Abstract
BackgroundDrug development for rare diseases is challenging, especially when these orphan drugs (OD) are intended for children. In 2007 the EU Paediatric Drug Regulation was enacted to improve the development of high quality and ethically researched medicines for children through the establishment of Paediatric Investigation Plans (PIPs). The effect of the EU Paediatric Drug Regulation on the marketing authorisation (MA) of drugs for children with rare diseases was studied.MethodsData on all designated orphan drugs, their indication, MA, PIPs and indication group (adult or child) were obtained from the European Medicines Agency (EMA). The outcome and duration of the process from orphan drug designation (ODD) to MA, was compared, per indication, by age group. The effect of the Paediatric Drug Regulation, implemented in 2007, on the application process was assessed with survival analysis.ResultsEighty-one orphan drugs obtained MA since 2000 and half are authorised for (a subgroup of) children; another 34 are currently undergoing further investigations in children through agreed PIPs. The Paediatric Drug Regulation did not significantly increase the number of ODDs with potential paediatric indications (58% before vs 64% after 2007 of ODDs, p = 0.1) and did not lead to more MAs for ODs with paediatric indications (60% vs 43%, p = 0.22). ODs authorised after 2007 had a longer time to MA than those authorised before 2007 (Hazard ratio (95% CI) 2.80 (1.84-4.28), p < 0.001); potential paediatric use did not influence the time to MA (Hazard ratio (95% CI) 1.14 (0.77-1.70), p = 0.52).ConclusionsThe EU Paediatric Drug Regulation had a minor impact on development and availability of ODs for children, was associated with a longer time to MA, but ensured the further paediatric development of drugs still off-label to children. The impact of the Paediatric Drug Regulation on research quantity and quality in children through PIPs is not yet clear.
Highlights
Rare diseases are defined as life-threatening or chronically debilitating conditions with such a low prevalence that special combined efforts are needed to ensure adequate medical care
We describe the drug application process from orphan drug designation (ODD) to marketing authorisation (MA) and analyse the effect of the Paediatric Drug Regulation on the success rate and time course of obtaining MA
A Paediatric Investigation Plan (PIP) has to include all subsets of the paediatric population, but waivers for the entire paediatric population or for certain age groups are granted when one of the following conditions are met: the condition only occurs in the adult population; clinical studies cannot be expected to be of significant therapeutic benefit or are not feasible; the product is considered unsafe or ineffective in children
Summary
Rare diseases are defined as life-threatening or chronically debilitating conditions with such a low prevalence that special combined efforts are needed to ensure adequate medical care. A low prevalence still equals to approximately 250,000 patients in the Community for diseases near the cut-off point. There are between 5000 and 8000 rare diseases identified so far, affecting an estimated 30 million EU citizens [2]. Over 80% of rare diseases have a genetic background, with the great majority being single-gene defects, multifactorial and chromosomal defects exist. Rare diseases can occur at any age but approximately half of these have their onset at birth or during childhood [4]. Drug development for rare diseases is challenging, especially when these orphan drugs (OD) are intended for children. The effect of the EU Paediatric Drug Regulation on the marketing authorisation (MA) of drugs for children with rare diseases was studied
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