Type-II variations: questions and answers

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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.

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1. What changes are considered type-II variations?

Commission Regulation (EC) No 1234/2008 (the Variations Regulation) defines a major variation of type II as a variation that is not an extension of the marketing authorisation (line 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?

The CHMP Co-Rapporteur is normally not involved in the assessment of a type II variation application concerning quality, non-clinical and clinical including product information changes and RMP updates.

However, the involvement of the CHMP Co-Rapporteur is in most cases deemed necessary for the assessment of a new therapeutic indication or modification of an approved indication (i.e. type II variations under category C.I.6.a).

The MAH should therefore inform the Agency (procedure manager) 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.

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

Regarding the submission of a Type II variation application to the (Co-) Rapporteurs, please see also Question “How and to whom shall I submit my Type II Variation application” below.

3. Is the PRAC Rapporteur involved in type II variations?

The PRAC Rapporteur will be involved in the assessment of all type II variations that include an updated RMP, and also usually when non-interventional post-authorisation safety study (PASS) results are provided. The latter refers to both imposed non-interventional studies (PASS category 1 and 2 in the RMP, and reflected in Annex II) and non-imposed non-interventional studies (PASS category 3 in the RMP). Please also refer to “How should non-clinical and/or clinical study reports be provided?” for further guidance on the submission of PASS results.

Depending on the type of data provided, either CHMP or PRAC may take the lead in the assessment of the variation. This will be decided at the time of the validation and will be communicated to the applicant.

In certain cases, where this was not a-priori identified, the CHMP may still request the involvement of the PRAC in the assessment of an application.

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

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

Marketing authorisation holders 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

5. How shall I present my type II Variation application? Rev. June 2017

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 EU-CTD format.

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

The Commission ‘Variations Guidelines’ further specifies which elements should be included in a Type II variation application. More specifically, a type II variation application should contain the following elements:

Module 1

  • 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.
  • If the variation addresses a specific post-authorisation measure (PAM), the applicant should refer to the PAM reference number in the cover letter, application form and clinical and/or non-clinical overview, as appropriate. In case the reference number for the PAM has not been confirmed by the Agency, a description of the commitment/measure is sufficient at time of submission.
  • The applicant may provide relevant documents as attachments to the cover letter, e.g.Agency requests for variations implementing changes for generic/hybrid/biosimilar medicinal products, CHMP PAM assessment reports, PRAC PSUSA assessment reports and Scientific Advice letters etc.
  • Procedure number - The procedure number will be assigned by the EMA only upon receipt of an eCTD application and does not need to be included by the applicant at the time of submission.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) including the details of the marketing authorisation(s) 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 clearly described in the ’scope’ section of the form.
  • The ‘present/proposed’ section in the application form should reflect all proposed changes to the English Product Information (SmPC, Annex II, labelling and package leaflet) as current and proposed text. Alternatively, if the proposed changes are extensive the applicant may instead provide the ‘present/proposed’ comparison as part of a separate annex to the application form. In this case, the applicant should include in the ‘present/proposed’ section of the application form a cross-reference to this annex.

Presenting all changes in a ‘present/proposed’ format is a mandatory requirement in addition to the updated Product Information provided in module 1.3.1 (see below).

For type II variations concerning quality changes, the ‘present/proposed’ table (or attachment) should reflect all changes applied for.Dossier section numbers should be provided to the lowest level possible and, where feasible, include the precise current and proposed wording as reflected in the relevant sections of the dossier. Where this is not feasible, a summary of the change(s) applied for should be included in the section.

