Rethinking Risk in Pediatric Research

Ramsey P. , The Patient as Person: Explorations in Medical Ethics (New Haven: Yale University Press, 2002).

Ramsey P. , “The Enforcement of Morals: Nontherapeutic Research on Children,” Hastings Center Report 6, no. 4 (1976): 21–30; McCormick R. A. , “Experimentation in Children: Sharing in Sociality,” Hastings Center Report 6, no. 6 (1976): 41–46; May W. E. , Human Existence, Medicine, and Ethics: Reflections on Human Life (Chicago: Franciscan Herald Press, 1977); Capron A. M. , “Legal Considerations Affecting Clinical Pharmacological Studies in Children,” Clinical Research 21, no. 2 (1973): 141–150; Bartholome W. G. , “Parents, Children, and the Moral Benefits of Research,” Hastings Center Report 6, no. 6 (1976): 44–45; Curran J. , “A Problem of Consent: Kidney Transplantation in Minors,” New York University Law Review 34, no. 5 (1959): 891–898.

See Ramsey , supra note 2.

McCormick R. A. , “Proxy Consent in the Experimentation Situation,” Perspectives in Biology and Medicine 18, no. 1 (1974): 2–20.

See Capron , supra note 2; Bartholome , supra note 2; Curan, supra note 2; Ackerman T. F. , “Moral Duties of Parents and Nontherapeutic Clinical Research Procedures Involving Children,” Bioethics Quarterly 2, no. 2 (1980): 94–111.

National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, Report and Recommendations on Research Involving Children, September 6, 1977 [hereinafter cited as National Commission].

Id., at 7–8.

Id., at 10.

Id., at xx-xxi.

U.S. Department of Health and Human Services (DHHS), Protection of Human Subjects, Additional DHHS Protections for Children Involved as Subjects in Research, 45 C. F. R. 46, Subpart D [hereinafter cited as DHHS]; Freedman B. Fuks A. Weijer C. , “In Loco Parentis: Minimal Risk as an Ethical Threshold for Research upon Children,” Hastings Center Report 23, no. 2 (1993): 13–19.

45 CFR 46.102i.

Janofsky J. Starfield B. , “Assessment of Risk in Research on Children,” Pediatics 98, no. 5 (1981): 842–846.

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 291, no. 4 (2004): 476–482; Institute of Medicine, Ethical Conduct of Clinical Research Involving Children (Washington, D. C.: National Academies Press, 2004): At 120–121 [hereinafter cited as IOM].

Resnik D. B. , “Research Participation and Financial Inducements,” American Journal of Bioethics 1, no. 2 (2001): 34–56, at 36.

Kopelman L. M. , “Pediatric Research Regulations under Legal Scrutiny: Grimes Narrows Their Interpretation,” Journal of Law, Medicine & Ethics 30, no. 1 (2002): 38–49, at 42.

Id., at 42; Kopelman L. M. , “What Conditions Justify Risky Nontherapeutic or ‘No Benefit’ Pediatric Studies: A Sliding Scale Analysis,” Journal of Law, Medicine & Ethics 32, no. 4 (2004): 749–758, at 750.

Fisher C. B. Kornetsky S. Z. Prentice E. D. , “Determining Risk in Pediatric Research with No Prospect of Direct Benefit: Time for a National Consensus on the Interpretation of Federal Regulation,” American Journal of Bioethics 7, no. 3 (2007): 5–10; see Kopelman , supra note 15; Wendler D. Belsky L. Thompson K. M. Emanuel E. J. , “Quantifying the Federal Minimal Risk Standard: Implications for Pediatric Research without a Prospect of Direct Benefit,” JAMA 294, no. 7 (2005): 826–832.

In the literature, the “absolute standard” is referred to as the “uniform standard” as well as the “objective standard.”19. National Bioethics Advisory Committee, Ethical and Policy Issues in Research Involving Human Participants, 2001, Bethesda, MD [hereinafter cited as NBAC].

See National Commission, supra note 6, at xx.

Kopelman L. M. , “Minimal Risk as an International Ethical Standard in Research,” Journal of Medicine and Philosophy 29, no. 3 (1994): 351–378, at 361.

See NBAC, supra note 19; IOM, supra note 13, at 121; National Human Research Protections Advisory Committee (NHRPAC), Children's Workgroup Report (Draft), available at <http://ohrp.osophs.dhhs.gov/nhrpac/mtg04–01/child-workgroup4-5-1.pdf> (last visited May 2007).

See Kopelman , supra note 15, at 42.

See IOM, supra note 13, at 121.

See Kopelman , supra note 15; IOM, supra note 13.

