Ethical Considerations in Conducting Pediatric Research

  • Michelle Roth-Cline
  • Jason Gerson
  • Patricia Bright
  • Catherine S. Lee
  • Robert M. Nelson
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 205)

Abstract

The critical need for pediatric research on drugs and biological products underscores the responsibility to ensure that children are enrolled in clinical research that is both scientifically necessary and ethically sound. In this chapter, we review key ethical considerations concerning the participation of children in clinical research. We propose a basic ethical framework to guide pediatric research, and suggest how this framework might be operationalized in linking science and ethics. Topics examined include: the status of children as a vulnerable population; the appropriate balance of risk and potential benefit in research; ethical considerations underlying study design, including clinical equipoise, placebo controls, and non-inferiority designs; the use of data monitoring committees; compensation; and parental permission and child assent to participate in research. We incorporate selected national (USA) and international guidelines, as well as regulatory approaches to pediatric studies that have been adopted in the USA, Canada, and Europe.

Keywords

Ethics Pediatrics Children Subpart D International guidelines Extrapolation Component analysis Equipoise Risk assessment Choice of control group Placebo Minor increase Scientific necessity Minimal risk Direct benefit Parental permission Child assent 

References

  1. Ackerman TF (1995) Phase I pediatric oncology trials. J Pediatr Oncol Nurs 12(3):143–145PubMedGoogle Scholar
  2. Ad hoc group for the development of implementing guidelines for Directive 2001/20/EC (2008) Ethical considerations for clinical trials on medicinal products with the paediatric population. Ad hoc group for the development of implementing guidelines for Directive 2001/20/EC relating to good clinical practice in the conduct of clinical trials on medicinal products for human use. http://ec.europa.eu/health/files/eudralex/vol-10/ethical_considerations_en.pdf. Accessed 10 Dec 2010
  3. American Academy of Pediatrics (1977) Committee on drugs. Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Pediatrics 60(1):91–101Google Scholar
  4. American Academy of Pediatrics (1995) Committee on drugs. Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Pediatrics 95(2):286–294Google Scholar
  5. Bagley SJ, Reynolds WW, Nelson RM (2007) Is a “wage-payment” model for research participation appropriate for children? Pediatrics 119(1):46–51. doi: 10.1542/peds.2006-1813 PubMedCrossRefGoogle Scholar
  6. Balfour-Lynn IM, Lees B, Hall P, Phillips G, Khan M, Flather M, Elborn JS (2006) Multicenter randomized controlled trial of withdrawal of inhaled corticosteroids in cystic fibrosis. Am J Respir Crit Care Med 173(12):1356–1362. doi: 200511-1808OC [pii] 10.1164/rccm.200511-1808OC PubMedCrossRefGoogle Scholar
  7. Bartholome W (1996) Ethical issues in pediatric research. In: Vanderpool HY (ed) The ethics of research involving human subjects. University Publishing Group, Fredrick, MDGoogle Scholar
  8. Canadian Institutes of Health Research (1998; with 2000, 2002 and 2005 amendments) Tri-council policy statement: ethical conduct for research involving humans. Canadian Institutes of Health Research – Natural Sciences and Engineering Research Council of Canada and Social Sciences and Humanities Research Council of Canada. http://www.pre.ethics.gc.ca/english/policystatement/introduction.cfm. Accessed 10 Dec 2010
  9. Carroll TW, Gutmann MP (2010) The limits of autonomy: the Belmont report and the history of childhood. J Hist Med Allied Sci 60(1):82–115. doi: 10.1093/jhmas/jrq021 Google Scholar
