Worksharing of variations (veterinary medicines)

In order to avoid duplication of evaluation, Article 65 of the Regulation (EU) 2019/6 sets out the possibility for an MAH to submit in a single application one or more identical variations requiring assessment (VRA) affecting more than one marketing authorisation, which may be nationally or centrally authorised, from the same marketing authorisation holder¹. In this ‘worksharing procedure’, 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 act as the ‘reference authority’. In all other cases, a national competent authority chosen by the Coordination Group for Mutual Recognition and Decentralised Procedures – veterinary (CMDv), taking into account the recommendation of the MAH, will act as the ‘reference authority’.

Purely national marketing authorisations can be included in worksharing procedures.

Based on Articles 64 and 65 of the Regulation (EU) 2019/6, respectively, grouping or worksharing of variations is possible only for variations that do not appear in the list of variations not requiring assessment (VNRA) established in accordance with Article 60(1). Consequently, VNRA are excluded from grouping or worksharing, even when consequential or related to variations requiring assessment (VRA) included in the grouping or worksharing.

¹ Applicants belonging to the same mother company or group of companies and applicants having concluded agreements or exercising concerted practices concerning the placing on the market of the medicinal products concerned, have to be taken as the same marketing authorisation holder. 

References

• Regulation (EU) 2019/6 of the European Parliament and of the Council on veterinary medicinal products
• Commission Implementing Regulation (EU) 2021/17 establishing a list of variations not requiring assessment in accordance with Regulation (EU) 2019/6 of the European Parliament and of the Council
• EMA/CMDv Guidance on the details of the classification of variations requiring assessment according to Article 62 of Regulation (EU) 2019/6 for veterinary medicinal products and on the documentation to be submitted pursuant to those variations
• EMA/CMDv Procedural advice for requests for the classification of variations not already listed in Commission Implementing Regulation (EU) 2021/17 or EMA/CMDv Guidance on the details of the classification of variations requiring assessment according to Article 62 of Regulation (EU) 2019/6

In order to be eligible for the worksharing procedure, identical change(s) should apply to the different veterinary medicinal products concerned, with either no or very 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 sets for each veterinary medicinal product concerned which each require a separate product-specific assessment, such changes will not be able to benefit from the worksharing procedure.

At the start of a worksharing procedure the ‘present’ situation does not have to be identical for all MAs included in the WS application, as long as the variation application form reflects the same ‘proposed’ situation for all MAs involved.

Grouped VRA can be subject to a worksharing procedure, provided that the same group of variations requiring assessment applies to all veterinary medicinal products concerned by the worksharing procedure and the changes must be identical for all products. Please refer to Q&A on VRA for more information on groupings.  

Examples of changes which would be considered suitable for evaluation under worksharing:

Clinical / pharmacovigilance

• Implementation of class labelling
• Changes to multiple generic MAs containing the same active substance
• Changes to single-substance MA and fixed-combination MA containing the same active substance
• Proposal for combination use, affecting both MAs

Quality

• Changes to the active substance master file
• Update of the Certificate of European Pharmacopeia.
• Revision of test method for the active substance

References

• Q&A: VRA

In order to facilitate the planning of a worksharing procedure, MAHs are advised to inform the Agency at least two months in advance of the submission of a variation or group of variations to be subject to a worksharing procedure, together with an explanation as to why the MAH believes that a worksharing procedure is suitable, by means of a ‘letter of intent’.

The ‘letter of intent’ should include the following information:

• List of the products
• Scope of variation(s)
• Confirmation that all MAs belong to the same MAH
• Explanation / justification for suitability of worksharing
• Rapporteurs and the Reference Authority of the veterinary medicinal products concerned, if applicable
• Target submission date
• MAH contact person for the worksharing procedure

A template is available for a ' letter of intent '. The letter of intent should be sent to vet.applications@ema.europa.eu. If the proposed worksharing procedure includes nationally authorised medicinal products, the Agency will share the letter of intent with the CMDv.

Upon receipt of the letter of intent, the Agency will appoint a procedure coordinator and will decide whether the proposed worksharing procedure is acceptable. Subsequently, the Agency will initiate the appointment of a rapporteur for the procedure.

