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 as amended (¹) (‘the Variations Regulation’) governs the procedure for variations to the terms of marketing authorisations.

Under Article 4 of the Variations Regulation the Commission is required to draw up guidelines on (i) the details of the various categories of variations, (ii) the operation of the procedures laid down in Chapters II, IIa, III and IV of the Variations Regulation and (iii) the documentation to be submitted pursuant to these procedures.

These guidelines apply to variations of marketing authorisations for medicinal products granted in accordance with Regulation (EC) No 726/2004 of the European Parliament and of the Council (²) and Directive 2001/83/EC of the European Parliament and of the Council (³). They are intended to facilitate the interpretation and application of the Variations Regulation. They provide details on the application of the relevant procedures, including the steps to be taken, from the submission of a notification or an application for a variation to the final outcome of the procedure.

The Annex to these guidelines provides details of the classification of variations into the categories defined in Article 2 of the Variations Regulation: minor variations of Type IA, minor variations of Type IB and major variations of Type II. It also provides further details, where appropriate, on the scientific data to be submitted for specific variations and how this data should be documented.

The Variation Regulation was amended in 2021, through Commission Delegated Regulation (EU) 2021/756 (⁴) and, also in 2024, the Variation Regulation was amended, through Commission Delegated Regulation (EU) 2024/1701 (⁵), in order to achieve efficiency gains and to reduce the administrative burden for the pharmaceutical industry and to better use the resources of the competent authorities through simplified and streamlined procedures, ensuring the same standards for quality, efficacy and safety of medicines.

These present guidelines replace the 2013 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 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 (⁶) (the ‘2013 guidelines’).

The present guidelines reflect the 2024 amendment of the Variations Regulation and will apply from 15 January 2026. Submissions made prior to that date should follow the 2013 guidelines.

The present guidelines will be updated in accordance with Article 4 of the Variations Regulation, taking into account the Agency’s recommendations on unforeseen variations, as referred to in Article 5, leading to new classifications of variations.

The electronic version of the present guidelines, which may include new classifications of variations and the updates to the guidelines, will be published by the Commission on its website.

Definitions of terms used in these guidelines are provided in Directive 2001/83/EC, Regulation (EC) 726/2004 and in the Variations Regulation.

For the purpose of these guidelines:

  ‘centralised procedure’ means the procedure for granting marketing authorisations set out in Regulation (EC) No 726/2004;

  ‘mutual recognition procedure’ and ‘decentralised procedure’ mean the procedure for granting marketing authorisations set out in Chapter 4 of Directive 2001/83/EC;

  ‘purely national procedure’ means the procedure for granting marketing authorisations by a Member State in accordance with Directive 2001/83/EC outside the mutual recognition and decentralised procedure;

  ‘centrally authorised medicinal products’ means all marketing authorisations granted in accordance with the centralised procedure described above;

  ‘nationally authorised medicinal products’ means all marketing authorisations granted in accordance with the mutual recognition, decentralised and purely national procedures described above;

  ‘variations for mutual recognition procedure’ means the variation procedures conducted for applications concerning marketing authorisations granted in accordance with Chapter 4 of Directive 2001/83/EC as described above (via both the ‘mutual recognition procedure’ and the ‘decentralised procedure’);

  ‘Member States concerned’ means, in accordance with Article 2(6) of the Variations Regulation, a Member State whose competent authority has granted a marketing authorisation for the medicinal product in question;

  ‘concerned Member States’ means all Member States concerned except the reference Member State;

  ‘national competent authority’ means the competent authority of the Member State, in accordance with Article 2(9) of the Variations Regulation, that has granted a marketing authorisation under a purely national procedure;

  ‘the Agency’ means the European Medicines Agency;

  ‘relevant authority’ means the competent authority of each Member State concerned, or the Agency, in the case of centrally authorised medicinal products; and

  ‘reference authority’ means, in the context of the super-grouping and worksharing procedure, the Agency, where at least one of the marketing authorisations concerned is a centralised marketing authorisation, or the competent authority of the Member State chosen by the holder and accepted by that competent authority, or chosen by the coordination if none of the competent authorities of the Member States agrees to act as the reference authority, in the other cases.

2.   PROCEDURAL GUIDANCE ON THE HANDLING OF VARIATIONS

Marketing authorisations lay down the terms under which the marketing of a medicinal product is authorised in the EU. They comprise:

— a decision granting the marketing authorisation (including the summary of the product characteristics and any conditions, obligations, or restrictions affecting the marketing authorisation, or changes to the labelling or the package leaflet related to changes to the summary of the product characteristics) issued by the relevant authority; and

— a technical dossier containing the data submitted by the holder in accordance with Articles 8(3) to 11 of Directive 2001/83/EC and Annex I thereto, Article 6 of Regulation (EC) No 726/2004 and Article 7 of Regulation (EC) No 1394/2007 of the European Parliament and of the Council (⁷).

The Variations Regulation governs the procedures for amending a decision granting the marketing authorisation and the technical dossier.

However, changes to the labelling or package leaflet that are not connected to the summary of product characteristics are not governed by the procedures of the Variations Regulation, in which case the procedure laid down in Article 61(3) of Directive 2001/83/EC should be followed instead.

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 restrictions.

Submission of a variation application

An application for a variation shall be made electronically in the eCTD format (⁸), in accordance with the instructions laid down by the relevant authority, and 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) (⁹) as follows:

— A cover letter.

— The completed EU electronic variation application form (eAF) (available at https://esubmission.ema.europa.eu), including (i) the details of the marketing authorisations concerned, (ii) a description of all individual variations submitted, (iii) the variation code as laid down in the Annex to these guidelines, its electronic version or a recommendation issued in accordance with Article 5 of the Variations Regulation and (iv), where applicable, confirmation that all documentation requirements have been met.

