Type-II variations: questions and answers

  • Email
  • Help

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

Back to top

1. What changes are considered type-II variations? Rev. February 2015

Commission Regulation (EC) No 1234/2008 (the Variations Regulation) defines a major variation of type II as a variation that is not an extension and that may have a significant impact on the quality, safety or efficacy of a medicinal product.

The Variations Regulation and the variations guideline set out a list of changes to be considered as type-II variations. In addition, any other change that may have a significant impact on the quality, safety or efficacy of the medicinal product must be submitted as a type-II variation. Refer also to 'when will my variation application be considered a type-II variation or an extension application?' below.

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

References

2. Is the co-rapporteur involved in type-II variations? Rev. February 2015

The Committee for Medicinal Products for Human Use (CHMP) co-rapporteur is normally not involved in the assessment of a type-II-variation application concerning quality, pre-clinical and most of the clinical summary-of-product-characteristics (SmPC) changes.

The involvement of the CHMP co-rapporteur is however deemed necessary for new indications.

The MAH should therefore inform the Agency (IIquery@ema.europa.eu) of an upcoming Type II application for a new indication at least 2 months before submission, so that the CHMP is informed of the future submission and can agree on the Co-Rapporteur’s involvement.

The involvement of the CHMP Co-Rapporteur in other Type II variations will be decided by the CHMP on a case-by-case basis.

Furthermore a PRAC Rapporteur may be involved, where applicable.

At the time of validation the Agency will inform the MAH of the involvement of the CHMP Co-Rapporteur and/or PRAC Rapporteur through the assessment timetable which will refer to the relevant assessment reports expected from the Co-Rapporteur and/or PRAC Rapporteur, as appropriate.

Regarding the submission of a type-II-variation application to the (co-)rapporteurs, see 'How and to whom should I submit my type-II-variation application?'

3. Can I group the submission of type-II variations? Can they be grouped with other types of variations? Rev. February 2015

MAHs may choose to group the submission of several type-II variations for the same product into one application, provided that this corresponds to one of the cases listed in annex III of the Variations Regulation or when this has been agreed upfront with the Agency.

It is also possible for a marketing authorisation holder to group a Type II variation with other variation(s) (e.g. Type IB or IA variations) or extension applications. Such grouped submissions will follow the assessment timetable of the highest variation in the group. Please also refer to What types of variations can be grouped?

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

References

4. How shall I present my type-II-variation application? Rev. July 2015

A type-II-variation application should contain the elements listed in annex IV of the Variations Regulation and should be presented in accordance with the appropriate headings and numbering of the European Union (EU) common-technical-document (CTD) format.

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

  • 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.
  • 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 GuidanceHow is an EMA Application/Procedure Number attributed?
  • The completed electronic EU variation application form (eAF) or the application form including the details of the marketing authorisation concerned. Where a variation leads to or is the consequence of other variations, a description of the relation between these variations should be provided in the appropriate section of the application form. All proposed changes should be declared in the ‘type of changes’ section of the form, and be clearly described in the 'scope' section of the form.
  • Reference to the part of the 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.
  • Supporting data relating to the proposed variations.
  • Update or addendum to quality summaries, non-clinical overviews and clinical overviews, as relevant. When non-clinical or clinical study reports are submitted, even if only one, their relevant summaries should be included in module 2.
  • For variations submitted to implement changes requested by the Agency or for generic, hybrid or biosimilar medicinal products, a copy of the request should be annexed to the cover letter.
  • In case that the changes affect SmPC, labelling and/or package leaflet, the revised product information Annexes must be submitted (see also: Type II variations - “When do I have to submit revised product information? In all languages?”).

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

For queries relating to the presentation of the application, please contact the Agency. Please also refer to “Who should I contact if I have a question when preparing my application?”.

Please also refer to the following questions which address orphan and paediatric related aspects ‘What specific requirements apply to my Type II variation for a new orphan indication?’, ‘What should I consider in case I wish to add a new non-orphan therapeutic indication to my orphan medicinal product?’ and ‘Do I need to address any paediatric requirements in my type II variation application?’.

