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EMEA’s journey towards better medicines for children


SAFER MEDICINES FOR CHILDREN ARE A PRIORITY

The European Medicines Agency (EMEA) is living in momentous times for child health in the European Union (EU), thanks to the introduction in 2007 of the Paediatric Regulation (1). Together with its partners in the European medicines network and all its stakeholders, the EMEA faces the extraordinary challenge of providing better medicines for children in Europe. In this, its 13th year of operation, the EMEA has made implementing the Paediatric Regulation a key priority. The impact of this work on the Agency’s resources is big, but the expected benefits for child health outweigh these considerations as the EMEA pursues its mission to promote and protect public health in the EU.

Given that 20% of the EU population (approximately 100 million people) is under 16 years old, the importance of making appropriate medicines available to them is paramount. However, available figures show that more than 50% of medicines currently used to treat children in Europe have not been specifically tested for use in children, nor are they authorised for use in this population segment (2).

To respond to this lack of suitably authorised medicines for paediatric use, the European Parliament and Council adopted the Paediatric Regulation on a proposal of the European Commission, which aims to:

  • Facilitate the development and availability of medicines for children under 18 years old;
  • Ensure that medicines for use in children are of high quality, ethically researched and authorised appropriately;
  • Improve the availability of information on the use of medicines for children.

These aims are to be met without subjecting children to unnecessary trials, nor delaying the authorisation of medicinal products for use in adults. To achieve this ambitious objective, the Paediatric Regulation is underpinned by a system of obligations, incentives and rewards.

A new regulatory framework for pharmaceutical companies

As of 26 July 2008, companies applying for marketing authorisation for a new medicinal product will be obliged to submit the results of studies conducted with that medicine in paediatric populations. These studies must be conducted in accordance with a paediatric investigation plan (PIP): a drug-development plan that specifies the timing and measures proposed by the company for studies in all subsets of the paediatric population affected by the condition concerned.


OPPORTUNITIES FOR FUNDING RESEARCH AREAVAILABLE

This obligation is binding for companies developing a medicinal product for the EU. It can, however, be waived for medicines that are unlikely to benefit children, and, in some cases, the studies may be deferred until after the medicine has been authorised for use in adults. The reward for conducting the clinical studies in children in compliance with a PIP will be a six-month extension of the patent, in the form of an extension of the supplementary protection certificate (in the case of currently unauthorised products), provided that the results, including those that are negative, are presented in the product information, and provided that authorisation is obtained in all EU Member States.

Orphan-designated medicines (for rare diseases) are subject to the same obligations, and will be rewarded with two years of market exclusivity in addition to the existing 10 years’ exclusivity. In the case of authorised, patent-protected products, there is an obligation, as of 26 January 2009, to submit the results of studies in compliance with a PIP when seeking a variation or extension of the marketing authorisation for a new indication, new route of administration or new pharmaceutical form. As with new medicines, waivers or deferrals may also be granted, and the reward is a six-month extension of the supplementary protection certificate.

PUMA: a new type of marketing authorisation for off-patent medicines

Off-patent medicines developed specifically for paediatric use and with an appropriate formulation will be able to benefit from an optional new type of marketing authorisation: the paediatric-use marketing authorisation (PUMA). The rewards for a PUMA – provided that studies are conducted in compliance with an agreed PIP – will be 10 years of data protection and the possibility of retaining the brand name of the medicinal product.

The Paediatric Committee

At the heart of the EMEA’s new responsibilities under the Paediatric Regulation is the establishment of the Paediatric Committee (PDCO) in July 2007 – the fifth scientific committee within the EMEA. The PDCO will be composed of one expert representing each of the 27 EU Member States (including five members of the Agency’s existing Committee for Medicinal Products for Human Use), one expert representing each of the EEA-EFTA countries, and a total of six members representing healthcare professionals’ and patients’ associations. The PDCO’s main responsibility will be the assessment and agreement of PIPs, waivers and deferrals.

PIPs or waiver applications should be submitted for agreement of the PDCO not later than upon completion of the human pharmacokinetic studies in adults (except in duly justified cases), which is the end of phase i, so as to ensure that companies have enough time to conduct studies in children, if safe to do so, before applying for a marketing authorisation. Applications for PIPs and waivers have been accepted for validation by the EMEA since 20 June 2007, using the templates finalised by the EMEA and published on the Agency’s website.

EU-wide research network

In order to support this major public health drive for better medicines for children, the EMEA is developing an EU-wide research network of existing national and European networks, investigators and centres with specific expertise in the performance of studies in the paediatric population. The aims of this are to build up competences at European level, to facilitate the conduct of studies and to avoid their duplication. Setting up the paediatric research network will be an important task of the Paediatric Committee, which will build on work already done by the EMEA before the Paediatric Regulation came into force.

Paediatric needs

In this long-term commitment to enriching the availability of medicines for the paediatric population, the Paediatric Committee will also set up, by 26 January 2009, an inventory of paediatric needs. This inventory will be based on a survey being conducted in the Member States to establish all existing uses of medicinal products in children (including off-label medicines), which should be completed by the end of 2008. Preliminary lists (available on the EMEA website) were established by the Agency’s Paediatric Working Party (PEG), which, over six years, prepared the groundwork for the EMEA’s implementation of the Paediatric Regulation. In its lists, the PEG identified approximately 300 conditions in various therapeutic areas considered to be “needs” on the basis of seriousness, prevalence and scope of therapeutic options available, among other criteria.