— A detailed present /proposed table must also be provided for all changes included in the submission. Where a variation is a consequence of, or related to, another variation, a description of the relationship between these variations should be provided in the appropriate section of the eAF. Where a variation is considered unclassified, a detailed justification for its submission as a minor variation of Type IB (or major variation of Type II upon request from the holder when submitting the variation) must be included. Where a minor variation of Type IA is submitted, the date of implementation and confirmation that all conditions have been met should be provided.

— The relevant documentation or data in support of the proposed variation, including, where applicable, any documentation specified in the Annex to these guidelines, should be provided. Where the variation affects the summary of product characteristics, labelling, package leaflet or the obligations and conditions of a centrally authorised medicinal product, the revised summary of product characteristics, labelling and package leaflet (‘the product information’) presented in the appropriate format should be included. For minor variations of Type IA or Type IB, translations of the product information should also be provided at the time of submission. In all other cases they should be provided immediately after a favourable opinion on the procedure for centrally authorised medicinal products, or, within seven (7) days of the end of the mutual recognition or decentralised procedure. Where the overall design and readability of the outer and immediate packaging or package leaflet is affected by the variation, the relevant authorities should be provided with mock-ups or specimens.

— In the case of (super-)grouping of variations concerning several marketing authorisations, or worksharing procedure, a common cover letter and eAF should be submitted along with supporting documentation for each variation applied for and, where applicable, revised product information for each medicinal product concerned. This will allow the relevant authorities to update the dossier of each marketing authorisation included in the (super-) grouping or worksharing procedure with the relevant amended or new information.

— In the case of variations requested by the competent authority resulting from new data submitted, e.g. in accordance with post-authorisation conditions or pharmacovigilance obligations, a copy of the request should be attached to the cover letter.

— In the case of a major variation of Type II or extension of marketing authorisation, an update or addendum to quality overall summaries, and non-clinical and clinical overviews should be provided, where relevant. Where non-clinical or clinical study reports are submitted, even if there is only one, a summary should be included in Module 2.

— In case of an extension to the marketing authorisation, supporting data relating to the proposed extension should be provided. Guidance on the appropriate additional studies required for such extensions can be found in Annex II to Chapter 1 of Volume 2A of the Notice to Applicants (¹⁰). Additionally, a full Module 1 should be provided, with justifications for the absence of data or documents included in the relevant section of Module 1.

Further details on the technical requirements regarding the submission of variations applications are provided on the websites of the Agency and the coordination group (CMDh) (¹¹).

Any information relating to the implementation of a particular variation should be provided by the holder immediately upon request from the relevant authority.

Where a group of variations consists of different types of variation, the group must be submitted and handled according to the ‘highest’ variation type included in the group.

Where justified, the Agency and the CMDh, as applicable, may publish certain cases where related changes would be acceptable within a single variation application without grouping.

2.1. Minor variations of Type IA

This section provides guidance on the application of Articles 7, 7a, 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.

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

2.1.1. Submission of minor variations of Type IA

Minor variations of Type IA do not require prior examination by the competent authorities before they can be implemented by the holder. However, a notification of the minor variation of Type IA must be submitted simultaneously to all relevant authorities within 12 months of implementation.

Minor variations of Type IA requiring immediate notification in accordance with the Annex to these guidelines should, in contrast to the above, be submitted immediately after implementation to ensure the continuous supervision of the medicinal product.

2.1.1.1. Grouping

Pursuant to Articles 7(2) and 13d(2) of the Variations Regulation (‘grouping’), the holder may submit several minor variations of Type IA for the same marketing authorisation under a single notification. For purely national procedures, such a notification may also cover one or several identical minor variations of Type IA for several marketing authorisations granted in the same Member State.

Without acceptance from the relevant authorities, a grouping of minor variations of Type IA not requiring immediate notification (for one marketing authorisation only), regardless of the route of the marketing authorisation procedure, may be used only within the context of an annual update, as described below (see Section 2.1.1.3).

2.1.1.2. Super-grouping

In addition to the above, under Article 7a of the Variations Regulation, a group of minor variations of Type IA may be submitted in a single notification for several marketing authorisations owned by the same holder, provided that the variations notified are identical for all marketing authorisations concerned (‘super-grouping’). Super-grouping is possible in the following cases:

— One or several minor variations of Type IA listed in chapters E and Q of the Annex to these guidelines notified at the same time for several marketing authorisations granted in accordance with the mutual recognition, decentralised or purely national procedure in several Member States.

— One or several minor variations of Type IA notified at the same time for several marketing authorisations granted in accordance with the mutual recognition or decentralised procedure and the reference Member State is the same for those procedures.

— One or several minor variations of Type IA notified at the same time for several marketing authorisations granted in accordance with the centralised procedure.

— One or several variations of Type IA notified at the same time for several marketing authorisations granted in accordance with the mutual recognition, decentralised or purely national procedure in several Member States provided that the reference authority, in consultation with the concerned authorities, agrees to the proposed super-grouping.

As experience is acquired over time, additional cases may be identified in the future, in which case appropriate operational guidance will be provided on the Agency and CMDh websites accordingly.

2.1.1.3. Annual update of minor variations of Type IA not requiring immediate notification

Minor variations of Type IA not requiring immediate notification shall be collected and submitted as (i) an annual update, (ii) part of a grouping, together with variations of other types (as described in Section 2.2.1 and 2.3.1 of the guideline) or (iii) part of a super-grouping (as described above in Section 2.1.1.2). In the case of more than one minor variation of Type IA the annual update must meet the conditions for grouping or super-grouping, as specified above.

