Type 1b Variation Classification Essay

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.

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:

1. What changes are considered Type IB variations? Rev. July 2015

Commission Regulation (EC) No 1234/2008 (‘the Variations Regulation’) defines a minor variation of Type IB as a variation which is neither a Type IA variation nor a Type II variation nor an Extension. Such minor variations must be notified to the National Competent Authority/European Medicines Agency (‘the Agency’) by the Marketing Authorisation Holder (MAH) before implementation, but do not require a formal approval. However, the MAH must wait a period of 30 days to ensure that the application is deemed acceptable by the National Competent Authority/the Agency before implementing the change (“Tell, Wait and Do” procedure).

The “Commission guideline on the details of the various categories of variations” (‘the Classification Guideline’), contains examples of changes which are considered as Type IB variations. In addition, any change which is not an Extension and whose classification is not determined taking into account the Classification Guideline and the recommendations delivered pursuant to Article 5 of the Variations Regulation, is considered a Type IB variation by default.

When one or more of the conditions established in the Classification Guideline for a Type IA variation are not met, the concerned change may be submitted as a Type IB variation unless the change is specifically classified as a major variation of Type II.

For changes which are submitted as default Type IB variations, the Agency will determine during validation whether the proposed classification as Type IB variation is appropriate before the start of the evaluation procedure (see also “How shall my Type IB variation be handled?”).

References

2. Is the (Co-) Rapporteur involved in Type IB variations? Rev. July 2015

Upon validation of the notification by the Agency, the Rapporteur will be involved in the evaluation of such Type IB variations “How shall my Type IB variation be handled (timetable)”?

The Co-Rapporteur is not involved in the assessment of Type IB variations, however a copy of the complete Type IB notification must also be submitted to all CVMP members (including the Co-Rapporteur) after validation.

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

 MAHs may choose to group the submission of several Type IB variations for the same product into one application. It is also possible for a MAH to group a Type IB variation with other variation(s) for the same product (e.g. Type IA, Type II, Extension), where applicable.

Allowed groupings are listed in Annex III of the Variations Regulation. Other groupings have to be agreed in advance with the Agency. Any proposal to group clinical and quality variations should be adequately justified.

Such grouped submissions will follow the review procedure of the highest variation in the group. Please also refer to “What type of variations can be grouped?”.

                   

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

References

4. How shall I present and submit my Type IB variation? Rev. January 2017

A Type IB 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 IB variation application:

  • Cover letter (for groupings, include a short overview of the nature of the changes and indicate whether it is an allowed grouping in Annex III of the variations regulation or the grouping has been agreed with the Agency). The Agency has published a new formatted table template to be inserted in cover letters, found here.
  • The completed EU variation application form (as published on the Commission’s website in Volume 6C of the Notice to applicants), including the details of the marketing authorisation concerned. Where a variation is considered a Type IB by default, a detailed justification for its submission as a Type IB application must be included. MAHs are reminded that the variation application form should be signed by the official contact person. Should the official contact person not be available, an official letter of authorisation confirming the delegation of signature to a different person should be enclosed.
  • Reference to the part of the Classification Guideline, or reference to the published Article 5 Recommendation, if applicable, used for the relevant application.
  • Relevant documentation in support of the proposed variation including all documentation as specified in the Commission’s Classification Guideline.
  • For variations submitted to implement changes requested by the Agency or for generic/hybrid/biosimilar medicinal products, where no new additional data are submitted by the MAH, a copy of the request should be annexed to the cover letter.
  • If applicable, the revised summary of product characteristics, labelling and/or package leaflet as a full set of annexes.

Grouped variations

For grouped variations concerning one marketing authorisation, all variations must be declared in the variation application form. The documentation requirements for each type of variation in the group must be adhered to. However, the supportive documentation for all variations concerned should be submitted as one integrated package (i.e. there is no need to submit a separate documentation package for each variation).The present-proposed section of the application form should clearly identify the relevant dossier sections in support of each variation. For grouped variations concerning more than one marketing authorisation please refer to ”What is worksharing and what types of variations can be subject to worksharing?".

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. The MAH is responsible for ensuring that the variation complies fully with the data and documentation requirements as specified in the Classification Guideline and in the Procedural Guideline. The MAH should pay particular attention to grouping of variations, for which each change should be clearly identified as well as the related supportive documentation. A confusing dossier presentation will not facilitate rapid procedures.

Submission of Type IB Applications

Type IB variation applications should be addressed to vet.applications@ema.europa.eu

One electronic copy of the Variation application form and supportive documentation should be submitted to the Agency, together with an original, signed cover letter.

Where applicable, revised product information Annexes should be provided in electronic (Word and PDF) format.

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.

One electronic copy should also be sent to the Rapporteur at the time of submission for evaluation.

Submission to other CVMP members should be done according to their dossier requirements.

