions of this Chapter or its suspension or withdrawal is necessary for the protection of public health, the Member State concerned shall forthwith refer the matter to the Committee for the application of the products laid down in Articles 13 and 14.

2. Without prejudice to the provisions of Article 12, in exceptional cases, where urgent action is essential to protect public health, until a definitive decision is adopted a Member State may suspend the marketing and the use of the medicinal product concerned on its territory. It shall inform the Commission and the other Member States no later than the following working day of the reasons for its action.

Article 15b

Articles 15 and 15a shall apply by analogy to medicinal products authorized by Member States following an opinion of the Committee given in accordance with Article 4 of Directive 87/22/EEC before 1 January 1995.

Article 15c

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

2. By 1 January 2001, the Commission shall publish a detailed review of the operation of the procedures laid down in this chapter and shall propose any amendments which may be necessary to improve these procedures.

The Council shall decide, under the conditions provided for in the Treaty, on the Commission proposal within one year of its submission.';

2. the third subparagraph of Article 22 (1) is replaced by the following:

'In the case of medicinal products imported from a third country, where appropriate arrangements have been made by the Community with the exporting country to ensure that the manufacturer of the medicinal product applies standards of good manufacturing practice at least equivalent to those laid down by the Community and to ensure that the controls referred to under (b) have been carried out in the exporting country, the qualified person may be relieved of responsibility for carrying out those controls.';

3. the following Chapter Va is inserted after Article 29:

'CHAPTER Va

Pharmacovigilance

Article 29a

In order to ensure the adoption of appropriate regulatory decisions concerning the medicinal products authorized within the Community, having regard to information obtained about adverse reactions to medicinal products under normal conditions of use, the Member States shall establish a pharmacovigilance system. This system shall be used to collect information useful in the surveillance of medicinal products, with particular reference to adverse reactions in human beings, and to evaluate such information scientifically.

Such information shall be collated with data on consumption of medicinal products.

This system shall also collate information on frequently observed misuse and serious abuse of medicinal products.

Article 29b

For the purpose of this Directive, the following definitions shall apply:

- "adverse reaction " means a reaction which is harmful and unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis or treatment of disease or the modification of physiological function,

- "serious adverse reaction " means an adverse reaction which is fatal, life-threatening, disabling, incapacitating, or which results in or prolongs hospitalization,

- "unexpected adverse reaction " means an adverse reaction which is not mentioned in the summary of product characteristics,

- "serious unexpected adverse reaction " means an adverse reaction which is both serious and unexpected.

Article 29c

The person responsible for placing the medicinal product on the market shall have permanently and continuously at his disposal an appropriately qualified person responsible for pharmacovigilance.

That qualified person shall be responsible for the following:

(a) the establishment and maintenance of 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 and collated at a single point within the Community;

(b) the preparation for the competent authorities of the reports referred to in Article 29d, in such form as may be laid down by those authorities, in accordance with the relevant national or Community guidelines;

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

Article 29d

1. The person responsible for placing the medicinal product on the market shall be required to record and to report all suspected serious adverse reactions which are brought to his attention by a health care professional to the competent authorities immediately, and in any case within 15 days of their receipt at the latest.

2. In addition, the person responsible for placing the medicinal product on the market shall be required to maintain detailed records of all other suspected adverse reactions which are reported to him by a health care professional.

Unless other requirements have been laid down as a condition of the granting of authorization, these records shall be submitted to the competent authorities immediately upon request or at least every six months during the first two years following authorization, and once a year for the following three years. Thereafter, the records shall be submitted at five-yearly intervals together with the application for renewal of the authorization, or immediately upon request. These records shall be accompanied by a scientific evaluation.

Article 29e

The Member States shall take all appropriate measures to encourage doctors and other health care professionals to report suspected adverse reactions to the competent authorities.

The Member States may impose specific requirements on medical practitioners, in respect of the reporting of suspected serious or unexpected adverse reactions, in particular where such reporting is a condition of the authorization.

Article 29f

The Member States shall ensure that reports of suspected serious adverse reactions are immediately brought to the attention of the Agency and the person responsible for placing the medicinal product on the market, and in any case within 15 days of their notification, at the latest.

Article 29g

In order to facilitate the exchange of information about pharmacovigilance within the Community, the Commission, in consultation with the Agency, Member States and interested parties, shall draw up guidance on the collection, verification and presentation of adverse reaction reports.

This guidance shall take account of international harmonization work carried out with regard to terminology and classification in the field of pharmacovigilance.

