Q&A: Type II 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 changes are considered Type II variations?

Commission Regulation (EC) No 1234/2008 (‘the Variations Regulation’) defines a major variation of Type II as a variation which is not an extension and which may have a significant impact on the Quality, Safety or Efficacy of a medicinal product.

The Variations Regulation and the Classification Guideline set-out a list of changes to be considered as Type II variations. In addition, any other change which may have a significant impact on the quality, safety or efficacy of the medicinal product must be submitted as a Type II variation. Please refer also to “When will my variation application be considered a Type II variation or an extension application?”.

During validation of an ‘unforeseen’ variation, submitted by the MAH as a Type IB variation, the Agency may consider that the proposed variation may have a significant impact on the quality, safety or efficacy of the medicinal product. In such case, the marketing authorisation holder will be requested to revise and supplement its variation application so that the requirements for a Type II variation application are met (see also ”How shall my Type IB variations be handled (timetable)?”).

References

2. Is the co-rapporteur involved in Type II variations?

The co-rapporteur is normally not involved in the assessment of a Type II variation application concerning quality, safety and most of the clinical SPC changes.

The involvement of the co-rapporteur is however deemed necessary for new indications and new non-food target species.

The MAH should therefore inform the Agency of an upcoming Type II application for a new indication at least 2 months before submission, so that the CVMP can agree on the co-rapporteur’s involvement and be informed of the future submission.

The involvement of the co-rapporteur in other Type II variations will be decided by the CVMP on a case-by-case basis. The Agency will inform the MAH accordingly.

Regarding the submission of a Type II variation application to the (co-) rapporteurs, please see also “How and to whom shall I submit my Type II Variation application”.

3. Can I group the submission of Type II variations? Can they be grouped with other types of variations?

Marketing authorisation holders may choose to group the submission of several Type II variations for the same product into one application, provided that this corresponds to one of the cases listed in Annex III of the Variations Regulation or when this has been agreed previously with the Agency.

It is also possible for a marketing authorisation holder to group a Type II variation with other variation(s) submission (e.g. Extension, Type IB or IA variations), where applicable. Such grouped submissions will follow the review procedure of the highest variation in the group. Please also refer to ”What types of variations can be grouped?”.

Where the same Type II variation(s) affect one or more marketing authorisations from the same holder, the marketing authorisation holder may choose to submit these variations as one application for ‘worksharing’. Please also refer to ”What is worksharing and what types of variations can be subject to worksharing?”).

References

4. How shall I present my Type II variation application? Rev. January 2017

A Type II variation application should contain the elements listed in Annex IV of the Variations Regulation and should be presented in accordance with the appropriate headings and numbering of the dossier format.

The Commission “Guideline on the operation of the procedures laid down in Chapters II, III and IV of Commission Regulation (EC) No 1234/2008 “ (‘the Procedural Guideline’) further specifies which elements should be included in a Type II variation application:

  • Cover letter - the Agency has published a new formatted table template to be inserted in cover letters, found here.
  • The completed EU variation application form, including the details of the marketing authorisation concerned. Where a variation leads to or is the consequence of other variations, a description of the relation between these variations should be provided in the appropriate section of the application form. All proposed changes should be declared in the ‘Type of changes’ section of the form, and be clearly described in the “scope” section of the form.
  • Reference to the part of the Commission Classification Guideline or reference to the published Article 5 Recommendation, if applicable, used for the relevant application.
  • Supporting data relating to the proposed variation(s).
  • Update or Addendum to the detailed critical summaries (quality, safety, efficacy as appropriate). When safety or clinical study reports are submitted, even if only one, their relevant summary(ies) should be included.
  • For variations submitted to implement changes requested by the Agency or for generic/hybrid/biosimilar medicinal products, a copy of the request should be annexed to the cover letter.
  • Where the changes affect SPC, labelling and/or package leaflet, the revised product information Annexes must be submitted (see also: Type II variations - “When do I have to submit revised product information? In all languages?”).

It should be noted that the responsibility for the quality of the submitted documentation lies with the MAH and is crucial to the overall process.