  • Reference to the variation scope laid down in the ‘Variations Guidelines’ or reference to the published Article 5 recommendation, if applicable, should be made. The extract(s) of the ‘Variations Guidelines’ should preferably be submitted as a separate annex in module 1.2. In case of groupings the corresponding classification scopes should be indicated as many times as needed taking into account that one classification scope is to be indicated per variation.
  • Module 1.3.1 – In case changes to the Product Information are proposed, a revised full set of annexes (SmPC, Annex II, labelling and package leaflet) should be provided in English. The application must include clean and highlighted versions of the annexes, clearly showing all proposed amendments in track changes.The clean version should be provided as a PDF document in module 1.3.1 and the highlighted version preferably as a word document as part of the ‘working documents’ outside the eCTD structure. In addition, the proposed Product Information should always be included in the eCTD submission as a pdf version with track changes, as a comparison of the present and proposed wording in the application form and/or as an attachment to the application form. Please also refer to Question “When do I have to submit revised product information? In all languages?” below.
  • Module 1.4.1 – Information about the quality expert (signed and dated expert statement + CV) is mandatory for all type II variations including or referring to quality data in module 3. The quality expert is accountable for the quality overview/addendum (see below in section on Module 2).
  • Module 1.4.2 – Information about the non-clinical expert (signed and dated expert statement + CV) is mandatory for all type II variations including or referring to non-clinical data. The non-clinical expert is accountable for the non-clinical overview/addendum (see below in section on Module 2).
  • Module 1.4.3 - Information about the clinical expert (signed and dated expert statement + CV) is mandatory for all type II variations including or referring to clinical data and/or applications including an updated version of the Risk Management Plan (RMP). The clinical expert is accountable for the clinical overview/addendum (see below in section on Module 2).
  • Module 1.5.3 – When the applicant requests consideration of an additional year of market protection in accordance with Article 14(11) of Regulation (EC) No 726/2004 or an additional year of data protection in accordance with Article 10(5) of Directive 2001/83/EC, a report should be provided in this module. For further details on the content of the report, reference should be made to Eudralex Volume 2B for the Commission ‘Guidance on elements required to support the significant benefit in comparison with existing therapies of a new therapeutic indication in order to benefit from an extended (11 years) marketing protection period’ or ‘Guidance on a new therapeutic indication for a well-established substance’.
  • Module 1.8.2 - updated RMP (with revision date and version number) if applicable. When an updated RMP is proposed, the application should include both a clean and highlighted version of the revised RMP, clearly showing all proposed changes in track changes.All parts and modules of the clean RMP should be submitted in one single PDF-file. The highlighted version should also be provided as a word document in the ‘working documents’ outside the eCTD structure (see below). Please also refer to “Risk Management Plan (RMP): questions and answers”.
  • Working documents outside the eCTD structure: Additional Word formats of certain documents are required to facilitate the assessment i.e. ‘tracked changes’ versions for SmPCs, RMPs or other documents specified by the Agency. These should be provided in the separate folder ‘XXXX-working documents’. Further details can be found in the TIGes Harmonised Guidance for eCTD Submissions in the EU. It is generally not necessary to include the RMP annexes in the ‘working document’ version (unless annexes are being revised).
  • Module 1.9 – if applicable - Statement indicating that clinical trials conducted outside the EU meet the ethical requirements of Directive (EC) No 2001/20/EC, together with a listing of all trials (protocol numbers), and third countries involved. This is relevant when clinical trial reports are submitted.

Module 2

  • Module 2.3 – Update or addendum to the quality summary. A quality summary is mandatory for all quality type II variations. The document should discuss the data provided and address the impact on the Product Information (if any) and on the overall benefit/risk balance.
  • Module 2.4 - Update or addendum to the non-clinical overview. A non-clinical overview /addendum is mandatory for all non-clinical type II variations regardless of the impact on the Product Information. The document should discuss the data provided, address the impact on the Product Information and/or the RMP (if any), and conclude on the impact on the overall benefit/risk balance.
  • Module 2.5 – Update or addendum to the clinical overview. A clinical overview/addendum is mandatory for all clinical type II variations regardless of the impact on the Product Information. The document should discuss the data provided, address the impact on the Product Information and/or the RMP (if any), and conclude on the impact on the overall benefit/risk balance. It should be noted that a clinical overview/addendum is mandatory also for type II variations that only concern an update of the RMP.
  • Module 2.6 – Non-clinical summary(ies). Whenever non-clinical study reports are provided, even if only one, relevant non-clinical summary(ies) are mandatory.
  • Module 2.7 – Clinical Summary(ies). Whenever clinical study reports for interventional studies are submitted, even if only one, relevant clinical summary(ies) are mandatory. However, it should be noted that summaries are not required for non-interventional studies.

Modules 3, 4 and 5

  • Supporting quality, non-clinical and/or clinical data/study reports relating to the proposed variation(s), including literature references, should be provided.

