Regulatory Intervention in Paediatric Medicines

Regulators in both the EU and the US have attempted to stimulate paediatric-drug development with incentives offering extended periods of patent protection, but are these actions having the desired effects?
Sep 01, 2012

Nathan Jessop
Paediatric-drug development is an area that has lagged in terms of regulatory attention in the EU, partly because of the difficulties in establishing consistent regulations between the different member states. The US introduced its Pediatric Rule in the late 1990s, but the EU's own Paediatric Regulation (Regulation (EC) 1901/2006) only came into force in January 2007. The European Commission is preparing to report back to the European Parliament in 2013 on the 5-year experience with the Paediatric Regulation.

The problem with paediatrics

Many drugs currently used for children in the EU have not been specifically tested in paediatric populations (defined in Europe as 0–17 years of age) during development because of the ethical concerns of involving children in clinical trials. In the EU, research papers have suggested that this is the case for over half of paediatric medicines (1). Most products are tested in adults, but not necessarily in the same indication as used for paediatrics because they are often prescribed to children off label at the discretion of physicians. The decision over what medicines to prescribe to children may also vary between member states because of differing national laws and regulatory systems.

The Paediatric Regulation provides harmonised guidance and incentives for developing safe and effective paediatric medicines in Europe. The regulation requires all applications for marketing authorisations submitted to EMA to include either a product-specific waiver or a paediatric investigation plan (PIP) approved by the EMA's Paediatric Committee (PDCO). The PIP must contain a full proposal all paediatric studies, including their timings, the age groups concerned and all the age-appropriate formulations. In some cases, it is possible to defer the start of some or all of the paediatric studies until after a marketing authorisation has been granted (based on studies in adults).

The regulation also offers incentives for paediatric development. Upon completion of an agreed paediatric plan, to the satisfaction of regulatory authorities, the medicinal product will be granted an extra 6 months patent protection through an extension of the duration of its Supplementary Protection Certificate (SPC). This incentive applies if the product is authorised in all EU member states and the relevant information from the paediatric studies (whether negative or positive) is incorporated into the summary of product characteristics. Interestingly, if such conditions are fulfilled, the extension will apply whether the data generated support a paediatric indication or not. Once a PIP is completed and has been validated by the regulator, a compliance statement is issued, which can be presented to the National Patent Offices.

Another aspect of the EU's Paediatric Regulation was the establishment of a new type of marketing authorisation, the paediatric use marketing authorisation (PUMA), which was intended to encourage the development of off-patent products for use in paediatric populations. Only medicines intended solely for use in children are eligible for a PUMA, which, if granted (via the EU's Centralised Procedure), may lead to a new period of market exclusivity of 10 years (1, 2).

In July, EMA presented a routine report to the European Commission (EC) on the companies that benefited from the Paediatric Regulation in 2011 (3). For 2011, EMA reported that its Paediatric Committee (PDCO) adopted 107 positive opinions on paediatric investigation plans (PIP), a similar number to 2010. The Agency is planning to reveal full details of these decisions later in 2012 (3).

Statistics show that the introduction of the Paediatric Regulation has prompted greater drug development with children in mind. In 2008, 81 PIPs were agreed by the PDCO, but by 2009 this jumped to 122 (4). In a 2011 published analysis, it was documented that the highest number of PIPs were for endocrinology (13.4%), oncology (11%) and infectious (10.8%) and cardiovascular diseases (7.1%) (5). Overall, the proportion of paediatric trials as a percentage of all clinical trials was only considered to have increased to a modest extent, although it was suggested that this might be because more than 80% of paediatric trials had been deferred until after adult drug development (5).

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