2.8.2013

EN

Official Journal of the European Union

C 223/1

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Guidelines on the details of the various categories of variations, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission 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 and on the documentation to be submitted pursuant to those procedures

2013/C 223/01

Table of Contents

1.	INTRODUCTION

2.	PROCEDURAL GUIDANCE ON THE HANDLING OF VARIATIONS

2.1.	Minor variations of Type IA

2.1.1.

Submission of Type IA notifications

2.1.2.

Type IA variations review for mutual recognition procedure

2.1.3.

Type IA variations review for purely national procedure

2.1.4.

Type IA variations review for centralised procedure

2.2.	Minor variations of Type IB

2.2.1.

Submission of Type IB notifications

2.2.2.

Type IB variations review for mutual recognition procedure

2.2.3.

Type IB variations review for purely national procedure

2.2.4.

Type IB variations review for centralised procedure

2.3.	Major variations of Type II

2.3.1.

Submission of Type II applications

2.3.2.

Type II variations assessment for mutual recognition procedure

2.3.3.

Outcome of Type II variations assessment for mutual recognition procedure

2.3.4.

Type II variations assessment for purely national procedure

2.3.5.

Outcome of Type II variations assessment for purely national procedure

2.3.6.

Type II variations assessment for centralised procedure

2.3.7.

Outcome of Type II variations assessment in centralised procedure

2.4.	Extensions

2.4.1.

Submission of Extensions applications

2.4.2.

Extension assessment for national procedure

2.4.3.

Extension assessment for centralised procedure

2.5.	Human influenza vaccines

2.5.1.

Submission of variations for annual update of human influenza vaccines applications

2.5.2.

Variations assessment for mutual recognition procedure

2.5.3.

Variations assessment for purely national procedure

2.5.4.

Variations assessment in centralised procedure

2.6.	Urgent Safety Restrictions

2.7.	Statement of compliance under the Paediatric Regulation

3.	PROCEDURAL GUIDANCE ON WORKSHARING

3.1.	Submission of variation(s) application under worksharing

3.2.	Worksharing assessment not involving medicinal products authorised under the centralised procedure

3.3.	Outcome of the worksharing assessment not involving medicinal products authorised under the centralised procedure

3.4.	Worksharing assessment involving medicinal products authorised under the centralised procedure

3.5.	Outcome of the worksharing assessment involving medicinal products authorised under the centralised procedure

4.

ANNEX

1.   INTRODUCTION

Commission 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 (1) (‘the Variations Regulation’) governs the procedure for the variation of marketing authorisations. It has been amended by Commission Regulation (EU) No 712/2012 (2).

Article 4(1) of the Variations Regulation charges the Commission with the task of drawing up guidelines on the details of the various categories of variations, on the operation of the procedures laid down in Chapters II, IIa, III and IV of that Regulation as well as on the documentation to be submitted pursuant to these procedures.

These guidelines apply to the variations of marketing authorisations for medicinal products for human use and veterinary medicinal products granted in accordance with Regulation (EC) No 726/2004 of the European Parliament and of the Council (3), Directives 2001/82/EC (4) and 2001/83/EC (5) of the European Parliament and of the Council, and Council Directive 87/22/EEC (6). They are intended to facilitate the interpretation and application of the Variations Regulation. They provide details on the application of the relevant procedures, including a description of all the relevant steps from the submission of an application for a variation to the final outcome of the procedure on the application.

In addition, the Annex to these guidelines provides details of the classification of variations into the following categories as defined in Article 2 of the Variations Regulation: minor variations of Type IA, minor variations of Type IB and major variations of Type II and provides further details, where appropriate, on the scientific data to be submitted for specific variations and how this data should be documented. The Annex to these guidelines will be regularly updated, taking into account the recommendations provided in accordance with Article 5 of the Variations Regulation as well as scientific and technical progress.

Definitions relevant to these guidelines are provided in Directive 2001/82/EC, Directive 2001/83/EC, and Regulation (EC) No 726/2004 as well as in the Variations Regulation. In addition, for the purpose of these guidelines, marketing authorisation holders belonging to the same mother company or group of companies and marketing authorisation holders having concluded agreements or exercising concerted practices concerning the placing on the market of the relevant medicinal product have to be taken as the same marketing authorisation holder (7) (‘holder’).

Reference in these guidelines to the ‘centralised procedure’ is to be understood as the procedure for granting marketing authorisations set out in Regulation (EC) No 726/2004. Reference to the ‘mutual recognition procedure’ is to be understood as the procedure for granting marketing authorisations set out in Directive 87/22/EEC, Articles 32 and 33 of Directive 2001/82/EC, and Articles 28 and 29 of Directive 2001/83/EC. Marketing authorisations granted following a referral under Articles 36, 37 and 38 of Directive 2001/82/EC or Articles 32, 33 and 34 of Directive 2001/83/EC that has led to complete harmonisation are to be considered as marketing authorisations granted under the mutual recognition procedure also. Reference to the ‘purely national procedure’ is to be understood as the procedure for granting marketing authorisations by a Member State in accordance with the acquis outside the mutual recognition procedure.

Reference in this guideline to ‘Member States concerned’, in accordance with Article 2(6) of the Variations Regulation, is to be understood as each Member State whose competent authority has granted a marketing authorisation for the medicinal product in question. Reference to ‘concerned Member States’ is to be understood as all Member States concerned except the reference Member State. Reference to ‘national competent authority’ is to be understood as the authority that has granted a marketing authorisation under a purely national procedure.

Reference in these guidelines to the Agency means the European Medicines Agency.

2.   PROCEDURAL GUIDANCE ON THE HANDLING OF VARIATIONS

A marketing authorisation lays down the terms under which the marketing of a medicinal product is authorised in the EU. A marketing authorisation is composed of:

(i)	a decision granting the marketing authorisation issued by the relevant authority; and

(ii)

a technical dossier with the data submitted by the applicant in accordance with Article 12(3) to Article 14 of Directive 2001/82/EC and Annex I thereto, Article 8(3) to Article 11 of Directive 2001/83/EC and Annex I thereto, Articles 6(2) and 31(2) of Regulation (EC) No 726/2004, or Article 7 of Regulation (EC) No 1394/2007.

The Variations Regulation governs the procedures for the amendment of the decision granting the marketing authorisation and of the technical dossier.

However, in the case of medicinal products for human use, the introduction of changes to the labelling or package leaflet that is not connected with the summary of product characteristics is not governed by the procedures of the Variations Regulation. In accordance with Article 61(3) of Directive 2001/83/EC, these changes are to be notified to the relevant competent authorities and they may be implemented if the competent authority has not objected within 90 days.

These guidelines cover the following categories of variations, defined in Article 2 of the Variations Regulation:

—	Minor variations of Type IA

—	Minor variations of Type IB

—	Major variations of Type II

—	Extensions

—	Urgent safety restriction

The reference Member State, the national competent authority or the Agency (8) is available to address any questions which holders may have regarding a particular upcoming variation. Where appropriate, a pre-submission discussion may be organised with the reference Member State, the national competent authority or the Agency in order to obtain further regulatory and procedural advice.

It must be noticed that where a group of variations consists of different types of variations, the group must be submitted and will be handled according to the ‘highest’ variation type included in the group. For instance, a group consisting of an extension and a major variation of Type II will be handled as an extension application; a group consisting of minor variations of Type IB and Type IA will be handled as a Type IB notification.

Where reference is made in these guidelines to the submission of variations’ notifications or applications, the number of copies to be submitted will be made public for each type of procedure by the Agency as regards the centralised procedure; by the coordination groups established by Article 31 of Directive 2001/82/EC as regards veterinary medicinal products and Article 27 of Directive 2001/83/EC as regards medicinal products for human use (‘the coordination group’) as regards the mutual recognition procedure, and by the national competent authority as regards the purely national procedure.

The application form for variations to a marketing authorisation for medicinal products (human and veterinary) is available at http://ec.europa.eu/health/documents/eudralex/vol-2/index_en.htm

Any information related to the implementation of a given variation should be immediately provided by the holder upon the request of the relevant authority.

2.1.   Minor variations of Type IA

Hereby guidance is provided on the application of Articles 7, 8, 11, 13a, 13d, 13e, 14, 17, 23 and 24 of the Variations Regulation to minor variations of Type IA.

The Variations Regulation and the Annex to these guidelines set out a list of changes to be considered as minor variations of Type IA. Such minor variations do not require any prior approval, but must be notified by the holder within 12 months following implementation (‘Do and Tell’ procedure). However, certain minor variations of Type IA require immediate notification after implementation, in order to ensure the continuous supervision of the medicinal product.