The applicant can cross refer to information already included in the same dossier by using hyperlinks in modules 3, 4 and/or 5 rather than re-submitting the data again.

See also “How should I present a grouped-variation application?”and “How should I present a variation application under worksharing?”

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

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

 

References

6. How shall I present my application for a new or modified therapeutic indication?

In addition to the requirements foreseen in the question above, the following considerations specifically apply to applications concerning a new or a modified indication (please refer to question ‘What is considered a new or modified therapeutic indication?’):

  • The sections in the application form on orphan medicinal products and paediatric requirements should be completed for all type II variation applications under category C.I.6.a that concern a new indication. In case of doubt, advice can be requested from the Agency in advance of the submission.

Please also refer to Q&As on ‘What aspects should I consider at time of submission of a type II variation if there are orphan medicinal products designated or authorised for a condition related to my proposed therapeutic indication?’, ‘Do I need to confirm the maintenance of my orphan designation when applying for a type II variation?’, ‘Can a non-orphan therapeutic indication be added to an already authorised orphan medicinal product?’ and ‘Do I need to address any paediatric requirements in my type II variation application?’.

  • Module 1.3.4 - Consultation with target patient groups (user testing results) or a justification why this was not considered necessary should be provided for all type II variation applications under category C.I.6.a.
  • Module 1.6 – Environmental Risk Assessment (ERA), where applicable. Expert assessment with or without study report(s) or justification why not considered necessary and the CV and signature of the expert should be provided for all type II variation applications under category C.I.6.a.
  • Module 1.7.1 – Similarity assessment, as applicable. See above and also refer to Q&A ‘What aspects should I consider at time of submission of a type-II variation if there are orphan medicinal products designated or authorised for a condition related to my proposed therapeutic indication?’.
  • Module 1.8.2 - Updated RMP (with revision date and version number) or justification where not considered necessary should be provided for all type II variations applications under category C.I.6.a. The justification, where applicable, should be included in module 1.8.2 or alternatively in the cover letter and/or the clinical overview.
  • Module 1.10 – Paediatric information – if applicable - should be provided for all type II variation applications under category C.I.6.a that concern a new indication. In case of doubt, advice can be requested from the Agency in advance of the submission.

Please also refer to the following questions which address paediatric related aspects ‘Do I need to address any paediatric requirements in my type II variation application?’ and ‘What is considered a new or modified therapeutic indication?’.

7. How and to whom shall I submit my Ttype II Variation application?

See question on “How and to whom shall I submit my application?”.

8. When shall I submit my type II variation application?

The assessment timetable and hence the submission deadline applicable to a type II variation application depends on the committees involved in the assessment, the amount of assessment needed and whether the CHMP Opinion will be followed by an amendment of the Commission Decision granting the Marketing Authorisation within two months.

There are two types of submission deadlines and consequently procedure start dates: monthly and weekly ones. Weekly starts are applicable to the majority of type II variation applications received by the Agency. The following minority of type II variations applications follow a monthly start date:

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

Specific monthly start dates apply for variations involving the PRAC. Opinions for monthly start variations requiring Commission Decision within two months from CHMP Opinion (including extensions of indication) are adopted during the week of the CHMP plenary meeting. Opinions for monthly start variations involving the PRAC and not requiring Commission Decision within two months are adopted during the week of the PRAC plenary meeting. Opinions for weekly start variations are adopted independently of the committee plenary meetings.

For variations following the weekly start, the Agency may need to amend the timetable if during the procedure the need for discussion at plenary / involvement of other committees (e.g. PRAC), working parties (i.e. BWP) or for immediate EC decision arise.

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 by contacting the allocated procedure manager. The Agency will inform the MAH of the applicable timetable in the validation confirmation e-mail. For more information see also Question ‘How shall my Type II application be handled (timetable)?’.

For both weekly-start and monthly-start assessment timetables, the MAH should submit their application at the latest by the recommended submission dates published on the Agency’s website Please refer to “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

9. How shall my Type II application be handled (timetable)?

Upon receipt of a technically valid application, a dedicated procedure manager (PM) will be assigned to the procedure. The PM will perform the validation of the application content. 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 (TT).

