Grouping of variations: questions and answers

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This page lists questions that marketing-authorisation holders (MAHs) may have on grouping of 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.

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

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

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

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1. What types of variations can be grouped?

Article 7.2(a) of the Variations Regulation sets out the possibility for an MAH to group several type-IA and -IAIN variations under a single notification to the same relevant authority:

  • Several type-IA or -IAIN affecting one medicinal product

This means for instance that a type-IA variation that 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 or -IAIN affecting several medicinal products from the same MAH, provided that these 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 products concerned have to be taken as the 'same MAH'1.

All medicinal products concerned should be authorised through the centralised procedure.

Articles 7.2(b) and 7.2(c) 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 notification or application.
 

      

 

 

 

 

 

Article 7.2(b) applies for groupings that are listed in annex III of the Regulation whilst Article 7.2(c) applies for groupings of variations which are not listed in annex III, but which have been agreed with the Agency.

In the case of groupings under Article 7.2(c), it is recommended that the grouping is agreed between the holder and the Agency at least two months before submission.

Where the same type-IB or type-II variation or group of variations affects several medicinal products from the same MAH, the MAH may choose to submit these variations as one application for worksharing.

References


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

2. What groups of variations would be considered acceptable? Rev. December 2016

There are no conditions 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 Regulation, or, if they do not fall within one of those cases, when the grouping of the variations has 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 holder believes that the proposed group 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 (e.g. the following cases would not in principle be acceptable: both variations result in changes to the PI or all variations affect the RMP). However, applicants are generally encouraged to group related variations whenever possible e.g. variations affecting clinical safety, variations including only non-clinical studies or variations including only drug-drug interaction studies.In these cases, the scopes are related and it would be meaningful for the respective variations to be reviewed simultaneously.
  • Quality, Non-clinical and Clinical changes can normally not be grouped unless justified
  • Quality variations to the active substance can normally not 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.
  • Studies undertaken in different patient populations should in general not be grouped unless the applicant can justify why it would be beneficial to assess them together (e.g. supportive of overall clinical safety).

Table 1 presents some examples of acceptable groups of variations listed in Annex III of the Regulation, with further clarification on how such groups will be considered in practice.

Table 2 presents some examples of other groups of variations, which the Agency would or not in principle consider acceptable. Some concrete examples are also provided to illustrate proposed groupings that could be considered acceptable or not.

These tables will be reviewed and updated regularly, in view of accumulated experience.

Table 1. Grouping examples according to Article 7.2(b) of the Variation Regulation (Cases for grouping variations listed in Annex III)

1

One of the variations in the group is an extension of the marketing authorisation.

Other clinical or non-clinical changes linked to the extension (e.g. a new indication) can be grouped with the Extension application. Quality changes affecting the drug substance and/or drug product can also be included in the group.

 

Example: Extension of the marketing authorisation for a new strength/pharmaceutical form + Type II variation for new therapeutic indication concerning the already authorised strength(s)/ pharmaceutical form(s).

2

One of the variations in the group is a major variation of type II; all other variations in the group are variations which are consequential to this major variation of type II.

“A consequential variation is regarded as a change, which is an unavoidable and direct result of another change (i.e. the ‘main change’) and not simply a change which occurs at the same time.”

 

Example: Type II for new indication + Type IB or IA for addition of a new pack size required for the use in this new indication. Grouping of non-consequential quality changes may also be acceptable, under Article 7.2(c) other groups to be agreed with the Agency.

 

Table 2. Grouping examples according to Article 7.2(c) of the Variation Regulation (Cases for grouping variations agreed by the Agency)

1

Grouping of variations relating to active substance or finished product (but not to both)

Grouping acceptable

 

Example: type IB - extension of re-test period of the active substance + type IB - changes in the storage conditions of the active substance.

