This page provides detailed guidance for companies intending to apply for a paediatric investigation plan (PIP), waiver or deferral, as well as for companies that already have an agreed PIP. The information is available as questions and answers, which the European Medicines Agency (EMA) revises as necessary.
Applicants should consult this procedural advice in conjunction with the following key document:
- Guideline on the format and content of applications for agreement or modification of a paediatric investigation plan and requests for waivers or deferrals and concerning the operation of the compliance check and on criteria for assessing significant studies
For general enquiries, including general information on PIP and waiver applications, modification procedures and compliance checks, please send a question to the EMA.
Unique product identifier number
The Agency will automatically assign unique product identifier (UPI) numbers to medicines reaching the Agency for paediatric investigation plans, orphan designation, scientific advice or protocol assistance.
Applicants will receive the UPI number by e-mail. They should quote this number every time they contact the Agency for any matter related to this specific medicine.
When making submissions to the Agency, applicants should group electronic documents into one or a few compressed (zip) files. Each zip file should not exceed 40 Mb.
When forms or templates for the electronic submission of documents are amended by the Agency, applicants can use the new forms immediately after they are published on the website; however, the old forms will still be accepted for three months after the date of the amendment.
A full list of templates and forms needed for submission of applications is available: PIPs: Templates Forms and Submission dates.
Table of contents
- Applying for a PIP, waiver or deferral
- Articles 7 and 8: Definitions
- Articles 33 and 35: Marketing a medicine authorised for a paediatric indication
- Compliance statement
- Modifying an agreed PIP
- Request for confirmation of the applicability of the Agency decision on class waivers
- PIP decisions
- Transfers and changes in contact details
- European Network for Paediatric Research at the European Medicines Agency (Enpr-EMA)
Applying for a PIP, waiver or deferral
- How and when should I submit a PIP letter of intent?
Please notify the Agency of the intent to submit an application for a PIP or a request for waiver or deferral, using the form for the letter of intent.
The letter of intent is expected at least two months before the planned start of procedure.
Please send the letter of intent to email@example.com (only), using the Agency's secure e-mail system, Eudralink . Please do not send letters of intent or applications to individual e-mail addresses within the Agency.
If you do not have a Eudralink account, please visit the online EMA Service Desk in order to open one. If you do not have a specific EMA referee contact, please use 'paediatric' as the referee.
After submitting your letter of intent, if not already assigned for a different procedure at the EMA, you will receive a Unique Product Identifier (UPI) for your medicinal product; please use the UPI for every future procedure at the Agency (not limited to paediatric ones). You will also be subsequently informed of the procedure number, which should be mentioned in the actual application and in all related correspondence, and of the assigned PDCO rapporteur and Peer Reviewer for your procedure.
- When should I submit the application for a PIP or waiver?
According to Article 16 of the Paediatric Regulation, applications should be submitted, unless duly justified, 'not later than upon completion of the human pharmacokinetic (PK) studies’, as specified in Section 5.2.3 of Part 1 of Annex 1 of Directive 2001/83/EC. Recital 10 of the Regulation states that 'paediatric investigation plans should be submitted early during product development, in time for studies to be conducted in the paediatric population, where appropriate, before marketing authorisation applications are submitted. It is appropriate to set a deadline for the submission of a PIP in order to ensure early dialogue between the sponsor and the Paediatric Committee.
The timing of submission should not be later than the end of healthy subject or patient PK, which can coincide with the initial tolerability studies, or the initiation of the adult phase-II studies (proof-of-concept studies); it cannot be after initiation of pivotal trials or confirmatory (phase-III) trials. Applicants are welcome to submit their PIP applications during or even before initial PK studies in adults. Submitting a PIP application for a new active substance during confirmatory or phase-III trials in adults, or after starting clinical trials in children, is likely to be considered unjustified.
Applicants are advised to request a pre-submission meeting to facilitate successful validation and assessment.
Practical advice on completion of the application form (part A)
In part A of the application form, applicants should mention the date of completion (last patient last visit) of the last basic PK study in adults.
Failing to provide a date of completion of PK studies in adults should be justified. Late submission of the PIP or waiver application should be justified as well (add information in the scientific document, parts B-E).
Practical advice on submission of the application to the Agency
Please submit your application for a PIP or waiver according to the published deadlines for submission to the Agency. These are set according to the Paediatric Committee (PDCO) meeting dates.
Submission deadlines are available on PIPs: Templates Forms and Submission dates.
- To whom and how should I submit the PIP or waiver application?
Please submit your application to the Agency, the appointed Paediatric Committee (PDCO) Rapporteur and the Peer Reviewer in parallel (see question above “How and when should I submit a PIP letter of intent?” to see how to receive the names of the Rapporteur and Peer Reviewer). The contact details and required submission details of PDCO members and alternates are available at Mailing list for PIPs.
EMA strongly recommends using the eSubmission Gateway or the eSubmission Web Client for the submission of applications to the Agency. More information on how to register and connect to the Gateway / Web Client can be found in the eSubmission website together with detailed information on the required naming conventions and file formats. As PDCO members do not currently have access to the eSubmission gateway, applicants must also send their application to the Rapporteur and Peer reviewer as explained in the above paragraph.
The Agency will still accept applications sent on CD or DVD accompanied by a cover letter. Please notethat Blu-ray discs are not acceptable.
Please refer to 'What information should be provided in the cover letter accompanying the application?' below.
Please indicate the Agency's procedure number (PIP number) clearly on the cover letter and on the CD or DVD. Please note that the CD or DVD should reach the Agency before or on the day of the published deadlines for submission (available on PIPs: Templates Forms and Submission dates). If it is not possible to comply with this deadline, the documents can be sent via Eudralink to firstname.lastname@example.org on or before the published deadline.
Applications by Eudralink, to email@example.com, will be accepted to meet the submission deadline; however, they should be followed by the CD or DVD shortly after.