References

5. How and to whom shall I submit my type-II-variation application?

See Other question 5. How and to whom shall I submit my application?.

6. Which submission dates (weekly or monthly) are applicable for my type II variation and when shall I submit my application? Rev. February 2015

As of March 2015 the Agency has introduced weekly start dates for the assessment of type II variations applications, in addition to the already existing monthly start dates. The aim of the new timetables (hereafter called ‘weekly-start timetables’, as opposed to ‘monthly-start timetables’) is to increase submission flexibility and allowing certain types of type II variation to start and conclude independently of the CHMP meeting periodicity.

The weekly-start timetables are applicable for the majority of the Type II variation applications that are received by the Agency.

The following minority of type II variations applications will continue to follow the monthly-start timetables:

  • extensions of indication
  • variations involving PRAC, CAT in addition to the CHMP (e.g. variations including an RMP update, assessment of non-interventional PASS results or variations for ATMPs) and
  • other variations requiring amendment of the Commission Decision granting the Marketing Authorisation within two months from CHMP Opinion (See also Question ‘Which post-opinion steps apply to my Type II variation and when can I implement the approved changes?’).

Opinions for these variations will be adopted during the CHMP plenary meetings.

For variations following the weekly-start timetable, should the need for discussion at plenary meeting or for immediate EC decision arise during the procedure, the Agency will accommodate the need for committee discussion and/or adoption of the Opinion at the CHMP plenary.

In case there is uncertainty before submission as to which timetables and submission deadlines are to be followed, MAHs can request the advice of the Agency using the pre-submission query service (IIquery@ema.europa.eu). In exceptional cases when a variation application is only identified as falling in one of the above three categories during validation, the Agency shall inform the MAH that the monthly start timetable will apply. For more information see also Question ‘How shall my Type II application be handled (timetable)?’.

In the case of both weekly and monthly start assessment timetables, the MAH shall submit their application at the latest by the recommended submission dates published on the Agency’s website (See also “Human Medicines – Procedural Timetables / Submission dates”). MAHs are reminded of their legal obligation to submit forthwith any information that becomes available which might entail the variation of the MA.

Where the CHMP requests the submission of a variation following the assessment of a post-authorisation measure (PAM), Specific Obligation (SO) or signal, MAHs must submit the corresponding variation application within the requested timeframe.

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

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

References

7. How will my type-II application be handled (timetable)? Rev. July 2015

Assessment of type II variations following a 60 day timetable may, depending on whether they need to follow the CHMP plenary meeting periodicity or not (See above Q 6. Which submission dates (weekly or monthly) are applicable for my type II variation and when shall I submit my application?), either start on a weekly basis or on specific monthly dates. Type II variation procedures following a 30-day timetable (e.g. urgent safety issues) or a 90-day timetable (i.e. new indication or amendment of an existing one) will always follow the monthly-start timetable.

For variations following a weekly-start timetable, the opinion or request for supplementary information will be adopted by the CHMP independently of the plenary meetings.

Upon receipt of a technically valid application, a dedicated Procedure Manager (PM) will be assigned to the procedure. The PM will perform validation of the content of the application. Supplementary information may be requested in order for the validation to be finalised and the procedure will commence at the next available start date after resolution of issues identified during validation. The Agency will inform the MAH of the outcome of the validation and timetable.

Variations following a 60-day timetable

(= standard timetable):

Condition:

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

Variations assessed by the CHMP only:

DayAction
Day 1Start of evaluation
Day 36Receipt of CHMP Rapporteur’s Assessment Report
Day 50Comments by other CHMP members
Day 53Receipt of CHMP Rapporteur’s updated Assessment Report*
Day 60

Adoption of the CHMP Opinion

[or Request for supplementary information]

*Updated assessment reports are optional, depending on comments received by other committee members.