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

MAHs are encouraged to avoid submitting Type IB variation applications shortly before or during the Agency holiday periods (e.g. end July and Christmas).

References

5. When shall I submit my Type IB variation?

In order to facilitate the linguistic review process of product information for certain variations which have been downgraded from Type II to Type IB, the Agency has published recommended submission dates for Type IB variations requiring linguistic review (See also “Recommended submission dates”)

Some examples of Type IB variations where a linguistic review will be performed are listed below:

  • C.I.3.a) Implementation of change(s) requested by the Agency following the assessment of an Urgent Safety Restriction, class labelling, a Periodic Safety Update report, Risk Management Plan Follow up Measure/Specific Obligation, data submitted under Article 45/46 of Regulation (EC) No 1901/2006, or amendments to reflect a competent authority Core SPC
  • Other default safety and efficacy Type IB variations affecting the product information.

Some examples of Type IB variations where a linguistic review will not be performed are:

  • C.I.2.a) Change in the Summary of Product Characteristics, Labelling or Package Leaflet of a generic/hybrid/biosimilar medicinal products following assessment of the same change for the reference product
  • Deletion of information from the product information

The linguistic review process will be normally performed within the 30 day timeframe for assessment of the Type IB variations on the translations submitted at the start of the procedure.

A separate set of recommended submission dates is applicable for type IB variations included in a worksharing submission or for Type IB variations submitted as part of a group including Type II variations and/or extensions (included in the same “Recommended submission dates” document).

The Agency considers that despite the downgrading of certain variations to Type IB it is important from a public health protection point of view to continue to ensure high quality and consistent product information of centrally authorised medicinal products in all Member States.

Where the CVMP requests a Type IB variation following the assessment of a PSUR, FUM or SO, following adoption of class-labelling or requests a Type IB variation for generic/hybrid/biosimilar medicinal products following assessment of the same change for the reference product, 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.

References

6. How shall my Type IB variation be handled (timetable)?

Upon receipt of a Type IB application, the Agency will handle the application as follows:

a) Handling of Type IB variations included in the Classification Guideline (‘foreseen’) or covered by an Article 5 Recommendation:

The Agency will check within 5 working days whether the variation is correct and complete (‘validation’) before the start of the evaluation procedure.

DAYACTION
Day xReceipt of Type IB variation
Day x+1Start of Agency validation
Day x+5Agency validation
(in case of missing information, this period will be extended)

Issues identified during validation will be notified to the MAH by Eudralink or fax. 

The Agency will send to the MAH a confirmation of the positive outcome of the validation and the start date of the procedure.

DAYACTION
Day 1Start of evaluation
by Day 20Receipt of Rapporteur’s Assessment Report
by Day 30(Non-)acceptance of the variation

Within 30 days following the acknowledgement of receipt of a valid application, the Agency will notify the MAH and the Commission of the outcome of the procedure. If the Agency has not sent the holder its opinion on the application within 30 days, the application shall be deemed acceptable.

In case of an unfavourable outcome the MAH may, within 30 days, amend the application to take due account of the grounds for the non-acceptance of the variation. If the MAH does not amend the application as requested, the application shall be rejected.

Within 30 days of receipt of the amended application, the Agency will inform the MAH and the Commission of its final
(non-)acceptance of the variation and whether the Commission Decision granting the Marketing Authorisation requires any amendments.

Where Type IB Variations affect the Annexes to the Marketing Authorisation, such changes can be implemented without awaiting the 12-monthly update of the Commission Decision and the agreed change(s) should be included in the Annexes of any subsequent Regulatory Procedure.

b) Handling of Type IB variations claimed by the MAH to be IB variations by default:

The Agency will check within 5 working days whether the proposed change can be considered a minor variation of Type IB, and whether the application is correct and complete (‘validation’) before the start of the evaluation procedure. In exceptional cases, the Agency may have to consult with the Rapporteur on the appropriate classification of the variation, which may lead to a slightly longer validation period (up to 10 working days).

When the Agency is of the opinion that the proposed variation may have a significant impact on the quality, safety or efficacy of the medicinal product, the MAH will be notified that the applied change cannot be handled as a Type IB and that the variation will have to be reclassified as a Type II variation. As a consequence, the 

MAH will be requested to revise and supplement their variation application so that the requirements for a Type II variation application are met.

Following receipt of the valid revised variation application, a Type II assessment procedure will be initiated according to the Agency procedural timetables for Type II variation.

When the Agency is of the opinion that the proposed variation can be considered a Type IB variation, the MAH will be informed of the outcome of the validation and of the start date of the procedure. The Type IB application will be handled as set-out in section a) above.

c) Handling of Groupings of Minor Variations (Type IB/Type IA)

For grouping of minor variations, where not all of the changes applied for can be positively validated, all valid and not valid variations will be clearly listed in the validation outcome document.

