Enabling Development of Paediatric Medicines in Europe: 10 Years of the EU Paediatric Regulation

Background & AimAs part of the EU paediatric regulation, the paediatric use marketing authorisation (PUMA) was introduced, with an aim to stimulate research in existing compounds that are off-patent and/or to help transform known off-label use into authorised use.1 However, success has been limited, with only a few products gaining a PUMA, such as Sialanar 320 micrograms/mL glycopyrronium (equivalent to 400 micrograms/mL glycopyrronium bromide). A distinct challenge to overcome in this area is the development of more ‘age appropriate formulations’, particularly with an excipient composition and load that is suitable for paediatric patients. This project aims to establish an excipient screening platform, supplemented with analytical characterisation of materials, which will act as a decision making tool to accelerate and de-risk the production of age appropriate paediatric medicines.MethodTo develop this excipient screening platform, a list of drugs that require an age appropriate formulation was produced using the ‘needs for paediatric medicines’ documents provided by the European medicines agency (EMA),2whilst common problematic excipients in paediatrics were identified using an EMA reflection paper.3 Literature and prescribing data were also reviewed to ensure drugs selected would benefit from an age appropriate formulation. Differential scanning calorimetry (DSC) to determine compatibility of selected drugs with widely used excipients was carried out using a TA DSCQ200 instrument (TA Instruments, New Castle, DE) with TA Instruments Universal Analysis 2000 software. Data was collected under nitrogen atmosphere (50 mL min−1) using pierced flat-bottomed TZero aluminium pans (sample mass about 2 mg) and heating rate of 10 °C min−1 in the range from 50 to 400°C. For samples containing both the drug and an excipient, 1 mg of each was measured out and gently mixed with a spatula for one minute.ResultsThe most common class of drugs identified as requiring age appropriate formulations were related to cardiovascular disorders and neurology, whilst the majority of drugs identified also exhibit poor aqueous solubilities. Some identified problematic excipients include ethanol, sodium benzoate and sorbitol; however, these excipients may still be used in paediatric formulations, as long as they are below certain concentrations (for example, ethanol concentration should not exceed 0.5% w/v for under 6 years old). Two drugs identified through the initial screening, carvedilol and nifedipine, were analysed by DSC, alone and then alongside starch from corn and starch 1500; the resulting DSC curves showed no changes in peak size, position (peak onset temperatures for nifedipine and carvedilol were observed at 173.2°C and 117.3°C, respectively) and shape, as well as no additional peaks, therefore suggesting compatibility between the tested samples.ConclusionThis first phase of the development of an excipient screening platform will continue to scan several different excipients with selected active pharmaceutical ingredients (APIs) in order to create compatibility profiles. The excipient screening platform generated will accelerate and de-risk the production of age appropriate formulations, as it would allow screening for potential incompatibilities and acceptability, alongside informing formulation of appropriate oral paediatric dosage forms.ReferencesEuropean Commission. State of Paediatric Medicines in the EU. 10 years of the EU Paediatric Regulation. COM (2017) 626. Available at: https://ec.europa.eu/health/sites/health/files/files/paediatrics/docs/2017_childrensmedicines_report_en.pdfNeeds for paediatric medicines - European Medicines Agency [Internet]. 2019 [cited 28 June 2019]. Available from: https://www.ema.europa.eu/en/human-regulatory/research-development/paediatric-medicines/needs-paediatric-medicinesReflection paper: formulations of choice for the paediatric population [Internet]. European Medicines Agency. 2019 [cited 28 June 2019]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-formulations-choice-paediatric-population_en.pdf

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The EU paediatric regulation:

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2010.06.011 ◽

2011 ◽

Vol 21 (8) ◽

pp. 565-570 ◽

Cited By ~ 11

Author(s):

Violeta V. Stoyanova-Beninska ◽

Tamar Wohlfarth ◽

Maria Isaac ◽

Luuk J. Kalverdijk ◽

Henk van den Berg ◽

...

Keyword(s):

Paediatric Regulation ◽

The Eu

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More medicines for children: impact of the EU paediatric regulation

Archives of Disease in Childhood ◽

10.1136/archdischild-2017-313309 ◽

2018 ◽

Vol 103 (6) ◽

pp. 557-564 ◽

Cited By ~ 9

Author(s):

Sofia Nordenmalm ◽

Paolo Tomasi ◽

Chrissi Pallidis

Keyword(s):