Variations assessed by PRAC^ and CHMP:

DayAction
Day 1Start of evaluation
Day 30Receipt of CHMP# Rapporteur’s Assessment Report
Day 33Receipt of PRAC* Rapporteur’s Assessment Report
Day 38Comments by other PRAC members
Day 39Receipt of PRAC Rapporteur’s updated Assessment Report*
Day 46PRAC outcome
Day 50Comments by other CHMP members
Day 53Receipt of CHMP Rapporteur’s updated Assessment Report**
Day 60Adoption of the CHMP Opinion
[or Request for supplementary information]

**Updated assessment reports are optional, depending on comments received by other committee members.
^The PRAC is involved in the assessment of a type II variation, e.g. when a RMP is submitted within the variation.
#There is(are) no CHMP Rapporteur’s assessment report(s) in case of PRAC-led variations.

Variations following a 30-day timetable

Condition:

  • Changes which, in the opinion of the Committee, would benefit from a shortened assessment having regard to the urgency of the matter in particular for safety issues

Variations assessed by the CHMP only:

DayAction
Day 1Start of evaluation
Day 15Receipt of CHMP# Rapporteur’s Assessment Report
Day 20Comments by other CHMP Members
Day 23Receipt of CHMP# and PRAC Rapporteur’s updated Assessment Report*
Day 30Adoption of the CHMP Opinion
[or Request for supplementary information]

*Updated assessment reports are optional, depending on comments received by other committee members.

Variations assessed by PRAC^ and CHMP:

DayAction
Day 1Start of evaluation
Day 6Receipt of PRAC Rapporteur’s Assessment Report
Day 8Comments by other PRAC Members
Day 9Receipt of PRAC Rapporteur’s updated Assessment Report*
Day 15Receipt of CHMP Rapporteur’s Assessment Report
Day 16PRAC outcome
Day 20Comments by other CHMP Members
Day 23Receipt of CHMP Rapporteur’s updated Assessment Report*
Day 30Adoption of the CHMP Opinion
[or Request for supplementary information]

*Updated assessment reports are optional, depending on comments received by other committee members.
^The PRAC is involved in the assessment of a type II variation, e.g. when a RMP is submitted within the variation.
#There is(are) no CHMP Rapporteur’s assessment report(s) in case of PRAC-led variations.

In exceptional cases, this timetable could be further shortened.

Variations following 90-day timetable

Condition:

  • For variations concerning changes to or addition of therapeutic indications.
DayAction
Day 1Start of evaluation
Day 56Receipt of CHMP (Co-) Rapporteur’s Assessment Report
Day 63Receipt of PRAC^ Rapporteur’s Assessment Report
Day 68Comments by other PRAC members
Day 76PRAC outcome
Day 80Comments by other CHMP members
 Day 83Receipt of CHMP Rapporteurs’ Joint Assessment Report
Day 90Adoption of the CHMP Opinion
[or Request for supplementary info]

^The PRAC is normally involved in the assessment of type II variation applications following the 90-day TT, because an (updated) RMP is usually expected to be submitted as part of the application. Absence of an RMP update should be justified at the time of submission.

In case issues which prevent the adoption of an Opinion are identified, the CHMP will adopt a request for supplementary information together with a deadline for submission of the requested data by the MAH and a timetable for the assessment of the MAH’s responses. The MAH will receive the adopted timetable together with the request for supplementary information. The clock will be stopped until the receipt of the requested supplementary information.

Any response to a request for supplementary information must be sent to the Agency, the (Co-) Rapporteur and all CHMP members, as well as PRAC members where appropriate.

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

The CHMP assessment of responses will take up to 30 or 60 days depending on the complexity and amount of data provided by the MAH. Upon receipt of the responses from the MAH, the procedure will be re-started following a weekly-start or monthly-start timetable according to the same principles as the ones applied at the initial start of procedure.

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

References

8. Which post-opinion steps apply to my type-II variation and when can I implement the approved changes? Rev. February 2015

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

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.

Re-examination

Art. 9(2) of Regulation (EC) No 726/2004, also applies to CHMP Opinions adopted for Type II variation applications. This means that the MAH may give written notice to the Agency/CHMP that he wishes to request a re-examination within 15 days of receipt of the opinion (after which, if he does not appeal, the opinion shall be considered as final). The grounds for the re-examination request must be forwarded to the Agency within 60 days of receipt of the opinion. In case the MAH requests that the committee consults a Scientific Advisory Group (SAG) in connection with the re-examination, the applicant should inform the CHMP as soon as possible of this request.

