Safety, dosing, and pharmaceutical quality for studies that evaluate medicinal products (including biological products) in neonates

Journal name:
Pediatric Research
(2017)
Volume:
81,
Pages:
692–711
DOI:
doi:10.1038/pr.2016.221
Received
Accepted
Accepted article preview online
Advance online publication

Abstract

The study of medications among pediatric patients has increased worldwide since 1997 in response to new legislation and regulations, but these studies have not yet adequately addressed the therapeutic needs of neonates. Additionally, extant guidance developed by regulatory agencies worldwide does not fully address the specificities of neonatal drug development, especially among extremely premature newborns who currently survive. Consequently, an international consortium from Canada, Europe, Japan, and the United States was organized by the Critical Path Institute to address the content of guidance. This group included neonatologists, neonatal nurses, parents, regulators, ethicists, clinical pharmacologists, specialists in pharmacokinetics, specialists in clinical trials and pediatricians working in the pharmaceutical industry. This group has developed a comprehensive, referenced White Paper to guide neonatal clinical trials of medicines – particularly early phase studies. Key points include: the need to base product development on neonatal physiology and pharmacology while making the most of knowledge acquired in other settings; the central role of families in research; and the value of the whole neonatal team in the design, implementation and interpretation of studies. This White Paper should facilitate successful clinical trials of medicines in neonates by informing regulators, sponsors, and the neonatal community of existing good practice.

