Abstract
Over the past two decades, there has been growing concern over the lack of proper medication for children. This review attempts to evaluate the current progress of EU Pediatric Regulation made since 2007. The lack of properly evaluated pediatric medication has for long been a source of concern in the European Union. The drugs that were used in the past were often not properly evaluated, and dosage was arbitrarily calculated. Therefore, it was necessary to establish the Pediatric Regulation (EC no. 1901/2006) in the EU which would mandate research for pediatric drugs. Current legislations in place not only require mandatory research by pharma industry but also have guidelines to direct the quality of pediatric research performed. The main aim of this regulation was to advance high-quality research and development of pediatric drugs, thereby increasing the availability of safe and effective drugs for children. It also aimed to improve the information available on existing pediatric drugs. It has been 9 years since the pediatric regulation was framed. The pharma industry now sees pediatric research as an integral process of development. Drug companies which develop plans for a new drug, new form of drug, new indication, or new route of administration for adults are obliged to integrate in their development plan similar research for pediatric populations as well.
Conclusion: It is hoped that the implementation of the current legislation will be reflected better in the future by the marketing of better and safer drugs for the pediatric population. The upcoming assessment to the European Commission in 2017 will further inform us on the impact after 10 years implementation of the legislation.
What is Known: • The lack of properly evaluated pediatric medication has for long been a source of concern in the European Union. • Therefore, it was necessary to establish the EU Pediatric Regulation which would mandate research for pediatric drugs. |
What is New: • It has been 9 years since the pediatric regulation was framed, and the teething problems are slowly being overcome and the regulation is being used with increasing confidence. • As the Regulation is due for revision in 2017, this paper gives a current perspective on the impact of the regulation on availability and access to medicine for children. |
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Notes
EMA annual reports are available at http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/document_listing/document_listing_000208.jsp&mid=WC0b01ac058002933a)
Abbreviations
- BPCA:
-
Best Pharmaceuticals for Children Act
- EuPFI:
-
European Pediatric Formulation Initiative
- EU:
-
European Union
- EMA:
-
European Medicines Agency
- Enpr-EMA:
-
European Network of Pediatric Research at the European Medicines Agency
- ENCCA:
-
European Network for Cancer Research in Children and Adolescents
- FDA:
-
Food and Drug Administration
- FDAMA:
-
Food and Drug Administration Modernization Act
- FDASIA:
-
Food and Drug Administration Safety and Innovation Act
- GRiP:
-
Global Research in Pediatrics–Network of Excellence
- ICH:
-
International Conference on Harmonization
- iCAN:
-
International Children’s Advisory Network
- PDCO:
-
Pediatric Committee
- PIP:
-
Pediatric Investigation Plan
- PREA:
-
Pediatric Research Equity Act
- R&D:
-
Research and Development
- RESPECT:
-
Relating Expectations and Needs to the Participation and Empowerment of Children in Clinical Trials
- STEP:
-
Safety and Toxicity of Excipient Toxicity
- US:
-
United States
References
Bar-Shalom D (2014) Necessity of rethinking oral pediatric formulations. Clin Ther 36:180–183
Batchelor HK, Marriott JF (2015) Formulations for children: problems and solutions. Br J Clin Pharmacol 79:405–418
Bavdekar SB (2013) Pediatric clinical trials. Perspect. Clin Res 4:89–99
Bogue C et al (2016) Special article: 2014 pediatric clinical trials forum. Pediatr Res 79:662–669
