Skip to main content
SpringerLink
Log in

Conducting Drug Treatment Trials in Children: Opportunities and Challenges

  • Review Article
  • Published:
Pharmaceutical Medicine Aims and scope Submit manuscript

Abstract

Children were often referred to as “therapeutic orphans” in the past due to different reasons such as ethical, regulatory, economic, scientific, etc., ones. They were exposed to avoidable risks while missing out on therapeutic advances. Pediatric patients have suffered from a lack of scientific and regulatory standards (e.g., proper drug testing, authorization of medicines for their use, etc.), although the pharmaceutical legislative framework, which ensures the high standards of safety, quality, and efficacy of medicinal products for use in adults, was developed primarily in response to past “drug disasters,” mainly involving children. The adoption of pediatric regulatory initiatives first in the USA and then in Europe and other countries and regions has significantly changed the worldwide frameworks and permanently changed pediatric drug research and development. This article tries to give various perspectives with historical context, a review of the different challenges and opportunities as well as important stakeholders in pediatric drug development. The pediatric trial networks are probably the most important stakeholder that enables efficient patient recruitment, access to better resource utilization, and global collaboration of different stakeholders necessary for performing quality and well-designed clinical trials.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Ackerman TF. The ethics of drug research in children. Paediatr Drugs. 2001;3:29–41.

    Article  CAS  PubMed  Google Scholar 

  2. Matsui D, Kwan C, Steer E, Rieder MJ. The trials and tribulations of doing drug research in children. Can Med Assoc J. 2003;169:1033–4.

    Google Scholar 

  3. Rieder M, Hawcutt D. Design and conduct of early phase drug studies in children: challenges and opportunities. Br J Clin Pharmacol. 2016;82(5):1308–14. https://doi.org/10.1111/bcp.13058.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Juskewitch JE, Tapia CJ, Windebank AJ. Lessons from the Salk polio vaccine: methods for and risks of rapid translation. Clin Transl Sci. 2010;3(4):182–5. https://doi.org/10.1111/j.1752-8062.2010.00205.x.

    Article  PubMed  Google Scholar 

  5. Stiller CA, Kroll ME, Pritchard-Jones K. Population survival from childhood cancer in Britain during 1978–2005 by eras of entry to clinical trials. Ann Oncol. 2012;23:1–6.

    Article  Google Scholar 

  6. Moore P. Children are not small adults. Lancet. 1998;352(9128):630. https://doi.org/10.1016/S0140-6736(05)79591-X.

    Article  CAS  PubMed  Google Scholar 

  7. Conroy S, McIntyre J, Choonara I, Stephenson T. Drug trials in children: problems and the way forward. Br J Clin Pharmacol. 2000;49(2):93–7. https://doi.org/10.1046/j.1365-2125.2000.00125.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shaddy RE, Dennes C, The Committee on Drug and the Committee on Pediatric Research. Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Pediatrics. 2010;125:850–60.

    Article  PubMed  Google Scholar 

  9. Sammons HM. Avoiding clinical trials in children. Arch Dis Childhood. 2011;96:291–2.

    Article  Google Scholar 

  10. Turner MA, Catapano M, Hirschfeld S, Giaquinto C. Global research in paediatrics. Pediatric drug development: the impact of evolving regulations. Adv Drug Deliv Rev. 2014;73:2–13. https://doi.org/10.1016/j.addr.2014.02.003.

    Article  CAS  PubMed  Google Scholar 

  11. Shirkey H. Editorial comment. Therapeutic orphans. Pediatrics. 1968;72:119–20.

    CAS  Google Scholar 

  12. Abozaid GM, Kerr K, McKnight A, Al-Omar HA. Criteria to define rare diseases and orphan drugs: a systematic review protocol. BMJ Open. 2022;12(7): e062126. https://doi.org/10.1136/bmjopen-2022-062126.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Rare and orphan diseases. NCLS. Available at: https://www.ncsl.org/health/rare-and-orphan-diseases. Accessed 10 August 2023.

  14. Qosa H, Hassan HE, Younis IR. Overview of clinical pharmacology packages of new drug applications approved for the treatment of rare diseases. J Clin Pharmacol. 2022;62(Suppl 2):S72–8. https://doi.org/10.1002/jcph.2167.

    Article  CAS  PubMed  Google Scholar 

  15. EMA. Orphan designation: Overview. Available at https://www.ema.europa.eu/en/human-regulatory/overview/orphan-designation-overview. Accessed 10 August 2023.

  16. Epps C, Bax R, Croker A, et al. Global regulatory and public health initiatives to advance pediatric drug development for rare diseases. Ther Innov Regul Sci. 2022;56(6):964–75.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Austin MA, Hutter CM, Zimmern RL, Humphries SE. Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol. 2004;160:407–20.

    Article  PubMed  Google Scholar 

  18. Goldstein JL, Schrott HG, Hazzard WR, et al. Hyperlipidemia in coronary heart disease. II. genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J Clin Invest. 1973;52:1544–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Andersen GE, Lous P, Friis-Hansen B. Screening for hyperlipoproteinemia in 10,000 Danish newborns. Follow-up studies in 522 children with elevated cord serum VLDL-LDL-cholesterol. Acta Paediatr Scand. 1979;68:541–5.

    Article  CAS  PubMed  Google Scholar 

  20. Akioyamen LE, Genest J, Shan SD, et al. Estimating the prevalence of heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis. BMJ Open. 2017;7: e016461. https://doi.org/10.1136/bmjopen-2017-016461.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Hu P, Dharmayat KI, Stevens CA, et al. Prevalence of familial hypercholesterolemia among the general population and patent with atherosclerotic cardiovascular disease. Circulation. 2020;141:1742–59.

    Article  PubMed  Google Scholar 

  22. Nordestgaard BG, Chapman MJ, Humphries SE, et al. European Atherosclerosis Society Consensus Panel. Familial hypercholesterolemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013;34(45):3478–90. https://doi.org/10.1093/eurheartj/eht273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Williams K, Thomson D, Seto I, et al. Standard 6: age groups for pediatric trials. Pediatrics. 2012;129(suppl 3):S153–60.

    Article  PubMed  Google Scholar 

  24. Intini A, Bonifazi D, Migliaccio G. Challenges and new frontiers in the paediatric drug discovery and development [Internet]. Drug discovery and development—new advances. IntechOpen; 2020. Available at https://doi.org/10.5772/intechopen.85635. Accessed 10 August 2023.

