See Levine, R.J., Ethics and Regulation of Clinical Research, 2d ed. (New Haven: Yale University Press, 1988): At 236 (lack of capacity); Glantz, L.H., “Research with Children,” American Journal of Law and Medicine, 24 (1998): 213–44, at 215–19 (subjects of abuse).Google ScholarPubMed

See discussion of these events infra Section I.Google Scholar

The statute, commonly called the “Modernization Act” or “FDAMA,” will be discussed infra Section II.A.Google Scholar

See discussion of regulations infra Section II.B.Google Scholar

See generally Wilson, J.T., “An Update on the Therapeutic Orphan,” Pediatrics, 104 (1999 Supp.): 585–90.Google Scholar

Approximately 18,000 children will be needed as research subjects over the next few years. Warner, S., “In Clinical Trials, Children are the Newest Subjects,” The Philadelphia Inquirer, Aug. 6, 2000, at E1.Google Scholar

See discussion of these and other ethical issues infra Sections III and IVGoogle Scholar

See Department of Health and Human Services, Office of Inspector General, “Institutional Review Boards: A Time for Reform” (June 1998): 1–25, at ii, 5–6 [hereinafter cited as OIG Report, “A Time for Reform”].Google Scholar

See OIG Report, “A Time for Reform,” supra note 8, at ii, 5–6. See also Woodward, B., “Challenges to Human Subject Protections in US Medical Research,” JAMA, 282 (1999): 1947–52, at 1949.Google Scholar

See Brainard, J., “Will a ‘Fresh Face’ Bring a New Approach to Federal Protection of Human Subjects?” Chronicle of Higher Education, July 21, 2000 at A21-A22 (research suspended at eight institutions in two years); Weiss, R. and Nelson, D., “U.S. Halts Cancer Tests in Okla.,” Washington Post, July 11, 2000, at A1. Recently, President Clinton urged Congress to permit the imposition of monetary penalties for any failure to protect human subjects adequately. Presidential Press Release, “Statement on Steps to Enhance the Safety of Clinical Trials,” Weekly Compilation of Presidential Documents, May 23, 2000, at 95 (visited Oct. 28, 2000) <http://www.access.gpo.gov/nara/nara003.html>.Google Scholar

See Arnold, L.E. et al., “Ethical Issues in Biological Psychiatric Research with Children and Adolescents,” Journal of the American Academy of Child and Adolescent Psychiatry, 34 (1995): 929–39 (considering issues such as maturity and compensation in the context of mental health research).Google Scholar

Notably, it permits distinctions between children based on stages of development, rather than a one-size-fits-all approach. See discussion infra Section IVGoogle Scholar

See, for example, Goldner, J.A., “An Overview of Legal Controls on Human Experimentation and the Regulatory Implications of Taking Professor Katz Seriously,” Saint Louis University Law Journal, 38 (1993): 63–134, at 90–92; Levine, supra note 1, at 69–70. See also Glantz, L.H., “Conducting Research with Children: Legal and Ethical Issues,” Journal of the American Academy of Child and Adolescent Psychiatry, 34 (1996): 1283–91, at 1285.Google Scholar

See, for example, Goldner, supra note 13, at 94.Google Scholar

See, for example, Holder, A.R., “Constraints on Experimentation: Protecting Children to Death” (Commentary), Yale Law & Policy Review, 6 (1988): 137–56, at 141–42.Google Scholar

See, for example, Stolberg, S.G., “FDA Officials Fault Penn Team in Gene Therapy Death,” New York Times, Dec. 9, 1999, at A22 (discussing the death of Jesse Gelsinger).Google Scholar

“Drug study blamed in baby's death: 9-month old was part of heartburn medical trial,” Milwaukee Journal Sentinel, April 28, 2000, at A9. Apparently, the consent form erroneously identified the drug as one that already had been approved by the FDA. Id.Google Scholar

See Franks, A.L., Steinberg, K.K., “Encouraging News from the SERM Frontier” (Editorial), JAMA, 281(1999): 2243–44, and Grady, D., “Breast Cancer Drug Approved for New Use,” New York Times, July 1, 2000, at A14 (breast cancer); infra Section I.B (AIDS). Recently, clinical trials have shown promising results in the treatment of sepsis, a deadly disease that thus far has not responded to treatment. “Lilly Reports Sepsis Drug Passes Advanced Trials,” New York Times, June 30, 2000, at A18.Google Scholar

See National Institutes of Health, “NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research,” 59 Fed. Reg. 14,508–513 (March 28, 1994); Food and Drug Administration, “Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs,” 58 Fed. Reg. 39,406–413 (July 22, 1993). See generally Rothenberg, K.H., “Gender Matters: Implications for Clinical Research and Women's Health Care,” Houston Law Review, 32 (1996): 1201–72, at 1218–41 (chronicling history of research with women).Google Scholar

For example, an estimated 12,400 children and young people will be diagnosed with cancer this year, of which 2,300 children will die. American Cancer Society, “Cancer Facts and Figures 2000, Special Section: Childhood Cancer” (visited Oct. 21, 2000) <http://www.cancer.org/statistics/cff2000/special.html>. As of December 1999, there were approximately 5,500 children younger than 13 living with HIV or AIDS. Centers for Disease Control and Prevention, HIV/AIDS Surveillance Report, 11, no. 2 (1999): 1–44, at 7..+As+of+December+1999,+there+were+approximately+5,500+children+younger+than+13+living+with+HIV+or+AIDS.+Centers+for+Disease+Control+and+Prevention,+HIV/AIDS+Surveillance+Report,+11,+no.+2+(1999):+1–44,+at+7.>Google Scholar

