Paediatric investigation plans: questions and answers

According to Article 16 of the Paediatric Regulation, applications should be submitted, unless duly justified, 'not later than upon completion of the human pharmaco-kinetic (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.

Practical advice on completion of the application form (part A)

Applicants should mention in the electronic form for paediatric-investigation-plan application and request for waiver - also referred to as Part A - 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 also be justified in  Template for scientific document (part B-F) .

Procedural timelines to observe:

Submission deadlines are outlined in the following document: Submission deadlines for paediatric applications 2021-2024 .

These are set according to the Paediatric Committee (PDCO) plenary meetings .

Research Product Identifier (RPI)

From 10 October 2021, an RPI number will be mandatory for paediatric investigation plans (PIPs), modifications of agreed PIPs, and requests for waivers. Applicants are therefore advised to obtain the RPI number well in advance of any planned submission. See further information under point 1.1 in Guidance on paediatric submissions.

From January 2018 EMA only accepts applications submitted via the eSubmission Gateway / eSubmission Web Client. Applicants should follow the Guidance on paediatric submissions on naming conventions and file formats published on the eSubmission Gateway and eSubmission Web Client\paediatric submissions page, and submit the application according to the published submission deadlines and in line with User Guidance for submissions via eSubmission Gateway / Web Client using xml delivery files.

Read the summary of changes in xml delivery file for paediatric submissions introduced on 19 November 2020.

The Agency and the PDCO no longer accept CD or Eudralink submissions.

The Agency will appoint one of its scientific officers as paediatric coordinator after receipt of the full application, unless a pre-submission meeting is requested (see below).

In the case of validation issues, the additional and modified files should be sent to the Agency using the eSubmission Gateway or eSubmission Web Client. Please do not resend documents that have not been modified.

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 files, this should be communicated to the Agency so that it is possible to print, select the text and images, and copy them into another application;
• 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 all files following the naming convention in the Guidance on paediatric submissions 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'. Please ensure the file names are short.
• the reference list (in part F of the) 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);
• Please ensure you have an RPI number as of 10 October 2021; See 1.1

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. 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.

There are mandatory fields; please ensure you have the necessary information to complete the fields well in advance of the submission deadline. See also question 1.1.

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.

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 question 2.1. 'When is my product considered 'not authorised in the Community' below).

RPI number will be a mandatory field from 10 October 2021; see 1.1.

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 question 9. '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 publication of the EMA decision 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. In case of changes, please refer to Q&A 9.1 (Changes of applicant/addressee and contact details: how to notify the Agency?).

RPI number 

It will be a mandatory field from 10 October 2021; see 1.1. The assignment of an RPI has no regulatory consequences on the status or classification of the product.

For the scientific document of the application (parts B - F), applicants should use Template for scientific document (part B-F) 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 F) together, and then repeat the information for each subsequent condition. As a rule, parts B to F should be submitted as a single Word file, with page numbers on each page.

The scientific document (parts B to F) 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.

The list of references should be provided in alphabetical order.

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 AskEMA.

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.

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. The package 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.

PDCO opinion

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 authorised contact person of 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 re-examination of the opinion starts the day after the applicant has opened the Eudralink message with the attached opinion the first time. Eudralink automatically records the 'access by' date.

EMA decision

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, PDCO Request for modification according to Art 17(2) of the Paediatric Regulation (Regulation (EC) No 1901/2006) 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 PDCO requests for modification and draft summary reports to the authorised contact person of the applicants within 10 days after the end of PDCO plenary meetings. For more information and precise dates, see PDCO meetings. Please note that during Business Continuity this may take longer.

Please note that EMA is not legally obliged to provide summary reports to the applicant at day 30 and day 90 stages of the procedure.

According to Art 17(2) of the Paediatric Regulation (Regulation (EC) No 1901/2006), on 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 agreed PIPs 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.

As of January 2018, EMA only accepts submissions via the eSubmission Gateway or the eSubmission Web Client. Applicants should follow the Guidance on paediatric submissions on the required naming conventions and file formats published on the eSubmission Gateway and eSubmission Web Client\paediatric submissions page.