By way of an exception, individual submissions of one or several minor variations of Type IA may be accepted by the relevant authority, taking into account the cases listed on the Agency and CMDh websites.

2.1.2. Minor variations of Type IA review under the mutual recognition and purely national procedures

The reference Member State or the competent authority of a Member State, reviews the minor variation of Type IA within 30 days of receipt.

By day 30, the reference Member State or the competent authority of a Member State informs the holder and, where applicable, the concerned Member States, of the outcome of that review. Where the marketing authorisation requires any amendment to the decision granting said marketing authorisation, all Member States concerned shall amend the decision granting the marketing authorisation in accordance with the accepted variation within six (6) months of receiving the outcome of the review, 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 a single notification, the holder is informed which variations have been accepted or rejected following the review. The marketing authorisation holder must cease to implement any rejected variation.

2.1.3. Minor variations of Type IA review under the centralised procedure

The Agency reviews the minor variation of Type IA within 30 days of receipt, and the Agency provides the rapporteur with a copy of the minor variation of Type IA for information purposes only.

By day 30, the Agency informs 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 informs the Commission and sends the revised documentation. In such cases, the Commission amends the decision granting the marketing authorisation within 12 months.

Where one or several minor variations of Type IA are submitted as part of a single notification, the Agency clearly informs the holder which variations have been accepted or rejected following its review. The marketing authorisation holder must cease to implement any rejected variation.

2.2. Minor variations of Type IB

This section provides guidance 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. After confirmation of a valid notification, and the notification of the start of the procedure, the holder must wait for 30 days before implementing the change to ensure that the notification is deemed acceptable by the relevant authorities.

2.2.1. Submission of minor variations of Type IB

Notifications of minor variations of Type IB must be submitted by the holder simultaneously to all relevant authorities.

2.2.1.1. Grouping

Holders may group under a single notification the submission of several minor variations of Type IB regarding the same marketing authorisation, or alternatively, group the submission of one or more minor variations 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 where this has been previously agreed with the reference Member State, the national competent authority or the Agency as appropriate.

In the case of 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 variations 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) that the competent authority has previously agreed to the grouping.

2.2.1.2. Worksharing

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 must submit these variations as a single application for worksharing (see Section 3 on worksharing). If a submission has been made as one or several variations but not including all affected marketing authorisations owned by the same holder in a single application as ‘worksharing’, the holder shall amend their application.

2.2.2. Variations of Type IB review under the mutual recognition and purely national procedures

Notifications of a minor variation of Type IB notification shall be handled as follows:

Within seven (7) days, the reference Member State or the national competent authority, as applicable, checks whether the proposed change can be considered a minor variation of Type IB and whether the notification is valid (‘validation’) before the start of the procedure.

Where the proposed variation is not considered or classified as a minor variation of Type IB in accordance with the Annex to these guidelines (including any updated electronic version of these guidelines), or in a recommendation pursuant to Article 5 of the Variations Regulation, and the reference Member State or the national competent authority, as applicable, is of the opinion that it may have a significant impact on the quality, safety or efficacy of the medicinal product, the holder and the concerned Member States, where applicable, shall be informed immediately. In such cases, the holder is asked to amend their application and to complete it in accordance with the requirements for a major variation of Type II. Once the valid revised variation application has been received, a major variation of Type II assessment procedure is initiated (see Section 2.3.2).

Where the reference Member State or the national competent authority as applicable, is of the opinion that the proposed variation can be considered a minor variation of Type IB, the holder is informed of the outcome of the validation and notified of the start of the procedure.

Within 30 days of the acknowledgement of receipt of a valid notification and the notification of the start of the procedure, the competent authority notifies the holder of the outcome of the procedure. If the competent authority has not notified the holder of the outcome of the procedure within 30 days of the start of the procedure, the notification is deemed to have been accepted.

In the event of an unfavourable outcome, the holder may be asked to amend the notification within 30 days to take account of the grounds for that outcome. If the holder does not do so, the variation is deemed to have been rejected.

Within 30 days of receipt of the amended notification, the reference Member State or the national competent authority, as applicable, informs the holder of acceptance or rejection of the variation, including the grounds for the unfavourable outcome. Where applicable, the concerned Member States are informed of this.

Where a group of minor variations has been submitted as part of a single notification, the reference Member State or the national competent authority, as applicable, informs the holder and the concerned Member States as to which variations have been accepted or rejected. The holder may withdraw single variations from that group of variations during the procedure before the reference Member State or the national competent authority has finalised the review.

Where necessary, the relevant authorities will amend the marketing authorisation within six (6) months of the closure of the procedure. However, the accepted minor variations of Type IB may be implemented without waiting for the marketing authorisation to be amended.

2.2.3. Minor variations of Type IB review under the centralised procedure

The Agency handles notifications of a minor variation of Type IB as follows:

Within seven (7) days, the Agency checks whether the proposed change can be considered a minor variation of Type IB and whether the notification is valid (‘validation’) before the start of the procedure.

Where the proposed variation is not considered or classified as a minor variation of Type IB in accordance with the Annex to these guidelines (including any updated electronic version of these guidelines), or 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 is informed of the unfavourable outcome. In such cases, the holder is asked to amend their application and to complete it in accordance with the requirements for a major variation of Type II. Once the valid revised variation application has been received, a major variation of Type II assessment procedure is initiated (see Section 2.3.5).

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

The rapporteur is involved in assessing the notification of the minor variation of Type IB.

Within 30 days of the acknowledgement of receipt of a valid notification and the notification of the start of the procedure, the Agency notifies the holder of the outcome. If the Agency has not notified the holder of the outcome of the procedure within 30 days of the start of the procedure, the notification is deemed to have been accepted.

