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Research with Children

Published online by Cambridge University Press:  24 February 2021

Leonard H. Glantz
Leonard H. Glantz*
Affiliation:
Boston University School of Public Health; 1970, Boston University; 1973, Boston University
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Extract

In the United States we have very mixed feelings about research with human subjects. The Nuremberg Code (the Code), which provides a foundation for the protection of human subjects, was written by American judges in the context of trying Nazi doctors who committed atrocious acts of human experimentation on concentration camp inmates. The Code provides ten common-sense guidelines controlling research. For example, a researcher may not conduct research on human subjects without that subject's informed consent, or if there is an a priori reason to believe that the research will cause death or disabling injury to the subject. What is remarkable about the creation of the Code is that it was thought to be necessary to document and impose the most fundamental moral principles on researchers. The Code demonstrates a remarkable suspicion of research with human subjects and those who perform such research.

Type
Articles
Information
American Journal of Law & Medicine , Volume 24 , Issue 2-3 , 1998 , pp. 213 - 244
Copyright
Copyright © American Society of Law, Medicine and Ethics and Boston University 1998

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References

1 See Annas, George J. & Grodin, Michael A., Introduction to THE NAZI DOCTORS AND THE NUREMBERG CODE: HUMAN RIGHTS IN HUMAN EXPERIMENTATION 5 (Annas, George J. & Grodin, Michael A. eds., 1992)Google Scholar [hereinafter THE NAZI DOCTORS].

2 See id. at 3-6.

3 See The Nuremberg Code, reprinted in THE NAZI DOCTORS, supra note 1, at 2, 2. Pertinent parts of the Nuremberg Code read as follows:

  1. 1.

    1. The voluntary consent of the human subject is absolutely essential. This means that the person involved should have the legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means of by which it is conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment.

    The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity.

  2. 2.

    2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature.

  3. 3.

    3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study that the anticipated results will justify the performance in the experiment.

  4. 4.

    4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.

  5. 5.

    5. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects.

  6. 6.

    6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.

  7. 7.

    7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death.

  8. 8.

    8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment.

  9. 9.

    9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible.

  10. 10.

    10. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of good faith, superior skill, and careful judgment required of him, that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject.

Id.

4 See id.

5 See id.

6 See generally Michael A. Grodin, Historical Origins of the Nuremberg Code, in THE NAZI DOCTORS, supra note 1, at 121, 121-22 (noting that the Code was meant to serve as a code of research ethics).

7 See generally Robert F. Drinan, Nuremberg Principles in International Law, in THE NAZI DOCTORS, supra note 1, at 174, 178 (describing the influence of the Code as the “first impetus to the worldwide movement for international human rights“).

8 See generally Grodin, supra note 6, at 121-22 (noting that the Code was written in response to acts by a medical community that was “out of control” and that scientists had “placed the lives of small children on the same level as those of rats“).

9 See, e.g., ROBERT J. LEVINE, ETHICS AND REGULATION OF CLINICAL RESEARCH 68-71 (2d ed. 1986) (describing the Tuskegee Syphilis Study, the Willowbrook Studies, the Jewish Chronic Disease Hospital Study and the San Antonio Contraceptive Study as four studies that have been subjected to ethical scrutiny).

10 See generally JAMES H. JONES, BAD BLOOD: THE TUSKEGEE SYPHILIS EXPERIMENT (1993) (recounting the Tuskegee syphilis experiments).

11 See LEVINE, supra note 9, at 70.

12 See ADVISORY COMMITTEE ON HUMAN RADIATION EXPERIMENTS, FINAL REPORT 227-668 (1995).

13 See Lederer, Susan E. & Grodin, Michael, Historical Overview: Pediatric Experimentation, in CHILDREN AS RESEARCH SUBJECTS: SCIENCE, ETHICS, AND LAW 3,19 (Grodin, Michael A. & Glantz, Leonard H. eds., 1994)Google Scholar [hereinafter CHILDREN AS RESEARCH SUBJECTS] (“The vulnerable and disadvantaged were repeatedly exploited to further the ‘medical advances’ of physicians and scientists.“)-

14 For instance, development of xenotransplantation, polio vaccines and genetic engineering techniques have all involved children. See Michael A. Grodin & Leonard H. Glantz, Preface to CHILDREN AS RESEARCH SUBJECTS, supra note 13, at vii, vii.

15 See Lederer & Grodin, supra note 13, at 7-11.

16 NATIONAL ACADEMY OF SCIENCES, EXPERIMENTS WITH HUMANS: VALUES IN CONFLICT (1975).

17 See generally Glantz, Leonard H., Conducting Research with Children: Legal and Ethical Issues, 35 J. AM. ACAD. CHILD & ADOLESCENT PSYCHIATRY 1283, 1283-84 (1996)CrossRefGoogle Scholar (discussing the mixed emotions involved with research on human subjects in general and the increased vulnerability of children).

