Regulatory Intervention in Paediatric Medicines

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Pharmaceutical Technology Europe

Pharmaceutical Technology Europe, Pharmaceutical Technology Europe-09-01-2012, Volume 24, Issue 9

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?

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.

Nathan Jessop

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).


It has been suggested by independent observers that the impact of the Paediatric Regulation should be closely monitored to assess whether it meets the needs it originally set out to address (1).

Authors in the US have expressed concern about the effect of the US Pediatric Rule because the paediatric studies reported to FDA did not necessarily address the most urgent needs in paediatric drug development (6). In the US, some of the major areas that received attention in terms of paediatric drug development were antidepressants and mood stabilisers, lipid-lowering preparations, HIV antivirals, and nonsteroidal antiinflammatory and anti-rheumatic drugs. These areas were identified as having more in common with the largest commercial markets for adult medicines rather the needs of the paediatric population. In particular, the authors reported that among the drugs granted paediatric exclusivity, there were 5 out of the "Top 10" prescription drugs with the highest sales figures in North America in 2005, generating combined sales of $24.1 billion (6).

The authors also looked at the European situation and suggested that the EU approach to stimulating the development of off-patent drugs for paediatric use, through a PUMA, might go some way to counteracting industry's desire to focus only on drugs that were already generating considerable sales in the adult market. In general, they remained concerned that attempts by US and EU regulators to stimulate paediatric drug development may not have the desired effect and would be merely seen by pharmaceutical companies as a commercial opportunity to expand sales in existing adult market areas (6).

In its July report, EMA commented that several companies had failed to comply with the Paediatric Regulation (3). In 2011, the number of delayed PIP applications was 44, which was an improvement over the 65 noted in 2010. However, the length of delay was greater in 2011 than it had been the previous year. Out of the 44 delayed PIP applications, only 4 were considered to have a valid justification for the delay. Twelve applications did not include any justification at all. While noting these delays, it is unclear from the report what action the EMA intends to take now against the offending parties. Apart from repeating the requirements that a PIP must be submitted in a timely manner, no potential punishments are actually detailed. The regulators only hint that the Commission Regulation on financial penalties (Commission Regulation (EU) No 488/2012) may be a future deterrent.

Tackling the issues

European regulators are actively working to make progress on practical issues with respect to paediatric clinical trials. The setting up of the European Network of Paediatric Research at EMA (Enpr–EMA) in May 2010 was a key development (3, 7). Although it does not perform clinical trials, fund studies or research, or decide on areas for paediatric research, Enpr–EMA contributes to greater scientific understanding in the field and improves administrative competence at a European level. Enpr-EMA has members both inside and outside of the EU to represent various therapeutic areas, age groups and specific activities in paediatric medicine, such as pharmacovigilance. Enpr–EMA also holds annual workshops to discuss progress, with the last one being held in March 2012. At is 2012 meeting, Enpr–EMA discussions were still focused on how members could best collaborate and what approaches could be used to ensure representation from different stakeholders. Membership of the network is based on self assessment. According to the EMA's latest figures, 34 networks have submitted their self-assessment reports. At present, there are two networks that potentially fulfil all minimum criteria, but clarification over some issues is required before they can become members. Fourteen others still to meet the minimum qualifying criteria (3). The original deadline for networks to complete the self-assessment procedure was July 2010, suggesting that progress at Enpr–EMA is occurring slowly and it is too early to document an impact on paediatric development.


The introduction of the EU's Paediatric Regulation has led to an increase in clinical trials involving paediatric subjects, but it is unclear whether the effects are what regulators initially desired. In particular, there is concern that the pharmaceutical industry is viewing the incentives as ways to expand sales for products that are already serving adult markets, rather than determining what paediatric medical needs are and prioritising these areas for drug development. From a practical perspective, Enpr–EMA promises much in terms of improving understanding of the field of paediatric drug development and ensuring that Europe has administrative processes conducive to approving such research. The EC is due to report to the European Parliament in 2013 on the impact of the Paediatric Regulation. This time may also be an effective point at which to assess progress with Enpr–EMA.


1. M. Watzl, "The New Paediatric Regulation in the EU – Development, Implications and Comparison with US Experiences in Paediatric Drug Development" (German Society for Regulatory Affairs website, 2007),, accessed 1 Aug. 2012.

2. MHRA, "Medicines for children. Medicines and Healthcare products Regulatory Agency" (MHRA website, 2012),, accessed 1 Aug.

3. EMA, "Report to the European Commission: EMA/480331/2012" (EC website, 2012),, accessed 1 Aug. 2012. 2012.

4. P. Tomasi "The Paediatric Regulation as an instrument for European paediatric research. ENPREMA" (EMA website, 2011),, accessed 1 Aug. 2012.

5. T.M. Olski et al. Eur. J. Clin. Pharmacol. 67 (3), 245-52 (2011).

6. I. Boots et al., Eur. J. Pediatr. 166 (8), 849–855 (2007).

7. EMA, "European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA)" (EMA website, 2012)., accessed 1st Aug. 2012.