These childhood diseases include asthma and hyperactivity. See Pharmaceutical Research and Manufacturers of America (PhRMA), “New Medicines in Development for Children: A 2000 Survey,” 1–23, at 21 (visited Oct. 21, 2000) <http://www.phrma.org/searchcures/newmeds/children2000/MedChild2000.pdf> [hereinafter cited as PhRMA, “2000 Survey”] (approximately 5 million American children suffer from asthma, the most common chronic childhood illness); id. at 22 (attention deficit hyperactivity disorder affects over 2 million children).+[hereinafter+cited+as+PhRMA,+“2000+Survey”]+(approximately+5+million+American+children+suffer+from+asthma,+the+most+common+chronic+childhood+illness);+id.+at+22+(attention+deficit+hyperactivity+disorder+affects+over+2+million+children).>Google Scholar

This practice, termed “off-label use,” is defined infra Section I.A.Google Scholar

See, for example, Rosato, J.L., “The Ultimate Test of Autonomy: Should Minors Have a Right to Make Decisions Regarding Life-Sustaining Treatment?” Rutgers Law Review, 49 (1996): 1–103, at 18.Google Scholar

The competence required to consent to treatment and to consent to research is similar, although more maturity may be necessary to consent to research. Weithorn, L.A. and Scherer, D.G., “Children's Involvement in Research Participation Decisions: Psychological Considerations,” in Grodin, M.A., Glantz, L.H., eds., Children as Research Subjects (New York: Oxford University Press, 1994): 133–79, at 147–48.Google Scholar

See Carr, A., “When your child is gravely ill and doctors say a clinical trial offers the best hope, some parents find they'll do whatever it takes,” Chicago Daily Herald, April 9, 1998, at 1 (Suburban Living Section).Google Scholar

See Glantz, supra note 1, at 219. See also Langer, D.H., “Medical Research Involving Children: Some Legal and Ethical Issues,” Baylor Law Review, 36 (1984): 1–39, at 37.Google Scholar

See Department of Health and Human Services, Office of Inspector General, “Recruiting Human Subjects: Pressures in Industry-Sponsored Clinical Research” (June 2000): 1–79, at 12–15 [hereinafter cited as OIG Report, “Recruiting Human Subjects”]. See generally Glantz, supra note 13, at 1286 (“researcher's allegiance is primarily to the creation of knowledge,” not patient care).Google Scholar

See, for example, Holder, supra note 15, at 139–40; Shirkey, H., “Editorial Comment: Therapeutic Orphans,” Pediatrics, 104 (1999): 583–84.Google Scholar

See Salbu, S.R., “Off-Label Use, Prescription, and Marketing of FDA-Approved Drugs: An Assessment of Legislative and Regulatory Policy,” Florida Law Review, 51 (1999): 181–227, at 188–92.Google Scholar

See, for example, Niederhauser, V.P., “Prescribing for Children: Issues in Pediatric Pharmacology,” The Nurse Practitioner, 22 (1997): 16–30, at 23–30.Google Scholar

See American Academy of Pediatrics, Committee on Drugs, “Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations” (Feb. 1995): 1–13, at 1 (visited Oct. 22, 2000) <http://www.aap.org/policy/00655.html> [hereinafter cited as AAP Guidelines]. See also S. 2178, 104th Cong. (1996), 142 Cong. Rec. S11,992 (daily ed. Sept. 30, 1996) (statement by Senator Dodd introducing the Better Pharmaceuticals for Children Act, subsequently incorporated into FDAMA) [hereinafter cited as Senator Dodd]; Abramson, J.S., Holland, M.E., “Off Label Use of Antimicrobial Agents in Infants, Children and Adolescents: A Time for Action,” The Pediatric Infectious Disease Journal, 17, no. 8 (1998): 739–44, at 742. See generally Henry, V., “Off-Label Prescribing: Legal Implications,” Journal of Legal Medicine, 20 (1999): 365–83.CrossRefGoogle Scholar

Only one-fifth of all drugs on the market have been labeled for use by infants and children. 62 Fed. Reg. 43,899–916, at 43,902, col. 1 (1997). Furthermore, 60 to 70 percent of drugs have no indication for their use in children under age 12, and 95 percent of drugs used in neonatology are administered off-label. DeBenedette, V., “Suffer the Children,” Drug Topics, 142 (Jan. 19, 1998): At § 2. See also Zito, J.M., et al., “Trends in the Prescribing of Psychotropic Medications to Preschoolers,” JAMA, 283 (2000): 1025–30 (documenting significant increase in the use of psychotropic drugs in preschool children, mostly off-label).Google Scholar

See Abramson, , Holland, supra note 31, at 739. See also National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, Research Involving Children: Report and Recommendations, DHEW Pub. No. (OS) 77–0004 (Washington, D.C.: U.S. Gov't Printing Office, 1977): 1–154, at 23–26 [hereinafter cited as Commission Report].Google Scholar

