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

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.

PDF versions of Q&As (the entire post-authorisation guidance)

European Medicines Agency post-authorisation procedural advice for users of the centralised procedure

Reference Number: EMEA-H-19984/03 Rev. 107

English (EN) (2.63 MB - PDF)

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European Medicines Agency post-authorisation procedural advice for users of the centralised procedure: document with track changes

Reference Number: EMEA-H-19984/03 Rev. 107

English (EN) (2.65 MB - PDF)

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Commission Regulation (EC) No 1234/2008 (the Variations Regulation) defines a type-II variation as a major variation 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 changes that may have a significant impact on the quality, safety or efficacy of a medicinal product must be submitted as a type-II variation.

Certain changes to a marketing authorisation, however, have to be considered to fundamentally alter the terms of this authorisation and therefore cannot be granted following a variation procedure. These changes are to be submitted as 'Extensions of marketing authorisations' and are listed in annex I of the Variations Regulation.

This annex lists three main categories of 'changes requiring an extension of marketing authorisation':

  • changes to the active substance;
  • changes to the strength, pharmaceutical form and route of administration;
  • other changes specific to veterinary medicinal products to be administered to food-producing animals or change or addition of target species.

As the case may be, an authorisation or a modification to the existing marketing authorisation will have to be issued by the European Commission.

The European Commission has published a guideline to clarify the terms 'pharmaceutical form' and 'strength' and to include relevant examples for this classification: Guideline on the categorisation of new applications versus variation applications.

This guideline on categorisation should be read in conjunction with the European Directorate for the Quality of Medicines and Healthcare (EDQM) guidance: Standard terms: Introduction and guidance for use, Regulation (EC) No 1234/2008 and Regulation (EC) No 1901/2006 and understood as follows:

  • changes to a centralised marketing authorisation listed below should be submitted as variations according to the guideline on the details of the various categories of variations to the terms of marketing authorisations:

    • addition or replacement of a presentation for a solution for injection with a different immediate container (e.g. vial, syringe, prefilled pen, cartridge or ampoule);
    • addition or replacement of a presentation for an eye-drop solution with a different immediate container.

These changes would not fall into the scope of Article 8 of Regulation (EC) No 1901/2006 (refer to 'What is a 'new pharmaceutical form' in the context of Article 8?').

In case of doubt, the MAH is advised to contact the Agency in advance of the submission.

References

The (invented) name of the medicinal product will be the same for the “extension” as it is for the existing Marketing Authorisation of the medicinal product. The addition of a qualifier (suffix) (e.g. Invented name + qualifier) is not possible within the same Marketing Authorisation as this would result in a different (invented) name. It should be clear that the complete name of the medicinal product is commonly composed of the “invented name, followed by the strength, pharmaceutical form”. The pharmaceutical form should be described by the European Pharmacopoeia's full standard term. If the appropriate standard term does not exist, a new term may be constructed from a combination of standard terms (should this not be possible, the Competent Authority should be asked to request a new standard term from the European Directorate for Quality of Medicines (EDQM) of the Council of Europe).

References

Extension applications are generally supported by a substantial amount of data, especially if accompanied by an extension of indication or other changes to the authorised therapeutic indication. As a result, the assessment timeframe is typically the same as for an initial marketing authorisation (see also question “How shall my extension applications be handled (timetable)”) and significant assessment resources need to be committed for the assessment by the Rapporteur and often also from the Co-Rapporteur (see also question “Is the Co-Rapporteur involved in extension applications”). For this reason, MAHs are requested to give advance notice of their intention to submit an extension application 6 months in advance of submission. This can be achieved by means of an email to the Product Lead, BusinessPipeline@ema.europa.eu, MAAvalidations@ema.europa.eu, the Rapporteur, Co-Rapporteur and, if applicable, PRAC Rapporteur, summarising the scope of the intended application and specifying the target submission date. The information will be used for planning purposes by the Agency and the Rapporteurs’ assessment teams.

The CHMP co-rapporteur is normally not involved in the assessment of an extension application.

However, if the extension application is grouped with a type-II variation for a new indication, the CHMP co-rapporteur would normally be involved.

Furthermore, a Pharmacovigilance Risk Assessment Committee rapporteur may be involved, where applicable.