Product Information ◽

Positive Impact ◽

The European Union ◽

Medicinal Products ◽

Paediatric Regulation ◽

Line Extension ◽

Pharmaceutical Form ◽

Paediatric Drug Development ◽

Medicines For Children ◽

The Eu

IntroductionThis paper focuses on the authorisation of new medicines, new indications and new pharmaceutical forms or strengths for use in children and also on the availability of paediatric information in the product information of centrally authorised medicinal products following the enforcement of the Paediatric Regulation on 26 January 2007.ObjectivesTo investigate whether the Paediatric Regulation has led to more medicines available for children in the European Union (EU) and if more information on paediatric use is now available in the product information of medicines authorised via the centralised procedure.Materials and methodsWe retrospectively analysed the centrally authorised medicinal products in the EU that had an approval for an initial marketing authorisation, a type II variation, or a line extension during the years 2004–2006 and 2012–2014. Medicinal products not subjected to the obligations of the Paediatric Regulation were excluded.ResultsIn 2004–2006, 20 new medicines and 10 new indications were centrally authorised for paediatric use compared with 26 new medicines and 37 new indications in 2012–2014. The number of medicines with a new pharmaceutical form or strength for use in children was eight in 2004–2006 and seven in 2012–2014. There was a huge increase in the number of products with changes of paediatric relevance in the summary of product characteristics in 2012–2014 compared with 2004–2006.ConclusionsThe entry into force of the Paediatric Regulation has had a positive impact on paediatric drug development with more medicines available for children in the EU and substantially more information available for clinicians on paediatric use in the product information.

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TEDDY NoE project in the framework of the EU Paediatric Regulation

Pharmaceuticals Policy and Law ◽

10.3233/ppl-2009-0206 ◽

2009 ◽

Vol 11 (1,2) ◽

pp. 13-21 ◽

Cited By ~ 1

Author(s):

A. Ceci ◽

P. Baiardi ◽

F. Bonifazi ◽

C. Giaquinto ◽

M.J. Mellado Peña ◽

...

Keyword(s):

Paediatric Regulation ◽

The Eu

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Successful private–public funding of paediatric medicines research: lessons from the EU programme to fund research into off-patent medicines

European Journal of Pediatrics ◽

10.1007/s00431-014-2398-z ◽

2014 ◽

Vol 174 (4) ◽

pp. 481-491 ◽

Cited By ~ 17

Author(s):

L. Ruggieri ◽

◽

V. Giannuzzi ◽

P. Baiardi ◽

F. Bonifazi ◽

...

Keyword(s):

Public Funding ◽

Patent Medicines ◽

The Eu ◽

Paediatric Medicines ◽

Fund Research

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Paediatric Medicines in Europe: The Paediatric Regulation—Is It Time for Reform?

Frontiers in Medicine ◽

10.3389/fmed.2021.593281 ◽

2021 ◽

Vol 8 ◽

Author(s):

Maddalena Toma ◽

Mariagrazia Felisi ◽

Donato Bonifazi ◽

Fedele Bonifazi ◽

Viviana Giannuzzi ◽

...

Keyword(s):

Clinical Studies ◽

Marketing Authorisation ◽

Drug Status ◽

Similar Data ◽

Medicinal Products ◽

Paediatric Regulation ◽

European Paediatric ◽

Paediatric Indication ◽

Active Substances ◽

Paediatric Medicines

Objectives: In this paper, we investigated the effects of the European Paediatric Regulation (EC) N° 1901/2006 with respect to satisfying the paediatric therapeutic needs, assessed in terms of the increased number of paediatric medicinal products, new therapeutic indications in specific high-need conditions (neonates, oncology, rare disease, etc.) and increased number of paediatric clinical studies supporting the marketing authorisation.Methods: We analysed the paediatric medicinal products approved by the European Medicines Agency in the period January 2007-December 2019, by collecting the following data: year of approval, active substance, legal basis for the marketing authorisation, type of medicinal product (i.e., chemical, biological, or ATMP), orphan drug status, paediatric indication, Anatomical Therapeutic Chemical code (first-level), number and type of paediatric studies. Data were compared with similar data collected in the period 1996–2006.Results: In the period January 1996–December 2019, in a total of 1,190 medicinal products and 843 active substances, 34 and 38%, respectively, were paediatric. In the two periods, before and after the Paediatric Regulation implementation, the paediatric/total medicinal products ratio was constant while the paediatric/total active substances ratio decreased. Moreover, excluding generics and biosimilars, a total of 106 and 175 paediatric medicines were granted a new paediatric indication, dosage or age group in the two periods; out of 175, 128 paediatric medicines had an approved Paediatric Investigational Plan. The remaining 47 were approved without an approved Paediatric Investigational Plan, following the provisions of Directive 2001/83/EC and repurposing an off-patent drug. The analysis of the clinical studies revealed that drugs with a Paediatric Investigational Plan were supported by 3.5 studies/drug while drugs without a Paediatric Investigational Plan were supported by only 1.6 studies/drug.Discussion: This report confirms that the expectations of the European Paediatric Regulation (EC) N° 1901/2006 have been mainly satisfied. However, the reasons for the limited development of paediatric medicines in Europe, should be further discussed, taking advantage of recent initiatives in the regulatory field, such as the Action Plan on Paediatrics, and the open consultation on EU Pharmaceutical Strategy.

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