Where a Type IB by default variation, within a group of variations, has to be reclassified as a Type II variation, the MAH will be requested to confirm whether this variation should remain in the group. If confirmed, the whole group will be handled as a Type II variation, as set out in section b) above.

Where several Type IB variations are submitted as part of one application, it will be clearly specified in the final Agency notification which variation(s) have been accepted or rejected following assessment, unless some of the variations have been withdrawn by the MAH during the procedure (see “How will grouped variation applications be handled (timetable)? What will be the outcome of the evaluation of a grouped application?”).

7. What fee do I have to pay for a Type IB variation?

For information on the fee applicable for Type IB 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.

For 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 IB variations, whether consequential or not, will each attract a separate Type IB 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.

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

For Type IB variations, if the variation is considered ‘invalid’ (i.e. an assessment process cannot be started), an administrative fee will be charged by the Agency. 

References

8. Do I have to submit mock-ups?

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

Reference

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

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

  • All EEA language versions: complete set of Annexes electronically only in Word format (highlighted tracked changes) and in PDF (clean)
  • 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 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(s) 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 procedure(s) 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), translations of the revised Annex A in all EU languages should be provided as separate documents in Word format (clean) and PDF, together with the variation application. Where the variation introduces a new EU sub-number, the sub-number should be requested from the Agency before submission and should subsequently be included in the SPC, labelling and PL texts as part of the variation application (see also “How to obtain new EU sub-numbers before submitting a Type IB variation for an additional presentation?”). In case of a deletion of a pharmaceutical form/strength(s), such prior liaison with Agency is not required, and the amended Annex A and product information Annexes should be provided as part of the Variation application.
10. How do I obtain new EU sub-numbers before submitting a Type IB variation for an additional presentation (e.g. new pack-size)?

In the specific case of a Type IB Variation for an additional presentation, the new EU marketing authorisation sub-number should be requested from the Agency before submission. To do so, please contact  vet.applications@ema.europa.eu.

11. How and when will the updated Annexes become part of the Marketing Authorisation?

Upon finalisation of a valid Type IB application affecting the Annexes to the Commission Decision, the Commission Decision will be updated within 12 months. However, Type IB Variations affecting the Annexes can be implemented without awaiting the update of the marketing authorisation and the agreed Type IB changes should be included in the Annexes of any subsequent Regulatory Procedure.

12. 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

13. When applying for a new pack size, what is considered within the range/outside the range (classification category B.II.e.5)? - Updated December 2017

The introduction of a new pack size (i.e. additional to currently approved pack sizes) should be submitted as a variation under subindent B.II.e.5.a) according to the variations classification guidelines.

Range is defined from the smallest to the biggest approved pack size (not from ‘0’) for the same pharmaceutical form and strength. The pack size equals to the number of units of the pharmaceutical form (e.g. tablets, sachets, ampoules, etc.) contained per outer packaging. Pack sizes not included within this range are considered to be outside of the range.

For the addition of a new pack size where the number of units of the pack is within the range of the currently approved pack sizes for the strength and pharmaceutical form, applicants should submit a variation B.II.e.5.a.1 (IAIN).

For the addition of a new pack size where the number of units of the pack is outside the range of the currently approved pack sizes for the strength and pharmaceutical form, applicants should submit a variation B.II.e.5.a.2 (IB).

In support of a timely introduction of new pack sizes to the market, the EMA accepts the following approach for the introduction of various pack sizes falling outside the range within a single grouped submission. The biggest or the smallest pack size per strength outside the range should be classified as B.II.e.5.a.2 (IB). This presentation defines the new limits of the range so that any intermediate pack size for the strength and pharmaceutical form can be classified as B.II.e.5.a.1 (IAIN).

Some examples are provided below to illustrate the principles explained above.

Example 1

The 20 mg strength of ‘Veterinary Medicinal Product A’ currently has two approved pack sizes of 30 and 60 tablets for the pharmaceutical form ‘film-coated tablets’ and the MAH intends to apply for a new pack size of 45 tablets. The introduction of a new pack size of 45 tablets for the 20 mg strength is considered within the range of approved packs (30-60 tablets) and should be classified as variation B.II.e.5.a.1 (IAIN).

Example 2

The 20 mg strength of ‘Veterinary Medicinal Product A’ currently has two approved pack sizes of 30 and 60 tablets for the pharmaceutical form ‘film-coated tablets’ and the MAH intends to apply for a new pack size of 90 tablets. The introduction of a new pack size of 90 tablets for the 20 mg strength is considered outside the range of approved packs (30-60 tablets)and should be classified as variation B.II.e.5.a.2 (IB).

Example 3

The 20 mg strength of ‘Veterinary Medicinal Product A’ currently has two approved pack sizes of 30 and 60 tablets for the pharmaceutical form ‘film-coated tablets’ and the MAH intends to apply for two new pack sizes of 90 and 120 tablets at the same time. The introduction of a new pack size of 120 tablets for the 20 mg strength is considered outsidethe range of packs and should be classified as variation B.II.e.5.a.2 (IB). This pack size defines a new limit for the range (30-120), so that the introduction of a pack size of 90 tablets can be classified as a variation B.II.e.5.a.1 (IAIN). The MAH should therefore apply for a grouped variationof 1 x type IB - B.II.e.5.a.2 and 1 x type IAIN - B.II.e.5.a.1.