2

Grouping of variations relating to active substance and linked variations relating to finished product

Grouping acceptable

 

 

Example: type IB - changes to a test procedure of the active substance + type IA - deletion of a non-significant in-process control of the finished product.

3

Grouping of quality and administrative variations

Grouping acceptable (administrative change can be combined with quality change when PI Annexes are affected).

Example: type IB - extension of the shelf life of the finished product + type IA(IN) - change in the name of a manufacturer responsible for batch release + type IA - change in ATC Code.

4

Grouping of several non-clinical studies

Grouping acceptable.

Example: Provision of final study reports for 7 non-clinical in vivo studies, one of which results in consequential changes to the SmPC. The study report affecting the PI should be submitted as part of one type II variation under category C.I.4 and the remaining 6 reports as part of 6 type II variations under category C.I.13 (one variation per study report). As all 7 studies are non-clinical the scopes are related and it is considered meaningful for these variations to be reviewed simultaneously. Thus, the MAH should submit one grouped application including one type II variation under category C.I.4 and six type II variations under category C.I.13.

5

Grouping of several drug-drug interaction studies

e.g. type II - interaction study with Rifampicin + type II- interaction study with oral contraceptive

Grouping acceptable; 1 type II variation scope per interaction study, but type II variations can be grouped in 1 application.

6

Grouping of several safety changes with similar implementation timelines

Grouping acceptable

Example 1: Update of section 4.4 of the SmPC with regard to venous thrombolic events and haemorrhage events, and update of section 4.8 of the SmPC to include unrelated new ADRs, all following an update of the MAH’s product core safety data sheet based on three different sets of data.

The addition of information on venous thrombolic events to SmPC section 4.4 is based on the analysis of one data set and requires one type II variation under category C.I.4.

The addition of information on haemorrhage events to SmPC section 4.4 is based on the analysis of another data set and therefore requires one additional type II variation under category C.I.4.

The addition of the new ADRs is in this case not consequential to the changes to SmPC section 4.4 above and is supported by another data set. Thus, the addition of the new ADRs to SmPC section 4.8 constitutes one additional scope and will therefore require an additional variation under category C.I.4.

The applicant should in this case submit one grouped application including 3 type II variations under category C.I.4. The three variations are all related to clinical safety and a common assessment is meaningful.

Example 2: Update of section 4.8 of SmPC to add three new ADRs - dyspnoea and chromaturia following a review of the MAH’s safety database upon request by PRAC following a PSUSA procedure and Kounis syndrome following the MAH’s own signal detection.

As the three ADRs are supported by two separate data sets the MAH should submit two variations as part of a grouped application; one type II variation under category C.I.3.b to add dyspnoea and chromaturia and one type II variation under category C.I.4 to add Kounis syndrome. Both variations are related to clinical safety and it is meaningful to assess them together.

7

Grouping of several variations affecting the product information with different recommended or expected approval timelines

Grouping not acceptable

Example 1: Type IA(IN) to implement the outcome of signal assessment and type II safety variation.

The implementation of the signal recommendation (which includes all language translations) is meant to allow the immediate implementation of the updated Product Information wording. Grouping with a type II variation would delay the implementation, therefore this is not acceptable.

Example 2: Type IB variation to implement agreed wording in the Product Information and type II (non) clinical variation.

In principle, the grouping is not acceptable as it would delay the implementation of the agreed wording due to longer timelines and possible need for linguistic review for the type II variation.

Example 3: Type II variation to propose an extension of the authorised indication. In addition, the applicant proposes an update of the SmPC regarding hepatotoxicity based on a review of the MAH’s safety data base undertaken upon request by the CHMP following a previous PAM assessment, and an update of section 4.4 of the SmPC regarding pulmonary toxicity following a literature review.

Given the long assessment timelines for an extension of indication application and the fact that a grouped approach would delay the implementation of new safety information, the proposed grouping would not be acceptable. Hence, the extension of indication application should be submitted as a separate stand-alone type II variation under category C.I.6.a.