In the event of an unfavourable outcome, the holder may be asked to amend the notification within 30 days and to take due account of the grounds for the unfavourable outcome. If the holder does not amend the notification within 30 days as requested, the notification is rejected.

Within 30 days of receipt of the amended notification, the Agency informs the holder whether the variation has been accepted or rejected, including the grounds for an unfavourable outcome.

Where a group of minor variations is submitted as part of a single notification, the Agency informs the holder which variations have been accepted or rejected. The holder may withdraw single variations from the group of variations during the procedure before the Agency has finalised its assessment.

Where the opinion of the Agency is favourable and the variation affects the terms of the Commission decision granting the marketing authorisation, the Agency notifies the Commission and sends the relevant documentation. Where necessary, the Commission amends the marketing authorisation within 12 months. However, the accepted minor variation of Type IB may be implemented without waiting for the amendment of the Commission decision granting the marketing authorisation. The agreed variations are included in the annexes to any ongoing or subsequent regulatory procedure triggering the need to issue a Commission decision.

2.3. Major variations of Type II

This section provides guidance 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 by the relevant authorities before implementation.

2.3.1. Submission of major variations of Type II

Applications for major variations of Type II must be submitted by the holder simultaneously to all relevant authorities.

2.3.1.1. Grouping

Holders may group under a single application the submission of several major variations of Type II regarding the same marketing authorisation, or alternatively, group the submission of one or more major variations 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 where this has been agreed previously with the reference Member State, the national competent authority or the Agency, as appropriate.

In the case of 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 variations 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) that competent authority has previously agreed to the grouping.

2.3.1.2. Worksharing

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 must submit these variations as a single application for worksharing (see Section 3 on ‘worksharing’). If a submission has been made as one or several variations but not including all affected marketing authorisations owned by the same holder in a single application as worksharing, the holder shall amend their application.

2.3.2. Major variations of Type II assessment under the mutual recognition and purely national procedures

Upon receiving a variation of Type II application, the application is handled as follows:

Before the start of the procedure the reference Member State or the national competent authority, as applicable, acknowledges receipt of a valid application of a major variation of Type II. The holder and the concerned Member States, where applicable, are informed of the timetable also before the start of the procedure.

In the case of the mutual recognition procedure, the reference Member State draws up a draft assessment report and a decision on the application in accordance with the timetable provided. These are then circulated to the holder, for information, and to concerned Member States, which send their comments to the reference Member State within the deadlines set out in the timetable.

During the procedure, the reference Member State or national competent authority, as applicable, may ask the holder to provide additional information, in which case the procedure is suspended until the information has been received.

2.3.3. Outcome of variation of Type II assessment under the mutual recognition procedure

After receiving the holder’s response, the reference Member State finalises the draft assessment report and the decision on the application and circulates to the concerned Member States for comments and to the holder for information.

Within 30 days of receiving the assessment report and the decision, the concerned Member States acknowledge the decision and inform the reference Member State accordingly, unless a potential serious risk to public health is identified that prevents a concerned Member State from so doing. The Member State in question must inform the reference Member State within 30 days, and give detailed grounds for its position.

The reference Member State then refers the application to the coordination group for the application of Article 29(3), (4), and (5) of Directive 2001/83/EC to the points of disagreement and informs the holder and the concerned Member States accordingly. The holder is not entitled to initiate a referral.

Where an application concerning a grouping of variations that includes at least a major variation of Type II is referred to the coordination group, the decision on the variations not subject to the referral are suspended until the referral procedure has been completed. This also applies to referrals to the Committee for Medicinal Products for Human Use (‘the Committee’) under Articles 32 to 34 of Directive 2001/83/EC. However, only variations on which a potential serious risk to human health has been identified – i.e. not the whole group of variations – are discussed by the coordination group and where applicable by the Committee.

The reference Member State informs the holder and the concerned Member States of the acceptance or rejection of the variation, including the grounds for an unfavourable outcome.

Where several major variations of Type II, or a group of major variations of Type II with other minor variations have been submitted as a single application, the reference Member State informs the holders and the concerned Member States which variations have been accepted or rejected. The holder may withdraw single variations from the group of variations during the procedure before the reference Member State has finalised the procedure.

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

Once the variations have been accepted, within two months the competent authorities of the Member States concerned shall, where necessary, amend the marketing authorisation to reflect the variations, provided that the documents necessary for the amendment of the marketing authorisation have been submitted to the Member States concerned.

Variations relating to safety issues must be implemented immediately.

2.3.4. Outcome of major variation of Type II assessment under the purely national procedure

After receiving the holder’s response, the national competent authority finalises its decision on the application and informs the holder as to whether the variation has been accepted or rejected, including the grounds for an unfavourable outcome.

Where several major variations of Type II, or a group of major variations of Type II with other minor variations, have been submitted as a single application, the national competent authority informs the holder which variations have been accepted or rejected. The holder may withdraw single variations from the group of variations during the procedure before the national competent authority has finalised its assessment.

After it has accepted the variation, within two months the competent authority of the Member State, where necessary, amends the marketing authorisation to reflect the variation, provided that it has received the documents necessary for the amendment of the marketing authorisation.

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

Variations relating to safety issues must be implemented immediately.

2.3.5. Major variation of Type II assessment under the centralised procedure

Upon receiving a variation of Type II, the Agency handles the application as follows:

The Agency acknowledges receipt of a valid application of a major variation of Type II before the start of the procedure. The holder is informed of the timetable at the start of the procedure.

The Agency draws up an assessment report and an opinion on the application. During the procedure, the Agency may ask the holder to provide additional information, in which case the procedure is suspended until the information has been received.

