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Children in Medical ResearchAccess versus Protection$

Lainie Friedman Ross

Print publication date: 2006

Print ISBN-13: 9780199273287

Published to Oxford Scholarship Online: May 2006

DOI: 10.1093/0199273286.001.0001

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From 1966 to 2005: Balancing Protection and Access in Pediatric Research

From 1966 to 2005: Balancing Protection and Access in Pediatric Research

Chapter:
(p.12) 1 From 1966 to 2005: Balancing Protection and Access in Pediatric Research
Source:
Children in Medical Research
Author(s):

Lainie Friedman Ross (Contributor Webpage)

Publisher:
Oxford University Press
DOI:10.1093/0199273286.003.0002

Abstract and Keywords

This chapter examines the changes in policies regarding children in research between 1966 and 2003. It reviews Henry Beecher’s famous article, Ethics and Clinical Research, which described 22 projects published after World War II that he found to be of questionable ethics; Paul Ramsey’s examination of the ethical problems in medicine; debates over the moral permissibility of children’s participation in nontherapeutic research; the government’s policy shift from an exclusive focus on protecting children from research risks to promoting greater access by children in research during the early 1990s; and international research ethics. It is shown that new policies have encouraged pediatric pharmacological testing and have led to some improved pediatric labeling.

Keywords:   pediatric research, medical research, children, nontherapeutic research, medical ethics

1. Introduction

The modern history of the ethics of human experimentation in the United States begins in 1966 with the publication of Henry Beecher's famous article, ‘Ethics and Clinical Research’.[1] One could argue that I should begin two decades earlier with the Nuremberg trials and the Nuremberg Principles of Research Ethics,[2] but as David Rothman, a medical historian notes, ‘Neither the horrors described at the Nuremberg trial nor the ethical principles that emerged from it had a significant impact on the American research establishment,’ because they did not seem ‘directly relevant to the American scene.’[3]

Prior to 1966, children were frequently subjects in research because they were convenient: researchers would often experiment on their children, servants, or slaves.[4] Children could also be recruited from institutions. Alfred Hess, the medical director of the Hebrew Infant Asylum in New York City, explained the scientific advantage of enrolling institutionalized children: it permitted ‘conditions which are insisted on in considering the course of experimental infection among laboratory animals, but which can rarely be controlled in a study of infection in man.’[5] Children were also ‘cheap’ in the sense that they were non‐valued or viewed as expendable commodities. One researcher explicitly stated that he used child subjects because they were ‘cheaper than calves’.[6] Lederer and Grodin describe the role of children in medical research in the century prior to 1966 as largely one of child abuse.[7]

The concerns expressed by Beecher and others led to the introduction of research regulations in the 1970s. Because of the special vulnerability of children, additional regulations were developed to protect them. These regulations effectively served to restrict participation of children in research. Beginning in the 1990s, however, there has been a movement to include children on the grounds that their exclusion has made them ‘therapeutic orphans’.[8] This chapter will examine the changes in policies regarding children in research between 1966 and 2003.

(p.13) 2. Beecher Revisited

In ‘Ethics and Clinical Research’, Beecher described twenty‐two research projects published post‐World War II that he found to be of questionable ethics.[9] Beecher noted that these studies were not unique but were chosen to illustrate the wide range of unethical practices (e.g., withholding effective treatment, knowingly exposing subjects to drugs that could be expected to cause serious side‐effects, and lack of informed consent). Although Beecher described the studies in enough detail to convince the reader of the ethical problems, he intentionally did not name the researchers, their institutions, or the journals in which these articles were published. Others, however, did.[10]

Of the twenty‐two research studies, four involved child subjects. The best known of these is the Willowbrook study, a study that involved institutionalized mentally retarded children at the Willowbrook State School in Staten Island, New York.[11] The study cited by Beecher is one of many studies on hepatitis conducted by Krugman and Ward and colleagues in the 1950s and 1960s at Willowbrook, where they served as consultants in infectious diseases.[12] They were interested in understanding the natural history of hepatitis in order to develop a vaccine. The specific objectives of the study cited by Beecher were (1) to detect viremia during the incubation period, the early icteric phase, and clinically inapparent infection; and (2) to determine the period of infectivity in both stool and blood. To do this, the researchers admitted new residents to the isolation unit where they were given doses of hepatitis derived from other Willowbrook residents either by intramuscular injection or by oral intake. The research confirmed the presence of the virus in infected children two to three weeks before the onset of jaundice and demonstrated viremia in children with subclinical infections, two discoveries that have important implications for the spread of the virus.[13]

Beecher argued that the research design was not consistent with the World Medical Association's (WMA) code of ethics, a code that does not permit ‘weaken[ing] the physical or mental resistance of a human being except from strictly therapeutic or prophylactic indications imposed in the interest of the patient’.[14] Beecher did not question the scientific importance of the research but argued against its methodology. He argued that there was no right to risk an injury to one person for the benefit of others.[15] This, I might add, is particularly true of vulnerable individuals who cannot consent to be used in this way.

Despite widespread criticism, Krugman maintained the studies were ethical. In various publications, he attempted to justify infecting the children deliberately on the grounds that most newly admitted children became infected at Willowbrook in the first six to 12 months of institutionalization.[16] In response to criticism that the research took advantage of the overcrowded and therefore unsanitary conditions of the institution, (p.14) Krugman responded that ‘We were not qualified to deal with the societal problems, but we believed that we could help control the existing medical problem of hepatitis.’[17]

Krugman argued further that he designed the study so as to minimize risk. For example, he only enrolled children between the ages of three and ten years in whom hepatitis was known to be especially mild; and the children were only infected with strains of hepatitis from other residents at Willowbrook, strains that were known to be mild.[18] Beecher rejected these arguments, pointing out that Stokes and Neefe had demonstrated in 1945 the utility of gamma globulin in reducing or ameliorating infectious hepatitis,[19] and questioned why it was not given to all of Krugman's subjects. Of note, Krugman was well aware of gamma globulin and had used it in an earlier hepatitis study.[20]

Beecher questioned the informational content provided to the parents in the informed consent process. Although Krugman repeatedly stated that parental permission was obtained, Beecher noted that ‘nothing is said regarding what was told them [the parents] concerning the appreciable hazards involved’.[21] Specifically, Beecher was concerned as to whether parents were told that some children might develop potentially fatal cirrhosis. Although Joan Giles, a pediatrician who worked at Willowbrook throughout the experiments, claimed that she gave as full an explanation as she could, the information she is quoted as providing did not include the potentially serious risks.[22]

Beecher also questioned whether the parents were able to give voluntary consent. In 1954, parents were informed by letter that admission to Willowbrook was closed due to overcrowding. Shortly thereafter, parents received a second letter, advising them that there were vacancies in the hepatitis unit and that, if they would volunteer their children for that study, the children could be admitted.[23] According to Jack Hammond, the administrator of Willowbrook, this was not meant to be manipulative: ‘Where do you find new admissions except by canvassing the people who have applied for admission?’[24] Nevertheless, public and professional criticism led to the cessation of this manner of recruitment.