The CHMP will appoint different CHMP (Co-) Rapporteurs, to co-ordinate the re-examination procedure. In case a PRAC Rapporteur is deemed necessary, he/she will be appointed. Within 60 days from the receipt of the grounds for re-examination, the CHMP will consider whether its opinion is to be revised. If considered necessary, an oral explanation can be held within this 60 days timeframe.

Linguistic review

Where the product information is affected, a linguistic review of the Product Information changes will be performed. The linguistic review will start 5 days after the CHMP plenary meeting following the adoption of the CHMP opinion on the variation. The monthly linguistic review will cover all procedures affecting the annexes concluded since the latest linguistic review. The EPAR update will also consolidate all procedures concluded since the latest EPAR update.

Decision-making process

Upon receipt of a favourable CHMP opinion that requires amendments to the decision granting the marketing authorisation, the Commission will amend the marketing authorisation to reflect the variation within two months for the variations listed under Article 23(1a)(a) or within one year for other type-II variations.

Article 23(1a)(a) provides for a two-month timeframe for amending the decision granting the marketing authorisation for the following variations:

  • variations related to the addition of a new therapeutic indication or to the modifications of an existing one;
  • variations related to the addition of a new contra-indication;
  • variations related to a change in posology;
  • variations related to changes to the active substance of a seasonal, prepandemic or pandemic vaccine against human influenza;
  • other Type II variations that are intended to implement changes to the decision granting the marketing authorisation due to a significant public health concern.

All the other type-II variations will follow a yearly timeframe for update of the respective Commission decision.

 

Implementation

Type II variations listed in Article 23(1a)(a) may only be implemented once the Commission has amended the marketing authorisation and has notified the MAH accordingly. Variations related to safety issues, including urgent safety restrictions, must be implemented within a time-frame agreed by the MAH and the Agency.

Type II variations which do not require any amendment of the marketing authorisation or which follow a yearly update of the respective Commission Decision can be implemented once the MAH has been informed of the favourable outcome by the Agency. However, it is expected that where the variation includes changes to the product information, the MAH waits for the finalisation of the linguistic review process by the Agency before implementing the variation, as appropriately checked translations are considered essential for a correct implementation of the variation.

The agreed change(s) should be included in the Product Information Annexes of any subsequent regulatory procedure.

Date of revision of the text

 

The date of revision of the text to be included in section 10 of the SmPC and corresponding section of the package leaflet for variations affecting the product information should be as follows:

  • For type II variations listed in Article 23(1a)(a) this should be the date of the Commission Decision amending the marketing authorisation;
  • For type II variations not listed in Article 23(1a)(a), which follow a yearly timeframe for update of the respective Commission decision, this should be the date of the adoption of the positive CHMP opinion on the variation to the terms of the marketing authorisation.

This date corresponds to the date of EC decision or CHMP opinion when that specific annex was affected.

References

9. What fee do I have to pay for a type-II variation?

For information on the fees applicable for type-II 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. Reduced type-II fees may apply to certain variations.

For type-II variations that introduce 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.

Grouped type-II variations, whether consequential or not, will each attract a separate type-II 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 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 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 formatted table template.

Guidance on how to pay an invoice is available.

For type-II variations, if the variation is considered ‘invalid’ (i.e. an assessment process can not be started), an administrative fee will be charged by the Agency. See fees payable to the European Medicines Agency.

If an inspection is required, an inspection fee will be requested in addition (see 'what is the fee for a good-manufacturing-practice inspection?').