The Agency will appoint a Paediatric Coordinator, among its Scientific Officers, after receipt of the full application unless a pre-submission meeting is requested (see below). Should you have any questions in the meantime, please send them to firstname.lastname@example.org.
When you request a confirmation of the applicability of class waiver in the cover letter for a PIP or waiver application, please clearly indicate the proposed therapeutic indication for which the confirmation is sought.
In the case of validation issues, the additional and modified files should be sent via Eudralink to the Agency, the rapporteur and the peer reviewer, including a letter listing the changes.
On receipt of the Agency's letter confirming the start of procedure, you should immediately send the validated application to each of the other PDCO members and alternates as the per the PDCO mailing list for sending PIP and waiver applications.
- What information should be provided in the cover letter accompanying the application?
You should clearly identify in the cover letter that it is an application for a PIP, a request for a waiver or deferral, or a request for a modification of an agreed PIP. You should also mention the procedure number (PIP number). You should also declare that all electronic versions (Word and PDF) are identical.
Finally, you should mention the ‘check-sum’ number received when the electronic application template form is saved in the cover letter, and the UPI number (see above).
- What are the technical requirements for the electronic submission of PIP or waiver applications?
Part A of the application form should be submitted as an electronically signed form; please refer to information on e-signature on http://esubmission.ema.europa.eu/eSignatures.html.
Alternatively, if you are unable to submit an electronically signed form, then two PDF files are required: one electronic version (see 'How do I use the electronic template for PIP or waiver application (part A)?' below), and one printed, signed and scanned into a file version.
The key-elements form should be used to propose key elements for all completed, ongoing and proposed future steps in the pharmaceutical development for children, and for non-clinical and clinical studies. This form should be used to list the key elements, as proposed by the applicant as a basis for the PDCO Opinion, in short bullet-point style.
The key-elements form should template for scientific document (part B-E) not include background, explanations, justifications, legal requirements (e.g. consent) or additional detailed information. This information should be included in the scientific document (part B-E). For this purpose, the with guidance for applicants is available. The information and discussion to be provided in this template should be provided in accordance with the European Commission Guideline on the Format and Content of PIP applications.
In contrast to the key-elements form, the template for scientific document (part B-E) should provide a more detailed description of the proposed studies or measures.
All other annexes to the application form should be provided, as far as possible, as both PDF and Word files.
The scientific documentation (parts B to E, including the list of references) should also be submitted both as a single PDF file and a single Word file. See 'How should I present the scientific documentation (parts B to E and references in the separate part F)?' below for more details on the scientific documentation (parts B to E).
The investigator’s brochure (if any) and the copy of the latest European Union Risk-Management Plan should be submitted both as single PDF files and single Word files. If this is not possible, you should use PDF files with text that can be copied.
Please include a letter of authorisation for up to two people authorised to communicate with the Agency during the procedure (as a printed, signed and scanned file, in PDF format).
Please note the following requisites for your application:
- although not recommended, if you set up a password (or other security settings) to protect the confidentiality of data in the Word and PDF files, this should be communicated to the Agency and the Paediatric Committee (PDCO) delegates so that it is possible to print, select the text and images, and copy them into another application;
- please ensure that the fonts used in the original documents are embedded into the PDF document, so that the text appears as intended;
- please do not use internal or external hyperlinks to websites, references, tables or pictures;
- please avoid scanning physical documents or generating PDF image files as far as possible. When a document is only available on paper, please ensure that the scanned version is readable both on screen and when printed out. The scan resolution should be 300 dots per inch (dpi) in black and white - this represents a good compromise between legibility and file size;
- please name the PDF files so they can be easily identified, and do not merge application forms into a single PDF file. For referenced publications, please use single files (one per reference) and name them as first author and year, for example as 'Smith PH et al 2004.pdf'.
- the reference list (in part F) should be set in alphabetical order by first author’s surname;
please provide all documents in electronic format, including the investigator’s brochures and the risk management plan (if any).
- How do I use the electronic template for PIP or waiver application (part A)?
To submit an application for a PIP or waiver (part A) and for the description of the key elements please use the Agency's templates (available on PIPs: templates, forms and submission dates).
Please do not start to fill in the template within your web browser as you may not be able to save the content. A downloaded local copy should be used instead.
The electronic application form should be created and saved using the latest version of Adobe Reader (at least version 8.0).
The application form is a dynamic PDF For instance, some buttons allow you to add or delete fields (e.g. 'add substance', 'delete substance'), some checkboxes are exclusive, the date fields propose a calendar, drop down lists are used, etc.
When you access the published electronic form, only the first page is displayed. You must first tick one of the three boxes as appropriate, in order to view the complete form. If the wrong box is selected by mistake, a new form must be used, as it is not possible to modify the initial selection made on this first page. However, for all the other items of the application form you can correct the information if needed, without creating a new form.
Several versions of the application form can be saved, if needed, as you fill in the information required in the form. All sections of the application form must be filled in as far as possible. When saving the form, you will receive a ‘check-sum’ number once you have filled in all fields highlighted in yellow. The form will only generate the ‘check sum’ after completion of all mandatory fields.
- What information should I include in the electronic template for PIP or waiver applications (part A)?
The Guideline on the format and content of applications for agreement or modification of a paediatric investigation plan and requests for waivers or deferrals and concerning the operation of the compliance check and on criteria for assessing significant studies, from the European Commission, specifies the information to be included in the application.
For products that are already authorised, the PIP application should cover all the existing and the new indications, pharmaceutical forms and routes of administrations (where relevant), in keeping with the Global Marketing Authorisation concept (see 'When is my product considered 'not authorised in the Community' below).
Proposed pharmaceutical form(s)
(in relation to the proposed paediatric development, page 1)
In this section, for authorised products, all existing pharmaceutical forms and new pharmaceutical forms under development for the proposed PIP should be listed, irrespective of whether you request a waiver, or a PIP with or without deferral. You should specify whether the pharmaceutical form is under development or is already authorised.