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

References

5. What pre-submission steps will apply to my Type II variation? New November 2016

In order to facilitate the planning of a Type II variation, MAHs are advised to send a notification of intent for a type II variation by email to vet applications mailbox (vet.applications@ema.europa.eu) at least one month, but preferably 3 months, before submitting the application.

The notification of intent to submit should provide the following information:

  • Type(s) and scope of variation(s)
  • MAH target submission date
  • MAH contact person for the type II variation

Upon receipt of the notification of intent, the Agency will appoint a coordinating procedure manager and will subsequently inform the rapporteur and co-rapporteur, if involved.

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

  • the variation(s) concern(s) the implementation of urgent safety-related changes;
  • the variation(s) concern(s) the implementation of changes requested by CVMP (e.g. following PSUR or FUM assessment).
6. How and to whom shall I submit my Type II variation application? Rev. January 2017

Submissions should be made in accordance with the guideline on e-submissions.

Type II variation applications 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.

The electronic copy of the Variation application form and supportive documentation should be submitted simultaneously to the (Co-)Rapporteurs.

Any additional information/documentation requested by Agency prior to the start of the procedure should be equally provided to (Co-)Rapporteurs.

Upon validation by the Agency, the MAH should forthwith send one electronic copy of the Type II variation application to the other CVMP members, including any additional data or information supplied during the validation phase (as appropriate).

References

7. When shall I submit my Type II variation application? Rev. July 2015

The MAH should submit Type II application(s) at the latest by the recommended submission dates published on the Agency’s website (See also Recommended submission dates).

MAHs are reminded, especially for safety issues, that once new information becomes available which might entail the variation of the MA, MAHs should submit any variation application resulting from the fulfilment of recommendations, conditions and/or Specific Obligations (SOs) and/or Periodic Safety Update Reports (PSURs) at the same time as the fulfilment of the recommendation, condition/ SO or submission of the PSUR, rather than awaiting the assessment of those data by CVMP.

Where the CVMP requests the submission of a variation following the assessment of a PSUR, recommendation, condition or SO, or following adoption of class-labelling, MAHs must submit the corresponding variation application at the latest within 2 months following the adoption of the relevant assessment conclusion.

Variation applications reflecting the outcome of an Urgent Safety Restriction (USR) shall be submitted immediately and in any case no later than 15 days after the initiation of the USR to the Agency. This applies to USRs initiated by the MAH or imposed by the European Commission.

Implementation of agreed wording changes following the above mentioned procedures for which no additional data are submitted by the MAH will follow a Type IB variation procedure.

References

8. How shall my Type II application be handled (timetable)?

The Agency will acknowledge receipt of a valid application of a Type II variation and shall start the procedure in accordance with the official starting dates published on the EMA website.

The submission deadlines and full procedural detailed timetables are published on the Agency website Recommended submission dates

One of the following timetables (TT) shall apply:

For a 60 day TT (standard time-table):

Conditions:

All standard Type II variations; i.e. excluding those qualifying for a 30- or 90-day TT(see below)

DAYACTION
Day 1Start of evaluation
Day 30Receipt of (Co-) Rapporteur’s Assessment Report
Day 50Comments by other CVMP members
Day 60Adoption of the CVMP Opinion
[Or Request for supplementary information]

For a 30 day TT:

Condition:

  • Changes, which in the opinion of the Committee, would benefit from a shortened assessment, having regard to the urgency of the matter, in particular for safety issues.
DAYACTION
Day 1Start of evaluation
Day 20Receipt of Rapporteur’s Assessment Report
Day 25Comments by other CVMP members
Day 30Adoption of the CVMP Opinion
[Or Request for supplementary information]

In exceptional cases, this timetable could even be shortened.

For a 90 day TT:

Condition:
For variations concerning changes to or addition of therapeutic indications

DAYACTION
Day 1Start of evaluation
Day 60Receipt of Rapporteur Assessment Report
Day 80Comments by other CVMP members
Day 90Adoption of the CVMP Opinion
[Or Request for supplementary info]

MAHs are encouraged to contact the Agency in advance of the submission, in case clarification on the timetable for a specific variation is needed.

The MAH will be informed of the adopted timetable at the start of the procedure.