A second study cited by Beecher that enrolled some pediatric subjects involved Triacetyloleandomycin (TriA), an antibiotic used to treat acne. Recent research had found that the drug caused more hepatic toxicity than originally thought. Ticktin and Zimmerman undertook their study to determine the incidence and type of hepatic dysfunction.[25] They enrolled fifty subjects, aged 13 to 39 years, who were residents of Laurel Children's Center (an institution for children who were ‘mental defectives or juvenile delinquents’) for two months or longer. The subjects were healthy except for acne, and were treated with TriA for three to four weeks. Blood tests were (p.15) performed on enrollment, at two weeks, at completion of treatment, and at various intervals after the drug was discontinued. Two weeks after the beginning of TriA administration, over half of the patients had evidence of liver abnormalities that worsened with further treatment and resolved within weeks of discontinuing the treatment. Liver biopsies were performed on eight subjects who showed marked liver abnormalities (six of whom had symptoms). Four of the eight patients were given a ‘challenge’ dose of TriA and were subjected to repeat liver biopsy. Three of the four again developed liver dysfunction. Liver function returned to normal in all three within one week.

The study raises a number of ethical issues similar to the Willowbrook study, in that it enrolled institutionalized individuals, particularly children and those with mental retardation. Enrolling institutionalized children for acne studies may be even more troublesome than the hepatitis research because the knowledge generated from the hepatitis studies would be of particular relevance to institutionalized children whereas the acne studies would not. Fortunately there was no long‐term damage, but as Beecher pointed out, ‘[a]n experiment is ethical or not at its inception, it does not become ethical post hoc—ends do not justify means.’[26]

A third study in Beecher's article involved eighteen children aged 3.5 months to 18 years of age who were to undergo surgery for congenital heart disease.[27] Eleven of the eighteen children would undergo an unnecessary thymectomy as part of the operation; the other seven would serve as controls. They would also undergo unnecessary skin homografts from an unrelated donor. The objective was to study the effect of thymectomy on skin homografts in immunologically competent children. As Beecher noted: ‘Total thymectomy is occasionally, although not usually part of the primary cardiovascular surgery involved, and whereas it may not greatly add to the hazards of the necessary operation its eventual effects in children are not known.’[28] As such, the study raised ethical concerns because it subjected the children to the serious and unnecessary risks of thymectomy and skin grafts without any expected therapeutic benefit to the children.[29]

The fourth study to enroll children involved twenty‐six healthy newborns (less than 48 hours old). The objective was to determine whether ureteral reflux can occur in the normal bladder.[30] The infants were catheterized and were radiographed while the bladder was filling and during voiding. Six weeks later their urine was reexamined; none had developed infection, although as Beecher notes, the potential long‐term risks of the X‐ray exposure were not known.[31]

Beecher's concerns were echoed and amplified by Maurice Pappworth, a consultant general physician in the UK who catalogued hundreds of (p.16) unethical published studies in his book Human Guinea Pigs: Experimentation on Man (1967).[32] Pappworth devoted an entire chapter to examples of unethical pediatric research, mainly from the US and the UK.[33] The studies include two articles by British researchers published in the Lancet in October 1953. One study investigated the safety of giving large amounts of intravenous ammonium chloride to children to see whether it could be used for the relief of severe alkalosis.[34] The investigators enrolled five infants with pyloric stenosis who might benefit, and two infants with severe hydrocephalus and normal metabolic profiles as controls. The other study examined the relationship between diet and phenylketonuria (PKU).[35] These investigators enrolled a girl with PKU who had responded well to a special diet and was challenged with a large dose of phenylalanine without her mother's knowledge. Her blood and behavioral responses were compared with the responses of a healthy child who was also fed a diet with a large dose of phenylalanine. The former child's blood level and behavior dramatically worsened with the phenylalanine challenge, whereas the latter child's plasma phenylalanine level and behavior were not changed.[36]

The two studies evoked a letter of protest that was published in the next issue of the Lancet. Fisher lamented the ‘use of normal children (or children suffering from some irrelevant disease) as controls in clinical research’.[37] He argued that children should not be exposed to any risk in medical research ‘unless there is a reasonable chance, or at least a hope, that the child may benefit thereby’.[38]

Both sets of researchers responded. Bickel and Gerrard argued that the exposure of a healthy volunteer child subject to large amounts of phenylalanine was known to be harmless.[39] In defense of the ammonium chloride study, Holt argued that he was not in major disagreement with Fisher, but that he used a broader concept of benefit: ‘no procedure should be carried out involving risk or discomfort without a reasonable chance of benefit to that child or other children.’[40] This revision changes the benefit: risk analysis from the individual to the group level. In a follow‐up letter, Leys rejected the revision, arguing that research not designed with the sole intention of providing benefit to the individual can be performed only on competent adults who freely give their consent.[41]

The studies can also be criticized on other grounds. The ammonium chloride study can be criticized for its use of disabled children as controls merely because they were available.[42] The PKU study can be criticized for not seeking the mother's consent. The mother was not even informed that a challenge dose would be given. She was described as ‘distressed that her daughter had lost in a few days all the ground gained in the previous ten months’.[43]

(p.17) Other studies criticized by Pappworth included nontherapeutic cardiac catheterizations, both in children with cardiac disease (e.g., to show that active rheumatic carditis interferes with the functional efficiency of the heart, a fact already well established) and in children without cardiac defects (to determine normal pressures in the pulmonary artery during the first few months of life).[44] Pappworth also documented several studies investigating vesico‐ureteric reflux in healthy infants published in the 1950s.[45] The vesico‐ureteral study cited by Beecher was published in 1964.[46] The redundancy of the data makes it even more ethically questionable.