  25. Bell DA, Watts GF. Progress in the care of familial hypercholesterolaemia. Med J Aust. 2016;205:232–6.

    Article  PubMed  Google Scholar 

  26. Luirink IK, Wiegman A, Kusters DM, Hof MH, Groothoff JW, de Groot E, Kastelein JJP, Hutten BA. 20-year follow-up of statins in children with familial hypercholesterolemia. N Engl J Med. 2019;381:1547–56.

    Article  CAS  PubMed  Google Scholar 

  27. McGowan MP, Hosseini Dehkordi SH, Moriarty PM, Duell PB. Diagnosis and treatment of heterozygous familial hypercholesterolemia. J Am Heart Assoc. 2019;8(24): e013225. https://doi.org/10.1161/JAHA.119.013225.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Park K, Vishnevetskaya K, Vaidyanathan J, Burckart GJ, et al. Pediatric drug development studies for familial hypercholesterolemia submitted to the US Food and Drug Administration between 2007 and 2020. J Clin Pharmacol. 2022;62(3):397–408. https://doi.org/10.1002/jcph.1973.

    Article  CAS  PubMed  Google Scholar 

  29. Dharmage SC, Perret JL, Custovic A. Epidemiology of asthma in children and adults. Front Pediatr. 2019;7:246. https://doi.org/10.3389/fped.2019.00246.

    Article  PubMed  PubMed Central  Google Scholar 

  30. CDC. National Health Interview Survey (NHIS). 2019–2021. Available at https://www.cdc.gov/asthma/most_recent_data_national_asthma_data.htm. Accessed 10 August 2023.

  31. Ioniuc I, Miron I, Lupu VV, Starcea IM, et al. Challenges in the pharmacotherapeutic management of pediatric asthma. Pharmaceuticals. 2022;15:1581. https://doi.org/10.3390/ph15121581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gaga M, Zervas E, Samitas K, Bel EH. Severe asthma in adults: an orphan disease? Clin Chest Med. 2012;33(3):571–83. https://doi.org/10.1016/j.ccm.2012.06.008.

    Article  PubMed  Google Scholar 

  33. Peri F, Amaddeo A, Badina L, et al. T2-low asthma: a discussed but still orphan disease. Biomedicines. 2023;11(4):1226. https://doi.org/10.3390/biomedicines11041226.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Daniel 1:11–16. In: The Holy Bible. Revised standard version. New York: American Bible Society; 1995.

  35. Askitopoulou H, Vgontzas AN. The relevance of the Hippocratic Oath to the ethical and moral values of contemporary medicine. Part I: the Hippocratic Oath from antiquity to modern times. Eur Spine J. 2017;27(7):1481–90. https://doi.org/10.1007/s00586-017-5348-4.

    Article  PubMed  Google Scholar 

  36. Bavdekar SB. Pediatric clinical trials. Perspect Clin Res. 2013;4(1):89–99. https://doi.org/10.4103/2229-3485.106403.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Burns JP. Research in children. Crit Care Med. 2003;31(3 Suppl):S131–6. https://doi.org/10.1097/01.CCM.0000054905.39382.58.

    Article  PubMed  Google Scholar 

  38. Glantz LH. Conducting research with children: legal and ethical issues. J Am Acad Child Adolesc Psychiatry. 1996;35(10):1283–91. https://doi.org/10.1097/00004583-199610000-00015.

    Article  CAS  PubMed  Google Scholar 

  39. Hirschfeld S. Clinical trials involving children: history, rationale, regulatory framework, and technical considerations. Available at https://obgynkey.com/clinical-trials-involving-children-history-rationale-regulatory-framework-and-technical-considerations/. Accessed 22 August 2023.

  40. Boylston A, Williams AE. Zabdiel Boylston’s evaluation of inoculation against smallpox. J R Soc Med. 2008;101(9):476–7. https://doi.org/10.1258/jrsm.2008.08k008.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Stewart AJ, Devlin PM. The history of the smallpox vaccine. J Infect. 2006;52(5):329–34. https://doi.org/10.1016/j.jinf.2005.07.0.

    Article  PubMed  Google Scholar 

  42. Boylston AW. Clinical investigation of smallpox in 1767. N Engl J Med. 2002;346(17):1326–8. https://doi.org/10.1056/NEJM200204253461714.

    Article  PubMed  Google Scholar 

  43. Jenson AB, Ghim SJ, Sundberg JP. An inquiry into the causes and effects of the variolae (or Cow-pox. 1798). Exp Dermatol. 2016;25:178–80. https://doi.org/10.1111/exd.12925.

    Article  PubMed  Google Scholar 

  44. Smith KA. Edward Jenner and the smallpox vaccine. Front Immunol. 2011;14(2):21. https://doi.org/10.3389/fimmu.2011.00021.

    Article  Google Scholar 

  45. Fisher DJ. Resurgence of rabies: a historical perspective on rabies in children. Arch Pediatr Adolesc Med. 1995;149:306–12.

    Article  CAS  PubMed  Google Scholar 

  46. Lederer SE, Grodin MA. Historical overview: pediatric experimentation. In: Glanz LH, editor. Children as research subjects: science, ethics, and law. New York: Oxford University Press; 1994. p. 3–25.

    Google Scholar 

  47. Diekema DS. Conducting ethical research in pediatrics: a brief historical overview and review of pediatric regulations. J Pediatr. 2006;149(1 Suppl):S3–11. https://doi.org/10.1016/j.jpeds.2006.04.043.

    Article  PubMed  Google Scholar 

  48. Bercovici K. Orphans as guinea pigs. Nation. 1921;112:911–3.

    Google Scholar 

  49. Sass HM. Reichsrundschreiben 1931: pre-Nuremberg German regulations concerning new therapy and human experimentation. J Med Philos. 1983;8(2):99–111. https://doi.org/10.1093/jmp/8.2.99.

    Article  CAS  PubMed  Google Scholar 

  50. Fox GJ, Orlova M, Schurr E. Tuberculosis in newborns: the lessons of the “Lübeck Disaster” (1929–1933). PLoS Pathog. 2016;12(1): e1005271. https://doi.org/10.1371/journal.ppat.1005271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. The Nuremberg Code. Trials of war criminals before the Nuremberg military tribunals, vol. 10. Washington, DC: U.S. Government Printing Office; 1949. p. 181–2.

    Google Scholar 

  52. Weindling P, von Villiez A, Loewenau A, Farron N. The victims of unethical human experiments and coerced research under national socialism. Endeavor. 2016;40(1):1–6. https://doi.org/10.1016/j.endeavour.2015.10.005.