18 See Lederer & Grodin, supra note 13, at 4-18 (tracing the history of using children as research subjects, which often amounted to child abuse).

19 Glantz, supra note 17, at 1284.

20 See Lederer & Grodin, supra note 13, at 4-18.

21 See id. at 4.

22 See id. at 4-5.

23 See id. at 5.

24 See id.

25 See id.

26 See id. at 5-6.

27 See id. at 6.

28 Id. (quoting Hess, Alfred F., The Use of a Series of Vaccines in the Prophylaxis and Treatment of an Epidemic of Pertussis, 63 JAMA 1007, 1007 (1914)CrossRefGoogle Scholar).

29 See id. at 7.

30 See id.

31 See id.

32 See id. at 9.

33 See id.

34 See id. at 11.

35 See id.

36 Id. at 12.

37 Id. at 14.

38 Letter from Francis Payton Rous, to William C. Black (July 21, 1941), quoted in Lederer & Grodin, supra note 13, at 3, 14.

39 See Bickel, Horst et al., Preliminary Communication: Influence of Phenylaline Intake on Phenylketonuria, 2 LANCET 812, 812 (1953)CrossRefGoogle Scholar.

40 See id.

41 See id.

42 See id.

43 See id.

44 See JAY KATZ, EXPERIMENTATION WITH HUMAN BEINGS 1007-10 (1972).

45 See id. at 1008.

46 See id.

47 See PRESIDENT's ADVISORY COMMITTEE ON HUMAN RADIATION EXPERIMENTS 102 (1996).

48 See KATZ, supra note 44, at 1007-10 (providing excerpts of letters from scholars debating the ethics of using mentally retarded children in medical experimentation at the Willowbrook State School).

49 See id.

50 It is important to note that adults have widely mistreated children throughout history in a variety of contexts. See P. Thomas, Mason, Child Abuse and Neglect, Part I: Historical Overview, Legal Matrix, and Social Perspectives, 50 N.C. L. REV. 293, 294-313 (1972)Google Scholar. The cruel exploitation of child labor is well documented. See, e.g., 2 CHILDREN AND YOUTH IN AMERICA: A DOCUMENTARY HISTORY 601 (Robert Bremner ed., 1971). The misuse of children as research subjects is likely one more example of the historical disregard for children's rights and welfare rather than an aberration in the treatment of children.

51 See Additional Protections for Children Involved as Subjects in Research, 45 C.F.R. § 46.401-.409 (1997).

52 T.D. v. New York State Office of Mental Health, 626 N.Y.S.2d 1015, 1016 (Sup. Ct. 1995), affd and modified 650 N.Y.S.2d 173 (App. Div. 1996), affd and modified 690 N.E.2d 1259 (N.Y. 1997).

53 See Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients, 62 Fed. Reg. 43,900, 43,900 (1997) (proposed Aug. 15, 1997).

54 See id.

55 Id. The Food and Drug Administration (FDA) listed 10 drugs widely used for children that contained no or inadequate labeling for use with children. See id. For example, in 1994 Albuterol, an inhalation solution, was prescribed 1,626,000 times for children with asthma under the age of 12; Zoloft, an antidepressant, was prescribed 248,000 times for children under the age of 16; Ritalin, a treatment for attention deficit disorders and narcolepsy, was prescribed 226,000 times for children under the age of six; and Prozac, a treatment for obsessive compulsive disorder and depression, was prescribed 349,000 times for children under the age of 16 including 3000 times for children under one. See id.

56 See id.

57 See National Institutes of Health, NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects (Mar. 6, 1998) http://www.nih.gov/grants/guide/-notice-files/not98-024.html. These guidelines are in response to the concern that medical treatments applied to children are often based on research done only in adults. See id.

58 See Glantz, supra note 17, at 1283.

59 See id. at 1284.

60 See generally Capron, Alexander M., Legal Considerations Affecting Clinical Pharmacological Studies in Children, 21 CLINICAL RES. 141, 146 (1972)Google Scholar (advocating prohibiting the use of economic rewards or incentives to parents).

61 See generally Lederer & Grodin, supra note 13, at 11-18 (citing examples of the exploitation of children in medical research in the twentieth century).

62 See Glantz, supra note 17, at 1284.

63 See Leonard H. Glantz, The Law of Human Experimentation with Children, in CHILDREN AS RESEARCH SUBJECTS, supra note 13, at 103,103-04.

64 See generally Robert E. Cooke, Vulnerable Children, in CHILDREN AS HUMAN SUBJECTS, supra note 13, at 193, 193-95, 200-07 (discussing intrinsic factors, such as a child having a terminal illness or AIDS, that lead to greater vulnerability to any child in research).

