Q&A: Worksharing of variations

Article 20 of the Variations Regulation sets out the possibility for a MAH to submit the same Type IB or Type II variation, or the same group of variations affecting more than one marketing authorisation from the same MAH, in one application.

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”¹.

Extensions are excluded from worksharing.

Based on Articles 7 and 20 of the Variations Regulation, when a group of variations only consists of Type IA/ IAIN variations affecting several marketing authorisations, this is considered as a “group” of variations and not a “worksharing” procedure. However, it is possible to include a group of Type IA/IAIN variations with a Type IB or Type II variation, which is submitted for a worksharing procedure. In such case, the review of the Type IA/IAIN variation will be performed as part of the worksharing procedure.

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

Where at least one of the concerned marketing authorisations has been authorised via the centralised procedure, the Agency will be the ‘reference authority’. 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.

References

• Commission Regulation (EC) No 1234/2008
• Commission Regulation (EU) No 712/2012 amending Regulation (EC) No 1234/2008
• Variations Guidelines (2013/C 223/01)

¹ See Commission Communication 98/C 229/03 OJ C 229, 22.7.1998, p. 4.

In order to benefit from a worksharing procedure, it is expected that the same changes will 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’ changes 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 benefit from worksharing.

Grouped variations can be subject to a worksharing procedure, provided that the same group of variations applies to all veterinary medicinal products concerned by the worksharing procedure.

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
• PSUR outcome implementation for MAs with same active substance

Quality

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

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 provide the following information:

• Types and scope of variations
• Overview of MAs concerned
• Confirmation that all MAs belong to the same MAH
• Explanation / justification for suitability of worksharing
• Rapporteurs and Reference Member States (RMS) 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 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 the application includes a new indication or (new) non-food-producing target animal species) 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 MAH will be informed accordingly.

A shorter pre-submission phase is envisaged in cases where:

• a proposed worksharing procedure relates to duplicate MAs for the ‘same’ medicinal product authorised via the centralised procedure only;
• the variations subject to the worksharing procedure concern the implementation of urgent safety-related changes;
• the variations subject to the worksharing procedure concern the implementation of changes requested by CVMP (e.g. following PSUR or PAM assessment).

Worksharing procedure for multiple centrally authorised veterinary medicinal products (‘duplicates’):

The submission of a formal letter of intent is not required. However, MAHs are advised to request a worksharing number from vet.applications@ema.europa.eu detailing the list of products, the intended submission date and the scope of variation they are planning to apply for (a draft cover letter is also accepted) at least two months in advance of the submission of the variation/group of variations. This is especially valid when the rapporteurs for each centrally authorised product are different and the CVMP will need to appoint one rapporteur for this specific worksharing procedure.

The submission requirements as set out in the post-authorisation guidance sections for the different types of variations 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 letterfor 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 a PSUR or post-authorisation measure e.g. condition, 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 commitment/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

• Variations Guidelines (2013/C 223/01)
• 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 veterinary procedural submissions 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 Member States (MSs), even if some products are not relevant to some MSs – 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.

References

• Dossier requirements for submission of MA and MRL applications to the EMA and to members of the CVMP  

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 for centralised and maximum-residue-limit procedures  published on the Agency’s website.

In general, variations submitted for worksharing will follow a 60-day evaluation timetable. This period may however be reduced to 30 days having regard to the urgency of the matter, particularly for safety issues, or may be extended to 90 days for Type II variations concerning changes or additions to the therapeutic indication and other variations listed in Part 2 of Annex V of the Variations Regulation. Implementation of agreed changes for which no new additional data are submitted by the MAH may also follow a 30 day timetable, provided that only centrally authorised veterinary medicinal products are part of the worksharing and this is agreed by the Agency.

For the detailed evaluation timetable, please refer to the Q&A on Type II variations 'How shall my Type II application be handled (timetable)'?

Upon finalisation of the review of the variations subject to the worksharing procedure, the CVMP will adopt an opinion reflecting the final outcome of the procedure. Such opinion will also list any variations (e.g. as part of a group, or for a specific medicinal product) which are not considered approvable, unless they had been withdrawn by the MAH during the procedure. The same general principles as for grouped variations apply,  see the Q&A on grouping of variations “What will be the outcome of the evaluation of a grouped variation application”?

Note:

The Annex A for each centrally authorised veterinary medicinal product included in the worksharing procedure will be annexed to the CVMP opinion.

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

References

• Template for Annex B
• Recommended submission dates for centralised and maximum-residue-limit procedures

Upon adoption of the CVMP 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), as well as whether the Commission decisions granting the Community marketing authorisations require any amendments.

Where the outcome of the procedure is favourable and the Commission decisions granting the marketing authorisations require amendments, the Agency will inform the Commission accordingly.

Re-examination

Article 34(2) of Regulation (EC) No 726/2004 also applies to CVMP opinions adopted for worksharing procedures. This means that the MAH may give written notice to the Agency/CVMP 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

Upon receipt of the final CVMP opinion that requires amendments to the decisions granting the marketing authorisations, the Commission shall amend the marketing authorisation for each centrally authorised veterinary medicinal product to reflect the approved variations within two months for the variations listed under Article 23(1a)(a), or within one year for other variations. A single 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 by Day +27. (See also: 'When do I have to submit revised product information? In all languages?').

The below timeline only applies in case of 2-monthly update.

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 where necessary, amend the national marketing authorisations within 60 days.

Implementation

Type IB variations approved via a worksharing procedure may be implemented upon receipt of the favourable CVMP opinion.

Type II variations listed in Article 23(1a)(a) may only be implemented once the Commission has amended the marketing authorisation and has notified the MAH accordingly.

Type II variations (including those which contain grouped Type IB variations) approved via a worksharing procedure, which do not require any amendment of the marketing authorisation or which follow a yearly update of the respective Commission decision can be implemented once the MAH has been informed of the favourable outcome by the Agency. However, it is expected that where the variation includes changes to the product information, the MAH waits for the finalisation of the linguistic review process by the Agency before implementing the variation, as appropriately checked translations are considered essential for a correct implementation of the variation.

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

Variations related to safety issues, including urgent safety restrictions, must be implemented within a timeframe agreed by the MAH and the Agency.

References

• Regulation (EC) No 726/2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency
• Commission Regulation (EC) No 1234/2008
• Commission Regulation (EU) No 712/2012 amending Regulation (EC) No 1234/2008
• Variations Guidelines (2013/C 223/01)
• Procedural guidance on re-examination of CVMP opinions .
• Linguistic review process of product information in the centralised procedure - veterinary

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 where the invoice should be sent to 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 (day 0)

• English language: 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):
  - 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)

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.

According to Article 23 of Regulation (EC) N° 1234/2008, Commission decisions on worksharing procedures will be adopted without a Standing Committee procedure. Consequently, there will be no further revision of the translations of the Annexes after Day +25.

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.

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.

Please note that if a worksharing procedure on a 30-day timetable (e.g. urgent safety variations) requires a linguistic review of the product information, this will take place in parallel with the scientific assessment.

For those variations which affect the Annex A (e.g. introduction of a new presentation), the following principles apply:

Upon adoption of the opinion, the Agency will prepare and send to the MAH the revised English Annex A for each CAP reflecting the new/amended presentation.

After CVMP opinion (day +5), the MAH provides the Agency with the electronic versions of the complete set of Annexes in all languages as well as the translations of the revised Annex A for each CAP as a separate Word and PDF document.

References

• The linguistic review process of product information in the centralised procedure – Veterinary
• Q&A: Type II variations