Read the summary of changes in xml delivery file for paediatric submissions introduced on 19 November 2020.

CD and Eudralink submissions are no longer accepted by the Agency or the PDCO.

The response package should be submitted according to the published deadlines for submission available on PIPs: Templates forms and submission dates.

Applicants may request a meeting via teleconference to clarify any details of the PDCO's request for modification. Please refer to question 1.10. 'What are the options to interact regarding paediatric procedures?'.

It is expected that the modified PIP application will be submitted within three months of the PDCO's 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 any questions related to a specific paediatric procedure contact the paediatric coordinator (communicated to the applicant in, for example, Start and Re-start of procedure EudraLink messages).

General questions, or if you do not know who the paediatric coordinator is for your procedure, are to be addressed via AskEMA.

Please note that the paediatrics(@ema.europa.eu) inbox was discontinued on 31 May 2020.

Interactions during clock-stop and prior to the submission

Following receipt of a PDCO request for modification (refer to question 1.9. 'How should I answer the PDCO's request for modifications of a PIP?'), applicants may request a clarification teleconference.

Additionally, if required, a pre-submission interaction with the paediatric coordinator is possible in writing to address any regulatory/administrative questions about the submission.

Pre-assessment of the scientific documents is not the aim of these interactions.

Requests should be accompanied by:

1. Questions to be addressed (mandatory), which EMA will review and determine the appropriate channel for addressing them.
2. Preferred timing (week/time of the day) for the interaction, avoiding PDCO meeting weeks , and noting that EMA cannot always accommodate applicants’ preferences.
3. Pre-submission interaction letter of intent form .

This documentation should be submitted, via the eSubmission Gateway / eSubmission Web Client, two months prior to the intended (re)submission date (PIPs: Templates forms and submission dates), and observing the Guidance on paediatric submissions .

Should the questions be suitable for a teleconference, the applicant will be requested to provide the following, once a timeslot is confirmed:

• Toll free numbers for all participants
• Agenda with agreed questions
• List of participants
• Draft application, as complete as possible (Part A, Parts B-F and Key elements form), two weeks prior to the meeting; applicable to pre-submission teleconferences only.

Applicants should submit a post-meeting summary within two weeks of the teleconference (EMA participants may comment where necessary).

Please note that the capacity to hold a teleconference meeting may be affected during Business Continuity.

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.

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.

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.

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.

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.

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 question 2.1. '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.

Article 7 of the Paediatric Regulation applies in principle to advanced-therapy medicinal products (ATMPs).

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.

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   eSubmission Gateway / eSubmission Web Client. The Agency will update the Article 33 Register accordingly.

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 via eSubmission Gateway / eSubmission Web Client as pdf and Word documents, in line with the Guidance on paediatric submissions .

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 final 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.

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 hearing with 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 an 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. Where necessary due to timelines, to enable an oral explanation hearing, the applicant may request adjustment of the timing for the start of re-examination procedure.

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 electronically via EudraLink. Please refer to 'How and when can I expect feedback on my application?'.

The decision of the Agency will be adopted within 10 days of the adoption of the final opinion, and will be made public.

In reference to Art 23 of the Paediatric Regulation (Regulation (EC) No 1901/2006), the PDCO may be requested to give its opinion on whether studies conducted by the applicant are in compliance with the agreed paediatric investigation plan.

Should you wish a compliance check to be conducted, please submit your request via the eSubmission Gateway / eSubmission Web Client in line with published Guidance on paediatric submissions, observing the established submission deadlines.

For further details please refer to the published Compliance check Q&A document.

Note:

It is strongly recommended the compliance check is requested in advance of your planned marketing authorisation (MA) submission (a partial/interim compliance check may be requested) to minimise the risk of potential delays to the MA submission validation.

The naming of the route of administration, pharmaceutical form and active substance should be in line with the preceding EMA decision, unless an INN has been approved meanwhile.

Please also refer to “How and when can I expect feedback on my application?”

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.