    Article  Google Scholar 

  53. Weindling P. Painful and sometimes deadly experiments which Nazi doctors carried out on children. Acta Paediatr. 2022;111(9):1664–9. https://doi.org/10.1111/apa.16310.

    Article  PubMed  Google Scholar 

  54. Nuremberg Code (1947). BMJ. 1996;313(7070):1448.

  55. World Medical Association—The Declaration of Geneva. Adopted by the 2nd general assembly of the World Medical Association, Geneva, Switzerland, September 1948 and amended by the 22nd World Medical Assembly, Sydney, Australia, August 1968 and the 35th World Medical Assembly, Venice, Italy, October 1983 and the 46th WMA General Assembly, Stockholm, Sweden, September 1994 and editorially revised by the 170th WMA Council Session, Divonne-les-Bains, France, May 2005 and the 173rd WMA Council Session, Divonne-les-Bains, France, May 2006 and amended by the 68th WMA General Assembly, Chicago, USA, October 2017. Available at https://www.wma.net/policies-post/wma-declaration-of-geneva/. Accessed 10 August 2023.

  56. International Code of Medical Ethics. Available at https://www.wma.net/wp-content/uploads/2006/09/International-Code-of-Medical-Ethics-2006.pdf. Accessed 20 October 2023.

  57. UN General Assembly. Universal declaration of human rights. United Nations, 217 (III) A, 1948, Paris, art. 1. Available at http://www.un.org/en/universal-declaration-human-rights/. Accessed 10 August 2023.

  58. World Medical Association. Declaration of Helsinki. Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, September 1989 48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 52nd WMA General Assembly, Edinburgh, Scotland, October 2000 53rd WMA General Assembly, Washington, DC, USA, October 2002 (Note of Clarification added) 55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 59th WMA General Assembly, Seoul, Republic of Korea, October 2008 64th WMA General Assembly, Fortaleza, Brazil, October 2013. Available at https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/. Accessed 02 August 2023.

  59. Beecher HK. Ethics and clinical research. N Engl J Med. 1966;274(24):1354–60. https://doi.org/10.1056/NEJM196606162742405.

    Article  CAS  PubMed  Google Scholar 

  60. Davidson AJ, O’Brien M. Ethics and medical research in children. Pediatr Anesth. 2009;19:994–1004. https://doi.org/10.1111/j.1460-9592.2009.03117.x.

    Article  Google Scholar 

  61. Goldby S, Krugman S, Pappworth MH, et al. Willobroke letters: criticism and defence. Lancet. 1971;1(7702):749.

    Article  CAS  PubMed  Google Scholar 

  62. Krugman S. The Willowbrook hepatitis studies revisited: ethical aspects. Rev Infect Dis. 1986;8(1):157–62. https://doi.org/10.1093/clinids/8.1.157.

    Article  CAS  PubMed  Google Scholar 

  63. Baudoin JL. Biomedical experimentation on the mentally handicapped: ethical and legal dilemmas. Med Law. 1990;9(4):1052–61.

    Google Scholar 

  64. West D. Radiation experiments on children at the Fernald and Wrentham schools: lessons for protocols in human subject research. Account Res. 1998;6(1–2):103–25. https://doi.org/10.1080/08989629808573922.

    Article  PubMed  Google Scholar 

  65. Advisory Committee on Human Radiation Experiments. The human radiation experiments. New York: Oxford University Press; 1996.

    Google Scholar 

  66. Tuskegee Syphilis Study 2008. DUJS online. Available at https://sites.dartmouth.edu/dujs/2008/11/12/a-wake-up-call-for-bioethics-examining-the-tuskegee-syphilis-study/. Accessed 25 August 2023.

  67. Brandt AM. Racism and research: the case of the Tuskegee Syphilis Study. Hastings Cent Rep. 1978;8(6):21–9.

    Article  CAS  PubMed  Google Scholar 

  68. Brawley OW. The study of untreated syphilis in the negro male. Int J Radiat Oncol Biol Phys. 1998;40(1):5–8. https://doi.org/10.1016/s0360-3016(97)00835-3.

    Article  CAS  PubMed  Google Scholar 

  69. Cuerda-Galindo E, Sierra-Valenti X, González-López E, López-Muñoz F. Syphilis and human experimentation from World War II to the present: a historical perspective and reflections on ethics. Actas Dermosifiliogr. 2014;105(9):847–53. https://doi.org/10.1016/j.ad.2013.08.012.

    Article  CAS  PubMed  Google Scholar 

  70. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report: ethical principles and guidelines for the protection of human subjects of research. Washington, DC: U.S. Government Printing Office; 1979. DHEW Publication No. (OS) 78-0013 and No. (OS) 78-0014.

  71. Zion D, Gillam L, Loff B. The Declaration of Helsinki, CIOMS, and the ethics of research on vulnerable populations. Nat Med. 2000;6(6):615–7. https://doi.org/10.1038/76174.

    Article  CAS  PubMed  Google Scholar 

  72. Lurie P, Wolfe S. Unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries. NEJM. 1997;337:853–85.

    Article  CAS  PubMed  Google Scholar 

  73. Council for International Organizations of Medical Sciences. Proposed international guidelines for biomedical research involving human subjects. Geneva, Switzerland: Council for International Organizations of Medical Sciences; 1982. Available at https://cioms.ch/publications/product/proposed-international-guidelines-for-biomedical-research-involving-human-subjects/. Accessed 26 August 2023.

  74. Council for International Organizations of Medical Sciences. Ethics and research on human subjects. International guidelines. Geneva, Switzerland: Council for International Organizations of Medical Sciences; 1992. Available at https://cioms.ch/publications/product/ethics-and-research-on-human-subjects-international-guidelines/. Accessed 26 August 2023.

  75. Council for International Organizations of Medical Sciences. International ethical guidelines for biomedical research involving human subjects. Geneva, Switzerland: Council for International Organizations of Medical Sciences; 2002. Available at: https://cioms.ch/publications/product/international-ethical-guidelines-for-biomedical-research-involving-human-subjects-2/. Accessed 26 August 2023.

  76. Council for International Organizations of Medical Sciences. International Ethical Guidelines for Health-Related Research Involving Humans. Geneva, Switzerland: Council for International Organizations of Medical Sciences; 2016. Available at: https://cioms.ch/publications/product/international-ethical-guidelines-for-health-related-research-involving-humans/. Accessed 26 August 2023.

  77. United Nations General Assembly. Convention on the rights of the child. Part 1, Article1, A/RES/44/25, 61st plenary meeting. 20 Nov 1989. Available at https://www.un.org/documents/ga/res/44/a44r025.htm. Accessed 20 October 2023.

