It has been estimated that more than 50% of medicines used to treat children in Europe have not been tested for use in children, neither have they been authorised for use in the care of children. On 26 January 2007, new EU legislation on medicines for children enters into force. The Paediatric Medicines Regulation1 aims to balance the ethical issues raised by conducting trials on children with concerns arising from the treatment of children with products which have not been tested on them and the effects, both positive and negative, of which have not been assessed. The Regulation aims to increase the development of medicines that are intended to treat children, to encourage research into medicines for use in treating children and to improve the quality and quantity of information available in this area.
All pharmaceutical companies seeking to sell their medicines in the EU have an interest in this legislation, whether or not the products are intended to treat children. Indeed, applicants for marketing authorisations for new medicines and line extensions at EU and EU Member State level must comply with its stringent requirements. The requirements apply irrespective of whether or not the medicinal product for which authorisation is sought is intended to be administered in children. However, they do not apply to generic products, biosimilars, hybrids, products containing substances acknowledged to have well-established medicinal use, herbal medicines and homeopathic medicines.
The Regulation is also of particular interest to pharmaceutical companies seeking to develop offpatent medicinal products for use in children. Indeed, it provides for a new type of marketing authorisation called a Paediatric Use Marketing Authorisation.
The Regulation imposes an extensive system of requirements on companies and provides for penalties for non-compliance. However, it also offers rewards and other incentives.
The Regulation introduces the requirement that applications for marketing authorisations for new medicinal products include either the results of studies in the paediatric population that have been carried out in accordance with an agreed Paediatric Investigation Plan (PIP), or proof of having obtained a waiver or deferral from this obligation.
This obligation also applies to applications for extension of an existing authorisation for products that are currently covered by either, a supplementary protection certificate (SPC) or, by a patent that will be eligible for an SPC, to cover a new indication, new pharmaceutical form or new route of administration.
The obligation applies irrespective of whether or not the medicinal product for which authorisation is sought is intended to be administered to children. It applies equally to both centrally authorised and nationally authorised products.
The Regulation provides for the establishment at EU level of an expert Paediatric Committee (PDCO) within the European Medicines Agency (EMEA). It will be made up of five experts from the Committee for Human Medicinal Products (CHMP), representatives of the 22 EU Member States that are not previously represented by members of the CHMP, three health professionals appointed by the European Commission, and three representatives of patients’ associations, also appointed by the European Commission. It is with this Committee that an undertaking applying for either a marketing authorisation for a new medicinal product, or a variation or extensions for existing patent protected medicinal products must agree a PIP. The purpose of a PIP is to generate data determining the conditions under which the medicinal product may be used to treat children.
The requirement to agree a PIP does not extend to generic products, biosimilars, hybrids, products containing substances acknowledged to have well-established medicinal use, herbal medicines and homeopathic medicines.
Waivers and Deferrals
An undertaking may seek either a waiver or a deferral from the Committee from the obligation to provide paediatric studies. A waiver may be granted where evidence is provided that the medicinal product, or class of products, is likely to be ineffective or unsafe in part or all of the paediatric population, where the disease or condition for which the product or class or products is intended occurs only in the adult population, or where a specific medicinal product does not represent a significant therapeutic benefit over existing treatments.
A request to have initiation or completion of some or all of the measures included in the programme deferred may accompany submission of a PIP. A request for a deferral must be justified on scientific or technical grounds or on grounds related to public health.
In order to increase the availability of information and to avoid unnecessarily repeating studies, details on these clinical trials will be included in the EU database of clinical trials (EudraCT). Guidance will be drawn up on the nature of the information to be included and on which information will be made public.
The European Commission or the national regulatory authority must ensure that the marketing authorisation application complies with the agreed PIP. Provision is made in the Regulation to permit the CHMP, the competent authority, or the undertaking to ask the Committee’s opinion on compliance of the marketing authorisation application with the PIP. The CHMP or a competent authority may also ask the Committee’s opinion on the quality, safety and efficacy of the product for its use in children.