References

10. 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, please refer to the document ‘Checking process of mock-ups and specimens of outer/immediate labelling and package leaflet of human medicinal products in the centralised procedure, 3.4 Other post-authorisation procedures

References

11. When do I have to submit revised product information? In all languages? Rev. February 2015

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

At submission

  • English language: complete set of Annexes electronically only in Word format (highlighted)

At CHMP Opinion (Day 0)

  • English language: complete set of finally agreed Annexes electronically only in Word format (highlighted and clean)

After CHMP Opinion (Day +5, for variations on a weekly-start timetable, this is 5 days after the CHMP plenary meeting following the adoption of the CHMP opinion)

  • All EU languages (incl. NO+IS): complete set of annexeselectronically only in Word format (highlighted)

After Linguistic check (Day +25, for variations on a weekly-start timetable, this is 25 days after the CHMP plenary meeting following the adoption of the CHMP opinion)

  • All EU languages (incl. NO+IS): complete set of annexes electronically only in Word format (highlighted) and in PDF (clean)

Overview:

DayLanguage*Post-opinion linguistic review timetable
0EnglishElectronically
Word format (highlighted)
+5All European Economic AreaElectronically
Word format (highlighted)
+25All European Economic AreaElectronically
Word format (highlighted)

*Complete set of annexes, i.e. annexes I, II, IIIA and IIIB submitted as one document per language.

The ‘complete set of Annexes’ includes Annex, I, II, IIIA and IIIB i.e. all SmPC, labelling and PL texts for all strengths and pharmaceutical forms of the product concerned, as well as Annex II.

The complete set of Annexes must be presented sequentially (i.e. Annex I, II, IIIA, IIIB) as one document for each official EU language. Page numbering should start with "1" (bottom, centre) on the title page of Annex I. The ‘QRD Convention’ published on the Agency’s website should be followed. When submitting the full set of Annexes in PDF format, this should be accompanied by the completed formatting checklist which provides guidance on how to correctly prepare the PDF versions.

The electronic copy of all languages should be provided as part of the variation application on the Gateway / Web Client package. Highlighted changes should be indicated via ‘Tools – Track changes’. Clean versions should have all changes ‘accepted’.

Icelandic and Norwegian language versions must always be included.

The annexes provided should only reflect the changes introduced by the variation concerned. However, in exceptional cases where MAHs take the opportunity to introduce minor linguistic amendments in the texts (e.g further to a specimen check) 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, this listing may be provided as a separate document attached to the application form. Any changes not listed will not be considered as part of the variation application.

In such cases, and in cases where any other ongoing procedures may affect the product information annexes, the MAH is advised to contact the Agency in advance of submission or finalisation of the procedure concerned.

For those variations that affect Annex A (e.g. introduction of a new presentation), the following principles apply:

  • Upon adoption of the opinion, the Agency will prepare and send to the MAH the revised English Annex A reflecting the new/amended presentation.

  • After CHMP Opinion (Day +5, for variations on a weekly-start timetable, this is 5 days after the CHMP plenary meeting following the adoption of the CHMP opinion), the MAH provides the Agency with the electronic versions of the complete set of Annexes in all languages as well as the translations of the revised Annex A as a separate word document.
12. What changes will trigger new EU number(s) (additional presentation(s))? New Apr 2015

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,
  • Change in composition (e.g. change in excipients),

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 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, IBquery@ema.europa.eu or IIquery@ema.europa.eu.

13. What is the procedure for assignment of new European Union sub-numbers for a type-II variation concerning additional presentations?

At the time of the adoption of a CHMP opinion for a type-II variation that includes additional presentations, the Agency will assign the new European Union sub-numbers and include them in the revised annex A of the medicinal product, which will be transmitted to the MAH together with the CHMP opinion and respective annexes.

The MAH should include the newly assigned numbers in all language versions of annex A and in all applicable sections of the product information, which are submitted following the CHMP opinion for linguistic review.

14. Will there be any publication on the outcome of my type-II variation?

The meeting highlights following each CHMP meeting give information on opinions in relation to new indications, changes to an existing indication, and additions, changes to or removals of contraindications. This includes the name of the product, the name of the MAH and the indication. Where applicable, the CHMP gives also an update on safety information.