For authorised, off-patent products intended for a future PUMA application, only the pharmaceutical form(s) discussed in the PIP should be mentioned. You should also specify whether each of the pharmaceutical form is under development or is authorised.
Here, ‘authorised’ means authorised in at least one Member State of the European Union.
Request for a waiver
In this section, if there is more than one condition in your application, you should repeat the information for each condition, by clicking on the 'add' button. To delete a condition, click 'delete'.
You should select the appropriate age group or other paediatric subset where the waiver applies. You have the ability to select specific groups that differ from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) classification, if this is more appropriate.
Please tick the grounds for the waiver for each age group/subset mentioned in this section.
For products belonging to a class of medicinal products included in the Agency's list of class waivers, see 'What shall I submit if my product belongs to a class listed in the Agency's decision on class waivers?'
Name of the active substance
You should select the appropriate nomenclature following the priority order. There is no need to select more than one nomenclature. If you use a chemical formula name, please add the company code.
Details of the medicinal product
The proposed pharmaceutical form mentioned on page 1 should be associated here with the corresponding route(s) of administration. If an additional formulation is under development (an adult formulation for example), it should be listed here. Please use the list of standard terms from the European Pharmacopoeia.
Date of completion of human pharmacokinetic studies in adults / planned submission of application
For technical reasons, these dates must be input in the format dd/mm/yyyy. If an exact date cannot be specified, you should select the last month of the proposed interval, and select the last day of that month by default (e.g. 31/07/2020 for July 2020, or for January-July 2020).
The same rules apply if you would like to select a trimester for example, please use the last month of the trimester. Please note that these dates are not binding, but are important for the discussion on deferrals.
Person authorised to communicate with the EMA during the procedure and after the decision
EMA communicates exclusively with the authorised contact person appointed by the applicant in 'part A' of the application. Applicants may prefer to use a generic professional email address for the authorised person, to ensure a smooth and timely communication flow.
EMA sends all of its communications, including the PDCO opinions and the EMA decisions, electronically only to the appointed contact person's email address, unless requested in writing otherwise.
Therefore, applicants should keep EMA informed of any change to the contact person or contact details. For more information, see Is there a procedure for changing the PIP applicant name or details?
Contact point for the applicant for public enquiries from interested parties
At the time of the publication of the decision on a PIP, including a deferral or waiver on the Agency's website, this contact will be made public. A generic e-mail address and telephone number (and fax if available) are therefore preferable.
The text 'Checksum: All yellow fields must be completed in order to get a checksum code' is displayed at the foot of each page while the form is being filled in.
If you decide to print or save, this text will change to a series or combination of numbers and letters, e.g. 'Checksum: d13f91951bbde7ce5f0b71dce3f348f9afc52d6b'.
Please note that it will only change when all yellow fields have been filled in. It prompts the user with a warning message.
Once the checksum has been activated, it tracks changes to the document, and the combination will change each time there is a change in the document.
- How should I present the scientific documentation (parts B to E and references in the separate part F)?
For the scientific document of the application (parts B to E), applicants are invited to use the pre-formatted template (available on PIPs: Templates Forms and Submission dates), which includes specific guidance.
If several conditions are included in the same PIP or waiver application (for authorised products, or if you plan to submit indications in more than one condition at the time of initial marketing authorisation), you should address all parts related to one condition first (parts B to E) together, and then repeat the information for each subsequent condition. As a rule, parts B to E should be submitted as a single file (both in Word and PDF format) in the electronic version, with page numbers on each page.
The scientific part of the application (parts B to E) should be as concise and as short as possible, but still explicit and readable as a self-standing document. Avoid repetition and Word hyperlinks. The application should be particularly specific in part D.
Although the documentation should be comprehensive, please keep the total number of pages in your application below 40 per condition (excluding references), if possible.
Any request for a deferral should include the proposal of the studies and timelines to be deferred.
If you require additional information or clarification, please refer to the European Commission’s Guideline on the format and content of applications for agreement or modification of a paediatric investigation plan and requests for waivers or deferrals and concerning the operation of the compliance check and on criteria for assessing significant studies. If still in doubt, please write to your assigned Paediatric Coordinator or send a question to the European Medicines Agency.
- Can I submit a single PIP or waiver application in case of multiple marketing authorisations or marketing authorisation applications?
For a medicinal products with multiple marketing authorisations (MAs) or future or ongoing marketing authorisation applications (MAAs),a single PIP decision can be used , provided that the marketing authorisation holder (MAH) or applicant are considered the same according to the Commission communication on the Community marketing authorisation procedures for medicinal products (98/C 299/03) (see 'How do I apply for a modification of an agreed PIP?' and 'Will Article 7 or Article 8 of the Paediatric Regulation apply to my application, taking into account the global marketing authorisation concept?'). Therefore, a single PIP application or a request for a waiver can be submitted to cover all of the marketing authorisations and applications for the medicinal product concerned.
It is recommended that there is only one single PIP or waiver applicant identified for the submission of the application. This applicant will be the addressee of the Agency's decision; however, an appropriate PIP or waiver Decision (covering the proposed indication[s], route[s] of administration and pharmaceutical form[s]) can be used by an applicant who is not the PIP addressee, to satisfy the requirements of Article 7 or Article 8.
- How and when can I expect feedback on my application?
As of 1 August 2016, all communications and documents containing confidential information, including the PDCO opinion and the EMA decision will be transmitted to the contact person authorised to communicate with the Agency during the procedure (as per 'part A' of the application) as a PDF document via EudraLink.
Therefore, applicants should keep EMA informed of any change to the contact person or contact details. For more information, see Is there a procedure for changing the PIP applicant name or details?
Applicants should download and archive the message and its attachments immediately upon receipt. These will expire in 90 days.
Alternatively, applicants may request a paper copy of the EMA decision and PDCO opinion instead of the electronic receipt, in writing prior to the adoption of the documents.