65 See. e.g., Pierce v. Society of Sisters, 268 U.S. 510, 534-35 (1925); Meyer v. Nebraska, 262 U.S. 390,402(1923).

66 See, e.g., West Va. State Bd. of Educ. v. Barnette, 319 U.S. 624, 636 (1943).

67 See Wisconsin v. Yoder, 406 U.S. 205, 234 (1972).

68 See In re Seiferth, N.E.2d 820, 823 (N.Y. 1955). But see In re Sampson, 278 N.E.2d 918, 919 (N.Y. 1972) (ordering surgery to ameliorate nonlife-threatening condition).

69 See In re Hofbauer, 393 N.E.2d 1009, 1014 (N.Y. 1979).

70 Where death would result from the absence of standard medical treatment, such as necessary blood transfusions, courts uniformly override parental refusals to authorize treatment. See. e.g., Jehovah's Witness of Wash. v. King County Hosp., 278 F. Supp. 488 (W.D. Wash. 1967), aff'd 390 U.S. 598 (1968); In re Green, 292 A.2d 387 (Pa. 1972); In re Hudson, 126 P.2d 765 (Wash. 1942).

71 See generally In re Phillip B., 156 Cal. Rptr. 48 (Ct. App. 1979) (respecting the parents’ decision not to operate on their child).

72 See, e.g., id.

73 See GEORGE J. ANNAS ET AL., INFORMED CONSENT TO HUMAN EXPERIMENTATION: THE SUBJECT's DILEMMA 80-82 (1977).

74 See Curran, William J., A Problem of Consent: Kidney Transplantation in Minors, 34 N.Y.U. L. REV. 891,892(1959)Google Scholar.

75 See ANNAS ET AL., supra note 73, at 80-81 (discussing Masden v. Harrison, No. 68651 Eq. (Mass. June 12, 1957)); see also Curran, supra note 74, at 891 (addressing the Masden case and the issue of consent in transplants involving minors).

76 See Curran, supra note 74, at 893.

77 See id.

78 See ANNAS ET AL., supra note 73, at 81.

79 Id.; Curran, supra note 74, at 894-95.

80 See Curran, supra note 74, at 893 (discussing Foster v. Harrison, No. 68674 Eq. (Mass. Nov. 20, 1957); Huskey v. Harrison, No. 68666 Eq. (Mass. Aug. 30, 1957)).

81 See ANNAS ET AL., supra note 73, at 81.

82 See id.

83 See, e.g., Curran, supra note 74, at 894 (noting that in deciding whether to authorize a medical procedure, courts questioned each donor twin to determine whether the twin understood the nature and consequences of the operation and fully and freely consented to it).

84 445 S.W.2d 145 (Ky. 1969).

85 See id. at 149.

86 See id. at 146.

87 See id. at 147-48.

88 See id. at 147.

89 See id. at 149-50.

90 Id. at 151.

91 289 A.2d 386 (Conn. Super. Ct. 1972).

92 See id. at 387-91.

93 See id. at 389.

94 Id. at 390.

95 See id. at 391.

96 See id. at 390.

97 See id. 389-90. In this case, the court ascertained the parents’ motivation in consenting to the medical procedure based on views solicited from the family's clergyman, the defendant physicians and the guardians ad litem for both the donor and donee. See id.

98 See id. at 390.

99 284 So. 2d 185 (La. Ct. App. 1973).

100 See id. at 186-87.

101 See id. at 187.

102 See id.

103 See id.

104 Id. at 187.

105 226 N.W.2d 180 (Wis. 1975).

106 See id. at 181.

107 See id.

108 See id.

109 See id. at 182.

110 Id. at 181.

111 See, e.g., id. at 182; In re Richardson, 284 So. 2d 185, 187 (La. Ct. App. 1993).

112 The consent of the parent or guardian is required in these cases even though such consent alone does not appear sufficient to authorize the nonbeneficial invasion of the child's or ward's body.

113 See, e.g., Hart v. Brown, 289 A.2d 386, 390 (Conn. Super. Ct. 1972); Strunk v. Strunk, 144 S.W.2d 145, 149 (Ky. 1969).

114 See, e.g., Hart, 289 A.2d at 390; Strunk, 144 S.W.2d at 146.

115 See In re Richardson, 284 So. 2d at 187; In re Guardianship of Pescinski, 226 N.W.2d 180, 181 (Wis. 1975).

116 See, e.g.. Hart, 289 A.2d at 387.

117 It is not unusual for families to make choices that seem to put one child more at risk than another or that benefits one child more than another. For example, parents might have enough resources to send both of their children to the local community college or one to an Ivy League university. The family is certainly empowered to choose to send one of the children to the university although the other child would suffer detriment. Similarly, the family in the transplant situation could decide not to have the healthy child act as a donor out of concern that both children could end up impaired or even dead. This means the parents could refuse a relatively safe procedure on the healthy child even though that would lead to the death of the sick, but curable, child. Undoubtedly, courts would uphold such a parental decision. See, e.g., Curran v. Bosze, 566 N.E.2d 1319, 1332-39, 1345 (111. 1990) (describing risks and benefits of bone marrow transplant for the possible donors—three-and-a-half-year-old healthy twins—and the possible recipient, their halfbrother who had a 99% chance of death without a transplant and a 30% to 40% chance of fatal graftversus- host disease with the transplant; ultimately sustaining the twins’ custodial parent's refusal to consent); see also Korins, Janet B., Bosze, Curran v.; Toward a Clear Standard for Authorizing Kidney and Bone Marrow Transplants Between Minor Siblings, 16 VT. L. REV. 499, 500, 522-27 (1992)Google Scholar (identifying deficiencies in the Curran court's analysis and advocating a hybrid standard that synthesizes the principles of deference to parental consent and donor consent).

