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Commission Regulation (EC) No 1084/2003 of 3 June 2003 concerning the examination of variations to the terms of a marketing authorisation for medicinal products for human use and veterinary medicinal products granted by a competent authority of a Member State (Text with EEA relevance) Official Journal L 159 , 27/06/2003 P. 0001 - 0023

Commission regulation (EC) No 1084/2003 of 3 June 2003 concerning the examination of variations to the terms of a marketing authorisation for medicinal products for human use and veterinary medicinal products granted by a competent authority of a Member State (Text with EEA relevance) THE COMMISSION OF THE EUROPEAN COMMUNITIES, Having regard to the Treaty establishing the European Community, Having regard to Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use(1), and in particular Article 35(1) thereof, Having regard to Directive 2001/82/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to veterinary medicinal products(2), and in particular Article 39(1) thereof, Whereas: (1) In the light of practical experience in the application of Commission Regulation (EC) No 541/95 of 10 March 1995 concerning the examination of variations to the terms of a marketing authorisation granted by a competent authority of a Member State(3), as amended by Regulation (EC) No 1146/98(4), it is appropriate to simplify the procedure for varying the terms of a marketing authorisation. (2) Some of the procedures laid down in Regulation (EC) No 541/95 should therefore be adjusted but without departing from the general principles on which those procedures are based. (3) In consequence of the adoption of Directives 2001/82/EC and 2001/83/EC, which codified Community legislation in the field of veterinary medicinal products and medicinal products for human use respectively, references to provisions of that legislation should be updated. (4) This Regulation should continue to apply also to the examination of applications for variation of the terms of a marketing authorisation granted under Council Directive 87/22/EEC(5) repealed by Directive 93/41/EEC(6). (5) It is appropriate to provide for a simplified and rapid notification procedure to enable the introduction of certain minor changes, which do not affect the approved quality, safety or efficacy of the product, without prior evaluation by the reference Member State. However, for other types of minor variation evaluation of the submitted documentation by the reference Member State should still be required. (6) In cases where the evaluation procedure is maintained the reference Member State should evaluate the file on behalf of all Member States concerned in order to avoid duplication of work. (7) The various types of minor variation should be classified according to the conditions to be fulfilled in order to determine the procedure to follow; it is particularly necessary to give a precise definition of the type of minor variation for which no prior evaluation is needed. (8) It is necessary to clarify the definition of an "extension" to a marketing authorisation, although it should still be possible to submit a separate, full application for a marketing authorisation for a medicinal product which has already been authorised, but under a different name and with a different summary of product characteristics. (9) It is appropriate to allow national authorities of the reference Member States to reduce the evaluation period in urgent cases or to extend it in the case of a major variation entailing important changes. (10) The time-frame for the procedure to be followed where the competent authority imposes urgent safety restrictions should be clarified. (11) Further clarification should be introduced as regards revision of the summary of product characteristics, labelling and package leaflet/insert; nevertheless the procedures laid down in this Regulation should not apply to changes to the labelling or to the package leaflet/insert which are not consequential to changes to the summary of product characteristics. (12) For the sake of clarity, it is appropriate to replace Regulation (EC) No 541/95. (13) The measures provided for in 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: Article 1 Subject matter This Regulation lays down the procedure for the examination of notifications of and applications for variations to the terms of a marketing authorisation 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 set out in Articles 17, 18 and 28(4) of Directive 2001/83/EC or Articles 21, 22 and 32(4) of Directive 2001/82/EC, and medicinal products for which there has been a referral to the procedures set out in Articles 32, 33 and 34 of Directive 2001/83/EC or Articles 36, 37 and 38 of Directive 2001/82/EC. Article 2 Scope This Regulation shall not apply to: (a) extensions of marketing authorisations which fulfil the conditions set out in Annex II to this Regulation; (b) transfers of a marketing authorisation to a new holder; (c) changes to the maximum residue limit as defined in Article 1(1)(b) of Council Regulation (EEC) No 2377/90(7). The extensions referred to in point (a) of the first paragraph shall be examined in accordance with the procedure referred to in Article 17 of Directive 2001/83/EC and in Article 21 of Directive 2001/82/EC. Article 3 Definitions For the purposes of this Regulation, the following definitions shall apply: 1. "Variation to the terms of a marketing authorisation" means: (a) for medicinal products for human use: an amendment to the contents of the documents referred to in Articles 8 to 12 of Directive 2001/83/EC; (b) for veterinary medicinal products: an amendment to the contents of the documents referred to in Articles 12 to 15 of Directive 2001/82/EC. 2. A "minor variation" of Type IA or Type IB means a variation listed in Annex I which fulfils the conditions set out therein. 3. A "major variation" of Type II means a variation which cannot be deemed to be a minor variation or an extension of the marketing authorisation. 4. "Reference Member State" means the Member State which, for a given medicinal product, has produced the assessment report which served as the basis for the procedures referred to in Article 1 or alternatively the Member State chosen in this respect by the marketing authorisation holder with a view to application of this Regulation. 5. "Urgent safety restriction" means an interim change to the product information concerning particularly one or more of the following items in the summary of product characteristics, the indications, posology, contraindications, warnings, target species and withdrawal periods, due to new information having a bearing on the safe use of the medicinal product. Article 4 Notification procedure for minor variations type IA 1. With regard to minor variations of type IA, the marketing authorisation holder (hereinafter referred to as the holder) shall submit simultaneously to the competent authorities of the Member States where the medicinal product has been authorised a notification accompanied by: (a) all necessary documents including those amended as a result of the variation; (b) a list of the Member States concerned and an indication of the reference Member State for the medicinal product under consideration; (c) the relevant fees provided for in the applicable national rules in the Member States concerned. 