15. What specific requirements apply to my Type II variation for a new orphan indication?

Type-II variations for a new indication that is the same as the indication of an authorised orphan medicinal product should include relevant information in module 1.7 of the application, based on the following considerations:

  • in accordance with Article 8.1 of Regulation (EC) No 141/2000, where a marketing authorisation in respect of an orphan medicinal product has been granted in all Member States, the Community and the Member States shall not, for a period of 10 years, accept another application for marketing authorisation, or grant a marketing authorisation or accept an application to extend an existing marketing authorisation, for the same therapeutic indication, in respect of a similar medicinal product;
  • Where a designated orphan medicinal product has been authorised for the condition which covers the proposed therapeutic indication being applied for, and a period of market exclusivity is in force, the MAH must submit a report in Module 1.7.1 addressing the possible “similarity” with the authorised orphan medicinal product (even if the concerned product does not have orphan designation).

  • If the medicinal product is deemed to be “similar” to an authorised orphan medicinal product, the MAH must furthermore provide justification in Module 1.7.2 that one of the derogations laid down in Article 8.3, paragraphs (a) to (c) of the same Regulation applies, namely:
    • the holder of the marketing authorisation for the original orphan medicinal product has given his consent to the second applicant, or;
    • the holder of the marketing authorisation for the original orphan medicinal product is unable to supply sufficient quantities of the medicinal product, or;
    • the second applicant can establish in the application that the second medicinal product, although similar to the orphan medicinal product already authorised, is safer, more effective or otherwise clinically superior.

Further details can be found in the European Commission guideline on aspects of the application of Article 8(1) and (3) of Regulation (EC) No 141/2000: Assessing similarity of medicinal products versus authorised orphan medicinal products benefiting from market exclusivity and applying derogations from that market exclusivity.

Even if the variation does not concern an orphan designated product, all MAHs should still check whether their claimed new indication would potentially overlap with the indication of authorised orphan medicinal products, as listed in the Community register of designated orphan medicinal products, and include the relevant documentation in their variation application as set out above.

References

16. What should I consider if I wish to add a new non-orphan therapeutic indication to my orphan medicinal product?

As it is not possible to combine orphan and non-orphan indications within the same marketing authorisation, as provided for in Article 7(3) of Regulation (EC) No 141/2000 (the Orphan Regulation), if you wish to extend the therapeutic indications of your orphan medicinal product to include additional non-orphan therapeutic indications, you will have to consider the following options:

References

17. Do I need to address any paediatric requirements in my type-II variation application?

Regulation (EC) No 1901/2006, as amended (the Paediatric Regulation) lays down obligations, rewards and incentives for the development and placing on the market of medicines for use in children. The Paediatric Regulation places some obligations for the applicant when developing a new medicinal product as well as new uses of an authorised product, in order to ensure that medicines to treat children are subject to ethical research of high quality and are appropriately authorised for use in children, and to improve collection of information on the use of medicines in the various subsets of the paediatric population. The paediatric population is defined as the population between birth and the age of 18 years (meaning up to but not including 18 years).

As set out in Article 8 of the Paediatric Regulation, applications for new indications, new pharmaceutical forms or new routes of administration concerning an authorised medicinal product protected either by a supplementary protection certificate or by a patent that qualifies for the granting of such a certificate must include one of the following documents or data in order to be considered valid:

  • the results of all studies performed and details of all information collected in compliance with an agreed paediatric investigation plan (PIP). This means that the application will have to include the PIP decision but also the results in accordance with the agreed PIP;
  • an Agency decision on a PIP including the granting of a deferral. This means that the application will have to include the PIP decision including the deferral granted and if applicable, any completed studies;
  • an Agency decision granting a product-specific waiver;
  • an Agency decision granting a class waiver, together with the Agency’s confirmation letter of applicability if requested by the MAH.

This requirement applies irrespective of the type of application submitted for such a change, i.e. variation or extension (or new marketing-authorisation application), and irrespective of whether the change is related to adult or paediatric use.

To define what a ‘new indication’ is for the purpose of the application of Article 8, please refer to what is a new indication in the context of Article 8?

Where results of PIP studies do not support a paediatric indication, the corresponding proposal for amending the product Information may be submitted as part of a variation C.I.4 as per the guideline on the details of the various categories of variations: variations related to significant modifications to the SmPC.  Applicants are requested to mention the following sentence in the application form of the variation including the paediatric results and in the cover letter the following statement in the section ‘precise scope and background for change’: ‘submission of paediatric study results performed in compliance with a <completed> paediatric investigation plan which do not support a paediatric indication.'