  78. International Conference on Harmonisation. Guideline on good Clinical Practice. Available at https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf. Accessed 20 October 2023.

  79. WMA Declaration of Taipei on Ethical Considerations regarding Health Databases and Biobanks—WMA—The World Medical Association. Available at https://www.wma.net/policies-post/wma-declaration-of-taipei-on-ethical-considerations-regarding-health-databases-and-biobanks/. Accessed 20 October 2023.

  80. Morales-Olivas FJ, Morales-Carpi C. Clinical trials in children. Rev Recent Clin Trials. 2006;1(3):251–8. https://doi.org/10.2174/157488706778250087.

    Article  CAS  PubMed  Google Scholar 

  81. Rago L, Santoso B. Drug regulation: history, present and future. In: van Boxtel CJ, Santoso B, Edwars IR (eds) Drug benefit and risks. International textbook of pharmacology, 2nd revision. IOS Press and Uppsala Monitoring Centre; 2008. Available from https://www.researchgate.net/publication/265533479_Drug_Regulation_History_Present_and_Future_1. Accessed 26 August 2023.

  82. Bren L. The road to the biotech revolution: highlights of 100 years of biologics regulation. FDA Consum. 2006;40(1):50–7.

    PubMed  Google Scholar 

  83. Coleman TS. Early developments in the regulation of biologics. Food Drug Law J. 2016;71(4):544–607.

    PubMed  Google Scholar 

  84. Paine MF. Therapeutic disasters that hastened safety testing of new drugs. Clin Pharmacol Ther. 2017;101(4):430–4. https://doi.org/10.1002/cpt.613.

    Article  CAS  PubMed  Google Scholar 

  85. Wax PM. Elixirs, diluents, and the passage of the 1938 federal food, drug, and cosmetic act. Ann Intern Med. 1995;122(6):456–61. https://doi.org/10.7326/0003-4819-122-6-199503150-00009.

    Article  CAS  PubMed  Google Scholar 

  86. WHO Calls for Immediate Action After Cough Syrup Deaths in Gambia, Uzbekistan. Available on https://news.abplive.com/news/world/who-calls-for-immediate-action-after-cough-syrup-deaths-in-gambia-uzbekistan-1577619. Accessed 28 August 2023.

  87. Sutherland JM. Fatal cardiovascular collapse of infants receiving large amounts of chloramphenicol. Am J Dis Child. 1959;97:761–7.

    CAS  Google Scholar 

  88. Burns LE, Hodgmnan JE, Cass AB. Fatal circulatory collapse in premature infants receiving chloramphenicol. N Engl J Med. 1959;261:1318–21. https://doi.org/10.1056/NEJM195912242612604.

    Article  CAS  PubMed  Google Scholar 

  89. Weiss CF, Glazko AJ, Weston JK. Chloramphenicol in the newborn infant. N Engl J Med. 1960;262:787–94.

    Article  CAS  PubMed  Google Scholar 

  90. Kim JH, Scialli AR. Thalidomide: the tragedy of birth defects and the effective treatment of disease. Toxicol Sci. 2011;122(1):1–6. https://doi.org/10.1093/toxsci/kfr088.

    Article  CAS  PubMed  Google Scholar 

  91. McBride W. Thalidomide and congenital malformations. Lancet. 1961;1:358.

    Google Scholar 

  92. Vargesson N. Thalidomide-induced teratogenesis: history and mechanisms. Birth Defects Res C Embryo Today. 2015;105(2):140–56. https://doi.org/10.1002/bdrc.2109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kelsey FO. Thalidomide update: regulatory aspects. Teratology. 1988;38(3):221–6.

    Article  CAS  PubMed  Google Scholar 

  94. Mansel-Jones D. The role of the committee on safety of drugs. Br Med Bull. 1970;26(3):257–9. https://doi.org/10.1093/oxfordjournals.bmb.a070794.

    Article  CAS  PubMed  Google Scholar 

  95. Shakir SA. Bill Inman: drug safety physician and pharmacoepidemiologist. Drug Saf. 2006;29(3):187–8. https://doi.org/10.2165/00002018-200629030-00002.

    Article  PubMed  Google Scholar 

  96. Evans SJW. Is the yellow card road going in the right direction? Drug Saf. 2015;2015(38):517–8. https://doi.org/10.1007/s40264-015-0293-9.

    Article  Google Scholar 

  97. Vianna FSL, Schüler-Faccini L, Leite JCL, et al. Recognition of the phenotype of thalidomide embryopathy in countries endemic for leprosy: new cases and review of the main dysmorphological findings. Clin Dysmorphol. 2013;22(2):59–63. https://doi.org/10.1097/MCD.0b013e32835ffc58.

    Article  PubMed  Google Scholar 

  98. FDA. The pediatric exclusivity provision. 2001. Available at https://www.orangebookblog.com/PEP_status.pdf. Accessed 05 August 2023.

  99. US Congress. Best pharmaceuticals for children act. Available at https://www.congress.gov/107/crpt/srpt79/CRPT-107srpt79.pdf. Accessed 05 August 2023.

  100. US Congress. Pediatric research equity act of 2003. 2003. Available at https://www.congress.gov/108/plaws/publ155/PLAW-108publ155.pdf. Accessed 05 August 2023.

  101. FDA. Food and Drug Administration amendments act (FDAAA) of 2007. 2007. Available at https://www.fda.gov/regulatory-information/selected-amendments-fdc-act/food-and-drug-administration-amendments-act-fdaaa-2007. Accessed 05 August 2023.

  102. Zettler ME. The RACE for children act at one year: progress in pediatric development of molecularly targeted oncology drugs. Expert Rev Anticancer Ther. 2022;22(3):317–21. https://doi.org/10.1080/14737140.2022.2032664.

    Article  CAS  PubMed  Google Scholar 

  103. Pediatric study plans: content of and process for submitting initial pediatric study plans and amended initial pediatric study plans. Available at https://www.fda.gov/media/86340/download. Accessed 01 March 2024.

  104. Pediatric drug development: regulatory considerations—complying with prea and qualifying for pediatric exclusivity under the BPCA. Available at https://www.fda.gov/media/168201/download. Accessed 01 March 2024.

  105. Pediatric drug development under the pediatric research equity act and the best pharmaceuticals for children act: scientific considerations. Available at https://www.fda.gov/media/168202/download. Accessed 01 March 2024.