According to Art 22 of the Paediatric Regulation (Regulation (EC) No 1901/2006), the applicant may request a modification of an agreed paediatric investigation plan if they encounter difficulties with its implementation as to render the plan unworkable or no longer appropriate.

Note: it is not possible to change or add a new active substance via modification of an agreed PIP procedure - this requires submission of a separate PIP application. Naming of the active substance(s) should be in line with the preceding EMA decision, unless an INN has been approved meanwhile. Changes to or addition of route of administration or pharmaceutical form are permitted.

The request needs to be submitted via the eSubmission Gateway / eSubmission Web Client according to Guidance on paediatric submissions and published submission deadlines.

According to Art 25(1) of the Paediatric Regulation (Regulation (EC) No 1901/2006), the PDCO will adopt an opinion at day 60, accepting or refusing the proposed changes.

Please also refer to question 1.8. “How and when can I expect feedback on my application?”

RPI number will be a mandatory field from 10 October 2021; see 1.1.

Please consult here the current list and detailed guidance of class waivers.

If in doubts, you may request a confirmation of whether the scope of the Agency's decision on a class waiver is applicable to a product you are developing.

Requirements

Please complete and send the following request, as a Word file, via the eSubmission Gateway / eSubmission Web Client in line with published Guidance on paediatric submissions :

• Request for confirmation of the applicability of the Agency’s decision on class waivers template

Review and outcome

Your request will be reviewed and outcome adopted by the PDCO. You will be informed of the outcome via e-mail once available (we strive to inform you within two months). The outcome will be also published in the PDCO minutes after Committee plenary where minutes are adopted.

In case it is considered that the class waiver is applicable to your product, the confirmation is to be included in any subsequent relevant application for marketing authorisation, extension or variation, to facilitate the validation.

In case it is considered that the class waiver is not applicable to your product, you will need to submit a request for product-specific waiver or a paediatric investigation plan.

Information on an ongoing request and an outcome communication (if already available) should be always attached to all relevant paediatric submissions.

You will be also informed in case an area of high interest for paediatric development is identified and hence PIP is recommended.

Yes. You are encouraged to share the 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.

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.

Submit the compiled PDF via the eSubmission Gateway / Web Client. Please follow the User guide to XML delivery file creation  using the six-digit number of the PIP procedure.

Upon review by the Paediatric Committee, the outcome will be communicated to the applicant .

For more information, see European Medicines Agency policy on changes in scope of PIP decisions .

If a EMA decision addressee wishes to inform the Agency of the discontinuation of the paediatric medicine development as agreed in a PIP, a notification of discontinuation should be submitted. Please use this  template  and sign the notification by the latest authorised person to communicate with EMA.

The signed notification should be submitted via the eSubmission Gateway and/or the Web Client (https://pgateway.ema.europa.eu/ui/, please refer to the User guide to XML delivery file creation).

Please note that if the PIP has been submitted as part of a marketing authorisation application in order to comply with the requirements of Article 7 of the Paediatric Regulation (as a condition of the validation of the respective application) and a marketing authorisation was granted based on this application, then there is a legal obligation to complete that PIP. The same applies if there has been a successful post-authorisation application, where the PIP was included in order to comply with the requirements of Article 8 of the Paediatric Regulation.

Any changes to applicant’s particulars for paediatric procedures should be notified to the Agency without delay via the eSubmission Gateway / eSubmission Web Client in line with published Guidance on paediatric submissions and User Guidance for submissions via eSubmission Gateway / Web Client using xml delivery files, submitting the following document(s):

• Notification of change form as an active PDF form (containing active fields), i.e. not flattened, printed or a scanned PDF which should be electronically-signed by the authorised contact person
  
  (Note: The form should be downloaded and saved before being completed, using for example “Save target as” function. To report any technical issues with the form, please use the EMA Service Desk portal. If you are unable to submit an electronically-signed dynamic PDF form, then two files are required - one unsigned PDF containing the active live fields plus one scanned copy of the PDF with wet signature)
   
• Letter(s) of authorisation (LoA), as wet signed scanned electronic copy, if:
  • the applicant/addressee’s legal entity changes (Note: it is to be issued by the new legal entity authorising the contact person co-signing the Notification on their behalf).
    and
  • the currently authorised contact person is no longer available to sign the Notification (Note: it is to be issued by the current applicant/addressee authorising the new contact person signing the Notification on their behalf);

A separate Notification is to be submitted for each procedure unless all particulars (current and new) are identical for several procedures. In such cases, please contact the Agency via ASK EMA before submission. 