Assessment of type II variations following a 60-day timetable may either follow a weekly or a monthly start date, depending whether the CHMP plenary meeting periodicity needs to be observed or not (See also question “When shall I submit my application?” above).

Extensions of indication on a 90-day timetable always follow the monthly start timetable as they require Commission Decision within two months from CHMP Opinion and discussion during the CHMP plenary meeting.

The majority of type II variation procedures following a 30-day timetable (e.g. urgent safety issues) will most commonly follow the monthly start timetable. This is because they are likely to require Commission Decision within two months from CHMP Opinion and discussion during the CHMP plenary meeting.

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. The MAH can also provide their responses to a request for supplementary information during the procedure in line with the weekly re-start dates.

Variations following a 60 day TT (= 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 or variations involving the PRAC (refer to question ‘Is the PRAC Rapporteur involved in Type II Variations?’) not requiring Commission Decision within two months from CHMP Opinion:

DayAction
Day 1Start of evaluation
Day 36Receipt of CHMP# Rapporteur’s Assessment Report
Day 43^Receipt of PRAC Rapporteur’s Assessment Report
Day 47^Comments by other PRAC members
Day 50Comments by other CHMP members
Day 51^Receipt of PRAC Rapporteur’s updated Assessment Report*
Day 53Receipt of CHMP# Rapporteur’s updated Assessment Report*
Day 58^PRAC outcome
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.

#There is(are) no CHMP Rapporteur’s assessment report(s) in case of PRAC-led variations.

^Steps not applicable for CHMP-only variations.

Variations assessed by PRAC (refer to question ‘Is the PRAC Rapporteur involved in Type II Variations?’) and CHMP requiring Commission Decision within two months from CHMP Opinion:

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 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 following a 30 day TT:

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 or variations involving the PRAC (refer to question ‘Is the PRAC Rapporteur involved in Type II Variations?’) not requiring Commission Decision within two months from CHMP Opinion:

DayAction
Day 1Start of evaluation
Day 15Receipt of CHMP# Rapporteur’s Assessment Report
Day 17^Receipt of PRAC Rapporteur’s Assessment Report
Day 20^Comments by other PRAC members
Day 20Comments by other CHMP Members
Day 21^Receipt of PRAC Rapporteur’s updated Assessment Report*
Day 23Receipt of CHMP# and PRAC Rapporteur’s updated Assessment Report*
Day 28^PRAC outcome
Day 30

Adoption of the CHMP Opinion

[or Request for supplementary information]

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

#There is(are) no CHMP Rapporteur’s assessment report(s) in case of PRAC-led variations.

^ Steps not applicable for CHMP-only variations.

Variations assessed by PRAC (refer to question ‘Is the PRAC Rapporteur involved in Type II Variations?’) and CHMP requiring Commission Decision within two months from CHMP Opinion:

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 30

Adoption of the CHMP Opinion

[or Request for supplementary information]

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

In exceptional cases, this timetable could be further shortened.

Variations following a 90 day TT:

Condition:

  • For variations concerning changes to or addition of therapeutic indications or for grouped variation agreed with the Agency
DayAction
Day 1Start of evaluation 
Day 56Receipt of and CHMP (Co-) Rapporteur’s Assessment Report 
Day 63^Receipt of PRAC Rapporteur’s Assessment Report 
Day 68Comments by other PRAC members^ 
Day 69^Receipt of PRAC Rapporteur’s updated Assessment Report 
Day 76^PRAC outcome 
Day 80Comments by other CHMP members 
Day 83Receipt of CHMP Rapporteurs’ Joint Assessment Report 
Day 90

Adoption 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 these are usually extensions of indication for which an (updated) RMP is normally 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.

In certain cases, the MAH may be able to respond within a few days from the CHMP adoption of the request for supplementary information. In such cases provided that the assessment of the MAH’s responses could be dealt with in 30 days, an Opinion (or additional request for supplementary information) could be adopted at the next CHMP plenary meeting. For variations following the weekly-start timetable, clock-stops in increments of weeks i.e. shorter than one month can apply. Usually, MAHs will require a clock-stop of one month in order to prepare the responses to the request for supplementary information. For clock-stops longer than 1 month the MAH should send a justified request to the EMA for agreement by the Rapporteur (and if the Rapporteur considers it necessary, by the CHMP). Such requests should ideally be sent at the latest before the adoption of the request for supplementary information. However, a request for an extension of the adopted response timetable can also be submitted during the clock-stop period after the applicant has received the adopted CHMP request for supplementary information but before the expected submission date for the responses.