118 Compare In re Pescinski, 226 N.W.2d at 180 (finding that an incompetent not living at home was not permitted to donate a kidney), with Strunk, 144 S.W.2d at 146 (finding that an incompetent not living at home was permitted to donate a kidney by a 4 to 3 split court).

119 See, e.g., Strunk, 144 S.W.2d at 151.

120 See supra notes 84-98 and accompanying text.

121 576 S.W.2d 493 (Tex. App. 1979).

122 See id. at 500.

123 Id.

124 See ANGELA RODDEY HOLDER, LEGAL ISSUES IN PEDIATRICS AND ADOLESCENT MEDICINE

125 (2d ed. rev. 1985).

125 See id.

126 See id.

127 See id. at 127.

128 See id. at 125.

129 See id.

130 See id. at 133.

131 See id.

132 See English, Abigail, Guidelines for Adolescent Health Research: Legal Perspectives, 17 J. ADOLESCENT HEALTH 227, 282-83 (1995)CrossRefGoogle Scholar.

133 See, e.g., MASS. GEN. LAWS ch. 112, § 12F (1996).

134 See Carter v. Cangello, 164 Cal. Rptr. 361, 362 (Ct. App. 1980).

135 The mature minor rule has been incorporated into both the First and Second Restatement of Torts. See RESTATEMENT (SECOND) OF TORTS § 892A (1979); RESTATEMENT (FIRST) OF TORTS § 59(1) (1934). “To be effective, the consent must be given by one who has the capacity to give i t … . If the person consenting is a child … [the] consent may still be effective if he is capable of appreciating the nature, extent and probable consequences of the conduct consented to ….” RESTATEMENT (SECOND) OF TORTS § 892A cmt. b.

136 See Bakker v. Welsh, 108 N.W. 94, 96 (Mich. 1906).

137 See Cardwell v. Bechtol, 724 S.W.2d 739, 745-48 (Tenn. 1987).

138 See id. at 744.

139 See id. at 749.

140 See id.

141 See id.

142 443 U.S. 622(1979).

143 See id. at 642-44.

144 See id. at 650. The Court also ruled that a state may establish a procedure, such as a judicial proceeding in which the minor's maturity may be established. See id. at 643-44. But once a judge determines that the minor is able to understand the nature and consequences of the abortion decision, that decision is hers alone to make. See id. at 650. At that point, she has all the rights of an adult woman in regard to abortion. See id. at 642-43.

145 See Lois A. Weithorn & David G. Scherer, Children's Involvement in Research Participation Decisions: Psychological Considerations, in CHILDREN AS RESEARCH SUBJECTS, supra note 13, at 133, 154.

146 Id. at 152. Fourteen is also the age that the Tennessee Supreme Court adopted under the “Rule of Sevens” as the point at which minors are presumed to be able to give their consent to medical care. See Cardwell, 724 S.W.2d at 745.

147 See HOLDER, supra note 124, at 134; Wadlington, Walter, Minors and Health Care: The Age of Consent, 11 OSGOODE HALL L.J. 115, 119(1973)Google Scholar.

148 See Wadlington, supra note 147, at 124.

149 See generally id. (stating that jurisdictions, which have dropped all age restrictions for consent to medical care related to drug use or early sexual activity, are motivated by fear that minors will forgo care if forced to consult with parents in these situations).

150 See, e.g., Younts v. St. Francis Hosp., 469 P.2d 330, 332 (Kan. 1970); Bakker v. Welsh, 108 N.W. 94, 95 (Mich. 1906); Cardwell, 724 S.W.2d at 741-42.

151 443 U.S 622, 642 (1979).

152 The doctor-patient relationship is quite different from the researcher-subject relationship. In the doctor-patient relationship, the doctor's only goal is improving the welfare of her patient. See Katz, Jay, Human Experimentation and Human Rights, 38 ST. LOUIS U. L.J. 7, 7 (1993)Google Scholar. In the researcher-subject relationship, the researcher's goal may be primarily, or solely, the creation of new knowledge. See id. In the researcher-patient relationship, the subject is a means to an end. See id.

153 126 F.2d 121 (D.C. Cir. 1941).