References

  1. General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products. Draft Guidance for Industry. 2014. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm425885.pdf.
  2. Guideline on the Investigation of Medicinal Products in the Term and Preterm Neonate. 2007. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003750.pdf.
  3. International Conference on Harmonization: Clinical Investigation of Medicinal Products in the Pediatric Population E11. 2000. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E11/ICH_E11_R1_Step_2_25Aug2016_Final.pdf.
  4. Tri-Council policy statement 2: ethical conduct for research involving humans. 2014. http://www.pre.ethics.gc.ca/pdf/eng/tcps2-2014/TCPS_2_FINAL_Web.pdf. http://www.pre.ethics.gc.ca/pdf/eng/tcps2-2014/Highlights_of_Changes_EN.pdf.
  5. Survey of Current Guidance for Child Health Clinical Trials. The StaR Child Health Project: Standards for Research with Children. 2009. http://www.who.int/childmedicines/publications/GUIDANCECHILDHEALTH.pdf.
  6. 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. 2006. http://ec.europa.eu/health/files/eudralex/vol-1/reg_2006_1901/reg_2006_1901_en.pdf.
  7. US Food and Drug Administration Modernization Act of 1997. 1997. http://www.fda.gov/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCAct/FDAMA/FullTextofFDAMAlaw/default.htm.
  8. Best Pharmaceuticals for Children Act Page. 2002. http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=107_cong_public_laws&docid=f:publ109.107.
  9. Pediatric Research Equity Act of 2003. 2003. http://www.gpo.gov/fdsys/pkg/PLAW-108publ155/pdf/PLAW-108publ155.pdf.
  10. US Food and Drug Administration Safety and Innovation Act. 2012. http://www.gpo.gov/fdsys/pkg/PLAW-112publ144/pdf/PLAW-112publ144.pdf.
  11. Laughon MM, Avant D, Tripathi N, et al. Drug labeling and exposure in neonates. JAMA Pediatr 2014;168:1306.
  12. Stiers JL, Ward RM. Newborns, one of the last therapeutic orphans to be adopted. JAMA Pediatr 2014;168:1068.
  13. Turner MA. Clinical trials of medicines in neonates: the influence of ethical and practical issues on design and conduct. Br J Clin Pharmacol 2015;79:3708.
  14. Engle WA. A recommendation for the definition of “late preterm” (near-term) and the birth weight-gestational age classification system. Semin Perinatol 2006;30:27.
  15. Engle WA; American Academy of Pediatrics Committee on Fetus and Newborn. Age terminology during the perinatal period. Pediatrics 2004;114:13624.
  16. Sengupta S, Carrion V, Shelton J, et al. Adverse neonatal outcomes associated with early-term birth. JAMA Pediatr 2013;167:10539.
  17. Allegaert K, Anderson BJ, van den Anker JN, Vanhaesebrouck S, de Zegher F. Renal drug clearance in preterm neonates: relation to prenatal growth. Ther Drug Monit 2007;29:28491.
  18. Calkins K, Devaskar SU. Fetal origins of adult disease. Curr Probl Pediatr Adolesc Health Care 2011;41:15876.
  19. Thompson H, Frederico N, Smith SR, Chowdhury M, Dicks P, Preston J, Thompson C. iCAN: Providing a voice for children and families in pediatric research. Therapeutic Innovation & Regulatory Science 2015;49:673679.
  20. Concept paper on the involvement of children and young people at the Paediatric Committee (PDCO). 2012. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/09/WC500132555.pdf.
  21. International Children’s Advisory Network. 2015. http://www.icanresearch.org/.
  22. Guidance for industry: E6 Good clinical practice. Consolidated guidance. 1996. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073122.pdf.
  23. Gauda EB. Knowledge gained from animal studies of the fetus and newborn: Application to the human premature infant. ILAR J 2006;47:14.
  24. Nathanielsz PW. Animal models that elucidate basic principles of the developmental origins of adult diseases. ILAR J 2006;47:7382.
  25. Festing MF. Design and statistical methods in studies using animal models of development. ILAR J 2006;47:514.
  26. Inder T, Neil J, Yoder B, Rees S. Patterns of cerebral injury in a primate model of preterm birth and neonatal intensive care. J Child Neurol 2005;20:9657.
  27. Bourgeois T, Delezoide AL, Zhao W, et al. Safety study of Ciprofloxacin in newborn mice. Regul Toxicol Pharmacol 2016;74:1619.
  28. Roth-Cline M, Nelson RM. Ethical considerations in conducting pediatric and neonatal research in clinical pharmacology. Curr Pharm Des 2015;21:561935.
  29. Kauffman RE, Kearns GL. Pharmacokinetic studies in paediatric patients. Clinical and ethical considerations. Clin Pharmacokinet 1992;23:1029.
  30. Kearns GL. Impact of developmental pharmacology on pediatric study design: overcoming the challenges. J Allergy Clin Immunol 2000;106(3 Suppl):S12838.