According to Art 25(1) of the Paediatric Regulation (Regulation (EC) No 1901/2006), the PDCO opinion with its annex(es) and appendix (summary report) will be transmitted electronically to the applicant within ten days of its adoption by the PDCO. For full details and dates, see PDCO meetings.
The 30-days period entitling the applicant to request a reexamination of the opinion starts the day after the applicant has opened the Eudralink messgage with the attached opinion the first time. Eudralink automatically record the 'access by' date.
According to Art 25(5) of the Paediatric Regulation (Regulation (EC) No 1901/2006), EMA issues its decision within ten days after the period for re-examination has elapsed. This EMA decision is also transmitted to the applicant electronically, with the same modalities as the PDCO opinion.
Start and restart of procedure letters and draft summary reports
EMA provides the procedural timelines in its communication of the start and restart of the procedure on the day via Eudralink, in line with the submission date. For more information, see PIPs: templates, forms and submission dates).
EMA aims to provide drafts summary reports to applicants within one week after the end of PDCO plenary meeting. For more information and precise dates, see PDCO meetings.
Please note that EMA is not legally obliged to provide summary reports to the applicant at these stages of the procedure.
- How should I answer the PDCO’s request for modifications of a PIP?
At day 60 of the procedure, you may be requested by the PDCO to propose modifications to the plan. In this case, the procedure will be suspended until the Agency has received the response document from the applicant. The request for modifications to the plan is contained in the last section of the summary report and is established on the basis of both the evaluation of the application (summary report) and the PDCO discussions and conclusions at day 30 and day 60 of the procedure.
The following documents should be submitted:
- a response document to the request for modifications, where each of the issues should be listed and addressed point by point. This document should be submitted both as a PDF and as a Word format file;
- a modified Part A electronic application form (please note that this is required in most cases, including situations where a waiver or deferral are no longer requested or where they are now being proposed);
- a new key-elements form if the modifications also affect this document (please do not change the text in the field 'study identifier(s)');
- investigator's brochure if a new version is available;
- New bibliographical references.
There is no need to resubmit unchanged documents already included in the validated application.
Applicants may request a meeting via teleconference to clarify any details of the PDCO's request for modification. Please submit your request to email@example.com, including suggestions for potential dates and times (outside of PDCO plenary meeting weeks), as well as draft questions to be discussed.
At least one week before the teleconference, you should submit a list of questions to be discussed, together with a draft answer, as complete as possible. Applicants are reminded that pre-assessment is not the aim of the teleconference.
Please consult the question “To whom and how should I submit the PIP or waiver application?” above for information on the technical modalities to provide your response to the PDCO.
The response package should be sent in parallel to the EMA, rapporteur, peer reviewer and all other members and alternates of the Paediatric Committee. The contact and submission details to the Paediatric Committee (PDCO) members and alternates, for the purpose of sending applications, are available at Mailing list for PIPs.
It is expected that the modified PIP application will be submitted within three months of the PDCO request for modification. It is acknowledged that in some cases the applicant may need more time to propose modifications to the application. In all cases, submissions should be made in accordance with the published dates for the restart of the procedure.
For the purpose of planning activities, you are kindly requested to inform the Agency of the intended date of submission, whenever possible, at least one month prior to the actual submission by e-mail to firstname.lastname@example.org and to the paediatric coordinator.
- Is it possible to have a meeting before the application for PIP or waiver is actually submitted?
The Agency offers a presubmission meeting and now, as a pilot, an early interaction meeting before the application for a PIP or waiver is submitted.
The early paediatric interaction meeting (pilot):
- timing: very early stages of development;
- purpose: to discuss potential paediatric needs and scope of development.
The purpose of the early paediatric interaction meeting is to foster efficient development of safe and efficacious medicines for children.
This initiative is in a pilot phase up until June 2016 and currently only a limited number of applications are accepted. The PDCO/EMA will choose the most appropriate candidates from the applications received, prioritising, for instance, medicines for rare diseases or high paediatric need. A review will be undertaken at the end of the pilot phase and the procedure may be modified according to the experience gained.
The early paediatric interaction is a meeting to facilitate and encourage early dialogue between applicants and the EMA/PDCO regarding the strategy for the paediatric development programme of the medicine, in advance of a PIP application. Applicants may request this meeting to discuss their paediatric strategy at the very early stages of development, when paediatric needs and the respective paediatric population are not yet clear from the available information. This meeting is not intended for situations when applicants are ready to submit their PIP application. In these situations, the Agency offers presubmission teleconferences to assist with the validation process.
The main objective of the meeting, conducted preferably as a videoconference, is to discuss the potential paediatric needs for the medicine and the scope of its development for use in the paediatric population, taking into account the properties of the future medicinal product and its overall development.
Applicants should submit a request for an early paediatric interaction meeting with a letter of intent and a briefing document based on the template (maximum five pages) at least two months prior to the expected meeting date to email@example.com. Following the request, an EMA paediatric coordinator and a PDCO representative will be appointed. After a first review of the document, additional participants from other EMA Offices or National Competent Authorities may be invited as needed. A date and time for the early paediatric interaction teleconference will be arranged in due course.
Applicants should provide all additional information and a brief slide presentation on the application at least five working days prior to the meeting. After the meeting, companies should submit minutes structured in the same way as the briefing document within ten working days, on which EMA/PDCO participants may comment if necessary.
The presubmission meeting:
- timing: when PIP is nearly ready for submission;
- purpose: to ensure a smooth validation.
The purpose of the presubmission meeting is to ensure a smooth validation and subsequent procedure; pre-assessment of the scientific documents is not the aim of the teleconference. The Agency aims to offer the possibility of presubmission meetings via teleconference to all applicants.
Applicants should submit a request for a presubmission meeting with a letter of intent to firstname.lastname@example.org at least two months prior to the planned date of the PIP application. EMA will inform the applicant about the date of the teleconference in due course.