AAP Guidelines, supra note 31, at 1.Google Scholar

See, for example, Webber, D.W., ed., AIDS and the Law, 3d ed. (New York: Wiley Law Publications, 1997): §§ 1.18–1.21.Google Scholar

See, for example, Fentimen, L.C., “AIDS as a Chronic Illness: A Cautionary Tale for the End of the Twentieth Century,” Albany Law Review, 61 (1998): 989–1011, at 991; Salbu, S.R., “The FDA and Public Access to New Drugs: Appropriate Levels of Scrutiny in the Wake of HIV, AIDS, and the Diet Drug Debacle,” Boston University Law Review, 79 (1999): 93–152, at 108.Google Scholar

See Mariner, W.K., “AIDS Research and the Nuremberg Code,” in Annas, G.J., Grodin, M.A., eds., The Nazi Doctors and the Nuremberg Code: Human Rights in Human Experimentation (New York: Oxford University Press, 1992): At 291–92. See generally Greenberg, M.D., “AIDS, Experimental Drug Approval, and the FDA New Drug Screening Process,” New York University Journal of Legislation and Public Policy, 3 (1999–2000: 295–350, at 310–11 (recent expansion in research began with pressure from AIDS activists).Google Scholar

See Fentimen, supra note 36, at 989–91. See also Salbu, supra note 36, at 109.Google Scholar

See Levine, C., Dubler, N.N., Levine, R.J., “Building a New Consensus: Ethical Principles and Policies for Clinical Research on HIV/AIDS,” IRB, 13, nos. 1–2 (1991): 1–17, at 2.CrossRefGoogle Scholar

See Salbu, supra note 36, at 119 (“The Modernization Act's loosening of requirements is the result of an era that fundamentally altered our government's conception of pharmaceutical regulation”). Compare with Greenberg, supra note 37, at 344 (responses to AIDS patients were codified in FDAMA).Google Scholar

See Stolberg, S.G., “A Revolution in AIDS Drugs Excludes the Tiniest Patients,” New York Times, Sept. 8, 1997, at A1, A14. See generally Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, “Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection” (Jan. 7, 2000): 1–61 (visited Oct. 28, 2000) <http://hivatis.org/guidelines/Pediatric/Text/ped_12.pdf>.Google Scholar

See generally Levine, , Dubler, , Levine, supra note 39, at 14–15 (moral balance requires including children in clinical trials).Google Scholar

See supra note 10 (citing recent shut-downs). See also Stolberg, S.G., “Teenager's Death Is Shaking Up Field of Human Gene-Therapy Experiments,” New York Times, Jan. 27, 2000, at A20.Google Scholar

65 Fed. Reg. 37,136–137 (2000). See also “New Office for Human Research Protections Created, Dr. Greg Koski Named Director,” HHS News (June 6, 2000) (visited Oct. 28, 2000) <http://www.hhs.gov/news/press/2000pres/20000606.html>..>Google Scholar

See Vergano, D., “Drug Trials Vex Medical Ethics, Academic Experts Put Testing by Private Companies Under a Microscope,” USA Today, Aug. 8, 2000, at D9 (private money spent on clinical drug trials increased significantly in last two years).Google Scholar

For other references to this analogy, see, for example, Hearing of the Senate Health, Education, Labor and Pensions Committee of the Food and Drug Administration (Oct. 21, 1999) (statement of Myron Genel). See also Abramson, Holland, supra note 31, at 744.Google Scholar

111 Stat. 2296 (1997). The legislation was signed into law on November 21, 1997, and became effective 90 days later.Google Scholar

21 U.S.C. § 355a (1994 & Supp. III 1997).Google Scholar

Food and Drug Administration, “FDA Guidance for Industry, Qualifying for Pediatric Exclusivity Under § 505A of the Federal Food, Drug and Cosmetic Act” (Sept. 1999): 1–22 [hereinafter cited as FDA, “Pediatric Exclusivity Guidance”]; 21 U.S.C. § 355a(a), (b). “Active moiety” is defined, inter alia, in 21 C.F.R. § 314.108(a) (2000).Google Scholar

21 U.S.C. § 355a; FDA, “Pediatric Exclusivity Guidance,” supra note 49, at 2–3.Google Scholar

See Food and Drug Administration, “Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients,” 63 Fed. Reg. 66,631–672, at 66,633, col. 3 (Dec. 2, 1998) [hereinafter cited as “new FDA regulations”] (discussing shortcomings in Modernization Act).Google Scholar

See Dodd, Senator supra note 31.Google Scholar

The FDA has issued 137 Written Requests for pediatric studies under § 505A of the Federal Food, Drug, and Cosmetic Act (visited Oct. 29, 2000) <http://www.fda.gov/cder/pediatric/wrlist.htm>..>Google Scholar

According to the Pharmaceutical Research and Manufacturers of America, 217 medicines and vaccines for children are currently in development, and clinical trials for 52 medicines are set to begin. See PhRMA, “2000 Survey,” supra note 21, at 1.Google Scholar

See Food and Drug Administration, Center for Drug Evaluation and Research, “Patent Term Extension and New Patients” (November 28, 2000) (visited December 7, 2000) <http://www.fda.gov/cder/orange/docket.pdf>..>Google Scholar

Hearing of the Senate Health, Education, Labor and Pensions Committee of the Food and Drug Administration (Oct. 21, 1999) (prepared statement of Alan F. Homer, president and chief executive officer of PhRMA).Google Scholar