3. Ramsey and the Ethics of Nontherapeutic Research

In 1970, Beecher published Research and the Individual, a more comprehensive critique of current research practices.[47] He described the critique as one offered by an investigator and stated that there was a ‘pressing need for a philosopher's approach, but only by one so wise that he can competently resolve the enormous complexities of the problems involved’.[48] The philosophical approach was provided that same year by Paul Ramsey, a moral theologian who had just spent a year as a visiting scholar at Georgetown Medical School. In 1970, Ramsey published an examination of the ethical problems in medicine, problems he described as consonant with (and only a particular case of) the ethics of a wider human community.[49] He argued that the major task of medical ethics ‘is to reconcile the welfare of the individual with the welfare of mankind; both must be served’.[50] Ramsey was concerned that medical research had developed a momentum and life of its own. He believed that there could be situations where one would have to choose between knowledge and morality ‘in opposition to our long‐standing prejudice that the two must go together’.[51]

Ramsey argued that medicine and medical ethics demanded ‘a determination of the rightness or wrongness of the action and not only of the good to be obtained … Medical ethics is not solely a benefit‐producing ethics even in regard to the individual patient, since he should not always be helped without his will.’[52] The patient's will was expressed by a free and adequately informed consent. In medical research, consent allows researcher and subject to become joint adventurers in a common cause and serves ‘as a canon of loyalty expressive of the faithfulness‐claims of persons in medical investigation,’[53] thereby placing ‘an independent moral limit upon the fashion in which the rest of mankind can be made the ultimate beneficiary of these procedures’.[54]

Ramsey was not the first non‐physician to venture into medical ethics. Over a decade earlier, Joseph Fletcher, another Protestant theologian, had published Morals and Medicine.[55] Fletcher analyzed ethical issues in health care from the patient's point of view. He argued that for individuals to act as (p.18) responsible moral beings, they needed information to make an informed choice. In trying to understand why Fletcher did not stimulate dialogue but Ramsey did, Rothman argues:

[T]o bring outsiders into medical decision making, to have philosophers take a place at the bedside, in effect to substitute bioethics for medical ethics would require far more than one man adopting a new approach. It would demand nothing less than a revolution in public attitudes toward medical practitioners and medical institutions.[56]

As Rothman notes, such a revolution in attitudes was precisely what was occurring in the 1960s, epitomized by the patients' rights and civil rights movements.

Ramsey, like Fletcher and Beecher, placed great emphasis on informed consent. Ramsey argued that the need for consent raises particular problems for those individuals who cannot give consent, such as young children:

[C]hildren, who cannot give a mature and informed consent, should not be made the subjects of medical experimentation unless, other remedies having failed to relieve their grave illness, it is reasonable to believe that the administration of a drug as yet untested or insufficiently tested on human beings, or the performance of an untried operation, may further the patient's own recovery.[57]

Ramsey did not deny that parents had moral authority to consent on behalf of their children, but he argued that their moral authority was limited: ‘no parent is morally competent to consent that his child shall be submitted to hazardous or other experiments having no diagnostic or therapeutic significance for the child himself.’[58] He noted that Beecher and Pappworth had been criticized for assuming that the failure to mention consent meant that the physicians failed to obtain it. Ramsey went further: it is not a question of whether the researchers obtained parental consent, but rather, ‘the point is rather that morally no parent should consent—or be asked to consent to any such thing even if he is quite capable of doing so, and even if in fact his informed consent was obtained in all cases where this fact is not mentioned in the reports.’[59]

The problem, according to Ramsey, is that ‘[t]o attempt to consent for a child to be made an experimental subject is to treat a child as not a child. It is to treat him as if he were an adult person who has consented to become a joint adventurer.’[60] It is also to treat him solely as a means which violates the Kantian principle of respect for persons.[61] Thus, for Ramsey, research on children was ethical only if it had some relation to the child's own health and informed parental or guardian consent was obtained.[62] This is true even if there is no risk, or no discernible risk, because ‘a subject can be wronged without being harmed’.[63] That is, even if the child did not have any interests diminished or defeated by his participation, the child's right not (p.19) to be used as a means was abrogated. The child was wronged (his rights were violated) whether or not any interests were defeated.[64]

For Ramsey, then, parents must act as fiduciaries and can only authorize their child's participation in research that will promote the child's medical interests.[65] Duane Alexander, a pediatrician and director of the National Institute of Child Health and Human Development (NICHD) since the 1980s, writes about Ramsey's impact on pediatric research: ‘Although this position did not receive wide support, it stimulated and stirred debate in the ethics community that brought the issue of children in research to the forefront.’[66]

A lawsuit filed in 1973 made the same claim as Ramsey: ‘parents and guardians had no legal authority to consent to the participation of a child or a ward in nontherapeutic research irrespective of the degree of risk.’[67] James Neilsen was an attorney and faculty member at the University of California at San Francisco. As a member of the University's Committee on Human Experimentation, he opposed a protocol that would study the development of allergies and asthma in children whose families had a history of these disorders, as well as normal control subjects from families without an allergic history. The protocol involved drawing blood and administering pharmaceutical agents to the children. When the committee unanimously approved the study at a meeting at which Neilsen was not present, Neilsen sued the committee and his own university. Although the case was never decided, Alexander notes that ‘it left investigators and research regulators shivering in their boots, and the shock waves it sent though the research community and the reaction and response it engendered in terms of regulations for protecting children in research cannot be overestimated.’[68]

The primary motivation for refuting Ramsey's position is consequentalistic: excluding children from research will have long‐term negative consequences on the well‐being of children in general. Ramsey did not deny the danger of prohibiting children from participating in all nontherapeutic research because it would harm children as a class, but his solution was to exhort researchers to ‘sin bravely’: the trustworthy researcher was the one who did ‘not deny the moral force of the imperative he violates’.[69]

4. The Debate Widens

The National Commission was established in the 1970s to examine issues revolving around human subject protections. In the National Commission's report, Research Involving Children, the National Commission examined the issue of whether the participation of children in nontherapeutic research was morally permissible.[70] The National Commission examined Ramsey's (p.20) position and counter‐arguments that would permit the participation of children in some minimal risk nontherapeutic research.