2. A notification shall only concern one type IA variation. Where several type IA variations are to be made to the terms of a single marketing authorisation, a separate notification shall be submitted in respect of each type IA variation sought; each such notification shall also contain a reference to the other notifications. 3. By way of derogation from paragraph 2, where a type IA variation to the marketing authorisation leads to consequential type IA variations, a single notification may cover all such variations. The single notification shall contain a description of the relation between these consequential type IA variations. 4. Where a variation requires consequential revision of the summary of product characteristics, labelling and package leaflet/insert, this is considered as part of the variation. 5. If the notification fulfils the requirements set out in paragraphs 1 to 4, the competent authority of the reference Member State shall within 14 days following receipt of the notification acknowledge the validity of this notification and shall inform the other competent authorities concerned and the holder accordingly. Each competent authority concerned shall, where necessary, update the marketing authorisation, which has been granted pursuant to Article 6 of Directive 2001/83/EC or Article 5 of Directive 2001/82/EC. Article 5 Notification procedure for minor variations type IB 1. With regard to minor variations of type IB, the holder shall submit simultaneously to the competent authorities of the Member States where the medicinal product has been authorised, the notification accompanied by: (a) all necessary documents, including those amended as a result of the variation; (b) a list of Member States concerned and an indication of the reference Member State for the medicinal product under consideration; (c) the relevant fees provided for in the applicable national rules in the Member States concerned. 2. A notification shall only concern one type IB variation. Where several type IB variations are to be made to the terms of a single marketing authorisation, a separate notification shall be submitted in respect of each type IB variation sought; each such notification shall also contain a reference to the other notifications. 3. By way of derogation from paragraph 2, where a type IB variation to the marketing authorisation leads to consequential type IA or type IB variations, a single type IB notification may cover all such consequential variations. The single notification shall contain a description of the relation between these consequential type I variations. 4. Where a variation requires consequential revision of the summary of product characteristics, labelling and package leaflet/insert, this is considered as part of the variation. 5. If the notification fulfils the requirements set out in paragraphs 1 to 4, the competent authority of the reference Member State shall acknowledge receipt of a valid notification and shall start the procedure set out in paragraphs 6 to 11. 6. If, within 30 days of the date of the acknowledgement of receipt of a valid notification the competent authority of the reference Member State has not sent the holder its opinion provided for in paragraph 8, the notified variation shall be deemed to have been accepted by all competent authorities of the Member States concerned. The competent authority of the reference Member State shall inform the other competent authorities of the Member States concerned to this effect. 7. Each competent authority concerned shall, where necessary, update the marketing authorisation which has been granted pursuant to Article 6 of Directive 2001/83/EC or Article 5 of Directive 2001/82/EC. 8. Where the competent authority of the reference Member State is of the opinion that the notification cannot be accepted, it shall, within the period referred to in paragraph 6, inform the holder who has submitted the notification, stating the grounds on which its opinion is based. 9. Within 30 days of receipt of the opinion referred to in paragraph 8, the holder may amend the notification in order to take due account of the grounds set out in the opinion. In that case the provisions of paragraphs 6 and 7 shall apply to the amended notification. 10. If the holder does not amend the notification, the notification shall be deemed to have been rejected. The competent authority of the reference Member State shall forthwith inform the holder and the other competent authorities concerned accordingly. 11. Within 10 days of providing the information referred to in paragraph 10, competent authorities of the Member States concerned or the holder may refer the matter to the Agency for application of Article 35(2) of Directive 2001/83/EC or Article 39(2) of Directive 2001/82/EC. Article 6 Approval procedure for major variations type II 1. With regard to major variations of type II, the holder shall submit simultaneously to the competent authorities of the Member States where the medicinal product has been authorised an application accompanied by: (a) the relevant particulars and supporting documents referred to in Articles 8 to 12 of Directive 2001/83/EC or Articles 12 to 15 of Directive 2001/82/EC; (b) the supporting data relating to the variation applied for; (c) all documents amended as a result of the application; (d) an addendum to or update of existing expert reports/overviews/summaries to take account of the variation applied for; (e) a list of the Member States concerned by the application for the major variation type II and an indication of the reference Member State for the medicinal product under consideration; (f) the relevant fees provided for in the applicable national rules in the Member States concerned. 2. An application shall only concern one type II variation. Where several type II variations are to be made to a single marketing authorisation, a separate application shall be submitted in respect of each variation sought; each such application shall contain also a reference to the other applications. 3. By way of derogation from paragraph 2, where a type II variation leads to consequential variations, a single application may cover all such variations. The single application shall contain a description of the relation between these consequential variations. 4. Where a variation requires consequential revision of the summary of product characteristics, labelling and package leaflet/insert, this is considered as part of the variation. 5. If the application fulfils the requirements set out in paragraphs 1 to 4, the competent authorities of the Member States concerned shall forthwith notify the competent authority of the reference Member States about the receipt of the valid application. 6. The competent authority of the reference Member State shall inform the other competent authorities of the Member States concerned and the holder of the date of the start of the procedure set out in paragraphs 7 to 13. 