Example 4

The 20 mg and 40 mg strengths of ‘Veterinary Medicinal Product B’ currently each have two approved pack sizes of 2 and 10 pre-filled syringes for the pharmaceutical form ‘solution for injection’. The MAH intends to apply for four new pack sizes:

  • 5 and 30 pre-filled syringes for the 20 mg strength;
  • 5 and 30 pre-filled syringes for the 40 mg strength

For the 20 mg strength, the introduction of a new pack size of 5 pre-filled syringes strength is considered within the range of approved packs (2-10)and should be classified as variation B.II.e.5.a.1 (IAIN) and the introduction of a new pack size of 30 pre-filled syringes is considered outsidethe range of approved packs (2-10) and should be classified as variation B.II.e.5.a.2 (IB).

For the 40 mg strength, the introduction of a new pack size of 5 pre-filled syringes strength is considered within the range of approved packs (2-10)and should be classified as variation B.II.e.5.a.1 (IAIN) and the introduction of a new pack size of 30 pre-filled syringes is considered outsidethe range of approved packs (2-10)and should be classified as variation B.II.e.5.a.2 (IB).

The MAH should therefore apply to the EMA for a grouped variation for the abovementioned scopes.

Example 5

The 50 mg strength of ‘Veterinary Medicinal Product C’ currently has two approved pack sizes of 10 and 30 tablets for the pharmaceutical form‘film coated tablets’ and the MAH intends to apply for a multipackof 30 (3x10) tablets. The introduction of a multipack 30 (3x10) tablets for the 50 mg strength is considered within the range of approved packs (10-30) and should be classified as variation B.II.e.5.a.1 (IAIN).

IMPORTANT

  • For variations introducing additional presentations or pack sizes, each additional presentation or pack size attracts separate fees (x additional presentations = x separate fees). Each presentation and pack size should therefore be declared as a separate variation on the variation application form under the section ‘variations included in this application’. There is an exception to this principle for vaccines authorised as multi-strain dossiers, in which case the single Type II concerning the replacement or addition of a serotype, strain, antigen or combination of serotypes, strains or antigens for a veterinary vaccine against avian influenza, foot-and-mouth disease or bluetongue (variation classification C.II.4) also covers within its scope the addition of associated presentations.
  • Changes to strength, pharmaceutical form and route of administration are to be submitted as an extension of a marketing authorisation.
  • For additional guidance on changes to existing presentation that can trigger new EU number(s) please see Q10, Q11 and Q15 of the EMA’s regulatory guidance for human medicinal products on Type IA, Type IB and Type II variations, respectively.

This page lists questions that marketing-authorisation holders (MAHs) may have on type-IB variations. 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.

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.

1. What changes are considered type-IB variations?

Commission Regulation (EC) No 1234/2008 (‘the Variations Regulation’) defines a minor variation of type IB as a variation that is neither a type-IA variation nor a type-II variation nor an extension. Such minor variations must be notified to the national competent authority or the European Medicines Agency by the MAH before implementation, but do not require a formal approval. Upon acknowledgement of receipt of a valid notification, the MAH must wait a period of 30 days to ensure that the notification is deemed acceptable by the national competent authority or the Agency before implementing the change ('tell, wait and do' procedure).

The European Commission guidelines on the details of the various categories of variations, on the operation of the procedures laid down in chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 and on the documentation to be submitted pursuant to those procedures (the Variations Guideline) contains examples of changes that are considered as type-IB variations. In addition, any change that is not an extension and whose classification is not determined taking into account the Classification Guideline and the recommendations delivered pursuant to Article 5 of the Variations Regulation is considered a type-IB variation by default.

When one or more of the conditions established in the Classification Guideline for a type-IA variation are not met, the concerned change may be submitted as a type-IB variation unless the change is specifically classified as a major variation of type II.

For changes which are submitted as default type-IB variations, the Agency will determine during validation whether the proposed classification as type-IB variation is appropriate before the start of the evaluation procedure (see 'how will my type-IB variation be handled?' below).

References

2. Is the (co-)rapporteur involved in type-IB variations?

Upon validation of the notification by the Agency, the Rapporteur will be involved in the evaluation of Type IB variations “How shall my Type IB variation be handled (timetable)”?

The Co-Rapporteur is not involved in Type IB variations.

3. Can I group the submission of type-IB variations? Can they be grouped with other types of variation?

MAHs may choose to group the submission of several type-IB variations for the same product into one notification. It is also possible for a MAH to group a type-IB variation with other variations for the same product (e.g. type IA, type II, extension), where applicable.

