Extensions of marketing authorisations: questions and answers

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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.

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. When will my variation application be considered a type-II-variation or an extension application? Rev. November 2016

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

2. Extension applications: will my invented name change?

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

3. Is the (co-)rapporteur involved in extension applications?

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.

4. How should I present my extension application? Rev. August 2017

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 cover letter should contain the template table to facilitate submission and registration.
  • 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 case that the changes affect the SmPC, labelling and/or package leaflet, the revised product information Annexes must be submitted (see also: Extension applications - “When do I have to submit revised product information? In all languages?”).

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

For queries 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

5. What aspects should I consider at time of submission of my application for an extension of marketing authorisation of my medicinal productan extension application if there are orphan medicinal products designated or authorised for a condition related to my proposed therapeutic indication?

Article 8(1) of Regulation (EC) No 141/2000 (the 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 Regulation (EC) No 1234/2008 (the Variations Regulation), e.g. a new pharmaceutical form or route of administration, you will have to indicate 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 the respective application form.

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 orphans.

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 a similarity report in module 1.7.1 addressing the possible similarity between your medicinal products and the orphan medicinal products that 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;
  • therapeutic indication.

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 medicinal products versus authorised orphan medicinal products benefiting from market exclusivity and applying derogations from that market exclusivity.

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

  • the holder of the marketing authorisation for the orphan medicinal product has given its 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;
  • 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;
  • the applicant can establish that its 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.

For information on the procedure and timetable for assessment of similarity and, where applicable, derogation report against authorised orphan medicinal products, refer to what is the procedure and timetable for assessment of similarity and, where applicable, derogation report vis-à-vis authorised orphan medicinal products?

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 whether new orphan medicinal products have been authorised for the same condition 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.

References

6. Do I need to confirm the maintenance of my orphan designation when applying for an extension application? NEW November 2016

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 sent directly to the Orphan Medicines Office at orphandrugs@ema.europa.eu.
  • 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 sent directly to the Orphan Medicines Office at orphandrugs@ema.europa.eu.

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

7. Can a non-orphan therapeutic indication be added to an already authorised orphan medicinal product? New March 2016

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.

8. Can a new indication based on less comprehensive data be added to an already authorised medicinal product? NEW November 2016

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.

9. Can I group the submission of extensions with other types of 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

10. How, when and to whom shall I submit my extension application?

See Other question 5. on How and to whom shall I submit my 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").

11. How will my extension application be handled (timetable)?

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 will ensure that the opinion of the CHMP is given within 210 days in accordance with the following standard timetable, which can be shortened in certain circumstances, upon request of the MAH to the CHMP, agreement from the rapporteur and adoption by CHMP.

Day

Action

1

Start of the procedure

80

CHMP 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.

100

The rapporteur, other CHMP members and the Agency receive comments from the members of the CHMP.

115

CHMP members and the Agency receive a draft list of questions (including draft overall conclusions and draft overview of the scientific data) from the rapporteur.

120

The 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:

Day

Action

150

CHMP 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.

170

Comments from CHMP members to the rapporteur.

180

CHMP 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.

181

Restart of the clock and oral explanation.

185

Final draft of English SmPC, labelling and package leaflet sent by MAH to the rapporteur, the Agency and other CHMP members.

By 210

Adoption 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:

Day

Action

1

Start of the procedure

80

CHMP 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.

87

The PRAC rapporteur circulates the RMP assessment report and proposed RMP list of questions.

100

The rapporteur, other CHMP members and the Agency receive comments from members of the CHMP.

101-104

The PRAC adopts the PRAC RMP assessment overview and advice for the day-120 list of questions.

115

CHMP members and the Agency receive a draft list of questions (including draft overall conclusions and draft overview of the scientific data) from the rapporteur.

120

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:

Day

Action

150

CHMP 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.

167

The PRAC adopts the PRAC RMP assessment overview and advice for the day-180 list of outstanding issues.

170

Comments from CHMP members to the rapporteur.

180

CHMP 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.

181

Restart of the clock and oral explanation.

181 to 210

Final draft of English SmPC, labelling and package leaflet sent by MAH to the rapporteur, the Agency and other CHMP members.

197

The PRAC adopts the final PRAC RMP assessment overview and advice.

By 210

Adoption of the CHMP opinion and assessment report.

Re-examination

Article 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 Agency and CHMP that it wishes to request a re-examination within 15 days of receipt of the opinion (after which, if it 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. The CHMP will appoint different CHMP (co-)rapporteurs to coordinate the appeal procedure. If a PRAC rapporteur is deemed necessary, he or 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

12. What fee do I have to pay for an extension application? Rev. August 2016

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

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 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 standalone notifications of purchase order numbers that are not associated with a dossier. Applicants not requiring a purchase order number on the invoice should also clearly state this in the cover letter. Applicants are requested to provide this information in the formatted table template.

Guidance on how to pay an invoice is available.

Where an extension application is considered ‘invalid’ (i.e. an assessment process can not be started), an administrative fee will be charged by the Agency (see also explanatory note on fees payable to the EMA).

References

13. Do I have to submit mock-ups and specimens?

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.

14. When do I have to submit revised product information? In all languages? Rev. April 2016

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 and in word format is submitted and reviewed.
  • 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 new Product Information linguistic review process for new applications in the Centralised Procedure (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 "1" (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 formatting checklist which provides guidance 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.

References

15. What is the procedure for assignment of new EU sub-numbers for an extension including additional presentations?

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.

16. Will there be any publication on the outcome of my extension application?

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

17. Do I need to address any paediatric requirements in my extension application?

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

As set out in Article 8 of the Paediatric Regulation, applications for new indications, new pharmaceutical forms 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 <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 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 PIP compliance verification at the European Medicines Agency. Applicants are strongly recommended to apply for the compliance check before submission of the marketing-authorisation application 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 are available under questions and answers: PIP guidance and questions and answers on the procedure of PIP compliance verification at the European Medicines Agency.

References

18.Who should I contact if I have a question when preparing my application and during the procedure? Rev. June 2016

If you cannot find the answer to your question in the Question and Answer (Q&A) when preparing your application or during the procedure, please contact the Procedure Manager responsible for your product.

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