One such argument was provided by Richard McCormick, a Catholic theologian. McCormick challenged Ramsey's arguments using a natural law approach. He argued, contra Ramsey, that parental consent ‘is morally valid precisely insofar as it is a reasonable presumption of the child's wishes’.[71] McCormick held that there are ‘certain identifiable valuables that we ought to support, attempt to realize, and never directly suppress because they are definitive of our flourishing and well‐being.’[72] The child, then, would want to participate as a research subject because he ought to do so. That is, the child would choose to participate because

To pursue the good that is human life means not only to choose and support this value in one's own case, but also in the case of others when the opportunity arises. In other words, the individual ought also to take into account, realize, make efforts in behalf of the lives of others also, for we are social beings and the goods that define our growth and invite to it are goods that reside also in others.[73]

McCormick also objected to Ramsey's second argument, that using children as research subjects is contrary to the Kantian principle that persons should never be treated solely as a means, but always simultaneously as an ends, on the grounds that it presumes an atomistic view of humans. Humans are social beings whose good transcends their individual good. Participation as a research subject is consistent with treating the child as an end understood to mean a social being.[74]

Ramsey rebutted McCormick's arguments on the grounds that they were too broad and could require the participation of adults in research projects to which they do not give their consent.[75] While McCormick was willing to tolerate such enforced good Samaritanism,[76] most ethicists and legal scholars are not.

Robert Veatch sought to justify the participation of children by arguing that Ramsey's position takes a highly individualistic understanding of moral responsibility that denies the child's membership in a social community.[77] Although his position is similar to McCormick's, Veatch argues using the language of rights and consent rather than natural law. Veatch acknowledged the ‘dangers of balancing individual rights with obligations to serve the common welfare are great especially in cases where consent cannot be used as a mechanism to judiciously waive those rights.’[78] Nevertheless, he argued that ‘in cases of minimal risk when information to be obtained would be of great value and can be obtained in no other way, there must be some contribution to the general welfare which can be expected without consent.’[79] While Veatch would respect a child's dissent, he believes that where the subject cannot or does not refuse, parental permission should (p.21) make participation acceptable ‘it is reasonable to treat the individual, non‐consenting subject as a means to an end, under very limited and circumscribed conditions’, [80] Parental approval serves as the best check to make sure that individual rights are not unduly compromised. For Ramsey, the problem with this position is that it presumes a technological imperative at the expense of the respect (and possibly well‐being) of the child by subjecting them to risk without consent.[81]

A third argument to support the participation of children in research was offered by Stephen Toulmin. He suggested that the argument should not begin with the question of what children ought to do. Rather, the argument should begin by considering whether there are any presumptions that children could not reasonably object to if they were capable of understanding what is at stake and of making a decision in their own right.[82] Victor Worsfold offered the other side of this argument. Rather than arguing that the child should be permitted to participate in research when he could not reasonably object to his participation, he argued that the child should be permitted to participate in research to which the reasonable child would approve in retrospect. Citing Rawls, he explained:

As we know less and less about a person, we act for him as we would act for ourselves from the standpoint of the original position. We try to get for him the things he presumably wants whatever else he wants. We must be able to argue that with the development or the recovery of his rational powers, the individual in question will accept our decision on his behalf and agree with us that we did the best thing for him.[83]

One problem with both Toulmin's and Worsfold's arguments is the ambiguity of what is reasonable, and how to accommodate an option that some parents would find reasonable and other parents would not.[84] Ramsey did not deny the value of the reasonable person standard, but he argued that it conflates the ‘circumstances in which an informed and prudent adult would reasonably be expected to volunteer himself’ as the standard for determining ‘those circumstances in which a child may be volunteered by someone else’.[85] The reasonable person standard permits a parent to authorize a child's participation in an activity; it does not mean that the option is or ought to be required.

Whereas Ramsey sought to exclude all children from nontherapeutic research, McCormick, Veatch, Toulmin, and Worsfold sought to justify the morality of any child's participation in such research. Others have sought to refute Ramsey by finding a middle ground, arguing for the moral permissibility of allowing some children, such as older children who can express a preference, to participate as research subjects. For example, Beecher argued that parents can authorize a child's participation to promote the child's moral development: ‘Parents have the obligation to inculcate into their children attitudes of unselfish service. One could hope that this might be (p.22) extended to include participation in research for the public welfare, when it is important and there is no discernible risk.’[86] Similarly, Bartholome argued that parents can authorize their child's participation in order to promote their children's moral education.[87]

Both Beecher and Bartholome believed that parental consent was necessary but not sufficient. Beecher argued for both the child's and the parents’ informed consent and as such, only permitted children over the age of 14 to serve as research subjects.[88] Bartholome took a more liberal view and allowed for the participation of children with their parents’ consent if the children could give assent.[89] By assent, Bartholome meant that the child could meaningfully agree to participate, even though the agreement was not legally binding. The purpose of procuring the children's assent was to demonstrate respect for their evolving personhood and to show that they were not being treated solely as a means.

One objection to the positions of Beecher and Bartholome is offered by Ackerman. Ackerman agrees that parents can authorize their children's participation to serve moral goals. In fact, he contends that parents have a moral duty to guide the activities of their children because children rely upon adults for this guidance. Respect for a child requires that parents ‘carefully direct his “choices” ’.[90] However, unlike Beecher and Bartholome, Ackerman argues that requiring the child's assent makes a mockery both of our duties to children and of their limited present‐day capabilities to act autonomously: ‘We cannot decide how to intervene in a child's life by projecting what he will come to approve or accept. For what he will come to accept is partly a product of the interventions we make.’[91] In addition, he states that children are usually ill‐prepared to refuse requests by their physicians and parents.[92] Instead, Ackerman argues that parents alone can and must decide whether their children should participate as research subjects.