Where issues are identified which prevent the adoption of an Opinion, the CVMP will adopt a request for supplementary information together with a timetable stating the date by when the MAH must submit the requested data. The clock will be stopped until the receipt of the supplementary information. Any response to a request for supplementary information must be sent directly to the EMA, all CVMP members and the (Co-) Rapporteur.

As a general rule, a clock-stop of up to 1 month will apply. For clock-stops longer than 1 month the MAH should send a justified request to the Agency for agreement by CVMP. Such requests should be sent after receipt of the Assessment Report, and at the latest before the CVMP meeting at which the request for supplementary information will be adopted. In exceptional cases (e.g. in the case of new indications or where the variation requires an inspection) a clock-stop of up to a maximum of 6 months may be applied.

For any follow-on request for supplementary information, an additional clock-stop of up to 1 month will be applied in general; a maximum of 2 months may be applied when justified.

The MAH will receive the adopted timetable together with the request for supplementary information or follow-on request.

The CVMP assessment of responses will take up to 30 or 60 days depending on the complexity and amount of data provided by the MAH.

An oral explanation to the CVMP can be held at the request of the CVMP or the MAH, where appropriate.

References:

9. Which post-opinion steps apply to my Type II variation and when can I implement the approved changes? Rev. July 2015

Upon adoption of the CVMP opinion, the Agency will inform the MAH and the Commission within 15 days as to whether the CVMP opinion is favourable or unfavourable (including the grounds for the unfavourable outcome), as well as whether the Commission Decision granting the marketing authorisation requires any amendments.

Re-examination
Article 34 (2) of Regulation (EC) No 726/2004, also applies to CVMP Opinions adopted for Type II variation applications. 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
Upon receipt of the final CVMP opinion, the Commission shall, where necessary, amend the marketing authorisation to reflect the variation within 2 months or within 12 months depending on the variation.

Although the Variation Regulation has provided for a total decision-making process of 75 days for Type II variations (i.e. 15 days for opinion transmission + 60 days for updating of the MA), the Agency will continue to apply the existing post-opinion timeframes, as set-out in the European Medicines Agency Post-Opinion Linguistic Checking Procedure document. This means that the Agency, in cooperation with the QRD members and the MAH will aim to providing final, checked translations to the Commission by Day +27. (see also: “When do I have to submit revised product information? In all languages?”).

      

Where a group of variations to the terms of one marketing authorisation submitted as part of one variation have been approved, the Commission will update the marketing authorisation with one single decision to cover all the approved variations.

Implementation
 

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

Type II variations 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.

References

10. What fee do I have to pay for a Type II Variation?

For information on the fee applicable for Type II variations, please refer to the explanatory note on fees payable to the European Medicines Agency. Such fee covers all authorised strengths, pharmaceutical forms and presentations of a given medicinal product Reduced Type II fees may apply to certain variations, as specified in the “Explanatory note on fees payable to the European Medicines Agency”.

For Type II variations which introduce additional presentation/pack-size(s), each additional presentation/pack-size attracts separate fees (x additional presentations x separate fees). Each presentation/pack-size should therefore be declared as a separate variation on the variation application form.

Grouped Type II variations, whether consequential or not, will each attract a separate Type II fee.

The Agency will issue an invoice following the notification of the administrative validation to the applicant and fees will be payable within 30 calendar days of the date of the invoice. The invoice will be sent to the billing address indicated by the MAH and will contain clear details of the product and procedures involved, the type of fee, the amount of the fee, the bank account to where the fee should be paid and the due date for payment.

To facilitate this operation, applicants/MAHs who are requesting a Purchase Order Number on the Agency invoice should quote this Number clearly on the cover letter of a given application. The Agency will no longer accept separate notifications of Purchase Order Numbers not associated with the dossier.

If the applicants/MAHs do not require a Purchase Order Number on the Agency invoice, this must also be clearly stated in the cover letter.

For more information about fees and fee payment in the Centralised Procedure,

For Type II variations, if the variation is considered ‘invalid’ (i.e. an assessment process can not be started), an administrative fee will be charged by the Agency (see also Explanatory note on fees payable to the European Medicines Agency).

