Submitting results of paediatric studies

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.

References

• Article 46 of Regulation (EC) No 1901/2006

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.

References

• 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

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 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.
• In order to facilitate the registration of the submission, marketing authorisation holders are required to fill in all the submission attributes through the eSubmission delivery file UI.
• A completed PAM submission form with the full description of the PAM. The description should mention the due date (6 months from the completion of study). This form will ensure the correct classification of the submission, involvement of designated Committees(s) and timetable to be applied.
• 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”.

References

• ICH Topic E3, Note for Guidance on Structure and Content of Clinical Study Reports, CPMP/ICH/137/95

Information is available on ‘Submitting a post-authorisation application’.

The following 60-day timetable shall apply to the assessment of the paediatric study submitted by the MAH:

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).

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.

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.

References

• European public assessment reports