If Ackerman is correct, then we are back to the original positions of Ramsey and McCormick: either it is or it is not morally permissible for parents to decide whether to enroll (any) child in low‐risk nontherapeutic research. Ackerman argues that it is morally permissible, but contra McCormick, his argument is based on a broader view of parental responsibility, including the responsibility of teaching children to be contributors to the moral community.[93] Elsewhere, I too have argued that Ramsey's conception of parental responsibility as fiduciary is too narrow and that parents can and should be allowed to enroll their children (of all ages) in minimal‐risk research.[94] In brief, I have argued that parental autonomy should be respected unless their decision is disrespectful of the child's developing personhood. Parents who value participation in social projects like advancing science may try to inculcate similar values into their child. Even if the child never shares in these goals, they are goals which responsible parents may try to inculcate.

(p.23) 5. The National Commission and the Federal Regulations regarding Human Subject Protections

The controversy initiated by Ramsey regarding the moral permissibility of the participation of children in nontherapeutic research continued to be debated in the moral, legal, and medical communities as attempts to write federal guidelines began. In 1973, the National Institutes of Health (NIH) convened an outside advisory group of researchers, ethicists, and lawyers to discuss the issues and provide recommendations for research generally and for research involving certain vulnerable populations. Draft regulations for research in general and for research involving children were published in the fall of 1973,[95] but as Alexander explains, ‘[s]oon thereafter it became clear that there would be a national commission, so no further action was taken until the commission made its recommendations.’[96]

The National Commission published over twenty reports and appendices in the 1970s, the most oft‐cited of which is the Belmont Report.[97] The National Commission's report, Research Involving Children, was published one year earlier.[98] Based on the National Commission's reports, the Department of Health, Education and Welfare (DHEW) proposed regulations in 1978 and 1979.[99] These regulations were finalized in the early 1980s by the newly reorganized Department of Health and Human Services (DHHS).[100] Subpart A of these regulations focuses on human subject protections generally. It is known as the Common Rule because it has been adopted by sixteen federal agencies and departments of the US government, and was most recently revised in 1991.[101] Subpart D provides additional protections for research involving children, and minor revisions were made in 1991.[102]

Although the National Commission acknowledged the need for research on children, it also realized that ‘the vulnerability of children, which arises out of their dependence and immaturity raises questions about the ethical acceptability of involving them in research’.[103] To minimize these problems, the Commission established strict criteria that research must satisfy. At a minimum, these criteria require that:

  1. 1. The research is scientifically sound and significant.

  2. 2. Where appropriate, studies have been conducted first on animals and adult humans, then on older children, prior to involving infants.

  3. 3. Risks are minimized by using the safest procedures consistent with sound research design and by using procedures performed for diagnostic or treatment purposes whenever feasible.

  4. (p.24)
  5. 4. Adequate provisions are made to protect the privacy of children and their parents and to maintain confidentiality of data.

  6. 5. Subjects will be selected in an equitable manner.

  7. 6. The conditions of all applicable subsequent conditions are met, including adequate provisions being made for the assent of the child and permission of their parents or guardians.[104]

The National Commission recommended additional criteria depending upon the level of risk and harm that the research entailed, the risk/benefit ratio of the proposed project, and the comparative risk/benefit ratio of the alternatives. Local institutional review boards (IRBs) would be created to ensure that these safeguards were fulfilled, including the adequacy of the consent process.[105] These guidelines, particularly the requirement to conduct, when possible, studies enrolling less vulnerable populations first, served to restrict the participation of children in medical research.

6. From Protection to Access

The justification for the additional guidelines for child subjects was the child's need for protection. This focus on protection, however, may partly explain the underfunding and understudy of the health issues unique to children.[106] In the early 1990s, various governmental agencies shifted from an exclusive focus on protecting children from research risks to promoting greater access by children in research. Two reasons for these policy changes are: (1) the concern of the pediatric community that many pharmaceuticals and therapies prescribed to children had never been tested in children;[107] and (2) the response of the Food and Drug Administration (FDA) to the politicization of drug testing and approval by AIDS activists.[108] The AIDS activists successfully challenged a system they deemed too slow and they secured passage of an accelerated approval process.[109] However, the lag time between FDA approval of new drugs, often based solely on adult trials, and the initiation of clinical trials in children results in a persistent delay of pediatric drug information.[110]

One of the early attempts to improve pediatric drug information came in 1994, when the FDA published specific requirements on content and format of pediatric labeling for human prescription drugs.[111] The FDA required drug manufacturers to survey existing data and determine whether those data were sufficient to support additional pediatric use information in the labeling of their drugs. The response was disappointing. New labeling proposals for approximately 430 drugs and biologic supplements were submitted, of which 75% did not improve pediatric use information. More than half (p.25) simply requested the addition: ‘Safety and effectiveness in pediatric patients have not been established.’[112]

An FDA ruling in 1979 required specific pediatric labeling information, particularly if the drug were approved for a pediatric indication. As the FDA noted, however, the rule was self‐limited in that ‘it neither requires nor is intended to require that studies be performed to develop data for inclusion in prescription drug labeling’.[113] If there were no approved pediatric use, the statement ‘Safety and effectiveness in pediatric patients have not been established’ was sufficient.[114]

The 1994 FDA ruling went further than the 1979 ruling in several ways. First, the agency acknowledged the difficulties of conducting classic placebo‐controlled trials in pediatric patients and allowed for some extrapolation of adult data if ‘the FDA found that the course of the disease and the drug's effects are sufficiently similar’.[115] In addition, the FDA maintained its legal authority to compel new pediatric drug studies and required drug sponsors to submit supplemental applications of pediatric information if supported by available data. This change not withstanding, the FDA again clarified that the 1994 rule ‘does not add a new requirement that sponsors carry out new pediatric studies’.[116]

In June 1996, the American Academy of Pediatrics (AAP) and NICHD sponsored a workshop on the ‘Inclusion of Children in Clinical Research’[117] where it was suggested that current policy may be too little, too late.[118] Part of the support for increasing pediatric participation in research, particularly in pharmaceutical research, is that while major advances have been made during the past half century in adult medicine, only much more modest advances have been made in pediatrics. Almost three decades earlier, Shirkey expressed his frustration with the lack of financial support by government and industry for pediatric drug investigation.[119] Consider, for example, that more than 80% of drugs prescribed to children have never been tested on them.[120] The danger is that unless these drugs are tested on children, there are neither data for safety or efficacy nor dosing guidelines, and every child remains an experiment. Policies promulgated by different government agencies in the late 1990s attempted to overcome this gap.

