LegalizeCommission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products (Text with EEA relevance)
CHAPTER I
GENERAL PROVISIONS
Article 1
Subject matter and scope
Article 2
Definitions
For the purposes of this Regulation, the definitions in Article 1 of Directive 2001/83/EC shall apply.
The following definitions shall also apply:
‘Minor variation of type IA’ means a variation which has only a minimal impact, or no impact at all, on the quality, safety or efficacy of the medicinal product concerned;
‘Major variation of type II’ means a variation which is not an extension and which may have a significant impact on the quality, safety or efficacy of the medicinal product concerned;
‘Extension of a marketing authorisation’ or ‘extension’ means a variation which is listed in Annex I and fulfils the conditions laid down therein;
‘Minor variation of type IB’ means a variation which is neither a minor variation of type IA nor a major variation of type II nor an extension;
‘Member State concerned’ means a Member State whose competent authority has granted a marketing authorisation for the medicinal product in question;
6a. ‘Reference authority’ means: (a) the Agency where at least one of the marketing authorisations concerned is a centralised marketing authorisation; (b) the competent authority of the Member State chosen by the holder and accepted by that competent authority, or chosen by the coordination group referred to in Article 27 of Directive 2001/83/EC if none of the competent authorities of the Member States agrees to act as the reference authority, in the other cases;
‘Relevant authority’ means:
(a) the competent authority of each Member State concerned; (b) in the case of centralised marketing authorisations, the Agency;
‘Urgent safety restriction’ means an interim change in the terms of the marketing authorisation due to new information having a bearing on the safe use of the medicinal product;
‘Purely national marketing authorisation’ means any marketing authorisation granted by a Member State in accordance with the acquis outside the mutual recognition or decentralised procedure and that has not been subject to a complete harmonisation following a referral procedure.
Article 3
Classification of variations
By way of derogation from paragraph 2, a variation which is not an extension and whose classification is undetermined after application of the rules provided for in this Regulation shall be considered a major variation of type II in the following cases:
(a) upon request from the holder when submitting the variation;
(b) where the competent authority of the reference Member State referred to in Article 28 of Directive 2001/83/EC (‘the reference Member State’), in consultation with the other Member States concerned, or the Agency in the case of a centralised marketing authorisation, or the competent authority in the case of a purely national marketing authorisation, concludes, following the assessment of validity of a notification in accordance with Article 9(1), Article 13b(1), or Article 15(1) of this Regulation and taking into account the recommendations delivered pursuant to Article 5, that the variation may have a significant impact on the quality, safety or efficacy of the medicinal product concerned.
Article 4
Guidelines
The Agency, in cooperation with the competent authorities of the Member States, shall report annually to the Commission on recommendations on unforeseen variations referred to in Article 5 that result in new classification of variations and provide information on necessary updates to be included in the guidelines referred to in paragraph 1.
The Commission shall without undue delay consider the report and integrate new classification of variations and necessary updates to the guidelines.
Article 5
Recommendation on unforeseen variations
Prior to the submission of a variation whose classification is not provided for in this Regulation, a holder may request a recommendation on the classification of the variation as follows:
(a) from the Agency, where the variation refers to a marketing authorisation granted under Regulation (EC) No 726/2004;
(b) from the competent authority of the Member State concerned, where the variation refers to a purely national marketing authorisation;
(c) from the competent authority of the reference Member State, in the other cases.
Where a recommendation is requested from the Agency as set out in the first subparagraph, point (a), it shall consult the coordination group if the recommendation is expected to result in a new classification of variation.
Where a recommendation is requested from the competent authority of the Member State concerned or of the reference Member State as set out in the first subparagraph, points (b) and (c), the relevant authority shall consult the coordination group and the Agency, if the recommendation is expected to result in a new classification of variation.
The recommendations shall be consistent with the guidelines referred to in Article 4(1). It shall be delivered within 60 days following receipt of the request and sent to the holder, the Agency, and the coordination group.
The recommendation referred to in the first subparagraph shall be consistent with the guidelines referred to in Article 4(1). It shall be delivered within 60 days following receipt of the request and sent to the holder, the Agency, and the competent authorities of all Member States.
Article 6
Variations leading to the revision of product information
Where a variation leads to the revision of the summary of product characteristics, labelling or package leaflet, this revision shall be considered as part of that variation.
Article 6a
Additional regulatory tools
For certain changes to the chemical, pharmaceutical and biological information for a medicinal product a holder may rely on a range of process parameters, quality attributes, protocols or summary documents, upon agreement of the relevant authority and subject to the conditions referred to in the Annexes and the guidelines referred to in Article 4(1) with regard to the specific regulatory tool.