Applicants should provide a list of questions to be discussed, together with a draft application, as complete as possible (part A, parts B-E and the studies form) at least five working days prior to the teleconference. After the meeting, companies should submit minutes within ten working days, on which EMA/PDCO participants may comment if necessary.
Articles 7 and 8: Definitions
- When is my product considered 'not authorised in the Community'?
Applications for a marketing authorisation in respect of a medicinal product for human use which is not authorised in the European Union at the time of entry into force of Regulation (EC) No 1901/2006 have to comply with the requirements of Article 7 of Regulation (EC) No 1901/2006.
In accordance with Article 8 of Regulation (EC) No 1901/2006, the requirements of Article 7 shall also be applicable to the authorisation of new indications, new pharmaceutical forms or new routes of administration of authorised medicinal products which are protected by a supplementary protection certificate or by a patent which qualifies for the granting of a supplementary protection certificate.
Since Articles 7 and 8 refer respectively to ‘a medicinal product for human use which is not authorised in the Community’ and to an ‘authorised medicinal product’, at the time of submitting a new stand-alone application, it is necessary to establish whether the product applied for is considered or not a 'medicinal product for human use which is not authorised in the Community’. In this context, the global marketing authorisation concept, as defined in Article 6(1), 2nd subparagraph of Directive 2001/83/EC applies.
The global marketing authorisation includes the initial authorisation and all variations and extensions thereof, as well as any additional strengths, pharmaceutical forms, administration routes or presentations authorised, through separate procedures and under a different name, granted to the marketing authorisation holder of the initial authorisation. For further reference, see the notice to applicants, chapter 1, section 2.3. Thus, the global marketing authorisation concept applies to products belonging to the same marketing authorisation holder: according to the Commission communication on the Community marketing authorisation procedures for medicinal products (98/C 299/03), applicants belonging to the same mother company or group of companies, or which are 'licensees', have to be considered as one.
- Will Article 7 or Article 8 of the Paediatric Regulation apply to my future regulatory application, taking into account the global marketing authorisation concept?
The global marketing authorisation (GMA) concept, together with the notion of ‘same marketing authorisation holder’, is used to determine whether an application concerns a ‘medicinal product for human use which is authorised or not in the Community’ and whether Article 7 or 8 applies.
The following is applicable both for orphan-designated and non-orphan medicinal products:
- If you do not hold any other marketing authorisation for that substance in the EU, the medicinal product subject of the application will not be considered as authorised, and consequently, the future regulatory application will fall under Article 7.This is regardless of whether the product is protected by a supplementary protection certificate (SPC)/qualifying patent for a SPC, or whether it is a new or known active substance.
- If you hold another marketing authorisation for that substance, independently of the procedure of authorisation, the medicinal product subject of the application will be considered as already ‘authorised’, in keeping with the GMA concept. Consequently, Article 7 will not apply.
- If an already ‘authorised’ medicinal product is protected by a supplementary protection certificate (SPC) or a patent that qualifies for a SPC, Article 8 shall apply to any regulatory application (a variation or an extension) to add a new indication, pharmaceutical form or route of administration. In this case, the PIP or waiver decision shall cover the existing and any new indication, pharmaceutical form or route of administration of the medicinal product concerned by the GMA.
For example, if company A holds a marketing authorisation in indication A for a product containing substance x (still patented), and company B (a subsidiary of company A) intends to apply for a new stand-alone marketing authorisation for substance x in a new indication B, the product will be considered as ‘already authorised’ based on the GMA concept, and company B will be required to cover also indication A in its PIP (i.e. Article 8 applies).
The GMA approach will apply to variations, extensions and new marketing authorisation applications falling under the requirements of Article 7 and 8. Where relevant, you should also consider whether a modification to an agreed or ongoing PIP or waiver decision is required in case the GMA concept had not been applied, in order to avoid difficulties at validation of your subsequent regulatory submission.
When an active substance from the 'same marketing authorisation holder' is or will be the subject of two marketing authorisations, one covering orphan indications and another covering non-orphan indications, those marketing authorisations would not be considered as part of the same GMA in light of Articles 7 and 8 of the Paediatric Regulation. In such situation, it is recommended to liaise with the EMA for further clarification of the regulatory implications.
- What is a new indication in the context of Article 8?
Both 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 and the guideline on a new therapeutic indication for a well established substance provide a definition of what is considered a new indication, i.e.:
- a new target disease;
- different stages or severity of a disease;
- an extended target population for the same disease, e.g. based on a different age range or other intrinsic or extrinsic factors;
- a change from first-line treatment to second-line treatment (or second-line to first-line treatment), or from combination therapy to monotherapy, or from one combination therapy (e.g. in the area of cancer) to another combination;
- change from treatment to prevention or diagnosis of a disease;
- change from treatment to prevention of progression of a disease or to prevention of relapses of a disease;
- change from short-term treatment to long-term maintenance therapy in chronic disease.
For the purpose of the application of Article 8, the same guideline should be followed.
However, case-by-case assessment may be needed for particular situations to define whether a criterion of the 'extended target population' is fulfilled. For example, a modification of the product information may not be considered as a new indication in the following cases:
- information on the use of the medicinal product in the authorised target diseases in patients with renal or hepatic impairment;
- information on the use of the medicinal product in the authorised target diseases in pregnant women;
- for vaccines, information on the concomitant administration with other vaccines.
The Agency encourages applicants to make contact in advance of a planned submission in order to clarify paediatric requirements and to anticipate any regulatory issues that could prevent the validation of the application.
- What is a 'new pharmaceutical form' in the context of Article 8?
A 'combined term' is used in some cases to further characterise a pharmaceutical form. It may be a combination of dosage forms, a combination of dosage forms and routes or methods of administration, container or administration device.
Where a combined term is constructed by a combination of a dosage form and a container or administration device, it may not in certain cases be considered as a new pharmaceutical form in the light of Article 8 of the Paediatric Regulation.
In addition, a change of standard term for a presentation of a medicinal product resulting from the deletion of a solvent is also not considered to be a new pharmaceutical form.