  31. Ward RM, Tammara B, Sullivan SE, et al. Single-dose, multiple-dose, and population pharmacokinetics of pantoprazole in neonates and preterm infants with a clinical diagnosis of gastroesophageal reflux disease (GERD). Eur J Clin Pharmacol 2010;66:55561.
  32. Anderson BJ, Woollard GA, Holford NH. A model for size and age changes in the pharmacokinetics of paracetamol in neonates, infants and children. Br J Clin Pharmacol 2000;50:12534.
  33. Friis-Hansen B. Body water compartments in children: changes during growth and related changes in body composition. Pediatrics 1961;28:16981.
  34. Friis-Hansen B. Body composition during growth. In vivo measurements and biochemical data correlated to differential anatomical growth. Pediatrics 1971;47:Suppl 2:264274.
  35. Aranda JV, Sitar DS, Parsons WD, Loughnan PM, Neims AH. Pharmacokinetic aspects of theophylline in premature newborns. N Engl J Med 1976;295:4136.
  36. Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology–drug disposition, action, and therapy in infants and children. N Engl J Med 2003;349:115767.
  37. McNamara PJ, Alcorn J. Protein binding predictions in infants. AAPS PharmSci 2002;4:E4.
  38. Brodersen R, Honoré B. Drug binding properties of neonatal albumin. Acta Paediatr Scand 1989;78:3426.
  39. Odell GB. The distribution and toxicity of bilirubin. E. Mead Johnson address 1969. Pediatrics 1970;46:1624.
  40. Wennberg RP, Ahlfors CE, Rasmussen LF. The pathochemistry of kernicterus. Early Hum Dev 1979;3:35372.
  41. Robertson A, Karp W, Brodersen R. Bilirubin displacing effect of drugs used in neonatology. Acta Paediatr Scand 1991;80:111927.
  42. Fink S, Karp W, Robertson A. Ceftriaxone effect on bilirubin-albumin binding. Pediatrics 1987;80:8735.
  43. Leeder JS. Translating pharmacogenetics and pharmacogenomics into drug development for clinical pediatrics and beyond. Drug Discov Today 2004;9:56773.
  44. Leeder JS, Kearns GL, Spielberg SP, van den Anker J. Understanding the relative roles of pharmacogenetics and ontogeny in pediatric drug development and regulatory science. J Clin Pharmacol 2010;50:137787.
  45. Garner CR, Park KB, French NS, et al. Observational infant exploratory [(14)C]-paracetamol pharmacokinetic microdose/therapeutic dose study with accelerator mass spectrometry bioanalysis. Br J Clin Pharmacol 2015;80:15767.
  46. Turner MA, Mooij MG, Vaes WH, et al. Pediatric microdose and microtracer studies using 14C in Europe. Clin Pharmacol Ther 2015;98:2347.
  47. Roth-Cline M, Nelson RM. Microdosing studies in children: A US regulatory perspective. Clin Pharmacol Ther 2015;98:2323.
  48. Aperia A, Broberger O, Elinder G, Herin P, Zetterström R. Postnatal development of renal function in pre-term and full-term infants. Acta Paediatr Scand 1981;70:1837.
  49. Engle WD, Arant BS Jr. Renal handling of beta-2-microglobulin in the human neonate. Kidney Int 1983;24:35863.
  50. Rhodin MM, Anderson BJ, Peters AM, et al. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol 2009;24:6776.
  51. Daood M, Tsai C, Ahdab-Barmada M, Watchko JF. ABC transporter (P-gp/ABCB1, MRP1/ABCC1, BCRP/ABCG2) expression in the developing human CNS. Neuropediatrics 2008;39:2118.
  52. Dawson PA, Karpen SJ. Intestinal transport and metabolism of bile acids. J Lipid Res 2015;56:108599.
  53. Rodriguez W, Selen A, Avant D, et al. Improving pediatric dosing through pediatric initiatives: what we have learned. Pediatrics 2008;121:5309.
  54. Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol 2008;48:30332.
  55. Anderson BJ, Holford NH. Mechanistic basis of using body size and maturation to predict clearance in humans. Drug Metab Pharmacokinet 2009;24:2536.
  56. Koukouritaki SB, Manro JR, Marsh SA, et al. Developmental expression of human hepatic CYP2C9 and CYP2C19. J Pharmacol Exp Ther 2004;308:96574.
  57. Lacroix D, Sonnier M, Moncion A, Cheron G, Cresteil T. Expression of CYP3A in the human liver–evidence that the shift between CYP3A7 and CYP3A4 occurs immediately after birth. Eur J Biochem 1997;247:62534.
  58. Allegaert K, van Schaik RH, Vermeersch S, et al. Postmenstrual age and CYP2D6 polymorphisms determine tramadol o-demethylation in critically ill neonates and infants. Pediatr Res 2008;63:6749.
  59. Blake MJ, Castro L, Leeder JS, Kearns GL. Ontogeny of drug metabolizing enzymes in the neonate. Semin Fetal Neonatal Med 2005;10:12338.
  60. Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology–drug disposition, action, and therapy in infants and children. N Engl J Med 2003;349:115767.
  61. Cohen-Wolkowiez M, Watt KM, Hornik CP, Benjamin DK Jr, Smith PB. Pharmacokinetics and tolerability of single-dose daptomycin in young infants. Pediatr Infect Dis J 2012;31:9357.
