COMMISSION REGULATION (EC) No 541/95 of 10 March 1995 concerning the examination of variations to the terms of a marketing authorization granted by a competent authority of a Member State
THE COMMISSION OF THE EUROPEAN COMMUNITIES,
Having regard to the Treaty establishing the European Community,
Having regard to Council Directive 75/319/EEC of 20 May 1975, on the approximation of provisions laid down by law, regulations or administrative action relating to medicinal products (1), as last amended by Council Directive 93/39/EEC (2) of 14 June 1993, and in particular Article 15 thereof,
Having regard to Council Directive 81/851/EEC of 28 September 1981, on the approximation of legislation of the Member States relating to veterinary medicinal products (3), as last amended by Council Directive 93/40/EEC (4), and in particular Article 23 thereof,
Whereas, appropriate provisions should be adopted for the examination of variations to the terms of a marketing authorization of medicinal products which have benefited from the procedures of mutual recognition foreseen in Articles 7 and 7a of Council Directive 65/65/EEC of 26 January 1965 on the approximation of provisions laid down by law, regulation or administrative action relating to medicinal products (5), as last amended by Directive 93/39/EEC, in Article 9 (4) of Council Directive 75/319/EEC or in Articles 8, 8a and 17 (4) of Council Directive 81/851/EEC, and medicinal products for which there has been a referral to the procedures foreseen by Articles 13 and 14 of Directive 75/319/EEC or Articles 21 and 22 of Directive 81/851/EEC;
Whereas, these provisions should also apply to the examination of applications to vary the terms of a marketing authorization which had been considered within the scope of application 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 (6);
Whereas, it is appropriate to include a notification system or administrative procedures concerning minor variations for which it is necessary to precisely define minor variations;
Whereas, moreover, it is necessary to distinguish from amongst those variations which do not qualify as minor variations, those which must be considered to so fundamentally alter the marketing authorization, particularly from the point of view of the quality, safety or efficacy of a medicinal product, that a new application for a marketing authorization would be required;
Whereas, the provisions of this Regulation are in accordance with the opinion of the Standing Committee on Medicinal Products for Human use and the Standing Committee on Veterinary Medicinal Products,
HAS ADOPTED THIS REGULATION:
Scope and definitions
Article 1
1. This Regulation lays down the procedure for the examination of applications for variations to the terms of a marketing authorization of medicinal products which have been considered within the scope of application of Directive 87/22/EEC, of medicinal products having benefited from the procedures of mutual recognition foreseen in Articles 7 and 7a of Directive 65/65/EEC, Article 9 (4) of Directive 75/319/EEC or Articles 8, 8a and 17 (4) of Directive 81/851/EEC, and medicinal products for which there has been a referral to the procedures foreseen by Articles 13 and 14 of Directive 75/319/EEC or Articles 21 and 22 of Directive 81/851/EEC.
2. This Regulation does not impede the marketing authorization holder(s) from taking provisional urgent safety restrictions in the event of risk to public or animal health. The holder(s) shall forthwith inform the national competent authorities. If the competent authorities have not raised any objections within 24 hours, the urgent safety restrictions may be introduced and the applications for this variation shall be submitted to the national competent authorities for the application of the procedures set out in Articles 6 and 7 of this Regulation.
Article 2
For the purposes of this Regulation, the following definitions shall apply:
1. Variation to the terms of a marketing authorization:
- for medicinal products for human use: an amendment to the contents of the documents referred to in Articles 4 and 4a of Directive 65/65/EEC, in the Annex of Directive 75/318/EEC and in Article 2 of Directive 75/319/EEC, such as they existed at the moment of the decision on the marketing authorization or after approval of any previous variations; except where a new application for a marketing authorization must be presented pursuant to Annex II of this Regulation;
- for veterinary medicinal products: an amendment to the contents of the documents referred to in Articles 5, 5a and 7 of Directive 81/851/EEC such as they existed at the moment of the decision on the marketing authorization or after approval of any previous variation; except where a new application for a marketing authorizaton must be presented pursuant to Annex II of this Regulation.
2. Reference Member State: the Member State which, for a given medicinal product, has produced the assessment report which served as the basis for the Community procedures foreseen in Article 1 of this Regulation or alternatively the Member State chosen in this respect by the authorization holder with a view to application of this Regulation.
3. Urgent safety restriction: an interim change to product information by the marketing authorization holder restricting the indication(s), and/or dosage, and/or target species of the medicinal product; or adding a contra-indication, and/or warning due to new information having a bearing on the safe use of the product.
Article 3
1 (a) A 'minor variation' (type I) means a variation as defined in Article 2 and listed in Annex I to this Regulation, provided the conditions for such variations laid down in the said Annex are met.
(b) A 'major variation' (or type II) means a variation as defined in Article 2 which cannot be deemed to be a type I variation within the meaning of the preceding paragraph.
2. For the purposes of this Regulation, transfer of marketing authorization to a new holder, except for the situations covered by point 3 of Annex I to this Regulation shall not be considered as a variation in the meaning of Article 2 (1).
Notification procedure for minor variations
Article 4
1. (a) To obtain a type I variation, an identical application shall be submitted simultaneously to the national competent authorities of the different Member States where the medicinal product has been authorized; it shall be accompanied by documents demonstrating that the conditions laid down in Annex I of this Regulation for the requested variation have been met and all documents amended as a result of the application.