Extension applications should be presented as follows in accordance with the appropriate headings and numbering of the EU-CTD format:

  • 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 completed electronic EU application form dated and signed by the official contact person as specified in Section 2.4.3. The EMA strongly recommends the use of a single electronic application form per submission, even if the submission concerns multiple strengths/pharmaceutical forms. The MAH should carefully fill-in the following sections of the application form i.e.:
    • In case of an extension of application, section 1.3 “Yes” should be ticked;
    • The precise scope of the change needs also to be filled-in;
    • The legal basis for an extension application corresponds to the legal basis of the initial application for the medicinal product. Therefore, relevant boxes of section 1.4 should be ticked.

Note: If the extension application is grouped with other variation(s), the variation application form should be appended to this application form. See also “What type of variations can be grouped?”

  • Supporting data relating to the proposed extension must be submitted. Some guidance on the appropriate additional studies required for applications under Article 10 of Directive 2001/83/EC or Extension Applications (also called “Annex I applications”) are available in Annex II to Chapter 1 of the Notice to Applicants
  • A full Module 1 should be provided, with justifications for absence of data/documents included in the relevant section(s) of Module 1 (e.g. in case ‘user testing’ is considered not necessary by the MAH, a justification should be included in section 1.3.4).
  • Update/Addendum to quality summaries/non-clinical overviews and clinical overviews, if appropriate, must be submitted using the appropriate headings and numbering of the EU-CTD format. When (a) non-clinical/clinical study report(s) are submitted, even if only one, their relevant summaries should be included in Module 2.
  • Module 3 of the application should only contain the relevant quality information related to the proposed extension, unless the extension is part of a group.

In order to facilitate the registration of the submission, marketing authorisation holders are required to fill in all the submission attributes through the eSubmission delivery file UI.

EMA is encouraging applicants to use the checklist to facilitate the preparation of the dossier and make the validation process more efficient. The filled-in checklist should be submitted as part of the Extension Application dossier.

In case that the changes affect the SmPC, labelling and/or package leaflet, the revised product information (PI) Annexes must be submitted (see also: Extension applications - “When do I have to submit revised product information? In all languages?”).

Working documents outside the eCTD structure:

Word formats of certain documents are required to facilitate the assessment. Applicants should include the PI, the RMP, the Module 2.3 – Update or addendum to the quality summary, Module 2.4 - Update or addendum to the non-clinical overview, Module 2.5 – Update or addendum to the clinical overview, Module 2.6 – Non-clinical summary(ies), Module 2.7 – Clinical Summary(ies) as well as the summary of the main efficacy results, when applicable in Word format as part of the ‘working documents’ outside the eCTD structure. Further details can be found in the Harmonised Technical Guidance for eCTD Submission in the EU. It is generally not necessary to include the RMP annexes in the ‘working document’ version (unless annexes are being revised).

The above requirements also apply to the submission of the validation checklist for Extension application(s) and the responses to List of Questions / List of Outstanding Issues.

Submission of responses to list of questions/list of outstanding issues:

The MAH should use the Template for response to list of questions/list of outstanding issues: Quality / Non-clinical / Clinical to respond to the List of Questions / List of Outstanding Issues. The MAH is expected to respond to all the questions directly in this response template document and submit both PDF and Word versions with their official responses in eCTD. 

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 related to the presentation of the application, please contact the Agency. Alternatively, MAHs may request a pre-submission meeting with the Agency to clarify any outstanding points.

Please also refer to the following questions which address orphan and paediatric related aspects ‘Do I need to confirm the maintenance of my orphan designation when applying for an Extension Application?’ and ‘Do I need to address any paediatric requirements in my extension application?’.

References

Article 8(1) of the Regulation (EC) No 141/2000 (“Orphan Regulation”) prevents the Agency and the Member States from accepting, for a period of 10 years, another application for a marketing authorisation, or granting a marketing authorisation or accepting an application to extend an existing marketing authorisation, for the same therapeutic indication, in respect of a similar medicinal product.

Therefore, if your application concerns an extension of a marketing authorisation, as defined in Annex I of the Regulation (EC) No 1234/2008 (“Variations Regulation”), e.g. a new pharmaceutical form or route of administration, you will have to indicate in the respective application form if any medicinal product has been designated as an orphan medicinal product for a condition relating to the therapeutic indication proposed in your application.