Bourgeois FT et al (2012) Pediatric versus adult drug trials for conditions with high pediatric disease burden. Pediatrics 130:285–292
Brasseur D (2014) Understanding the paediatric regulation: who got the wrong end of the stick? Regul Rapp 11:9–13
Breitkreutz J (2008) European perspectives on pediatric formulations. Clin Ther 30:2146–2154
Byrne-Davis LMT, Salmon P, Gravenhorst K, Eden TOB, Young B (2010) Balancing high accrual and ethical recruitment in paediatric oncology: a qualitative study of the ‘look and feel’ of clinical trial discussions. BMC Med Res Methodol 10:101
Ceci A et al (2015) Clinical trials in paediatrics — regulatory and methodological aspects, drug discovery and development - from molecules to medicine. In: Vallisuta O (ed). InTech. doi:10.5772/60611. Available at: http://www.intechopen.com/books/drug-discovery-and-development-from-molecules-tomedicine/clinical-trials-in-paediatrics-regulatory-and-methodological-aspects
Ceci A et al (2002) Medicines for children licensed by the European Agency for the Evaluation of medicinal products. Eur J Clin Pharmacol 58:495–500
Corny J, Lebel D, Bailey B, Bussières J-F (2015) Unlicensed and off-label drug use in children before and after pediatric governmental initiatives. J Pediatr Pharmacol Ther JPPT 20:316–328
Davis JM, Turner MA (2015) Global collaboration to develop new and existing drugs for neonates. JAMA Pediatr 169:887
Early dialogue to support development of medicines for children. (2015). Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2015/06/news_detail_002348.jsp&mid=WC0b01ac058004d5c1. Accessed 9 Mar 2016
European Comission (2014) Better, faster treatment for children with cancer. 1 February. Available at: http://ec.europa.eu/programmes/horizon2020/en/news/better-faster-treatment-children-cancer
European Medicines Agency (2012) 5-year Report to the European Commission. doi:EMA/428172/2012
European Medicines Agency (2013) Revised priority list for studies on off-patent paediatric medicinal products. EMA/PDCO/98717/2012 Rev. 2013/14 12. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Other/2009/10/WC500004017.pdf. Accessed 13 Jul 2016
European Medicines Agency. European Medicines Agency and US Food and Drug Administration release joint proposal to facilitate clinical investigation of new medicines for Gaucher disease in children. EMA/44410/2014 9 (2014). Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2014/05/WC500166587.pdf. Accessed 31 Mar 2016
European Medicines Agency policy on changes in scope of paediatric investigation plan (PIP) decisions (EMA/472551/2012). (2012). Available at: www.ema.europa.eu/docs/en_GB/document_library/Other/2012/07/WC500130439.pdf. Accessed 9 Mar 2016
European Medicines Agency. Annual Report 2015. (2015). Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Annual_report/2016/05/WC500206482.pdf. Accessed 14 Jul 2016
FDA; EMA (2007) Principles of interactions: between EMEA and FDA pediatric therapeutics. Jun
Fernandes RM, van der Lee JH, Offringa M (2009) A systematic review of the reporting of data monitoring committees’ roles, interim analysis and early termination in pediatric clinical trials. BMC Pediatr 9:77
Fernandes RM, van der Lee JH, Offringa M (2011) Data monitoring committees, interim analysis and early termination in paediatric trials. Acta Paediatr 100:1386–1392
Global Research in Paediatrics - Network of Excellence. Available at: http://www.grip-network.org/index.php/cms/en/Home. Accessed 9 Mar 2016
Gonzales K (2010) Medication administration errors and the pediatric population: a systematic search of the literature. J Pediatr Nurs 25:555–565
Guideline on pharmaceutical development of medicines for paediatric use EMA/CHMP/QWP/805880/2012 Rev. 2. (2013). Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/07/WC500147002.pdf. Accessed 10 Mar 2016
Hirschfeld S, Saint-Raymond A (2011) In: Seyberth WH, Rane A, Schwab M (eds) Pediatric Clinical Pharmacology 245–268 (Springer Berlin Heidelberg). doi:10.1007/978–3–642-20195-0_12