See Kopelman , supra note 16; IOM, supra note 13; NBAC, supra note 19; Wendler , supra note 17.

See Wendler , supra note 17, at 827.

See NBAC, supra note 19, at 83.

See Kopelman , supra note 21, at 363.

See National Commission, supra note 6, at xx.

See Kopelman , supra note 21, at 360; Kopelman L. M. , “Children as Research Subjects: Moral Disputes, Regulatory Guidance, and Recent Court Decisions,” Mount Sinai Journal of Medicine 73, no. 3 (2006): 596–604, at 598.

See Kopelman , supra note 21, at 360; Kopelman , supra note 31, at 598.

See Kopelman , supra note 16; Kopelman , supra note 31.

See Wendler , supra note 17; IOM, supra note 13; Kopelman , supra note 21.

See Kopelman , supra note 31, at 598; Kopelman , supra note 20, at 361.

See Kopelman , supra note 31, at 598.

See IOM, supra note 13, at 124.

Id., at 124.

Id., at 125.

See Wendler , supra note 17.

See NBAC, supra note 19.

Council for International Organizations of Medical Science (CIOMS), International Ethical Guidelines for Biomedical Research Involving Human Subjects , 2002, available at <http://www.cioms.ch/frame_guidelines_nov_2002.htm> (last visited June 4, 2008); see Kopelman , supra note 21.

Hoffman R. P. Vicini P. Sivitz W. I. Cobelli C. , “Pubertal Adolescent Male-Female Differences in Insulin Sensitivity and Glucose Effectiveness Determined by the one Compartment Minimal Model,” Pediatric Research 48, no. 3 (2000): 384–388.

Report of the Meeting of Experts Convened by OPRR to Review NICHD Application, Cognitive Function and Hypoglycemia in Children with IDDM , September 20, 1993 (accessed by FOIA). While the induction of hypoglycemia was considered to be no more than minimal risk, the combination of procedures and discomforts rendered the study as more than minimally risky and it was approved (with stipulations) under 407.

Letter from Gary L. Chadwick, Executive Director, University of Rochester Research Subjects Review Board, to Clifford C. Scharke, Senior Advisor, Office for Human Research Protections, April 18, 2001. The letter concerned proposed protocol entitled Genetics of Non-Syndromic Clefting.

Minutes of a Meeting, September 21, 2005, Recombinant Advisory Committee, U.S. Department of Health and Human Services, National Institutes of Health, Bethesda, MD.

See DHHS, supra note 10, at 46.407.

Kopelman L. M. Murphy T. F. , “Ethical Concerns about Federal Approval of Risky Pediatric Studies,” Pediatrics 113, no. 6 (2004): 1783–1789.

U. S. Department of Health and Human Services, available at <http://www.hhs.gov/ohrp/children/> (last visited June 4, 2008); protocols unavailable on the DHHS Web site were accessed by FOIA request, July 2005.

Ross L. F. , “Children in Medical Research: Balancing Protection and Access: Has the Pendulum Swung Too Far?” Perspectives in Biology and Medicine 47, no. 4 (2004): 519–536; Ross L. F. , Children in Medical Research: Access Versus Protection (Oxford and New York: Oxford University Press and Clarendon Press, 2006): At 243–271; see Kopelman Murphy , supra note 48.

Id. ( Kopelman Murphy ).

Ross L. F. , “Lessons to Be Learned from the 407 Process,” Health Matrix 15, no. 2 (2005): 401–421.

See National Commission, supra note 6, at 12.

Id., at 12.

Id., at 127.

Id., at 140.

Id., at 127.

See Kopelman Murphy , supra note 48.

Letter from Steven Peckman, Associate Director, Human Subjects Research, UCLA, to J. Thomas Puglis, Director, Office for Human Research Protections, November 13, 2000. The letter concerned proposed protocol entitled “A Phase I/II Study to Evaluate the Safety and Immunogenicity of ALVAC HIV Vaccines Along and with AIDSVAX gp 120 in Children Born to HIV-Infected Mothers”; final determination of the study was unavailable.

Letter from Donald L. Rosenstein, Chair, NIMH IRB, to Michael Gottesman, Deputy Director, March 5, 2004. The letter concerned proposed protocol entitled “Effects of a Single Dose of Dextroamphetamine in Attention Deficit Hyperactivity Disorder: A Function Magnetic Resonance Study,” and is available at <http://www.hhs.gov/ohrp/panels/jre-view01/irbreq.pdf> (last visited June 4, 2008).

Letter from Bernard A. Schwetz, Director, Office for Human Research Protection, to Christina V. Beato, Assistant Secretary for Health, April 12, 2006. The letter concerned proposed protocol entitled “Gonadotropin Releasing Hormone (GnRH) Agonist Test in Disorders of Puberty,” and is available at <http://www.hhs.gov/ohrp/children/ppssn/HHSDetrLtr.pdf> (last visited June 4, 2008).