The timelines for the Committee to assess responses depends on the complexity and amount of data to be provided to the holder. The timetable for assessment can be found on the Agency’s website.

An oral explanation may be held at the request of the Committee or the holder, where appropriate.

2.3.6. Outcome of major variation of Type II assessment under the centralised procedure

Once an opinion has been adopted, the Agency informs the holder within 15 days as to whether the opinion is favourable or unfavourable, including the grounds for an unfavourable opinion.

Where several major variations of Type II, or a group of major variations of Type II with other minor variations have been submitted as a single application, the Agency issues an opinion on the outcome of the procedure. That opinion includes a list of any variations not considered acceptable. The holder may withdraw single variations from the group of variations during the procedure before the Agency has adopted the opinion.

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

Where the opinion of the Agency is favourable and the variation affects the terms of the Commission decision granting the marketing authorisation, the Agency notifies the Commission of its opinion and the grounds for that opinion, and sends the necessary documents to amend the marketing authorisation.

Upon receiving the opinion and the relevant information, regarding the cases set out in Article 23(1a) of the Variations Regulation, the Commission amends the marketing authorisation within two months.

In the case of other variations, the Commission amends the decision granting the marketing authorisation within 12 months.

An accepted major variation of Type II requiring an amendment to the Commission decision granting the marketing authorisation within two months may only be implemented once the holder has been informed of the Commission decision. Where the amendment of the decision granting the marketing authorisation is not required within two months, or where the accepted variation does not affect the terms of that decision, the variation 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 immediately.

2.4. Extensions

Annex I of the Variations Regulation sets out a list of changes to be considered as extensions. Under Article 19 of the Variations Regulation, such applications are evaluated in accordance with the same procedure for granting the initial marketing authorisation to which they refer. The extension may either be granted as a new marketing authorisation or included in the initial marketing authorisation to which it refers.

Extension applications must be submitted by the holder simultaneously to all relevant authorities.

Holders may group under a single application the submission of several extensions, or alternatively, group 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 where this has been agreed previously with the reference Member State, the national competent authority or the Agency, as applicable. No worksharing of extension applications is foreseen in the Variations Regulation.

2.5. Annual update on human influenza and human coronavirus vaccines

This section provides guidance on the application of Articles 12, 13f and 18 of the Variations Regulation to the annual update on human influenza vaccines.

A special ‘fast track’ variation procedure is available to deal with the annual change in active substances for the annual update of a human influenza vaccine and with a view to meeting the EU recommendation for human influenza virus strains vaccine composition for the coming season.

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

The ‘fast track’ procedure consists of two steps: the first is to assess the administrative and quality data elements, such as the summary of product characteristics, labelling and package leaflet, and the chemical, pharmaceutical, and biological documentation; the second is to evaluate any additional data.

Holders are advised to discuss annual update submissions in advance with the reference Member State, the national competent authority or the Agency, as appropriate.

Where relevant, an annual update procedure for human coronavirus vaccines will be laid down by the Agency. That procedure applies after an announcement published on the Agency’s website. The announcement shall also mention the details of the procedure, including the timeframe for application.

Human influenza and coronavirus vaccines may be updated outside the annual procedure. In such cases, the relevant authority shall be contacted in advance to discuss this course of action, the data package (including Module 3 structure and content) and the timetable.

Furthermore, Article 21 of the Variations Regulation provides for a special urgent procedure for human influenza or human coronavirus pandemics, as recognised by the Commission, pursuant to Regulation (EU) 2022/2371 of the European Parliament and of the Council (¹²) (please see Section 2.6).

2.5.1. Submission of variation applications for an annual update of human influenza vaccines

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.

2.5.2. Variations assessment for an annual update of human influenza vaccines under the mutual recognition procedure

The reference Member State handles applications for an annual update as follows:

The reference Member State acknowledges receipt of a valid application within seven (7) days and informs the holder and the Member States concerned of the start of the procedure.

The reference Member State prepares an assessment report and a decision on the application, considering first the administrative and quality data. The reference Member State must send the assessment and the draft decision within 45 days, as laid down in the Variations Regulation. Accordingly, in order to allow for sufficient time for the assessment of additional data (such as clinical and stability data) – the reference Member State is expected to conclude its assessment of the administrative and quality data within 30 days of receiving a valid application.

The reference Member State may ask the holder to provide additional information, such as clinical or stability data, in which case it informs the concerned Member States. When a request for additional information is sent to the holder, the procedure is suspended until the requested information has been received.

The reference Member State then sends its assessment report and draft decision to the concerned Member States. Within 12 days of receipt, the concerned Member States adopt a decision and inform the holder and the reference Member State of that decision.

2.5.3. Variations assessment for an annual update of human influenza vaccines under the purely national procedure

The national competent authority handles applications for an annual variation of human influenza vaccines as follows:

The national competent authority acknowledges receipt of a valid application of an annual variation human influenza vaccine and informs the holder.

During the evaluation period, the national competent authority may ask the holder to provide additional information, such as clinical or stability data, in which case the procedure is suspended until the requested information has been received.

Within 45 days of receiving a valid application, the national competent authority finalises the evaluation, including its decision on the application, and informs the holder as to whether the variation has been accepted or rejected, including the grounds for an unfavourable outcome.

2.5.4. Variations assessment for an annual update of human influenza and human coronavirus vaccines under the centralised procedure

The Agency handles applications for an application for an annual update of human influenza vaccines as follows:

The Agency acknowledges receipt of a valid application of an annual variation human influenza vaccine within seven days and informs the holder of the start of the procedure.

The Agency has up to 55 days, from the start of the procedure, to assess the application. It draws up an assessment report and an opinion on the application. The Agency may ask the holder to provide additional information, such as clinical or stability data, in which case the procedure is suspended until the requested information has been received.