The FDA proposed the Pediatric Rule in 1997 to increase the number of drugs and biological products for which there is adequate pediatric use information.[121] Finalized in 1998 and effective beginning 1 April 1999, the Pediatric Rule required manufacturers of certain new drugs and biological products to conduct studies to provide adequate pediatric labeling.[122] The Pediatric Rule was not enforced because of the success of the Food and Drug Administration Modernization Act (FDAMA) passed by Congress in 1997.[123] FDAMA provided strong economic incentives for (p.26) conducting pediatric studies by offering pharmaceutical companies an additional six months of patent exclusivity for testing of medications in children. In January 2002, the law was reenacted for another five years as the Best Pharmaceuticals for Children Act.[124] What studies are needed to earn additional exclusivity are negotiated and may involve pharmacokinetic testing or a phase III clinical trial. Exclusivity can be granted even if the results of the studies are negative or inconclusive.[125] According to a January 2001 status report to Congress, FDAMA has been highly effective in generating pediatric studies on many drugs, although some categories of drugs and some age groups remain inadequately studied.[126]

Although not enforced, the Pediatric Rule was suspended in March 2002 in response to a lawsuit.[127] However, it was quickly reinstated in April 2002 ‘after members of Congress complained that the FDA was injuring children's health and introduced legislation to force the agency to reinstate the mandate’.[128] In October 2002, the US District Court for the District of Columbia struck down the Pediatric Rule on the grounds that it exceeded the FDA's statutory authority.[129] Congress passed the Pediatric Rule as federal legislation in November 2003.[130]

Whereas the Pediatric Rule requires testing of all new pharmaceuticals, the incentives under FDAMA and BPCA refer only to pharmaceuticals that are still under patent. Pharmaceutical companies do not have incentives to study drugs that are approved but no longer under patent. For this reason, the BPCA provided for government sponsorship of pediatric trials on off‐patent drugs. In January 2003, the DHHS announced $25 million in new government support for research on twelve drugs commonly prescribed for children.[131]

The NIH also issued new policy guidelines in 1998 to increase the enrollment of children in research studies.[132] All NIH‐funded research must now include a plan for the inclusion of children, unless there is good justification to exclude them. The NIH encourages compliance by stating on the Frequently Asked Questions (FAQ) section of its Web site that the exclusion of children may affect the priority score given to determine grant funding.[133]

In 1999 and 2000, the Office for the Protection of Research Risks [now known as the Office for Human Research Protections (OHRP)] suspended research at a number of major universities for failure of researchers and institutions to protect human subjects.[134] Possibly due to concerns of institutional reprisal if federal oversight were not sought, the OHRP received over two dozen requests for 407 panels in 2001.[135] CFR §46.407 permits research involving children that cannot be approved locally to be reviewed nationally by a panel of experts convened by the Secretary of DHHS.[136] Although CFR §46.407 had been invoked quite infrequently prior to the year 2000, eleven panels were convened between February 2001 and October 2003, and public comments were sought for six.[137]

(p.27) In October 2000, Congress passed the Children's Health Act that included a Pediatric Research Initiative (Title X).[138] The legislation was designed to make pediatric research—research specifically addressed at children's illnesses and conditions—a high priority. Nevertheless, although funding for pediatric research is increasing, it is increasing at a slower rate than medical research generally; in recent years, pediatric research has slipped from 12.5% to about 12% of the NIH budget.[139]

The Children's Health Act also provided specific instructions intended to ensure that pediatric subjects would continue to have additional protections. It required that within six months of its passage the Secretary of DHHS ‘shall require that all research involving children that is conducted, supported, or regulated by DHHS be in compliance with Subpart D’.[140] In order to comply with this policy, the FDA wrote interim rules in April 2001 that adopted most of Subpart D for all research subject to its regulatory authority.[141] The Act also required DHHS to conduct a review of Subpart D and to consider ‘any modifications necessary to ensure the adequate and appropriate protection of children participating in research’.[142] In May 2001, the report was promulgated.[143] It found that ‘the current DHHS regulations under Subpart D of 45 CFR Part 46 are sound, effective and well‐crafted … Furthermore, these regulations are robust and flexible, and as such, are useful and appropriate for regulating all types of research involving children as subjects, including biomedical and behavioral research’. [144] In that vein, it recommended that Subpart D not be modified and that DHHS should provide detailed guidance including the clarification of certain terms such as ‘minimal risk’, ‘prospect of direct benefit’, and ‘minor increase over minimal risk’. It also recommend guidance on whether payment may be provided to children involved in research or their parents.[145]

The responsibility to provide further guidance on these topics was assigned to the Institute of Medicine (IOM) in the Best Pharmaceuticals for Children Act of 2002.[146] The IOM report was released in March 2004.[147] The report seeks to promote access, but it also acknowledges that ‘[i]n some cases, ethical standards will preclude some otherwise desirable research’.[148] The IOM committee offers two controversial recommendations that could promote access. First, the IOM committee argues in support of payment to children who are subjects in pediatric research (see Chapter 8). Second, the IOM committee argues in support of permitting parental waivers of consent for certain types of research (see Chapter 5).

The actions of Congress, the FDA, NIH, and OHRP in the last decade have been designed to promote greater participation of children in research, despite general concerns regarding human subject protections more generally.[149] The reaffirmation of Subpart D under the Children's Health Act and the convening of 407 review panels by OHRP are signs that the policies (p.28) to promote greater access of children in research can be accomplished without necessarily undermining the additional protections that were recommended for pediatric subjects by the National Commission and implemented in the federal regulations.