Letter, from Irene Stith-Coleman, Division of Policy, planning, and Special Protections, Office for Human Research Protections, to Stewart Laidlaw, Director, Research and Educational Institute, Harbor-UCLA Medical Center, January 24, 2003. The letter is available at <http://www.hhs.gov/ohrp/dpanel/determ.pdf> (last visited June 4, 2008).

NIH Grant Application, Protocol entitled “Precursors to Diabetes in Japanese American Youth,” University of Washington, Children's Hospital and Regional Medical Center, and Veteran's Administration Medical Center, available at <http://www.hhs.gov/ohrp/pdjay/grant.htm> (last visited June 4, 2008).

See IOM, supra note 13, at 133–134.

See 45 C. F. R. 46.407, supra note 10.

See IOM, supra note 13, at 134.

Couzin J. , “Clinical Trials: Diabetes' Brave New World,” Science 300, no. 5627 (2003): 1862–1865.

See supra note 63.

Letter from Bernard A. Schwetz, Acting Director, Office for Human Research Protection, to Surgeon General and Acting Assistant Secretary for Health, May 27, 2003. The letter concerned proposed protocol entitled “Precursors to Diabetes in Japanese American Youth,” available at <http://www.hhs.gov/ohrp/pdjay/hhsdetr.pdf> (last visited June 4, 2008).

Shamoo A. E. Tauer C. A. , “Ethically Questionable Research with Children: The Fenfluramine Study,” Accountability in Research 9, nos. 3–4 (2002): 143–166.

Pine D. S. Coplan J. D. Wasserman G. A. Miller L. S. Fried J. E. , “Neuroendocrine Response to Fenfluramine Challenge in Boys: Associations with Aggressive Behavior and Adverse Rearing,” Archives of General Psychiatry 54, no. 9 (1997): 839–846.

Sharav V. H. , Author Response to Letter Regarding “Children in Clinical Research: A Conflict of Moral Values,” (in American Journal of Bioethics 3, no. 1) American Journal of Bioethics 4, no. 3 (2004): W35–W37.

McGlashan T. H. Zipursky R. B. Perkins D. Addington J. , “Randomized, Double-Blind Trial of Olanzapine Versus Placebo in Patients Prodromally Symptomatic for Psychosis,” American Journal of Psychiaty 163, no. 5 (2006): 790–799; McGlashan T. H. Zipursky R. B. Perkins D. Addington J. , “The PRIME North America Randomized Double-Blind Clinical Trial of Olanzapine Versus Placebo in Patients at Risk of Being Prodromally Symptomatic for Psychosis. I. Study Rationale and Design,” Schizophrenia Research 61, no.

Id.; see Sharav , supra note 73.

Coffey M. J. Wilfond B. Ross L. F. , “Ethical Assessment of Clinical Asthma Trials Including Children Subjects,” Pediatrics 113, no. 1 (2004): 87–94.

See Ross , supra note 50.

Food and Drug Administration (FDA), “Specific Requirements on Content and Format of Labeling, Part II,” Federal Register 59, no. 238 (1994): 64240–64250.

Food and Drug Administration Modernization Act (FDAMA), Pub. L. No. 105–115, 105th Congress (1997); Best Pharmaceuticals for Children Act, Pub. L. No. 107–109, 107th Congress (January 4, 2002).

See Ross , supra note 50; National Institutes of Health (NIH), Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects , 1998, available at <http://grants2.nih.gov/grants/guide/notice-files/not98–24.html> (last visited June 4, 2008).

Glass K. C. Speyer-Ofenberg M. , “Incompetent Persons as Research Subjects and the Ethics of Minimal Risk,” Cambridge Quarterly of Healthcare Ethics 5, no. 3 (1996): 362–372; Ross L. F. , Children, Families, and Health Care Decision-Making (Oxford: Clarendon Press, 1998).

Rodwin M. A. , “Strains in the Fiduciary Metaphor: Divided Physician Loyalties and Obligations in a Changing Health Care System,” American Journal of Law and Medicine 21, nos. 2–3 (1995): 241–257; Miller P. B. Weijer C. , “Fiduciary Obligation in Clinical Research,” Journal of Law, Medicine & Ethics 34, no. 2 (2006): 424–440.

Benjamin D. K. Jr. Smith P. B. Murphy D. Roberts R. , “Peer-Reviewed Publication of Clinical Trials Completed for Pediatric Exclusivity,” JAMA 296, no. 10 (2006): 1266–1273.

See Ross , supra note 50.