Where necessary, based on the Agency’s opinion, the Commission may amend the decision granting the marketing authorisation.

That procedure may be implemented in the case of a human coronavirus vaccine once an announcement has been published on the Agency’s website. The announcement includes the details of the procedure, including the timetable for application. In the absence of such a dedicated procedure, any update of a human coronavirus vaccine should be processed in accordance with Section 2.6 below.

2.6. Human vaccines to address a potential or recognised public health emergency in the Union

Under Annexes I and II to the Variations Regulation, updates may be made to the active substance of authorised human influenza vaccines, coronavirus vaccines or any other human vaccine that has the potential to address a public health emergency in the European Union.

As reflected in Annex II, such changes are classified as major variations of Type II.

Holders are advised to discuss the submission of such variations in advance with the Agency or, as applicable, the reference Member State or the national competent authority, in order to consider the appropriateness of the change to the active substance, taking into account (i) the epidemiological situation, (ii) the level of urgency, (iii) the data package including Module 3 structure and (iv) the timelines.

Any other variation to authorised human influenza vaccines, coronavirus vaccines or any other human vaccine that has the potential to address a public health emergency in the Union, that is not directly linked to the changes to the active substance follows the relevant variation procedures set out in other sections of the present guidelines. For coronavirus vaccines or any other human vaccine that has the potential to address a public health emergency in the Union, it may be permissible to add the active substance under the same marketing authorisation, subject to the agreement of the relevant authorities. This may lead to the co-existence of different versions of the vaccine (e.g. different serotypes, strains, antigens or coding sequences or combination of serotypes, strains, antigens, or coding sequences).

In order to ensure the appropriate differentiation of the different versions of the vaccine, and to facilitate traceability and pharmacovigilance monitoring, holders shall include qualifiers or abbreviations in the invented name. Furthermore, in the case of the above-mentioned co-existence, differentiation in the packaging of the different versions of the vaccine will be of paramount importance.

Under Article 21 of the Variations Regulation, during a public health emergency recognised by the Commission pursuant to Regulation (EU) 2022/2371, where certain pharmaceutical, non-clinical or clinical data are missing, the relevant authority may – by way of an exception and for a limited time – accept a variation to the terms of a marketing authorisation for a human vaccine pertaining to the pathogen causing the public health emergency.

2.7. Urgent Safety Restrictions

Under Article 22 of the Variations Regulation in the event of a risk to public health in the case of medicinal products, the holder may take provisional ‘urgent safety restrictions’.

This means interim changes being made to the terms of the marketing authorisation due to new information that has a bearing on the safe use of the medicinal product. These urgent changes must subsequently be introduced via a corresponding variation in the marketing authorisation.

The holder must immediately notify all relevant authorities of the restrictions to be introduced.

If no objections have been raised by the relevant authority within 24 hours of receiving that information, the urgent safety restrictions are deemed to have been accepted. They must be implemented within a timeframe agreed between the reference Member State, the national competent authority or the Agency, and the holder.

Urgent safety restrictions may also be imposed by the Commission in relation to centrally authorised medicinal products or by the relevant authorities of the Member States in the event of a risk to public health related to medicinal products.

The corresponding variation application concerning the urgent safety restrictions, whether requested by the holder or imposed by the Commission or the relevant authorities of the Member States, must be submitted to all relevant authorities by the holder as soon as possible, within 15 days.

2.8. 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 (¹³) (‘the Paediatric Regulation’) provides for rewards upon receipt of the statement of compliance in case of the completion of a paediatric investigation plan and the inclusion of the results of the studies in the product information:

— Under Article 36(1) of the Paediatric Regulation, the holder of a supplementary protection certificate is entitled to a six-month extension of the period referred to in Regulation (EC) No 469/2009 of the European Parliament and of the Council (¹⁴) 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 the Paediatric Regulation, 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 of the European Parliament and of the Council (¹⁵) to 12 years under certain conditions, including the addition of the compliance statement to the marketing authorisation.

Where a medicinal product has been authorised, Article 23a of the Variations Regulation provides for a procedure to add a compliance statement to the marketing authorisation once the requirements provided in the Paediatric Regulation have been met. The compliance statement should be included in a relevant variation, e.g. submission of the results of PIP studies, following the PIP completion, to the relevant authority. Once it has been verified that all relevant conditions have been 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 provides the holder with confirmation that the compliance statement has been included in the technical dossier within 30 days of the conclusion of the relevant assessment.

3. PROCEDURAL GUIDANCE ON WORKSHARING

Under Article 20 of the Variations Regulation, holders are required to submit in a single application the same minor variation of Type IB, the same major variation of Type II, or the same group of variations corresponding to one of the cases listed in Annex III of the Variations Regulation or agreed with the reference Member State, the national competent authority or the Agency (as appropriate) which does not contain any extension, affecting several marketing authorisations in more than one Member State and owned by the same holder, granted via the national, mutual recognition, decentralised or centralised procedures, in any combination.

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’) examines the variation on behalf of the other concerned authorities. Where at least one centralised marketing authorisation is concerned, the reference authority will be the Agency. If no centralised marketing authorisation is involved in worksharing, the reference authority is chosen by the holder. If none of the competent authorities proposed by the holder agrees to act as reference authority, the coordination group chooses the reference authority.

In order to use a worksharing procedure, the same change shall apply to the different medicinal products concerned with no or limited need for assessment of any potential product-specific impact. Therefore, where the ‘same’ change to different marketing authorisations requires the submission of individual supporting data for specific medicinal products concerned or separate product-specific assessment, such changes cannot benefit from worksharing.