154 See id. at 123.

155 See id. at 121.

156 See id.

157 See id. at 122, 123.

158 See id. at 121.

159 See id. at 122. In fact, this finding is an example of one of the earlier applications of the mature minor doctrine.

160 See id. at 122.

161 See id. at 123.

162 See id. at 122-23.

163 Id. at 122 (emphasis added).

164 Id.

165 See id.

166 See id. at 123.

167 See id.

168 See id.

169 See id.

170 549 N.E.2d 322 (111. App. Ct. 1989).

171 See id. at 323.

172 See id.

173 See id. at 325.

174 See id. at 324.

175 See id. at 328.

176 See id. at 325-27.

177 See id. at 328.

178 Id.

179 See generally In re Sampson, 317 N.Y.S.2d 641, 651 (Fam. Ct. 1970) (noting that “courts have unequivocally upheld the power of the state to authorize the administration of a blood transfusion over the religious objections of the parent where the blood transfusion was shown to be necessary for the preservation of the minor's life or the success of needed surgery“), aff'd, 278 N.E.2d 918 (N.Y. 1972).

180 See In re E.G., 549 N.E.2d at 328. 181 It should also be noted that the court's ruling gives decisional authority to the family member who desires the life-saving treatment to be administered. In a sense, the court gives consent authority to the party agreeing to “beneficial” treatment. See id.

182 See supra notes 73-98 and accompanying text.

183 See ANNAS ET AL., supra note 73, at 80-81.

184 See Hart v. Brown, 289 A.2d 386, 389 (Conn. Super. Ct. 1972).

185 See, e.g., ANNAS ET AL., supra note 73, at 87.

186 See, e.g., id. at 86-87.

187 See, e.g., id.

188 45 C.F.R. §§ 46.101-.124 (1997).

189 See id. § 46.101(a)(2).

190 See id. §46.107.

191 See id. §46.111.

192 See id. §46.116.

193 See id. §§ 46.117-.120.

194 See id. §§ 46.401-.409. It should be noted that the final children's regulations that were adopted in 1981 are considerably less stringent than the regulations as they were originally proposed. For example, the original proposed regulations required review by a “Protection Committee,” in addition to review by an institutional review board (IRB), which was to monitor the subject's continued willingness to participate in the research, the selection of subjects, the reasonableness of the parents consent and some other matters. See Protection of Human Subjects; Policies and Procedures, 38 Fed. Reg. 31,738 (1973). There were several other safeguards that do not appear in the current regulations. See id.

195 See, e.g., 45 C.F.R. § 46.408.

196 Id. § 46.402(a). This is unlike the National Institutes of Health (NIH) policy described above that defines children as people under 21 years of age. See National Institutes of Health, supra note 57.

197 See, e.g., MASS. GEN. LAWS ch. 112, § 12F (1996).

198 See 45 C.F.R. § 46.402(a).

199 For example, he would have to give informed consent pursuant to 45 C.F.R. § 46.116. If he were incapable of doing so, he could not be included in the research without the consent of a “legally authorized representative,” a parent in a child's case. See id. § 46.116.

200 See id. § 46.402.

201 See, e.g., MASS. GEN. LAWS ch. 112, § 12F (1996).

202 See supra notes 133-52 and accompanying text.

203 See 45 C.F.R. § 46.404.

204 “Assent” is defined as the “child's affirmative agreement to participate in research. Mere failure to object should not, absent affirmative agreement, be construed as assent.” Id. § 46.402(b). It should be noted that under the children's regulations, no one gives consent. Rather the child assents and the parent gives permission. See id. § 46.402(c).

205 See id. § 46.404.

206 See id. § 46.405.

207 See id.

208 See id. For example, testing a new drug for which there is evidence of safety and effectiveness for the treatment of a currently incurable childhood illness would fall under this section.

209 The assent of the child is not required for some research conducted under this section. If the child is incapable of giving assent because of her young age, for example, research in this category can still be done. See id. § 46.408(a). Even if the child is capable of giving assent, if the research holds out a “prospect of direct benefit that is important to the health or well-being of the [child] and is only available in the context of the research,” the assent of the child is not required. Id.

210 See id. § 46.405(a).

211 See id. § 46.406.

212 See id. § 46.406(a).

213 See id. § 46.406(b).

214 See id. § 46.406(c).

215 See id.

216 See id.

217 See infra notes 224-306 and accompanying text.

218 See 45 C.F.R. § 46.407.

219 See id.

220 See Glantz, supra note 17, at 1287.

221 See Katz, supra note 152, at 13-14.

222 See Glantz, supra note 17, at 1288.

223 See 45 C.F.R. § 46.406(a).

224 Id. § 46.102(i).

225 See id. § 46.101(a).

226 As one group of commentators notes, the risks to children living in Belfast and Edinburgh are quite different. See Benjamin Freedman et al., In Loco Parentis: Minimal Risks as an Ethical Threshold for Research upon Children, HASTINGS CENTER REP., Mar-Apr. 1993, at 13, 17-18. As such, the commentators opine that the “minimal risk” definition may permit a Western researcher who is frustrated by restrictions on his research to “shop” for “a community whose children are sufficiently destitute or underprotected that even exposure to heinous risks fall with in the daily expected routine” and justify such a selection as “accommodating cultural differences.” See id. at 18.