  10. CIOMS (2002) International ethical guidelines for biomedical research involving human subjects. Council for International Organizations of Medical Sciences (CIOMS) in collaboration with the World Health Organization (WHO). http://www.cioms.ch/publications/layout_guide2002.pdf. Accessed 10 Dec 2010
  11. Department of Health Education and Welfare (1973) Protection of human subjects: policies and procedures. Fed Regist 38(221):31738–31749Google Scholar
  12. Department of Health Education and Welfare (1978a) Notice of proposed rule-making: subpart D – additional protections for children. Fed Regist 43:31785Google Scholar
  13. Department of Health Education and Welfare (1978b) Research involving children: report and recommendations of the national commission for the protection of human subjects of biomedical and behavioral research. Fed Regist 43(9):2083–2114Google Scholar
  14. Department of Health Education and Welfare (1979) Protection of human subjects; proposed establishment of regulations. Fed Regist 44(80):24106–24111Google Scholar
  15. Department of Health Education and Welfare (1983) Subpart D: additional protections for children involved as subjects in research. Fed Regist 48:9818–9820Google Scholar
  16. European Parliament and the Council (2001) Directive 2001/20/EC of the European Parliament and the Council on the approximation of the laws, regulations, and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. Off J Eur Commun 121:34Google Scholar
  17. European Union (2008) Ethical considerations for clinical trials on medicinal products conducted with the paediatric population. Eur J Health Law 15(2):223–250CrossRefGoogle Scholar
  18. Federal Agency for Medicines and Health Products (Belgium) (2004) Law of May 7th 2004: unofficial consolidated version. http://www.fagg-afmps.be/en/human_use/medicines/Medicines/research_development/clinical_trials/index.jsp. Accessed 10 Dec 2010
  19. Fisher CB, Kornetsky SZ, Prentice ED (2007) Determining risk in pediatric research with no prospect of direct benefit: time for a national consensus on the interpretation of federal regulations. Am J Bioeth 7(3):5–10. doi: 10.1080/15265160601171572 PubMedCrossRefGoogle Scholar
  20. Food and Drug Administration (2001) Additional safeguards for children in clinical research. Fed Regist 66(79):20589–20600Google Scholar
  21. Food and Drug Administration (2007) Food and Drug Administration Amendments Act of 2007 – Pediatric Research Equity Act (reauthorization), 110th Congress ed: H.R. 3580, Public Law 110-85Google Scholar
  22. Food and Drug Administration Amendments Act of 2007. Title VI: Pediatric Research Equity Act of 2007. Pub. L. no. 110-85, 121 Stat 823 (2007)Google Scholar
  23. Fost N (1998) Ethical dilemmas in medical innovation and research: distinguishing experimentation from practice. Semin Perinatol 22(3):223–232PubMedCrossRefGoogle Scholar
  24. Friedman A, Robbins E, Wendler D (2010) Which benefits of research participation count as ‘Direct’? Bioethics. doi: BIOT1825 [pii] 10.1111/j.1467-8519.2010.01825.x PubMedGoogle Scholar
  25. Gifford F (2007) So-called “clinical equipoise” and the argument from design. J Med Philos 32(2):135–150. doi: 777158743 [pii] 10.1080/03605310701255743 PubMedCrossRefGoogle Scholar
  26. ICH (1996) International Conference on Harmonisation E6(R1): guideline for good clinical practice. http://www.ich.org/LOB/media/MEDIA482.pdf. Accessed 10 Dec 2010
  27. ICH (2000) International Conference on Harmonisation Guidance on E11 clinical investigation of medicinal products in the pediatric population. Available via HSR. http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm129477.pdf. Accessed 10 Dec 2010