Applicants should include a rationale supporting the proposed changes to the product information  in the clinical overview. In particular, if the PIP is completed and the results of all studies are available, the applicant should discuss whether the generated data support or not the intended paediatric indications stated in the PIP.

Inclusion of the results of all studies performed in compliance with an agreed PIP requirement in the product information is a prerequisite for benefiting from the paediatric reward (Article 36(1) of Regulation (EC) No 1901/2006).

As for all applications including results of studies performed in compliance with an agreed PIP, the applicant should also include an overview table of the PIP results in module 1.10, indicating which applications they were or are going to be submitted in, the status of the applications and their location in the present application.

In addition, in accordance with Article 8, the PIP or waiver application and the related decision should cover both the new and existing indications, routes of administration and pharmaceutical forms of the authorised medicinal product, taking into account the global-marketing-authorisation (GMA) concept together with the notion of the ‘same MAH’. Further information can be found in the procedural advice on applications for PIPs, waivers and modifications.

The data and documents required should be included in module 1.10 of the EU CTD dossier.

The following types of application are exempt from the application of Article 8:

  • generic medicinal products (Art 10(1) of Directive 2001/83/EC);
  • hybrid medicinal products (Art 10(3) of Directive 2001/83/EC);
  • similar biological medicinal products (Art 10(4) of Directive 2001/83/EC);
  • medicinal products containing active substances of well-established medicinal use (Art 10a of Directive 2001/83/EC).

Furthermore, when planning submission of their marketing-authorisation application, the applicant has to take into account also the need for a PIP compliance check.

Such a compliance check consists of verifying that the fulfilments of the measures as mentioned in the PIP decision including the timelines for the conduct of the studies or collection of the data are fulfilled. The compliance check procedure is explained in the questions and answers on the procedure of PIP compliance verification at the European Medicines Agency. Applicants are strongly recommended to apply for the compliance check before submission of the marketing-authorisation application in order not to delay the validation phase.

Further details on the format, timing and content of PIP or waiver applications as well as on the compliance check can be found in the Commission guideline. In addition, deadlines for submission of PIP or waiver applications, application templates as well as procedural advice regarding applications for PIPs, waivers and modifications and validation of new marketing-authorisation applications, variation or extension applications and compliance check with an agreed PIP are available.

References

18. What can be considered an editorial change and how can it be submitted as part of a type IA/IB/II variation? NEW May 2015

The European Commission 'Variations Guidelines’ 2013/C 223/01 specifies 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.”. Changes that can be classified as a variation as per Variations Guidelines are not considered editorial changes and should be submitted under the appropriate variation category.

Editorial changes in module 3

Provided that the above condition is fulfilled, the following changes to the Module 3 may be considered editorial: adding headers for ease of use, reordering of existing information without changing the meaning, alignment of information among/within the sections provided that it can be demonstrated what is the correct reference that had been previously agreed (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.

In practice for the Agency, “that part of the dossier” can cover sections up to the fourth level of the eCTD, as follows “3.2.S.x” or “3.2.P.x”. For example, if a variation affects section 3.2.S.2.1 editorial changes can be submitted in sections from 3.2.S.2.1 to 3.2.S.2.7.

Editorial changes should always be clearly identified in the application form as following: A brief description of the editorial changes should be provided in the Precise Scope. All the editorial changes should be listed in the present/proposed table, and a justification as to why the holder considers them ‘editorial’ (i.e. why they should not trigger a specific variation) should be provided for each change.

In addition, the MAH should provide a declaration in the ‘Precise scope and background…’ section of the application form 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 submitted within which the editorial changes are being submitted.

If the editorial changes affect sections not impacted by any upcoming variation, the MAH may consider submitting these changes as a separate type IB variation (B.I.z or B.II.z respectively).

Editorial changes in module 4 and 5

Editorial changes in module 4 and 5 are not foreseen. Please contact us (IAquery@ema.europa.eu, IBquery@ema.europa.eu or IIquery@ema.europa.eu as relevant) in advance of an upcoming submission.