Where a marketing authorisation includes an indication for paediatric use the label must display a symbol to reflect this. The European Commission will select the symbol to be used by 26 January 2008.
Appropriate steps to ensure the maintenance of supply of products approved for paediatric use have been addressed in the Regulation. Where, following expiry of the data protection and market protection periods for which the Regulation provides, the marketing authorisation holder intends to withdraw the product from the market, it must comply with certain specific requirements. The undertaking must inform the EMEA of its intention to withdraw the product no less than six months before the product is removed from the market. It must also transfer the marketing authorisation or allow a third party which has declared its intention to continue to place the product on the market to use the pharmaceutical, pre-clinical and clinical documentation contained in the file of the medicinal product.
There are a range of rewards for undertakings for compliance with the PIP. This includes undertakings that have products for which paediatric development is already in progress when the Regulation enters into force. However, these will benefit only if “significant” studies contained in an agreed PIP are completed after entry into force of the Regulation on 26 January 2007. The European Commission will draw up guidelines on how to assess whether or not studies are significant.
For newer medicines benefits include:
- six months extension of the SPC to which the product is entitled;
- two years extension of market exclusivity for orphan medicines. The reward is for conducting studies in the paediatric population and is therefore granted even when a paediatric indication is not authorised provided that the results of the studies conducted are reflected in the SPC and, where appropriate, the package leaflet;
- optional access to the centralised EU level procedure for marketing authorisation applications that include one or more paediatric indications on the basis of studies conducted in accordance with the agreed PIP.
For older medicines, a new type of marketing authorisation, a Paediatric Use Marketing Authorisation (PUMA) will be available. This type of authorisation, for which eight years’ data protection and 10 years’ market protection are provided, will apply solely to products for which the patent has expired and which are not protected by an SPC. It covers therapeutic indications developed exclusively for use in the paediatric population in accordance with an agreed PIP. Optional access to the centralised EU level procedure is available for PUMAs. The medicinal product granted a PUMA can use the existing brand name for the corresponding product authorised in adults.
The Regulation envisages penalties at EU and national level for non-compliance with its provisions. Each Member State is required to determine effective, proportionate and persuasive penalties and to inform the European Commission of these penalties by 26 October 2007. At the request of the EMEA, the European Commission may also impose financial penalties for breaches of the provisions of the Regulation in relation to products authorised according to the centralised procedure. The Commission shall make public the names of those penalised for infringement of the Regulation or of its implementing measures and the amounts of, and reasons for, the financial penalties imposed
The legislation is a regulation. It is therefore directly applicable, which means that it takes immediate effect in all the Member States. The regulation entered into force on 26 January 2007. However, it provides that some of its provisions will enter into force later on. Indeed, the dates by which the obligations to agree a PIP enter into force have been staggered. For medicinal products that have not yet been authorised by 26 January 2007, the date of entry into force of the Regulation, the obligation enters into force on 26 July 2008. Although the PIP request should, in principle, be submitted no later than the completion of the relevant human pharmacokinetic studies in adults, if a product is already developed beyond such studies (beyond Phase I), this legal deadline for submission of the PIP is not applicable.
For previously authorised products protected either by a supplementary protection certificate (SPC) or else by a patent that will be eligible for an SPC, and for which variation or extension of an existing authorisation is sought, the obligation enters into force on 26 January 2009. In the meantime, companies may approach the Paediatric Committee, which will be established by 26 July 2007, to agree a PIP.
Furthermore, the Paediatric Use Marketing Authorisation (PUMA) will be available from 26 July 2007.
The Regulation should lead to increased assurance concerning the quality, safety and efficacy of medicinal products prescribed for paediatric use. However, obligations are strict. It remains to be seen whether the industry will consider the benefits for which the Regulation provides adequate to compensate for the additional studies undertaken and costs involved.