7. International Research Ethics

The World Medical Association (WMA) was founded in September 1947 when physicians from twenty‐seven different countries met at the First General Assembly in Paris.[150] The WMA adopted the Declaration of Geneva, an update of the Hippocratic Oath in 1948,[151] and the International Code of Medical Ethics in 1949.[152] In 1962, the British Medical Journal (BMJ) published a draft code of ethics on human experimentation that was presented to the General Assembly of the WMA in September 1961.[153] The draft code provided general principles regarding human subjects and examined the different considerations necessary for ‘experiments for the benefit of the patient (i.e. therapeutic research) and ‘experiments conducted solely for the acquisition of knowledge’ (i.e. nontherapeutic research). It was revised and adopted in 1964.[154] As is true of the Nuremberg Code, the Declaration of Helsinki sought to minimize risk, and to ensure that the importance of the objective outweighs the inherent risks and burdens to the subject. In its first revision (1975), the Declaration of Helsinki went further than the Nuremberg Principles in the absolute respect owed to each individual subject: ‘In medical research on human subjects, considerations related to the well‐being of the human subject should take precedence over the interests of science and society.’[155] A utilitarian calculation that the benefits outweigh the risks to society was necessary but not sufficient; there was also a need to focus on the well‐being of each individual subject.

Although the Nuremberg Principles are silent regarding the ethics of children in human experimentation, other countries and international organizations have attempted to examine the ethical issues and develop policies regarding the role of children in human experimentation. In its draft code, the WMA specifically addressed several questions raised if children are to participate in research: (1) whose consent is necessary?; (2) which children can morally participate in research?; and (3) in what types of research can they morally participate?[156] The WMA concluded that parents or lawful guardians should make decisions on behalf of their children and that the informed consent of parents or guardians was necessary. Thus, children in institutions and not under the care of relatives should not be the subjects of human experimentation. With respect to nontherapeutic research, the draft code specifically stated that ‘persons incapable of giving consent because of age … should not be used as subjects.’[157]

(p.29) There were significant changes from the draft code of 1962 and the Declaration of Helsinki adopted by the WMA in 1964. Two of these changes relate to research on children. First, the ethics of involving institutionalized subjects was no longer mentioned. Second, the WMA specifically allowed for parents or legal guardians to consent for their children's participation in therapeutic and nontherapeutic research.[158] In all revisions, the Declaration of Helsinki permits the participation of children in both therapeutic and nontherapeutic research. More recent formulations of the Declaration make clear that children ‘should not be included in research unless the research is necessary to promote the health of the population represented and this research cannot instead be performed on legally competent persons'.[159] In addition, the Declaration of Helsinki now requires both the consent of the legally authorized representative and the assent of the child when feasible.[160] Unlike the US federal regulations, the Declaration of Helsinki does not state if there are particular types of research (e.g., therapeutic research) in which the child's dissent may be overridden.

Other countries have guidelines regarding the participation of children that are more restrictive than those in the US, although they also evolved in the 1990s to allow greater access. In the UK, the Medical Research Council (MRC) explicitly stated in 1962–3 that according to English Law, all children can participate in therapeutic research but children younger than 12 years were not permitted to participate in nontherapeutic research.[161] For children above the age of 12 years, participation in nontherapeutic research was permitted but required the child's full informed consent. Parental permission was also recommended.[162] Beecher contacted the MRC to provide legal citations for their position. Sir Harvey Druitt KCB responded to Beecher by explaining that the MRC statement was based upon his advice although he could not cite any statute or case law.[163] Beecher was not convinced and Curran and Beecher concluded that

There should be strong reasons in professional judgment for the use of immature children (those under 14 years of age) in any clinical investigation where there is no direct benefit intended for the child. However such involvement should not be ruled out as illegal and unethical in all circumstances. Neither American nor English laws demands such a flat and sweeping condemnation.[164]

By 1980, three additional British organizations had promulgated guidelines regarding the participation of children in research. They are more liberal than the MRC statement of 1962–3.[165] The British Paediatric Association (BPA) began its guidelines with four premises, one of which rejected the MRC's position on nontherapeutic research: ‘nontherapeutic research’ is ‘not necessarily either unethical or illegal’.[166]

(p.30) In 1986, the Institute of Medical Ethics (UK) Working Group on the Ethics of Clinical Research Investigations (Working Group) proposed new recommendations.[167] Their recommendations are quite similar to (and refer frequently to) the 1977 National Commission report Research Involving Children. The prime concern of the Working Group was that research should not be ‘against the interests of any individual child’.[168] This is in sharp contrast with the MRC requirement that research participation needs to be in the best interest of each particular child.[169] However, Nicholson et al. argued that children should only be subjects if there is a specific and demonstrable need to perform the research on children and no other route to the relevant knowledge is available.[170] In addition, new procedures were to be tested on animals and adults first.

Like the US National Commission, the UK Working Group chose the age of 7 as the age at which a child's assent must be sought.[171] While the Working Group opined that parents should be allowed to override the refusal of assent by the child under age 14 for therapeutic research, it argued that nontherapeutic research should require the child's assent.[172] Non‐therapeutic research for children under age 7 was not considered. For children over age 14, the Working Group argued that their consent was binding for both therapeutic and nontherapeutic research.[173] In addition, it recommended that nontherapeutic research procedures should not be carried out if, using the language of the National Commission, they involve more than a minor increase over minimal risk to any individual child subject.[174]

Revised guidelines for the ethical conduct of medical research involving children were issued by the MRC in 1991,[175] and by the BPA [now the Royal College of Paediatrics and Child Health (RCPCH)] in 1992 [176] and 2000.[177] All three statements reaffirm a preference for doing research on adults. Regarding the participation of children in nontherapeutic research, both of the revised RCPCH statements state that ‘[a] research procedure that is not intended directly to benefit the child subject is not necessarily either unethical or illegal.’[178] The MRC used the language of the Working Group stating that nontherapeutic research could be ethical if it were ‘not against [the child's] interests’.[179] All recommend procuring the assent of the child for all research even when it is not legally required (therapeutic research). The RCPCH statements also recommended against any financial inducements to families, although it permitted expenses to be paid.[180]

Although the British guidelines are more protective than the US guidelines, they are evolving to permit greater access, a policy evolution that one British sociologist, Priscilla Alderson, notes has not been morally examined.[181]

(p.31) 8. Conclusion: Balancing Access and Protection

The new policies have encouraged increased pediatric pharmacological testing and have led to some improved pediatric labeling.[182] In Chapter 13, however, I will show some disturbing evidence that the new policies are encouraging the participation of children in research even when the researchers do not plan to do subset analyses, thereby exposing children subjects to risks without providing benefits to children as a class.