The Agency encourages applicants to make contact well in advance of a submission in order to clarify paediatric requirements and to anticipate any regulatory issues which could prevent validation of an application.
- Does Article 7 or Article 8 of the Paediatric Regulation apply to my informed consent application?
Applications under Article 10c of Directive 2001/83/EC (informed-consent applications) are not excluded from the scope of the Paediatric Regulation. The applicant will have to declare in the application form whether the conditions as specified in article 7 or 8 apply to their informed consent application. Any subsequent application for a new indication, pharmaceutical form or route of administration would need to comply with the requirements as laid down in article 8, if the medicinal product is covered by a Supplementary Protection Certificate (SPC) or a patent qualifying for an SPC.
- Do the requirements of Article 7 of the Paediatric Regulation apply to fixed-dose combination products?
Article 7 of the Paediatric Regulation applies to fixed-dose combination medicinal products, which were not authorised in the European Union by 26 July 2008.
The global marketing authorisation (GMA) concept in relation to the fixed-dose combination concerned, together with the notion of ‘same marketing authorisation holder’ (MAH) are used to determine whether an application for a fixed-dose combination product concerns a medicinal product which is authorised or not as a fixed-dose combination in the European Union, and therefore whether Article 7 or 8 applies (see 'When is my product considered 'not authorised in the Community'?').
Example 1: Fixed-combination medicinal product authorised: substance A 5 mg / substance B 10 mg tablets:
The application concerns substance A 5 mg / substance B 10 mg capsules (not tablets) by the same MAH. This will be considered part of the GMA, therefore Article 8 applies, due to the change in the pharmaceutical form.
Example 2: Fixed-combination medicinal product authorised: same as above (substance A 5 mg / substance B 10 mg tablets):
The application however concerns substance A 10 mg / substance B 10 mg tablets by the same MAH. This is not a new medicinal product as the medicinal product is already authorised and this new strength falls within the same GMA. Therefore, Article 7 does not apply and neither does Article 8, as the conditions of this article are not met. A change in strength does not trigger Article 8.
- Does Article 7 of the Paediatric Regulation apply to advanced-therapy medicinal products?
Article 7 of the Paediatric Regulation applies in principle to advanced-therapy medicinal products (ATMPs).
Articles 33 and 35: Marketing a medicine authorised for a paediatric indication
- Is there an obligation to market a medicine which is authorised for a paediatric indication, following completion of an agreed paediatric investigation plan, and the product has already been marketed with other indications?
If a medicinal product is authorised for a paediatric indication following completion of an agreed paediatric investigation plan and the product has already been marketed with other indications in a Member State, the marketing-authorisation holder should place the product including the paediatric investigation on the market of the Member State where the medicinal product is authorised for the paediatric indication within two years of the date of the marketing authorisation for the paediatric indication.
This applies to nationally authorised and centrally authorised products.
The date of placing the medicinal product on the market should be understood as the date of first release into the distribution chain.
The Agency makes these deadlines public for all medicinal products that are authorised for a paediatric indication, following completion of an agreed paediatric investigation plan. For the complete list, also known as the Article 33 Register, see Deadlines for placing paediatric medicines on the market.
- Where can I declare that the medicinal product has been placed on the market?
When a product has been placed on the market of the relevant Member State(s) with a new paediatric indication after completion of an agreed PIP, the marketing-authorisation holder can declare it by informing the EMA Paediatric Medicines Office via email at email@example.com or Eudralink. The Agency will update the Article 33 Register accordingly.
- What should I do if I want to discontinue placing on the market a medicinal product authorised for a paediatric indication, where I have benefited from the rewards or incentives under Article 36, 37 or 38 of the Paediatric Regulation and these periods of protection have expired?
If a medicinal product is authorised for a paediatric indication, and the marketing-authorisation holder has benefited from the rewards and incentives under Articles 36, 37 or 38, and those periods of protection have expired, and if the marketing-authorisation holder intends to discontinue placing the medicinal product on the market, the marketing-authorisation holder should comply with two requirements as follows:
- inform EMA of its intention to discontinue the placing on the market of the product no less than six months before the discontinuation;
- transfer the marketing authorisation or allow a third party, which has declared its intention to continue placing the medicinal product on the market, to use the pharmaceutical, pre-clinical and clinical documentation contained in the file of the product in question on the basis of the Article 10c of Directive 2001/83/EC.
The Agency will make this information public.
The requirements described above apply to nationally and centrally authorised products, when the marketing-auhtorisation holder has the intention to discontinue placing the product on the market in any country of the European Union.
The date of discontinuation of placing the medicinal product on the market should be understood as the date of the last release into the distribution chain.
Contact point: firstname.lastname@example.org
- What is the procedure to request a re-examination of the Paediatric Committee opinion on my PIP or waiver application?
After receiving a PDCO Opinion, an applicant may submit to the Agency a written request, citing detailed grounds, for a re-examination of the opinion, within 30 days following receipt of the opinion.
Within 30 days following receipt of a request for re-examination, the Paediatric Committee, having appointed a new rapporteur and peer reviewer, will issue a new opinion, confirming or revising its previous opinion.
To facilitate planning, it is recommended that the person authorised to communicate for the applicant gives written notice (email/Eudralink) to the Agency of any intent to request re-examination of the opinion within 10 days of receipt of the opinion (date of mail delivery record).
When re-examination is requested, the applicant should submit the detailed grounds for re-examination within 30 days of receipt of the opinion. The detailed grounds should be submitted to the Agency electronically via Eudralink, as pdf and Word documents.
The grounds should also be submitted to the PDCO members and alternates according to the contact details for the PDCO provided on the EMA website.
The grounds for the re-examination should be based only on the original information and scientific data provided in the application for a PIP and/or waiver and/or request for modification, which were previously available to the PDCO and on which the initial opinion is based. This may include new analyses of the same data, or a compromise proposal, e.g. minor protocol amendments to a previously proposed study. Significant changes to the previous plan cannot be part of the re-examination process.