A rapporteur (and co-rapporteur, when applicable) will be appointed by the CVMP for the procedure. It is expected that the (co-)rapporteur will be one of the rapporteurs of the centrally authorised medicinal products or a CVMP member representing one of the RMSs for the nationally authorised products.

The submission requirements as set out in the post-authorisation Q&A for variations requiring assessment will also apply to variations subject to worksharing, but the application should be provided as one integrated submission package per product, covering all variations applied for.

This should include a cover letter and an application form, together with separate supportive documentation for each medicinal product concerned and revised product information (if applicable) for each medicinal product concerned.

• One cover letter addressed to the Agency and national competent authorities, if nationally authorised veterinary medicinal products are part of the worksharing procedure, clearly indicating that the application is submitted for a worksharing procedure, together with a short overview of all veterinary medicinal products concerned with their respective rapporteurs and RMSs, as well as an overview of the submission format for the different products, if applicable. If nationally authorised products are part of the worksharing procedure, the MAH should also include a confirmation that the worksharing applications have been submitted to all Member States where the products concerned are authorised and that the relevant national fees have been paid. A letter of authorisation for the MAH contact person for the worksharing procedure should be provided with the worksharing application.

If a variation is submitted because it has been requested as an outcome arising from another pre-/
post-authorisation procedure (including as a result of signal detection or a post-authorisation measure (PAM), e.g. (specific) obligation, recommendation), then this should be clearly mentioned in the cover letter for the resulting variation, identifying the related EMA procedure number from which the variation arose. In case the reference number for the PAM has not been confirmed by the Agency, a description of the measure is sufficient at time of submission (or contact vet.applications@ema.europa.eu to check for the PAM reference number).

• One completed EU variation application form, listing all medicinal products concerned and declaring all variations included in the group in the section ‘type of changes’, as well as a justification for the proposed worksharing (and grouping if applicable) in the ‘precise scope and background’ section of the application form. The response from the Agency on the acceptability of the worksharing application, further to the submission of the letter of intent, should be attached to the application form.
• If nationally authorised veterinary medicinal products are part of the worksharing procedure, relevant product and Member State details should be provided as annex B to the application form, using the template for annex B, clearly differentiating between national MAs authorised via MRP/DCP and purely-national MAs.
• Supporting documentation for each product (including the revised summary of product characteristics, labelling and package leaflet, if applicable). 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.
• Where the overall design and readability of the outer and immediate packaging and/or package leaflet is affected, the Agency may request the Applicant to provide specimens and mock-ups on a case-by-case basis.

For queries relating to the presentation of the application, please contact vet.applications@ema.europa.eu.

Reference

• EMA/CMDv Guidance on the details of the classification of variations requiring assessment according to Article 62 of Regulation (EU) 2019/6 for veterinary medicinal products and on the documentation to be submitted pursuant to those variations
• Electronic application forms website
• Template for Annex B

The worksharing application must be submitted at the same time to all relevant authorities, i.e. in case the application consists of centrally and nationally authorised veterinary medicinal products, to the Agency and all Member States where the products concerned are authorised.

Submission to the European Medicines Agency:

Applicants should use the eSubmission Gateway / Web Client for all variations requiring assessment (VRA) submitted to the Agency. The complete worksharing dossier should be submitted for each centrally authorised product included in the worksharing application.

For more information, including links to guidance on registration with the system see the Veterinary eSubmission website.

Submission to the National Competent Authorities:

Where nationally authorised medicinal products are part of the worksharing, the same application as submitted to the Agency should be submitted to all relevant Member States (MSs), i.e. all MS where the concerned marketing authorisations are authorised – the reference below on dossier requirements outlines the additional submission requirements for the national competent authorities in the case of worksharing procedures involving centrally- and nationally-authorised products. This will allow all involved parties (the Agency, MSs and CVMP members) to receive the full data for the worksharing application.

If amendments are requested by the Agency as a result of the validation, updated documentation should also be submitted to the MSs.

The dossier requirements mentioned in the references should be followed for worksharing applications.