  106. Saitou H, Nakatani D, Myoui A, et al. Pediatric drug development in Japan: current issues and perspectives. Clin Pediatr Endocrinol. 2020;29(1):1–7. https://doi.org/10.1297/cpe.29.1.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Nakamura H, Ono S. Chapter 16. The Japanese perspective. In: Mulberg AE, editor. Pediatric drug development. 2nd ed. Chichester, UK: Wiley-Blackwell; 2013.

    Google Scholar 

  108. Inagaki R, Narukawa M. Paediatric drug development in Japan: a study over the past 15 years. Res Sq. 2023. https://doi.org/10.1203/rs.3.rs-3322635/v1.

    Article  Google Scholar 

  109. Official Journal of the European Union. Regulation (EC) No. 1901/2006 of the European Parliament and of the Council, 2006. Available at https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32006R1901&from=EN. Accessed 05 August 2023.

  110. Chiaruttini G, Felisi M, Bonifazi D. Challenges in paediatric clinical trials: how to make it feasible. Manage Clin Trials. 2018. https://doi.org/10.5772/intechopen.72950.

    Article  Google Scholar 

  111. Proposal for a Regulation of the European Parliament and of the Council laying down Union procedures for the authorization and supervision of medicinal products for human use and establishing rules governing the European Medicines Agency, amending Regulation (EC) No. 1394/2007 and Regulation (EU) No. 536/2014 and repealing Regulation (EC) No. 726/2004, Regulation (EC) No. 141/2000 and Regulation (EC) No. 1901/2006. Available at https://health.ec.europa.eu/publications/proposal-regulation-laying-down-union-procedures-authorisation-and-supervision-medicinal-products_eng. Accessed 06 March 2024.

  112. EU Pharma Legislation Review Series: The EU’s proposals to amend its pharmaceutical laws released today. Available at https://www.insideeulifesciences.com/2023/04/26/eu-pharma-legislation-review-series-the-eus-proposals-to-amend-its-pharmaceutical-laws-released-today/. Accessed 06 March 2024.

  113. Heikkinen I, Eskola S, Acha V, et al. Role of innovation in pharmaceutical regulation: a proposal for principles to evaluate EU General Pharmaceutical Legislation from the innovator perspective. Drug Discov Today. 2023;28(5):103526. https://doi.org/10.1016/j.drudis.2023.103526.

    Article  PubMed  Google Scholar 

  114. Hofer MP, Criscuolo P, Shah N, et al. Regulatory policy and pharmaceutical innovation in the United Kingdom after Brexit: initial insights. Front Med (Lausanne). 2022;9:1011082. https://doi.org/10.3389/fmed.2022.1011082.

    Article  PubMed  Google Scholar 

  115. UNICEF. The state of the world’s children 2006: excluded and invisible: UNICEF. 2006.

  116. Bryce J, Black RE, Victora CG. Millennium Development Goals 4 and 5: progress and challenges. BMC Med. 2013;11(1):225.

    Article  PubMed  PubMed Central  Google Scholar 

  117. World Health Assembly (2007). Resolution WHA60.20 “Better medicines for children”. Available at https://apps.who.int/gb/archive/pdf_files/WHA60/A60_25-en.pdf. Accessed 05 August 2023.

  118. Watts G. WHO launches a campaign to make drugs safer for children. BMJ. 2007;335(7632):1227. https://doi.org/10.1136/bmj.39423.581042.D.

    Article  PubMed  PubMed Central  Google Scholar 

  119. World Health Organisation. Medicines for children: resources, progress reports, and scientific publications: medicines: medicines for children. Fact sheet No 34; 2010. Available at https://www.who.int/mediacentre/factsheets/fs341/en/index.html. Accessed 10 August 2023.

  120. Zipursky A. The programme for global paediatric research. Clin Invest Med. 2011;34(6):E32.

    Article  Google Scholar 

  121. Global Forum for Health Research. The 10/90 report on health research 2003–2004. Geneva, Switzerland: Global Forum for Health Research; 2004. Available at https://announcementsfiles.cohred.org/gfhr_pub/assoc/s14789e/s14789e.pdf. Accessed 06 March 2024.

  122. Nor Aripin KN, Sammons HM, Choonara I. Published pediatric randomized drug trials in developing countries, 1996–2002. Paediatr Drugs. 2010;12(2):99–103.

    Article  PubMed  Google Scholar 

  123. Dunne J, Murphy MD, Rodriguez WJ. The globalization of pediatric clinical trials. Pediatrics. 2012;130(6):e1583–91.

    Article  PubMed  Google Scholar 

  124. Joseph PD, Caldwell PH, Tong A, Hanson CS, Craig JC. Stakeholder views of clinical trials in low- and middle-income countries: a systematic review. Pediatrics. 2016;137(2): e20152800. https://doi.org/10.1542/peds.2015-2800.

    Article  PubMed  Google Scholar 

  125. Drain PK, Parker RA, Robine M, Holmes KK, Bassett IV. Global migration of clinical research during the era of trial registration. PLoS ONE. 2018;13(2): e0192413. https://doi.org/10.1371/journal.pone.0192413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Khoja A, Kazim F, Ali NA. Barriers to conducting clinical trials in developing countries. Ochsner J. 2019;19(4):294–5. https://doi.org/10.31486/toj.19.0068.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Alemayehu C, Mitchell G, Nikles J. Barriers for conducting clinical trials in developing countries—a systematic review. Int J Equity Health. 2018;17(1):37. https://doi.org/10.1186/s12939-018-0748-6.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Nundy S, Gulhati CM. A new colonialism? Conducting clinical trials in India. N Engl J Med. 2005;352:1633–6.

    Article  CAS  PubMed  Google Scholar 

  129. Glickman SW, McHutchison JG, Peterson ED, et al. Ethical and scientific implications of the globalization of clinical research. N Engl J Med. 2009;360:816–23.

    Article  CAS  PubMed  Google Scholar 

  130. Chirac P, Torreele E. Global framework on essential health R&D. Lancet. 2006;367:1560–1.

    Article  PubMed  Google Scholar 

  131. Pediatric Medicines Regulator’s Network (PmRN). Available at https://www.who.int/teams/regulation-prequalification/regulation-and-safety/regulatory-convergence-networks/paediatric-regulators. Accessed 10 August 2023.

  132. Strengthening clinical trials to provide high-quality evidence on health interventions and to improve research quality and coordination. Available at https://apps.who.int/gb/ebwha/pdf_files/WHA75/A75_R8-en.pdf. Accessed 06 March 2024.