227 See, e.g., Ash, Peter et al., Gun Acquisition and Use by Juvenile Offenders, 275 JAMA 1754, 1754 (1996)CrossRefGoogle Scholar. Moreover, the victims of firearm-related homicides are much more likely to be African American adolescent males than any other group. See id.

228 See Glantz, supra note 17, at 1287.

229 See id. at 1287-88.

230 See id.

231 See Freedman et al., supra note 226, at 13.

232 See id. at 15.

233 See id. at 18.

234 See id. at 15.

235 45 C.F.R. § 46.406 (1997).

236 See Freedman et al., supra note 226, at 15.

237 See id. at 15-16.

238 See id. at 17-18.

239 See id.

240 See id.

241 See 45 C.F.R. § 46.406(c) (1997).

242 Id. § 46.406(d).

243 See id. § 46.408(b).

244 Id. § 46.408(a).

245 For discussion on the role of dual consent, see Part V.

246 See 45 C.F.R. § 46.406(b). Although the regulations themselves seem to provide no barrier to parents permitting their young children to be subjected to nonbeneficial research, the regulations explicitly note that they do “not affect any state or local laws or regulations which may otherwise be applicable and which provide additional protection for human subjects.” Id. § 46.101(f). IRBs are required to be composed in such a manner that they are able to ascertain the “acceptability” of proposed research in terms of “applicable law.” See id. § 46.107(a). Thus, if state law or regulation imposes legal restrictions on parental authority to consent to nonbeneficial research, these restrictions would be applicable to even federally funded research and the IRB is obligated to determine and enforce these state restrictions. See id. §§ 41.101(f), 46.107(a).

247 See RAMSEY, PAUL, THE PATIENT AS PERSON: EXPLORATIONS IN MEDICAL ETHICS 13 (1970)Google Scholar.

248 See id.

249 See The Nuremberg Code, supra note 3, at 2.

250 See Leonard H. Glantz, The Influence of the Nuremberg Code on U.S. Statutes and Regulations, in THE NAZI DOCTORS, supra note 1, at 183, 185. The subsequently promulgated “Declaration of Helsinki” of the World Medical Association explicitly permits surrogate consent for research that could benefit individual subjects. See World Med. Ass'n, Declaration of Helsinki IV, reprinted in THE NAZI DOCTORS, supra note 1, at 339, 341-42 (as amended by the 41st World Medical Assembly, Hong Kong, Sept. 1989). But in the category of “non-therapeutic” research, the Declaration merely says, “The subjects should be volunteers.” See id. at 339 (Helsinki Declaration § III.2). This would appear to preclude surrogate consent.

251 RAMSEY, supra note 247, at 11-12.

252 See id. at 13.

253 See id.

254 As Paul Ramsey puts it: To attempt to consent for a child to be made an experimental subject is to treat the child not as a child. It is to treat him as if he were an adult person who has consented to become a joint adventurer in the common cause of medical research. If the grounds for this are alleged to be the presumptive or implied consent of the child, this must simply be characterized as a violent and false presumption. Non-therapeutic, non-diagnostic experimentation involving human subjects must be based on true consent if it is to proceed as a human enterprise. No child or adult incompetent can choose to become a participant of medical undertakings, and no one else on earth should decide to subject these people to investigations having no relation to their own treatment. That is a canon of loyalty to them. This they claim of us simply by being a human child or incompetent. When he is grown, the child may put away childish things and become a true volunteer. This is the meaning of being a volunteer: that a man enter and establish a consensual relation in some joint venture for medical progress—where before he could not, nor could anyone else “volunteer” him for submission to unknown possible hazards for the sake of good to come. Id. at 14. 255 See supra note 99 and accompanying text.

256 See McCormick, Richard A., Proxy Consent in the Experimentation Situation, 18 PERSP. BIOLOGY & MED. 2, 11-14 (1974)CrossRefGoogle Scholar, reprinted in ROBERT H. MNOOK1N & D. KELLY WEISBERG, CHILD, FAMILY AND STATE 667,668 (3d ed. 1995).

257 Id. at 669. Ramsey responded to Richard McCormick, arguing that children are not moral agents and therefore saying what they “ought” to do is a fiction. See Paul Ramsey, A Reply to Richard McCormick: The Enforcement of Morals: Nontherapeutic Research on Children. HASTINGS CENTER REP., Aug. 1976, at 21, 24-25, reprinted in MNOOKIN & WEISBERG, supra note 256, at 670, 670. Further, Ramsey notes that adults often do not act in ways they ought to act, and that we do not require adults to act in ways we deem are desirable. See id.

258 See McCormick, supra note 256, at 669.

259 Id.

260 Id.

261 See id.

262 See id.

263 650 N.Y.S.2d 173 (App. Div. 1995).