Transparency and provision of information

As part of its commitment to transparency and the provision of information to the public, the EMEA will publish paediatric data in product information, including when study results identify safety issues. Protocols and results of clinical trials performed in children, whether inside or outside the EU, will also be made public, through the EU clinical trials database (EudraCT). Together with the European Commission and Member States, the Agency will develop guidelines on transparency of paediatric clinical trials data. In addition, information on paediatric medicines will be included in EudraPharm (3), the database funded by the European Commission and implemented by the EMEA to provide public access to information on all centrally authorised medicines in the EU.

The paediatric symbol

A symbol, to be selected by the European Commission on a recommendation from the Paediatric Committee, will have to be included on the packaging of all medicinal products with a paediatric indication – whether new or already authorised, and regardless of the route of authorisation – to help identify the product as being authorised for use in children. This requirement should be fulfilled within two years of the publication of the symbol (the European Commission will make the symbol available by 26 January 2008) and the package leaflet must be modified to include an explanation of the symbol.

Safer medicines for children: an EMEA priority

The safety of medicines – including those for children – is one of the EMEA’s primary concerns. There is a clear need to ensure that pharmacovigilance mechanisms are adapted to meet the specific challenges of collecting safety data for the paediatric population, including data on possible long-term effects. It may also be necessary to conduct further studies on the efficacy of medicines used in the paediatric population following their authorisation. To address these concerns, the Paediatric Regulation contains an obligation for applicants to indicate in their marketing authorisation application how they propose to ensure the long-term follow-up of possible adverse reactions to the use of their medicinal product, and of its efficacy in the paediatric population. Where there is a particular cause for concern, the applicant should submit and implement a risk management plan and/or perform specific post-marketing studies as a condition for the granting of the marketing authorisation. In order to contribute to the establishment in Europe of reinforced pharmacovigilance measures for paediatric medicines, the EMEA is an active participant in the European Network of Centres of Pharmacoepidemiology and Pharmacovigilance (ENCePP) – a network of academic centres for intensive drug monitoring.

Boosting research

As part of EU-wide efforts to boost research into new therapeutic solutions for children, opportunities for academics and companies to fund their research in this area are available through the EU’s Seventh Framework Programme for Research and Technological Development (FP7) (4), which offers 30 million euro over the first two years of the programme specifically for research into off-patent medicines for paediatric use. Support will be given to studies intended to provide evidence for the appropriate use and appropriate formulations of off-patent products currently used off-label in paediatric populations, linked with the priority list of identified off-patent medicines published by the EMEA. The deadline for proposals under the FP7 programme is 18 September 2007.

Other specific FP7 topics will address research issues relating to child health and paediatric diseases, including:

  • Innovative approaches for the development of vaccines for young children;
  • Child and adolescent mental disorders;
  • Paediatric formulations of drugs for HIV/AIDS, malaria and tuberculosis;
  • Diabetes in children.

Impact of the Paediatric Regulation on the EMEA

This new legislative framework for paediatric medicines increases both the scope and the complexity of the Agency’s activities. The initial forecast from the beginning of the year that the EMEA will receive approximately 400 requests or applications relating to paediatric activities – involving paediatric investigation plans, waivers and scientific advice – has recently been revised and is now expected to be 50-70% higher. The implementation of the Paediatric Regulation will also bring about an increased workload in the area of scientific advice, which is provided free of charge to companies developing medicines intended for paediatric use. Scientific advice can be requested prior to submission of a PIP or during the PIP implementation process, and can include advice on pharmacovigilance and risk-management systems. The Agency began providing free paediatric scientific advice in January 2007.

Co-operation is the key to success

In its journey to improve the health of children in Europe, the Agency is working side by side with the EU institutions and Member States, as well as with representatives of patients’ and healthcare professionals’ organisations. In doing so, the Agency can draw on the great expertise and knowledge available within the European medicines network, in the spirit of co-operation that has served the European regulatory system for medicines so well in the past. The same philosophy of co-operation applies in the international arena too, where, notably, the EMEA, the European Commission and the US Food and Drug Administration (FDA) have recently established – under the EU/FDA confidentiality arrangements – principles for interaction and exchange of information on paediatric matters, as part of efforts to pave the way for global development of medicines for children.

There is no doubt that the Paediatric Regulation brings an increased number of tasks for the Agency. However, it is undeniably a valuable legislative tool that will serve Europe well as it responds to the need for improved health of its children.

More complete information about the Paediatric Regulation, the Paediatric Committee and EMEA procedures for applications is available in a dedicated “Medicines for children” section of the EMEA website: www.emea.europa.eu

 

1. Regulation (EC) No 1901/2006 of the European Parliament and of the Council on medicinal products for paediatric use, as amended by Regulation (EC) No 1902/2006.

2. S. Conroy S et al. BMJ. 2000;320:79-82. M. Chalumeau et al. Arch. Dis. Child. 2000;83:502-505.

3. EudraPharm online database: http://eudrapharm.eu

4. More information about FP7 is available at:
http://ec.europa.eu/research/fp7/index_en.cfm

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