  133. WHO guidance for best clinical practices. Available at https://cdn.who.int/media/docs/default-source/research-for-health/2023-07_who-guidance-for-best-practices-for-clinical-trials_draft-for-public-consultation.pdf?sfvrsn=7a5c9fa5_4. Accessed 06 March 2024.

  134. EMA. ICH Topic E 11; Clinical Investigation of Medicinal Products in the Paediatric Population. 2001. Available at https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-1.pdf. Accessed 05 August 2023.

  135. EMA. ICH E11(R1) guideline on clinical investigation of medicinal products in the pediatric population; 2017. Available at https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e11r1-guideline-clinical-investigation-medicinal-products-pediatric-population-revision-1_en.pdf. Accessed 05 August 2023.

  136. ICH guideline E11A on pediatric extrapolation. ICH; 2022. Available at https://www.ema.europa.eu/en/documents/scientific-guideline/draft-ich-guideline-e11a-pediatric-extrapolation-step-2b_en.pdf. Accessed 06 March 2024.

  137. Hoppu K. Can we get the necessary clinical trials in children and avoid the unnecessary ones? Eur J Clin Pharmacol. 2009;65:747–8. https://doi.org/10.1007/s00228-009-0675-y.

    Article  PubMed  Google Scholar 

  138. Spriggs M, Caldwell PH. The ethics of pediatric research. J Paediatr Child Health. 2011;47(9):664–7. https://doi.org/10.1111/j.1440-1754.2011.02166.x.

    Article  PubMed  Google Scholar 

  139. Rose CD. Ethical conduct of research in children: pediatricians and their IRB (Part 1 of 2). Pediatrics. 2017;139(5): e20163648. https://doi.org/10.1542/peds.2016-3648.

    Article  PubMed  Google Scholar 

  140. Roth-Cline M, Gerson J, Bright P, et al. Ethical considerations in conducting pediatric research. Handb Exp Pharmacol. 2011;205:219–44. https://doi.org/10.1007/978-3-642-20195-0_11.

    Article  PubMed  Google Scholar 

  141. Bartholome WG. Ethical issues in pediatric research. In: Vanderpool HY, editor. The ethics of research involving human subjects: facing the 21st century. Hagerstown, MD: University Publishing Group; 1996.

    Google Scholar 

  142. Nelson DK, Skinner D, Guarda S, et al. Obtaining consent from both parents for pediatric research: what does “reasonably available” mean? Pediatrics. 2013;131(1):e223–9. https://doi.org/10.1542/peds.2012-1278.

    Article  PubMed  PubMed Central  Google Scholar 

  143. Kern SE. Challenges in conducting clinical trials in children: approaches for improving performance. Expert Rev Clin Pharmacol. 2009;2(6):609–17. https://doi.org/10.1586/ecp.09.40.

    Article  PubMed  PubMed Central  Google Scholar 

  144. Grabowski H, Vernon J, DiMasi JA. Returns on research and development for 1990s new drug introductions. Pharmacoeconomics. 2002;20(Suppl 3):11–29. https://doi.org/10.2165/00019053-200220003-00002.

    Article  PubMed  Google Scholar 

  145. Li JS, Eisenstein EL, Grabowski HG, et al. The economic return of clinical trials performed under the pediatric exclusivity program. JAMA. 2007;297:480–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Baker-Smith CM, Benjamin DK Jr, Grabowski HG, et al. The economic returns of pediatric clinical trials of antihypertensive drugs. Am Heart J. 2008;156:682–8.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Carr M. The small- and medium-sized enterprises office (SME Office) at the European Medicines Agency. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2010;53:20–3.

    Article  CAS  PubMed  Google Scholar 

  148. Auby P. Pharmaceutical research in pediatric populations and the new EU paediatric legislation: an industry perspective. Child Adolesc Psychiatry Ment Health. 2008;2(1):38. https://doi.org/10.1186/1753-2000-2-38.

    Article  PubMed  PubMed Central  Google Scholar 

  149. Hutton JL. The ethics of randomized controlled trials: a matter of statistical belief? Health Care Anal. 1996;4(2):95–102. https://doi.org/10.1007/BF02251209.

    Article  CAS  PubMed  Google Scholar 

  150. Gamalo M, Bucci-Rechtweg C, Nelson RM, et al. Extrapolation as a default strategy in pediatric drug development. Ther Innov Regul Sci. 2022;56:883–94. https://doi.org/10.1007/s43441-021-00.

    Article  PubMed  Google Scholar 

  151. Melosky B, Reardon DA, Nixon AB, Subramanian J, Bair AH, Jacobs I. Bevacizumab biosimilars: scientific justification for extrapolation of indications. Future Oncol. 2018;14(24):2507–20. https://doi.org/10.2217/fon-2018-0051.

    Article  CAS  PubMed  Google Scholar 

  152. Burckart GJ, Kim C. The revolution in pediatric drug development and drug use: therapeutic orphans no more. J Pediatr Pharmacol Ther. 2020;25(7):565–73. https://doi.org/10.5863/1551-6776-25.7.565.

    Article  PubMed  PubMed Central  Google Scholar 

  153. Kelly LE, Dyson MP, Butcher NJ, Balshaw R, London AJ, Neilson CJ, Junker A, Mahmud SM, Driedger SM, Wang X. Considerations for adaptive design in pediatric clinical trials: study protocol for a systematic review, mixed-methods study, and integrated knowledge translation plan. Trials. 2018;19(1):572. https://doi.org/10.1186/s13063-018-2934-7.

    Article  PubMed  PubMed Central  Google Scholar 

  154. U.S. Food and Drug Administration: adaptive designs for clinical trials of drugs and biologics guidance for industry. Silver Spring: Food and Drug Administration; 2019. Available at https://www.fda.gov/media/78495/download. Accessed 5 November 2023.

  155. van der Lee JH, Wesseling J, Tanck MW, et al. Sequential design with boundaries approach in pediatric intervention research reduces sample size. J Clin Epidemiol. 2010;63(1):19–27. https://doi.org/10.1016/j.jclinepi.2009.07.005131.

    Article  PubMed  Google Scholar 

  156. Day S, Jonker AH, Lau LPL, et al. Recommendations for the design of small population clinical trials. Orphanet J Rare Dis. 2018;13:195. https://doi.org/10.1186/s13023-018-0931-2.

    Article  PubMed  PubMed Central  Google Scholar 

  157. Bauer P, König F. Adaptive paediatric investigation plans, a small step to improve regulatory decision making in drug development for children? Pharm Stat. 2016;15(5):384–6. https://doi.org/10.1002/pst.1762.