The Annex to these guidelines clarifies the conditions which must be met in order for a change to follow a Type IA notification procedure, and specifies which minor variations of Type IA must be notified immediately following implementation.

2.1.1.   Submission of Type IA notifications

Minor variations of Type IA do not require prior examination by the authorities before they can be implemented by the holder. However, at the latest within 12 months from the date of the implementation, the holder must submit simultaneously to all Member States concerned, to the national competent authority, or to the Agency (as appropriate) a notification of the relevant variation(s). It is possible for a holder to include a minor variation of Type IA which is not subject to immediate notification in the submission of a minor variation of Type IA for immediate notification or with any other variation. The conditions laid down in Article 7(2)(a), 7(2)(b), 7(2)(c), 13d(2)(a), 13d(2)(b) or 13d(2)(c) of the Variations Regulation (as appropriate) should be fulfilled.

The holder may group several minor variations of Type IA under a single notification, as established in Articles 7(2) and 13d(2) of the Variations Regulation. Specifically, two possibilities exist for the grouping of variations of Type IA:

(1)	The holder may group several minor variations of Type IA regarding the terms of one single marketing authorisation provided that they are notified at the same time to the same relevant authority.

(2)	The holder may group one or more minor variations of Type IA to the terms of several marketing authorisations under a single notification provided that the variations are the same for all marketing authorisations concerned and they are notified at the same time to the same relevant authority.

The 12 months deadline to notify minor variations of Type IA allows holders to collect Type IA variations for their medicinal products during a year. However, the notification of these variations in a single submission is only possible where the conditions for grouping apply (same variations for all medicinal products concerned). Therefore, it may be the case that the submission of variations implemented over a period of 12 months (so called ‘annual report’) requires several submissions; e.g. one referring to a single minor variation of Type IA, another referring to group of minor variations of Type IA to the terms of one marketing authorisation, and another referring to group of the minor variations of Type IA to the terms of several marketing authorisations.

The notification must contain the elements listed in Annex IV to the Variations Regulation, presented as follows in accordance with the appropriate headings and numbering of ‘The rules governing medicinal products in the European Union’, Volume 2B, Notice to applicants (‘EU-CTD’) format or the Notice to applicants Volume 6B format (veterinary medicinal products when EU-CTD format is not available):

—	Cover letter.

—

The completed EU variation application form (published in the Notice to applicants), including the details of the marketing authorisation(s) concerned, as well as a description of all variations submitted together with their date of implementation as applicable. Where a variation is the consequence of, or related to, another variation, a description of the relation between these variations should be provided in the appropriate section of the application form.

—

Reference to the variation code as laid down in the Annex to these guidelines, indicating that all conditions and documentation requirements are met or, where applicable, reference to a classification recommendation published in accordance with Article 5 of the Variation Regulation used for the relevant application.

—	All documentation specified in the Annex to these guidelines.

—

In case that the variations affect the summary of product characteristics, labelling or package leaflet: the revised product information presented in the appropriate format, as well as the relevant translations. Where the overall design and readability of the outer and immediate packaging or package leaflet is affected by the minor variation of Type IA, mock-ups or specimens should be provided to the reference Member State, the national competent authority or the Agency.

For variations in the mutual recognition procedure, the reference Member State should additionally receive the list of dispatch dates indicating the Type IA Variation procedure number, the dates on which the applications have been sent to each Member State concerned and confirmation that the relevant fees have been paid as required by the competent authorities concerned.

For variations in the purely national procedure confirmation that the relevant fee has been paid as required by the national competent authority.

For variations in the centralised procedure, the relevant fee for the minor variation(s) of Type IA, as provided for in Council Regulation (EC) No 297/95 (9), should be paid in accordance with the Agency’s financial procedures.

For grouped minor variations of Type IA concerning several marketing authorisations from the same holder in accordance with Article 7 or 13d of the Variations Regulation, a common cover letter and application form should be submitted together with separate supportive documentation and revised product information (if applicable) for each medicinal product concerned. This will allow the relevant authorities to update the dossier of each marketing authorisation included in the group with the relevant amended or new information.

2.1.2.   Type IA variations review for mutual recognition procedure

The reference Member State will review the Type IA notification within 30 days following receipt.

By Day 30, the reference Member State will inform the holder and concerned Member States of the outcome of its review. In case the marketing authorisation requires any amendment to the decision granting the marketing authorisation, all Member States concerned will update the decision granting the marketing authorisation within 6 months following the receipt of the outcome of the review sent by the reference Member State, provided that the documents necessary for the amendment of the marketing authorisation have been submitted to the Member States concerned.

Where one or several minor variations of Type IA are submitted as part of one notification, the reference Member State will inform the holder which variation(s) have been accepted or rejected following its review. The marketing authorisation holder must not implement the rejected variation(s).

While in the case of minor variations of Type IA, failure to provide all necessary documentation in the application will not necessarily lead to the immediate rejection of the variation if the holder provides any missing documentation immediately upon the request of the relevant authority, it should be highlighted that a minor variation of Type IA may in specific circumstances be rejected with the consequence that the holder must immediately cease to apply already implemented variations concerned.

2.1.3.   Type IA variations review for purely national procedure

The national competent authority will review the Type IA notification within 30 days following receipt.

By Day 30, the national competent authority will inform the holder of the outcome of its review. In case the marketing authorisation requires any amendment to the decision granting the marketing authorisation, the national competent authority will update the decision granting the marketing authorisation within 6 months following the date of information to the holder of the outcome of the review, provided that the documents necessary for the amendment of the marketing authorisation have been submitted to the national competent authority.

Where one or several minor variations of Type IA are submitted as part of one notification, the national competent authority will inform the holder which variation(s) have been accepted or rejected following its review.

While in the case of minor variations of Type IA, failure to provide all necessary documentation in the application will not necessarily lead to the immediate rejection of the variation if the holder provides any missing documentation immediately on request of the relevant authority, it should be highlighted that a minor variation of Type IA may in specific circumstances be rejected with the consequence that the holder must immediately cease to apply already implemented variations concerned.

2.1.4.   Type IA variations review for centralised procedure

The Agency will review the Type IA notification within 30 days following receipt, without involvement of the rapporteur for the product concerned appointed by the Committee for Medicinal Products for Human Use or by the Committee for Veterinary Medicinal Products. However, a copy of the Type IA notification will be submitted by the Agency to the rapporteur for information.

By Day 30, the Agency will inform the holder of the outcome of its review. Where the outcome of the assessment is favourable and the Commission decision granting the marketing authorisation requires any amendment, the Agency will inform the Commission and transmit the revised documentation. In such case, the Commission will update the decision granting the marketing authorisation at the latest within 12 months.

Where one or several minor variations of Type IA are submitted as part of one notification, the Agency will clearly inform the holder which variation(s) have been accepted or rejected following its review.

While in the case of minor variations of Type IA, failure to provide all necessary documentation in the application will not necessarily lead to the immediate rejection of the variation if the holder provides any missing documentation immediately on request of the Agency, it should be highlighted that a minor variation of Type IA may in specific circumstances be rejected with the consequence that the holder must cease to apply already implemented variations concerned.

2.2.   Minor variations of Type IB

Hereby guidance is provided on the application of Articles 7, 9, 11, 13b, 13d, 13e, 15, 17, 23 and 24 of the Variations Regulation to minor variations of Type IB.

The Variations Regulation and the Annex to these guidelines set out a list of changes to be considered as minor variations of Type IB. Such minor variations must be notified before implementation. The holder must wait a period of 30 days to ensure that the notification is deemed acceptable by the relevant authorities before implementing the change (‘Tell, Wait and Do’ procedure).

2.2.1.   Submission of Type IB notifications

Notifications for minor variations of Type IB must be submitted by the holder simultaneously to all Member States concerned, to the national competent authority or to the Agency (as appropriate).

Holders may group under a single notification the submission of several minor variations of Type IB regarding the same marketing authorisation, or group the submission of one or more minor variation(s) of Type IB with other minor variations regarding the same marketing authorisation, provided that this corresponds to one of the cases listed in Annex III of the Variations Regulation, or when this has been agreed previously with the reference Member State, the national competent, authority or the Agency (as appropriate).

In addition, for medicinal products authorised under purely national procedures, the holder may also group several minor variations of Type IB affecting several marketing authorisations in a single Member State, or one or more minor variation(s) of Type IB with other minor variations affecting several marketing authorisations in a single Member State provided that (i) the variations are the same for all the marketing authorisations concerned, (ii) the variations are submitted at the same time to the national competent authority, and (iii) the national competent authority has previously agreed to the grouping.