7. Within 60 days from the start of the procedure, the competent authority of the reference Member State shall prepare an assessment report and a draft decision which shall be addressed to the other competent authorities concerned. This period may be reduced having regard to the urgency of the matter particularly for safety issues. This period may be extended to 90 days for variations concerning changes to or addition of the therapeutic indications. This period shall be extended to 90 days for variations concerning a change to or addition of a non-food producing target species. 8. Within the periods laid down in paragraph 7, the competent authority of the reference Member State may request the holder to provide supplementary information within a time limit set by that competent authority. The procedure shall be suspended until such time as the supplementary information has been provided. In this case the periods laid down in paragraph 7 may be extended for a further period to be determined by the competent authority of the reference Member State. The competent authority of the reference Member State shall inform the other competent authorities concerned. 9. Within 30 days following receipt of the draft decision and the assessment report, the other competent authorities of the Member States concerned shall recognise the draft decision and inform the competent authority of the reference Member State to this effect. The competent authority of the reference Member State shall close the procedure and shall inform the other competent authorities concerned and the holder accordingly. 10. Each competent authority concerned shall, where necessary, amend the marketing authorisation concerned which has been granted pursuant to Article 6 of Directive 2001/83/EC or Article 5 of Directive 2001/82/EC in conformity with the draft decision referred to paragraph 9. 11. Decisions concerning variations related to safety issues shall be implemented within a timeframe as agreed between the competent authority of the reference Member State and the holder in consultation with the other competent authorities of the Member States concerned. 12. If within the period laid down in paragraph 9, mutual recognition by one or more of the competent authorities of the draft decision of the competent authority of the reference Member State is not possible, the procedure referred to in Article 35(2) of Directive 2001/83/EC or Article 39(2) of Directive 2001/82/EC shall apply. 13. Within 10 days of the end of the procedure mentioned in paragraph 8 and in case where the competent authorities of the Member States concerned by the application are of the opinion that the variation cannot be accepted, the holder may refer the matter to the Agency for application of Article 35(2) of Directive 2001/83/EC or Article 39(2) of Directive 2001/82/EC. Article 7 Human influenza vaccines 1. With regard to variations to the terms of the marketing authorisations for human influenza vaccines, the procedure set out in paragraphs 2 to 5 shall apply. 2. Within 30 days following the date of the start of the procedure, the competent authority of the reference Member State shall prepare an assessment report on the basis of the quality documents referred to in Module 3 of Annex I to Directive 2001/83/EC and a draft decision which shall be addressed to the other competent authorities concerned. 3. Within the period laid down in paragraph 2, the competent authority of the reference Member State may request the holder to provide supplementary information. It shall inform the other competent authorities of the Member States concerned. 4. Within 12 days of receipt of the draft decision and the assessment report, the other competent authorities of the Member States concerned shall recognise the draft decision and inform the competent authority of the reference Member State to this effect. 5. The clinical data and, where appropriate, data concerning the stability of the medicinal product, shall be addressed by the holder to the competent authority of the reference Member State and to the other competent authorities of the Member States concerned, at the latest 12 days following the end of the time limit laid down in paragraph 4. The competent authority of the reference Member State shall evaluate these data and draft a final decision within 7 days of the receipt of the data. The other competent authorities concerned shall recognise the final draft decision and, within 7 days of the receipt of the draft final decision, adopt a decision in conformity with the final draft decision. 6. If, in the course of the procedure laid down in paragraphs 2 to 5, a competent authority raises a question of public health which they consider poses an obstacle to the mutual recognition of the decision to be taken, the procedure referred to in Article 35(2) of Directive 2001/83/EC shall apply. Article 8 Pandemic situation with respect to human diseases In case of a pandemic situation with respect to the human influenza virus, duly recognised by the World Health Organisation or by the Community in the framework of Decision No 2119/98/EC of the European Parliament and of the Council(8), competent authorities may exceptionally and temporarily consider the variation to the terms of the marketing authorisation for human influenza vaccines to be accepted after an application has been received and before the end of the procedure laid down in Article 7. Nevertheless, complete clinical safety and efficacy data can be submitted during this procedure. In case of a pandemic situation with respect to human diseases other than the human influenza virus, the first paragraph and Article 7 may be applied mutatis mutandis. Article 9 Urgent safety restrictions 1. If the holder, in the event of risk to public or animal health, takes urgent safety restrictions, he/she shall forthwith inform the competent authorities thereof. If the competent authorities have not raised any objections within 24 hours following receipt of that information, the urgent safety restrictions shall be deemed to have been accepted. The urgent safety restriction shall be implemented within a timeframe, as agreed with the competent authorities. The corresponding variation application reflecting the urgent safety restriction shall be submitted immediately and in any case not later than 15 days after the initiation of the urgent safety restriction, to the competent authorities for the application of the procedures set out in Article 6. 