In all cases, the request and grounds for re-examination are forwarded to the PDCO. The PDCO will appoint a new Rapporteur and a new Peer reviewer for the re-examination procedure. The PDCO may involve, if necessary, additional experts. The Paediatric Co-ordinator will remain the same for the re-examination.
A teleconference may be held with the applicant, the newly appointed Rapporteur and the Peer reviewer, the Paediatric Coordinator and any experts (if appointed) immediately after their appointment.
The revised summary report will be circulated for comments to the PDCO members and alternates and appointed expert(s).
In the frame of the re-examination procedure, the applicant may be heard by the rapporteur and peer reviewer directly. The Paediatric Coordinator should be always involved. The Paediatric Coordinator and the PDCO should be informed in writing about the details of any contact with the applicant.
The applicant will receive the draft revised summary report including comments of the Paediatric Co-ordinator, the Rapporteur and Peer-reviewer for information only.
The applicant may be invited to an oral explanation in front of the PDCO during the re-examination procedure. Where possible, the expert(s) involved in the application will be invited to attend the PDCO discussion.
The PDCO will consider whether its opinion should be revised and will adopt a final PDCO opinion. However, as the end of the 30-day period may not coincide with a PDCO meeting, there may be no opportunity for oral explanation in front of the PDCO once the grounds have been fully assessed, and the PDCO opinion will be adopted by a written procedure only. To allow for a possible oral explanation, the applicant might consider requesting the matter to be discussed and the opinion adopted at the next PDCO meeting.
In case of withdrawal of the re-examination request by the applicant, the previous opinion will become final.
The Agency will forward the final opinion, including the final summary report, to the applicant by courier or recorded mail.
The decision of the Agency will be adopted within 10 days of the adoption of the opinion after re-examination, and will be made public.
- How is the compliance statement with an agreed completed PIP issued and published for centrally authorised medicinal products?
Article 28(3) of the Paediatric Regulation states, 'if the application complies with all the measures contained in the agreed completed PIP and if the summary of product characteristics reflects the results of studies conducted in compliance with that agreed PIP, the competent authority shall include within the marketing authorisation a statement indicating compliance of the application with the agreed completed PIP.'
If the application is for a centralised marketing authorisation, the compliance statement is included in the Commission decision. Decisions granting a marketing authorisation are published in the Community register of medicinal products for human use.
Since November 2012, if the application is for varying the terms of an existing centralised marketing authorisation, the compliance statement will be included in the technical dossier of the marketing authorisation. Therefore, when the opinion is adopted by the Committee for Medicinal Products for Human Use (CHMP), the Agency provides the holder with a confirmation that the statement is included in the technical dossier by means of an annex to the cover letter of the opinion.
This annex is also published on the webpage for the medicine (see European public assessment reports).
For details on paediatric requirements when submitting an application for a new marketing authorisation, an extension or type-II variation to a marketing authorisation, see Paediatric requirements for marketing authorisation applications.
Modifying an agreed PIP
- How do I apply for a modification of an agreed PIP?
You should send a letter of intent to email@example.com, at least two months before the planned submission date of a modification of an agreed PIP, using the same template as for an initial application. The letter of intent should mention the original PIP number. The scope of the proposed modification of the agreed PIP should be summarised briefly.
You will be informed of the names of the assigned rapporteur and peer reviewer as soon as appointed together with the number for the modification procedure. This number should be mentioned in all related correspondence. You will be informed of the name of the Agency paediatric coordinator immediately after the start of procedure. If possible, the PDCO will appoint the same rapporteur, peer reviewer and paediatric coordinator for the modification as for the initial application. The PDCO may involve additional experts if necessary.
The application should be submitted according to the published deadlines for submission (available on PIPs: Templates Forms and Submission dates). It should be submitted to the Agency and to all PDCO members and alternates at the same time.
The contact and required submission details of the Paediatric Committee (PDCO) members and alternates are available at Mailing list for PIPs.
Please consult the question “To whom and how should I submit the PIP or waiver application?” and those below it for information on the technical modalities to submit your application.
Your application should include the following:
- a new part-A electronic application form. Do not use the application form from the previous procedure. Even if the information in part A has not changed, a new form should be downloaded and completed again (generating a new check-sum number). Please ensure that the correct boxes on page 4 are ticked in order to clearly refer to the desired outcome (e.g. if at least one waiver or at least one deferral were already granted and no changes are required, the boxes should still be ticked);
- the request for modification of an agreed paediatric investigation plan. Please ensure that the need or rationale for the modification is clearly indicated on this form. Please send this form in Word format;
- the key-elements form. This should reflect all the proposed updated key elements, according to the applicant’s new requests as well as the previously agreed key elements not subject to change. Further details are to be provided in the scientific document (parts B-E). Please copy the text in the field 'study identifier' from the latest PIP decision into the updated key elements form, to identify the studies being modified;
- the template for scientific document (part B-E). Please note that although this should follow the same structure as for an initial PIP (parts B-E), only the relevant sections supporting the changes need to be completed.
Please note that while requests for changes to or additions of routes of administration or pharmaceutical forms are permissible, it is not possible to change the active substances or add new ones. Do not include modified documentation in parts B to F that are not related to a requested modification of the key elements of the measures and timelines.
You will receive the draft summary report for information after the first discussion (day 30). The PDCO may invite you to a teleconference or an oral explanation. The PDCO will adopt an opinion at day 60, refusing or accepting the proposed changes. The updated annex of the PDCO opinion will list all the measures and timelines of the new agreed PIP: the unchanged ones and those that have been modified.
The opinion, including the final summary report, will be notified to the contact person authorised by the applicant within ten days, after adoption by the PDCO. The decision-making phase will follow the same procedures as for the initial PIP application.
Request for confirmation of the applicability of the Agency decision on class waivers
- What should I submit if my product is included in a class listed in the Agency's decision on class waivers?