63 Fed. Reg. at 66,633.Google Scholar

See id. at 66,636, col. 2, sec. H. See also discussion infra Section II.B.Google Scholar

Id. at 66,632, col. 2.Google Scholar

63 Fed. Reg. 66,631–672 (1998), effective April 1, 1999.Google Scholar

21 C.F.R. § 314.55 (2000).CrossRefGoogle Scholar

Id. The term “substantial number of pediatric patients” is not defined in the regulation itself, but the FDA in its Final Notice defines the term to mean 50,000 pediatric patients with the disease or condition for which the drug or biological product is indicated. 63 Fed. Reg. at 66, 636, col. 1. The term “meaningful therapeutic benefit” is defined at § 314.55(c)(5). Other grounds for waiver include where “necessary studies are impossible to highly impractical,” or where “[t]here is evidence strongly suggesting that the drug product would be ineffective or unsafe in all pediatric age groups.” Id.Google Scholar

63 Fed. Reg. at 66, 636, col. 2.Google Scholar

21 C.F.R. § 314.55(b).Google Scholar

Id. § 201.23 (2000).Google Scholar

See supra note 62.Google Scholar

21 C.F.R. § 201.23(b)(1). See also 63 Fed. Reg. at 66,653–654 (FDA describing “compelling circumstances” under which studies will be required of already-marketed drugs).Google Scholar

Drug manufacturers have twenty months from the effective date of April 1, 1999, to comply with these regulations, unless a waiver or deferment is granted by the FDA. 63 Fed. Reg. at 66,632.Google Scholar

See OIG Report, “A Time for Reform,” supra note 8, at 1–4.Google Scholar

45 C.F.R. §§ 46.401–46.408 (1999).Google Scholar

AAP Guidelines, supra note 31.Google Scholar

“FDA Ethics Working Group Consensus Statement on the Pediatric Advisory Subcommittee's November 15, 1999 Meeting” (April 19, 2000) (visited Oct. 28, 2000) <http://www.fda.gov/cder/pediatric/ethics-statement.htm> [hereinafter cited as Consensus Statement]. [hereinafter cited as Consensus Statement].' href=https://scholar.google.com/scholar?q=“FDA+Ethics+Working+Group+Consensus+Statement+on+the+Pediatric+Advisory+Subcommittee's+November+15,+1999+Meeting”+(April+19,+2000)+(visited+Oct.+28,+2000)++[hereinafter+cited+as+Consensus+Statement].>Google Scholar

International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, “E11: Clinical Investigation of Medicinal Products in the Pediatric Population,” which was originally published at 65 Fed. Reg. 19,777–781 (April 12, 2000). The most recent version is available at <http://www.ifpma.org/pdfifpma/E11step4.pdf> (visited October 30, 2000) [hereinafter cited as Guidance E11]. The NIH also has issued policies related to research with children that reflect the current presumption in favor of including children. See National Institutes of Health, “NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects” (March 6, 1998) (visited Oct. 28, 2000) <http://grants.nih.gov/grants/guide/notice-files/not98–024.html> [hereinafter cited as NIH Guidelines]. The NIH Guidelines will be discussed and contrasted to the other authorities where appropriate. Overall, the NIH Guidelines favor conducting research with children and excluding them only under certain circumstances. Id. at 3–4. Specifically, the NIH Guidelines require the investigator to have a section in the research plan entitled, “Participation of Children”; the section should delineate the investigator's plan to include children, the justification for any exclusion of children, and the expertise of the investigative team in dealing with children who are the ages of the subjects. Id. at 2–3.+(visited+October+30,+2000)+[hereinafter+cited+as+Guidance+E11].+The+NIH+also+has+issued+policies+related+to+research+with+children+that+reflect+the+current+presumption+in+favor+of+including+children.+See+National+Institutes+of+Health,+“NIH+Policy+and+Guidelines+on+the+Inclusion+of+Children+as+Participants+in+Research+Involving+Human+Subjects”+(March+6,+1998)+(visited+Oct.+28,+2000)++[hereinafter+cited+as+NIH+Guidelines].+The+NIH+Guidelines+will+be+discussed+and+contrasted+to+the+other+authorities+where+appropriate.+Overall,+the+NIH+Guidelines+favor+conducting+research+with+children+and+excluding+them+only+under+certain+circumstances.+Id.+at+3–4.+Specifically,+the+NIH+Guidelines+require+the+investigator+to+have+a+section+in+the+research+plan+entitled,+“Participation+of+Children”;+the+section+should+delineate+the+investigator's+plan+to+include+children,+the+justification+for+any+exclusion+of+children,+and+the+expertise+of+the+investigative+team+in+dealing+with+children+who+are+the+ages+of+the+subjects.+Id.+at+2–3.>Google Scholar

See OIG Report, “Recruiting Human Subjects,” supra note 27, at 26–34. See also OIG Report, “A Time for Reform,” supra note 8; Weir, R.F., Peters, C., “Affirming the Decisions Adolescents Make About Life and Death,” Hastings Center Report, 27, no. 6 (1997): 29–40, at 32–37.CrossRefGoogle Scholar