Editorial changes to the product information in module 1.3.1

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 variation impacting the product information.

Changes in the scientific content cannot be accepted as an editorial change. These changes should be classified under the scope of the relevant variation as per Variations Guidelines (e.g. Type II C.I.4). If no relevant scope is available, a variation type IB C.I.z may be appropriate.

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

Editorial changes should generally not be submitted as a separate variation and therefore no reference to a variation category is required. Should there be no upcoming variation to include the editorial changes, these could also be submitted as a stand-alone IB C.I.z if they affect the English SmPC or an Art. 61(3) notification if they only affect the PIL/labelling. If other languages are affected and in case no variation affecting the product information is upcoming, the applicants are advised to contact the Agency 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).

The editorial changes should be clearly identified in the application form as editorial changes. A brief description of the editorial changes should be provided in the precise scope of the application form. Furthermore, editorial changes should be presented in the present/proposed table or provided as a separate Annex. A statement confirming that the proposed editorial change(s) do(es) not change the content of the previously approved Product information should be provided.

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 the appropriate pre-submission query email address IAquery@ema.europa.eu, IBquery@ema.europa.eu or IIquery@ema.europa.eu as relevant.

References

19. Who should I contact if I have a question when preparing my application?

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: IIquery@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 II please choose one of the relevant email addresses available to you (either IBquery@ema.europa.eu or IIquery@ema.europa.eu). 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. A dedicated Procedure Manager (PM) will be assigned to the procedure once your application has been validated. You will be able to contact this PM throughout the procedure.

20. Who is my contact at the European Medicines Agency during an application procedure for extension of indication? NEW April 2015

The management of an application procedure for extension of indication follows the principles outlined for initial marketing authorisation application (MAA) evaluations (see separate Q&A).

The procedure manager (PM) is the primary contact for the applicant prior to submission and throughout the procedure until the decision is granted by the European Commission. The MAH will be notified of the allocated PM at time of confirmation of validation of the application.

The PM will serve as the main liaison person between the EMA product team, the Rapporteurs and the applicant. The PM, in close co-operation with the EMA product lead (EPL) and the rapporteurs, will ensure that the applicant is kept informed of all aspects related to the MAA evaluation.

The applicant should contact the PM for all questions regarding the evaluation procedure, including

  • Requests for guidance in the pre-submission phase, such as the pre-submission meeting;
  • Any type of procedural questions during the evaluation, such as availability of assessment reports and opinion documents;
  • Discussion on timetables including requests for extension of clock-stops etc.
  • Any question where guidance related to the evaluation procedure is needed; in such cases the PM will address or liaise and redirect as appropriate.

At certain milestones during the evaluation procedure, the EPL will contact the applicant for a direct exchange to facilitate the discussion on the scientific evaluation. These include:

  • Preparation and conduct of clarification meetings (where applicant requests such meeting);
  • Immediate feedback regarding scientific aspects from committee plenary discussions, where required;
  • Expectations relating to the oral explanation, including topics to be addressed;
  • Discussion of required post-authorisation measures;
  • Late-stage revisions of the product information before adoption of the final opinion.

These interactions occur in close co-operation with the Rapporteurs. Occasionally other members from the EMA Product team may contact the applicant directly to facilitate the discussion on specific aspects (e.g. risk management).

Where the applicant is in direct contact with the EPL or another member of the EMA Product Team the PM should always be copied in the correspondence.

Please see other relevant questions and answers in the EMA pre-authorisation guidance "What is the role of the EMA product team?" and "Who is my contact at the European Medicines Agency during a marketing authorisation application (MAA) evaluation procedure?" and in the EMA post-authorisation guidance "Who is my contact at the European Medicines Agency during post-authorisation procedures?" and "Who is my contact at the European Medicines Agency during the post-authorisation phase outside any evaluation procedures?".

How useful is this page?

Average rating:

 Based on 36 ratings

Add your rating:

See all ratings
6 ratings
2 ratings
2 ratings
8 ratings
18 ratings