  28. ICH (2001) International Conference on Harmonisation E10: choice of control group and related issues in clinical trials available via HSR. http://www.fda.gov/RegulatoryInformation/Guidances/ucm125802.htm. Accessed 10 Dec 2010
  29. Institute of Medicine (2004) IOM committee on clinical research involving children: ethical conduct of clinical research involving children. National Academies Press, Washington, DC, 2010/07/30 ednGoogle Scholar
  30. Kimmelman J (2009) Ethics of cancer gene transfer clinical research. Methods Mol Biol 542:423–445PubMedCrossRefGoogle Scholar
  31. Kimmelman J (2010) Gene transfer and the ethics of first-in-human research: lost in translation, 1st edn. Cambridge University Press, Cambridge, UKGoogle Scholar
  32. King NM (2000) Defining and describing benefit appropriately in clinical trials. J Law Med Ethics 28(4):332–343PubMedCrossRefGoogle Scholar
  33. Kipnis K (2003) Seven vulnerabilities in the pediatric research subject. Theor Med Bioeth 24(2):107–120PubMedCrossRefGoogle Scholar
  34. Kodish E (2003) Pediatric ethics and early-phase childhood cancer research: conflicted goals and the prospect of benefit. Account Res 10(1):17–25PubMedGoogle Scholar
  35. Kopelman LM (2000) Children as research subjects: a dilemma. J Med Philos 25(6):745–764PubMedCrossRefGoogle Scholar
  36. Lie RK, Emanuel E, Grady C, Wendler D (2004) The standard of care debate: the Declaration of Helsinki versus the international consensus opinion. J Med Ethics 30(2):190–193PubMedCrossRefGoogle Scholar
  37. London AJ (2000) The ambiguity and the exigency: clarifying ‘standard of care’ arguments in international research. J Med Philos 25(4):379–397PubMedCrossRefGoogle Scholar
  38. London AJ (2007) Two dogmas of research ethics and the integrative approach to human-subjects research. J Med Philos 32(2):99–116. doi: 10.1080/03605310701255727 PubMedCrossRefGoogle Scholar
  39. Macklin R (2001) After Helsinki: unresolved issues in international research. Kennedy Inst Ethics J 11(1):17–36PubMedCrossRefGoogle Scholar
  40. Medical Research Council (2004) Medical research involving children. Medical Research Council, LondonGoogle Scholar
  41. Miller FG, Brody H (2007) Clinical equipoise and the incoherence of research ethics. J Med Philos 32(2):151–165. doi: 777158978 [pii] 10.1080/03605310701255750 PubMedCrossRefGoogle Scholar
  42. Miller FG, Wendler D, Wilfond B (2003) When do the federal regulations allow placebo-controlled trials in children? J Pediatr 142(2):102–107. doi: S0022-3476(02)40245-4 [pii] 10.1067/mpd.2003.43 PubMedCrossRefGoogle Scholar
  43. Miller M (2000) Phase I cancer trials. A collusion of misunderstanding. Hastings Cent Rep 30(4):34–43PubMedCrossRefGoogle Scholar
  44. National Commission (1979) The Belmont Report: ethical principles and guidelines for the protection of human subjects of research from the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. National Commission, Washington, DCGoogle Scholar
  45. Nelson R (2006) Issues in the Institutional Review Board Review of PET scan protocols. In: Charron M (ed) Practical pediatric PET imaging. Springer, New YorkGoogle Scholar
  46. Nelson RM (2007) Minimal risk, yet again. J Pediatr 150(6):570–572. doi: 10.1016/j.jpeds.2007.03.040 PubMedCrossRefGoogle Scholar
  47. Nelson RM (2010) The scientific and ethical path forward in pediatric product development. http://www.bioethics.nih.gov/hsrc/slides/Nelson%20-%20NIH%20HSP%20Course%2010-20-2010.pdf. Accessed 10 Dec 2010
  48. Nelson RM, Lewis LL, Struble K, Wood SF (2010) Ethical and regulatory considerations for the inclusion of adolescents in HIV biomedical prevention research. J Acquir Immune Defic Syndr 54(Suppl 1):S18–S24. doi: 10.1097/QAI.0b013e3181e2012e PubMedGoogle Scholar