  62. Yanni SB, Smith PB, Benjamin DK Jr, Augustijns PF, Thakker DR, Annaert PP. Higher clearance of micafungin in neonates compared with adults: role of age-dependent micafungin serum binding. Biopharm Drug Dispos 2011;32:22232.
  63. Qualification of novel methodologies for medicine development. 2016. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000319.jsp&mid=WC0b01ac0580022bb0.
  64. Biomarker Qualification Program. 2016. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/BiomarkerQualificationProgram/default.htm.
  65. Amur S, Frueh FW, Lesko LJ, Huang SM. Integration and use of biomarkers in drug development, regulation and clinical practice: a US regulatory perspective. Biomark Med 2008;2:30511.
  66. Bai JP, Barrett JS, Burckart GJ, Meibohm B, Sachs HC, Yao L. Strategic biomarkers for drug development in treating rare diseases and diseases in neonates and infants. AAPS J 2013;15:44754.
  67. Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J 2005;5:613.
  68. Leeder JS. Developmental pharmacogenetics: a general paradigm for application to neonatal pharmacology and toxicology. Clin Pharmacol Ther 2009;86:67882.
  69. Guideline on key aspects for the use of pharmacogenomic methodologies in the pharmacovigilance evaluation of medicinal products. 2014. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/01/WC500160232.pdf.
  70. European Medicines Agency: Paediatric investigation plans. 2015. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000293.jsp&mid=WC0b01ac0580025b91.
  71. Dunne J, Rodriguez WJ, Murphy MD, et al. Extrapolation of adult data and other data in pediatric drug-development programs. Pediatrics 2011;128:e12429.
  72. Concept paper on extrapolation of efficacy and safety in medicine development. 2012. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/04/WC500142358.pdf.
  73. Pediatric Research and Science Activities. 2016. http://www.fda.gov/ScienceResearch/SpecialTopics/PediatricTherapeuticsResearch/ucm106614.htm.
  74. Wade KC, Wu D, Kaufman DA, et al.; National Institute of Child Health and Development Pediatric Pharmacology Research Unit Network. Population pharmacokinetics of fluconazole in young infants. Antimicrob Agents Chemother 2008;52:40439.
  75. Ascher SB, Smith PB, Watt K, et al. Antifungal therapy and outcomes in infants with invasive Candida infections. Pediatr Infect Dis J 2012;31:43943.
  76. Benjamin DK Jr, Hudak ML, Duara S, et al.; Fluconazole Prophylaxis Study Team. Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial. JAMA 2014;311:17429.
  77. Smith PB, Cohen-Wolkowiez M, Castro LM, et al.; Meropenem Study Team. Population pharmacokinetics of meropenem in plasma and cerebrospinal fluid of infants with suspected or complicated intra-abdominal infections. Pediatr Infect Dis J 2011;30:8449.
  78. van den Anker JN, Pokorna P, Kinzig-Schippers M, et al. Meropenem pharmacokinetics in the newborn. Antimicrob Agents Chemother 2009;53:38719.
  79. Hudak BB, Egan EA. Impact of lung surfactant therapy on chronic lung diseases in premature infants. Clin Perinatol 1992;19:591602.
  80. Kwong MS, Egan EA, Notter RH, Shapiro DL. Double-blind clinical trial of calf lung surfactant extract for the prevention of hyaline membrane disease in extremely premature infants. Pediatrics 1985;76:58592.
  81. Notter RH, Egan EA, Kwong MS, Holm BA, Shapiro DL. Lung surfactant replacement in premature lambs with extracted lipids from bovine lung lavage: effects of dose, dispersion technique, and gestational age. Pediatr Res 1985;19:56977.
  82. Howie SR. Blood sample volumes in child health research: review of safe limits. Bull World Health Organ 2011;89:4653.
  83. Heidmets LT, Metsvaht T, Ilmoja ML, Pisarev H, Oselin K, Lutsar I. Blood loss related to participation in pharmacokinetic study in preterm neonates. Neonatology 2011;100:1115.
  84. Leroux S, Turner MA, Guellec CB, et al.; TINN (Treat Infections in NeoNates) and GRiP (Global Research in Paediatrics) Consortiums. Pharmacokinetic studies in neonates: The utility of an opportunistic sampling design. Clin Pharmacokinet 2015;54:127385.
  85. Castagnola M, Inzitari R, Fanali C, et al. The surprising composition of the salivary proteome of preterm human newborn. Mol Cell Proteomics 2011;10:M110.003467.
  86. Lee TC, Charles BG, Steer PA, Flenady VJ. Saliva as a valid alternative to serum in monitoring intravenous caffeine treatment for apnea of prematurity. Ther Drug Monit 1996;18:28893.
  87. 21 CFR Sec. 50.53 Clinical investigations involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subjects’ disorder or condition. 2015. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=50&showFR=1&subpartNode=21:1.0.1.1.20.4.
