Q&A: Worksharing of variations

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Once a veterinary product has received approval from the Commission (the “Commission Decision”) all further procedures connected with the product will fall under “Post-Authorisation Procedures”.

This guidance provides an overview for a number of procedures that occur frequently and addresses a number of questions which Marketing Authorisation Holders (MAHs) may have.

More information on this post-authorisation procedural advice Q&A.

As of 1 January 2017 it is mandatory for applicants to use the eSubmission Gateway / Web Client for all veterinary procedural submissions to the Agency. For more information, including links to guidance on registration with the system, see:

Additional information

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1. What is worksharing and what types of variations can be subject to worksharing? Rev. July 215

Article 20 of Commission Regulation (EC) N° 1234/2008 (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 product(s) 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 Variation(s) 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, taking into account the recommendation of the holder, will act as the ‘reference authority’.

References

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

2. What variation(s) would be considered acceptable for worksharing?

In order to benefit from a worksharing procedure, it is expected that the same change(s) will apply to the different medicinal products concerned, with either no or limited need for assessment of a potential product-specific impact. Therefore, where the ‘same’ change(s) to different marketing authorisations require the submission of individual supportive data sets for each 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 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 ASMF
  • Update of CEP certificate
  • Revision of test method for the active substance

Additional examples will be regularly included in this document, to reflect accumulated experience

3. What pre-submission steps will apply to a worksharing procedure?

In order to facilitate the planning of a worksharing procedure, MAHs are advised to inform the Agency at least 3 months in advance of the submission of a variation/group of variations to be subject to a worksharing procedure, together with an explanation as to why the holder believes that a worksharing procedure is suitable, by means of a ‘letter of intent’.

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

  • Type(s) and scope of variation(s)
  • Overview of MAs concerned
  • Explanation that all MAs belong to the same MAH
  • Explanation / justification for suitability of worksharing
  • Rapporteurs and Reference Member States (RMS) of the medicinal products concerned, if applicable
  • MAH target submission date
  • MAH contact person for the worksharing procedure

A template for such a ‘letter of intent’ is available on the Agency’s website. The letter should be sent to vet.applications@ema.europa.eu. The Agency will share the letter of intent with the CMDv group, in case the proposed worksharing procedure includes nationally authorised medicinal products.

Upon receipt of the letter of intent, the Agency will appoint a coordinating project manager and will decide whether the proposed worksharing procedure is acceptable. Subsequently, the Agency will initiate the Rapporteur appointment procedure.

Following an ‘Expression of Interest’ and based on a rota system, the CVMP Chairman will appoint a Rapporteur (and Co-Rapporteur when the application includes a new indication or (new) non-food-producing target animal species) 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 multiple 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 FUM assessment).

Worksharing procedure for multiple centrally authorised medicinal products (‘duplicates’):
The submission of a formal letter of intent is not required. Marketing Authorisation Holders are advised to inform vet.applications@ema.europa.eu for the medicinal products concerned of the intention to submit a worksharing procedure at least one month in advance of the submission of the variation/group of variations.

4. How shall I present a variation application under worksharing? Rev. March 2017

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

  • One common cover letter, clearly indicating that the application is submitted for a worksharing procedure together with a short overview of all medicinal products concerned, with their respective Rapporteurs and RMSs, as well as an overview of the submission format for the different products, if applicable . Where MRP/DCPs 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 (= RMSs and CMSs) and that the relevant national fees have been paid. A formal letter with the worksharing applicant and contact person for the worksharing procedure should be provided with the worksharing application.

The Agency has published a new formatted table template to be inserted in cover letters, found here.

For queries relating to the presentation of the application, please contact the Agency.

  • 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 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).
  • Supportive documentation for each product (including the revised summary of product characteristics, labelling and/or 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 need for the provision of mock-ups should be discussed with the Agency on a case-by-case basis.

For queries relating to the presentation of the application, please contact the Agency.