As the two safety topics are supported by different sets of data they should be submitted as part of two separate type II variations under category C.I.4. However, as both scopes concern clinical safety they can be submitted as one grouped application.

Thus, the applicant should submit one stand-alone type II variation under category C.I.6.a and one grouped application including two type II variations under category C.I.4.

8

Grouping of variations affecting unrelated areas of the dossier and/or unrelated aspects of the product information

Not acceptable for grouping

Example 1: Type II variation under category C.I.4 to provide 3-year clinical data based on an interim study report from study A with consequential changes to sections 4.8 and 5.1 of the SmPC. In addition, the applicant proposed to provide the final CSR for study B with consequential changes to SmPC section 5.1, and the final CSR for a drug-drug interaction study C with consequential changes to SmPC section 4.5, as well as to take the opportunity to condense the existing text in SmPC section 4.8, to align the annexes with the latest QRD templates and to implement editorial changes in the SmPC.

The provision of the interim data from study A and the consequential PI changes constitutes one type II variation under category C.I.4.

The provision of the final CSR from study B with a consequential update to section 5.1 of the SmPC constitutes a separate assessment and therefore a separate type II variation under category C.I.4 is required.

As both studies A and B are clinical (safety and/or efficacy) and affect SmPC section 5.1 it would be meaningful for these variations to be reviewed simultaneously.

The final clinical study report for study C concerns a drug-drug interaction study which is not considered consequential or related and will require a separate assessment. Therefore a separate type II variation under category C.I.4 should be submitted.

The remaining proposed changes are considered relatively minor and can be included as part of the proposed application without the need for any additional scope i.e. any additional variation.

Thus, the applicant should in this case submit one grouped application including 2 type II variations under category C.I.4 and one separate stand-alone type II variation under category C.I.4.

9

Grouping of variations in unrelated populations

Not acceptable for grouping

Example 1: Data package supportive of 2 different indications e.g. renal cell carcinoma + non-small cell lung cancer. This would not be an acceptable grouping. Separate variations should be submitted. This is because the two indication changes may follow different timelines (i.e. number of Requests for Supplementary Information) and have different outcomes, so that the approval of one indication could be delayed because of the other.

Example 2: Provision of the final CSRs for 6 clinical phase 2 and 3 studies undertaken in the same patient population without consequential changes to the PI.

The applicant should submit 6 type II variations under category C.I.13. As all 6 studies are clinical and provide safety and/or efficacy data in the same patient population, the scopes are considered related and it is considered meaningful for these variations to be reviewed simultaneously.

Thus, the applicant should submit one grouped application including six type II variations under category C.I.13.

 

3. How shall I present a grouped variations application? Rev. December 2016

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 EU-CTD format.

The submission requirements as set-out in the PAG sections for the different types of variations will also apply to grouped variations, but the application should be provided as one integrated submission package (i.e. one eCTD sequence) covering all changes resulting from the variations.

  • 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 the grouping 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 completed electronic 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 CTD sections in support of each variation
  • If the group contains an Extension, also the Module 1.2 New Application Form duly completed for the Extension should be provided (see also ”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). For example, the clinical overview and summaries should cover all data submitted as part of a grouped application i.e. all variations included. Hence the applicant should not submit several separate overviews/summaries.
  • If applicable, one 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 need for the provision of mock-ups or specimens should be discussed with the Medical Information Sector of the Agency on a case-by-case basis.

Please also refer to “How shall I present my Type II Variation application?

For a (group of) Type IA/ IAIN variation(s) concerning several marketing authorisations, please refer to “How shall I present and submit my Type IA/IA IN Variation(s)?” and TIGes Harmonised Guidance.

 

References

4. What procedure number will be given to grouped variation applications? Rev. December 2016

Several type-IA or -IAIN variations affecting one medicinal product

The usual EMA procedure number for Type IA variations will be given, with the addition of the suffix “/G”. The EMA procedure number does not distinguish between Type IA or Type IAIN.