Article 7
Grouping of variations
By way of derogation from paragraph 1, the following shall apply:
(a) where minor variations of type IA to the terms of the same marketing authorisation are notified at the same time, a single notification as referred to in Article 8 or 14 may cover all such variations;
(b) where several variations to the terms of the same marketing authorisation are submitted at the same time, a single submission may cover all such variations provided that the variations concerned fall within one of the cases listed in Annex III;
(c) where several variations to the terms of the same marketing authorisation are submitted at the same time and the variations do not fall within one of the cases listed in Annex III, a single submission may cover all such variations provided that the competent authority of the reference Member State in consultation with the competent authorities of the Member States concerned or, in the case of a centralised marketing authorisation, the Agency agrees to such single submission.
The submission referred to in subparagraphs (b) and (c) shall be made simultaneously to all relevant authorities by means of the following:
(i) a single notification in accordance with Article 9 or 15 where at least one of the variations is a minor variation of type IB and the remaining variations are minor variations;
(ii) a single application in accordance with Article 10 or 16 where at least one of the variations is a major variation of type II and none of the variations is an extension;
(iii) a single application in accordance with Article 19 where at least one of the variations is an extension.
Article 7a
Super-grouping of variations
CHAPTER II
VARIATIONS TO MARKETING AUTHORISATIONS GRANTED IN ACCORDANCE WITH CHAPTER 4 OF DIRECTIVE 2001/83/EC
Article 8
Notification procedure for minor variations of type IA
The notification shall be submitted immediately after the implementation of the variation in the case of minor variations requiring immediate notification for the continuous supervision of the medicinal product concerned.
By way of derogation from the first subparagraph, in justified cases, the competent authority of the reference Member State may accept the immediate submission of the notification after the implementation of the variation.
Article 9
Notification procedure for minor variations of type IB
If the notification fulfils the requirement laid down in the first subparagraph, the competent authority of the reference Member State shall, after consulting the other Member States concerned, acknowledge receipt of a valid notification.
Where the notification is accepted by the competent authority of the reference Member State, the measures provided for in Article 11 shall be taken.
Within 30 days following the receipt of the unfavourable opinion, the holder may submit to all relevant authorities an amended notification in order to take due account of the grounds laid down in that opinion.
If the holder does not amend the notification in accordance with the second subparagraph, the notification shall be deemed rejected by all relevant authorities and the measures provided for in Article 11 shall be taken.
This Article shall not apply where a type IB variation request is submitted in a grouping that includes an extension. In such case, the procedure in Article 19 shall apply.
Article 10
‘Prior Approval’ procedure for major variations of type II
If the application fulfils the requirements laid down in the first subparagraph, the competent authority of the reference Member State shall acknowledge receipt of a valid application and inform the holder and the other relevant authorities that the procedure starts from the date of such acknowledgement.
The competent authority of the reference Member State may reduce the period referred to in the first subparagraph, having regard to the urgency of the matter, or may extend it to 90 days for variations listed in Annex V or for grouping of variations in accordance with Article 7(2), first subparagraph, point (c).
Within the period referred to in paragraph 2, 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. In this case:
(a) the competent authority of the reference Member State shall inform the other competent authorities concerned of its request for supplementary information;
(b) the procedure shall be suspended until such supplementary information has been provided;
(c) the competent authority of the reference Member State may extend the period referred to in paragraph 2.
If, within the period referred to in the first subparagraph, a relevant authority has not expressed its disagreement in accordance with Article 13, the decision shall be deemed recognised by that relevant authority.
Article 11
Measures to close the procedures of Articles 8 to 10
Where reference is made to this Article, the competent authority of the reference Member State shall take the following measures:
(a) it shall inform the holder and the other relevant authorities as to whether the variation is accepted or rejected;
(b) where the variation is rejected, it shall inform the holder and the other relevant authorities of the grounds for the rejection;
(c) it shall inform the holder and the other relevant authorities as to whether the variation requires any amendment to the decision granting the marketing authorisation.
Article 12
Human influenza vaccines
If the application fulfils the requirements laid down in the first subparagraph, the competent authority of the reference Member State shall acknowledge receipt of a valid application and inform the holder and the other relevant authorities that the procedure starts from the date of such acknowledgement.
The 45-day period referred to in the first subparagraph shall be suspended from the moment when the additional data referred to in paragraph 3 is requested until the data is submitted.
Article 13
Coordination group and arbitration
The party in disagreement shall give a detailed statement of the reasons for its position to all Member States concerned and to the holder.
