This page lists questions that marketing-authorisation holders (MAHs) may have on worksharing. It provides an overview of the European Medicines Agency's position on issues that are typically addressed in discussions or meetings with MAHs in the post-authorisation phase. Revised topics are marked 'New' or 'Rev.' upon publication.

A PDF version of the entire post-authorisation guidance is available:

European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

Reference Number: EMEA-H-19984/03 Rev. 107

English (EN) (2.63 MB - PDF)

First published: Last updated:
View

European Medicines Agency post-authorisation procedural advice for users of the centralised procedure: document with track changes

Reference Number: EMEA-H-19984/03 Rev. 107

English (EN) (2.65 MB - PDF)

First published: Last updated:
View

These questions and answers have been produced for guidance only and should be read in conjunction with the rules governing medicinal products in the European Union, volume 2, notice to applicants.

MAHs must in all cases comply with the requirements of Community legislation. Provisions that extend to Iceland, Liechtenstein and Norway by virtue of the European Economic Area agreement are outlined in the relevant sections of the text.

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 products concerned, have to be taken as 'the same MAH'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 or -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 and -IAIN variations with a type-IB or a type-II variation, which is submitted for a worksharing procedure. In such cases, the review of the type-IA or -IAIN variation will be performed as part of the worksharing procedure.

working_sharing_procedure_q1.jpg

 

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'.

Purely national marketing authorisations can be included in worksharing procedures submitted as of 4 August 2013.

References

1See page 4 of the Commission communication on the Community marketing authorisation procedures for medicinal products (page 4).

In order to benefit from a worksharing procedure, it is required that the same changes 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' changes 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

  • Changes to multiple generic marketing authorisations (MAs) containing the same active substance.
  • Changes to a single-substance MA and a fixed-combination MA containing the same active substance.
  • Proposal for combination use affecting both MAs.
  • Introduction or changes to the pharmacovigilance system.

Quality

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

Additional examples will be regularly included to reflect accumulated experience.

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 holder 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;
  • explanation that all MAs belong to the same MAH;
  • explanation / justification for suitability of worksharing;
  • rapporteurs' reference Member States (RMSs) and national competent authorities 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. To submit your request, raise a ticket via EMA Service Desk. Please click on “Finance Services”, then the Type of ticket request to be selected is “Request for high-level procedure or ASMF number” followed by sub-option “Workshare Procedure number”. The letter of intent should be attached to the EMA Service Desk ticket.

If you do not have an EMA Account, you may create one via the EMA Account Management portal.

Upon receipt of the letter of intent, the Product Lead (if the worksharing procedure contains at least one Type II variation) will review and decide whether the proposed worksharing procedure is acceptable. For worksharing procedures not including a Type II variation, the Agency appoints a Procedure Manager. Subsequently, the Agency will initiate the Rapporteur appointment procedure.

Following an expression of interest and based on a rota system, the Chair of the Committee for Medicinal Products for Human Use (CHMP) will appoint a rapporteur (and co-rapporteur when the application includes a new indication) for the procedure. It is expected that the (co-)rapporteur will be one of the rapporteurs of the centrally authorised medicinal products or a CHMP member representing one of the RMSs or national competent authorities for the nationally authorised products. The MAH will be informed accordingly.

A shorter presubmission 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 CHMP.

Worksharing procedure for multiple centrally authorised medicinal products ('duplicates')

The submission of a formal letter of intent is not required, however applicants are advised to request a WS number. The request should be submitted by raising a ticket via EMA Service Desk. Please click on “Finance Services”, then the Type of ticket request to be selected is “Request for high-level procedure or ASMF number” followed by sub-option “Workshare Procedure number”  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). Marketing Authorisation Holders are advised to submit such variations as usual. 

The submission requirements as set-out in the PAG 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 (eCTD sequence) per product, covering all variations applied for. Please refer to the eCTD Variations Q&A document, for guidance on the submission of variations in eCTD format.