When an inspection is required, please note that in addition an inspection fee will be requested (see also Pre-submission Guidance – “What is the fee for a GMP inspection?).

References

11. Do I have to submit mock-ups?

Please consult the Mock-ups section of this Q&A.

Reference

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

Where the Type II Variation affects SPC, labelling and/or package leaflet, the revised product information Annexes must be submitted as follows:

  • At submission (Day 0
    • English language: complete set of Annexes electronically only in Word format(highlighted):
  • After CVMP Opinion (Day +5)
    • All EU languages (incl. NO+IS): complete set of annexes electronically only in Word format (highlighted)
  • After Linguistic check (Day +25)
    • All EU languages (incl. NO+IS): complete set of annexes electronically only in Word format (highlighted) and in PDF (clean)

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

Overview:

DayLanguagePost-opinion linguistic review Timetable
0ENElectronically
Word format (highlighted)
+5All EEAElectronically
Word format (highlighted)
+25All EEAElectronically
Word format (highlighted)
PDF format (clean)

* = 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 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 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 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 as separate word document.

13. Will there be any publication on the outcome of my Type II variation? Rev. July 2015

The CVMP Press Release and CVMP Monthly Report following each CVMP meeting give information on opinions in relation to variations related to the addition of a new therapeutic indication or to the modification of an existing one, variations concerning the replacement or addition of a serotype, strain, antigen or combination of serotypes, strains or antigens for a veterinary vaccine, variations related to the addition of a new contraindication, variations related to the addition of a non- food producing target species or the modification of an existing one for veterinary medicinal products and variations related to changes to the withdrawal period for a veterinary medicinal product.

This will include the invented name of the product and the indication(s).

The variation assessment report, with all commercially confidential information deleted, will also be published further to the adoption of the Commission Decision for these variations.

14. What can be considered an editorial change and how can it be submitted as part of a Type IA/IB/II variation? - New June 2016

General principles

The European Commission’s ‘Variations Guidelines’ 2013/C 223/01 specify that “If amendments to the dossier only concern editorial changes, such changes should generally not be submitted as a separate variation, but they can be included in a variation concerning that part of the dossier. In such cases the changes should be clearly identified in the application form as editorial changes and a declaration that the content of the concerned part of the dossier has not been changed by the editorial changes beyond the scope of the variation submitted should be provided”. Changes that can be classified as a variation according to the Variations Guidelines are not considered editorial changes and should be submitted under the appropriate variation category.

In practice “that part of the dossier” (referred to above) can be taken to mean concerning Parts 2, 3 or 4, as appropriate.

Editorial changes should generally not be submitted as a separate variation and therefore no reference to a variation category is required when they are encompassed within another variation procedure. 

Within the section of the variation application form under the section on ‘Precise scope and background…’, the MAH should provide:

  • a brief description of the proposed editorial changes and a justification as to why they are considered ‘editorial’ (i.e. why they should not trigger a specific variation);
  • a declaration confirming that the changes proposed as editorial do not change the content of the concerned part(s) of the dossier beyond the scope of the variation within which the editorial changes are being submitted;
  • confirmation that all relevant parts of the dossier have been updated accordingly and are included within the variation package.

Additionally all the editorial changes should be listed in the present/proposed table (or provided as a separate annex that is cross-referred to from this table), identifying each related change in the dossier down the lowest section heading and page numbers where possible.

Any changes proposed by the applicants as editorial will be carefully considered by the Agency at time of submission and may be subject to further assessment at the same time as the variation. Proposed editorial changes that cannot be accepted as such will be rejected. In case of doubt, applicants can contact the Agency in advance of the planned submission using vet.applications@ema.europa.eu.

Editorial changes in Part 2 (quality)

The following may be considered as examples of editorial changes to Part 2: adding headers for ease of use, reordering of existing information without changing the meaning, alignment of information among/within the sections provided the correct reference that had been previously agreed can be demonstrated (e.g. alignment of information in flow charts to process description), punctuation changes and grammar/orthographic corrections that do not alter the meaning of the text.

Examples of changes that cannot be considered editorial: removal of specification parameters or manufacturing description, update of information to bring the dossier content in line with the current manufacturing process, etc.