Example: EMEA/H/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. A new procedure code (abbreviation) is used for groups of Type IA/ IAIN variations i.e. “IG”. As the ‘high-level’ number can not be allocated to one single product, the procedure number will therefore contain “xxxx” as a place-holder for the product number.

Example: EMEA/H/C/xxxx/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: PA-BUS@ema.europa.eu.

Please note that requesting this high level number in advance is mandatory for submissions sent via the eSubmission Gateway or Web Client since this number has to be included in the ‘naming convention of the file name’.

For each 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/H/C/prod_nb/IG0002/nn which was submitted as part of a Type IA/ IAIN group affecting several medicinal products “IG0002”)

  • 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/H/C/prod_nb/II/nn/G (grouping of Type II + Type IB variations)

Example: EMEA/H/C/prod_nb/IB/nn/G (grouping of 3 Type IB variations)

Example: EMEA/H/C/prod_nb/X/nn/G (grouping of Extension + Type II + Type IB variations)

MAHs are reminded that EMA 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.

5. Can grouped variations be subject to a worksharing procedure?

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 or -IAIN variations affecting several marketing authorisations, this is considered as a 'group' of variations and not a 'worksharing' procedure. However, it is possible to include a group of type-IA or -IAIN variations with a type-IB or type-II variation, which is submitted for a worksharing procedure.

6. How will grouped variation applications be handled (timetable)? What will be the outcome of the evaluation of a grouped variation application?

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.

When the group follows the timetable of the Type II variation, weekly-start timetables may apply to the assessment following the same principles as those applied to the assessment of Type II variations. For more information please refer to the following questions and answers from the post-authorisation guidance for Type II variations: ‘Which submission dates (weekly or monthly) are applicable for my type II variation and when shall I submit my application?’ and ‘ How shall my Type II application be handled (timetable)?’

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/Notification reflecting the final outcome of the procedure and in accordance with the ‘highest’ remaining approvable variation in the group. Such Opinion/Notification will therefore also list any variations which are not considered approvable, unless these have been withdrawn from the group by the holder 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 --> CHMP will adopt a positive opinion on the Type II variation only.

MAH does not withdraw the Extension from the group --> CHMP will adopt a ‘composite’ opinion 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 --> CHMP will adopt a ‘composite’ opinion 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 CHMP opinions on Extensions and Type II variations, the re-examination procedure set-out in Articles 9(2) and 34 (2) of Regulation (EC) No 726/2004 will apply.

7. How and when will the marketing authorisation be updated for grouped variations?

The post-opinion and decision-making process that will apply to grouped variations will generally be that of the ‘highest’ type of opinion or notification issued at the end of the procedure.

For information on the post-opinion and decision-making process for type-IA, -IB and -II variations, please refer to ‘how and when will the updated annexes become part of the marketing authorisation?’ and ‘which post-opinion steps apply to my type-II variation and when can I implement the approved changes?’

The decision granting the marketing authorisation following a grouped application will be amended, where necessary, within a year from the date of notification or CHMP opinion for the variation concerned with the exception of the following grouped variations:

  • groupings including an extension application, which will follow the decision-making process applicable to the extension application;
  • groupings including variations listed in Article 23.1a(a), for which the amendments to the decision granting the marketing authorisation will follow a two-month timeframe.

Where a group of type-IA or -IAIN variations to the terms of several marketing authorisations have been approved, the Commission will update the marketing authorisation with one decision per product concerned, following the yearly decision-making timeframes for type-IA and -IAIN variations.

8. What fee do I have to pay for grouped variations? Rev. August 2016

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 (e.g. orphans, generics) will apply to grouped variations.

Where a grouping application is considered ‘invalid’ (i.e. an assessment process can not 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. The Agency does not accept standalone 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 formatted table template.

Guidance on how to pay an invoice is available.

References

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