Clinical Trials in Children

Living reference work entry


Clinical trials in children are important and challenging. Many advances in pediatric health have occurred as a result of clinical trials, ranging from the polio vaccine to chemotherapy for childhood leukemia. Nevertheless, the majority of medications prescribed to children have never been evaluated in them. Relatively recent programs to encourage testing of drugs in children have yielded important new information about pharmacokinetics and pharmacodynamics in pediatric populations, often contrary to what might have been expected. Trials are required, therefore, in order to determine not only the effects of drugs but also safe doses of medications in light of developmental changes throughout childhood. In addition, clinical trials are necessary in children because they have conditions that adults may not have. Finally, as in the case of early treatment for childhood leukemia, trials in children can help inform treatment in adults with similar conditions. In the current era, there are multiple regulations and strategies to optimize safety of pediatric participants in trials. Trial design in children follows the same principles as any other trial, although particular attention needs to be paid to burden on the child and family and understanding parental perceptions of clinical trials. Pediatric drug formulations and devices may be particularly challenging to develop.


Clinical trials Pediatric IRB DSMB Safety Intermediate endpoints 


  1. (1932) BERLIN: appeal taken from the decision in the Luebeck case. JAMA 98(15):1316–1317Google Scholar
  2. American Academy of Pediatrics Task Force on Sudden Infant Death (2005) The changing concept of sudden infant death syndrome: diagnostic coding shifts, controversies regarding the sleeping environment, and new variables to consider in reducing risk. Pediatrics 116(5):1245–1255CrossRefGoogle Scholar
  3. Blalock ATH (1945) The surgical treatment of malformations of the heart. JAMA 128(3):189–202CrossRefGoogle Scholar
  4. Bogue C, DiMeglio LA, Maldonado S, Portman RJ, Smith PB, Sullivan JE, Thompson C, Woo H, Flinn S (2016) Special article: 2014 pediatric clinical trials forum. Pediatr Res 79(4):662–669CrossRefGoogle Scholar
  5. Boylston AW (2002) Clinical investigation of smallpox in 1767. N Engl J Med 346(17):1326–1328CrossRefGoogle Scholar
  6. Braunstein JB, Sherber NS, Schulman SP, Ding EL, Powe NR (2008) Race, medical researcher distrust, perceived harm, and willingness to participate in cardiovascular prevention trials. Medicine (Baltimore) 87(1):1–9CrossRefGoogle Scholar
  7. Caldwell PH, Butow PN, Craig JC (2002) Pediatricians’ attitudes toward randomized controlled trials involving children. J Pediatr 141(6):798–803CrossRefGoogle Scholar
  8. Caldwell PH, Butow PN, Craig JC (2003) Parents’ attitudes to children’s participation in randomized controlled trials. J Pediatr 142(5):554–559CrossRefGoogle Scholar
  9. Centers for Disease Control and Prevention (2017) Polio elimination in the United States. Accessed 14 June 2019
  10. Cotts T, Khairy P, Opotowsky AR, John AS, Valente AM, Zaidi AN, Cook SC, Aboulhosn J, Ting JG, Gurvitz M, Landzberg MJ, Verstappen A, Kay J, Earing M, Franklin W, Kogon B, Broberg CS, Alliance for Adult Research in Congenital Cardiology (2014) Clinical research priorities in adult congenital heart disease. Int J Cardiol 171(3):351–360CrossRefGoogle Scholar
  11. Cunningham-Erves J, Deakings J, Mayo-Gamble T, Kelly-Taylor K, Miller ST (2019) Factors influencing parental trust in medical researchers for child and adolescent patients’ clinical trial participation. Psychol Health Med 24(6):691–702CrossRefGoogle Scholar
  12. Holy Bible: New International Version (2011) Daniel 1:12–16. BiblicaGoogle Scholar
  13. Department of Health and Human Services (2018) Electronic code of Federal Regulations. Accessed 30 May 2019
  14. European Parliament (2006) Regulation (EC) No 1901/2006 of the European Parliament and of the Council on Medicinal Products for Paediatric Use: L 378/371–319. Accessed 30 May 2019
  15. Field MJ, Behrman RE (eds) (2004) Ethical conduct of clinical research involving children. National Academies Press, Washington, DCGoogle Scholar
  16. Food and Drug Administration (2018a) FDA guidance, use of liquids and/or soft foods as vehicles. Accessed 30 May 2019