Furthermore, where the same minor variation of Type IB or the same group of minor variations (as explained above) affect several marketing authorisations owned by the same holder, the holder may submit these variations as one application for ‘worksharing’ (see section 3 on ‘worksharing’).

The notification must contain the elements listed in Annex IV to the Variations Regulation, presented as follows in accordance with the appropriate headings and numbering of the EU-CTD format or the Notice to applicants Volume 6B format (veterinary medicinal products when EU-CTD format is not available):

—	Cover letter.

—

The completed EU variation application form (published in the Notice to applicants), including the details of the marketing authorisations(s) concerned. Where a variation is the consequence of or related to another variation, a description of the relation between these variations should be provided in the appropriate section of the application form. Where a variation is considered unclassified, a detailed justification for its submission as a Type IB notification must be included.

—

Reference to the variation code as laid down in the Annex to these guidelines, indicating that all conditions and documentation requirements are met or, where applicable, reference to a classification recommendation published in accordance with Article 5 of the Variation Regulation used for the relevant application.

—	Relevant documentation in support of the proposed variation including any documentation specified in the Annex to these guidelines.

—	For variations requested by the competent authority resulting from new data submitted, e.g. pursuant to post authorisation conditions or in the framework of pharmacovigilance obligations, a copy of the request should be annexed to the cover letter.

—

In case that the variations affect the summary of product characteristics, labelling or package leaflet: the revised product information presented in the appropriate format, as well as the relevant translations. Where the overall design and readability of the outer and immediate packaging or package leaflet is affected by the minor variation of Type IB, mock-ups or specimens should be provided to the reference Member State, the national competent authority or the Agency.

For variations in the mutual recognition procedure, the reference Member State should additionally receive the list of dispatch dates indicating the Type IB Variation procedure number, the dates on which the applications have been sent to each Member States concerned and confirmation that the relevant fees have been paid as required by the competent authorities concerned.

For variations in the purely national procedure confirmation that the relevant fee has been paid as required by the national competent authority.

For variations in the centralised procedure, the relevant fee for the minor variation(s) of Type IB, as provided for in Council Regulation (EC) No 297/95, should be paid in accordance with the Agency’s financial procedures.

2.2.2.   Type IB variations review for mutual recognition procedure

Upon receipt of a Type IB notification, the notification will be handled as follows:

The reference Member State will check within 7 calendar days whether the proposed change can be considered a minor variation of Type IB, and whether the notification is correct and complete (‘validation’) before the start of the evaluation procedure.

When the proposed variation is not considered a minor variation of Type IB following the Annex to these guidelines or has not been classified as a minor variation of Type IB in a recommendation pursuant to Article 5 of the Variations Regulation, and the reference Member State is of the opinion that it may have a significant impact on the quality, safety or efficacy of the medicinal product, the reference Member State will inform the concerned Member States and the holder immediately.

If the concerned Member States do not disagree within further 7 calendar days, the holder will be requested to revise its application and to complete it in accordance with the requirements for a major variation of Type II application. Following receipt of the valid revised variation application, a Type II assessment procedure will be initiated (see section 2.3.2).

If the concerned Member States disagree with the reference Member State, the reference Member State must take the final decision on the classification of the proposed variation having taken into account the comments received.

When the reference Member State is of the opinion that the proposed variation can be considered a minor variation of Type IB, the holder will be informed of the outcome of the validation and of the start date of the procedure.

Within 30 days following the acknowledgement of receipt of a valid notification, the reference Member State will notify the holder of the outcome of the procedure. If the reference Member State has not sent the holder its opinion on the notification within 30 days following the acknowledgement of receipt of a valid notification, the notification will be deemed acceptable.

In case of an unfavourable outcome, the holder may amend the notification within 30 days to take due account of the grounds for the non-acceptance of the variation. If the holder does not amend the notification within 30 days as requested, the variation will be deemed rejected by all concerned Member States.

Within 30 days of receipt of the amended notification, the reference Member State will inform the holder of its final acceptance or rejection of the variation(s) (including the grounds for the unfavourable outcome). Concerned Member States will be informed accordingly.

Where a group of minor variations were submitted as part of one notification, the reference Member State will inform the holder and the concerned Member States which variation(s) have been accepted or rejected following its review.

Where necessary, the relevant authorities will update the marketing authorisation within 6 months following closure of the procedure by the reference Member State, provided that the documents necessary for the amendment of the marketing authorisation have been submitted to the Member States concerned. However, the accepted minor variations of Type IB variation may be implemented without awaiting the update of the marketing authorisation.

2.2.3.   Type IB variations review for purely national procedure

Upon receipt of a Type IB notification, the notification will be handled as follows:

The national competent authority will check whether the proposed change can be considered a minor variation of Type IB, and whether the notification is correct and complete (‘validation’) before the start of the evaluation procedure.

When the proposed variation is not considered a minor variation of Type IB following the Annex to these guidelines or has not been classified as a minor variation of Type IB in a recommendation pursuant to Article 5 of the Variations Regulation, and the national competent authority is of the opinion that it may have a significant impact on the quality, safety or efficacy of the medicinal product, the holder will be requested to revise its application and to complete it in accordance with the requirements for a major variation of Type II application. Following receipt of the valid revised variation application, a Type II assessment procedure will be initiated (see section 2.3.4).

When the national competent authority is of the opinion that the proposed variation can be considered a minor variation of Type IB, the holder will be informed of the outcome of the validation and of the start date of the procedure.

Within 30 days following the acknowledgement of receipt of a valid notification, the national competent authority will notify the holder of the outcome of the procedure. If the national competent authority has not sent the holder its opinion on the notification within 30 days following the acknowledgement of receipt of a valid notification, the notification will be deemed acceptable.

In case of an unfavourable outcome, the holder may amend the notification within 30 days to take due account of the grounds for the non-acceptance of the variation. If the holder does not amend the notification within 30 days as requested, the variation will be deemed rejected by the national competent authority.

Within 30 days of receipt of the amended notification, the national competent authority will inform the holder of its final acceptance or rejection of the variation(s) (including the grounds for the unfavourable outcome).

Where a group of minor variations were submitted as part of one notification, the national competent authority will inform the holder which variation(s) have been accepted or rejected following its review.

Where necessary, the national competent authority will update the marketing authorisation within 6 months following closure of the procedure, provided that the documents necessary for the amendment of the marketing authorisation have been submitted to the national competent authority. However, the accepted minor variations of Type IB may be implemented without awaiting the update of the marketing authorisation.

2.2.4.   Type IB variations review for centralised procedure

Upon receipt of a Type IB notification, the Agency will handle the notification as follows:

The Agency will check within 7 calendar days whether the proposed change can be considered a minor variation of Type IB, and whether the notification is correct and complete (‘validation’) before the start of the evaluation procedure.

When the proposed variation is not considered a minor variation of Type IB following the Annex to these guidelines or has not been classified as a minor variation of Type IB in a recommendation pursuant to Article 5 of the Variations Regulation, and the Agency is of the opinion that it may have a significant impact on the quality, safety or efficacy of the medicinal product, the holder will be requested to revise its application and to complete it in accordance with the requirements for a major variation of Type II application. Following receipt of the valid revised variation application, a Type II assessment procedure will be initiated (see section 2.3.6).

When the Agency is of the opinion that the proposed variation can be considered a minor variation of Type IB, the holder will be informed of the outcome of the validation and of the start date of the procedure.

The rapporteur will be involved in the review of the Type IB notification.

Within 30 days following the acknowledgement of receipt of a valid notification, the Agency will notify the holder of the outcome of the procedure. If the Agency has not sent the holder its opinion on the notification within 30 days following the acknowledgement of receipt of a valid notification, the notification will be deemed acceptable.

In case of an unfavourable outcome, the holder may amend the notification within 30 days to take due account of the grounds for the non-acceptance of the variation. If the holder does not amend the notification within 30 days as requested, the notification will be rejected.

Within 30 days of receipt of the amended notification, the Agency will inform the holder of its final acceptance or rejection of the variation(s) (including the grounds for the unfavourable outcome).

Where a group of minor variations are submitted as part of one notification, the Agency will clearly inform the holder which variation(s) have been accepted or rejected following its review.

Where the opinion of the Agency is positive and the variation(s) affect(s) the terms of the Commission decision granting the marketing authorisation, the Agency will inform the Commission accordingly and transmit the relevant documentation. Where necessary, the Commission will update the marketing authorisation at the latest within 12 months. However, the accepted minor variation(s) of Type IB may be implemented without awaiting the update of the Commission decision granting the marketing authorisation and the agreed change(s) will be included in the annexes of any subsequent Regulatory Procedure.

2.3.   Major variations of Type II

Hereby guidance is provided on the application of Articles 7, 10, 11, 13, 13c, 13d, 13e, 16, 17, 23 and 24 of the Variations Regulation to major variations of Type II.

