Aim/objective: Since 2007, companies in the EU must submit paediatric investigation plans (PIPs) for new drugs, unless the PIP is waived and the review article investigated if that improve the child healthcare. Methods: We analysed the EU Paediatric Regulation (EUPR), PIP decisions, PIP decision patterns, EU key documents on "better medicines for children" and examined PIP studies versus the epidemiology described in the reference literature. We examined how PIPs translate into studies by checking www. clinicaltrials.gov and www.clinicaltrialsregister.org. We also investigated the medical sense of PIP-demanded clinical studies in adolescents. Results: The EUPR in Art. 2 (1) defines “paediatric population” as those between birth and 18 years. It lists challenges in dosing and safety of drugs in neonates and infants as if these challenges apply to anybody < 18 years. PIPs demand studies in adolescents although this group needs separate dose finding and efficacy studies only in exceptional cases, if at all. Most PIP studies in rare diseases are unfeasible: too many studies for too few patients in general. Two questionable PIP studies were discontinued in 2016, in one of them several patients died. Conclusions: Neonates and infants have immature organs, with resulting potential for drug over/underdosing. PIPs equalize the legal definition of childhood with a biological limit. The resulting automatism leads to a worldwide threat to children. Most PIP-demanded studies are medically senseless, some even worse. Ethics committees should reject questionable PIP studies and suspend such ongoing studies immediately.
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1. Adamson PC. Improving the outcome for children with cancer: development of targeted new agents. CA Cancer J Clin. 2015;65: 212-220.
2. A Phase I/II, Multicenter, Open-Label, Dose-Escalation Study Of The Safety And Pharmacokinetics Of Cobimetinib In Pediatric And Young Adult Patients With Previously Treated Solid Tumors. https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-004685-25 Accessed 20JAN2017.
3. A Study of Pembrolizumab (MK-3475) in Pediatric Participants With Advanced Melanoma or Advanced, Relapsed, or Refractory PD-L1-Positive Solid Tumors or Lymphoma (MK-3475-051/KEYNOTE-051). https://clinicaltrials.gov/ct2/show/NCT02332668 (Accessed 20JAN2017).
4. A Study to Determine Safety, Tolerability and Pharmacokineticsof Oral Dabrafenib In Children and Adolescent Subjects. https://clinicaltrials.gov/ct2/show/NCT01677741 (Accessed 20JAN2017).
5. Boots I, Sukhai RN, Klein RH, et al. Stimulation programs for pediatric drug research - do children really benefit? Eur J Pediatr. 2007; 166: 849-855.
6. BRIM-P. A study of Vemurafenib in pediatric patients with stage IIIC or stage IV melanoma harboring BRAFV600 mutations. https://clinicaltrials.gov/ct2/show/NCT01519323 (Accessed 20JAN2017).
7. Chitnis T, Tenembaum S, Banwell B et al. Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis. Mult Scler. 2012 Jan;18(1):116-27
8. Eichler I, Sala Soriano E. Close collaboration between academia, industry and drug regulators is required in the development of allergen products for specific immunotherapy in children. Allergy 2011: 66: 999-1004.
9. EMA website. www.ema.europa.eu (Accessed 20JAN2017)
10. EMA 2004: Evidence of harm from off-label or unlicensed medicines in children. www.ema.europa.eu/docs/en_GB/document_library/Other/2009/10/WC500004021.pdf
11. EMA 2011. EMA class waivers, http://www.ema.europa.eu/docs/en_GB/document_library/Other/2011/12/WC500119981.pdf (Accessed 20FEB2017).
12. EMA 2010. European Medicines Agency decision P/345/2010 of 20 December 2010 on a class waiver on condition(s) in accordance with Regulation (EC) No 1901/2006 of the European Parliament and of the Council. http://www.ema.europa.eu/docs/en_GB/document_library/Other/2009/11/WC500011500.pdf. Accessed 20JAN2017 (Accessed 20JAN2017).
13. EMA 2015. European Medicines Agency decision CW/0001/2015 of 23 July 2015 on class waivers, in accordance with Regulation (EC) No 1901/2006 of the European Parliament and of the Council. www.ema.europa.eu/docs/en_GB/document_library/Other/2015/07/WC500190385.pdf
14. EMA 2015. Better Medicines for Children. www.ema.europa.eu/docs/en_GB/document_library/Leaflet/2009/12/WC500026493.pdf
15. EMA2016. 10-year Report to the European Commission. General report on the experience acquired as a result of the application of the Paediatric Regulation. http://ec.europa.eu/health//sites/health/files/files/paediatrics/2016_pc_report_2017/ema_10_year_report_for_consultation.pdf. Accessed 20JAN2017 (Accessed 20JAN2017).