(b) The abovementioned documents shall include the list of Member States concerned by the application for the variation and shall identify the reference Member State for the medicinal product under consideration.
2. The Member States concerned shall forthwith notify the reference Member State about the receipt of the application. The reference Member State shall inform the Member States concerned and the marketing authorization holder(s) about the date of the start of the procedure.
3. An application within the meaning of paragraph 1 shall not concern more than one variation in the marketing authorization. Where several variations are to be made to a single marketing authorization, an application shall be submitted within the meaning of paragraph 1 in respect of each variation sought; each such application shall contain a reference to the other application(s).
4. By derogation to paragraph 3, where a variation in the marketing authorization entails one or more further changes, a single application may cover all such consequential variations. The single application shall describe the relation between the main variation and its consequential variations.
5. To be valid, an application within the meaning of paragraph 1 shall be consistent with the provisions of this Article and accompanied by the relevant fees provided for this purpose by the applicable national regulations.
Article 5
1. If, within 30 days of the date of the start of the procedure, the national competent authority of the reference Member State has not sent to the marketing authorization holder, who submitted the application, the notification provided for in paragraph 2 of this Article, the variation requested is deemed accepted by all Member States which have received the application.
2. Where one of the national competent authorities concerned cannot accept the request for the variation, that authority shall send objective grounds for non-acceptance to the reference Member State within a period of 20 days following the date of the start of the procedure. The reference Member State shall send, before the end of the period foreseen in paragraph 1, a notification with grounds to the marketing authorization holder who has submitted the application;
(a) within 30 days of receipt of the said notification, the marketing authorization holder may amend on one occasion only the application in order to take due account of the grounds set out in the notification. In that case the provisions of this present Article apply to the amended application and all applications foreseen by Article 4 are deemed to have been modified in the same sense;
(b) if the marketing authorization holder does not amend the application as provided for in (a) above, all applications are deemed to have been rejected. The national competent authority of the reference Member State shall forthwith notify the refusal to the marketing authorization holder and to the other concerned national competent authorities.
3. Within 10 days of the end of the procedure mentioned in paragraph 2 of this Article, and in cases of divergent positions among the national competent authorities of the concerned Member States leading to a refusal, the marketing authorization holder may refer the matter to the Agency for application of Article 15, last paragraph, of Directive 75/319/EEC or Article 23, last paragraph, of Directive 81/851/EEC.
Approval procedure for major variations
Article 6
1. (a) To obtain a type II variation, an identical application shall be submitted simultaneously to the national competent authorities of the different Member States where the medicinal product has been authorized. It shall be accompanied by the relevant particulars and supporting documents referred to in Article 2 (1) of this Regulation.
The application must also be accompanied by:
- the supporting data relating to the variation applied for,
- all documents amended as a result of the application,
- an Addendum to or updating of existing expert report(s) to take account of the variation applied for;
(b) The above mentioned documents shall include the list of Member States concerned by the application for the variation and shall identify the reference Member State for the medicinal product under consideration.
2. The Member States concerned shall forthwith notify the reference Member States about the receipt of the application. The reference Member State shall inform the Member States concerned and the marketing authorization holder(s) about the date of the start of the procedure.
3. An application within the meaning of paragraph 1 shall not concern more than one variation in the marketing authorization. Where several variations are to be made to a single marketing authorization, an application shall be submitted within the meaning of paragraph 1 in respect of each variation sought; each such application shall contain a reference to the other application(s).
4. By derogation to paragraph 3, where a variation in the marketing authorization entails one or more further changes, a single application may cover all such consequential variations. The single application shall describe the relation between the main variation and its consequential variations.
5. To be valid an application within the meaning of paragraph 1 shall be consistent with the provisions of this Article and accompanied by the relevant fees provided for this purpose by the applicable national regulations.
Article 7
1. Within 60 days following the date of the start of the procedure, the national competent authority of the reference Member State shall prepare an assessment report and a draft decision which shall be addressed to the other national competent authorities concerned.
2. Within that period, the competent authority of the reference Member State may send the marketing authorization holder a single request for information supplementary to that already supplied pursuant to Article 6. It shall inform the other competent authorities concerned. In this case the period shall be extended by a further 60 days. This period may be extended for a period to be determined by the competent authority on its own initiative or upon request of the marketing authorization holder.
3. Within 30 days following receipt of the draft decision and the assessment report, the other national competent authorities concerned shall accept this draft decision and inform the national competent authority of the reference Member State to this effect.
4. Each national competent authority concerned by the application for the variation shall adopt a decision in conformity with the draft decision foreseen in the preceding paragraph. The national decisions shall take effect on the day agreed after discussion between the national competent authority of the reference Member State and the marketing authorization holder in consultation with the other national competent authorities concerned.
5. If within the period foreseen in paragraph 3, mutual recognition by one or more national competent authorities of the draft decision of the national competent authority of the reference Member State is not possible, reference shall be made to the provisions of Article 15, last paragraph, of Directive 75/319/EEC or Article 23, last paragraph, of Directive 81/851/EEC.
Article 8
This Regulation shall enter into force on the third day following its publication in the Official Journal of the European Communities.
This Regulation shall be binding in its entirety and directly applicable in all Member States.
Done at Brussels, 10 March 1995.