264 See id. at 177.

265 Id. at 192. This view is almost identical to that adopted by the Medical Research Council in Britain. In regard to nontherapeutic research, the Council concluded:

Parents or guardians cannot in law consent to any treatment or procedure that is against the interests of the child…. [T]here is a respectable body of legal opinion which takes the view that there is no obstacle to the consent by a parent to a procedure which carries no greater risk for the child than the risks that reasonable parents commonly expose their children to in everyday life. This, we think, the same idea sometimes expressed by saying that non-therapeutic research involving children must not involve greater than “minimal” or “negligible risk.“

MEDICAL RESEARCH COUNCIL, THE ETHICAL CONDUCT OF RESEARCH ON CHILDREN 17 (1991). Examples of such minimal risk procedures are “observation of behavior, noninvasive physiological monitoring. Developmental assessments and physical examinations, changes in diet and obtaining blood and urine specimens.” See id. at 15.

266 See T.D., 650 N.Y.S.2d at 192.

267 It would appear that the appellate court's opinion has little if any precedential value in New York. The plaintiffs in the case brought this action to challenge regulations promulgated by the New York State Department of Mental Health, which pertained to research on its patients who were incapable of consenting. See id. at 175. The plaintiffs challenged those regulations on a number of grounds, including the argument that the office did not have statutory authority to promulgate the regulations. See id. at 178. The plaintiffs prevailed on this narrow ground in the trial court and in the appellate division. See id. The New York Court of Appeals affirmed this narrow ruling, and found that once the appellate division invalidated the regulation, it was unnecessary for it to rule on the other issues. See T.D. v. New York State Office of Mental Health, 690 N.E.2d 1259, 1259 (N.Y. 1997). Thus, the court said, the appellate division “issued an inappropriate advisory opinion” on these other matters. See id.

268 Stephan Haimowitz et al., Uninformed Decisionmaking: The Case of Surrogate Research Consent, HASTINGS CENTER REP., Nov .-Dec. 1997, at 9.

269 Id. at 11.

270 See Katz, supra note 152, at 7.

271 Haimowitz et al., supra note 268, at 11.

272 See id.

273 See id.

274 See discussion in supra note 152.

275 The authors noted that, although the decision to perform a lumbar puncture solely for research purposes is not made “casually,” the “procedure is performed daily in hospitals across the country and results in headaches lasting twenty-four hours in about 10 percent of cases.” See Haimowitz et al., supra note 268, at 11.

276 See Pine, Daniel S. et al., Neuroendocrine Response to Fenfluramine Challenge in Boys: Association with Aggressive Behavior and Adverse Rearing, 54 ARCHIVES GEN. PSYCHIATRY 839, 840(1997)CrossRefGoogle Scholar.

277 See id.

278 See id.

279 See id. at 839.

280 See id. at 840.

281 See id.

282 See id.

283 See id.

284 Id. at 841. The authors concluded that the study found “a positive correlation between aggression ratings and the prolactin response to the fenfluramine challenge.” See id. at 843. It also found a “correlation between the prolactin response to fenfluramine and maladaptive parent-child interaction patterns that are implicated in aggression” as calculated on the HOME subscales. Id. at 843. The study, however, did not compare these boys with a demographically similar group of boys without a family history of delinquency, did not perform a placebo challenge and measured the two “dynamic constructs“—the home environment and serotonergic activity—at a single time point. See id. at 844.

285 See id. at 839, 841.

286 See id. at 841.

287 See id. at 840.

288 See Freedman et al., supra note 226, at 18.

289 The most common adverse reactions from fenfluramine are drowsiness, diarrhea and dry mouth. See PHYSICIAN's DESK REFERENCE 2421 (52d ed. 1998). Less common reactions are dizziness, confusion, headache, mood changes, anxiety and some other symptoms. See id. Fenfluramine is related to amphetamines, though it differs somewhat chemically, and abuse of the drug has been associated with reports of euphoria and perceptual changes. See id. at 2420. Although these effects occurred in doses considerably higher than those administered to the children in this study, the drug has not been evaluated for use in children and knowledge of its effects on children are therefore unknown. See id. at 2421. Furthermore, when fenfluramine was administered in adults, needles were not inserted into the research subjects’ veins and left in for hours.

290 See supra note 251 and accompanying text.

291 See supra note 257 and accompanying text. In light of the adverse reactions to fenfluramine and the medical procedures used in the Pine study, “discernible” risks and discomforts exist. See Pine et al., supra note 276.

292 The authors noted that 36 of 54 eligible subjects agreed to participate, which would indicate that the assent of the children was obtained. See Pine et al., supra note 276, at 840. The study, however, fails to report any of the boys withdrawing their assent during the study. See id. This seems surprising given the conditions from which the boys were diagnosed to have suffered.