Reference

5. How and to whom shall I submit my variation application under worksharing? Rev. January 2017

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 medicinal products, to the Agency and all Member States where the products concerned are authorised.

Submission to the European Medicines Agency:

Variation applications for worksharing should be addressed to the attention of vet.applications@ema.europa.eu

From 1 January 2017 it will be mandatory for applicants to use the eSubmission Gateway / Web Client for all veterinary procedural submissions to the Agency. 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, even if some products are not relevant to some MSs. This will allow all the 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.

Submission to the Rapporteur and CVMP members:

When the submission address for Rapporteur/CVMP members is identical to the submission address for the national competent authorities, no additional submission of the application should be made to the Rapporteur/CVMP member concerned. However, the cover letter should be addressed to both the national competent authority and the CVMP member concerned.

When the submission address for Rapporteur/CVMP members is different from the submission address for the national competent authorities, 2 submissions of the full variation application for all products concerned should be made separately to the CVMP member concerned upon validation by the Agency.

For submission addresses for national competent authorities, please see the CMDv guidance. For submission addresses for CVMP members, please refer to the overview table on the Agency’s website.

The dossier requirements for post-authorisation submissions in the centralised procedure should be followed for worksharing applications.

References

6. What procedure number will be given to variation applications under worksharing?

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 medicinal product. A new procedure code (abbreviation) is used for worksharing procedures i.e. “WS”. As the ‘high-level’ number can not 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/003

For each 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/WS003 which was submitted as part of the 3rd worksharing procedure received by the Agency “WS/003”

Worksharing applications for a group of variations will include the suffix “/G” e.g. EMEA/V/xxxx/WS/004/G and EMEA/V/C/prod_nb/WS/004/G.

MAHs are reminded that Agency’s procedure numbers are allocated by the Agency upon receipt of the application. For worksharing procedures, the ‘high-level’ procedure number can be obtained from the Agency shortly before submission by sending your request with a copy of the draft cover letter to vet.applications@ema.europa.eu. However, in case of delayed submission, the indicated worksharing number may already have been allocated to another worksharing procedure submitted in the meantime.

7. How will variation applications under worksharing be handled (timetable)? What will be the outcome of the evaluation of a variation application under worksharing?

The MAH should submit the variation application for worksharing, at the latest by the recommended submission dates published on the Agency’s website (See also “Recommended Submission Dates“).

In general, variations submitted for worksharing will follow a 60-day evaluation timetable. This period may however be reduced 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.  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 medicinal products are part of the worksharing and this is agreed by the Agency.

For the detailed evaluation timetable, please refer to “How shall my Type II application be handled (timetable)”?

Upon finalisation of the review of the variations subject to the worksharing procedure, the Agency will issue 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 holder during the procedure. The same general principles as for grouped variations applies - see the PAG on grouping “What will be the outcome of the evaluation of a grouped variation application”?

Schematic structure of the CVMP Opinion and Annexes for an application under worksharing, consisting of centrally and nationally authorised medicinal products:

Note:

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

The Annex B includes information on the nationally authorised medicinal products included in the worksharing application (if applicable). A template for the Annex B is available on the Agency’s website.

8. How and when will the marketing authorisations be updated following a worksharing procedure? When can I implement the approved changes? rev. July 2015

Upon adoption of the CVMP Opinion on the worksharing procedure, the Agency will inform the MAH, the Commission and 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 Decision granting the Community marketing authorisations require any amendments.

Re-examination
Art. 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 he wishes to request a re-examination within 15 days of receipt of the opinion (after which, if he does not appeal, the opinion shall be considered as final). The grounds for the re-examination request must be forwarded to the Agency within 60 days of receipt of the opinion. In case the MAH requests that the committee consults a SAG in connection with the re-examination, the applicant should inform the CVMP as soon as possible of this request.