If you are developing a product which may be covered by the list of class waivers, you can request confirmation of whether the scope of the Agency decision on a class waiver is applicable to your product. This may facilitate the future validation of your subsequent application for marketing authorisation, extension or variation.
The Agency encourages applicants to provide background information on the product, such as its description or mechanism of action. If an area of high interest for paediatric development is identified, this will be communicated to you and this would allow you to submit a formal application for a PIP.
Confirmation of the applicability of the Agency decision on class waivers
If you wish to receive confirmation of applicability, you should fill in the template for confirmation of the applicability of the Agency's decision on class waivers and provide some background information on the product, for instance in the form of the investigator brochure.
The completed template and background information must be sent via Eudralink to firstname.lastname@example.org. No letters of intent or paper copies need be sent to the Agency. Upon review by the PDCO, you will receive an outcome letter confirming or not if your product is considered to fall under the scope of the Agency decision on class waivers.
If the PDCO considers that the class waiver is not applicable to your product, you should submit an application for a product-specific waiver (or a PIP).
For further information, please refer to the Agency's decisions on class waivers.
- May I disclose the PIP decision and the summary report to national competent authorities and ethics committees?
Yes. You are encouraged to share the PIP decision, including the opinion and the summary report with individuals and organisations of your choice, such as paediatric networks and the national competent authorities (and ethics committees) in the context of a clinical trial application. This may enable the networks and the authorities to better understand the rationale for certain protocol elements of the trial.
- What is the procedure to confirm the inclusion of an indication within a condition?
To request confirmation of whether an indication is part of a condition (in an agreed PIP or waiver decision), submit an electronic request entitled 'confirmation of inclusion of an indication within an agreed condition for decision number P/xxx/xxx, PIP EMEA-YYYYYY/PIPxx/xx' and provide relevant justification.
Send the request via Eudralink to email@example.com.
No letters of intent or paper copies are needed. Upon review by the Paediatric Committee, the applicant will receive an outcome letter.
For more information, see European Medicines Agency policy on changes in scope of PIP decisions.
- Is there a procedure to notify the Agency of the discontinuation of paediatric development covered by an agreed PIP decision?
If a PIP addressee wishes to inform the Agency, the reasons for discontinuation can be sent to firstname.lastname@example.org, using the specific template. The notification should be sent by the latest PIP contact person, and will be accepted if signed electronically or submitted as two separate PDF files, one of which should be scanned after signature.
The notification does not exempt an applicant from the obligation to complete the agreed PIP, if this exists.
Transfers and changes in contact details
- Is there a procedure to transfer the PIP or waiver decision to another applicant? What documentation should be submitted when the applicant for the regulatory submission is not the PIP addressee?
The Paediatric Regulation does not establish a specific procedure for transfer of rights and obligations between legal entities in relation to a PIP or waiver.
However, the Agency is aware that a PIP or waiver applicant or addressee may change based on a contractual agreement. It is therefore acknowledged that the applicant for a marketing authorisation may be different from the PIP or waiver addressee.
The Agency is not involved in the contractual agreement between the parties. However, in order to comply with the paediatric requirements of Articles 7, 8 or 30 of the Paediatric Regulation, any contractual agreement referring to a PIP or waiver decision should take the following requirements into consideration:
Module 1.10 of the regulatory application must include the full PIP or waiver decision (as notified to the original PIP or waiver applicant or PIP or waiver addressee), together with:
- a copy of the Paediatric Committee (PDCO) opinion on the compliance, with the compliance report (only if PIP compliance has already been verified by the PDCO);
- a compiled compliance check application (form PED3).
Changes of PIP or waiver applicant or addressee should be notified to the Agency at email@example.com for the Agency's database and for enquiries from interested parties, using this template both in Word format and as a printed, signed and scanned PDF file. The form must be signed by the authorised representative of both the initial and new applicant or addressee.
For a PIP or waiver that is already agreed, the Agency will publish the details of the new addressee on the Agency’s website, but the name of the initial addressee in the Agency’s decision will remain unchanged. The name of the new PIP or waiver addressee will only be reflected in subsequent PIP modifications or additional PIPs or waivers for the concerned medicinal product, if any.
For ongoing PIP, waiver or PIP-modification procedures, the opinion and decision will reflect the name of the new addressee. The name and contact details of the new addressee will be published on this website together with the decision, for enquiries from interested parties.
- Is there a procedure for changing the PIP applicant name or details?
For changes of PIP or waiver applicant's or addressee’s contact details only (i.e. when the applicant or addressee remains the same legal entity), please notify the Agency at firstname.lastname@example.org using this template both in Word format and as a printed, signed and scanned PDF file. The form must be signed by the company’s authorised representative.
For a PIP or waiver that is already agreed, the Agency will publish the new contact details on this website, but the initial contact details in the Agency’s decision will remain unchanged. The new contact details will only be reflected in subsequent PIP modifications or additional PIPs or waivers for the concerned medicinal product, if any.
For ongoing PIP, waiver or PIP-modification procedures, the opinion and decision will reflect the new contact details. The new contact details will also be published on this website together with the decision.
European Network for Paediatric Research at the European Medicines Agency (Enpr-EMA)
- Why should I consider involving paediatric networks when preparing the PIP?
Early involvement of clinical research networks may help to develop a PIP in a number of ways, and should be considered when preparing the application, as recommended in the EU Guideline on the Format and content of PIP and waiver applications.
Enpr-EMA, which is coordinated by the Agency, provides a contact point for a number of specialty and multi-specialty networks. Areas of expertise that can be offered by Enpr-EMA members are reported in the Enpr-EMA database.
Networks may provide assistance in the following areas:
- identification of existing databases;
- location of study sites and investigators to conduct natural history studies;
- access to clinicians who can provide data about patient throughput or develop bespoke feasibility assessments;
- definition of important paediatric needs, priorities and relevant outcomes;
- identification of acceptable trial procedures / visit schedules;
- clarification of other scientific questions.
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