2. Where competent authorities impose urgent safety restrictions on the holder, the holder shall be obliged to submit an application for a variation taking account of the safety restrictions imposed by the competent authorities. The urgent safety restriction shall be implemented within a timeframe, as agreed with the competent authorities. The corresponding variation application reflecting the urgent safety restriction, including appropriate documentation in support of the change, shall be submitted immediately and in any case not later than 15 days after the initiation of the urgent safety restriction, to the competent authorities concerned for the application of the procedures set out in Article 6. This paragraph is without prejudice to Article 36 of Directive 2001/83/EC and Article 40 of Directive 2001/82/EC. Article 10 Repeal Regulation (EC) No 541/95 is repealed. References to the repealed Regulation shall be construed as references to this Regulation. Article 11 This Regulation shall enter into force on the twentieth day following that of its publication in the Official Journal of the European Union. It shall apply from 1 October 2003. This Regulation shall be binding in its entirety and directly applicable in all Member States. Done at Brussels, 3 June 2003. For the Commission Erkki Liikanen Member of the Commission (1) OJ L 311, 28.11.2001, p. 67. (2) OJ L 311, 28.11.2001, p. 1. (3) OJ L 55, 11.3.1995, p. 7. (4) OJ L 159, 3.6.1998, p. 31. (5) OJ L 15, 17.1.1987, p. 38. (6) OJ L 214, 24.8.1993, p. 40. (7) OJ L 224, 18.8.1990, p. 1. (8) OJ L 268, 3.10.1998, p. 1. ANNEX I LIST AND CONDITIONS FOR MINOR VARIATIONS (TYPE IA AND IB) TO A MARKETING AUTHORISATION AS REFERRED TO IN ARTICLES 3 TO 5 Introductory statements The titles of the variations are numbered and subcategories depicted by letters and numbers in smaller font. The conditions necessary for a given variation to follow either a type IA or a type IB procedure are outlined for each subcategory and listed below each variation. To cover any other changes, it is necessary to submit applications for any consequential or parallel variations, which may be linked to the change applied for, at the same time and to clearly describe the relation between these variations. For notifications including a certificate of suitability from the European pharmacopoeia and when the variation concerns the dossier submitted for the certificate, the documentation required for this change is to be submitted to the European Directorate for the Quality of Medicines (EDQM). If the certificate is revised following evaluation of this change, any marketing authorisation concerned must be updated. In many cases this can be done through a type IA notification. A biological medicinal product is a product, the active substance of which is a biological substance. A biological substance is a substance that is produced by or extracted from a biological source and for which a combination of physico-chemical-biological testing and the production process and its control is needed for its characterisation and the determination of its quality. As a result, the following shall be considered as biological medicinal products: immunological medicinal products and medicinal products derived from human blood and human plasma as defined in Articles 1(4) and 1(10) of Directive 2001/83/EC, respectively; immunological veterinary medicinal products as defined in Article 1(7) of Directive 2001/82/EC; medicinal products falling within the scope of part A of the Annex to Council Regulation (EEC) No 2309/93(1); advanced therapy medicinal products as defined in part IV of Annex I to Directive 2001/83/EC. A change in the manufacturing process of a non-proteinaceous component due to a subsequent introduction of a biotechnology step can be made in accordance with the provisions of variations type I No 15 or No 21 as appropriate. This specific variation is without prejudice to other variations listed in this Annex which can be applied in this particular context. Introduction of a proteinaceous component obtained through a biotechnology process listed in part A of the Annex to Council Regulation (EEC) No 2309/93 in a medicinal product fall within the scope of said Regulation. Community legislation applicable to specific groups of products(2) shall be complied with. There is no need to notify the competent authorities of an updated monograph of the European pharmacopoeia or a national pharmacopoeia of a Member State in the case that compliance with updated monograph is implemented within 6 months of its publication and reference is made to the "current edition" in the dossier of an authorised medicinal product. For the purposes of this document, test procedure has the same meaning as analytical procedure and limits have the same meaning as acceptance criteria. The Commission, in consultation with member states, the Agency and interested parties, will draw up and publish detailed guidance on the documentation to be submitted. >TABLE> (1) OJ L 214, 24.8.1993, p. 1. (2) Food and food ingredients compliant with Regulation (EC) No 258/97 of the European Parliament and the Council (OJ L 43, 14.2.1997, p. 1), colours for use in foodstuffs within the scope of Council Directive 94/36/EC (OJ L 237, 10.9.1994, p. 13), food additives within the scope of Council Directive 88/388/EEC (OJ L 184, 15.7.1988, p. 61), extraction solvents within the meaning of Council Directive 88/344/EEC (OJ L 157, 24.6.1988, p. 28) as last amended by Directive 92/115/EEC (OJ L 409, 31.12.1992, p. 31) and foods or food ingredients derived from a biotechnology step which has been introduced into the manufacturing/production are not required to be notified as a variation to the terms of the marketing authorisation. ANNEX II CHANGES TO A MARKETING AUTHORISATION LEADING TO AN EXTENSION APPLICATION AS REFERRED TO IN ARTICLE 2 These changes, listed below, will be regarded as an "extension" application as referred to in Article 2. An extension to or a modification of the existing marketing authorisation will have to be granted by the competent authorities. The name of the medicinal product will be the same for the 'extension' as it is for the existing marketing authorisation of the medicinal product. The Commission, in consultation with Member States, the Agency and interested parties, will draw up and publish detailed guidance on the documentation to be submitted. Changes requiring an extension application 1. Changes to the active substance(s): (i) replacement of the active substance(s) by a different salt/ester complex/derivative (with the same therapeutic moiety) where the efficacy/safety characteristics are not significantly different; (ii) replacement by a different isomer, a different mixture of isomers, of a mixture by an isolated isomer (e.g. racemate by a single enantiomer) where the efficacy/safety characteristics are not significantly different; (iii) replacement of a biological substance or product of biotechnology with one of a slightly different molecular structure. Modification of the vector used to produce the antigen/source material, including a new master cell bank from a different source where the efficacy/safety characteristics are not significantly different; (iv) a new ligand or coupling mechanism for a radiopharmaceutical; (v) change to the extraction solvent or the ratio of herbal drug to herbal drug preparation where the efficacy/safety characteristics are not significantly different. 2. Changes to strength, pharmaceutical form and route of administration: (i) change of bioavailability; (ii) change of pharmacokinetics e.g. change in rate of release; (iii) change or addition of a new strength/potency; (iv) change or addition of a new pharmaceutical form; (v) change or addition of a new route of administration(1). 3. Other changes specific to veterinary medicinal products to be administered to food-producing animals: change or addition of target species. (1) For parenteral administration, it is necessary to distinguish between intra-arterial, intravenous, intramuscular, subcutaneous and other routes. For administration to poultry, respiratory, oral and ocular (nebulisation) routes used for vaccination are considered to be equivalent routes of administration.