In advance of submission of your application for an extension of your marketing authorisation, irrespective of whether your medicinal product has been designated as orphan or not, you are advised to check the Community register of orphan medicinal products, for information on medicinal products designated as orphan.

If any of the designated orphan medicinal products has been granted a marketing authorisation in the Union, and a period of market exclusivity is in force, you will have to provide in Module 1.7.1 a similarity report addressing the possible similarity between your medicinal products and the orphan medicinal product(s) which have received a marketing authorisation.

The assessment of similarity between two medicinal products takes into consideration the following criteria:

  • Principal molecular structural features,
  • Mechanism of action and
  • Therapeutic indication.

The critical report provided in Module 1.7.1 should address the possible similarity between the proposed new medicinal product and the authorised orphan medicinal products for each of these criteria.

If significant differences exist within one or more of these criteria, the two products will not be considered as similar. These criteria are explained in the Guideline on aspects of the application of Article 8(1) and 8(3) of Regulation (EC) No 141/2000: Assessing similarity of If significant differences exist within one or more of these criteria, the two products will not be considered as similar. Commission Regulation (EC) No 847/2000 provides additional specific considerations for the definition of similar active substance applicable to chemical, biological and advanced therapy medicinal products.

If your product is considered to be similar to any authorised orphan medicinal product, you will have to provide in Module 1.7.2 justification that one of the following derogations, laid down in Article 8(3) of the Orphan Regulation applies, i.e.:

(a) the holder of the marketing authorisation for the orphan medicinal product has given his consent for submission of your application, in which case a signed letter from the MAH of the orphan medicinal product should be provided confirming the consent for submission of an application for marketing authorisation;

(b) the holder of the marketing authorisation for the orphan medicinal product is unable to supply sufficient quantities of the medicinal product, in which case the applicant should provide a report including details of the supply shortage and justify that patients’ needs in the orphan indication are not being met;

(c) the applicant can establish that their product, although similar to the orphan medicinal product already authorised, is more effective, safer or otherwise clinically superior, in which case a critical report justifying clinical superiority to the authorised product must be provided.

The assessment of similarity is conducted in parallel to the evaluation of the extension application and follows the same timetable. The assessment includes the consultation of the Quality Working Party or the Biologicals Working Party for the aspects concerning the similarity of the molecular structures of the products.

Please note that if the Agency identifies a possible similarity issue not addressed by the applicant before validation, the applicant will be asked to complete the application with information on similarity and, if applicable, on one of the derogations. Validation of the application will only proceed once the applicant has submitted either a report justifying the lack of similarity or information justifying one of the derogations in Article 8(3).

As considerable time may elapse between validation of an application and adoption of an opinion, if applicants become aware of medicinal products which have been authorised as orphans for a condition related to the therapeutic indication proposed in their application, this information should be communicated promptly to the Agency in order to arrange for the submission of updated application form and modules 1.7.1 and 1.7.2, as applicable.

In any case, the Agency will check at certain milestones of the procedure, i.e. adoption of list of questions, request for supplementary information and prior to adoption of a CHMP opinion whether new orphan medicinal products have been authorised for the same condition.

References

If the product has been designated as orphan and the extension application also includes 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 submitted via the IRIS Platform.
  • for a new therapeutic indication falling within an already authorised orphan designation, the COMP will have to consider if the specific scope of the application 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 application either a justification that the application 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 submitted via the IRIS Platform.

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 Standard operating procedure for orphan medicinal product designation and maintenance.

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 any doubts, the Agency encourages applicants to contact the Orphan Medicines Office in advance of a planned submission in order to clarify orphan requirements. Please submit your message via Send a question to the European Medicines Agency.

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

References

Please refer to question "Can a non-orphan therapeutic indication be added to an already authorised orphan medicinal product?" in the questions and answer of type-II variations.

Please refer to question 'Can a new indication based on less comprehensive data be added to an already authorised medicinal product?' in the questions and answers on type-II variations.

MAHs may choose to group the submission of one or more extensions together with one or more other 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 possible for an MAH to group extensions with other variations submission (e.g. type-II, -IB or -IA variations), where applicable. Such grouped submissions will follow the review procedure of the highest variation in the group. Refer to 'what types of variations can be grouped?'

However, no worksharing of extension applications is foreseen in the Variations Regulation.