Allowed groupings are listed in annex III of the Variations Regulation. Other groupings have to be agreed in advance with the Agency. Any proposal to group clinical and quality variations should be adequately justified.

Such grouped submissions will follow the review procedure of the highest variation in the group. Please also refer to 'what type of variations can be grouped?' below.

 

Where the same minor type-IB variation affects more than one marketing authorisation from the same holder, the MAH may choose to submit these variations as one application for worksharing. Refer to 'what is worksharing and what type of variations can be subject to worksharing?' below.

References

4. How shall I present and submit my type-IB variation?

A Type IB variation notification 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 EU-CTD format.

In order to help MAHs ensuring that their type IB variations are complete and correct before submitting them to the Agency, it is strongly recommended to use the pre-notification checklist before submission of any type IB variation.

In order to facilitate the completion of a correct application form before submission to the Agency, MAHs are advised to consult the EMA/CMDh explanatory notes on the variation application form and the European Medicines Agency practical guidance on the application form for centralised type IA and IB variations.

The Commission ‘Variations Guidelines’ further specifies which elements should be included in a Type IB variation notification:

  • Cover letter (for groupings, include a short overview of the nature of the changes and indicate whether it is submitted under Article 7.2(b), i.e. it falls within one of the cases listed in Annex III of the variations regulation or it is submitted under Article 7.2(c), i.e. the grouping has been agreed with the Agency). The cover letter should contain the template table to facilitate submission and registration. The MAH should indicate when the exact same change is submitted for different products in separate IBs.
  • Procedure number - The procedure number will be assigned by the EMA only upon receipt of an eCTD application.For further details please refer to EMA Pre-submission Guidance 'How is an EMA Application/Procedure Number attributed?'
  • The completed electronic EU variation application form (eAF), including the details of the marketing authorisation concerned. Where a variation is considered a Type IB by default, a detailed justification for its submission as a Type IB notification must be included. MAHs are reminded that the variation application form should be signed by the official contact person as specified in section 2.4.3 of Part IA/Module 1. Should the official contact person not be available, an official letter of authorisation confirming the delegation of signature to a different person should be enclosed.
  • Reference to the variation code as laid down in the Annex to the Variations Guidelines, or reference to the published Article 5 Recommendation, if applicable, used for the relevant application. Applicable documentation should be clearly ticked on the extract provided, or marked as n/a if the case. If a documentation is n/a, a justification for its absence should be provided. The extract(s) can be submitted as a separate annex in module 1.2.
  • Relevant documentation in support of the proposed variation including all documentation as specified in the Annex of the Commission Variations Guidelines.
  • For variations submitted to implement changes requested by the Agency or for generic/hybrid/biosimilar medicinal products, where no new additional data are submitted by the MAH, a copy of the request should be annexed to the cover letter.
  • For procedures affecting product information without linguistic review, the revised summary of product characteristics (SmPC or Annex I), annex II, labelling (Annex IIIA) and/or package leaflet (Annex IIIB) as a full set of annexes per EU language (word highlighted and PDF clean) should be provided.
  • If the change affects Annex A, it should be provided as a separate set of document per EU language (word highlighted and pdf clean) (See specific requirements for procedures with and without linguistic review in section “When do I need a linguistic review for changes in the product information?” and “How should I submit revised product information? In all languages?”)
  • 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 Agency Labelling Review and Standards Office on a case-by-case basis.

Grouped variations

For grouped variations concerning one marketing authorisation, all variations must be declared in the variation application form. The documentation requirements for each type of variation in the group must be adhered to. However, the supportive documentation for all variations concerned should be submitted as one integrated package (i.e. there is no need to submit a separate documentation package for each variation).The present-proposed section of the application form should clearly identify the relevant eCTD sections in support of each variation. For grouped variations please refer to “Can I group the submission of Type IB variations? Can they be grouped with other types of variations?”. For grouped variations concerning more than one marketing authorisation please refer to ”What is worksharing and what types of variations can be subject to worksharing?&quot.

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. The MAH is responsible for ensuring that the Type IB variation complies fully with the data and documentation requirements as specified in the Variations Guidelines. The MAH should pay particular attention to grouping of variations, for which each change should be clearly identified as well as the related supportive documentation. A confusing dossier presentation may delay the procedure.

For more detailed queries on technical matters please contact the PA-BUS department. For procedural matters related to a Type IB notification for a specific product and in order to avoid rejection, please contact IBquery@ema.europa.eu (see also Question 12. “Who should I contact if I have a question when preparing my application?”).

Submission of Type IB Notifications

Please refer to Other question 5. How and to whom shall I submit my application.