Commission regulation (EC) No 1084/2003

of 3 June 2003

concerning the examination of variations to the terms of a marketing authorisation for medicinal products for human use and veterinary medicinal products granted by a competent authority of a Member State

(Text with EEA relevance)

THE COMMISSION OF THE EUROPEAN COMMUNITIES,

Having regard to the Treaty establishing the European Community,

Having regard to Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use(1), and in particular Article 35(1) thereof,

Having regard to Directive 2001/82/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to veterinary medicinal products(2), and in particular Article 39(1) thereof,

Whereas:

(1) In the light of practical experience in the application of Commission Regulation (EC) No 541/95 of 10 March 1995 concerning the examination of variations to the terms of a marketing authorisation granted by a competent authority of a Member State(3), as amended by Regulation (EC) No 1146/98(4), it is appropriate to simplify the procedure for varying the terms of a marketing authorisation.

(2) Some of the procedures laid down in Regulation (EC) No 541/95 should therefore be adjusted but without departing from the general principles on which those procedures are based.

(3) In consequence of the adoption of Directives 2001/82/EC and 2001/83/EC, which codified Community legislation in the field of veterinary medicinal products and medicinal products for human use respectively, references to provisions of that legislation should be updated.

(4) This Regulation should continue to apply also to the examination of applications for variation of the terms of a marketing authorisation granted under Council Directive 87/22/EEC(5) repealed by Directive 93/41/EEC(6).

(5) It is appropriate to provide for a simplified and rapid notification procedure to enable the introduction of certain minor changes, which do not affect the approved quality, safety or efficacy of the product, without prior evaluation by the reference Member State. However, for other types of minor variation evaluation of the submitted documentation by the reference Member State should still be required.

(6) In cases where the evaluation procedure is maintained the reference Member State should evaluate the file on behalf of all Member States concerned in order to avoid duplication of work.

(7) The various types of minor variation should be classified according to the conditions to be fulfilled in order to determine the procedure to follow; it is particularly necessary to give a precise definition of the type of minor variation for which no prior evaluation is needed.

(8) It is necessary to clarify the definition of an "extension" to a marketing authorisation, although it should still be possible to submit a separate, full application for a marketing authorisation for a medicinal product which has already been authorised, but under a different name and with a different summary of product characteristics.

(9) It is appropriate to allow national authorities of the reference Member States to reduce the evaluation period in urgent cases or to extend it in the case of a major variation entailing important changes.

(10) The time-frame for the procedure to be followed where the competent authority imposes urgent safety restrictions should be clarified.

(11) Further clarification should be introduced as regards revision of the summary of product characteristics, labelling and package leaflet/insert; nevertheless the procedures laid down in this Regulation should not apply to changes to the labelling or to the package leaflet/insert which are not consequential to changes to the summary of product characteristics.

(12) For the sake of clarity, it is appropriate to replace Regulation (EC) No 541/95.

(13) The measures provided for in 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:

Subject matter

This Regulation lays down the procedure for the examination of notifications of and applications for variations to the terms of a marketing authorisation 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 set out in Articles 17, 18 and 28(4) of Directive 2001/83/EC or Articles 21, 22 and 32(4) of Directive 2001/82/EC, and medicinal products for which there has been a referral to the procedures set out in Articles 32, 33 and 34 of Directive 2001/83/EC or Articles 36, 37 and 38 of Directive 2001/82/EC.

Article 2

Scope

This Regulation shall not apply to:

(a) extensions of marketing authorisations which fulfil the conditions set out in Annex II to this Regulation;

(b) transfers of a marketing authorisation to a new holder;

(c) changes to the maximum residue limit as defined in Article 1(1)(b) of Council Regulation (EEC) No 2377/90(7).

The extensions referred to in point (a) of the first paragraph shall be examined in accordance with the procedure referred to in Article 17 of Directive 2001/83/EC and in Article 21 of Directive 2001/82/EC.

Article 3

Definitions

For the purposes of this Regulation, the following definitions shall apply:

1. "Variation to the terms of a marketing authorisation" means:

(a) for medicinal products for human use: an amendment to the contents of the documents referred to in Articles 8 to 12 of Directive 2001/83/EC;

(b) for veterinary medicinal products: an amendment to the contents of the documents referred to in Articles 12 to 15 of Directive 2001/82/EC.

2. A "minor variation" of Type IA or Type IB means a variation listed in Annex I which fulfils the conditions set out therein.

3. A "major variation" of Type II means a variation which cannot be deemed to be a minor variation or an extension of the marketing authorisation.

4. "Reference Member State" means the Member State which, for a given medicinal product, has produced the assessment report which served as the basis for the procedures referred to in Article 1 or alternatively the Member State chosen in this respect by the marketing authorisation holder with a view to application of this Regulation.

5. "Urgent safety restriction" means an interim change to the product information concerning particularly one or more of the following items in the summary of product characteristics, the indications, posology, contraindications, warnings, target species and withdrawal periods, due to new information having a bearing on the safe use of the medicinal product.

Article 4

Notification procedure for minor variations type IA

1. With regard to minor variations of type IA, the marketing authorisation holder (hereinafter referred to as the holder) shall submit simultaneously to the competent authorities of the Member States where the medicinal product has been authorised a notification accompanied by:

(a) all necessary documents including those amended as a result of the variation;

(b) a list of the Member States concerned and an indication of the reference Member State for the medicinal product under consideration;

(c) the relevant fees provided for in the applicable national rules in the Member States concerned.

2. A notification shall only concern one type IA variation. Where several type IA variations are to be made to the terms of a single marketing authorisation, a separate notification shall be submitted in respect of each type IA variation sought; each such notification shall also contain a reference to the other notifications.