16. FDA. Best Pharmaceuticals for Children Act and Pediatric Research Equity Act July 2016. Status Report to Congress. www.fda.gov/downloads/ScienceResearch/SpecialTopics/PediatricTherapeuticsResearch/UCM509815.pdf (Accessed 20JAN2017).
17. Frattarelli DA, Galinkin JL, Green TP et al. Off-label Use of Drugs in Children. Pediatrics 2014, 133 (3), 563-567.
18. Hilts PJ. Protecting America›s Health: The FDA, Business, and One Hundred Years of Regulation. University of North Carolina Press 2004.
19. Kearns GL, Abdel-Rahman SM, Alander SW et al. Developmental Pharmacology - Drug Disposition, Action, and Therapy in Infants and Children. N Engl J Med. 2003;349(12):1157-1167.
20. Mentzer D. Progress review of the European Paediatric Regulatory Framework after six years of implementation. Int J Pharm. 2014 Aug 5;469(2):240-3.
21. Phase 2 study of Ipilimumab in children and adolescents (12 to < 18 Years) with previously treated or untreated, unresectable stage III or stage lV malignant melanoma. https://clinicaltrials.gov/ct2/show/NCT01696045.
22. Philip AG. The Evolution of Neonatology. Pediatr Res. 2005 Oct;58(4):799-815.
23. Regulation (EC) No 1901/2006 Of The European Parliament And Of The Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004. Official Journal of the European Union, 27.12.2006, L 378/1 - L 278/19 http://ec.europa.eu/health/files/eudralex/vol-1/reg_2006_1901/reg_2006_1901_en.pdfpdf (Accessed 20JAN2017).
24. Rocchi F, Paolucci P, Ceci A, Rossi P. The European paediatric legislation: benefits and perspectives. Italian Journal of Pediatrics 2010, 36:56 Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933611/pdf/1824-7288-36-56.pdf (Accessed 20JAN2017).
25. Rose K. Pediatric Pharmaceutical Legislation in the USA and EU and Their Impact on Adult and Pediatric Drug Development. In: Bar-Shalom D & Rose K: Pediatric Formulations - A Roadmap, AAPS & Springer, 2014: chapter 28, pp. 405-420.
26. Rose K. European Union Pediatric Legislation Jeopardizes Worldwide, Timely Future Advances in the Care of Children With Cancer. Clinical Therapeutics 2014, 36 (2), 163-177.
27. Rose K. New Drugs For Rare Diseases in Children. Clin Ther 2017, in press.
28. Rose K & Happle R. The Impact of Regulation on Pediatric Psoriasis Drug Approvals: The Challenge of the European Union (EU) Pediatric Investigation Plans. Pediatric Dermatology 2017, in press.
29. Rose K & Kopp MV. Pediatric investigation plans for specific immunotherapy: Questionable contributions to childhood health. Pediatr Allergy Immunol. 2015 Dec;26(8):695-701.
30. Rose K & Mueller T. Children with Multiple Sclerosis Should Not Become Therapeutic Hostages. Ther Adv Neurol Disord 2016, 9(5) 389-395.
31. Rose K & Walson PD. The contributions of the European Medicines Agency and its pediatric committee to the fight against childhood leukemia. Risk Manag Healthc Policy. 2015 Nov 5;8:185-205.
32. Rose K & Walson PD. Do the European Medicines Agency (EMA) Decisions Hurt Pediatric Melanoma Patients? Clin Ther 2017, in press.
33. Rose K & Senn S. Drug development: EU paediatric legislation, the European Medicines Agency and its Paediatric Committee - adolescents’ melanoma as a paradigm. Pharmaceutical Statistics 2014; 13(4): 211-213.
34. Shim KS. Pubertal growth and epiphyseal fusion. Ann Pediatr Endocrinol Metab. 2015 Mar;20(1):8-12.
35. Shirkey H. Therapeutic Orphans. Pediatrics 1999 Sep;104(3 Pt 2):583-584.
36. To Find a Safe Dose and Show Early Clinical Activity of Weekly Nab-paclitaxel in Pediatric Patients With Recurrent/ Refractory Solid Tumors https://clinicaltrials.gov/ct2/show/NCT01962103 (Accessed 20JAN2017).
37. Turner S, Nunn AJ, Fielding K, Choonara I. Adverse drug reactions to unlicensed and off-label drugs on paediatric wards. Acta Paediatr 1999, 88: 965-968.