  17. Food and Drug Administration (2018b) Code of federal regulations title 21: subpart H–accelerated approval of new drugs for serious life threatening illnesses. Accessed 29 May 2019
  18. Forrest SJ, Geoerger B, Janeway KA (2018) Precision medicine in pediatric oncology. Curr Opin Pediatr 30(1):17–24CrossRefGoogle Scholar
  19. Francis TJ (1955) Evaluation of the 1954 poliomyelitis vaccine field trial: further studies of results determining the effectiveness of poliomyelitis vaccine (Salk) in preventing paralytic poliomyelitis. J Am Med Assoc 158:1266–1270CrossRefGoogle Scholar
  20. Frei E, Freireich EJ, Gehan E, Pinkel D, Holland JF, Selawry O, Haurani F, Spurr CL, Hayes DM, James GW, Rothberg H, Sodee DB, Rundles RW, Schroeder LR, Hoogstraten B, Wolman IJ, Traggis DG, Cooper T, Gendel BR, Ebaugh F, Taylor R (1961) Studies of sequential and combination antimetabolite therapy in acute leukemia: 6-mercaptopurine and methotrexate. Blood 18:431–454CrossRefGoogle Scholar
  21. Greenberg RG, Gamel B, Bloom D, Bradley J, Jafri HD, Nambiar S, Wheeler C, Tiernan R, Smith PB, Roberts J, Benjamin DK Jr (2018) Parents’ perceived obstacles to pediatric clinical trial participation: findings from the clinical trials transformation initiative. Contemp Clin Trials Commun 9:33–39CrossRefGoogle Scholar
  22. Gross RE, Hubbard JP (1939) Surgical ligation of a patent ductus arteriosus: report of first successful case. JAMA 112:729–731CrossRefGoogle Scholar
  23. Guary J (2004) Only a quarter (25%) of U.S. adults would consider allowing a child of theirs to participate in a clinical research study. Health Care News 4(17):1–8Google Scholar
  24. Haig GM, Bockbrader HN, Wesche DL, Boellner SW, Ouellet D, Brown RR, Randinitis EJ, Posvar EL (2001) Single-dose gabapentin pharmacokinetics and safety in healthy infants and children. J Clin Pharmacol 41(5):507–514CrossRefGoogle Scholar
  25. Hoberman A, Shaikh N, Bhatnagar S, Haralam MA, Kearney DH, Colborn DK, Kienholz ML, Wang L, Bunker CH, Keren R, Carpenter MA, Greenfield SP, Pohl HG, Mathews R, Moxey-Mims M, Chesney RW (2013) Factors that influence parental decisions to participate in clinical research: consenters vs nonconsenters. JAMA Pediatr 167(6):561–566CrossRefGoogle Scholar
  26. Hoffman TM, Taeed R, Niles JP, McMillin MA, Perkins LA, Feltes TF (2007) Parental factors impacting the enrollment of children in cardiac critical care clinical trials. Pediatr Cardiol 28(3):167–171CrossRefGoogle Scholar
  27. Hoppu K, Koskimies O, Holmberg C, Hirvisalo EL (1991) Pharmacokinetically determined cyclosporine dosage in young children. Pediatr Nephrol 5(1):1–4CrossRefGoogle Scholar
  28. Le J, Bradley JS (2018) Optimizing antibiotic drug therapy in pediatrics: current state and future needs. J Clin Pharmacol 58(Suppl 10):S108–S122CrossRefGoogle Scholar
  29. Lu H, Rosenbaum S (2014) Developmental pharmacokinetics in pediatric populations. J Pediatr Pharmacol Ther 19(4):262–276Google Scholar
  30. Maayan-Metzger A, Kedem-Friedrich P, Kuint J (2008) Motivations of mothers to enroll their newborn infants in general clinical research on well-infant care and development. Pediatrics 121(3):e590–e596CrossRefGoogle Scholar
  31. Marceau LD, Welch LC, Pemberton VL, Pearson GD (2016) Educating parents about pediatric research: children and clinical studies website qualitative evaluation. Qual Health Res 26(8):1114–1122CrossRefGoogle Scholar
  32. Marceau LD, Cho E, Coleman J, Liao W, Dennin S (2018) Evaluating the film if not for me: children and clinical studies. Clin Pediatr (Phila) 328–335. Scholar
  33. Miller VA, Drotar D, Burant C, Kodish E (2005) Clinician-parent communication during informed consent for pediatric leukemia trials. J Pediatr Psychol 30(3):219–229CrossRefGoogle Scholar
  34. Morris MC, Besner D, Vazquez H, Nelson RM, Fischbach RL (2007) Parental opinions about clinical research. J Pediatr 151(5):532–537, 537 e531–535CrossRefGoogle Scholar
  35. Mudd LM, Pham X, Nechuta S, Elliott MR, Lepkowski JM, Paneth N, Michigan Alliance for the National Children’s Study (2008) Prenatal care and delivery room staff attitudes toward research and the National Children’s Study. Matern Child Health J 12(6):684–691CrossRefGoogle Scholar
  36. National Institutes of Health (1998) NIH policy and guidelines on the inclusion of children as participants in research involving human subjects. Accessed 30 May 2019
  37. Newburger JW, Takahashi M, Burns JC, Beiser AS, Chung KJ, Duffy CE, Glode MP, Mason WH, Reddy V, Sanders SP et al (1986) The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med 315(6):341–347CrossRefGoogle Scholar