3. By way of derogation from paragraph 2, where a type IA variation to the marketing authorisation leads to consequential type IA variations, a single notification may cover all such variations. The single notification shall contain a description of the relation between these consequential type IA variations.

4. Where a variation requires consequential revision of the summary of product characteristics, labelling and package leaflet/insert, this is considered as part of the variation.

5. If the notification fulfils the requirements set out in paragraphs 1 to 4, the competent authority of the reference Member State shall within 14 days following receipt of the notification acknowledge the validity of this notification and shall inform the other competent authorities concerned and the holder accordingly.

Each competent authority concerned shall, where necessary, update the marketing authorisation, which has been granted pursuant to Article 6 of Directive 2001/83/EC or Article 5 of Directive 2001/82/EC.

Article 5

Notification procedure for minor variations type IB

1. With regard to minor variations of type IB, the holder shall submit simultaneously to the competent authorities of the Member States where the medicinal product has been authorised, the notification accompanied by:

(a) all necessary documents, including those amended as a result of the variation;

(b) a list of Member States concerned and an indication of the reference Member State for the medicinal product under consideration;

(c) the relevant fees provided for in the applicable national rules in the Member States concerned.

2. A notification shall only concern one type IB variation. Where several type IB variations are to be made to the terms of a single marketing authorisation, a separate notification shall be submitted in respect of each type IB variation sought; each such notification shall also contain a reference to the other notifications.

3. By way of derogation from paragraph 2, where a type IB variation to the marketing authorisation leads to consequential type IA or type IB variations, a single type IB notification may cover all such consequential variations. The single notification shall contain a description of the relation between these consequential type I variations.

4. Where a variation requires consequential revision of the summary of product characteristics, labelling and package leaflet/insert, this is considered as part of the variation.

5. If the notification fulfils the requirements set out in paragraphs 1 to 4, the competent authority of the reference Member State shall acknowledge receipt of a valid notification and shall start the procedure set out in paragraphs 6 to 11.

6. If, within 30 days of the date of the acknowledgement of receipt of a valid notification the competent authority of the reference Member State has not sent the holder its opinion provided for in paragraph 8, the notified variation shall be deemed to have been accepted by all competent authorities of the Member States concerned.

The competent authority of the reference Member State shall inform the other competent authorities of the Member States concerned to this effect.

7. Each competent authority concerned shall, where necessary, update the marketing authorisation which has been granted pursuant to Article 6 of Directive 2001/83/EC or Article 5 of Directive 2001/82/EC.

8. Where the competent authority of the reference Member State is of the opinion that the notification cannot be accepted, it shall, within the period referred to in paragraph 6, inform the holder who has submitted the notification, stating the grounds on which its opinion is based.

9. Within 30 days of receipt of the opinion referred to in paragraph 8, the holder may amend the notification in order to take due account of the grounds set out in the opinion. In that case the provisions of paragraphs 6 and 7 shall apply to the amended notification.

10. If the holder does not amend the notification, the notification shall be deemed to have been rejected. The competent authority of the reference Member State shall forthwith inform the holder and the other competent authorities concerned accordingly.

11. Within 10 days of providing the information referred to in paragraph 10, competent authorities of the Member States concerned or the holder may refer the matter to the Agency for application of Article 35(2) of Directive 2001/83/EC or Article 39(2) of Directive 2001/82/EC.

Article 6

Approval procedure for major variations type II

1. With regard to major variations of type II, the holder shall submit simultaneously to the competent authorities of the Member States where the medicinal product has been authorised an application accompanied by:

(a) the relevant particulars and supporting documents referred to in Articles 8 to 12 of Directive 2001/83/EC or Articles 12 to 15 of Directive 2001/82/EC;

(b) the supporting data relating to the variation applied for;

(c) all documents amended as a result of the application;

(d) an addendum to or update of existing expert reports/overviews/summaries to take account of the variation applied for;

(e) a list of the Member States concerned by the application for the major variation type II and an indication of the reference Member State for the medicinal product under consideration;

(f) the relevant fees provided for in the applicable national rules in the Member States concerned.

2. An application shall only concern one type II variation. Where several type II variations are to be made to a single marketing authorisation, a separate application shall be submitted in respect of each variation sought; each such application shall contain also a reference to the other applications.

3. By way of derogation from paragraph 2, where a type II variation leads to consequential variations, a single application may cover all such variations. The single application shall contain a description of the relation between these consequential variations.

4. Where a variation requires consequential revision of the summary of product characteristics, labelling and package leaflet/insert, this is considered as part of the variation.

5. If the application fulfils the requirements set out in paragraphs 1 to 4, the competent authorities of the Member States concerned shall forthwith notify the competent authority of the reference Member States about the receipt of the valid application.

6. The competent authority of the reference Member State shall inform the other competent authorities of the Member States concerned and the holder of the date of the start of the procedure set out in paragraphs 7 to 13.

7. Within 60 days from the start of the procedure, the competent authority of the reference Member State shall prepare an assessment report and a draft decision which shall be addressed to the other competent authorities concerned.

This period may be reduced having regard to the urgency of the matter particularly for safety issues.

This period may be extended to 90 days for variations concerning changes to or addition of the therapeutic indications.

This period shall be extended to 90 days for variations concerning a change to or addition of a non-food producing target species.

8. Within the periods laid down in paragraph 7, the competent authority of the reference Member State may request the holder to provide supplementary information within a time limit set by that competent authority. The procedure shall be suspended until such time as the supplementary information has been provided. In this case the periods laid down in paragraph 7 may be extended for a further period to be determined by the competent authority of the reference Member State.