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

10. How should parallel type II variations that affect the product information be handled?

When two or several stand-alone type II variation applications are being submitted and/or assessed in parallel the following general principles apply:

  • Each variation should comprise only the supporting data and Product Information change(s) and/or RMP change(s) proposed in the context of the specific variation;
  • The assessment of the different variations will be independent and the procedures will be kept separate regardless of the anticipated timelines of the different procedures;
  • The Product Information from one variation should not include the proposed Product Information changes from a different variation, neither as highlighted nor as clean text.

In order to simplify the handling of different versions of the Product Information, submissions affecting the Product Information should be whenever possible combined in a grouped variation application, if allowed by grouping rules. Please also refer to “What groups of variations would be considered acceptable?”.

Once a CHMP opinion has been adopted for a type II variation, or a Commission Decision has been granted in case an immediate EC Decision applies, the approved Product Information can be used as baseline for the Product Information of any subsequent variation(s). The consolidation can be done at the time of any procedural milestone of the subsequent variation(s) e.g. as part of the MAH’s responses to a request for supplementary information, but in any case at the latest before the adoption of the CHMP opinion.

Once included, the already approved changes related to a previous variation should appear as clean text in both the clean and highlighted versions of the Product Information for subsequent variation(s). It should be noted that only the new proposed changes related to the subsequent variation should continue to be highlighted in tracked changes during that procedure.

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

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 i.e. all variations adopted in line with the ‘weekly-start’ timetables as well as those following the ‘monthly’ timetables that have had an opinion adopted at the CHMP plenary meeting in the same month will be included. The EPAR update will also consolidate all procedures concluded since the latest EPAR update.

In the event that the only change to the Product Information concerns deletion of text or a change to numerical characters e.g. shelf life of a finished product, no post-opinion linguistic review would be necessary.

In all cases, the amended Product Information in all languages should be provided by the MAH by the date specified in the translation timetable which is provided with the CHMP opinion.

Decision-Making Process

Upon receipt of a favourable CHMP opinion which requires amendments to the decision granting the marketing authorisation, the Commission shall amend the marketing authorisation to reflect the variation within 2 months, for the variations listed under Article 23(1a)(a) or within one year for the other type II variations.

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

  • Variations related to the addition of a new therapeutic indication or to the modifications of anexisting 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, pre-pandemic 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 (e.g. when a ‘Direct Healthcare Professional Communication’ (DHPC) is agreed).

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

Where a group of variations to the terms of one marketing authorisation submitted as part of one variation have been approved, the Commission will update the marketing authorisation with one single decision to cover all the approved variations.

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.

See also question “How should parallel type II variations that affect the Product Information (PI) be handled?” above.

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

12. What fee do I have to pay for a Type II Variation?

For information on the fee applicable for Type II variations, please refer to the explanatory note on fees payable to the European Medicines Agency. Such fee covers all authorised strengths, pharmaceutical forms and presentations of a given medicinal product. Reduced Type II fees may apply to certain variations, as specified in the Explanatory note on fees payable to the EMA.

For Type II variations which introduce additional presentation/pack-size(s), each additional presentation/pack-size attracts separate fees (x additional presentations x separate fees). Each presentation/pack-size should therefore be declared as a separate variation on the variation application form.

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

Guidance on how to pay an invoice can be found on our website.

For Type II variations, if the variation is finally considered ‘invalid’ (i.e. an assessment process cannot be started), an administrative fee will be charged by the Agency (see also Explanatory note on fees payable to the EMA).

In case an inspection is required, please note that in addition an inspection fee will be requested (see also Pre-submission Guidance – “What is the fee for a GMP inspection?”).