Submission to the rapporteur and CVMP members:

All VNeeS submissions for centrally authorised products (CAP) sent to EMA via the eSubmission Gateway/Web Client will be considered delivered to all National Competent Authorities’ representatives, alternates and scientific experts.

The dossier requirements mentioned in the references should be followed for worksharing applications.

References

• Dossier requirements for submission of MA and MRL applications to the EMA and to members of the CVMP
• Veterinary eSubmission website
• eSubmission Gateway and Web Client information website

The Agency will allocate a ‘high-level’ cross-products procedure number, which will be used for the handling of worksharing procedures affecting more than one veterinary medicinal product. The procedure code “WS” is used for worksharing procedures. As the ‘high-level’ number cannot be allocated to one single product, the procedure number will therefore contain “xxxx” as a place-holder for the product number.

Example: EMEA/V/xxxx/WS/0003

For each veterinary medicinal product concerned by the worksharing procedure the following worksharing number (which includes a reference to the “WS” procedure to which it belongs) will be allocated:

Example: EMEA/V/C/prod_nb/WS0003 which was submitted as part of the 3rd worksharing procedure received by the Agency “WS/0003”

Worksharing applications for a group of variations will include the suffix “/G” e.g. EMEA/V/xxxx/WS/0004/G and EMEA/V/C/prod_nb/WS/0004/G.

For worksharing procedures, the ‘high-level’ procedure number can be obtained from the Agency before submission by sending your request with a copy of the draft cover letter to vet.applications@ema.europa.eu.

MAHs are reminded that Agency’s procedure numbers are allocated by the Agency upon receipt of the application, according to a sequential order for the product concerned which is independent from the type of regulatory procedure submitted. MAHs should therefore carefully consider which will be the next sequential procedure number for the product concerned, taking into account all other regulatory procedures which were submitted previously (or in parallel), and indicate the correct procedure number on the variation application form.

The MAH should submit the variation application for worksharing at the latest by the recommended submission dates published on the Agency’s website.

In general, variations submitted for worksharing will follow the timetable of the lead variation.

Where products nationally authorised are included in a worksharing variation application, the procedure will generally follow a 60 day timetable, unless the changes to be implemented concern urgent safety matters.

The Annex B includes information on the nationally authorised veterinary medicinal products included in the worksharing application, and it will be annexed to the CVMP opinion, if applicable. A template for Annex B is available on the Agency website.

References

• Recommended submission dates
• Template for Annex B

Upon adoption of the opinion on the worksharing procedure, the Agency will inform the MAH and the Member States concerned (if applicable) as to whether the opinion is favourable or unfavourable (including the grounds for the unfavourable outcome).

Where the outcome of the procedure is favourable the Agency will inform the Commission accordingly.

Re-examination

Article 66(10) and (11) of Regulation (EU) 2019/6 establishes that the MAH may give written notice to the Agency that it wishes to request a re-examination within 15 days of receipt of the opinion. MAHs should refer to the EMA website for further specific guidance on re-examination of CVMP opinions.  

Decision-making process for centrally authorised medicinal products

For all VRA procedures, upon receipt of the final CVMP Opinion and, where applicable, the complete translations of the product information, the Commission shall amend the marketing authorisation, for each centrally authorised veterinary medicinal product, to reflect the approved variations within 30 days. A decision will be issued for each centrally authorised veterinary medicinal product.

The Agency will apply the post-opinion timeframes set out in the document on the linguistic review process of product information in the centralised procedure. The linguistic review will be performed on one set of Annexes of one centrally authorised medicinal product. In case of comments, it will be up to the MAH to correctly implement the same amendments in the other centrally authorised products, as appropriate.

The Agency, in cooperation with the QRD members and the MAH, will aim at providing final, checked translations for all centrally authorised products included in the worksharing procedure to the Commission within 27 days after adoption of the opinion, i.e. by Day +27. (See also: “When do I have to submit revised product information? In all languages?”).

MA updating process for nationally authorised medicinal products (if applicable)

Upon receipt of the final opinion, the Member States concerned shall approve the final opinion, inform the Agency accordingly and amend the national marketing authorisations.