The Variations Regulation and the Annex to these guidelines set out a list of changes to be considered as major variations of Type II. Such major variations require approval of the relevant competent authority before implementation.

2.3.1.   Submission of Type II applications

Notifications for major variations of Type II must be submitted by the holder simultaneously to all Member States concerned, to the national competent authority or to the Agency (as appropriate).

Holders may group under a single notification the submission of several major variations of Type II regarding the same marketing authorisation, or group the submission of one or more major variation(s) of Type II with other minor variations regarding the same marketing authorisation, provided that this corresponds to one of the cases listed in Annex III of the Variations Regulation, or when this has been agreed previously with the reference Member State, the national competent, authority or the Agency (as appropriate).

In addition, for medicinal products authorised under purely national procedures, the holder may also group several major variations of Type II affecting several marketing authorisations in a single Member State, or one or more major variation(s) of Type II with other minor variations affecting several marketing authorisations in a single Member State, provided that (i) the variations are the same for all the marketing authorisations concerned, (ii) the variations are submitted at the same time to the national competent authority, and (iii) the national competent authority has previously agreed to the grouping.

Furthermore, where the same major variation of Type II or the same group of variations (as explained above) affect several marketing authorisations owned by the same holder, the holder may submit these variations as one application for ‘worksharing’ (see section 3 on ‘worksharing’).

The application must contain the elements listed in Annex IV to the Variations Regulation, presented as follows in accordance with the appropriate headings and numbering of the EU-CTD format or the Notice to applicants Volume 6B format (veterinary medicinal products when the EU-CTD format is not available):

—	Cover letter.

—

The completed EU variation application form (published in the Notice to Applicants), including the details of the marketing authorisation(s) concerned. Where a variation is the consequence of or related to another variation, a description of the relation between these variations should be provided in the appropriate section of the application form.

—

Reference to the variation code as laid down in the Annex to these guidelines, indicating that all conditions and documentation requirements are met or, where applicable, reference to a classification recommendation published in accordance with Article 5 of the Variation Regulation used for the relevant application.

—	Supporting data relating to the proposed variation(s).

—	Update or Addendum to quality summaries, non-clinical overviews and clinical overviews (or expert reports for veterinary medicinal products) as relevant. When non-clinical or clinical study reports are submitted, even if only one, their relevant summary(ies) should be included in Module 2.

—	For variations requested by the competent authority resulting from new data submitted, e.g. pursuant to post authorisation conditions or in the framework of pharmacovigilance obligations, a copy of the request should be annexed to the cover letter.

—

In case that the variations affect the summary of product characteristics, labelling or package leaflet, the revised product information presented in the appropriate format, as well as the relevant translations. Where the overall design and readability of the outer and immediate packaging or package leaflet is affected by the major variation of Type II, mock-ups or specimens should be provided to the reference Member State, the national competent authority or the Agency.

For variations in the mutual recognition procedure, the reference Member State should additionally receive the list of dispatch dates indicating the Type II Variation procedure number, the dates on which the applications have been sent to each Member State concerned and confirmation that the relevant fee has been paid as required by the competent authorities concerned.

For variations in the purely national procedure confirmation that the relevant fee has been paid as required by the national competent authority.

For variations in the centralised procedure, the relevant fee for the Type II variation(s), as provided for in Council Regulation (EC) No 297/95, should be paid in accordance with the Agency’s financial procedures.

2.3.2.   Type II variations assessment for mutual recognition procedure

Upon receipt of a Type II application, the reference Member State will handle the application as follows:

If the application has been submitted simultaneously to all the Member States concerned and contains the elements listed in point 2.3.1, the reference Member State will acknowledge receipt of a valid application of a major variation of Type II. The procedure starts from the date of acknowledgement of the receipt of a valid application by the reference Member State. The holder and the concerned Member States will be informed of the timetable at the start of the procedure.

As a general rule, for major variations of Type II, a 60-day evaluation period will apply. This period may be reduced by the reference Member State having regard to the urgency of the matter, particularly for safety issues, or may be extended by the reference Member State to 90 days for variations listed in Part I of Annex V or for grouping of variations in accordance with Article 7(2)(c) of the Variations Regulation. For variations for veterinary medicinal products listed in Part 2 of Annex V of the Variations Regulation a 90-day period will apply.

The reference Member State will prepare a draft assessment report and a decision on the application according to the communicated timetable and will circulate them to the concerned Member States for comments as well as to the holder for information. The concerned Member States will send to the reference Member State their comments within the deadlines set out in the timetable.

Within the evaluation period, the reference Member State may request the marketing authorisation holder to provide supplementary information. The request for supplementary information will be sent to the holder together with a timetable stating the date by when the holder should submit the requested data and where appropriate the extended evaluation period. In general, a suspension of 1 month will typically apply. For longer suspension the holder should send a justified request to the reference Member State for agreement.

The procedure will be suspended until the receipt of the supplementary information. The evaluation of responses may take up to 30 or 60 days depending on the complexity and amount of data requested to the holder.

After receipt of the holder’s response, the reference Member State will finalise the draft assessment report and the decision on the application and will circulate them to the concerned Member States for comments as well as to the holder for information.

2.3.3.   Outcome of Type II variations assessment for mutual recognition procedure

By the end of the evaluation period, the reference Member State will finalise and submit the assessment report and its decision on the application to the concerned Member States.

Within 30 days following receipt of the assessment report and the decision, the concerned Member States will recognise the decision and inform the reference Member State accordingly, unless a potential serious risk to public health or a potential serious risk to human or animal health or to the environment (in the case of veterinary medicinal products) is identified that prevents a Member State from recognising the decision of the reference Member State. The Member State that, within 30 days following receipt of the assessment report and the decision of the reference Member State, identifies such a potential serious risk must inform the reference Member State and give a detailed statement of the reasons for its position.

The reference Member State will then refer the application to the corresponding coordination group for application of Article 33(3), (4) and (5) of Directive 2001/82/EC or Article 29(3), (4) and (5) of Directive 2001/83/EC to the matter of disagreement and will inform the holder and the concerned Member States accordingly. The holder is not entitled to trigger a referral.

Where an application concerning a grouping of variations that includes at least a variation Type II is referred to the coordination group, the decision on the variations not subject to the referral will be suspended until the referral procedure has concluded (including, where relevant, the referral to the Committee for Medicinal Products for Human Use under Articles 32 to 34 of Directive 2001/83/EC, or the Committee for Veterinary Medicinal Products pursuant to Articles 36 to 38 of Directive 2001/82/EC). However, only the variation(s) in respect of which a potential serious risk to human or animal health or to the environment has been identified will be discussed by the coordination group and eventually by the Committee for Medicinal Products for Human use or the Committee for Veterinary Medicinal Products, not the whole group.

The reference Member State will inform the concerned Member States and the holder about the approval or rejection of the variation(s) (including the grounds for the unfavourable outcome). Where several Type II variations, or a group of Type II variation(s) with other minor variations have been submitted as one application, the reference Member State will inform the holder and the concerned Member States which variation(s) have been accepted or rejected. The holder may withdraw single variations from the grouped application during the procedure (prior to the finalisation of the assessment of the reference Member State).

After a positive decision is communicated regarding variations with changes to the summary of product characteristics, labelling or package leaflet, the holder should submit, within 7 days, translations of the product information texts to all Member States concerned.

After approval of the variation(s), the competent authorities of the Member States concerned will, where necessary, amend the marketing authorisation to reflect the variation(s) within 2 months, provided that the documents necessary for the amendment of the marketing authorisation have been submitted to the Member States concerned.

The accepted major variation(s) of Type II can be implemented 30 days after the holder has been informed about the acceptance of the variation(s) by the reference Member State, provided that the necessary documents to amend the marketing authorisation have been submitted to the Member State concerned. In those cases where the application has been the object of a referral, the variation(s) must not be implemented until the referral procedure has concluded that the variation(s) is accepted. However, the variations in the group not subject to the referral may be implemented if so indicated by the reference Member State.

Variations related to safety issues must be implemented within a time-frame agreed between the reference Member State and the holder.

2.3.4.   Type II variations assessment for purely national procedure

Upon receipt of a Type II application, the national competent authority will handle the application as follows:

If the application contains the elements listed in point 2.3.1, the national competent authority will acknowledge receipt of a valid application of a major variation of Type II. The procedure starts from the date of acknowledgement of the receipt of a valid application. The holder will be informed of the timetable at the start of the procedure.