References

13. 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

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

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

At submission

  • English language: Revised complete set of product information annexes (SmPC, Annex II, labelling and package leaflet). The application must include a clean and highlighted version of the annexes, clearly showing all proposed changes in track changes.The clean version should be provided in module 1.3.1 and the highlighted version should be provided as a word document as part of the ‘working documents’ outside the eCTD structure. The provision of a highlighted word version is mandatory as it facilitates the review of the application. The highlighted version should additionally be provided as a PDF document in module 1.3.1. Alternatively, proposed changes should be documented in the ‘present/proposed table’ of the application form or in an annex to the application form (see also question “How shall I present my Type II Variation application?” above).

During the procedure

  • English language: The MAH should take into account the assessment feedback and provide revised versions of the highlighted product information as part of the responses to any requests for supplementary information during the procedure. The revised highlighted product information that is provided at these procedural mile stones should be submitted in line with the requirements outlined above ‘at submission’.

In addition, during the latter stages of the procedure there is often a need for an informal exchange between the applicant and the Rapporteur in preparation of the final CHMP opinion. During this process the MAH can provide any revised versions of the product information as well as comments/justifications by Eudralink/email in Word format. These product information versions are considered ‘working documents’ only and there is consequently no need to submit these updated product information proposals as part of a formal eCTD sequence (unless part of formal responses to a CHMP request for supplementary information).

See also question “How should parallel type II variations that affect the PI be handled?” above.

At CHMP Opinion (Day 0)

  • English language: complete set of finally agreed product information annexes electronically only in Word format (highlighted and clean). It is sufficient to provide the final agreed annexes by Eudralink/email at this stage (i.e. before the CHMP opinion). Furthermore, the final adopted annexes should always be provided post-opinion as part of an eCTD closing sequence.

After CHMP Opinion (Day +5, for all variations with an Opinion that month – both those on a weekly-start timetable and those on a monthly-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 all variations that month – both those on a weekly-start timetable and those on a monthly-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:

Day

Lang.*

Post-opinion linguistic review Timetable

0

EN

Electronically

Word format (highlighted)

+5

All EEA

Electronically

Word format (highlighted)

+25

All EEA

Electronically

Word format (highlighted)

* = complete set of Annexes i.e. Annex 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 package leaflet 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.

At the time of the submission and throughout the procedure, the annexes provided should only reflect as highlighted text the changes introduced by the specific variation concerned. However, following adoption of the CHMP opinion it may be necessary to consolidate the adopted annexes for separate variations running in parallel, i.e. when these conclude concurrently. In that case the linguistic review will be undertaken based on the consolidated version which should reflect as highlighted text all changes for the parallel variations adopted by the CHMP at that plenary meeting and including variations adopted earlier during the month in line with the weekly-start timetable.

The section “present/proposed” in the application form should clearly list all changes proposed to the English annexes. Any minor linguistic amendments introduced for other languages should be provided as a separate document attached to the application form.

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(s) concerned.

For those variations which affect the 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.

15. What changes will trigger new EU number(s) (additional presentation(s))?

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 the allocated procedure manager.

16. What is the procedure for assignment of new European Union sub-numbers for a type II variation concerning additional presentation(s)?

At the time of the adoption of a CHMP opinion for a type II variation which includes additional presentation(s), the Agency will assign the new EU sub-numbers and include them in the revised Annex A of the medicinal product, which will be transmitted to the marketing authorisation holder together with the CHMP Opinion and respective annexes.

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

17. 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 the addition, change or removal of a contraindication. This will include the name of the product, the name of the MAH, the indication(s). Where applicable, the CHMP gives also an update on safety information.

Please refer also to “What we publish on medicines and when?”.

References

18. What specific requirements apply to my type II variation for a new orphan indication?

Type II variations for a new indication, which 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 Members 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:

(a) the holder of the marketing authorisation for the original orphan medicinal product has given his consent to the second applicant, or

(b) the holder of the marketing authorisation for the original orphan medicinal product is unable to supply sufficient quantities of the medicinal product, or

(c) 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 theEuropean 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 on the Commission Website in the “Community register” of designated orphan medicinal products and include the relevant documentation in their variation application as set-out above.