The CVMP will appoint a different (Co-) Rapporteur, to co-ordinate the re-examination procedure. Within 60 days from the receipt of the grounds for re-examination, the CVMP will consider whether its opinion is to be revised. If considered necessary, an oral explanation can be held within this 60 days timeframe.

Decision-Making Process for centrally authorised medicinal products.
Upon receipt of the final CVMP opinion, the Commission shall, where necessary, amend the marketing authorisation for each centrally authorised medicinal product to reflect the approved variation(s) within 30 days. A single decision will be issued for each centrally authorised medicinal product.

The Agency will apply the existing post-opinion timeframes, as set-out in the Agency’s Post-Opinion Linguistic Checking Procedure document. The QRD linguistic check 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?”).

                

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 30 days, unless a referral procedure in accordance with Article 39 of Directive 2001/82/EC is initiated within 30 days following receipt of the final opinion.

For practical reasons it has been agreed that if a Member State cannot approve the final opinion of the reference authority, that Member State should initiate an Art. 39 referral within 10 days after distribution of the final opinion, in order to leave 20 days for the amendment of the marketing authorisations concerned. If a Member State does not initiate an art 39 referral within 10 days after distribution of the final opinion, the final opinion is considered approved by the Member State. For further information, please refer to the CMDv Best Practice Guide on Worksharing.

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

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 change(s) should be included in the Product Information Annexes of any subsequent regulatory procedure.

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

References

9. What fee do I have to pay for variation applications under worksharing?

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

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

More information about fees and fee payment in the Centralised Procedure.

References

10. When do I have to submit revised product information? In all languages?

In case the Variation(s) subject to worksharing affects SPC, labelling and/or package leaflet, the revised product information Annexes must be submitted as follows:

  1. Worksharing procedure for which a 60 or 90-Day timetable applies

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. NO+IS): complete set of annexes of one CAP
    electronically only
    in Word format (highlighted)

After Linguistic check (Day +25)

  • All EU languages (incl. NO+IS): 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 Art. 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.

  1. Variations for which a short (e.g. 30-Day) timetable applies

At submission (Day 0)

  • English language: complete set of Annexes for all CAPs
    electronically only
    in Word format (highlighted)
  • All EU languages (incl. NO+IS): complete set of annexes of one CAP
    electronically only
    in Word format (highlighted)

Day +25 after start of procedure

  • All EU languages (incl. NO+IS): complete set of annexes of all CAPs
    electronically only
    in Word format (highlighted) and in PDF (clean)

For such procedures (usually relating to Type IB variations) a linguistic review will take place in parallel to the scientific assessment. It is therefore expected that the texts provided at Day +25 after start of procedure will be the final texts.

Overview

DayLanguage*60- or 90-Day TimetableShort (e.g. 30-Day) Timetable
0EN
  • Electronically
  • Word format (highlighted)
  • All CAPs
  • Electronically
  • Word format (highlighted)
  • All CAPs
 Other EEA      ./
  • Electronically
  • Word format (highlighted)
  • One CAP
+5All EEA

After opinion

  • Electronically
  • Word format (highlighted)
  • One CAP
 
+25All EEA

After opinion

  • Electronically
  • Word format (highlighted)
  • PDF format (clean)
  • All CAPs

After start of procedure

  • Electronically
  • Word format (highlighted)
  • PDF format (clean)
  • All CAPs

* = 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 PL 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. The ‘QRD Convention’ published on the Agency’s website should be followed. When submitting the full set of Annexes in PDF format, this should be accompanied by the completed formatting checklist which provides guidance on how to correctly prepare the PDF versions.

The electronic copy of all languages should be provided as part of the variation application in the dossier for the product concerned, on CD-ROM/DVD. 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 Variation concerned. However, in exceptional cases where MAHs take the opportunity to introduce minor linguistic amendments in the texts (e.g. further to a specimen check) this should be clearly mentioned in the cover letter and in the 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 document attached 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 procedure(s) concerned.

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 document.

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