Hoppu K (2013) Reflection: medicines for children—science alone is not enough. Eur J Clin Pharmacol 69(Suppl 1):59–63
Hoppu K et al (2012) The status of paediatric medicines initiatives around the world—what has happened and what has not? Eur J Clin Pharmacol 68:1–10
ICH E11 Clinical Investigation of Medicinal Products in the Pediatric Population. International Council for Harmonisation (2000). Available at: http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/clinical-investigation-of-medicinal-products-in-the-pediatric-population.html. Accessed 14 Jul 2016
Ivanovska V, Rademaker CMA, van Dijk L, Mantel-Teeuwisse AK (2014) Pediatric drug formulations: a review of challenges and progress. Pediatrics 134:361–372
Jackson C, Turner R (2010) Paediatric clinical research and considerations for clinical trials. J Clin Stud 28–31
Jannin V, Lemagnen G, Gueroult P, Larrouture D, Tuleu C (2014) Rectal route in the twenty-first century to treat children. Adv Drug Deliv Rev 73:34–49
Karres J et al (2014) Joining forces: a call for greater collaboration to study new medicines in children and adolescents with type 2 diabetes. Diabetes Care 37:2665–2667
Knopf H et al (2013) Off-label medicine use in children and adolescents: results of a population-based study in Germany. BMC Public Health 13:631
Kozarewicz P (2014) Regulatory perspectives on acceptability testing of dosage forms in children. Int J Pharm. doi:10.1016/j.ijpharm.2014.03.057
Kreeftmeijer-Vegter AR, de Boer A, van der Vlugt-Meijer RH, de Vries PJ (2014) The influence of the European paediatric regulation on marketing authorisation of orphan drugs for children. Orphanet J Rare Dis 9:120
Laughon MM et al (2011) Innovative clinical trial design for pediatric therapeutics. Expert Rev Clin Pharmacol 4:643–652
Laventhal N, Tarini B, Lantos J (2013) Ethical issues in neonatal and pediatric clinical trials. Pediatr Clin N Am 59:1205–1220
Lazzeri M (2006) More urologic clinical trials in children are needed. Eur Urol 50:662–663
Lepola, P. et al. (2016a) Informed consent for paediatric clinical trials in Europe. Arch Dis Child 1–9. doi:10.1136/archdischild-2015-310001
Lepola P, Tansey S, Dicks P, Preston J, Dehlinger-Kremer M (2016b) Pharmaceutical industry and pediatric clinical trial networks in Europe—how do they communicate? Applied Clinical Trials. Available at: http://www.appliedclinicaltrialsonline.com/pharmaceutical-industry-and-pediatric-clinical-trial-networks-europe-how-do-they-communicate. Accessed 14 Jul 2016
Li JS et al (2012) Lessons learned from a pediatric clinical trial: the Pediatric Heart Network angiotensin converting enzyme inhibition in mitral regurgitation study 161:233–240
Lopez FL, Ernest TB, Tuleu C, Gul MO (2015) Formulation approaches to pediatric oral drug delivery: benefits and limitations of current platforms. Expert Opin Drug Deliv 12:1727–1740
Matsui D (2007) Assessing the palatability of medications in children. Paediatr Perinat Drug Ther 8:55–60
Mentzer D (2014) The paediatric regulation meets reality—present and future challenges. Regul. Rapp. 11:4–7
Momper JD, Mulugeta Y, Burckart GJ (2015) Failed pediatric drug development trials. Clin Pharmacol Ther 98:245–251
Nahata MC (1999) Lack of pediatric drug formulations. Pediatrics 104:607–609
Olski TM, Lampus SF, Gherarducci G, Saint Raymond A (2011) Three years of paediatric regulation in the European Union. Eur J Clin Pharmacol 67:245–252
Oosterwijk C (2014) Patient involvement in paediatric research. Int. J. Pharm. 13984. doi:10.1016/j.ijpharm.2014.03.059
Purohit VS (2012) Biopharmaceutic planning in pediatric drug development. AAPS J 14:519–522
Ranmal S, Tuleu C (2013) Demonstrating evidence of acceptability: the ‘catch-22’ of pediatric formulation development. Clin Pharmacol Ther 94:582–584
Richey RH et al (2013) Manipulation of drugs to achieve the required dose is intrinsic to paediatric practice but is not supported by guidelines or evidence. BMC Pediatr 13:81
