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.
- The Rules governing Medicinal Products in the European Union, Volume 6, Notice to Applicants
- Community Legislation
- 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 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?”).
- 2. Is the (Co-) Rapporteur involved in Type IB Variations?
Upon validation of the application by the Agency, the Rapporteur will be involved in the evaluation of such Type IB variations
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 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?”.
- 4. How shall I present and submit my Type IB Variation?
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 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 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.
- Where the overall design and readability of the outer and immediate packaging and/or package leaflet is affected, the need for the provision of mock-ups should be discussed with the Agency on a case-by-case basis.
For 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 sent to firstname.lastname@example.org
One electronic copy (CD-ROM or DVD or via Eudralink) 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.
One electronic copy should also be sent to the Rapporteur at the time of submission for evaluation.
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).
- 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”)
These submission dates are not 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.
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.
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.
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.
- Commission Regulation (EC) No 1234/2008 (OJ L334 of 12 December 2008)
- The Linguistic Review Process of Product Information in the Centralised Procedure
- 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.
DAY ACTION Day x Receipt of Type IB variation Day x+1 Start of Agency validation Day x+5 Agency 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.
DAY ACTION Day 1 Start of evaluation by Day 20 Receipt 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 6-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 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 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 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 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 said notification. 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. Where more than one procedure is processed in a given month a summary invoice or statement will be issued at the end of each month for payment within 30 days of the end of the month.
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. The applicants/MAHs should state the following sentence on the cover letter of each application:
Please quote Puchase Order Number ......... on the invoice.
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.
If the MAH withdraws the Type IA variation application before the review outcome fax has been sent out to the MAH, no fee will be retained.
For Type IB 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).
- Council Regulation (EC) No 297/95 (OJ L 35 of 15 February 1995), as amended
- "Explanatory note on fees payable to the European Medicines Agency)"
- 8. Do I have to submit mock-ups?
Where the Type IB variation affects the labelling and/or package leaflet, no mock-ups are required to be provided with the application.
Where the overall design and readability of the outer and immediate packaging and/or package leaflet is affected by the change then a mock-up should be submitted.
- The Revised Checking Process of Mock-Ups and Specimens (EMEA/14522/2007)
- 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) 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.
- 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 6 months. However, Type IB Variations affecting the Annexes can be implemented without awaiting the 6-monthly update of the marketing authorisation and the agreed Type IB changes should be included in the Annexes of any subsequent Regulatory Procedure.
At ‘month 6’ the Agency will send the complete set of Annexes, based on the latest approved Annexes and reflecting the Type IB change(s) introduced during the past 6 months as well as a line-listing of those Type IA/IB application(s).
Where an application 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 any Opinion affecting the Annexes is transmitted to the Commission within these 6 months, the changes of the Type IB application(s) concerned will already be included in the Annexes to the Opinion and will consequently be reflected in the resulting Commission Decision. This Commission Decision will therefore replace the 6-monthly updating of the MA for the Type IB application(s) 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 also diagram below)