This will include a cover letter and electronic application form, together with separate supportive documentation for each medicinal product concerned and revised product information (if applicable) for each medicinal product concerned. If applicable, the MAH should provide a revised RMP for each medicinal product as part of the application upfront.

  • One original cover letter addressed to the Agency and National Competent Authorities, in case nationally authorised 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 medicinal products concerned, with their respective Rapporteurs, RMSs and National Competent Authorities, as applicable. In case nationally authorised medicinal 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 (when a WS application contains at least 1 CAP, the submission should be made to EMA only using the eSubmission Gateway. For further information please consult the document: dossier requirements for NAPs). A formal letter with the worksharing applicant and contact person for the worksharing procedure should be provided with the worksharing application. A template cover letter for worksharing procedures including CAPs and nationally authorised medicinal products only is available on the Agency’s website.
  • One completed electronic 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 an Annex B to the application form (using the template available on the Agency’s website)
  • 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 or specimens should be discussed with the Medical Information Sector of the Agency on a case-by-case basis.
  • In principle, identical modules 2-5 will have to be provided for each product included in the worksharing.

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

References

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, the submission should be made to EMA only using the eSubmission Gateway. All NAP submissions (worksharing containing at least 1 CAP) sent to EMA via eSubmission Gateway/Web Client will be considered delivered to all National Competent Authorities representatives, alternates and experts of the scientific committees. No additional copies of submissions should be submitted directly to the NCAs on CD/DVD or via CESP as this might lead to validation issues and cause delays. All EMA submissions should be sent via EMA eSubmission Gateway/Web Client only.

Submission to the European Medicines Agency

From 1 March 2014, the use of the eSubmission Gateway or Web Client is mandatory for all electronic Common Technical Document (eCTD) submissions through the centralised procedure. The European Medicines Agency (EMA) no longer accepts submissions on CD or DVD. This applies to all applications for human medicines.

More information on how to register and connect to the Gateway / Web Client can be found in the eSubmission website and detailed information on how to submit can be found in eSubmission Gateway guidance documents. Applicants must not send duplicate submissions electronically or via CD-ROM or DVD or via CESP as this might lead to delays in the handling of applications.

An automated acknowledgement is sent from the system confirming whether the submission has passed the relevant technical validation criteria and whether it has been uploaded to the Agency’s review tool and made available via the Common Repository. Applicants must not send any accompanying hard media or separate paper cover letter as the cover letter will be in the relevant part of eCTD module 1 in PDF format.

Where applicable, revised product information Annexes (including Annex A, if applicable) should be included in electronic (Word and PDF) format in the same eSubmission Gateway or eSubmission Web Client package within a folder called ‘working documents’.  Where applicable changes in Word documents should be indicated using ‘Tools-Track Changes’. Clean PDF versions should have all changes ‘accepted’.

For Centrally Authorised medicinal products (eCTD mandatory)

An electronic copy containing the relevant eCTD sequence for each product, should be submitted to the Agency. The coordinating Product Lead (if worksharing procedure contains at least one Type II variation) or else the appointed Procedure Manager should be indicated in copy (“cc”) on the cover letter.

For nationally authorised medicinal products (eCTD)

eSubmission Gateway / Web Client package of the Variation application form and supportive documentation for each product should be submitted to the Agency in accordance with the “Dossier Requirements for referral, ASMF and NAP submissions (PASS107, Workshare, Signal Detection procedures) and ancillary medicinal substances in a medical device” document . Paper submissions are not accepted.

Submission to the National Competent Authorities

Where nationally authorised medicinal products are part of the worksharing, the applications are submitted to the Agency only via the eSubmission Gateway and there should not be additional parallel submissions to Member States, even if some products are not relevant to some MSs. All submissions are available to all NCAs via the Common Repository. The Common Repository provides access to all involved Parties (The Agency, MSs and Committee 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 via the eSubmission Gateway/Web Client and it will be available to the network via the Common Repository.