    Article  PubMed  Google Scholar 

  158. Hirschfeld S. Resource expectations for pediatric studies: correlation of study type and patient number for FDA labeling. J Clin Oncol. 2008;26:6632. https://doi.org/10.1200/jco.2008.26.15_suppl.6632.

    Article  Google Scholar 

  159. EudraLex. Ethical considerations for clinical trials on medicinal products conducted with minors, Revision 1. Available at https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/2017_09_18_ethical_consid_ct_with_minors.pdf. Accessed 17 September 2023.

  160. EMA. Concept Paper on the Involvement of Children and Young People at the Paediatric Committee (PDCO). Available at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/09/WC500132555.pdf. Accessed 16 September 2023.

  161. Scavone C, di Mauro G, Pietropaolo M, et al. The European clinical trials regulation (No. 536/2014): changes and challenges. Expert Rev Clin Pharmacol. 2019;12(11):1027–32. https://doi.org/10.1080/17512433.2019.1680282.

    Article  CAS  PubMed  Google Scholar 

  162. ICH. Impurities in new drug substances Q3A(R2). Available at https://database.ich.org/sites/default/files/Q3A%28R2%29%20Guideline.pdf. Accessed 20 October 2023.

  163. ICH. Impurities in new drug products Q3B(R2). Available at https://database.ich.org/sites/default/files/Q3B%28R2%29%20Guideline.pdf. Accessed 20 October 2023.

  164. ICH. Impurities: guideline for residual solvents Q3C(R6). Available at https://database.ich.org/sites/default/files/ICH_Q3C-R8_Guideline_Step4_2021_0422.pdf. Accessed 19 October 2023.

  165. ICH. Guideline for elemental impurities Q3D. Available at http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3D/Q3D_Step_4.pdf. Accessed 16 October 2023.

  166. WHO. Development of paediatric medicines: points to consider in pharmaceutical development. Available at http://www.who.int/medicines/areas/quality_safety/quality_assurance/Rev3-PaediatricMedicinesDevelopment_QAS08-257Rev3_17082011.pdf. Accessed 30 September 2023.

  167. Gupta A, Khan MA. Challenges of pediatric formulations: a FDA science perspective. Int J Pharm. 2013;457(1):346–8. https://doi.org/10.1016/j.ijpharm.2013.08.064.

    Article  CAS  PubMed  Google Scholar 

  168. EMA. Reflection paper: formulations of choice for the paediatric population. Available at https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-formulations-choice-paediatric-population_en.pdf, Accessed 20 October 2023.

  169. Zajicek A, Fossler MJ, Barrett JS, Worthington JH, Ternik R, Charkoftaki G, Lum S, Breitkreutz J, Baltezor M, Macheras P, et al. A report from the pediatric formulations task force: perspectives on the state of child-friendly oral dosage forms. AAPS J. 2013;15:1072–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Van Riet-Nales DA, Wang S, Saint-Raymond A, Robert JL. The EMA quality guideline on the pharmaceutical development of medicines for paediatric use. Int J Pharm. 2012;435:132–4.

    Article  PubMed  Google Scholar 

  171. Ivanovska V, Rademaker CM, van Dijk L, et al. Pediatric drug formulations: a review of challenges and progress. Pediatrics. 2014;134(2):361–72. https://doi.org/10.1542/peds.2013-3225.

    Article  PubMed  Google Scholar 

  172. Preis M, Breitkreutz J. Pediatric drug development and dosage form design. AAPS PharmSciTech. 2017;18(2):239–40. https://doi.org/10.1208/s12249-016-0705-x.

    Article  PubMed  Google Scholar 

  173. Klingmann V. Acceptability of mini-tablets in young children: results from three prospective cross-over studies. AAPS PharmSciTech. 2016. https://doi.org/10.1208/s12249-016-0639-3.

    Article  PubMed  Google Scholar 

  174. Kaguelidou F, Ouèdraogo M, Treluyer JM, et al. Paediatric drug development and evaluation: existing challenges and recommendations. Therapie. 2023;78(1):105–14. https://doi.org/10.1016/j.therap.2022.11.010.

    Article  PubMed  Google Scholar 

  175. Joseph PD, Craig JC, Caldwell PH. Clinical trials in children. Br J Clin Pharmacol. 2015;79(3):357–69. https://doi.org/10.1111/bcp.12305.

    Article  PubMed  PubMed Central  Google Scholar 

  176. World Health Assembly (2007). Resolution WHA60.20 “Better medicines for children”. Available on https://apps.who.int/gb/archive/pdf_files/WHA60/A60_25-en.pdf. Accessed 07 November 2023.

  177. Watts G. WHO launches a campaign to make drugs safer for children. Br Med J. 2007;335(7632):1227. https://doi.org/10.1136/bmj.39423.581042.DB.

    Article  Google Scholar 

  178. Hoppu K, Anabwani G, Garcia-Bournissen F, et al. The status of paediatric medicines initiatives around the world—what has happened and what has not? Eur J Clin Pharmacol. 2012;68:1–10. https://doi.org/10.1007/s00228-011-1089-1.

    Article  PubMed  Google Scholar 

  179. Pediatric Medicines Regulator’s Network (PmRN). Available at https://www.who.int/teams/regulation-prequalification/regulation-and-safety/regulatory-convergence-networks/paediatric-regulators. Accessed 7 November 2023.

  180. Greenberg RG, McCune S, Attar S, et al. Pediatric clinical research networks: role in accelerating development of therapeutics in children. Ther Innov Regul Sci. 2022;56:934–47. https://doi.org/10.1007/s43441-022-00453-6.

    Article  PubMed  PubMed Central  Google Scholar 

  181. Turner MA, Attar S, de Wildt SN, et al. Roles of clinical research networks in pediatric drug development. Clin Ther. 2017;39(10):1939–48. https://doi.org/10.1016/j.clinthera.2017.09.0015.

    Article  PubMed  Google Scholar 

  182. Ruperto N, Eichler I, Herold R, et al. A European network of paediatric research at the European medicines agency (Enpr-EMA). Arch Dis Child. 2012;97(3):185–8. https://doi.org/10.1136/archdischild-2011-300286.

    Article  PubMed  Google Scholar 

  183. Benjamin D. Clinical trials approach and the pediatric trials network. Available at https://slidetodoc.com/clinical-trials-approach-and-the-pediatric-trials-network/. Accessed 7 November 2023.

  184. The Children s Oncology Group (COG). Available at https://www.childrensoncologygroup.org. Accessed 5 August 2023.

  185. Childhood Liver Disease Research Network (ChiLDReN). Available at https://childrennetwork.org/About-The-Network/ChiLDReN. Accessed 5 August 2023.

