Q&A: Grouping of variations
VeterinaryRegulatory and procedural guidance
This guidance only applies to procedures initiated under Regulation (EC) No 1234/2008 and Regulation (EU) No 712/2012. before 28 January 2022. |
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.
The guidance published under Post-authorisation procedural Q&A provides an overview for different types of post-authorisation procedures that occur frequently and, in each case, addresses a number of questions which marketing authorisation holders (MAHs) may have.
Applicants should 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.
Additional information
- The Rules governing Medicinal Products in the European Union, Volume 6, Notice to Applicants
- Community Legislation
- Commission Regulation (EC) No 1234/2008 - referred to as the ‘Variations Regulation’
- 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 (2013/C 223/01) - referred to as the ‘Variations Guidelines’, and also as the ‘Classification Guideline’ or the ‘Procedural Guideline’
Article 7.2(a) of the Variations Regulation sets-out the possibility for a marketing authorisation holder to group several Type IA/IAIN variations under a single application to the same relevant authority:
- Several Type IA or IAIN affecting one medicinal product.
This means for instance that a Type IA variation which is normally not subject to immediate notification, can be included in the submission of a Type IAIN variation.
- one Type IA or IAIN affecting several medicinal products from the same MAH.
- several Type IA and/or IAIN affecting several medicinal products from the same MAH, provided that those variations are the same for all medicinal products and are submitted to the same relevant authority.
Applicants belonging to the same mother company or group of companies and applicants having concluded agreements or exercising concerted practices concerning the placing on the market of the medicinal product(s) concerned, have to be taken as “the same marketing authorisation holder”1
All medicinal products concerned should be authorised through the centralised procedure.
Article 7.2(b) of the Variations Regulation sets-out the possibility for a marketing authorisation holder to group several types of variations affecting one medicinal product, under a single application.
The cases for which this is allowed are listed in Annex III of the Regulation. Any other grouping of variations should first be agreed between the holder and the Agency at least 2 months before submission.
Where the same Type IB or Type II variation, or group of variation(s) affect several medicinal products from the same MAH, the MAH may choose to submit these variations as one application for 'worksharing'. Please also refer to 'Can grouped variations be subject to a worksharing procedure?'.
References
No conditions apply for the grouping of Type IA/IAIN variations concerning one medicinal product.
It must be noted however, that when submitting Type IA/IAIN variations as part of a group, the legal deadlines for submission of each variation should be respected i.e. a Type IAIN should always be submitted immediately, whether or not it is grouped with other variations, and any Type IA variation should always be submitted within 12 months following its implementation.
When grouping one or more Type IA/IAIN variations affecting several centrally authorised medicinal products from the same MAH, the variation or group of variations must be the same for all medicinal products concerned.
Grouping of other types of variations is only acceptable when they fall within one of the cases listed in Annex III of the Variations Regulation, or, if they do not fall within one of those cases, when the grouping of the variations had been agreed between the Agency and the MAH before submission.
MAHs are advised to inform the Agency at least 2 months in advance of the submission of a group of variations which are not listed in Annex III of the Regulation, together with a justification as to why the MAH believes that the proposed grouping should be acceptable.
When reviewing MAH proposals for grouping of variations, the Agency will consider the following general principles:
- Changes should be consequential and/or related i.e. meaningful to be reviewed simultaneously, although a proposal to submit a grouped application cannot be based on convenience alone. However, applicants are generally encouraged to group related variations whenever possible.
- Quality, safety and efficacy changes cannot normally be grouped unless justified.
- Quality variations to the active substance cannot normally be grouped with finished product variations, unless justified.
- Grouping should not delay the submission and implementation of updates to the safety information for the medicinal product.
References
Grouped variations applications 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.
- One cover letter, clearly indicating that the application concerns a group of variations as well as which type of variation is the highest in the group. 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, declaring all variations included in the group in the section ‘type of changes’, as well as a justification for the proposed grouping in the ‘precise scope and background’ section of the application form. The present-proposed section of the application form should clearly identify the relevant dossier sections in support of each variation.
- If the group contains an Extension, the MAA-Vet application form duly completed for the Extension should also be provided (see also Q&A on extension applications “How shall I present my extension application?”).
- Supportive documentation for all variations concerned, submitted as one integrated package (i.e. there is no need to submit a separate documentation package for each variation in the group).
- If applicable, revised summary of product characteristics, labelling and/or package leaflet, including all changes applied for.
- Where the overall design and readability of the outer and immediate packaging and/or package leaflet is affected, the Agency might request the Applicant to provide specimens and mock-ups on a case-by-case basis.
For a (group of) Type IA/IAIN variation(s) concerning several marketing authorisations, please refer to the Q&A on Type IA variations “How shall I present and submit my Type IA/IAIN variation(s)?”
References
Several Type IA/IAIN variations affecting one medicinal product:
The usual procedure number for Type IA variations will be given, with the addition of the suffix “/G”.
Example: EMEA/V/C/prod_nb/IA/nn/G
One or more Type IA/IAIN variations affecting several medicinal products:
The Agency will allocate a ‘high-level’ cross-products procedure number, which will be used for the handling of procedures which affect more than one medicinal product. The procedure code “IG” is used for groups of Type IA/IAIN variations. As the ‘high-level’ number cannot be allocated to one single product, the procedure number will therefore contain “xxxx” as a place-holder for the product number.
Example: EMEA/V/C/xxxx/IG/002
This ‘high-level’ procedure number can be obtained from the Agency shortly before submission by sending your request with a copy of the draft cover letter to vet.applications@ema.europa.eu.