References

Information is available on 'Submitting a post-authorisation application'. 

The MAH shall submit the Extension application in accordance with the recommended submission dates published on the Agency website (see "submission deadlines and full procedural timetables").

The MAH should submit the extension application in accordance with the recommended submission dates published on the Agency's website.

The submission deadlines and full procedural detailed timetables are published as a generic calendar: see submission dates. The published timetables identify the submission, start and finish dates of the procedures as well as other interim dates and milestones that occur during the procedure.

The Agency shall ensure that the opinion of the CHMP is given within 210 days (less any clock-stops for the applicant to provide answers to question from CHMP) in accordance with the following standard timetable. A positive opinion can be adopted either at Day 120 or Day 180 should no questions remain at these milestones. The duration of the clock-stop is described in the CHMP’s clock-stop rules. Any extension of the clock-stop must be agreed by the CHMP. If the MAH requests an extension of a clock-stop, the ‘Template for request of clock-stop extension’ should be completed and submitted to the EMA. The CHMP will review the justification for clock-stop extension. The MAHs are reminded that clock-stop extensions are agreed only exceptionally.

DayAction
1Start of the procedure
80CHMP members and the Agency receive the assessment report from the rapporteur. The Agency sends the assessment report to the MAH making it clear that it only sets out the rapporteur's preliminary conclusions. The report in no way binds the CHMP and is sent to the MAH for information only.
100The rapporteur, other CHMP members and the Agency receive comments from the members of the CHMP.
115CHMP members and the Agency receive a draft list of questions (including draft overall conclusions and draft overview of the scientific data) from the rapporteur.
120The CHMP adopts the list of questions as well as the overall conclusions and overview of the scientific data to be sent to the MAH by the Agency.
Clock stop 
121*Submission of the responses and restart of the clock.

*Target dates for the submission of the responses are published on this website

After receipt of the responses, the CHMP adopts a timetable for the evaluation of the responses. In general the following timetable will apply:

DayAction
150CHMP members and the Agency receive the response assessment report from the rapporteur. The Agency sends the assessment report to the MAH making it clear that it only sets out the rapporteur's preliminary conclusions. The report in no way binds the CHMP and is sent to the MAH for information only.
170Comments from CHMP members to the rapporteur.
180CHMP discussion and decision on the need for an oral explanation by the MAH. If oral explanation is needed, the clock is stopped to allow the MAH to prepare the oral explanation.
181Restart of the clock and oral explanation.
185Final draft of English SmPC, labelling and package leaflet sent by MAH to the rapporteur, the Agency and other CHMP members.
By 210Adoption of CHMP opinion and assessment report.

In cases where the PRAC is involved in the assessment of an extension application, e.g. when a risk-management plan (RMP) is submitted within the extension, the following time tables with PRAC milestones will apply:

DayAction
1Start of the procedure
80CHMP members and the Agency receive the assessment report from the rapporteur. The Agency sends the assessment report to the MAH making it clear that it only sets out the rapporteur's preliminary conclusions. The report in no way binds the CHMP and is sent to the MAH for information only.
87The PRAC rapporteur circulates the RMP assessment report and proposed RMP list of questions.
100The rapporteur, other CHMP members and the Agency receive comments from members of the CHMP.
101-104The PRAC adopts the PRAC RMP assessment overview and advice for the day-120 list of questions.
115CHMP members and the Agency receive a draft list of questions (including draft overall conclusions and draft overview of the scientific data) from the rapporteur.
120CHMP adopts the list of questions as well as the overall conclusions and overview of the scientific data to be sent to the MAH by the Agency.
Clock stop 
121*Submission of the responses and restart of the clock.

*Target dates for the submission of the responses are published on this website

After receipt of the responses, the CHMP adopts a timetable for the evaluation of the responses. In general the following timetable will apply:

DayAction
150CHMP members and the Agency receive the Response assessment report from the rapporteur. The Agency sends the assessment report to the MAH making it clear that it only sets out the rapporteur's preliminary conclusions. The report in no way binds the CHMP and is sent to the MAH for information only.
167The PRAC adopts the PRAC RMP assessment overview and advice for the day-180 list of outstanding issues.
170Comments from CHMP members to the rapporteur.
180CHMP discussion and decision on the need for an oral explanation by the MAH. If an oral explanation is needed, the clock is stopped to allow the MAH to prepare the oral explanation.
181Restart of the clock and oral explanation.
181 to 210Final draft of English SmPC, labelling and package leaflet sent by MAH to the rapporteur, the Agency and other CHMP members.
197The PRAC adopts the final PRAC RMP assessment overview and advice.
By 210Adoption of the CHMP opinion and assessment report.