The outcome of the procedures will be handled by Member States as normal variations as described in the CMDv BPG for Variation Requiring Assessment.

Implementation

VRA may only be implemented once the Commission has amended the marketing authorisation. The time limit for the implementation of VRA is set by the Commission and MAH will be notified accordingly.

The agreed changes should be included in the product information annexes of any subsequent regulatory procedure.

References

• Procedural advice to applicants/marketing authorisation holders on re-examination of CVMP opinions
• The linguistic review process of product information in the centralised procedure – veterinary (currently under review, link will be provided once available)
• CMDv BPG for Variation Requiring Assessment

For information on the fees applicable for worksharing applications, please refer to fees payable to the European Medicines Agency.

Where a worksharing application is considered ‘invalid’ (i.e. an assessment process cannot be started), an administrative fee may be charged by the Agency.

Only the worksharing applicant will be invoiced for the worksharing procedure. The details of the applicant to which the invoice should be sent should be clearly stated in the cover letter.

References

• Fees payable to the European Medicines Agency
• How to pay

If the variations subject to worksharing affect the SPC, labelling or package leaflet, the revised product information annexes must be submitted as follows:

• At submission

-    English language: a complete set of Annexes for all CAPs electronically only in Word format (highlighted)

• After CVMP opinion (day +5)

-    All EU languages (incl. Norwegian and Icelandic, and from 1 January 2022 onwards Irish for MAHs established in Ireland that have not submitted an Irish language derogation):
- if a linguistic review will be performed: complete set of annexes of one CAP electronically only in Word format (highlighted)
- if a linguistic review will not be performed: complete set of annexes for all CAPs
electronically only in Word format (highlighted) and in PDF (clean)

• After linguistic check (day +25)

-  All EU languages (incl. Norwegian and Icelandic): complete set of annexes for all CAPs electronically only in Word format (highlighted) and in PDF (clean bookmarked)

Only one centrally authorised medicinal product will undergo a linguistic check. In the cases where the changes to the product information may vary between products, the product with the most complex changes will generally be the one subject to linguistic check.

Overview in case of linguistic review:

* = complete set of Annexes i.e. Annex I, II, IIIA and IIIB submitted as one document per language

The ‘complete set of Annexes’ includes Annex I, II, IIIA and IIIB i.e. all SPC, labelling and package leaflet texts for all strengths and pharmaceutical forms of the product concerned, as well as Annex II. The complete set of Annexes must be presented sequentially (i.e. Annex I, II, IIIA, IIIB) as one document for each official EU language. Page numbering should start with "1" (bottom, centre) on the title page of Annex I. All Annexes should be in compliance with the ‘QRD Convention’ published on the Agency website. When submitting the full set of Annexes in PDF format, the formatting checklist and the user guide on how to generate PDF versions of the product information should be followed.

Highlighted changes should be indicated via ‘Tools – Track changes’. Clean versions should have all changes ‘accepted’.

Icelandic and Norwegian language versions must always be included. From 1 January 2022 onwards an Irish language version must be included for MAHs established in Ireland that have not submitted an Irish language derogation.

The Annexes provided should only reflect the changes introduced by the variations concerned. However, in exceptional cases where MAHs take the opportunity to introduce minor linguistic amendments in the texts or to align the product information with the latest QRD template, this should be clearly mentioned in the cover letter and in the precise scope section of the application form. In addition, the section “present/proposed” in the application form should clearly list the minor linguistic amendments introduced for each language. Alternatively, such listing may be provided as a separate annex to the application form. Any changes not listed will not be considered as part of the variation application. In such cases, and in cases where any other ongoing procedures may affect the product information Annexes, the MAH is advised to contact the Agency in advance of submission or finalisation of the procedures concerned.

References

• Product information: Reference documents and guidelines
• Formatting checklist (currently under review, link will be provided once available)
• The linguistic review process of product information in the centralised procedure - veterinary (currently under review, link will be provided once available)
• Q&As on VRA
• User guide on how to generate PDF versions of the product information - veterinary (currently under review, link will be provided once available)