For each veterinary medicinal product concerned by the group of variations, the following grouping number (which includes a reference to the “IG” group to which it belongs) will be given:
Example: EMEA/V/C/prod_nb/IG/002 which was submitted as part of the 2nd Type IA/ IAIN group affecting several medicinal products received by the Agency “IG/002”)
Several types of variations affecting one medicinal product:
The Agency’s procedure number will reflect the highest type of variation in the group, with the addition of the suffix “/G”.
Example: EMEA/V/C/prod_nb/II/nn/G (grouping of Type II + Type IB variations)
Example: EMEA/V/C/prod_nb/IB/nn/G (grouping of 3 Type IB variations)
Example: EMEA/V/C/prod_nb/X/nn/G (grouping of Extension + Type II + Type IB variations)
MAHs are reminded that procedure numbers are allocated by the Agency upon receipt of the application, according to a sequential order for the product concerned which is independent from the type of regulatory procedure submitted. MAHs should therefore carefully consider which will be the next sequential procedure number for the product concerned, taking into account all other regulatory procedures which were submitted previously (or in parallel), and indicate the correct procedure number on the variation application form.
Grouped variations can be subject to a worksharing procedure, provided that the same group of variations applies to all medicinal products concerned by the worksharing procedure. However, groups including an extension application are excluded from worksharing.
Based on Articles 7 and 20 of the Variations Regulation when the grouping only consists of Type IA/ IAIN variations affecting several marketing authorisations, this is considered as a 'group' of variations and not a 'worksharing' procedure. However, it is possible to include a group of Type IA/IAIN variation(s) with a Type IB or Type II variation, which is submitted for a worksharing procedure. In such case, the review of the Type IA/IAIN variation will be performed as part of the worksharing procedure.
References
A grouped variation application will be handled and will follow the review procedure of the ‘highest’ variation type in the group.
For example:
- a group of a Type II and 3 Type IB variations will follow the timetable of the Type II variation.
- a group of an Extension and a Type II variation will follow the timetable of the Extension.
In case of grouped Type IA/IAIN variations, the Agency will issue a notification reflecting which variations are accepted or rejected. The MAH shall immediately cease to apply the rejected variation s concerned.
For grouping of other types of 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 letter.
Upon finalisation of the review of the grouped variations, the Agency will issue an opinion or notification reflecting the final outcome of the procedure and in accordance with the ‘highest’ remaining approvable variation in the group. Such opinion or notification will therefore also list any variations which are not considered approvable, unless these have been withdrawn from the group by the MAH during the procedure.
For example:
- Extension + Type II --> Extension evaluation procedure. Extension receives a negative assessment outcome (e.g. quality issues); Type II (e.g. new indication) is however positive.
MAH withdraws the Extension from the group --> CVMP will adopt a positive opinion on the Type II variation only.
MAH does not withdraw the Extension from the group --> CVMP will adopt a ‘composite’ opinion on the Extension, reflecting both the negative Extension outcome as well as the positive Type II.
- Type II + Type IB --> Type II evaluation procedure. Type II receives a negative assessment outcome; Type IB is however positive.
MAH withdraws the Type II from the group --> Agency will issue a positive notification on the Type IB variation.
MAH does not withdraw the Type II from the group --> CVMP will adopt a ‘composite’ opinion on the Type II variation, reflecting both the negative Type II outcome as well as the positive Type IB.
In any case, the assessment report will mention the initial and complete scope of the application (listing all variations initially included in the group) and will clarify the procedural timelines and steps taken during assessment.
For CVMP opinions on Extensions and Type II variations, the re-examination procedure set-out in 34 (2) of Regulation (EC) No 726/2004 will apply.
References
- Regulation (EC) No 726/2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency
The post-opinion and decision-making process that will apply to grouped variations will be that of the ‘highest’ type of opinion or notification issued at the end of the procedure.
Similarly, grouped variations can be implemented according to the provisions corresponding to the ‘highest’ type of opinion or notification issued at the end of the procedure (except for Type IA variations which are by definition already implemented before notification).
For example, if a positive opinion on a Type II variation is adopted which also includes 3 Type IB variations, the decision-making procedure for a Type II opinion will apply.
If, however, the MAH withdraws the Type II, the Agency will issue a Type IB notification of outcome which will be subject to the 12-monthly MA updating procedure, and the Type IB application can be implemented without awaiting the 12-monthly MA update.
Where a group of variations to the terms of one MA have been approved, the Commission will update the MA with one single decision to cover all the approved variations for the product concerned, following the timeframes for the ‘highest’ variation reflected in the opinion or notification.
Where a group of Type IA/IAIN variations to the terms of several MAs have been approved, the Commission will update the MA with one decision per product concerned, following the decision-making timeframes for Type IA/IAIN variations.
Grouped variations, whether consequential or not, will each attract a separate fee corresponding to the fee payable for the individual variation concerned.
Each variation applied for should therefore be declared as a separate variation on the variation application form.
The rules for reduced fees or fee reductions depending on the type of product will apply to grouped variations.
Where a grouping application is considered ‘invalid’ (i.e. an assessment process cannot be started), an administrative fee may be charged by the Agency.
Only one applicant will be invoiced for the grouped procedure. The details of the applicant to whom the invoice should be sent should be clearly stated in the cover letter.
The fee will become due on the date of the notification of the administrative validation to the applicant and will be payable within 45 calendar days of the date of the notification. After approximately 15 days, an invoice will be sent to the applicants billing address held on the Agency’s file.
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 this in the cover letter or application form accompanying the dossier, as well as in the “Customer reference” box of the delivery file to be generated for submission via the EMA Gateway. The Agency does not accept standalone notifications of purchase order numbers that are not associated with a dossier.
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