Re-examination

Art. 9(2) of Regulation (EC) No 726/2004, also applies to CHMP Opinions adopted for Extension applications. This means that the MAH may give written notice to the EMA/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.
A positive opinion may be subject to re-examination as long as the request to re-examination relates to aspects of the opinion for which there had been objections by the Committee, further to which the applicant opted to amend the application. In such case, the applicant will need to reserve the right to re-examination when submitting the amended documentation, e.g. revised product information.
The CHMP will appoint different CHMP (Co-) Rapporteurs, to co-ordinate the appeal procedure. In case a PRAC Rapporteur is deemed necessary, he/she will be appointed. Within 60 days from the receipt of the grounds for appeal, the CHMP will consider whether its opinion is to be revised. If considered necessary, an oral explanation can be held within this 60-day timeframe. 

Decision-making process

Upon receipt of the final CHMP opinion, the Commission will, where necessary, amend the marketing authorisation to reflect the extension within the timeframes set-out in Article 9(1) of Regulation (EC) No 726/2004, i.e. within 67 days after adoption of the CHMP opinion. Detailed practical guidance on the post-opinion phase, including the linguistic checking of the amended product information annexes, is available on this website.

The outcome of the evaluation of an extension application in the centralised procedure will result in an extension or a modification of the initial marketing authorisation. Extensions may only be implemented once the Commission has amended the decision granting the marketing authorisation and has notified the holder accordingly.

References

For information on the fee applicable for an extension application for each new strength, new pharmaceutical form or new route of administration, please refer to the explanatory note on fees payable to the European Medicines Agency. Reduced extension fees apply to:

  • All quality extensions for which no new clinical data are submitted by the marketing authorisation holder.

If variations are grouped to this extension application, whether consequential or not, they will each attract a separate relevant 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 financial information and the customer purchase order number associated with the procedures invoiced (if provided in the eSubmission delivery file). The Agency does not accept stand-alone notifications of purchase order numbers that are not associated with a dossier.

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

Where an extension application is 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).

References

For information concerning submission of mock-ups and specimens in the framework of extension applications, please refer to Checking process of mock-ups and specimens of outer / immediate labelling and package leaflets of human medicinal products in the centralised procedure, 3.1 new marketing-authorisation applications and extension applications.

In case the Extension Application requires changes to the product information (e.g. new strength or pharmaceutical form), the same requirements as for a new application apply:

  • At submission and during assessment, only the English language clean and highlighted version of the product information both within the eCTD sequence (as pdf document) and in word format (working document) is submitted and reviewed. As an alternative to the submission of a highlighted product information as pdf within the eCTD sequence, proposed changes can be documented in the 'present/proposed table' of the application form or in an annex to the application form.

In addition, during the later stages of the procedure there is often a need for fast informal exchanges between the MAH 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 list of questions/outstanding issues).

  • Translations of the agreed SmPC, Annex II, labelling and package leaflet text in all languages are to be provided after adoption of the CHMP opinion. Icelandic and Norwegian language versions of the extension Annexes must be included.

More details on the translation requirements and on the linguistic review process, are available on the Agency's Website: The linguistic review process of product information in the centralised procedure - Human (EMEA/5542/02).

MAHs are reminded that, during assessment, the English product information Annexes should only include those SmPC, Labelling and/or PL relevant to the Extension Application concerned.

After adoption of the CHMP opinion, however, a complete set of Annexes for the medicinal product concerned must be submitted. A '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 &quot1&quot (bottom, centre) on the title page of Annex I. The electronic copy of all languages should be provided on the Gateway / Web Client package as part of the extension application.

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 Submission of day +25 /235 final product information annexes (human and veterinary) - QRD Form 2 and checklist which provides User guide on how to generate PDF versions of the product information - human on how to correctly prepare the PDF versions.