Food and Drug Administration, “Pediatric Patients; Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products; Proposed Rule,” 62 Fed. Reg. 43,899–916, at 43,906, col. 3 (Aug. 15, 1997) (adopted, “Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients; Final Rule,” 63 Fed. Reg. 66,631–672 (Dec. 2, 1998)).Google Scholar

63 Fed. Reg. at 66,634–636, 66,642–648, 66,655.Google Scholar

Id. at 66,655.Google Scholar

Id. at 66,654, 66,656. This role is being fulfilled by the Pediatric Advisory Subcommittee of the Center for Drug Evaluation and Research (CDER).Google Scholar

This statement, authored by the Pediatric Ethics Working Group, is intended to reflect the consensus of the Pediatric Advisory Subcommittee. Consensus Statement, supra note 73.Google Scholar

See discussion infra Section III.B.3.Google Scholar

This section was promulgated in 48 Fed. Reg. 9,818 (March 8, 1983) and amended 56 Fed. Reg. 28,032 (June 18, 1991).Google Scholar

See 45 C.F.R. §§ 46.101, 46.103 (1999).Google Scholar

For example, private drug research may only be subject to FDA requirements. See generally Department of Health and Human Services, “Protecting Human Research Subjects: Institutional Review Board Guidebook” (1993): At 2-19-2-20 [hereinafter cited as IRB Guidebook].Google Scholar

45 C.F.R. §§ 46.404–407 (1999). See generally Ross, L.F., “Children as Research Subjects: A Proposal to Revise the Current Federal Regulations Using a Moral Framework,” Stanford Law and Policy Review, 8 (1997): 159–70, at 167–70; Glantz, supra note 1, at 229–41; Katerberg, R.J., “Institutional Review Boards, Research on Children, and Informed Consent of Parents: Walking the Tightrope Between Encouraging Vital Experimentation and Protecting Subjects' Rights” (Note), Journal of College and University Law, 24 (1998): 545–79, at 551–67.Google Scholar

According to the regulations, “minimal risk” means that “[the] probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those encountered in daily life or during the performance of routine physical or psychological examinations or tests.” 45 C.F.R. § 46.102(i) (1999). It is unclear whether this determination is supposed to be made from the perspective of the average child or the particular child-subject. See IRB Guidebook, supra note 85, at 6–20. Compare Freeman, W.L., “Research with Radiation and Healthy Children: Greater Than Minimal Risk,” IRB, 16, no. 5 (Sept.–Oct. 1994): 1–5, at 2 (giving support for subjective standard), with Gordon, B., Prentice, E., Reitemeier, P., “The Use of Normal Children as Participants in Research on Therapy” (Case Study), IRB, 18, no. 3 (1996): 5–8, at 6 (giving support for objective standard). See also discussion infra note 100 and accompanying text (pointing out difficulties with defining “minimal risk”).CrossRefGoogle Scholar

45 C.F.R. § 46.404. See also 45 C.F.R. §§ 46.401, 46.408.Google Scholar

Id. § 46.405.Google Scholar

45 C.F.R. § 46.407.Google Scholar

Id. See Glantz, supra note 13, at 1287.Google Scholar

45 C.F.R. § 46.406(d).Google Scholar

Id. § 46.406(b), (c).Google Scholar

Id. §§ 46.406, 46.407, 46.408. Specifically, two-parent consent is required unless one parent is “deceased, unknown, incompetent, or not reasonably available, or … [where there is only one custodial parent].”Google Scholar

Id. § 46.402(b).Google Scholar

Id. § 46.408. Assent can be determined case by case or by protocol. Id. There is no fixed age at which children gain the capacity to assent, but it is assumed to be close to seven or eight years old. See AAP Guidelines, supra note 31, at 7; Commission Report, supra note 33, at 13. See also Weithorn, Scherer, supra note 24, at 143–49, 152–55.Google Scholar

See generally Rosato, supra note 23, at 17–49.Google Scholar

45 C.F.R. § 46.408(a).Google Scholar

See, for example, Ross, supra note 86, at 162–63; 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. See also Woodward, supra note 9, at 1949–50; Glantz, supra note 13, at 1287.Google Scholar

See discussion supra Section III.A.Google Scholar

See Consensus Statement, supra note 73, at para. 1; Pediatric Advisory Subcommittee, “Ethics Presentation Outline” (Nov. 5, 1999) (visited Oct. 29, 2000) <http:www.fda.gov/cder/pediatric/pedethics-1199.htm>. See also Pediatric Advisory Subcommittee, “Agenda,” including case studies (Nov. 15, 1999) (visited Oct. 29, 2000) <http://www.fda.gov/cder/pediatric/agenda1199.htm> [hereinafter cited as November 15 Agenda]..+See+also+Pediatric+Advisory+Subcommittee,+“Agenda,”+including+case+studies+(Nov.+15,+1999)+(visited+Oct.+29,+2000)++[hereinafter+cited+as+November+15+Agenda].>Google Scholar