References

19. Do I need to confirm the maintenance of my orphan designation when applying for a type II variation?

If the product has been designated as orphan and the application concerns a new therapeutic indication or a modification of an existing one, in order to ensure that the Marketing Authorisation only covers indications that fulfil the orphan designation criteria foreseen in Art 3 of Regulation (EC) No 141/2000, a COMP review may be required as following:

  • for a new therapeutic indication falling within a new orphan designation, i.e. an orphan designation other than the one(s) related to the already approved indication(s), the COMP will have to confirm the maintenance of the orphan designation before authorisation of the new indication. In this case, the sponsor should provide at the time of submission a maintenance report using the template provided on the EMA website. The maintenance report should be sent directly to the Orphan Medicines Office at orphandrugs@ema.europa.eu (please copy in the procedure manager).
  • for a new therapeutic indication falling within an already authorised orphan designation, the COMP will have to consider if the specific scope of the variation raises justified and serious doubts in respect to the fulfilment of the orphan designation criteria and indicate if a formal review process of the maintenance of the orphan designation is needed

To support this process, the MAH/sponsor is requested to provide at the time of submission of the variation either a justification that the variation does not raise doubts on the fulfilment of the orphan criteria or a maintenance report to justify that the orphan criteria are still met. The justification/ maintenance report should be sent directly to the Orphan Medicines Office at orphandrugs@ema.europa.eu (please copy in the procedure manager).

Further to the COMP preliminary discussion based on the sponsor’s justification/ maintenance report, a formal review process of the maintenance of the orphan designation for the applied indication will be triggered if this raises justified and serious doubts on the maintenance of the orphan designation.In this case, if previously only a justification was submitted, the MAH/sponsor will be requested to provide a maintenance report. The procedure for assessment will follow the usual procedure, as described in Review of orphan designation at the time of granting/varying a marketing authorisation (SOP/H/3190).

For the purpose of defining what is a new therapeutic indication or a modification of an existing one for the COMP review for post-authorisation extensions of indications,the Guideline on the elements required to support the significant clinical benefit in comparison to existing therapies of a new therapeutic indication in order to benefit from an extended (11-year) marketing protection should be followed.

In case of doubts, the Agency encourages applicants to contact the Orphan Medicines Office in advance of a planned submission in order to clarify orphan requirements (orphandrugs@ema.europa.eu).

Further information can be found on the dedicated EMA Website on Orphan designation.

References

20. Can a non-orphan therapeutic indication be added to an already authorised orphan medicinal product?

As provided for in Article 7(3) of the Orphan Regulation, it is not possible to combine within the same marketing authorisation orphan and non-orphan indications. In case 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 regulatory options:

  • To apply for a separate application for marketing authorisation covering the therapeutic indications which are outside the scope of the Orphan Regulation; in this case you will have to consider the procedure to request the submission of a multiple application to the European Commission, as explained in the Q&A “If I intend to submit multiple applications for the same medicinal product?
  • To request the withdrawal of the orphan designation from the Community register of Orphan Medicinal Products for your medicinal product.

If the orphan designation is not yet withdrawn at time of submission, the marketing authorisation holder should undertake in their cover letter to request the withdrawal the orphan designation from the Community register not later than 2 days after the receipt of the CHMP opinion.

Based on this commitment, the Agency will validate the variation / MA extension application pertaining to a non-orphan indication. If the MAH has not requested the withdrawal of the Orphan designation within the said deadline, nor requested re-examination in accordance with Article 16(4) of Commission Regulation (EC) No. 1234/2008, the validation of application will become automatically null and void with retroactive effect.

When addressing to the EC their request of removal from the Community register of orphan designated medicinal products, the MAH should also copy the EMA Procedure Manager in the correspondence.

References

21. Can a new indication based on less comprehensive data be added to an already authorised medicinal product?

According to Articles 14(7) and 14(8) of the Regulation (EC) No 726/2004, a marketing authorisation can be granted in certain situations based on less comprehensive data than normally required, i.e. a conditional marketing authorisation or marketing authorisation under exceptional circumstances, respectively.

Granting these types of authorisation is only foreseen in the context of an application for an initial marketing authorisation. Therefore, when a “standard”/“full” marketing authorisation has been already granted, it is not possible to subsequently change this authorisation into a conditional marketing authorisation or a marketing authorisation under exceptional circumstances. In such case, introduction of a new indication within the same marketing authorisation will have to comply with the standard data requirements. Alternatively, submission of a separate marketing authorisation (either conditional of under exceptional circumstances) may be required, taking into account also provisions concerning multiple applications.