Rieder M (2010) If children ruled the pharmaceutical industry: the need for pediatric formulations. Drug News Perspect 23:458–464
Rocchi F, Paolucci P, Ceci A, Rossi P (2010) The European paediatric legislation: benefits and perspectives. Ital J Pediatr 36:56
Rose K (2009) Challenges in pediatric drug development: a pharmaceutical industry perspective. Paediatr Drugs 11:57–59
Rose K (2014) European Union pediatric legislation jeopardizes worldwide, timely future advances in the care of children with cancer. Clin Ther 36:163–177
Ruggieri L et al (2015) Successful private–public funding of paediatric medicines research: lessons from the EU programme to fund research into off-patent medicines. Eur J Pediatr 174:481–491
Russo R, Capasso M, Paolucci P, Iolascon A (2011) Pediatric pharmacogenetic and pharmacogenomic studies: the current state and future perspectives. Eur J Clin Pharmacol 67(Suppl 1):17–27
Salunke S, Giacoia G, Tuleu C (2012) The STEP (safety and toxicity of excipients for paediatrics) database. Part 1-a need assessment study. Int J Pharm 435:101–111
Schirm E, Tobi H, de Jong-van den Berg LTW (2003) Risk factors for unlicensed and off-label drug use in children outside the hospital. Pediatrics 111:291–295
Standing JF, Khaki ZF, Wong ICK (2005) Poor formulation information in published pediatric drug trials. Pediatrics 116:e559–e562
Strickley RG, Iwata Q, Wu S, Dahl TC (2008) Pediatric drugs—a review of commercially available oral formulations. J Pharm Sci 97:1731–1774
Sukkar E (2014) Increasing paediatric medicines research in the European Union. Pharm J 293:1–5
Sun H et al (2014) Steps towards harmonization for clinical development of medicines in pediatric ulcerative colitis—global scientific discussion part 2. J Pediatr Gastroenterol Nutr 58:1
Thompson H et al (2015) iCAN: providing a voice for children and families in pediatric research. Ther Innov Regul Sci 49:673–679
Tishler CL, Reiss NS (2011) Pediatric drug-trial recruitment: enticement without coercion. Pediatrics 127:949–954
Turner MA, Catapano M, Hirschfeld S, Giaquinto C (2014) Paediatric drug development: the impact of evolving regulations. Adv Drug Deliv Rev 73:2–13
Vassal G, Geoerger B, Morland B (2013) Is the European pediatric medicine regulation working for children and adolescents with cancer? Clin Cancer Res 19:1315–1325
Walsh J, Bickmann D, Breitkreutz J, Chariot-Goulet M (2011) Delivery devices for the administration of paediatric formulations: overview of current practice, challenges and recent developments. Int J Pharm 415:221–231
Walsh J et al (2014) Playing hide and seek with poorly tasting paediatric medicines: do not forget the excipients. Adv Drug Deliv Rev 73:14–33
Waning B et al (2010) The global pediatric antiretroviral market: analyses of product availability and utilization reveal challenges for development of pediatric formulations and HIV/AIDS treatment in children. BMC Pediatr 10:74
Zajicek A et al (2013) A report from the pediatric formulations task force: perspectives on the state of child-friendly oral dosage forms. AAPS J 15:1072–1081
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WWL. Chin collected data and figures and drafted the manuscript. A. Joos commented and revised the final manuscript.
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WWL. Chin is an employee at the Hannover Medical School. A. Joos is an employee of MSD (Europe) Inc. The opinions expressed in this article are those of the authors and do not necessarily reflect the views of their employers or organizations. Both authors declare that they have no conflicts of interest in the research.
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Chin, W.W.L., Joos, A. Moving toward a paradigm shift in the regulatory requirements for pediatric medicines. Eur J Pediatr 175, 1881–1891 (2016). https://doi.org/10.1007/s00431-016-2781-z
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DOI: https://doi.org/10.1007/s00431-016-2781-z