References

5. When should I submit my type-IB variation?

There are no recommended submission dates for type IB variations with no changes to the product information or IB variations with changes to the product information which do not require linguistic review.The Agency has published recommended submission dates for Type IB variations requiring linguistic review The timetable for IB variations with linguistic review doesn’t apply to:

  • type IB variations included in a worksharing (WS) submission (as they follow WS timetable)
  • type IB variations submitted as part of a group including Type II variations and/or extensions (as they follow type II or extensions timetable).

(See specific requirements for procedures with and without linguistic review in section “When do I need a linguistic review for changes in the product information?” and “How should I submit revised product information? In all languages?”)

Where the CHMP requests a variation for generic/hybrid/biosimilar medicinal products following assessment of the same change for the reference product, 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.

References

6. When do I need a linguistic review for changes in the product information?

The linguistic review for IB variations will take place in parallel to the 30 day scientific assessment.

A linguistic review will, in general, be required for type IB variations with changes affecting the product information where the changes in wording have not previously undergone linguistic review.

Some examples of Type IB variations where a linguistic review will be performed include safety and efficacy Type IB variations affecting the product information, where the wording has not been provided by the Agency in all languages prior to the start of the procedure.

Some examples of Type IB variations where, in principle, a linguistic review will not be performed are:

  • Quality variations:
    • change in the shelf life of the finished product
    • change to the storage conditions of the finished product
    • change in the name and/or address of the marketing authorisation holder and batch release site
    • change in the name of the medicinal product
    • addition of new presentations or changes to the existing ones
  • C.I.2.a) Change in the Summary of Product Characteristics, Labelling or Package Leaflet of a generic/hybrid/biosimilar medicinal products following assessment of the same change for the reference product
  • Deletion of information from the product information
  • Change to a new version of QRD template (a linguistic review could be exceptionally deemed necessary if the change encompasses several QRD versions)
  • Implementation of safety signals following a recommendation from the PRAC where the translations have been provided to the applicant.

References

7. How will my type-IB variation be handled (timetable)?

Upon receipt of a Type IB notification, the Agency will handle the notification as follows:

a) Handling of Type IB variations included (‘foreseen’) in the Classification Guideline or covered by an Article 5 Recommendation:

Submission and validation

The Agency will check within 7 calendar days whether the variation is correct and complete (‘validation’) before the start of the evaluation procedure.

DayAction
Day xReceipt of type-IB variation
Day x+1Start of Agency validation

Day x+7

(in case of missing or incorrect information, 
period will be extended to accommodate a 
Validation Supplementary Information to the MAH)

Agency validation

Issues identified during validation will be notified to the MAH via email. The MAH will be requested to provide responses to the issues raised within 5 working days. Delayed or insufficient responses will lead to complete or partial invalidation (in case of groupings) of the application as only one request for supplementary information will be issued during the validation phase.

The Agency will send to the MAH a confirmation of the positive outcome of the validation and the start date of the procedure.

Evaluation

DayAction
Day 1Start of evaluation
By day 20Internal circulation of assessment report*
By day 30(Non-)acceptance of the variation

*Assessment Report will be sent to the applicant only at the end of the procedure not at Day 20 together with the notification IB.

Within 30 calendar days following the acknowledgement of receipt of a valid notification, the Agency will notify the MAH by Eudralink of the outcome of the procedure. The Eudralink message will contain “Notification of a Type IB variation to the terms of the Marketing Authorisation” and the Assessment Report. If the Agency has not sent the holder its opinion on the notification within 30 calendar days, the notification shall be deemed acceptable.

Submission of amended notification (responses to Request for Supplementary Information (RSI)):

DayAction
By day 30Non-acceptance of the variation (RSI)
By day 60Submission of an amended notification
(submission of responses to RSI by MAH)

In case of an unfavourable outcome the MAH may, within 30 calendar days, amend the notification to take due account of the grounds for the non-acceptance of the variation. If the MAH does not amend the notification as requested, the notification shall be rejected.

Evaluation (assessment of responses to RSI)

DayAction
Day 60Receipt of an amended notification
By day 80Internal circulation of assessment report
By day 90Final (Non-)acceptance of the variation

Within 30 calendar days of receipt of the amended notification, the Agency will inform the MAH of its final (non-)acceptance of the variation and whether the Commission Decision granting the Marketing Authorisation 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.

Where Type IB Variations affect the Annexes to the Marketing Authorisation, such changes can be implemented without awaiting the update of the Commission Decision and the agreed change(s) should be included in the Annexes of any subsequent Regulatory Procedure.

b)Handling of Type IB variations claimed by the MAH to be IB variations by default:

The Agency will check within 7 calendar days whether the proposed change can be considered a minor variation of Type IB, and whether the notification is correct and complete (‘validation’) before the start of the evaluation procedure. In exceptional cases, the Agency may have to consult with the Rapporteur on the appropriate classification of the variation, which may lead to a slightly longer validation period (up to 10 working days).