The Annexes provided should only reflect the changes introduced by the Extension application 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. Alternatively, a listing of proposed changes may be provided as a separate document attached to the cover letter. Any changes not listed, will not be considered as part of the extension application.

In cases where any other ongoing procedures may impact on the product information of the Extension Application, the MAH is advised to contact the Agency in advance of submission or finalisation of the procedure(s) concerned.

For extension applications which affect the Annex A (e.g. introduction of a new strength), the following principles apply:

Upon adoption of the Opinion, the Agency will prepare and send to the MAH the revised English Annex A. After CHMP Opinion (Day 215), 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.

Please be reminded that in accordance with Union data protection requirements, no personal data should be included in the annotated PIs. This applies to the English version submitted at the time of opinion, the draft translation versions of the PI in all the languages submitted at D215 as well as the final translations submitted at 235. Please submit annotated PIs in an anonymised format (i.e. names of the reviewers removed from the track-changes). If you do not wish to do so, please ensure that the individuals whose data is included consented to its sharing with EMA and its further sharing by EMA with third parties such as other marketing authorisation applicants, marketing authorisation holders and National Competent Authorities, as relevant. EMA expressly disclaims any liability or accountability for the presence of unnecessary personal data in the annotated PI submitted by the marketing authorisation holder.

References

At the time of the adoption of a CHMP opinion for an extension application that includes additional presentations, the Agency will assign new EU 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.

Information on opinions on extension applications is not given in the meeting highlights following each CHMP meeting, unless they are grouped with a type-II variation in relation to new indications, changes to an existing indication, addition, change or removal of a contraindication.

References

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 and 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, 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 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 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 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 in module 1.10 an overview table of the PIP results, indicating in which applications they were or are going to be submitted, 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 'same marketing-authorisation holder'. Further information can be found in questions and answers: PIP guidance.

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 compliance checks consist of verifying that the the measures as mentioned in the PIP decision, including the timelines for the conduct of the studies or collection of the data, have been fulfilled. The compliance-check procedure is explained in the Questions and answers on the procedure of paediatric-investigation-plan compliance verification at the European Medicines Agency, and paediatric rewards. Applicants are strongly recommended to apply for the compliance check before submission of the marketing-authorisation application so as 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 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 Paediatric medicines: Overview.

References

 

If you cannot find the answer to your question in the Q&A when preparing your application or during the procedure, please contact the Product Lead responsible for your product.

If the MAH wishes to withdraw their application for extension of marketing authorisation (MA) during assessment, it should inform the EMA Procedure Lead by providing a withdrawal letter stating that the MAH withdraws their application and indicating reasons for the withdrawal.

MAHs can address the withdrawal request to the CHMP Chairman at any point during the assessment (from validation of the application up until adoption of the CHMP opinion).

The withdrawal letter (as per the withdrawal letter template found in section 7 of the “Procedural advice on publication of information on withdrawals of applications”) should be dated and signed by the MAH/authorised representative of the MAH and sent to the EMA Procedure Lead, the EMA Procedure Assistant and product shared mailbox.

Of note, the Agency will charge the fee for the validated extension of MA, irrespective of its outcome (i.e., positive, negative or withdrawal) and publish information on withdrawn applications accordingly.

MAHs are advised that letters for withdrawal of extension of marketing authorisation will be published on the EMA’s website (after redaction of protected personal data).

In addition, the MAH should submit within 15 days from the date of withdrawal a consolidation sequence to remove the scientific and regulatory content of the withdrawn extension of MA application from the eCTD structure and include the withdrawal letter in this sequence. The submission type should be “consolidating”.

However, not all of the content submitted in the withdrawn submission should be removed from the eCTD structure. It is useful to retain certain administrative information in the eCTD structure and some scientific or regulatory information may be used in future submissions. Therefore, the following rules should be applied:

  • In Module 1: The original cover letter, application and tracking table form should not be removed from the eCTD structure. All other documents should be removed. Particular care should be taken to remove the versions of any labelling documents associated with the withdrawn extension of MA.
  • In Module 2: All summary documents should be removed from the eCTD structure.
  • In Module 3: All content files associated with the withdrawn extension of MA should be removed so that only the previously approved/submitted content remains in the eCTD structure.
  • In Modules 4 and 5: The MAH should not remove from the eCTD structure any content unless the Agency specifically requests to remove it.

References

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