As a general rule, for major variations of Type II, a 60-day evaluation timetable will apply. This period may be reduced by the national competent authority having regard to the urgency of the matter, particularly for safety issues, or may be extended to 90 days for variations listed in Part I of Annex V or for grouping of variations in accordance with Article 13d(2)(c) of the Variations Regulation. For variations for veterinary medicinal products listed in Part 2 of Annex V of the Variations Regulation a 90-day timetable will apply.

Within the evaluation period, the national competent authority may request the holder to provide supplementary information. The request for supplementary information will be sent to the holder together with a timetable stating the date by when the holder should submit the requested data and where appropriate the extended evaluation period.

The procedure will be suspended until the receipt of the supplementary information. As a general rule, a suspension of 1 month will apply. For longer suspension the holder should send a justified request to the national competent authority for agreement.

The evaluation of responses may take up to 30 or 60 days depending on the complexity and amount of data requested to the holder.

2.3.5.   Outcome of Type II variations assessment for purely national procedure

By the end of the evaluation period, the national competent authority will finalise the evaluation including its decision on the application and inform the holder about the approval or rejection of the variation(s) (including the grounds for the unfavourable outcome).

Where several Type II variations, or a group of Type II variation(s) with other minor variations have been submitted as one application, the national competent authority will inform the holder which variation(s) have been accepted or rejected. The holder may withdraw single variations from the grouped application during the procedure (prior to the finalisation of the assessment by the national competent authority).

After approval of the variation(s), the national competent authorities will, where necessary, amend the marketing authorisation(s) to reflect the variation(s) within 2 months provided that the documents necessary for the amendment of the marketing authorisation have been submitted to the national competent authority.

The accepted major variation(s) of Type II can be implemented after the holder has been informed about the acceptance of the variation(s) by the national competent authority, provided that the necessary documents to amend the marketing authorisation(s) have been submitted.

Variations related to safety issues must be implemented within a time-frame agreed between the national competent authority and the holder.

2.3.6.   Type II variations assessment for centralised procedure

Upon receipt of a Type II application, the Agency will handle the application as follows:

If the application submitted to the Agency contains the elements listed in point 2.3.1, the Agency will acknowledge receipt of a valid application of a major variation of Type II. By the date of acknowledgement of the receipt of a valid application, the Agency will start the procedure. The marketing authorisation holder will be informed of the adopted timetable at the start of the procedure.

As a general rule, for major variations of Type II, a 60-day evaluation timetable will apply. This period may be reduced by the Agency having regard to the urgency of the matter, particularly for safety issues, or may be extended by the Agency to 90 days for variations listed in Part I of Annex V or for grouping of variations in accordance with Articles 7(2)(c) of the Variations Regulation. For variations for veterinary medicinal products listed in Part 2 of Annex V of the Variations Regulation a 90-day timetable will apply.

Within the evaluation period, the Committee for Medicinal Products for Human Use or the Committee for Veterinary Medicinal Products may request supplementary information. The request for supplementary information or follow-on request will be sent to the holder together with the timetable stating the date by when the holder should submit the requested data and where appropriate the extended evaluation period.

The procedure will be suspended until the receipt of the supplementary information. In general, a suspension of up to 1 month will typically apply. For suspension longer than 1 month the holder should send a justified request to the Agency for agreement by the corresponding Committee. For any follow-on request for supplementary information, an additional procedural suspension of up to 1 month will be applied in general; a maximum of 2 months may be applied when justified.

The Committee assessment of responses may take up to 30 or 60 days depending on the complexity and amount of data to be requested to the marketing authorisation holder.

An oral explanation to the Committee for Medicinal Products for Human Use or the Committee for Veterinary Medicinal Products may be held at the request of the Committee or the holder, where appropriate.

2.3.7.   Outcome of Type II variations assessment in centralised procedure

Upon adoption of an opinion of the Committee for Medicinal Products for Human Use or the Committee for Veterinary Medicinal Products, the Agency will inform the marketing authorisation holder within 15 days as to whether the opinion is favourable or unfavourable (including the grounds for the unfavourable outcome).

Where several Type II variations, or a group of Type II variation(s) with other minor variations have been submitted as one application, the Agency will issue an opinion reflecting the final outcome of the procedure. Such opinion will also list any variations which are not considered approvable. The holder may withdraw single variations from the grouped application during the procedure (prior to the finalisation of the opinion of the Agency).

The re-examination procedure set-out in Articles 9(2) and 34(2) of Regulation (EC) No 726/2004 also applies to the opinions adopted for major variations of Type II applications.

Where the final opinion of the Agency is favourable and the variation(s) affects the terms of the Commission decision granting the marketing authorisation, the Agency will transmit to the Commission its opinion and the grounds for its opinion as well as the necessary documents to amend the marketing authorisation.

Upon receipt of the final opinion and the relevant information, the Commission will, where necessary, amend the marketing authorisation within 2 months in the following cases:

(i)	variations related to the addition of a new therapeutic indication or to the modification of an existing one;

(ii)	variations related to the addition of a new contraindication;

(iii)

variations related to a change in posology;

(iv)	variations related to the addition of a non-food producing target species or the modification of an existing one for veterinary medicinal products;

(v)	variations concerning the replacement or addition of a serotype, strain, antigen or combination of serotypes, strains or antigens for a veterinary vaccine;

(vi)	variations related to changes to the active substance of a seasonal, pre-pandemic or pandemic vaccine against human influenza;

(vii)

variations related to changes to the withdrawal period for a veterinary medicinal product;

(viii)

other type II variations that are intended to implement changes to the decision granting the marketing authorisation due to a significant public health concern or significant animal health or environmental concern in the case of veterinary medicinal products.

In the case of other variations, the Commission will, where necessary, amend the decision granting the marketing authorisation at the latest within 12 months.

The approved major variation(s) of Type II requiring amendment of the Commission decision granting the marketing authorisation within 2 months may only be implemented once the holder has been informed by the Commission accordingly. Where amendment of the decision granting the marketing authorisation is not required within 2 months, or where the approved variation(s) does not affect the terms of the Commission decision granting the marketing authorisation, the variation(s) may be implemented once the holder has been informed by the Agency that its opinion is favourable.

Variations related to safety issues must be implemented within a time-frame agreed between the Commission and the holder.

2.4.   Extensions

Annex I of the Variations Regulation sets out a list of changes to be considered as extensions. As established in Article 19 of the Variations Regulation, such applications will be evaluated in accordance with the same procedure as for the granting of the initial marketing authorisation to which it relates. The extension can either be granted as a new marketing authorisation or will be included in the initial marketing authorisation to which it relates.

2.4.1.   Submission of Extensions applications

Extension applications must be submitted to all Member States concerned, to the national competent authority, or to the Agency (as appropriate).

Holders may group under a single notification the submission of several extensions, or one or more extensions with one or more other variations, regarding the same marketing authorisation provided that this corresponds to one of the cases listed in Annex III of the Variations Regulation, or when this has been agreed previously with the reference Member State, the national competent, authority or the Agency (as appropriate). However, no worksharing of extensions applications is foreseen in the Variations Regulation.

The application must be presented as follows, in accordance with the appropriate headings and numbering of the EU-CTD format or the Notice to applicants Volume 6B format (veterinary medicinal products when the EU-CTD format is not available):

—	Cover letter.

—	The completed EU application form (published in the Notice To Applicants)

—	Supporting data relating to the proposed extension. Some guidance on the appropriate additional studies required for extension applications is available in Appendix IV to Chapter 1 of Volume 2A or 6A of the Notice to applicants.

—	A full Module 1 (Part 1 for veterinary medicinal products) should be provided, with justifications for absence of data or documents included in the relevant section(s) of Module 1 or Part 1.

—	Update or Addendum to quality summaries, non-clinical overviews and clinical overviews (or expert reports for veterinary medicinal products) as relevant. When non-clinical or clinical study reports are submitted, even if only one, their relevant summary(ies) should be included in Module 2.

—	In case that the extension affects the summary of product characteristics, labelling or package leaflet: the revised product information, presented in the appropriate format.

For extension applications in the mutual recognition procedure, the reference Member State should additionally receive the list of dispatch dates indicating the procedure number, the dates on which the applications have been sent to each Member State concerned and confirmation that the relevant fees have been paid as required by the competent authorities concerned.

For extension applications in the purely national procedure confirmation that the relevant fee has been paid as required by the national competent authority.

For extension applications in the centralise procedure, the relevant fee for the extension(s), as provided for in Council Regulation (EC) No 297/95, should be paid in accordance with the Agency’s financial procedures.

2.4.2.   Extension assessment for national procedure

Upon receipt of an extension application under the mutual recognition or the purely national procedure, it will be handled as an initial marketing authorisation application in accordance with Directive 2001/82/EC or Directive 2001/83/EC.