  88. Leong R, Vieira ML, Zhao P, et al. Regulatory experience with physiologically based pharmacokinetic modeling for pediatric drug trials. Clin Pharmacol Ther 2012;91:92631.
  89. Benjamin DK Jr, Smith PB, Jadhav P, et al. Pediatric antihypertensive trial failures: analysis of end points and dose range. Hypertension 2008;51:83440.
  90. Linakis MW, Roberts JK, Lala AC AC, et al. Challenges associated with route of administration in neonatal drug delivery. Clin Pharmacokinet 2016;55:185196.
  91. Guideline on pharmaceutical development of medicines for paediatric use. August 2013. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/07/WC500147002.pdf.
  92. Turner MA, Shah U. Why are excipients important to neonates? Curr Pharm Des 2015;21:56807.
  93. Brown WJ, Buist NR, Gipson HT, Huston RK, Kennaway NG. Fatal benzyl alcohol poisoning in a neonatal intensive care unit. Lancet 1982;1:1250.
  94. Gershanik J, Boecler B, Ensley H, McCloskey S, George W. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med 1982;307:13848.
  95. Excipients labelling EMA. 2003. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003412.pdf.
  96. Salunke S, Brandys B, Giacoia G, Tuleu C. The STEP (Safety and toxicity of excipients for paediatrics) database: part 2 - the pilot version. Int J Pharm 2013;457:31022.
  97. Yakkundi S, McElnay J, Millership J, et al. Use of dried blood spots to study excipient kinetics in neonates. Bioanalysis 2011;3:26913.
  98. Mulla H, Yakkundi S, McElnay J, et al. An observational study of blood concentrations and kinetics of methyl- and propyl-parabens in neonates. Pharm Res 2015;32:108493.
  99. Nellis G, Metsvaht T, Varendi H, et al.; ESNEE consortium. Potentially harmful excipients in neonatal medicines: a pan-European observational study. Arch Dis Child 2015;100:6949.
  100. Abdel-Rahman SM, Reed MD, Wells TG, Kearns GL. Considerations in the rational design and conduct of phase I/II pediatric clinical trials: avoiding the problems and pitfalls. Clin Pharmacol Ther 2007;81:48394.
  101. Klingmann V, Seitz A, Meissner T, Breitkreutz J, Moeltner A, Bosse HM. Acceptability of uncoated mini-tablets in neonates–a randomized controlled trial. J Pediatr 2015;167:893896.e2.
  102. Sherwin CM, Medlicott NJ, Reith DM, Broadbent RS. Intravenous drug delivery in neonates: lessons learnt. Arch Dis Child 2014;99:5904.
  103. Adaptive Design Clinical Trials for Drugs and Biologics. Guidance for Industry. 2010. http://www.fda.gov/downloads/Drugs/Guidances/ucm201790.pdf.
  104. Wang Y, Jadhav PR, Lala M, Gobburu JV. Clarification on precision criteria to derive sample size when designing pediatric pharmacokinetic studies. J Clin Pharmacol 2012;52:16016.
  105. Ethical Considerations for Clinical Trials on Medicinal Products conducted with the Paediatric Population 2008. http://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/ethical_considerations_en.pdf.
  106. Long D, Koren G, James A. Ethics of drug studies in infants: how many samples are required for accurate estimation of pharmacokinetic parameters in neonates? J Pediatr 1987;111(6 Pt 1):91821.
  107. Kauffman RE, Kearns GL. Pharmacokinetic studies in paediatric patients. Clinical and ethical considerations. Clin Pharmacokinet 1992;23:1029.
  108. Retout S, Comets E, Samson A, Mentré F. Design in nonlinear mixed effects models: optimization using the Fedorov-Wynn algorithm and power of the Wald test for binary covariates. Stat Med 2007;26:516279.
  109. Retout S, Duffull S, Mentré F. Development and implementation of the population Fisher information matrix for the evaluation of population pharmacokinetic designs. Comput Methods Programs Biomed 2001;65:14151.
  110. Retout S, Mentré F. Optimization of individual and population designs using Splus. J Pharmacokinet Pharmacodyn 2003;30:41743.
  111. Perlman SE, Saiman L, Larson EL. Risk factors for late-onset health care-associated bloodstream infections in patients in neonatal intensive care units. Am J Infect Control 2007;35:17782.
  112. Hawcutt DB, Rose AC, Fuerst-Recktenwald S, Nunn T, Turner MA. Points to consider when planning the collection of blood or tissue samples in clinical trials of investigational medicinal products in children, infants and neonates. In: Rose K, van den Anker JN, eds. Guide to Paediatric Drug Development and Clinical Research. Karger: Basel, 2009:99110.
  113. Ward RM, Kearns GL. Proton pump inhibitors in pediatrics: mechanism of action, pharmacokinetics, pharmacogenetics, and pharmacodynamics. Paediatr Drugs 2013;15:11931.
  114. Turner MA, Hill H. Pharmacovigilance in neonatal intensive care. In: Mimouni FB, van den Anker JN, eds. Neonatal Pharmacology. Karger: Basel, 2014;2840.
