Requirements for submission of paediatric information required by EU Paediatric Regulation

Submission of information on existing paediatric studies and paediatric use in accordance with the paediatric regulation

Issue and background
The Paediatric Regulation came into force in the EU on 26 January 2007, and is directly applicable in Member States. The Paediatric Regulation facilitates the development and accessibility of medicines for children, to ensure that such medicines are the subject of high quality research and that they are appropriately authorised, and to improve the information available on their use.

The Regulation includes several provisions that must be implemented by Marketing Authorisation (MA) holders, National Competent Authorities (NCAs) and the EMEA between July 2007 and January 2010.  This communication concerns submission by MA holders of line listings of paediatric studies required to satisfy Articles 32, 42, 45(1) and 46 of the Regulation. The purpose of collecting this information is three-fold:

• it will assist the prioritisation of assessment of existing and new studies which need to be submitted under Articles 45(1) and 46. The studies will be assessed on a work-sharing basis by NCAs with a view to updating product information where appropriate.
• it will also identify those products eligible for the future paediatric symbol provided for by the legislation (Article 32).
• it will provide data on existing uses of medicinal products in the paediatric population. This information needs to be collated by Member States and communicated to the EMEA by 26 January 2009 (Article 42).

Existing studies

Action for marketing authorisation holders
Marketing authorisation holders were required to submit information regarding existing paediatric studies to NCAs by 26 January 2008 at the latest using the standard templates referred to below.  The following mailbox was set up to receive submissions to the MHRA from 1 November 2007:
paediatricstudies@mhra.gsi.gov.uk

Procedural guidance for submission of information
The Co-ordination Group for Mutual Recognition and Decentralised Procedures Human – the CMD(h) – has published procedural guidance concerning the submission of this information.  The guidance is available below:

› Procedural guidance (external link)

In addition an EU questions and answers guide is available below:

› EU questions and answers (external link)

In summary, you must use templates agreed by CMD(h) for the entire EU, to submit line listings of paediatric studies for all authorised products (see below) approved for use in each Member State. 

It is not necessary to send study data at this stage

However, companies should ensure that the data associated with these studies is available should it be requested within 3 days of 26 January 2008, to satisfy the requirements of the Regulation.

Scope of requirement
The requirement to submit line-listings applies to all medicinal products for human use with a UK Marketing Authorisation (MA) with respect to Directive 2001/83/EC as amended.  The requirement therefore covers products authorised through purely national, mutual recognition and decentralised procedures with a UK MA, including over-the-counter products and homeopathic or herbal products if applicable. The requirements do not apply to homeopathic and traditional herbal use products which are the subject of a registration procedure. Line-listings for centrally authorised products must be submitted to the EMEA and MA holders should also send copies of the line-listings for nationally authorised products (including those authorised through MR or decentralised procedures) to the EMEA. Information should be provided on all studies in children using the relevant medicinal product, including published studies, whether or not the studies have been conducted by the MA holder. You should include all clinical studies and trials involving a paediatric population and relevant non-clinical studies, whether completed or discontinued and regardless of the region in which they were conducted.

The MHRA requires information to be provided for all products even if not currently marketed.  However, it would be helpful if you could indicate if the intention is to allow authorisations to lapse under the ‘sunset clause’.
› Sunset clause

Where MAs are undergoing a change of ownership process, the MA holder at the time of submission of the line-listing should provide the relevant information, together with details of the new MA numbers, if known.

Submission of templates
The following templates have been agreed to standardise the submission of this information across the EU:

• A line-listing of information for all products authorised by the National Competent Authority (NCA), whether or not paediatric studies exist. The editable format of the line-listing should be submitted to the MHRA (MS Excel spreadsheet). If the studies have already been submitted by the Agency, then this should be indicated in the relevant column but no further information or study details are necessary.
• The declaration at Annex I to the CMD(h) procedural guidance must be completed and returned to the MHRA. This declaration confirms that all authorised products are included in the listing, irrespective of whether paediatric use has been authorised. The declaration further confirms that where no study details are listed, the studies have already been submitted to the NCA. The results of such studies should be made available within 3 days of receipt of a request by the NCA in order to comply with the Regulation.
• At the same time as submitting the templates, MA holders are strongly recommended to provide a short critical expert overview to clarify the context of the study data and identify any potential regulatory consequences, for example proposals to amend the product information. This will assist assessment of studies in the work-sharing procedure.

The templates are available with the procedural guidance on the HMA website (external link).  The completed templates must be submitted electronically to the MHRA (Excel format) and copied to the EMEA at the following mailboxes:
paediatricstudies@mhra.gsi.gov.uk
paedstudies@emea.europa.eu

Studies completed after 26 January 2007
Information on studies conducted by MA holders completed after 26 January 2007 should be submitted within six months of completion using the line-listing template in the first instance. The results of such studies should be made available within 3 days of request by the NCA. Safety data (as opposed to studies) which have already been submitted as part of a Periodic Safety Update Report (PSUR) need not be resubmitted. The information is required even if the MA holder intends subsequently to submit a variation, for example, to extend the indication. It would be helpful if MA holders indicated such intentions when submitting their line-listings.

Again, at the same time as submitting the templates, MA holders are strongly recommended to provide a short critical expert overview to clarify the context of the data and identify any potential regulatory consequences, for example proposals to amend the product information.

Information on paediatric use
Information on paediatric use is required to identify medicinal products eligible for the paediatric symbol when it has been agreed (Article 32) and also to satisfy the requirement for Member States to collect data on existing paediatric use (Article 42).

Annex II to the CMD(h) procedural guidance contains a template for submitting line listings and SmPC wording regarding medicinal products that have been authorised for paediatric use. The deadline for submission of information on the wording of the SmPC (4.1 and/or 4.2) for medicinal products has been extended until 26 April 2008, although NCAs would welcome the information at the same time as the Article 45 line-listings described above.

Penalties
The Paediatric Regulation allows Member States to apply penalties which are effective, proportionate and dissuasive for infringement of its provisions or implementing measures. The MHRA will shortly be consulting on its proposed enforcement measures, but in the meantime, MA holders are reminded of their obligations to comply with provisions of the Articles described above.

Further information
If additional information is required, please contact the MHRA as follows:

For further information on submission procedures, please contact Aidan Hardy, Information Processing Unit
aidan.hardy@mhra.gsi.gov.uk

For enquiries on interpretation of the requirements of Articles 32, 42, 45(1) and 46, or other provisions of the Paediatric Regulation, please send an e-mail to specialpopulationsunit@mhra.gsi.gov.uk