2.4.3.   Extension assessment for centralised procedure

Upon receipt of an extension application, the Agency will handle the application as for an initial marketing authorisation application in accordance with Regulation (EC) No 726/2004.

2.5.   Human influenza vaccines

Hereby guidance is provided on the application of Articles 12, 13f and 18 of the Variations Regulation to the annual update of human influenza vaccines.

Because of the specificities inherent in the manufacturing of human influenza vaccines, a special ‘fast track’ variation procedure is applicable for the annual change in active substance for the purpose of the annual update of a human influenza vaccine in order to meet the EU recommendation for human influenza virus strain(s) vaccine composition for the coming season. In addition, a special urgent procedure is foreseen in Article 21 of the Variations Regulation for cases of pandemic situation.

Any other variations to human influenza vaccines follow the variation procedures foreseen in other sections of these Guidelines.

The ‘fast track’ procedure consists of two steps. The first step concerns the assessment of the administrative and quality data elements (summary of product characteristics, labelling and package leaflet, and the chemical, pharmaceutical and biological documentation). The second step concerns the assessment of additional data where necessary.

Marketing authorisation holders are advised to discuss the annual update submissions in advance with the reference Member State, the national competent authority or the Agency.

2.5.1.   Submission of variations for annual update of human influenza vaccines applications

Variations concerning changes to the active substance for the annual update of human influenza vaccines applications must be submitted to the reference Member State and to all concerned Member States, to the national competent authority or to the Agency (as appropriate).

The application must be presented in accordance with the appropriate headings and numbering of the EU-CTD format:

—	Cover letter.

—	The completed EU application form (published in the Notice to applicants)

—	Update or Addendum to quality summaries, non-clinical overviews and clinical overviews as relevant. When non-clinical or clinical study reports are submitted, even if only one, their relevant summary(ies) should be included in Module 2.

—	Supporting data relating to the proposed variation(s).

—	The revised product information, presented in the appropriate format.

In the case of applications for the annual update of human influenza vaccines under the mutual recognition procedure, the reference Member State should additionally receive the list of dispatch dates indicating the procedure number, the dates on which the applications have been sent to each Member States concerned and confirmation that the relevant fees have been paid as required by the competent authorities concerned.

In the case of applications for the annual update of human influenza vaccines under the purely national procedure confirmation that the relevant fee has been paid as required by the national competent authority.

In the case of applications for the annual update of human influenza vaccines under the centralised procedure, the relevant fee for the variation as provided for in Council Regulation (EC) No 297/95 should be paid in accordance with the Agency’s financial procedures.

2.5.2.   Variations assessment for mutual recognition procedure

Upon receipt of an application for the annual update, the reference Member State will handle the application as follows:

The reference Member State will acknowledge receipt of a valid application within 7 days and inform the holder and the Member States concerned of the start of the procedure.

The reference Member State will prepare an assessment report and a decision on the application. To this end, the reference Member State will consider first the administrative and quality data. As the reference Member State must sent the assessment and the draft Decision within the maximum deadline of 45 days foreseen in the Regulation, it is expected that, in order to allow for sufficient time for the assessment of additional data (notably clinical and stability data) where necessary, the reference Member State will typically conclude its assessment of the administrative and quality data within 30 days of the reception of a valid application.

The reference Member State may request the holder to submit additional information (notably clinical or stability data); in such a case, it will inform the concerned Member States. When a request for additional information is sent to the holder, the 45 days deadline is stopped until the requested information has been submitted by the holder.

The reference Member State will transmit its assessment report and draft Decision to the concerned Member States. Within 12 days from the reception date, the concerned Member States will adopt a decision accordingly and inform the holder and the reference Member State thereof.

2.5.3.   Variations assessment for purely national procedure

Upon receipt of an annual variation human influenza vaccines application, the national competent authority will handle the application as follows:

The national competent authority will acknowledge receipt of a valid application of an annual variation human influenza vaccine and inform the holder accordingly.

Within the evaluation period, the national competent authority may send the holder a request for supplementary information (notably clinical or stability data); in such a case, the 45 days deadline is stopped until the requested information has been submitted by the holder.

Within 45 days from the receipt of a valid application, the national competent authority will finalise the evaluation including its decision on the application and inform the holder about the approval or rejection of the variation(s) (including the grounds for the unfavourable outcome).

2.5.4.   Variations assessment in centralised procedure

Upon receipt of an annual variation human influenza vaccines application, the Agency will handle the application as follows:

The Agency will acknowledge receipt of a valid application of an annual variation human influenza vaccine within 7 days and inform the holder of the start of the procedure.

The Committee for Medicinal Products for Human Use has a maximum of 55 days from the start of the procedure to assess the application. The Committee may request the holder to submit additional information (notably clinical or stability data); in such a case, the 55 days deadline is stopped until the requested information has been submitted by the holder.

Where necessary and based on the final opinion from the Committee, the Commission will amend the decision granting the marketing authorisation and update the Community Register of Medicinal Products.

2.6.   Urgent Safety Restrictions

Article 22 of the Variations Regulation foresees that in the event of a risk to public health in the case of medicinal products for human use or in the event of a risk to human or animal health or to the environment in the case of veterinary medicinal products, the holder may take provisional ‘urgent safety restrictions’.

Urgent safety restrictions concern interim change(s) in the terms of the marketing authorisation due to new information having a bearing on the safe use of the medicinal product. These urgent changes must be subsequently introduced via a corresponding variation in the marketing authorisation.

The holder must immediately notify all Member States concerned, the national competent authority or the Agency (as appropriate) of the restrictions to be introduced.

If no objections have been raised by the relevant authority or the Agency (for centrally authorised medicinal products) within 24 hours following receipt of that information, the urgent safety restrictions are deemed accepted. They must be implemented within a time frame agreed between the reference Member State, the national competent authority or the Agency (as appropriate) and the holder.

Urgent safety restrictions may also be imposed by the Commission (for centrally authorised medicinal products) or by the national competent authorities (for nationally authorised medicinal products) in the event of a risk to public health in the case of medicinal products for human use or in the event of a risk to human or animal health in the case of veterinary medicinal products.

The corresponding variation application reflecting the urgent safety restrictions (whether requested by the holder or imposed by the Commission or the national competent authorities) must be submitted by the holder as soon as possible within 15 days.

2.7.   Statement of compliance under the Paediatric Regulation

Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004 (10) (‘Paediatric Regulation’) provides for rewards:

—

Under Article 36(1) of Regulation (EC) No 1901/2006, the holder of a patent or supplementary protection certificate is entitled to a 6-month extension of the period referred to in Article 13(1) and (2) of Regulation (EEC) No 1768/92 (11) (now: Regulation (EC) No 469/2009) under certain conditions, including the addition to the marketing authorisation of the statement referred to in Article 28(3) of the Paediatric Regulation (‘compliance statement’).

—

Under Article 37 of Regulation (EC) No 1901/2006, the holder of a marketing authorisation for an orphan medicinal product is entitled to an extension of the 10-year period referred to in Article 8(1) of Regulation (EC) No 141/2000 to 12 years under certain conditions, including the addition of the compliance statement to the marketing authorisation.

It follows that, for the purposes of benefiting from the rewards provided for under Articles 36 and 37 of the Paediatric Regulation, a variation to add the compliance statement in the marketing authorisation may be required.

Article 23a of the Variations Regulation simplifies the procedure to add the compliance statement in the marketing authorisation so that the rewards foreseen under Regulation (EC) No 1901/2006 may be sought as soon as possible once the requirements foreseen in the Paediatric Regulation have been complied with. Specifically, in order to include the compliance statement holders should submit a variation request to the relevant authority. After verification that all relevant conditions are met, the compliance statement is to be included by the relevant authority in the technical dossier of the marketing authorisation.

For the purposes of legal certainty, the relevant authority will provide the holder with a confirmation that the compliance statement has been included in the technical dossier within 30 days after the relevant assessment has been concluded. In the case of marketing authorisations granted under the centralised procedure, the confirmation that the compliance statement has been included in the marketing authorisation will be issued by the European Medicines Agency.

3.   PROCEDURAL GUIDANCE ON WORKSHARING

Article 20 of the Variations Regulation allows a holder to submit in one application the same Type IB, the same Type II variation, or the same group of variations corresponding to one of the cases listed in Annex III of the Regulation or agreed with the reference Member State, the national competent authority or the Agency (as appropriate) which does not contain any extension affecting

(i)	more than one purely national marketing authorisation of the same holder in more than one Member State; or

(ii)	more than one mutual recognition marketing authorisation of the same holder; or

(iii)

more than one centralised marketing authorisation of the same holder; or

(iv)	one or several purely national marketing authorisation(s) and one or several centralised marketing authorisation(s) of the same holder; or

(v)	one or several purely national marketing authorisation(s) and one or several mutual recognition marketing authorisation(s) of the same holder; or

(vi)	one or several mutual recognition marketing authorisation(s) and one or several centralised marketing authorisation(s) of the same holder; or

(vii)

one or several purely national marketing authorisation(s), one or several mutual recognition marketing authorisation(s) and one or several centralised marketing authorisation(s) of the same holder.