  49. Nelson RM, Ross LF (2005) In defense of a single standard of research risk for all children. J Pediatr 147(5):565–566. doi: 10.1016/j.jpeds.2005.08.051 PubMedCrossRefGoogle Scholar
  50. Office for Human Research Protections (2005) Appendix B: Secretary’s Advisory Committee on Human Research Protections (SACHRP) – Chair Letter to HHS Secretary Regarding Recommendations. http://www.hhs.gov/ohrp/sachrp/sachrpltrtohhssecApdB.html. Accessed 10 Dec 2010
  51. Ross L (2006) Phase I research and the meaning of direct benefit. J Pediatr 149(1 Suppl):S20–S24. doi: S0022-3476(06)00372-6 [pii] 10.1016/j.jpeds.2006.04.046 PubMedGoogle Scholar
  52. Rossi WC, Reynolds W, Nelson RM (2003) Child assent and parental permission in pediatric research. Theor Med Bioeth 24(2):131–148PubMedCrossRefGoogle Scholar
  53. Sankar P (2004) Communication and miscommunication in informed consent to research. Med Anthropol Q 18(4):429–446PubMedCrossRefGoogle Scholar
  54. Shaddy RE, Denne SC (2010) Clinical report – guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Pediatrics 125(4):850–860. doi: peds.2010-0082 [pii] 10.1542/peds.2010-0082 PubMedCrossRefGoogle Scholar
  55. Shah S, Whittle A, Wilfond B, Gensler G, Wendler D (2004) How do institutional review boards apply the federal risk and benefit standards for pediatric research? JAMA 291(4):476–482. doi: 10.1001/jama.291.4.476 PubMedCrossRefGoogle Scholar
  56. Snapinn SM (2000) Noninferiority trials. Curr Control Trials Cardiovasc Med 1(1):19–21PubMedCrossRefGoogle Scholar
  57. U.S. Department of Health and Human Services FDA (2006) Guidance for clinical trial sponsors: establishment and operation of clinical trial data monitoring committees. http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127073.pdf. Accessed 10 Dec 2010
  58. Unguru Y, Coppes MJ, Kamani N (2008) Rethinking pediatric assent: from requirement to ideal. Pediatr Clin North Am 55(1):211–222. doi: 10.1016/j.pcl.2007.10.016, xiiPubMedCrossRefGoogle Scholar
  59. Veatch RM (2007) The irrelevance of equipoise. J Med Philos 32(2):167–183. doi: 777159077 [pii] 10.1080/03605310701255776 PubMedCrossRefGoogle Scholar
  60. Weijer C, Miller PB (2004) When are research risks reasonable in relation to anticipated benefits? Nat Med 10(6):570–573. doi: 10.1038/nm0604-570 PubMedCrossRefGoogle Scholar
  61. Wendler D (2008) Is it possible to protect pediatric research subjects without blocking appropriate research? J Pediatr 152(4):467–470. doi: S0022-3476(07)00887-6 [pii] 10.1016/j.jpeds.2007.09.027 PubMedCrossRefGoogle Scholar
  62. Wendler D (2009) Minimal risk in pediatric research as a function of age. Arch Pediatr Adolesc Med 163(2):115–118. doi: 10.1001/archpediatrics.2008.524 PubMedCrossRefGoogle Scholar
  63. Wendler D, Glantz L (2007) A standard for assessing the risks of pediatric research: pro and con. J Pediatr 150(6):579–582. doi: 10.1016/j.jpeds.2007.02.018 PubMedCrossRefGoogle Scholar
  64. Wendler D, Miller FG (2007) Assessing research risks systematically: the net risks test. J Med Ethics 33(8):481–486. doi: 10.1136/jme.2005.014043 PubMedCrossRefGoogle Scholar
  65. World Medical Association (2008) Declaration of Helsinki – ethical principles for medical research involving human subjects. http://www.wma.net/en/30publications/10policies/b3/index.html. Accessed 10 Dec 2010

Copyright information

© Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  • Michelle Roth-Cline
    • 1
  • Jason Gerson
    • 1
  • Patricia Bright
    • 1
  • Catherine S. Lee
    • 1
  • Robert M. Nelson
    • 1
  1. 1.U.S. Department of Health and Human Services, Food and Drug AdministrationOffice of the Commissioner, Office of Pediatric TherapeuticsSilver SpringUSA

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