When the Agency is of the opinion that the proposed variation may have a significant impact on the quality, safety or efficacy of the medicinal product, the MAH will be notified that the applied change cannot be handled as a Type IB and that the variation will have to be reclassified as a Type II variation. As a consequence, the MAH will be requested to revise and supplement its variation application so that the requirements for a Type II variation application are met.

Following receipt of the valid revised variation application, a Type II assessment procedure will be initiated according to the Agency procedural timetables for Type II variation.

When the Agency is of the opinion that the proposed variation can be considered a Type IB variation, the MAH will be informed of the outcome of the validation and of the start date of the procedure. The Type IB notification will be handled as set-out in section a) above.

c)Handling of Groupings of Minor Variations (Type IB/Type IA)

For grouping of minor variations, where not all of the changes applied for can be positively validated, all valid and not valid variations will be clearly listed in the validation outcome correspondence.

Where a Type IB by default variation, within a group of variations, has to be reclassified as a Type II variation, the MAH will be requested to confirm whether this variation should remain in the group. If confirmed, the whole group will be handled as a Type II variation, as set out in b) above.

Where several Type IB variations are submitted as part of one notification, it will be clearly specified in the final Agency notification which variation(s) have been accepted or rejected following assessment, unless some of the variations have been withdrawn by the MAH during the procedure (see grouping Q&A).

8. What fee do I have to pay for a type-IB variation?

For information on the fee applicable for type-IB variations, please refer to fees payable to the European Medicines Agency. Such fees cover all authorised strengths, pharmaceutical forms and presentations of a given medicinal product.

For variations introducing additional presentations or pack sizes, each additional presentation or pack size attracts separate fees (x additional presentations = x separate fees). Each presentation and pack size should therefore be declared as a separate variation on the variation application form under the section ‘variations included in this application’.

Grouped type-IB variations, whether consequential or not, will each attract a separate type-IB fee.

The fee will become due on the date of the notification of the administrative validation to the applicant and fees will be payable within 45 calendar days of the date of the notification. After approximately 15 days, an invoice will be sent to the applicant's billing address held on the Agency’s files.

The invoice will contain details of the product and type of procedure involved, the fee amount, the customer purchase order number associated with the procedures invoiced and financial information.

Applicants requiring a purchase order number or similar references on the invoice are requested to clearly indicate it on the cover letter or application form accompanying the dossier. The Agency does not accept stand-alone notifications of purchase order numbers that are not associated with a dossier. Applicants not requiring a purchase order number on the invoice should also clearly state this in the cover letter. Applicants are requested to provide this information in the cover letter template.

Guidance on how to pay an invoice is available.

References

9. Do I have to submit mock-ups and specimens?

For information concerning submission of mock-ups and specimens in the framework of post-authorisation procedures, section 3.4 Other post-authorisation procedures in the document Checking process of mock-ups and specimens of outer / immediate labelling and package leaflets of human medicinal products in the centralised procedure.

10. How should I submit revised product information? In all languages?

In case the Type IB notification affects any of the annexes, i.e. annex A, SPC, annex II, labelling and/or package leaflet, the affected revised product information Annexes must be submitted as follows:

  1. For Type IB procedures without linguistic review of product information:

At submission, the MAH should provide:

  • within the eCTD sequence: complete set of annexes of the product information in all EEA languages in PDF (clean)
  • electronically: complete set of annexes of the product information in all EEA languages in word (highlighted)

If Annex A is affected, please submit all EEA language versions in word (highlighted) electronically and in PDF (clean) in eCTD.

  1. For Type IB procedures with linguistic review of product information:

At submission, the MAH should provide:

  • within the eCTD sequence: complete set of Annexes of the product information in EN (only) in PDF (clean)
  • electronically: complete set of Annexes of the product information in all EEA languages in word (highlighted)

If Annex A is affected, please submit all EEA language versions in word (highlighted) electronically and in PDF (clean) in eCTD.

Upon validation of the procedure the MAH will receive the timetable for the submission of the translations of the product information for linguistic review.

In all cases the ‘complete set of Annexes’ includes Annex A (if applicable), I, II, IIIA and IIIB i.e. all authorised presentations (if applicable), 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 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. 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(s) 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 (see also “What can be considered an editorial change and how can it be submitted as part of a type IA/IB/II variation?”).

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 procedure(s) 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 Type IB variations affecting Annex A where the variation introduces a new EU sub-number, the sub-number should be included in the Annex A and in the product information texts as part of the variation application (see also “How to obtain new EU sub-numbers for a Type IB variation concerning an additional presentation? (e.g. new pack-size)?”).

Similarly, in case of a deletion of a pharmaceutical form/strength(s), the amended Annex A and product information Annexes should be provided as part of the Variation application.

11. What changes will trigger new EU number(s) (additional presentation(s))? Rev. Dec 2017

Any changes in the number of units of medicinal product or medical device being an integral part of the medicinal product (e.g. prefilled syringes) will trigger a different EU number.
Differentiation should be made between the addition of a presentation where the two presentations will co-exist on the market on a long-term basis versus a replacement of a presentation where the new presentation will replace the previous one (it is expected that for a certain period of time, the two presentations will co-exist on the market until the stock of the previous presentation runs out).