In order to avoid duplication of work in the evaluation of such variations, a worksharing procedure has been established under which one authority (the ‘reference authority’), chosen amongst the competent authorities of the Member States and the Agency, will examine the variation on behalf of the other concerned authorities.

Where at least one of the concerned marketing authorisations has been authorised via the centralised procedure, the Agency will be the reference authority (section 3.4). In all other cases, a national competent authority chosen by the coordination group, taking into account the recommendation of the holder, will act as the reference authority (section 3.2).

In order to facilitate the planning of the procedure, holders are encouraged to inform the Agency or the coordination group and the proposed reference authority in advance of the submission of a variation or group of variations to be subject to a worksharing procedure.

In order to benefit from a worksharing procedure, it is necessary that the same change(s) will apply to the different medicinal products concerned with no need (or limited need) for assessment of a potential product-specific impact. Therefore, where the ‘same’ change(s) to different marketing authorisations require the submission of individual supportive data for specific medicinal products concerned or separate product-specific assessment, such changes cannot benefit from worksharing.

3.1.   Submission of variation(s) application under worksharing

A variation or group of variations presented for worksharing must be submitted as explained in sections 2.2-2.3 above and must be transmitted as one integrated submission package covering all variations for all medicinal products. This must include a common cover letter and application form, together with separate supportive documentation for each medicinal product concerned and revised product information (if applicable) for each medicinal product concerned. This will allow the Agency and the national competent authorities to update the dossier of each marketing authorisation included in the worksharing procedure with the relevant amended or new information.

The worksharing application must be submitted to all relevant authorities, i.e. all Member States where the products concerned are authorised and the Agency (for the centralised procedure).

3.2.   Worksharing assessment not involving medicinal products authorised under the centralised procedure

When the holder informs the coordination group of an upcoming worksharing procedure that does not affect any centralised marketing authorisation, the coordination group will at the next meeting decide on the reference authority, taking into account the proposal of the holder and, if applicable pursuant to the third subparagraph of Article 20(3) of the Variations Regulation, another relevant authority to assist the reference authority. The holder will be informed by the coordination group of the decision of which national competent authority will act as reference authority.

Upon receipt of a worksharing application, the reference authority will handle the application as follows:

The reference authority will acknowledge receipt of a valid application for worksharing. Immediately after acknowledging receipt of a valid application, the reference authority will start the procedure. The holder and the Member States concerned will be informed of the timetable at the start of the procedure.

As a general rule, worksharing procedures will follow a 60-day period or a 90-day evaluation period for variations listed in Part 2 of Annex V of the Variations Regulation. This period may however be reduced by the reference authority having regard to the urgency of the matter, particularly for safety issues, or may be extended to 90 days for variations listed in Part 1 of Annex V or for grouping of variations in accordance with Article 7(2)(c) or 13d(2)(c) of the Variations Regulation.

The reference authority will prepare an opinion according to the communicated timetable and will circulate it to the concerned Member States for comments as well as to the holder for information. Concerned Member States will send their comments within the deadlines set out in the timetable.

Within the evaluation period, the reference Member State may request the marketing authorisation holder to provide supplementary information. The request for supplementary information will be sent to the holder together with a timetable stating the date by when the holder should submit the requested data and, where appropriate, the extended evaluation period. In general, a suspension of 1 month will typically apply. For longer suspension the holder should send a justified request to the reference Member State for agreement.

The procedure will be suspended until the receipt of the supplementary information. The assessment of responses may take up to 30 or 60 days depending on the complexity and amount of data requested to the holder.

After receipt of the holder’s response, the reference Member State will finalise the draft opinion and will circulate it to the concerned Member States for comments as well as to the holder for information.

3.3.   Outcome of the worksharing assessment not involving medicinal products authorised under the centralised procedure

By the end of the evaluation period, the reference authority will issue its opinion on the application and inform the concerned Member States and the holder.

In case of a favourable opinion, the list of variations that are not considered approvable should be attached in the Opinion (if applicable). Variations may be considered approvable for some of the concerned products only. In case of an unfavourable outcome, the grounds for the unfavourable outcome should be explained.

Within 30 days following receipt of the opinion, the concerned Member States will recognise the opinion and inform the reference Member State accordingly, unless a potential serious risk to public health or a potential serious risk to human or animal health or to the environment (in the case of veterinary medicinal products) is identified that prevents a Member State from recognising the opinion of the reference Member State. The Member State that, within 30 days following receipt of the opinion of the reference Member State, identifies such a potential serious risk should inform the reference Member State and give a detailed statement of the reasons for its position.

The reference authority will then refer the application to the coordination group for application of Article 33(3), (4) and (5) of Directive 2001/82/EC or Article 29(3), (4) and (5) of Directive 2001/83/EC to the matter of disagreement and will inform the holder and the Member States concerned accordingly. The holder is not entitled to trigger a referral.

Where a referral to the coordination group is made, the procedure concerning the decision on the worksharing application will be suspended until a decision has been adopted on the referral procedure (including, where relevant, the referral to the Committee for Medicinal Products for Human Use under Articles 32 to 34 of Directive 2001/83/EC, or the Committee for Veterinary Medicinal Products pursuant to Articles 36 to 38 of Directive 2001/82/EC).

After a positive opinion is communicated regarding variations with changes to the summary of product characteristics, labelling or package leaflet, the holder should submit, within 7 days, translations of the product information texts to all Member States concerned.

Within 30 days following the approval of the opinion or, where a referral has been triggered, the notification of the agreement of the coordination group or the Commission decision (as applicable), the Member States concerned will amend the marketing authorisation(s) accordingly, provided that the documents necessary for the amendment of the marketing authorisation have been submitted to the Member States concerned.

Minor variation(s) of Type IB approved via a worksharing procedure, may be implemented upon receipt of the favourable opinion of the reference authority.

Major variation(s) of Type II (including those which contain grouped minor variation(s) of Type IB) approved via a worksharing procedure may be implemented 30 days after receipt of the favourable opinion from the reference authority provided that the necessary documentation to amend the marketing authorisation has been submitted to the Member States concerned. In those cases where the application has been the object of a referral, the variation(s) must not be implemented until the referral procedure has concluded that the variation(s) is accepted.

Variations related to safety issues must be implemented within a time-frame agreed between the marketing authorisation holder and the reference authority.

3.4.   Worksharing assessment involving medicinal products authorised under the centralised procedure

Upon receipt of a worksharing application that affects at least one centralised marketing authorisation, the Agency will handle the application as follows:

The Agency will acknowledge receipt of a valid worksharing application. Immediately after acknowledging the receipt of a valid application, the Agency will start the procedure. The holder will be informed of the adopted timetable at the start of the procedure.

The Agency will appoint a rapporteur (and in some cases also a co-rapporteur) to lead the assessment procedure.

In general, worksharing procedures will follow a 60-day evaluation timetable or a 90-day evaluation timetable for variations listed in Part 2 of Annex V of the Variations Regulation. This period may however be reduced by the reference authority having regard to the urgency of the matter, particularly for safety issues, or may be extended to 90 days for variations listed in Part 1 of Annex V or for grouping of variations in accordance with Article 7(2)(c) or 13d(2)(c).

Within the evaluation period, the Committee for Medicinal Products for Human Use or the Committee for Veterinary Medicinal Products may request supplementary information. The request for supplementary information or follow-on request will be sent to the holder together with the timetable stating the date by when the holder should submit the requested data and where appropriate the extended evaluation period.

The procedure will be suspended until the receipt of the supplementary information. In general, a suspension of up to 1 month will typically apply. For suspension longer than 1 month the holder should send a justified request to the Agency for agreement by the Committee for Medicinal Products for Human or the Committee for Veterinary Medicinal Products.

For any follow-on request for supplementary information, an additional clock-stop of up to 1 month will be applied in general; a maximum of 2 months may be applied when justified.

The Committee assessment of responses may take up to 30 or 60 days depending on the complexity and amount of data provided by the marketing authorisation holder.

An oral explanation to the Committee for Medicinal Products for Human Use or the Committee for Veterinary Medicinal Products can be held at the request of the relevant Committee or the marketing authorisation holder, where appropriate.