  186. Paediatric Rheumatology International Trials Organization (PRINTO). Available at https://www.printo.it. Accessed 7 November 2023.

  187. Pediatric European Network for the Treatment of AIDS (PENTA). Available at https://penta-id.org. Accessed 7 November 2023.

  188. Global Asthma Network. Available at http://globalasthmanetwork.org/index.php. Accessed 7 November 2023.

  189. Ren Z, Zajicek A. Review of the best pharmaceuticals for children act and the pediatric research equity act: what can the obstetric community learn from the pediatric experience? Semin Perinatol. 2015;39(7):530–1. https://doi.org/10.1053/j.semperi.2015.08.006.

    Article  PubMed  PubMed Central  Google Scholar 

  190. Pediatrics Trials Network. Available at https://pediatrictrials.org/. Accessed 7 November 2023

  191. Final Report Summary—GRIP (Global Research in Paediatrics). Available at https://cordis.europa.eu/project/id/261060/reporting. Accessed 7 November 2023.

  192. Preston J, Nafria B, Ohmer A, et al. Developing a more tailored approach to patient and public involvement with children and families in pediatric clinical research: lessons learned. Ther Innov Regul Sci. 2022;56(6):948–63. https://doi.org/10.1007/s43441-022-00382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Tsang VWL, West L, Woods C, et al. Role of patients and parents in pediatric drug development. Ther Innov Regul Sci. 2019;53(5):601–8. https://doi.org/10.1177/2168479018820875.

    Article  PubMed  PubMed Central  Google Scholar 

  194. Lagler FB, Hirschfeld S, Kindblom JM. Challenges in clinical trials for children and young people. Arch Dis Child. 2021;106:321–5.

    Article  PubMed  Google Scholar 

  195. Bourgeois FT, Murthy S, Pinto C, et al. Pediatric versus adult drug trials for conditions with high pediatric disease burden. Pediatrics. 2012;130(2):285–92. https://doi.org/10.1542/peds.2012-0139.

    Article  PubMed  PubMed Central  Google Scholar 

  196. McCune S, Portman RJ. Accelerating pediatric drug development: a 2022 special issue of Therapeutic Innovation & Regulatory Science. Ther Innov Regul Sci. 2022;56(6):869–72. https://doi.org/10.1007/s43441-022-00398-w.

    Article  PubMed  Google Scholar 

  197. Samuels S, Park K, Bhatt-Mehta V, et al. Pediatric efficacy extrapolation in drug development submitted to the US Food and Drug Administration 2015–2020. J Clin Pharmacol. 2023;63(3):307–13. https://doi.org/10.1002/jcph.2160.

    Article  CAS  PubMed  Google Scholar 

  198. US FDA. New pediatric labeling information database. Available at https://www.accessdata.fda.gov/scripts/sda/sdNavigation.cfm?sd=labelingdatabase. Accessed 10 October 2023.

  199. US FDA. Written requests issued. Available at https://www.fda.gov/drugs/development-resources/written-requests-issued. Accessed 30 September 2023.

  200. EMA Medicines. Available at https://www.ema.europa.eu/en/medicines/field_ema_web_categories%253Aname_field/Human. Accessed 10 October 2023.

  201. Pediatric Studies. ClinTrials.gov. Available at https://clinicaltrials.gov/search?cond=pediatric. Accessed 10 October 2023.

  202. Wharton GT, Murphy MD, Avant D, et al. Impact of pediatric exclusivity on drug labeling and demonstrations of efficacy. Pediatrics. 2014;134(2):e512–8.

    Article  PubMed  Google Scholar 

  203. Momper JD, Mulugeta L, Burckart GJ. Failed pediatric drug development trials. Clin Pharm Ther. 2015;98:245–51.

    Article  CAS  Google Scholar 

  204. Rose K. The challenges of pediatric drug development. Curr Ther Res Clin Exp. 2019;26(90):128–34.

    Article  Google Scholar 

  205. EMA. 10-year Report to the European Commission; General report on the experience acquired as a result of the application of the Paediatric Regulation. 2017. Available at https://health.ec.europa.eu/system/files/202006/paediatrics_10_years_ema_technical_report_0.pdf. Accessed 05 August 2023.

  206. Vernon JA, Shortenhaus SH, Mayer MH, et al. Measuring the patient health, societal and economic benefits of US pediatric therapeutics legislation. Pediatr Drugs. 2012;14(5):283–94.

    Google Scholar 

  207. Mehrotra N, Bhattaram A, Earp JC, et al. Role of quantitative clinical pharmacology in pediatric approval and labeling. Drug Metab Dispos. 2016;44(7):924–33.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. “Srebrnjak” Children’s Hospital, Clinical Trials Unit, 10000, Zagreb, Croatia

    Damir Erceg, Marina Jakirović & Mirjana Turkalj

  2. School of Medicine, Catholic University of Croatia, 10000, Zagreb, Croatia

    Damir Erceg & Mirjana Turkalj

  3. Faculty of Dental Medicine and Health, University of Osijek, “Josip Juraj Strossmayer”, 31000, Osijek, Croatia

    Damir Erceg

  4. Medical School, University of Osijek “Josip Juraj Strossmayer”, 31000, Osijek, Croatia

    Damir Erceg & Mirjana Turkalj

  5. Institute of Emergency Medicine of Zagreb County, 10410, Velika Gorica, Croatia

    Luka Prgomet

  6. Emergency Department, General Hospital Zabok, 49210, Zabok, Croatia

    Marina Madunić

Authors
  1. Damir Erceg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marina Jakirović
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Luka Prgomet
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marina Madunić
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mirjana Turkalj
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Damir Erceg.

Ethics declarations

Funding

No funding was received for the publication of this review.

Conflict of Interest

Damir Erceg, Marina Jakirović, Luka Prgomet, Marina Madunić, and Mirjana Turkalj declare no conflicts of interest/competing interests.

Ethics Approval

Not applicable.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Availability of Data and Material

Not applicable.

Code Availability

Not applicable.

Authors’ contributions

All authors participated in the literature search and writing of the manuscript. All authors read and approved the final version of the manuscript and agree to be accountable for the work.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Erceg, D., Jakirović, M., Prgomet, L. et al. Conducting Drug Treatment Trials in Children: Opportunities and Challenges. Pharm Med 38, 179–204 (2024). https://doi.org/10.1007/s40290-024-00523-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40290-024-00523-0

Search

Navigation