Where justified and agreed by the competent authorities of the Member States and the Agency, as applicable, holders may also choose to follow the worksharing procedure set out in this section where a minor variation of Type IB or a major variation of Type II, or a group of variations where at least one of the variations is a minor variation of Type IB or a major variation of Type II, that does not contain any extension relates to several marketing authorisations owned by several holders in more than one Member State.

3.1. Submission of variation application under worksharing

A variation or group of variations presented for worksharing must be submitted in the manner set out in Section 2 above and as one integrated submission package covering all variations for all medicinal products.

Worksharing applications must be submitted to all relevant authorities.

Worksharing procedures shall comply with the assessment period of the highest type of variation included.

3.2. Worksharing assessment involving medicinal products other than those centrally authorised

Where an upcoming worksharing procedure does not affect any centralised marketing authorisation, the holder informs the competent authority of the Member State preferred as reference authority before submitting the worksharing application. The chosen authority confirms that it agrees to act as the reference authority to the holder. Under the third subparagraph of Article 20(3) of the Variations Regulation, the coordination group may assign another relevant authority to assist the reference authority, if requested. If none of the competent authorities proposed by the holder agrees to act as the reference authority, the reference authority is chosen by the coordination group.

Upon receiving a worksharing application, the reference authority handles the application as follows:

The reference authority acknowledges receipt of a valid application for worksharing. The holder and the Member States concerned are informed of the timetable at the start of the procedure.

The reference authority draws up a draft opinion according to that timetable and circulates it to the concerned Member States, and to the holder, for information. The concerned Member States then send their comments within the deadlines set out in the timetable.

As part of the procedure, the reference authority may ask the marketing authorisation holder to provide additional information, in which case the procedure is suspended until the information has been received.

3.3. Outcome of the worksharing assessment involving medicinal products other than those centrally authorised

Having received the holder’s responses to the request for additional information, the reference authority finalises its opinion on the application and informs the concerned Member States and the holder.

In the case of a favourable opinion, a list of variations that are not considered acceptable are attached to the opinion. In the case of an unfavourable outcome, the grounds for that outcome should be explained.

Where applicable, the concerned Member States acknowledge the opinion within 30 days of receiving it and inform the reference authority, unless a potential serious risk to public health is identified that prevents a Member State from recognising the opinion of the reference authority. In such cases, the Member State in question shall inform the reference authority and give a detailed statement of the reasons for its position within 30 days of receiving the opinion.

The reference authority then refers the application to the coordination group for applying Article 29(3), (4) and (5) of Directive 2001/83/EC to the in matters on which there is disagreement and informs the holder and the Member States concerned accordingly. The holder is not entitled to initiate such a referral.

Where a referral to the CMDh is made, the procedure concerning the decision on the worksharing application is suspended until a decision has been adopted on the referral procedure. This also applies to referrals to the Committee under Articles 32 to 34 of Directive 2001/83/EC.

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

A minor variation of Type IB accepted in a worksharing procedure may be implemented once the reference authority has issued a favourable opinion.

Major variations of Type II, including those containing grouped minor variations of Type IB, and accepted in 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 cases where the application has been the object of a referral, the variation must not be implemented until the referral procedure has concluded that the variation has been accepted.

3.4. Worksharing assessment involving centrally authorised medicinal products

When an upcoming worksharing procedure affects a centralised marketing authorisation, the holder informs the Agency before submitting the worksharing application.

Upon receiving a worksharing application that affects at least one centralised marketing authorisation, the Agency handles the application as follows:

The Agency acknowledges receipt of a valid worksharing application and starts the procedure immediately. The holder is informed of the adopted timetable at the start of the procedure.

The Agency appoints a rapporteur, and in some cases also a co-rapporteur, to lead the procedure.

During the procedure, the Agency may request additional information, in which case the procedure is suspended until this information has been received. An oral explanation may be held at the request of the relevant Committee or the marketing authorisation holder, where appropriate.

3.5. Outcome of the worksharing assessment involving centrally authorised medicinal products

By the end of the procedure, the Agency adopts an opinion on the application, including the assessment report. The Agency informs the holder and Member States concerned. In case of disagreement with the opinion, holders may request a re-examination thereof in accordance with the procedure set out in Article 9(2) of Regulation (EC) No 726/2004.

Where the Agency’s opinion is favourable and the variation affects the terms of the Commission decision granting the marketing authorisation, the Agency sends the Commission its opinion and the grounds for its opinion along with any necessary documents to amend the marketing authorisation.

If the Agency considers that some variations are not acceptable, the list of variations that are not considered acceptable should be attached to the opinion. Variations may be considered acceptable for some of the medicinal products in question.

Upon receiving a favourable opinion by the Member States concerned or the Commission, the following steps are taken:

— For medicinal products authorised under the mutual recognition procedure or decentralised or purely national procedures, the Member States concerned must approve the opinion 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 variations of Type IB, except those grouped with major variations of Type II, may be implemented upon receiving a favourable opinion from the Agency.

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

— For centrally authorised medicinal products, upon receipt of the opinion and the relevant information, the Commission amends the marketing authorisation within two months in the cases set out in Article 23(1a) of the Variations Regulation. In the case of other variations, the Commission amends the decision granting the marketing authorisation within 12 months.

Minor variations of Type IB, except those grouped with major variations of Type II, may be implemented upon receipt of a favourable opinion of the Agency.

Major variations of Type II, and minor variations of Type IB grouped with a major variation of Type II, except variations that require the adoption of a Commission decision within two months, may be implemented 30 days after receipt of a 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: E) Administrative changes; Q) Quality changes; C) Safety, Efficacy and Pharmacovigilance changes and M) Specific changes to Plasma Master Files and Vaccine Antigen Master Files.