3.5.   Outcome of the worksharing assessment involving medicinal products authorised under the centralised procedure

By the end of the evaluation period, the Agency will adopt an opinion on the application, including the assessment report. The Agency will inform the holder and Member States concerned (if applicable). In case of disagreement with the opinion, holders may request a re-examination thereof in accordance with the procedure set out in Articles 9(2) and 34(2) of Regulation (EC) No 726/2004.

Where the opinion of the Agency is favourable and the variation(s) affects the terms of the Commission decision(s) granting the marketing authorisation, the Agency will transmit to the Commission its opinion and the grounds for its opinion as well as the necessary documents to amend the marketing authorisation.

If the Agency considers that some variations are not approvable, the list of variations that are not considered approvable should be attached in the Opinion. Variations may be considered approvable for some of the concerned products only.

Upon receipt of a favourable opinion by the Member States concerned or the Commission, the following steps apply:

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For medicinal products authorised under the mutual recognition procedure or purely national procedures, the Member States concerned must approve the opinion, inform the Agency accordingly and, where necessary, amend the national marketing authorisations within 60 days provided that the necessary documents to amend the marketing authorisation(s) have been submitted.

Minor variation(s) of Type IB (with the exception of those grouped with major variation(s) of Type II) may be implemented upon receipt of the favourable opinion of the Agency.

Major variation(s) of Type II (and those minor variation(s) of Type IB grouped with the Type II variation) may be implemented 30 days after receipt of the favourable opinion from the Agency provided that (i) the documents necessary for the amendment of the marketing authorisation(s) have been submitted to the Member States concerned, and (ii) the application has not been the object of a referral.

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For centrally authorised products, the Commission will, where necessary and provided that the necessary documents to amend the marketing authorisation(s) have been submitted, amend the relevant authorisation(s) within 2 months in the following cases: (i) variations related to the addition of a new therapeutic indication or to the modification of an existing one; (ii) variations related to the addition of a new contraindication; (iii) variations related to a change in posology; (iv) variations related to the addition of a non-food producing target species or the modification of an existing one for veterinary medicinal products; (v) variations concerning the replacement or addition of a serotype, strain, antigen or combination of serotypes, strains or antigens for a veterinary vaccine; (vi) variations related to changes to the active substance of a seasonal, pre-pandemic or pandemic vaccine against human influenza; (vii) variations related to changes to the withdrawal period for a veterinary medicinal product; (viii) other type II variations that are intended to implement changes to the decision granting the marketing authorisation due to a significant public health concern or significant animal health or environmental concern in the case of veterinary medicinal products.

In the case of other variations, the Commission will amend the decision granting the marketing authorisation at the latest within 12 months.

Minor variation(s) of Type IB (with the exception of those grouped with major variation(s) of Type II) may be implemented upon receipt of the favourable opinion of the Agency.

Major variation(s) of Type II (and those minor variation(s) of Type IB grouped with the Type II variation), with the exception of variations that require the adoption of a Commission decision within 2 months, may be implemented 30 days after receipt of the favourable opinion from the Agency, provided that the necessary documents to amend the marketing authorisation(s) have been submitted.

4.   ANNEX

This Annex consists of four chapters classifying variations related to: A) Administrative changes; B) Quality changes; C) Safety, Efficacy and Pharmacovigilance changes and D) Specific changes to Plasma Master Files and Vaccine Antigen Master Files.

Where reference has to be made to specific variations in this Annex, the variation in question should be quoted using the following structure: X.N.x.n (‘variation code’).

—	X refers to the capital letter of the chapter in this Annex where the variation is included (e.g. A, B, C or D)

—	N refers to the roman number of the section inside a chapter where the variation is included (e.g. I, II, III, etc.)

—	x refers to the letter of the subsection inside a chapter where the variation is included (e.g. a, b, c, etc.)

—	n refers to the number given in this Annex to a specific variation (e.g. 1, 2, 3, etc.)

For each chapter this Annex contains:

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A list of variations which should be classified as minor variations of Type IA or major variations of Type II in accordance with the definitions of Article 2 and Annex II to the Variations Regulation. It is also indicated which minor variations of Type IA require immediate notification as established in Article 8(1) of the Variations Regulation

—	A list of variations that should be considered as minor variations of Type IB,. It is noted that, in accordance with Article 3 of the Variations Regulation, this category applies by default. Accordingly, this Annex does not attempt to establish an exhaustive list for this category of variations.

This Annex does not deal with the classification of extensions as they are exhaustively listed in Annex I of the Variations Regulation. All changes specified in Annex I of the Variations Regulation must be considered extensions of the marketing authorisations; any other change can not be classified as such.

When one or more of the conditions established in this Annex for a minor variation of Type IA are not met, the concerned change may be submitted as a Type IB variation (‘Type IB by default’) unless the change is specifically classified as a major variation of Type II in this Annex or in a recommendation pursuant to Article 5 of the Variations Regulation, or unless the applicant considers that the changes may have a significant impact on the quality, safety or efficacy of the medicinal product.

If the competent authority considers that a variation submitted as a Type IB by default may have a significant impact on the quality, safety or efficacy of the medicinal product, it may request that the application be upgraded and processed as a Type II variation.

For the purpose of this Annex ‘test procedure’ has the same meaning as ‘analytical procedure’; ‘limits’ has the same meaning as ‘acceptance criteria’. ‘Specification parameter’ means the quality attribute for which a test procedure and limits are set, e.g. assay, identity, water content. The addition or deletion of a specification parameter therefore includes its corresponding test method and limits.

When several minor changes are taking place (e.g. to the same method or process or material) at the same time or in cases of a major update of the quality information for the active substance or the finished product, the applicant should take into account the overall impact of these changes on the quality, safety or efficacy of the medicinal product when considering the appropriate classification and submit them accordingly.

Specific supporting data for Type IB and Type II variations will depend on the specific nature of the change.

Furthermore, if a variation leads to a revision of the summary of product characteristics, labelling or package leaflet (jointly referred to as ‘the product information’), this change is considered part of that variation. In such cases updated product information has to be submitted as part of the application with the relevant translations. Mock-ups or specimens should be provided to the reference Member State, the national competent authority or the Agency.

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 reference is made to the ‘current edition’ in the dossier of an authorised medicinal product. Applicants are reminded that compliance with the updated monograph should be implemented within 6 months.

Any change to the content of the dossier that supports a European Pharmacopoeia Certificate of Suitability, should be submitted to the European Directorate for the Quality of Medicines (EDQM). However, if the certificate is revised following EDQM evaluation of this change, any marketing authorisation concerned must be updated accordingly.

With reference to Part III point 1 of Annex I of Directive 2001/83/EC, changes to Plasma Master Files (hereinafter PMFs) and Vaccine Antigen Master Files (VAMFs) follow the evaluation procedures for variations set-out in the Variations Regulation. Therefore, Chapter D in this guideline provides a list of variations which are specific to such PMFs or VAMFs. Following review of these variations, any marketing authorisation concerned must be updated in accordance with Chapter B.V of this guideline. In case the documentation of the human plasma used as starting material for a plasma derived medicinal product is not submitted as a PMF, variations to this starting material as described in the marketing authorisation dossier should also be handled in accordance with this Annex.

References in this Annex to changes to the marketing authorisation dossier mean addition, replacement or deletion, unless specifically indicated. If amendments to the dossier only concern editorial changes, such changes should generally not be submitted as a separate variation, but they can be included in a variation concerning that part of the dossier. In such cases the changes should be clearly identified in the application form as editorial changes and a declaration that the content of the concerned part of the dossier has not been changed by the editorial changes beyond the scope of the variation submitted should be provided. It should be noted that editorial changes include the removal of obsolete or redundant text but not the removal of specification parameters or manufacturing descriptions.

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(1)  OJ L 334, 12.12.2008, p. 7.

(2)  OJ L 209, 4.8.2012, p. 4.

(3)  OJ L 136, 30.4.2004, p. 1.

(4)  OJ L 311, 28.11.2001, p. 1.

(5)  OJ L 311, 28.11.2001, p. 67.

(6)  OJ L 15, 17.1.1987, p. 38.

(7)  OJ C 229, 22.7.1998, p. 4.

(8)  In this context, where reference is made to ‘reference Member State’, this applies to products approved via the mutual recognition procedure; where reference is made to ‘national competent authority’, this applies to products approved via purely national procedure; and where reference is made to the Agency, this applies to products approved via the centralised procedure.

(9)  OJ L 35, 15.2.1995, p. 1.

(10)  OJ L 378, 27.12.2006, p. 1.

(11)  From 6 July 2009, this Regulation has been repealed by Regulation (EC) No 469/2009.

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