The competent authority of the reference Member State shall inform the other competent authorities concerned.

9. Within 30 days following receipt of the draft decision and the assessment report, the other competent authorities of the Member States concerned shall recognise the draft decision and inform the competent authority of the reference Member State to this effect.

The competent authority of the reference Member State shall close the procedure and shall inform the other competent authorities concerned and the holder accordingly.

10. Each competent authority concerned shall, where necessary, amend the marketing authorisation concerned which has been granted pursuant to Article 6 of Directive 2001/83/EC or Article 5 of Directive 2001/82/EC in conformity with the draft decision referred to paragraph 9.

11. Decisions concerning variations related to safety issues shall be implemented within a timeframe as agreed between the competent authority of the reference Member State and the holder in consultation with the other competent authorities of the Member States concerned.

12. If within the period laid down in paragraph 9, mutual recognition by one or more of the competent authorities of the draft decision of the competent authority of the reference Member State is not possible, the procedure referred to in Article 35(2) of Directive 2001/83/EC or Article 39(2) of Directive 2001/82/EC shall apply.

13. Within 10 days of the end of the procedure mentioned in paragraph 8 and in case where the competent authorities of the Member States concerned by the application are of the opinion that the variation cannot be accepted, the holder may refer the matter to the Agency for application of Article 35(2) of Directive 2001/83/EC or Article 39(2) of Directive 2001/82/EC.

Article 7

Human influenza vaccines

1. With regard to variations to the terms of the marketing authorisations for human influenza vaccines, the procedure set out in paragraphs 2 to 5 shall apply.

2. Within 30 days following the date of the start of the procedure, the competent authority of the reference Member State shall prepare an assessment report on the basis of the quality documents referred to in Module 3 of Annex I to Directive 2001/83/EC and a draft decision which shall be addressed to the other competent authorities concerned.

3. Within the period laid down in paragraph 2, the competent authority of the reference Member State may request the holder to provide supplementary information. It shall inform the other competent authorities of the Member States concerned.

4. Within 12 days of receipt of the draft decision and the assessment report, the other competent authorities of the Member States concerned shall recognise the draft decision and inform the competent authority of the reference Member State to this effect.

5. The clinical data and, where appropriate, data concerning the stability of the medicinal product, shall be addressed by the holder to the competent authority of the reference Member State and to the other competent authorities of the Member States concerned, at the latest 12 days following the end of the time limit laid down in paragraph 4.

The competent authority of the reference Member State shall evaluate these data and draft a final decision within 7 days of the receipt of the data. The other competent authorities concerned shall recognise the final draft decision and, within 7 days of the receipt of the draft final decision, adopt a decision in conformity with the final draft decision.

6. If, in the course of the procedure laid down in paragraphs 2 to 5, a competent authority raises a question of public health which they consider poses an obstacle to the mutual recognition of the decision to be taken, the procedure referred to in Article 35(2) of Directive 2001/83/EC shall apply.

Article 8

Pandemic situation with respect to human diseases

In case of a pandemic situation with respect to the human influenza virus, duly recognised by the World Health Organisation or by the Community in the framework of Decision No 2119/98/EC of the European Parliament and of the Council(8), competent authorities may exceptionally and temporarily consider the variation to the terms of the marketing authorisation for human influenza vaccines to be accepted after an application has been received and before the end of the procedure laid down in Article 7. Nevertheless, complete clinical safety and efficacy data can be submitted during this procedure.

In case of a pandemic situation with respect to human diseases other than the human influenza virus, the first paragraph and Article 7 may be applied mutatis mutandis.

Article 9

Urgent safety restrictions

1. If the holder, in the event of risk to public or animal health, takes urgent safety restrictions, he/she shall forthwith inform the competent authorities thereof. If the competent authorities have not raised any objections within 24 hours following receipt of that information, the urgent safety restrictions shall be deemed to have been accepted.

The urgent safety restriction shall be implemented within a timeframe, as agreed with the competent authorities.

The corresponding variation application reflecting the urgent safety restriction shall be submitted immediately and in any case not later than 15 days after the initiation of the urgent safety restriction, to the competent authorities for the application of the procedures set out in Article 6.

2. Where competent authorities impose urgent safety restrictions on the holder, the holder shall be obliged to submit an application for a variation taking account of the safety restrictions imposed by the competent authorities.

The urgent safety restriction shall be implemented within a timeframe, as agreed with the competent authorities.

The corresponding variation application reflecting the urgent safety restriction, including appropriate documentation in support of the change, shall be submitted immediately and in any case not later than 15 days after the initiation of the urgent safety restriction, to the competent authorities concerned for the application of the procedures set out in Article 6.

This paragraph is without prejudice to Article 36 of Directive 2001/83/EC and Article 40 of Directive 2001/82/EC.

Article 10

Repeal

Regulation (EC) No 541/95 is repealed.

References to the repealed Regulation shall be construed as references to this Regulation.

Article 11

This Regulation shall enter into force on the twentieth day following that of its publication in the Official Journal of the European Union.

It shall apply from 1 October 2003.

This Regulation shall be binding in its entirety and directly applicable in all Member States.

Done at Brussels, 3 June 2003.

For the Commission

Erkki Liikanen

Member of the Commission

(1) OJ L 311, 28.11.2001, p. 67.

(2) OJ L 311, 28.11.2001, p. 1.

(3) OJ L 55, 11.3.1995, p. 7.

(4) OJ L 159, 3.6.1998, p. 31.

(5) OJ L 15, 17.1.1987, p. 38.

(6) OJ L 214, 24.8.1993, p. 40.