Proposed changes that require confirmation by the Rapporteur may only be accepted when submitted within the scope of an upcoming variation type IB or type II which impacts upon Part 2.

If editorial changes are required and there is no upcoming procedure, the MAH may consider submitting these changes as a separate, default Type IB variation (B.I.z or B.II.z, as appropriate).

Editorial changes in Parts 3 (safety & residues) and 4 (pre‑clinical & clinical)

Editorial changes in Parts 3 and 4 are not foreseen. Please contact vet.applicactions@ema.europa.eu in advance of an upcoming submission.

Editorial changes to the product information in Part 1.B (SPC, labelling and package leaflet)

Formatting changes, correction of typographical errors and/or mistakes to the English product information or other linguistic versions of the product information are considered editorial changes provided that the meaning of the text is not altered. These changes can be included within the scope of any upcoming procedure impacting on the product information.

Changes in the scientific content or meaning cannot be accepted as an editorial change. These changes should be classified under the scope of the relevant category as per the Variations Guidelines (e.g. Type II, C.I.4).

Proposed changes that may require confirmation by the Rapporteur or linguistic review will only be accepted when submitted within the scope of an upcoming variation type IB or type II which impacts upon the product information.

Should there be no upcoming regulatory procedure in which to include the editorial changes, these could also be submitted as a stand-alone, default Type IB variation e.g. under C.I.z if they affect the English product information. If other languages are affected and in case no procedure affecting the product information is upcoming, holders are advised to contact vet.applications@ema.europa.eu to discuss how to handle these necessary changes.

The MAH should liaise with the Agency without delay if the mistake concerns an incorrect or missing important information (e.g. contra-indication or adverse event) that could affect the safe and effective use of the medicinal product and/or lead to a potential medication errors (e.g. wrong strength, wrong posology, wrong route of administration).

References

15. Introduction of a new manufacturing site for the finished product. What changes can I submit under a single type II scope? (Classification category B.II.b.1) New June 2016

The following complex, related changes could be considered for submission under a single type II scope B.II.b.1 - Addition of a new finished product (FP) manufacturing site: changes to the manufacturing process, batch size and in-process controls to adapt to the new manufacturing site settings.

Complex, related changes submitted under a single type II should always be clearly identified in the application form as following: a clear description of all the related changes should be provided in the precise scope. All the related changes should be listed in the present/proposed table.

Changes affecting the FP not directly related to the introduction of the new manufacturing site such as changes in excipients, specification parameters /limits for the FP, container closure system including suppliers should be submitted as additional variation scopes.

Any pre-submission queries of any intended submission of complex related changes under one single type II scope should be addressed to vet.applications@ema.europa.eu.

16. When will my variation application be considered a Type II variation or an extension application?

Commission Regulation (EC) No 1234/2008 defines a Type II variation as a ‘major variation’ which may have a significant impact on the Quality, Safety or Efficacy of the medicinal product.

The Variations Regulation and the Classification Guideline set out a list of changes to be considered as Type II variations. In addition, any other change which may have a significant impact on the quality, safety or efficacy of the medicinal product must be submitted as a Type II variation.

Certain changes to a Marketing Authorisation, however, have to be considered to fundamentally alter the terms of this authorisation and therefore cannot be granted following a variation procedure. These changes are to be submitted as an ‘Extension application’ and are listed in Annex I of the Variations Regulation.

This Annex lists three main categories of “changes requiring an extension application”:

  1. Changes to the active substance(s)
  2. Changes to strength, pharmaceutical form and route of administration
  3. Other changes specific to veterinary medicinal products to be administered to food-producing animals; change or addition of target species

As the case may be, an authorisation or a modification to the existing Marketing Authorisation will have to be issued by the Commission.

As experience has shown difficulties in the classification of ‘extension’ applications versus ‘variation’ applications, particularly regarding the items pharmaceutical form and strength, the European Commission has published a guideline clarifying these terms and including relevant examples for such classification. (See also: “Guideline on the categorisation of Extension Applications (EA) versus Variations Applications (V) - October 2003”)

In cases of doubt, the MAH is advised to contact the Agency in advance of submission.

References

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