In principle, a replacement of one presentation by another presentation does not trigger a new EU number, unless the number of units of medicinal product or medical device being an integral part of the medicinal product (e.g. prefilled syringes) is changed.
Examples of changes in presentations for replacement, not triggering a new EU number (this is not an exhaustive list):

  • Replacement of the primary or secondary packaging,
  • Changes in the number of medical devices not being integral part of the medicinal product,
  • Change in composition (e.g. change in excipients),
  • Change in units per blisters (without change to the total number of units per pack).

Examples of changes in presentations for replacement, triggering a new EU number (this is not an exhaustive list):

  • 30 to 60 tablets,
  • 2 prefilled syringes containing the medicinal product instead of one prefilled syringe.

In case of addition, as the presentations will co-exist on the market, two packs with different contents cannot be covered by the same EU number and will be considered as different presentations.

Changes in the number of any unit (not restricted to the medicinal product) or changes in the specifications of any unit (not restricted to the medicinal product) contained in the pack will trigger a new EU number.

Examples of changes that will trigger new EU numbers (this is not an exhaustive list):

  • Introduction of an alternative injection kit with a different number of syringes or swabs,
  • Introduction of an alternative syringe of different volume or an alternative syringe with a needle guard,
  • Introduction of an alternative immediate (primary) packaging made from a different material,
  • Introduction of an alternative shape/dimension of a pharmaceutical form (pre-rolled sealant matrix versus flat, change in size of patch).

If you have any questions on any upcoming submission, please contact us using the relevant email addresses: IAquery@ema.europa.eu or IBquery@ema.europa.eu

12. How to obtain new EU sub-numbers for a Type IB variation concerning an additional presentation (e.g. new pack-size)? Rev. Dec 2017

In the specific case of a Type IB Variation for an additional presentation, the new EU marketing authorisation sub-number should be requested from the Agency before submission.

The request should be sent together with a checklist and a draft Annex A (in English only) to newEUnumber@ema.europa.eu with a copy to the product shared mailbox and should be made at least 5 working days in advance of the intended submission of the variation. Once a number has been allocated, this number should subsequently be included in the Annex A and Product Information Annexes submitted together with the Variation notification.

13. How and when will the updated annexes become part of the marketing authorisation?

For type-IB variations affecting the annexes to the Commission decision, the Commission decision will generally be updated within one year, unless the type-IB variation concerns any of the changes listed in Article 23.1a(a), for which the Commission decision will be updated within two months. This would include variations related to the addition of a new therapeutic indication or modification of an existing one, addition of a new contraindication or change in posology. It is expected that such variations would be processed as type-IB variations mainly in the framework of generics and hybrids following changes to the product information of the reference medicinal product.

However, all type-IB variations affecting the annexes can be implemented without awaiting the update of the marketing authorisation and the agreed type-IB changes should be included in the annexes of any subsequent regulatory procedure.

For type-IB variations subject to yearly update of the respective Commission decision, at the end of this yearly period, the Agency will send the complete set of annexes, based on the latest approved annexes and reflecting the type-IB changes introduced during the past year as well as a line-listing of those variations pending update of the Commission decision.

Where a notification contained several type-IB variations concerning one marketing authorisation, the Commission will update the marketing authorisation with one single decision to cover all the approved minor variations.

However, where a notification or opinion affecting the annexes that is followed by an immediate Commission decision is transmitted to the Commission within this yearly period, the changes of the type-IB notifications concerned will already be included in the annexes to the notification or opinion and will consequently be reflected in the resulting Commission decision. This Commission decision will therefore replace the yearly updating of the marketing authorisation for the type-IB notifications concerned.

On the occasion of the next type-IB variation affecting the annexes, the procedure outlined above will be repeated based on the new reference point of the next type IB concerned.

See the diagram below:

14. Who should I contact if I have a question when preparing my application or during the procedure?

If you cannot find the answer to your question in the Q&A when preparing your application, please contact us using the following email address: IBquery@ema.europa.eu

The Agency aims to respond to your query within 5 working days. To help us deal with your enquiry, please provide as much information as possible including the name of the product in your correspondence.

You should submit your query once and it is important that you submit it only to one dedicated email address. If you are uncertain of on a classification of a variation as type IB or type IA please choose one of the relevant email addresses available to you (either IBquery@ema.europa.eu or IAquery@ema.europa.eu). If you seek advice on the classification of change(s), please include your proposal for classification. Your query will be channelled internally to the relevant service(s) that will respond to you.

The above email address is only applicable when you have a pre-submission query. 

Type IB variations will be handled by a dedicated team of Procedure Managers (PM). A PM will be nominated upon receipt of the variation. You will be able to contact this PM throughout the procedure.

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