Submission to the Rapporteur and Committee members

All submissions sent to EMA via eSubmission Gateway/Web Client will be considered delivered to all National Competent Authorities’ representatives and alternates.

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

For a full overview of dossier requirements for National Competent Authorities of (Co-)Rapporteur and Committee members, including delivery addresses, please refer to the following document: Dossier requirements for Centrally Authorised Products (CAPs).

For requirements for non-eCTD format submissions, please refer to the “Dossier Requirements for referral, ASMF and NAP submissions (PASS107, Workshare, Signal Detection procedures) and ancillary medicinal substances in a medical device” document.

References

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 cannot be allocated to one single product, the procedure number will therefore contain “xxxx” as a place-holder for the product number.

Example: EMEA/H/C/xxxx/WS/0003

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/H/C/prod_nb/WS0003/nn which was submitted as part of the 3rd worksharing procedure received by the Agency “WS0003”

Worksharing applications for a group of variations will include the suffix “/G” e.g. EMEA/H/C/ xxxx/WS/0004/G and EMEA/H/C/prod_nb/WS0004/nn/G.

For all worksharing procedures, including those which contain nationally authorised medicinal products, the ‘high-level’ procedure number should be systematically obtained from the Agency shortly before submission by sending your request via EMA Service Desk with a letter of intent,  see question “What pre-submission steps will apply to a worksharing procedure?”.

The MAH must submit the variation application for worksharing at the latest by the recommended submission dates published under submission dates.

In general, variations submitted for worksharing will follow the 60-day evaluation timetable of Type II variations and weekly-start timetables may apply to the assessment following the same principles as those applied to the assessment of Type II variations. The 60-day period may 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. Type IB worksharing procedures assessed by CHMP only and not requiring linguistic review may also follow a weekly 30-day timetable.

For the detailed evaluation timetable, please refer to the PAG for Type II variations 'How shall my Type II application be handled (timetable)?' For more information on the weekly-start timetables, please refer to: 'Which submission dates (weekly or monthly) are applicable for my type II variation and when shall I submit my application?'

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 opinions will also list any variations (e.g. as part of a group, or for a specific medicinal product) that 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 grouping of variations: questions and answers.

Schematic structure of the CHMP opinion and annexes for an application under worksharing, consisting of centrally and nationally authorised medicinal products:

pbjouvgr915271116419967241.gif

Note:

  • Annex A for each centrally authorised medicinal product included in the worksharing procedure will be annexed to the CHMP opinion.
  • Annex B includes information on the nationally authorised medicinal products included in the worksharing application (if applicable). A Annex B Word template is available.

Upon adoption of the CHMP opinion on the worksharing procedure, the Agency will inform the MAH 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 Union marketing authorisations requires any amendments.

Where the outcome of the procedure is favourable and the Commission decision granting the marketing authorisation requires amendments, the Agency will inform the Commission accordingly.

Re-examination

Article 9(2) of Regulation (EC) No 726/2004 also applies to CHMP opinions adopted for worksharing procedures. This means that the MAH may give written notice to the Agency or CHMP that it wishes to request a re-examination within 15 days of receipt of the opinion (after which, if it does not appeal, the opinion will be considered final). The grounds for the re-examination request must be forwarded to the Agency within 60 days of receipt of the opinion. If the MAH requests that the Committee consult a scientific advisory group in connection with the re-examination, the applicant should inform the CHMP as soon as possible.

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

Decision-making process for centrally authorised medicinal products

Upon receipt of a favourable CHMP opinion that requires amendments to the decision granting the marketing authorisation, the Commission shall amend the marketing authorisation for each centrally authorised medicinal product to reflect the approved variations within two months, for the variations listed under Article 23(1a)(a) or within one year for the other variations. A single decision will be issued for each centrally authorised medicinal product.