Pediatric Advisory Subcommittee, “Ethical Issues” (transcript of Nov. 15 and 16, 1999 meeting) (visited Oct. 21, 2000) <http://www.fda.gov/ohrms/dockets/ac/99/transcpt/3563t1.pdf> [hereinafter cited as Pediatric Advisory Subcommittee Meeting] These case studies focused on the inclusion of healthy children in clinical trials for taste-testing an antibiotic approved for use in adults, a pharmacokinetic (PK) study of an anticonvulsant approved for adults, and a clinical trial for the single and multidose testing of an ophthalmic that already had been approved for use in adults. November 15 Agenda, supra note 102.+[hereinafter+cited+as+Pediatric+Advisory+Subcommittee+Meeting]+These+case+studies+focused+on+the+inclusion+of+healthy+children+in+clinical+trials+for+taste-testing+an+antibiotic+approved+for+use+in+adults,+a+pharmacokinetic+(PK)+study+of+an+anticonvulsant+approved+for+adults,+and+a+clinical+trial+for+the+single+and+multidose+testing+of+an+ophthalmic+that+already+had+been+approved+for+use+in+adults.+November+15+Agenda,+supra+note+102.>Google Scholar

Consensus Statement, supra note 73, at para. 3.Google Scholar

Id. at paras. 1 and 2.Google Scholar

Id. at para 2.Google Scholar

The psychological benefit to a donor child has been considered relevant to determining whether a child should be permitted to be a donor for an ill sibling. See Robbennolt, J.K., Weisz, V., Lawson, C.M., “Advancing the Rights of Children and Adolescents to be Altruistic: Bone Marrow Donation by Minors,” Journal of Law & Health, 9 (1994–1995): 213–45, at 231–32. See also Rosato, J.L., “Using Bioethics Discourse to Determine When Parents Should Make Health Care Decisions for Their Children: Is Deference Justified?,” Temple Law Review, 73 (2000): 1–68, at 58 n.350. See also Glantz, L.H., “The Law of Human Experimentation with Children,” in Grodin, M.A., Glantz, L.H., eds., Children as Research Subjects (New York: Oxford University Press, 1994): At 106–10 (for an overview of relevant case law).Google Scholar

Consensus Statement, supra note 73, at para. 2.Google Scholar

AAP Guidelines, supra note 31, at 1 (emphasis is in the original).Google Scholar

Id. at 4–6. See also NIH Guidelines, supra note 74, at 5–6.Google Scholar

AAP Guidelines, supra note 31, at 7–9.Google Scholar

Compare id. at 2–3, 9–11, with 45 C.F.R. §§ 46.401–46.408.Google Scholar

AAP Guidelines, supra note 31, at 10 (recruitment), 11–12 (conflicts).Google Scholar

Id. at 2.Google Scholar

Id. at 3.Google Scholar

Id. at 10.Google Scholar

See generally Rothman, K.J., Michels, K.B., “The Continuing Unethical Use of Placebo Controls,” N. Engl. J. Med., 331 (1994): 394–97; Glantz, supra note 13, at 1289. Recently, the Pediatric Advisory Subcommittee spent most of a day discussing the medico-ethical issues raised by placebo-controlled trials. Pediatric Advisory Subcommittee, “Agenda” (Sept. 11, 2000) (visited Oct. 29, 2000) <http://www.fda.gov/ohrms/dockets/ac/00/agenda/3641a1.pdf>.Google Scholar

AAP Guidelines, supra note 31, at 11.Google Scholar

Id. at 6.Google Scholar

Id. “The research should be aimed at preventing or treating the medical condition for which the adolescent can legally and ethically give consent.” Id.Google Scholar

Guidance E11, supra note 74.Google Scholar

65 Fed. Reg. at 19,777, col. 1. The most recent version of the document has been submitted for adoption by the countries' regulatory bodies, including the FDA. See International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, “The ICH Process for Harmonisation of Guidelines” (visited Oct. 31, 2000) <http://www.ifpma.org/ich4.html> (describing Steps 4 and 5). (describing Steps 4 and 5).' href=https://scholar.google.com/scholar?q=65+Fed.+Reg.+at+19,777,+col.+1.+The+most+recent+version+of+the+document+has+been+submitted+for+adoption+by+the+countries'+regulatory+bodies,+including+the+FDA.+See+International+Conference+on+Harmonisation+of+Technical+Requirements+for+Registration+of+Pharmaceuticals+for+Human+Use,+“The+ICH+Process+for+Harmonisation+of+Guidelines”+(visited+Oct.+31,+2000)++(describing+Steps+4+and+5).>Google Scholar

Guidance E11, supra note 74, § 1.1.Google Scholar

See id. §§1.4, 2.6.Google Scholar

See id. § 1.4. See generally Ryan, A.E., “Protecting the Rights of Pediatric Research Subjects in the International Conference on Harmonization of Technical Requirements for Human Use” (Comment), Fordham International Law Journal, 23 (2000): 848–934, at 928–34.Google Scholar

Guidance E11, supra note 74, §§ 2.1, 2.3 (when to initiate); 2.4 (types of studies). See also Ryan, supra note 127, at 932.Google Scholar

Guidance E11, supra note 74, § 2.5. See also Ryan, supra note 127, at 930–33.Google Scholar

Guidance E11, supra note 74, §§ 2.5.1–2.5.5. See also Ryan, supra note 127, at 932.Google Scholar

Guidance E11, supra note 74, § 2.6.Google Scholar

Compare id., with discussion supra Section III.B.3 (discussion of AAP Guidelines).Google Scholar