293 See 45 C.F.R. § 46.406(c) (1997).

294 Compare Pine et al., supra note 276, at 840 (discussing the research subjects’ conditions), with 45 C.F.R. § 46.406(c) (defining the requirements for research on children).

295 See Pine et al., supra note 276, at 840.

296 This is not to say that the study could not add to the body of knowledge in the area of the relationship of serotonin to aggression, although even the authors discuss the study's significant limitations. See id. at 844. But it would be a huge stretch to relate this study's goals with the requirements of the federal regulations.

297 It is not clear why parents agreed to participate in this protocol because it would cause them substantial inconvenience and subject their children to some risk. There is no mention of payment to the parents in the report of the study. See id. at 840.

298 Freedman et al., supra note 226, at 18.

299 See id.

300 See id.

301 Halperin, Jeffery M. et al., Serotonin: Aggression and Parental Psychopathology in Children with Attention-Deficit Hyperactivity Disorder, 36 J. AM. ACAD. CHILD & ADOLESCENT PSYCHIATRY 1391, 1393 (1997)CrossRefGoogle Scholar.

302 See id.

303 See id.

304 Cf. Katz, supra note 152, at 43-45 (discussing the ramifications of a study removing adults from medication to record the effects of withdrawal).

305 See Halperin et al., supra note 301, at 1393.

306 Cf. Katz, supra note 152, at 43-45 (discussing the difference between drug withdrawals in adult subjects in the research context as compared with the medical context).

307 Additional Protections for Children Involved as Subjects in Research, 48 Fed. Reg. 9814 (1983) (codified at 45 C.F.R. pt. 46).

308 See 45 C.F.R. §§ 46.201-.2U (1997).

309 See id. §§ 46.301-.306.

310 Regulations protecting fetuses as research subjects were adopted in 1975. See id. § 46.201. Those protecting prisoners as research subjects were adopted in 1978. See id. § 46.301.

311 See id. § 46.206(a)(1).

312 See id. §§ 46.401-.409.

313 See id. § 43.306.

314 See id. § 46.304(b).

315 See id. §§ 46.401-.409.

316 See Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients, 62 Fed. Reg. 43,900, 43,900 (1997) (proposed Aug. 15, 1997) [hereinafter New Drugs and Pediatric Patients].

317 See National Institutes of Health, supra note 57.

318 See New Drugs and Pediatric Patients, 62 Fed. Reg. at 43,900-02, 43,910.

319 See id. at 43,903.

320 National Institutes of Health, supra note 57.

321 Compare45 C.F.R. §§ 46.116, 46.305-306, 46.206-211 (requiring consent to be given before people may become participants in a research study), with National Institutes of Health, supra note 57 (requiring children to be included as research subjects in projects supported by the NIH).

322 See National Institutes of Health, supra note 57.

323 See id.

324 Id.

325 See id. (summarizing the children's regulations in a table); Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients, 62 Fed. Reg. 43,900, 43,906 (1997). Unlike the NIH, the FDA dedicates only one paragraph in its proposed regulations to the “Ethical Issues.” See id. at 43,906. It simply notes that there are special regulations for the protection of children and that the American Academy of Pediatrics (AAP) adopted guidelines for the ethical conduct of clinical studies in pediatric patients. See id. However, the FDA expressly sought comments on the ethical issues that may be raised by its proposal. See id. at 43,907.

326 See supra notes 58, 112, 187-93 and accompanying text.

327 See Committee on Drugs, American Academy of Pediatrics, Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations, 95 PEDIATRICS 286, 294 (1995)Google Scholar. Generally, placebos may be ethically employed in drug research involving children when four conditions are met: first, there is no commonly accepted therapy; second, if there is a commonly accepted therapy, it is of questionable efficacy, carries a high frequency of undesirable side-effects, or generates greater risks than benefits; third, the placebo is used to identify incidence and severity of undesirable side-effects by adding a new treatment to establish regimen; and fourth, the disease process is characterized by frequent, spontaneous exacerbations and remissions. See id. The Guidelines assumed that placebos could be used in pediatric studies if their use “does not place children at increased risk,” and these guidelines are designed to set forth such circumstances. See id. The Guidelines, however, do not permit the removal of children from commonly accepted therapies for the purpose of research. See id. If this is the case, how can the use of “washout” periods be acceptable in research not designed to directly benefit the child-subjects?

328 This is different from reimbursing parents for expenses associated with their child's participation in research, such as transportation, time off from work and meals. Furthermore, the reimbursement should be based on actual expenses incurred by the parent. The AAP recommends that payments to parents should only be made for direct or indirect costs incurred as a result of the study, and must not become an inducement for participation. See id. at 293.

329 See 45 C.F.R. § 46.408 (1997).

330 See Robert E. Cooke, Vulnerable Children, in CHILDREN AS RESEARCH SUBJECTS, supra note 13, at 193, 194-95.

331 See id. at 200-01. The institutionalized mentally infirm child represents the most studied class of subjects. See id. at 200.

332 See id. at 195.