  115. Du W, Lehr VT, Lieh-Lai M, et al. An algorithm to detect adverse drug reactions in the neonatal intensive care unit. J Clin Pharmacol 2013;53:8795.
  116. Conroy S, McIntyre J. The use of unlicensed and off-label medicines in the neonate. Semin Fetal Neonatal Med 2005;10:11522.
  117. American Academy of Pediatrics Committee on Drugs. Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Committee on Drugs, American Academy of Pediatrics. Pediatrics 1995;95:286294.
  118. Shaddy RE, Denne SC; Committee on Drugs and Committee on Pediatric Research. Clinical report–guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Pediatrics 2010;125:85060.
  119. Ward RM, Sherwin CM. Ethics of drug studies in the newborn. Paediatr Drugs 2015;17:3742.
  120. Kipnis K. Seven vulnerabilities in the pediatric research subject. Theor Med Bioeth 2003;24:10720.
  121. Release and Adoption of Health Canada Addendum to the ICH1 Guidance E11: Clinical Investigation of Medicinal Products in the Pediatric Population. 2003. http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/prodpharma/applic-demande/guide-ld/clini/e11_addendum-eng.pdf.
  122. EMEA Committee for medicinal products for human use: Guideline on data monitoring committees. 2005. http://osp.od.nih.gov/sites/default/files/resources/WC500003635.pdf.
  123. 2016 Edition of the International Compilation of Human Research Standards. 2016. https://www.hhs.gov/ohrp/international/compilation-human-research-standards/index.html.
  124. REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC. 2014. http://ec.europa.eu/health//sites/health/files/files/eudralex/vol-1/reg_2014_536/reg_2014_536_en.pdf.
  125. Protection of Human Subjects. Subpart D. Additional Protections for Children Involved as Subjects in Research. 48 FR 9818. Section 46.401-46.409. 1991. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartd.
  126. Shah S, Whittle A, Wilfond B, Gensler G, Wendler D. How do institutional review boards apply the federal risk and benefit standards for pediatric research? JAMA 2004;291:47682.
  127. Office for Human Research Protections (OHRP). Secretary’s Advisory Committee on Human Research Protections (SACHRP). Appendix B. 2005. https://www.hhs.gov/ohrp/sachrp-committee/recommendations/2005-july-28-letter-appendix-b/index.html.
  128. 21 CFR sec. 50.52 Clinical investigations involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects. 2015. http://www.ecfr.gov/cgi-bin/text-idx?SID=0f4329b2e4045a0a62b37bf42590c837&mc=true&node=se21.1.50_152&rgn=div8.
  129. Ward RM, Daniel CH, Kendig JW, Wood MA. Oliguria and tolazoline pharmacokinetics in the newborn. Pediatrics 1986;77:30715.
  130. Turner S, Nunn AJ, Fielding K, Choonara I. Adverse drug reactions to unlicensed and off-label drugs on paediatric wards: a prospective study. Acta Paediatr 1999;88:9658.
  131. Simons SH, van Dijk M, Anand KS, Roofthooft D, van Lingen RA, Tibboel D. Do we still hurt newborn babies? A prospective study of procedural pain and analgesia in neonates. Arch Pediatr Adolesc Med 2003;157:105864.
  132. Guidance for Clinical Trial Sponsors. Establishment and Operation of Clinical Trial Data Monitoring Committees. 2006. http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127073.pdf.
  133. Allmark P, Mason S. Improving the quality of consent to randomised controlled trials by using continuous consent and clinician training in the consent process. J Med Ethics 2006;32:43943.

Download references

Author information

Affiliations

  1. Department of Pediatrics, Divisions of Neonatology and Clinical Pharmacology, University of Utah, Salt Lake City, Utah

    • Robert M. Ward
  2. Department of Pediatrics and Duke Clinical Research Institute, Duke University, Durham, North Carolina

    • Daniel Benjamin
  3. Translational Informatics and Pediatric Network, Sanofi Pharmaceuticals, Bridgewater, New Jersey

    • Jeffrey S. Barrett
  4. Intensive Care and Department of Surgery, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands

    • Karel Allegaert
  5. The Neonatal Intensive Care Unit, University of Leuven, Leuven, Belgium

    • Karel Allegaert
  6. Pediatric Therapeutic Area, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey

    • Ronald Portman
  7. Department of Pediatrics, Floating Hospital for Children, Tufts Medical Center, and Tufts Clinical and Translational Science Institute, Tufts University, Boston, Massachusetts

    • Jonathan M. Davis
  8. Institute of Translational Medicine, University of Liverpool, Liverpool, UK

    • Mark A. Turner
  9. Critical Path Institute, Tucson, Arizona

    • ; the International Neonatal Consortium (INC)9

Corresponding author

Correspondence to:

Author details

Supplementary information

Additional data