CHAPTER IIa
VARIATIONS TO PURELY NATIONAL MARKETING AUTHORISATIONS
Article 13a
Notification procedure for minor variations of type IA
The notification shall be submitted immediately after the implementation of the variation in the case of minor variations requiring immediate notification for the continuous supervision of the medicinal product concerned.
By way of derogation from the first subparagraph, in justified cases, the competent authority of the Member State may accept the immediate submission of the notification after the implementation of the variation.
Article 13b
Notification procedure for minor variations of type IB
If the notification fulfils the requirement laid down in the first subparagraph, the competent authority shall acknowledge receipt of a valid notification.
Where the notification is accepted by the competent authority, the measures provided for in Article 13e shall be taken.
Within 30 days following the receipt of the unfavourable opinion, the holder may submit to the competent authority an amended notification in order to take due account of the grounds laid down in that opinion.
If the holder does not amend the notification in accordance with the second subparagraph, the notification shall be deemed rejected.
This Article shall not apply where a type IB variation request is submitted in a grouping that includes an extension. In such case, the procedure in Article 19 shall apply.
Article 13c
‘Prior Approval’ procedure for major variations of type II
If the application fulfils the requirements laid down in the first subparagraph, the competent authority shall acknowledge receipt of a valid application.
The competent authority may reduce the period referred to in the first subparagraph, having regard to the urgency of the matter, or may extend it to 90 days for variations listed in Annex V or for grouping of variations in accordance with Article 13d(2), first subparagraph, point (c).
Article 13d
Grouping of variations to purely national marketing authorisations
By way of derogation from paragraph 1 the following shall apply:
(a) where the same minor variation(s) of type IA to the terms of one or more marketing authorisations owned by the same holder are notified at the same time to the same competent authority, a single notification as referred to in Article 13a may cover all such variations;
(b) where several variations to the terms of the same marketing authorisation are submitted at the same time to the same competent authority, a single submission may cover all such variations provided that the variations concerned fall within one of the cases listed in Annex III;
(c) where the same variation(s) to the terms of one or more marketing authorisations owned by the same holder are submitted at the same time to the same competent authority and they are not covered under subparagraph (a) or (b), a single submission may cover all such variations provided that the competent authority agrees to such single submission.
The submission referred to in points (b) and (c) shall be made by means of the following:
(i) a single notification in accordance with Article 13b where at least one of the variations is a minor variation of type IB and the remaining variations are minor variations;
(ii) a single application in accordance with Article 13c where at least one of the variations is a major variation of type II and none of the variations is an extension;
(iii) a single application in accordance with Article 19 where at least one of the variations is an extension.
Article 13e
Measures to close the procedures of Articles 13a to 13c
Where reference is made to this Article, the competent authority shall take the following measures:
(a) it shall inform the holder as to whether the variation is accepted or rejected;
(b) where the variation is rejected, it shall inform the holder of the grounds for the rejection;
(c) where necessary, it shall amend the decision granting the marketing authorisation in accordance with the accepted variation within the time limit laid down in paragraph 1 of Article 23.
Article 13f
Human influenza vaccines
If the application fulfils the requirements laid down in the first subparagraph, the competent authority shall acknowledge receipt of a valid application.
The 45-day period referred to in the first subparagraph shall be suspended from the moment when the additional data referred to in paragraph 3 is requested until the data is submitted.
CHAPTER III
VARIATIONS TO CENTRALISED MARKETING AUTHORISATIONS
Article 14
Notification procedure for minor variations of type IA
The notification shall be submitted immediately after the implementation of the variation in the case of minor variations requiring immediate notification for the continuous supervision of the medicinal product concerned.
By way of derogation from the first subparagraph, in justified cases, the Agency may accept the immediate submission of the notification of the variation.
Article 15
Notification procedure for minor variations of type IB
If the notification fulfils the requirement laid down in the first subparagraph, the Agency shall acknowledge receipt of a valid notification.
Where the opinion of the Agency on the notification is favourable, the measures provided for in Article 17 shall be taken.
Within 30 days of receipt of the unfavourable opinion, the holder may submit to the Agency an amended notification in order to take due account of the grounds laid down in that opinion.
If the holder does not amend the notification in accordance with the second subparagraph, the notification shall be deemed rejected.
This Article shall not apply where a type IB variation request is submitted in a grouping that includes an extension. In such case, the procedure in Article 19 shall apply.
Article 16
‘Prior Approval’ procedure for major variations of type II
If the application fulfils the requirements laid down in the first subparagraph, the Agency shall acknowledge receipt of a valid application.
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