(7) OJ L 224, 18.8.1990, p. 1.

(8) OJ L 268, 3.10.1998, p. 1.

ANNEX I

LIST AND CONDITIONS FOR MINOR VARIATIONS (TYPE IA AND IB) TO A MARKETING AUTHORISATION AS REFERRED TO IN ARTICLES 3 TO 5

Introductory statements

The titles of the variations are numbered and subcategories depicted by letters and numbers in smaller font. The conditions necessary for a given variation to follow either a type IA or a type IB procedure are outlined for each subcategory and listed below each variation.

To cover any other changes, it is necessary to submit applications for any consequential or parallel variations, which may be linked to the change applied for, at the same time and to clearly describe the relation between these variations.

For notifications including a certificate of suitability from the European pharmacopoeia and when the variation concerns the dossier submitted for the certificate, the documentation required for this change is to be submitted to the European Directorate for the Quality of Medicines (EDQM). If the certificate is revised following evaluation of this change, any marketing authorisation concerned must be updated. In many cases this can be done through a type IA notification.

A biological medicinal product is a product, the active substance of which is a biological substance. A biological substance is a substance that is produced by or extracted from a biological source and for which a combination of physico-chemical-biological testing and the production process and its control is needed for its characterisation and the determination of its quality.

As a result, the following shall be considered as biological medicinal products: immunological medicinal products and medicinal products derived from human blood and human plasma as defined in Articles 1(4) and 1(10) of Directive 2001/83/EC, respectively; immunological veterinary medicinal products as defined in Article 1(7) of Directive 2001/82/EC; medicinal products falling within the scope of part A of the Annex to Council Regulation (EEC) No 2309/93(1); advanced therapy medicinal products as defined in part IV of Annex I to Directive 2001/83/EC.

A change in the manufacturing process of a non-proteinaceous component due to a subsequent introduction of a biotechnology step can be made in accordance with the provisions of variations type I No 15 or No 21 as appropriate. This specific variation is without prejudice to other variations listed in this Annex which can be applied in this particular context. Introduction of a proteinaceous component obtained through a biotechnology process listed in part A of the Annex to Council Regulation (EEC) No 2309/93 in a medicinal product fall within the scope of said Regulation. Community legislation applicable to specific groups of products(2) shall be complied with.

There is no need to notify the competent authorities of an updated monograph of the European pharmacopoeia or a national pharmacopoeia of a Member State in the case that compliance with updated monograph is implemented within 6 months of its publication and reference is made to the "current edition" in the dossier of an authorised medicinal product.

For the purposes of this document, test procedure has the same meaning as analytical procedure and limits have the same meaning as acceptance criteria.

The Commission, in consultation with member states, the Agency and interested parties, will draw up and publish detailed guidance on the documentation to be submitted.

>TABLE>

(1) OJ L 214, 24.8.1993, p. 1.

(2) Food and food ingredients compliant with Regulation (EC) No 258/97 of the European Parliament and the Council (OJ L 43, 14.2.1997, p. 1), colours for use in foodstuffs within the scope of Council Directive 94/36/EC (OJ L 237, 10.9.1994, p. 13), food additives within the scope of Council Directive 88/388/EEC (OJ L 184, 15.7.1988, p. 61), extraction solvents within the meaning of Council Directive 88/344/EEC (OJ L 157, 24.6.1988, p. 28) as last amended by Directive 92/115/EEC (OJ L 409, 31.12.1992, p. 31) and foods or food ingredients derived from a biotechnology step which has been introduced into the manufacturing/production are not required to be notified as a variation to the terms of the marketing authorisation.

ANNEX II

CHANGES TO A MARKETING AUTHORISATION LEADING TO AN EXTENSION APPLICATION AS REFERRED TO IN ARTICLE 2

These changes, listed below, will be regarded as an "extension" application as referred to in Article 2.

An extension to or a modification of the existing marketing authorisation will have to be granted by the competent authorities.

The name of the medicinal product will be the same for the 'extension' as it is for the existing marketing authorisation of the medicinal product.

The Commission, in consultation with Member States, the Agency and interested parties, will draw up and publish detailed guidance on the documentation to be submitted.

Changes requiring an extension application

1. Changes to the active substance(s):

(i) replacement of the active substance(s) by a different salt/ester complex/derivative (with the same therapeutic moiety) where the efficacy/safety characteristics are not significantly different;

(ii) replacement by a different isomer, a different mixture of isomers, of a mixture by an isolated isomer (e.g. racemate by a single enantiomer) where the efficacy/safety characteristics are not significantly different;

(iii) replacement of a biological substance or product of biotechnology with one of a slightly different molecular structure. Modification of the vector used to produce the antigen/source material, including a new master cell bank from a different source where the efficacy/safety characteristics are not significantly different;

(iv) a new ligand or coupling mechanism for a radiopharmaceutical;

(v) change to the extraction solvent or the ratio of herbal drug to herbal drug preparation where the efficacy/safety characteristics are not significantly different.

2. Changes to strength, pharmaceutical form and route of administration:

(i) change of bioavailability;

(ii) change of pharmacokinetics e.g. change in rate of release;

(iii) change or addition of a new strength/potency;

(iv) change or addition of a new pharmaceutical form;

(v) change or addition of a new route of administration(1).

3. Other changes specific to veterinary medicinal products to be administered to food-producing animals:

change or addition of target species.

(1) For parenteral administration, it is necessary to distinguish between intra-arterial, intravenous, intramuscular, subcutaneous and other routes. For administration to poultry, respiratory, oral and ocular (nebulisation) routes used for vaccination are considered to be equivalent routes of administration.