Nevertheless, if a product already has a conditional marketing authorisation, it is possible to modify (including extend) the indication and related specific obligations, provided that any modifications that are based on less comprehensive data comply with the requirements for a conditional marketing authorisation. These requirements are set out in Commission Regulation (EC) No 507/2006 (in particular Articles 2 and 4) and further elaborated in the respective “CHMP guideline on conditional marketing authorisation”.

Similarly, if a product has a marketing authorisation under exceptional circumstances, it is possible to modify (including extend) the indication and related specific obligations, provided that any modifications based on less comprehensive data comply with the requirements for a marketing authorisation under exceptional circumstances. These requirements are set out in Article 14 (8) of the Regulation (EC) No 726/2004 and in Part II of Annex I of Directive 2001/83/EC, and further elaborated in the respective “CHMP guideline on marketing authorisation under exceptional circumstances”.

References

22. 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 indication(s), new pharmaceutical form(s) and/or new route(s) of administration concerning an authorised medicinal product protected either by a supplementary protection certificate or by a patent which qualifies for the granting of such a certificate must include one of the following documents/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.

  • A decision of the EMA 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.

  • A decision of the EMA granting a product-specific waiver
  • A decision of the EMA 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(s) 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 is a ‘new indication’ for the purpose of the application of Article 8, please refer to the question 17 on the paediatric webpage: ‘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 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 in the clinical overview a rationale supporting the proposed changes to the Product Information. 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 indication(s) stated in the PIP.

Inclusion of the results of all studies performed in compliance with an agreed Paediatric Investigation Plan 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 in Module 1.10 an overview table of the PIP results, indicating in which application(s) they were/are going to be submitted, status of the application(s), as well as 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 ‘same marketing authorisation holder’. Further information can be found in the Procedural Advice document on “applications for PIPs, Waivers and Modifications” which is available on the Agency’s website under ‘Medicines for children’.

Those required data/documents should be included in Module 1.10 of the EU-CTD dossier.

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

  • Generics 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 substance(s) 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 to be done.

Such 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 document Questions and answers on the procedure of paediatric investigation plan compliance verification at the European Medicines Agency. Applicants are strongly recommended to apply for the compliance check before submission of the application to not 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 documents respectively regarding applications for PIPs, Waivers and Modifications and validation of new MAA, Variation/Extension applications and compliance check with an agreed PIP are available on the Agency’s website in section “Medicines for children”.

References

23. When will I get a PIP compliance statement?

The statement of compliance foreseen in Article 28(3) of Regulation (EC) No 1901/2006 is one of the prerequisites in order to be eligible for the paediatric rewards.

The following requirements have to be met for the paediatric investigation plan (PIP) compliance statement to be included in the technical dossier:

  • The MAH to include in Module 1.10 of the dossier a positive outcome of full PIP compliance check by the PDCO;
  • The results of all PIP measures should be included in the relevant modules of the dossier. If some results were already submitted, an overview table of the PIP results should be submitted in Module 1.10, indicating in which application(s) they were submitted, the status of the application(s) and the location of the last results submitted in the present application;
  • The results of all studies conducted according to the PIP reflected in the SmPC and, as applicable, Package Leaflet.

The MAH should submit the results of PIP studies or the remaining results if some were already submitted, as well as the elements mentioned above as part of a suitable variation or group of variations.

If all the above criteria are met, a PIP compliance statement will be included in the technical dossier.

The most appropriate variation classification will have to be determined based on the assessment required. A type II variation under one of the categories C.I.4 or C.I.6.a may be appropriate, depending on the proposed amendments to the product information. In some instances a type IB variation might be appropriate i.e. in situations when all data have already been assessed by the CHMP as part of a previous procedure and all results are already reflected in the product information.

For further details on the paediatric rewards please refer to “Questions and answers on the procedure of PIP compliance verification at EMA, and on paediatric rewards”.

24. Who is my contact at the European Medicines Agency during a type II variation, including extension of indications?

The procedure manager (PM) is the primary contact for the applicant prior to submission and throughout the procedure.

Extension of indication, follow the principles outlined for initial marketing authorisation application (MAA) evaluations (see separate Q&A).

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 of the application.

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?”.

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