Guidance E11, supra note 74, § 2.6.1.Google Scholar

See supra note 115 and accompanying text.Google Scholar

Guidance E11, supra note 74, § 2.6.2.Google Scholar

See supra note 116 and accompanying text.Google Scholar

Guidance E11, supra note 74, § 2.6.3.Google Scholar

A similar standard is articulated by the AAP. See AAP Guidelines, supra note 31, at 7 (waiver of assent where participation may be of such benefit that the child's welfare would be significantly jeopardized by failure to provide assent).Google Scholar

See also 45 C.F.R. § 46.408(a) (1999) (waiver permitted “[if] the IRB determines that … [the] procedure involved in the research holds out a prospect of direct benefit that is important to the health or well-being of the children” and is available only in the context of the research ….”Google Scholar

See supra notes 119–121 and accompanying text.Google Scholar

Guidance E11, supra note 74, § 2.6.3.Google Scholar

See discussion infra Section IV.A. For a discussion of additional inadequacies of Guidance E11, see Ryan, supra note 127, at 931–32.Google Scholar

See OIG Report, “A Time for Reform,” supra note 8, at iii–iv, 11–21; Department of Health and Human Services, Office of Inspector General, “Protecting Human Research Subjects: Status of Recommendations” (April 2000): 1–26, at 11–17. A bill recently has been introduced in the House of Representatives that would effect similar changes in research practices. Human Research Subject Protections Act of 2000, H.R. 4605, 106th Cong. (2d Sess. 2000). The National Bioethics Commission is also taking on these issues in an upcoming report.Google Scholar

Rosato, supra note 107, at 31.Google Scholar

See id. at 32 (discussing beneficence principle in context of medical treatment for children).Google Scholar

See id. at 32–33, 63–64 (discussing autonomy principle in context of medical treatment for children).Google Scholar

See id. at n.25 (citing articles by Professors James Dwyer, Barbara Bennett Woodhouse, and Wendy Anton Fitzgerald).Google Scholar

See generally Thompson, R.A., “Vulnerability in Research: A Developmental Perspective on Research Risk,” Child Development, 61 (1990): 1–16.Google Scholar

This recommendation was made by the AAP and the Pediatric Advisory Subcommittee. See discussion supra Section III.B.23. See also NIH Guidelines, supra note 74. The new bill to protect research subjects proposes that Subpart D be adopted by every federal agency as a matter of federal law. H.R. 4605, § 101.Google Scholar

See supra Section III.A.Google Scholar

See discussion supra Section III.B.1.Google Scholar

Id. See also Langer, supra note 26, at 16.Google Scholar

See discussion supra Section III.B.1.Google Scholar

See Holder, supra note 15, at 145–46; Weithorn, Scherer, supra note 24, at 144.Google Scholar

See discussion supra Section III.B.1.Google Scholar

See, for example, Weithorn, and Scherer, supra note 24, at 140–55. See also Leikin, S.L., “Minors' Assent or Dissent to Medical Treatment,” The Journal of Pediatrics, 102, no. 2 (1983): 169–76, at 171–74.Google Scholar

Weithorn, and Scherer, supra note 24, at 148; Leikin, S.L., “Minors' Assent, Consent, or Dissent to Medical Research,” IRB, 15, no. 2 (1993): 1–7, at 2–4, 6. See also Weir, R.F., Horton, J.R., “Genetic Research, Adolescents, and Informed Consent,” Theoretical Medicine, 16 (1995): 347–73, at 353–55 (reviewing literature).Google Scholar

See Bellotti v. Baird, 443 U.S. 622 (1979). See also Rosato, supra note 23, at 63–64 (discussing federal and state cases).Google Scholar

See In re E.G., 594 N.E.2d 322 (Ill. 1989). See also Rosato, supra note 23, at 51–67 (defining maturity in the context of refusal of life-sustaining treatment).Google Scholar

See Holder, supra note 15; Weir, and Horton, supra note 160; Leikin, supra note 160; Zinner, S.E., “The Elusive Goal of Informed Consent By Adolescents,” Theoretical Medicine, 16 (1995): 323–31.Google Scholar

See generally Rosato, supra note 23, at 17–49; Weir, and Peters, supra note 75, at 32–34.Google Scholar

See, for example, Rosato, supra note 23, at 29–32.Google Scholar

45 C.F.R. § 46.402 (1999). See also NIH Guidelines, supra note 74, at 5.Google Scholar

See, for example, English, A., “Guidelines for Adolescent Health Research: Legal Perspectives,” Journal of Adolescent Health, 17 (1995): 277–86, at 279.Google Scholar

Id. at 283.Google Scholar

See supra note 164 and accompanying text.Google Scholar

See supra note 165 and accompanying text.Google Scholar

See Santelli, J.S. et al., “Guidelines for Adolescent Health Research: A Position Paper for the Society for Adolescent Medicine,” Journal of Adolescent Health, 17 (1995): 270–76; Levine, R.J., “Adolescents as Research Subjects Without Permission of Their Parents or Guardians: Ethical Considerations,” Journal of Adolescent Health, 17 (1995): 287–97.Google Scholar

45 C.F.R. § 46.408(c) (1999).CrossRefGoogle Scholar

Compare Commission Report, supra note 33, at 17–19, with 45 C.F.R. § 46.408(c).Google Scholar

“Guidelines for Adolescent Health Research,” Journal of Adolescent Health, 17 (1995): 264–69 [hereinafter cited as Adolescent Guidelines].CrossRefGoogle Scholar