Article 23(1a)(a) provides for a two-month timeframe for amending the decision granting the marketing authorisation for the following variations:

  • variations related to the addition of a new therapeutic indication or to the modifications of an existing one;
  • variations related to the addition of a new contraindication;
  • variations related to a change in posology;
  • variations related to changes to the active substance of a seasonal, prepandemic or pandemic vaccine against human influenza;
  • other type-II variations that are intended to implement changes to the decision granting the marketing authorisation due to a significant public-health concern or significant animal-health or environmental concern in the case of veterinary medicinal products.

All the other variations will follow a yearly timeframe for update of the respective Commission decision.

The Agency applies the existing post-opinion timeframes, as set-out in The linguistic review process of product information in the centralised procedure - Human. 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 MAH at opinion stage in case of a worksharing procedure for a type-IB variation or by day +27 in case of a worksharing procedure for a type-II variation. Also see 'when do I have to submit revised product information? In all languages?'

ouieouts7344262973038884516.gif

 

Marketing-authorisation-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 CHMP 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 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 30 days after receipt of the favourable CHMP opinion. The agreed changes should be included in the annexes of any subsequent regulatory procedures.

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

References

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 can not 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.

For information about fees and fee payment in the Centralised Procedure, please refer to the Explanatory note on fees payable to the European Medicines Agency.

References

If the variations subject to worksharing affects the summary of product characteristics (SmPC), labelling or package leaflet, the revised product information annexes must be submitted as follows:

a. Worksharing procedure for type-II variations

At submission (day 0):

  • English language: Complete set of Annexes for all centrally authorised products (CAPs) electronically only in Word format (highlighted).

After CHMP opinion (day +5):

  • All European Union (EU) languages (including Norwegian and Icelandic): Complete set of annexes of one CAP electronically only in Word format (highlighted).

After linguistic check (day +25):

  • All EU languages (including Norwegian and Icelandic): Complete set of annexes of 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.

b. Worksharing procedures for type-IB variations

At submission (day 0):

  • English language: Complete set of Annexes for all CAPs electronically only in Word format (highlighted);
  • All EU languages (including Norwegian and Icelandic): Complete set of annexes of one CAP electronically only in Word format (highlighted).

Day +25 after start of procedure:

  • All EU languages (including Norwegian and Icelandic): Complete set of annexes of all CAPs electronically only in Word format (highlighted) and in PDF (clean).

For such procedures, 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

DayLanguages*Type-II variation(s)Type-IB variation(s)
0EnglishElectronically
Word format (highlighted)
All CAPs		Electronically
Word format (highlighted)
All CAPs
 Other European Economic Area-Electronically
Word format (highlighted)
One CAP
+5All European Economic AreaAfter opinion
Electronically
Word format (highlighted)
One CAP		/
+25All European Economic AreaAfter 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. annexes I, II, IIIA and IIIB submitted as one document per language.

The 'complete set of annexes' includes annexes I, II, IIIA and IIIB, i.e. all SmPC, 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). The Quality Review of Documents (QRD) convention to be followed for the European Medicines Agency QRD templates should be followed. When submitting the full set of annexes in PDF format, this should be accompanied by the completed Formatting check list for the product information (annexes) in PDF format - veterinary and following the User guide on how to generate PDF versions of the product information - human.

The electronic copy of all languages should be provided as part of the variation application in the eCTD for the product concerned, on Gateway / Web Client . 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 a 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 concerned.

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

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

After CHMP opinion (day +5), the MAH will provide 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.

Please be reminded that in accordance with Union data protection requirements, no personal data should be included in the annotated PIs. This applies to the English version submitted at the time of opinion, the draft translation versions of the PI in all languages submitted at D+5 as well as the final translations submitted at D+25. Please submit annotated PIs in an anonymised format (i.e. names of the reviewers removed from the track-changes). If you do not wish to do so, please ensure that the individuals whose data is included consented to its sharing with EMA and its further sharing by EMA with third parties such as other marketing authorisation applicants, marketing authorisation holders and National Competent Authorities, as relevant. EMA expressly disclaims any liability or accountability for the presence of unnecessary personal data in the annotated PI submitted by the marketing authorisation holder.

References

Share this page