Article 29h

Where as a result of the evaluation of adverse reaction reports a Member State considers that a marketing authorization should be varied, suspended or withdrawn, it shall forthwith inform the Agency and the person responsible for placing the medicinal product on the market.

In case of urgency, the Member State concerned may suspend the marketing of a medicinal product, provided the Agency is informed at the latest on the following working day.

Article 29i

Any amendments which may be necessary to update provisions of this Chapter to take account of scientific and technical progress shall be adopted in accordance with the procedure laid down in Article 37a.';

4. the following Chapter VIa is inserted after Article 37:

'CHAPTER VIa

Standing Committee procedures

Article 37a

Where the procedure laid down in this Article is to be followed the Commission shall be assisted by the Standing Committee on Medicinal Products for Human Use.

The representative of the Commission shall submit to the Committee a draft of the measures to be taken. The Committee shall deliver its opinion on the draft within a time limit which the Chairman may lay down according to the urgency of the matter. The opinion shall be delivered by the majority laid down in Article 148 (2) of the Treaty in the case of decisions which the Council is required to adopt on a proposal from the Commission. The votes of the representatives of the Member States within the Committee shall be weighted in the manner set out in that Article. The Chairman shall not vote.

The Commission shall adopt the measures envisaged if they are in accordance with the opinion of the Committee.

If the measures envisaged are not in accordance with the opinion of the Committee, or if no opinion is delivered, the Commission shall, without delay, submit to the Council a proposal relating to the measures to be taken. The Council shall act by a qualified majority.

If on the expiry of a period of three months from the date of referral to the Council, the Council has not acted, the proposed measures shall be adopted by the Commission.

Article 37b

Where the procedure laid down in this Article is to be followed the Commission shall be assisted by the Standing Committee on Medicinal Products for Human Use.

The representative of the Commission shall submit to the Committee a draft of the measures to be taken. The Committee shall deliver its opinion on the draft within a time limit which the Chairman may lay down according to the urgency of the matter. The opinion shall be delivered by the majority laid down in Article 148 (2) of the Treaty in the case of decisions which the Council is required to adopt on a proposal from the Commission. The votes of the representatives of the Member States within the Committee shall be weighted in the manner set out in that Article. The Chairman shall not vote.

The Commission shall adopt the measures envisaged if they are in accordance with the opinion of the Committee.

If the measures envisaged are not in accordance with the opinion of the Committee, or if no opinion is delivered, the Commission shall, without delay, submit to the Council a proposal relating to the measures to be taken. The Council shall act by a qualified majority.

If on the expiry of a period of three months from the date of referral to the Council, the Council has not acted, the proposed measures shall be adopted by the Commission, save where the Council has decided against the said measures by a simple majority.';

5. in Article 19a of Directive 75/319/EEC the reference to Article 2c of Directive 75/318/EEC shall be replaced by a reference to Article 37a.

Member States shall take all appropriate measures to comply with this Directive, with the exception of Article 1 (7), before 1 January 1995. They shall forthwith inform the Commission thereof.

Member States shall take all appropriate measures to comply with Article 1 (7) of this Directive before 1 January 1998. They shall forthwith inform the Commission thereof.

When Member States adopt these provisions, they shall contain a reference to this Directive or shall be accompanied by such reference at the time of their official publication. The methods of making such a reference shall be laid down by Member States.

Member States shall communicate to the Commission the text of the provisions of national law which they adopt in the field governed by this Directive.

This Directive is addressed to the Member States.

Done at Luxembourg, 14 June 1993.

For the Council

The President

J. TROEJBORG

(1) OJ No C 330, 31. 12. 1970, p. 18, and OJ No C 310, 30. 11. 1991, p. 22.(2) OJ No C 183, 15. 7. 1991, p. 187, and OJ No C 150, 31. 5. 1993.(3) OJ No C 269, 14. 10. 1991, p. 84.(4) OJ No L 147, 9. 6. 1975, p. 13. Directive last amended by Directive 92/27/EEC (OJ No L 113, 30. 4. 1992, p. 8).(5) OJ No 22, 9. 2. 1965, p. 369/65. Directive last amended by Directive 92/27/EEC (OJ No L 113, 30. 4. 1992, p. 8).(6) OJ No L 147, 9. 6. 1975, p. 1. Directive last amended by Commission Directive 91/507/EEC (OJ No L 270, 26. 9. 1991, p. 32).(7) See page 1 of this Official Journal.