This page lists questions that marketing-authorisation holders (MAHs) may have on submission of Article-46 paediatric studies. It provides an overview of the European Medicines Agency's position on issues that are typically addressed in discussions or meetings with MAHs in the post-authorisation phase. Revised topics are marked 'New' or 'Rev.' upon publication.
A PDF version of the entire post-authorisation guidance is available:
- European Medicines Agency post-authorisation procedural advice for users of the centralised procedure
These questions and answers have been produced for guidance only and should be read in conjunction with the rules governing medicinal products in the European Union, volume 2, notice to applicants.
MAHs must in all cases comply with the requirements of Community legislation. Provisions that extend to Iceland, Liechtenstein and Norway by virtue of the European Economic Area agreement are outlined in the relevant sections of the text.
- 1 . What is Article-46 paediatric study submission? Rev. July 2013
Article 46 of Regulation (EC) No 1901/2006 (the ‘Paediatric Regulation’) sets out the obligation for marketing-authorisation holders (MAHs) to submit any MAH-sponsored studies involving the use of an authorised medicinal product in the paediatric population to the competent authority, whether or not they are part of a paediatric investigation plan (PIP). For centrally authorised medicinal products, the studies should be submitted to the European Medicines Agency.
This includes clinical studies that are:
- completed or discontinued;
- published or not.
Studies should be submitted regardless of the region where they were performed, the aim, outcome, population studied or indication.
- Article 46 of Regulation (EC) No 1901/2006
- 2 . When should I submit my Article-46 paediatric-study application? Rev. December 2014
The MAH should submit the paediatric studies within six months of its completion and irrespective whether or not it is part of a PIP (completed/or not yet completed) or whether it is intended for submission later on as part of a variation, extension or new stand-alone marketing-authorisation application or not.
Completion of a study is defined in the Communication from the Commission - Guideline on the format and content of applications for agreement or modification of a PIP and requests for waivers or deferrals and concerning the operation of the compliance check and on criteria for assessing significant studies on the format and content of paediatric investigation plans. Clinical studies are deemed to have been completed on the date of the last visit of the last subject in the study or at a later point in time as defined in the protocol.
- Note for guidance on structure and content of clinical-study reports
- Communication from the Commission - Guideline on the format and content of applications for agreement or modification of a PIP and requests for waivers or deferrals and concerning the operation of the compliance check and on criteria for assessing significant studies
- 3 . How should I present my Article-46 paediatric-study application at submission? Rev. February 2014
A paediatric study is to be submitted pursuant to article 46 as a post-authorisation measure (‘stand-alone’ submission). However, if amendments to be introduced to Product Information are identified by the MAH, a variation (e.g. category C.1.4 or C.1.6) should be submitted directly containing the article 46 paediatric study.
The submission of an application under article 46 should include the following documents, preferably presented in accordance with appropriate headings and numbering of the EU-CTD format:
- Cover Letter (see template) including information on the context in which the article 46 paediatric study submission is made (e.g. stand-alone study or study included in a development program) and statement that there are no regulatory consequences identified by the MAH.
- A short critical expert overview clarifying the context of the data, including information on the pharmaceutical formulation used in the study, the existence of a suitable paediatric formulation and if relevant, conditions for an extemporaneous formulation
- Final clinical study report
- For a paediatric study that is part of a development program, a line listing (see template) of all the concerned studies
In case of submission of a variation including study relevant to article 46, the application should be presented in EU-CTD format accordingly to the guidance for variation (see also in guidance on variations). The following box should be ticked in the variation application form: “THIS APPLICATION RELATES TO PAEDIATRIC STUDIES SUBMITTED ACCORDING TO ARTICLE 45 OR 46 OF THE PAEDIATRIC REGULATION”.
- 4. How and to whom shall I present my article 46 paediatric study application? Rev. August 2014
Please refer to Question 5. Other - How and to whom shall I submit my application.
- 5. How shall the evaluation of my article 46 paediatric study application be handled (timetable), and what could be the outcome of the evaluation? NEW February 2014
The following 60-day timetable shall apply to the assessment of the paediatric study submitted by the MAH:
Day Action Day 1 Start of the procedure as per published timetable (see below) Day 30 Receipt of Rapporteur’s Assessment Report Day 45 CHMP Members’ comments Day 50 Receipt of Rapporteur’s updated Assessment Report (if necessary)
Day 60 (CHMP meeting)
(up to Day 90 if a Request for Clarification is needed)
CHMP adoption of conclusion or Request for Clarifications
The submission deadlines and full procedural detailed timetables are published as a generic calendar on the EMA website (see: submission deadlines and full procedural timetables).
The published timetables identify the submission, start and finish dates of the procedures as well as other interim dates/milestones that occur during the procedure.
The EMA will inform the MAH of the outcome of CHMP evaluation. The following may be envisaged depending on CHMP’s conclusion at D60:
- No amendment to the product information is required at this point of time.
- Further clarifications are required.The CHMP will request additional clarifications (directly linked to the paediatric study submitted) and a 30 days extension of the timeframe will normally apply.
- A variation is needed to amend the product information in accordance with the CHMP conclusion. The variation submission is normally requested within 60 days after adoption of the CHMP conclusion. If the MAH is unable to submit the variation within this timeframe, he must justify the delay and inform the EMA/Rapporteur and propose a new submission date.
At the time of finalising an opinion, it may be needed that the MAH generate additional data (see also guidance on post-authorisation measures).
- 6. Do I have to pay fees for the article 46 paediatric study submission? NEW February 2014
There is no fee payable for article 46 paediatric studies. However, the normal fees are applied to any variations containing Article 46 paediatric data or variations resulting from the assessment of such article 46 paediatric study submission.
- 7 . Will there be any publication on the outcome of my Article-46 paediatric study? Rev. July 2013
The assessment report of the procedure will be published on the European Medicines Agency website under the EPAR tab of the product after removal of commercially confidential information.
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