Upon receipt of the complete Notification submission, the Agency’s records will be updated accordingly.

See also: “Is there a procedure to transfer the PIP or waiver decision to another addressee? What documentation should be submitted when the applicant for the regulatory submission is not the PIP/waiver addressee?”

The Paediatric Regulation does not establish a specific procedure for transfer of rights and obligations between legal entities in relation to a paediatric investigation plan (PIP) or waiver.

The Agency is aware that the 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/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 addressee), together with:

• a copy of the Paediatric Committee (PDCO) opinion on the compliance, with the compliance report (if PIP compliance has already been verified by the PDCO);

or

• a completed compliance check application (Request for compliance check on agreed paediatric investigation plan form - PED3).

See also question: “Changes of applicant/addressee and contact details: how to notify the Agency?”

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.

Paediatric research network expertise is available for the entire drug development cycle, from scientific idea to clinical studies of the PIPs and safety follow-up after marketing authorisation. For recommended timing of network consultations please see  Network consultation recommendation

The opinion of and feedback from Enpr-EMA networks is of great value to the PDCO in order to best inform discussions on Paediatric Investigation Plans (PIPs). There are essentially three main routes of ad-hoc communication between individual Enpr-EMA networks and PDCO:

1. Communication on general topics related to paediatric clinical research or therapeutic areas

Official representatives of Enpr-EMA networks may at any time contact PDCO via letter or e-mail (enprema@ema.europa.eu) in order to communicate matters of general concern regarding paediatric clinical research.

2. Responses to PDCO requests for Enpr-EMA network comments

The PDCO may sometimes seek the opinions of Enpr-EMA networks on matters related to paediatric clinical research. The PDCO's request may concern general paediatric clinical questions or arise from the evaluation of a specific PIP. In the latter case PDCO's requests will not disclose any confidential product-related information.

Sometimes the PDCO may also recommend that a PIP applicant should seek advice from an Enpr-EMA network with regard to their ongoing PIP procedure.

Responses from the networks should be given as consolidated network advice by the official Enpr-EMA representative as opposed to the personal opinion of a key opinion leader.

3. Enpr-EMA networks' requests for communication in the context of a PIP procedure

Enpr-EMA networks may sometimes wish to communicate expected or experienced challenges concerning the conduct of (a) trial(s) included in an initial PIP under PDCO evaluation or in an already agreed PIP. In these cases - in order to comply with confidentiality requirements - communication should be between the PIP applicant and the PDCO, not between a specific network and the PDCO. The network involved should communicate with the PIP applicant and agree with them to contact the PDCO in the framework of a procedure for the agreement of an initial PIP or a procedure for the modification of an agreed PIP, as applicable.

Networks should follow the process below:

• Network identifies issues with clinical trial(s) which is/are part of an initial PIP under discussion or an agreed PIP.
• Network reports to the PIP applicant who takes this further to PDCO.
• PIP applicant submits to EMA responses to request for modifications (initial PIP procedure) or letter of intent (modification procedure for an agreed PIP) together with a request for a meeting with PDCO and involvement of (a) network representative(s).
• PIP applicant's request is to be accompanied by a signed letter from official Enpr-EMA representative of relevant network which states the name(s) of representative(s) of the network who would take part in the meeting with PDCO in order to provide the network's perspective independent from the PIP applicant's perspective.
• A discussion meeting with PDCO will be arranged at the applicant's request, preferably at day 90 in case of an initial PIP procedure, or at day 30 in case of a modification of an agreed PIP procedure, where the network representative(s) take part together with the applicant.