Where reference is be made to specific variations in this Annex, the variation in question should be quoted using the applicable elements of 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. E, Q, C or M),

— 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:

— A list of variations which should be classified as minor variation of Type IA or major variation of Type II in accordance with the definitions of Article 2 and Annex II to the Variations Regulation. It also indicates which minor variations of Type IA require immediate notification pursuant to Articles 8(1), 13a(1) and 14(1) of the Variations Regulation.

— A list of variations to be considered as minor variation of Type IB. In accordance with Article 3 of the Variations Regulation, this category applies by default. Accordingly, this Annex does not claim to be an exhaustive list for this category of variations.

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

When one or more of the conditions laid down in this Annex for a minor variation of Type IA are not met, the concerned change may be submitted as a minor variation of Type IB (‘Type IB by default’) under the same code, 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 holder 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 major variation of Type II.

For the purpose of this Annex, ‘test procedure’ has the same meaning as ‘analytical procedure’; ‘limits’ has the same meaning as ‘acceptance criteria’; ‘specification attribute’ 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 attribute therefore includes its corresponding test method and limits.

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

As regards the data package, the relevant supporting data for minor variations of Type IB and major variations of Type II will depend on the specific nature of the change.

In the event of a change in the therapeutic indication, posology or maximum daily dose, the quality documentation should be reviewed. Any resulting change to the quality documentation, e.g. the need to change impurity limits, will require the submission of the appropriate quality variation under chapter Q of this Annex.

Furthermore, if a variation leads to a revision of the product information, this change is considered part of that variation. In such cases, updated product information must be submitted as part of the application, along with translations. Mock-ups or specimens should be provided to the Member States concerned, the national competent authority or the Agency, as applicable.

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

References in the Annex to monographs of the European Pharmacopoeia are only applicable to active substance or excipient monographs or general monographs, i.e. finished product monographs are exempted.

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.

Under Part III, point 1 of Annex I to Directive 2001/83/EC, changes to Plasma Master Files (PMFs) and Vaccine Antigen Master Files (VAMFs) follow the evaluation procedures for variations set out in the Variations Regulation. Chapter M of this Annex provides a list of variations that are specific to such PMFs or VAMFs. Following a review of these variations, any marketing authorisation concerned must be updated in accordance with Chapter Q.V. of this Annex. In cases where 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 be handled in accordance with this Annex.

References in this Annex to changes to the marketing authorisation dossier mean addition, replacement or deletion, unless otherwise indicated. If amendments to the dossier are merely editorial changes, such changes should generally not be submitted as a separate variation. However, they may be included in a variation concerning that part of the dossier. In such cases, the changes should be clearly identified in the application form: editorial changes should be made along with a statement indicating that the content of the part of the dossier in question has not been changed by the editorial changes beyond the scope of the variation submitted. It should be noted that editorial changes include the removal of obsolete or redundant text but not the removal of specification attributes or manufacturing descriptions.

Additional information:

— Commission Regulation (EC) No 1234/2008

— EMA Procedural Guidance on Variations

— CMDh Procedural Guidance on Variations

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(¹)  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 (OJ L 334, 12.12.2008, p. 7, ELI: http://data.europa.eu/eli/reg/2008/1234/oj).

(²)  Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human use and establishing a European Medicines Agency (OJ L 136, 30.4.2004, p. 1, ELI: http://data.europa.eu/eli/reg/2004/726/oj).

(³)  Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (OJ L 311, 28.11.2001, p. 67, ELI: http://data.europa.eu/eli/dir/2001/83/oj).

(⁴)  Commission Delegated Regulation (EU) 2021/756 of 24 March 2021 amending Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products (OJ L 162, 10.5.2021, p. 1, ELI: http://data.europa.eu/eli/reg_del/2021/756/oj).

(⁵)  Commission Delegated Regulation (EU) 2024/1701 of 11 March 2024 amending Regulation (EC) No 1234/2008 as regards the examination of variations to the terms of marketing authorisations for medicinal products for human use (OJ L, 2024/1701, 17.6.2024, ELI: http://data.europa.eu/eli/reg_del/2024/1701/oj).

(⁶)   OJ C 223, 2.8.2013, p. 1.

(⁷)  Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (OJ L 324, 10.12.2007, p. 121, ELI: http://data.europa.eu/eli/reg/2007/1394/oj).

(⁸)   https://esubmission.ema.europa.eu/ectd/index.html.

(⁹)  EudraLex – Volume 2 – Pharmaceutical legislation on notice to applicants and regulatory guidelines for medicinal products for human use (https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-2_en).

(¹⁰)   https://health.ec.europa.eu/system/files/2019-07/vol2a_chap1_en_0.pdf.

(¹¹)  The coordination group as referred to in Article 31 of Directive 2001/83/EC is also referred to as Co-ordination Group for Mutual Recognition and Decentralised procedures – Human (CMDh).

(¹²)  Regulation (EU) 2022/2371 of the European Parliament and of the Council of 23 November 2022 on serious cross-border threats to health and repealing Decision No 1082/2013/EU (OJ L 314, 6.12.2022, p. 26, ELI: http://data.europa.eu/eli/reg/2022/2371/oj).

(¹³)  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 (OJ L 378 27.12.2006, p. 1, ELI: http://data.europa.eu/eli/reg/2006/1901/oj).

(¹⁴)  Regulation (EC) No 469/2009 of the European Parliament and of the Council of 6 May 2009 concerning the supplementary protection certificate for medicinal products (OJ L 152 16.6.2009, p. 1, ELI: http://data.europa.eu/eli/reg/2009/469/oj).

(¹⁵)  Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products (OJ L 18, 22.1.2000, p. 1, ELI: http://data.europa.eu/eli/reg/2000/141/oj).