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.
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CFR 50, Subpart D. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=50&showFR=1&subpartNode=21:1.0.1.1.19.4. Accessed 3 Jan 2011
CFR 50.3(k). http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=50.3. Accessed 3 Jan 2011
CFR 50.3(n). http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=50.3. Accessed 3 Jan 2011
CFR 50.3(o). http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=50.3. Accessed 3 Jan 2011
CFR 50.24. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=50.24. Accessed 3 Jan 2011
CFR 50.24(a)(7)(iv). http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=50.24. Accessed 3 Jan 2011
CFR 50.51. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=50.51. Accessed 3 Jan 2011
CFR 50.52. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=50.52. Accessed 3 Jan 2011
CFR 50.53. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=50.53. Accessed 3 Jan 2011
CFR 56.111(a)(1). http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=56.111. Accessed 3 Jan 2011
CFR 56.111(b). http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=56.111. Accessed 3 Jan 2011
CFR Part 50. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRsearch.cfm?CFRPart=50. Accessed 3 Jan 2011
CFR Part 56. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?cfrpart=56. Accessed 3 Jan 2011
CFR 46.408(c). http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.408. Accessed 3 Jan 2011
Ackerman TF (1995) Phase I pediatric oncology trials. J Pediatr Oncol Nurs 12(3):143–145
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
American Academy of Pediatrics (1977) Committee on drugs. Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Pediatrics 60(1):91–101
American Academy of Pediatrics (1995) Committee on drugs. Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Pediatrics 95(2):286–294
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
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
Bartholome W (1996) Ethical issues in pediatric research. In: Vanderpool HY (ed) The ethics of research involving human subjects. University Publishing Group, Fredrick, MD
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
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
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
Department of Health Education and Welfare (1973) Protection of human subjects: policies and procedures. Fed Regist 38(221):31738–31749
Department of Health Education and Welfare (1978a) Notice of proposed rule-making: subpart D – additional protections for children. Fed Regist 43:31785
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):2083–2114
Department of Health Education and Welfare (1979) Protection of human subjects; proposed establishment of regulations. Fed Regist 44(80):24106–24111
Department of Health Education and Welfare (1983) Subpart D: additional protections for children involved as subjects in research. Fed Regist 48:9818–9820
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 121:34
European Union (2008) Ethical considerations for clinical trials on medicinal products conducted with the paediatric population. Eur J Health Law 15(2):223–250
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
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
Food and Drug Administration (2001) Additional safeguards for children in clinical research. Fed Regist 66(79):20589–20600
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 110-85
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)
Fost N (1998) Ethical dilemmas in medical innovation and research: distinguishing experimentation from practice. Semin Perinatol 22(3):223–232
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
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
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
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
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
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 edn
Kimmelman J (2009) Ethics of cancer gene transfer clinical research. Methods Mol Biol 542:423–445
Kimmelman J (2010) Gene transfer and the ethics of first-in-human research: lost in translation, 1st edn. Cambridge University Press, Cambridge, UK
King NM (2000) Defining and describing benefit appropriately in clinical trials. J Law Med Ethics 28(4):332–343
Kipnis K (2003) Seven vulnerabilities in the pediatric research subject. Theor Med Bioeth 24(2):107–120
Kodish E (2003) Pediatric ethics and early-phase childhood cancer research: conflicted goals and the prospect of benefit. Account Res 10(1):17–25
Kopelman LM (2000) Children as research subjects: a dilemma. J Med Philos 25(6):745–764
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):190–193
London AJ (2000) The ambiguity and the exigency: clarifying ‘standard of care’ arguments in international research. J Med Philos 25(4):379–397
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
Macklin R (2001) After Helsinki: unresolved issues in international research. Kennedy Inst Ethics J 11(1):17–36
Medical Research Council (2004) Medical research involving children. Medical Research Council, London
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
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
Miller M (2000) Phase I cancer trials. A collusion of misunderstanding. Hastings Cent Rep 30(4):34–43
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, DC
Nelson R (2006) Issues in the Institutional Review Board Review of PET scan protocols. In: Charron M (ed) Practical pediatric PET imaging. Springer, New York
Nelson RM (2007) Minimal risk, yet again. J Pediatr 150(6):570–572. doi:10.1016/j.jpeds.2007.03.040
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
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
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
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
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
Rossi WC, Reynolds W, Nelson RM (2003) Child assent and parental permission in pediatric research. Theor Med Bioeth 24(2):131–148
Sankar P (2004) Communication and miscommunication in informed consent to research. Med Anthropol Q 18(4):429–446
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
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
Snapinn SM (2000) Noninferiority trials. Curr Control Trials Cardiovasc Med 1(1):19–21
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
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, xii
Veatch RM (2007) The irrelevance of equipoise. J Med Philos 32(2):167–183. doi:777159077 [pii] 10.1080/03605310701255776
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
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
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
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
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
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
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Roth-Cline, M., Gerson, J., Bright, P., Lee, C.S., Nelson, R.M. (2011). Ethical Considerations in Conducting Pediatric Research. In: Seyberth, H., Rane, A., Schwab, M. (eds) Pediatric Clinical Pharmacology. Handbook of Experimental Pharmacology, vol 205. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-20195-0_11
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