  38. Newburger JW, Sleeper LA, Gaynor JW, Hollenbeck-Pringle D, Frommelt PC, Li JS, Mahle WT, Williams IA, Atz AM, Burns KM, Chen S, Cnota J, Dunbar-Masterson C, Ghanayem NS, Goldberg CS, Jacobs JP, Lewis AB, Mital S, Pizarro C, Eckhauser A, Stark P, Ohye RG, Pediatric Heart Network Investigators (2018) Transplant-free survival and interventions at 6 years in the SVR trial. Circulation 137(21):2246–2253CrossRefGoogle Scholar
  39. Ohye RG, Sleeper LA, Mahony L, Newburger JW, Pearson GD, Lu M, Goldberg CS, Tabbutt S, Frommelt PC, Ghanayem NS, Laussen PC, Rhodes JF, Lewis AB, Mital S, Ravishankar C, Williams IA, Dunbar-Masterson C, Atz AM, Colan S, Minich LL, Pizarro C, Kanter KR, Jaggers J, Jacobs JP, Krawczeski CD, Pike N, McCrindle BW, Virzi L, Gaynor JW, for the Pediatric Heart Network Investigators (2010) Comparison of shunt types in the Norwood procedure for single-ventricle lesions. N Engl J Med 362(21):1980–1992CrossRefGoogle Scholar
  40. Pasquali SK, Lam WK, Chiswell K, Kemper AR, Li JS (2012) Status of the pediatric clinical trials enterprise: an analysis of the US registry. Pediatrics 130(5):e1269–e1277CrossRefGoogle Scholar
  41. Pemberton VL, Pearson GD (2019a) Children and clinical studies. Accessed 29 May 2019
  42. Pemberton VL, Pearson GD (2019b) Children and clinical studies – the kids files. Accessed 29 May 2019
  43. Pui CH, Evans WE (2013) A 50-year journey to cure childhood acute lymphoblastic leukemia. Semin Hematol 50(3):185–196CrossRefGoogle Scholar
  44. Rajakumar K, Thomas SB, Musa D, Almario D, Garza MA (2009) Racial differences in parents’ distrust of medicine and research. Arch Pediatr Adolesc Med 163(2):108–114CrossRefGoogle Scholar
  45. Reich WT (1995) Encyclopedia of bioethics. Macmillan, New York. Appendix 2762–2763CrossRefGoogle Scholar
  46. Robison LL, Armstrong GT, Boice JD, Chow EJ, Davies SM, Donaldson SS, Green DM, Hammond S, Meadows ST, Mertens AC, Mulvihill JJ, Nathan PC, Neglia JP, Packer RJ, Rajaraman P, Sklar CA, Stovall M, Strong LC, Yasui Y, Zeltzer LK (2009) The Childhood Cancer Survivor Study: a National Cancer Institute-supported resource for outcome and intervention research. J Clin Oncol 27(14):2308–2318CrossRefGoogle Scholar
  47. Shuster E (1997) Fifty years later: the significance of the Nuremberg Code. N Engl J Med 337(20):1436–1440CrossRefGoogle Scholar
  48. Singhal N, Oberle K, Darwish A, Burgess E (2004) Attitudes of health-care providers towards research with newborn babies. J Perinatol 24(12):775–782CrossRefGoogle Scholar
  49. Tait AR, Voepel-Lewis T, Malviya S (2004) Factors that influence parents’ assessments of the risks and benefits of research involving their children. Pediatrics 113(4):727–732CrossRefGoogle Scholar
  50. Torok RD, Li JS, Kannankeril PJ, Atz AM, Bishai R, Bolotin E, Breitenstein S, Chen C, Diacovo T, Feltes T, Furlong P, Hanna M, Graham EM, Hsu D, Ivy DD, Murphy D, Kammerman LA, Kearns G, Lawrence J, Lebeaut B, Li D, Male C, McCrindle B, Mugnier P, Newburger JW, Pearson GD, Peiris V, Percival L, Pina M, Portman R, Shaddy R, Stockbridge NL, Temple R, Hill KD (2018) Recommendations to enhance pediatric cardiovascular drug development: report of a multi-stakeholder think tank. J Am Heart Assoc 7(4):e007283.
  51. Tsukamoto K, Carroll KA, Onishi T, Matsumaru N, Brasseur D, Nakamura H (2016) Improvement of pediatric drug development: regulatory and practical frameworks. Clin Ther 38(3):574–581CrossRefGoogle Scholar
  52. Unguru Y, Sill AM, Kamani N (2010) The experiences of children enrolled in pediatric oncology research: implications for assent. Pediatrics 125(4):e876–e883CrossRefGoogle Scholar
  53. Varma S, Jenkins T, Wendler D (2008) How do children and parents make decisions about pediatric clinical research? J Pediatr Hematol Oncol 30(11):823–828CrossRefGoogle Scholar
  54. Wax PM (1995) Elixirs, diluents, and the passage of the 1938 Federal Food, Drug and Cosmetic Act. Ann Intern Med 122(6):456–461CrossRefGoogle Scholar

Authors and Affiliations

  1. 1.National Heart, Lung, and Blood Institute, National Institutes of HealthBethesdaUSA

Section editors and affiliations

  • Lawrence Friedman
    • 1
  • Nancy L Geller
    • 2
  1. 1.RockvilleUSA
  2. 2.Director, Office of Biostatistics ResearchNational Heart, Lung, and Blood Institute (NHLBI)BethesdaUSA

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