See English, supra note 167, at 277, 283. Weir, Horton, supra note 160, at 368–70; Pediatric Advisory Subcommittee Meeting, supra note 103 (testimony of Susan Kornetsky); Rogers, A.S. et al., “A Case Study in Adolescent Participation in Clinical Research: Eleven Clinical Sites, One Common Protocol, and Eleven IRBs,” IRB (Jan.–Feb. 1999).Google Scholar

Adolescent Guidelines, supra note 174, at 266.Google Scholar

Id. at 264–65.Google Scholar

See discussion supra Section II.Google Scholar

See Levine, supra note 171, at 290. See also American Academy of Pediatrics Committee on Bioethics, “Informal Consent, Parental Permission, and Assent in Pediatric Practice” (Feb. 1995): 1–7, at 4–5 (providing for mature minors to give informed consent to medical decisions).Google Scholar

See discussion supra Section IV.A.Google Scholar

Under 45 C.F.R. § 46.408(c), any waiver of parental permission must be consistent with federal and state law.Google Scholar

Adolescent Guidelines, supra note 174, at 265–66.Google Scholar

See discussion supra Section IV.Google Scholar

See generally Zinner, supra note 163. In the analogous abortion context, a parental consent requirement limits a minor's ability to decide. See Rosato, supra note 107, at 15–19, 64–65.Google Scholar

Adolescent Guidelines, supra note 174, at 266–67.Google Scholar

Id. at 267–68.Google Scholar

See, for example, Robbennolt, , Weisz, , and Lawson, supra note 107, at 243–45.Google Scholar

See Adolescent Guidelines, supra note 174, at 266–67 (explaining value of procedural protections).Google Scholar

Rogers, A.S., D'Angelo, L., Futterman, D., “Guidelines for Adolescent Participation in Research: Current Realities and Possible Resolutions,” IRB, 16, no. 4 (1994): 1–6, at 5 (allowing independent decision-making for nontherapeutic research, but only if the risk is no greater than minimal risk).CrossRefGoogle Scholar

See generally Ross, supra note 86, at 168–69 (giving significant deference to parents in this context); Oberman, M., “Minor Rights and Wrongs,” Journal of Law, Medicine and Ethics, 24 (1996): 127–38, at 135–36 (expressing particular concern with nontherapeutic research).Google Scholar

This protection is a variation of 45 C.F.R. § 46.406, but it eliminates references to the subject's disorder or condition since a reference to the subject is unnecessary.Google Scholar

This procedure is a variation on the national review process set forth in 45 C.F.R. § 46.407. See supra note 92 and accompanying text.Google Scholar

See 45 C.F.R. §§ 46.404–46.407 (1999).Google Scholar

Id. § 46.408 (1999).CrossRefGoogle Scholar

See Commission Report, supra note 33, at 17–19 (setting forth a number of examples where parents may inadequately protect children).Google Scholar

See discussion supra Section I.A.Google Scholar

Compare Langer, supra note 26, at 32 (cannot deny life-saving research to a child), with Holder, supra note 15, at 151 (should not force participation against parents' wishes).Google Scholar

See supra note 32 and accompanying text.Google Scholar

A similar approach is used in 45 C.F.R. § 46.406: “the intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social or educational situations. …”Google Scholar

See, for example, Guidance E11, supra note 74, § 2.6.3. See also Consensus Statement, supra note 73, at para. 2.Google Scholar

Compare Rosato, supra note 107, at 4–13; American Academy of Pediatrics Committee on Bioethics, “Religious Objections to Medical Care” (Feb. 1997): 1–4 (both sources discussing when denial of medical treatment constitutes abuse or neglect).Google Scholar

See supra note 37 and accompanying text.Google Scholar

See Pediatric Advisory Subcommittee Meeting, supra note 103 (considering the difficulties of applying strict rules and principles to various hypothetical scenarios).Google Scholar

See discussion supra Section III.B.3.Google Scholar

See discussion supra Section III.B.3–4.Google Scholar

Guidance E11, supra note 74, § 2.6.3; AAP Guidelines, supra note 31, at 5.Google Scholar

Guidance E11, supra note 74, § 2.6.5.Google Scholar

See Langer, supra note 26, at 7.Google Scholar

This approach seems inconsistent with the general approach to placebos recently adopted in the Declaration of Helsinki, which limits the use of placebos to situations where “no proven prophylactic, diagnostic, or therapeutic method exists.” World Medical Association Declaration of Helsinki, “Ethical Principles for Medical Research Involving Human Subjects” (October 2000): At para. 29 (visited Nov. 14, 2000) <www.wma.net/e/policy/17-c_e.html>..>Google Scholar

See discussion supra Section III.B.4.Google Scholar

A counselor-advocate for the mature minor also would be helpful for ensuring the thoughtfulness of her decision. See, for example, Adolescent Guidelines, supra note 174, at 266–67.Google Scholar

Guidance E11, supra note 74, § 2.6.1.Google Scholar

45 C.F.R. § 46.304 (1999).Google Scholar

National Bioethics Advisory Commission, “Research Involving Persons with Mental Disorders That May Affect Decisionmaking Capacity, Report and Recommendations of the National Bioethics Advisory Commission” (December 1998): 1–88, at 53–54.Google Scholar

Contra Glantz, supra note 1, at 242–44 (recommending that the FDA specifically lay out its position on a number of issues).Google Scholar