In Strangers at the Bedside, Rothman shows that many of the research reforms of the 1960s and 1970s that provided greater protection to research subjects were spurred on by the cultural and political changes of the era.[183] Changes in policy and practice since the 1990s reflect a change in attitude from the need to protect persons from research to the need to provide access in response to the cultural and political events surrounding the AIDS crisis. Although US policies regarding the participation of children in research allow greater access than the guidelines and recommendations for children in research in the UK and Europe, one can see a similar trend towards increased access in the guidelines in the UK as well.

Whereas the historical concern was that justice required equitable selection of research subjects to share the research burden; the focus is now on ensuring equity to share the benefits. It is not clear, however, that the data support the decision to abandon the more cautious approach. The clinical AIDS trials of the 1980s, in which only research subjects had access to potentially life‐saving medication, are not the archetypical model for medical research. Rather, much research is nontherapeutic, and even therapeutic research is not necessarily designed to promote the medical well‐being of all the subjects. For example, many clinical trials of ‘me‐too drugs’ are designed as placebo‐controlled trials, such that subjects are not even ensured standard of care. I discuss this further in Chapter 13.

In the Belmont Report, the National Commission wrote that ‘it can be considered a matter of social justice that there is an order of preference in the selection of classes of subjects (e.g., adults before children)’. [184] No compelling moral argument has been offered to justify abandoning this principle. Research involving children should be performed, when possible, only after safety and efficacy studies have been done on animals and adults, and only when such studies are necessary to improve the practice of pediatric medicine. Children should not be enrolled in research merely to expedite the accrual process, but only when the research is specifically designed to provide general pediatric information.

Throughout this book I argue that policies and practices regarding the participation of children must focus primarily on minimizing risks.[185] I will offer specific recommendations to revise Subpart D of the federal regulations (p.32) to provide greater protection where it is necessary and to remove obstacles that do not provide additional protection but interfere with access. My goal is to ensure appropriate safeguards without compromising access unnecessarily. However, sometimes human subject protections will retard progress. At other times, these protections may make scientific data unattainable. That is the price we must pay to ensure respect for human dignity.[186]

(p.33) (p.34) (p.35) (p.36) (p.37) (p.40) (p.43)

Notes:

(1.) Beecher, H. K., ‘Ethics and Clinical Research’, New England Journal of Medicine, 274 (1966), 1354–60.

(2.) Nuremberg Code. See Trials of War Criminals Before the Nuremberg Military Tribunals under Control Council Law No. 10, vol. II. Washington DC: US Government Printing Office, 1948. On the web at: http://www.ushmm.org/research/doctors/codeptx.htm.

(3.) Rothman, D. J. Strangers at the Bedside: A History of How Law and Bioethics Transformed Medical Decision Making. New York: Basic Books, 1991, 62.

Renewed interest in human experimentation in the 1960s was not unique to the US. According to Nicholson, a deputy director of the Institute of Medical Ethics (UK), public interest in the surveillance of medical experiments in the UK was renewed in 1962 following the thalidomide disaster. See Nicholson, R. H. (ed.), Medical Research with Children: Ethics, Law and Practice. Oxford: Oxford University Press, 1986, 3. It led to a statement by the Medical Research Council (UK) in its annual report for 1962–3 entitled ‘Responsibility in Investigations on Human Subjects’. See Medical Research Council (MRC) ‘Responsibility in Investigations on Human Subjects’, Report of the Medical Research Council for the Year 1962–63. London UK: Her Majesty's Secretary Office (HMSO), 1964, 21–5. Reprinted in Beecher, H. K. Research and the Individual, Boston, MA: Little, Brown & Co, 1970, 262–7. Of note, M. H. Pappworth, a British physician, published Human Guinea Pigs, a compendium of hundreds of unethical research studies published in the medical literature the year after Beecher's expose in the New England Journal of Medicine. See Pappworth, M. H., Human Guinea Pigs: Experimentation on Man. London, UK: Routledge & Kegan Paul Ltd, 1967, reprinted by Penguin Books Ltd, Harmondsworth, Middx., UK, 1969.

(4.) Lederer, S. E., and Grodin, M. A., ‘Historical Overview: Pediatric Experimentation’, in M. A. Grodin and L. H. Glantz (eds.), Children as Research Subjects: Science, Ethics, & Law. New York: Oxford University Press, 1994, 4.

(5.) Hess, A. F., ‘The Use of a Series of Vaccines in the Prophylaxis and Treatment of an Epidemic of Pertussis’, Journal of the American Medical Association, 63 (1914), 1007 as cited in Lederer and Grodin, ‘Historical Overview’, 6.

(6.) Swedish physician. Humane Society. Human Vivisection: Foundlings Cheaper than Animals. Washington, DC.: Humane Society, undated in Lederer and Grodin, ‘Historical Overview’, 12.

(7.) Lederer and Grodin, ‘Historical Overview’, 19.

(8.) The phrase is often attributed to H. Shirkey. Shirkey, H., ‘Therapeutic Orphans’, Journal of Pediatrics, 72 (1968), 119–20.

(9.) Beecher, ‘Ethics and Clinical Research’.

(10.) The full citations are reprinted in Appendix A of Rothman, Strangers, at 263–5.

(11.) Krugman, S., Ward, R., Giles, J. P., Bodansky, O., and Jacobs, A. M., ‘Infectious Hepatitis: Detection of Virus during the Incubation Period and in Clinically Inapparent Infection’, New England Journal of Medicine, 261 (1959), 729–34. This is case study 16 in Beecher's ‘Ethics and Clinical Research’.

(12.) See, e.g., Ward, R., Krugman, S., Giles, J. P., Jacobs. A. M., and Bodansky, O., ‘Infectious Hepatitis: Studies of its Natural History and Prevention’, New England Journal of Medicine, 258 (1958), 407–16; Krugman, S., Ward, R., Giles, J. P., and Jacobs, A. M., ‘Infectious Hepatitis: Studies on the Effect of Gamma Globulin and on the Incidence of Inapparent Infection’, Journal of the American Medical Association, 174 (1960), 823–30; and Krugman, S., and Ward, R., ‘Infectious Hepatitis: Current Status of Prevention with Gamma Globulin’, Yale Journal of Biology and Medicine, 34 (1961/2), 329–39.

(13.) Krugman et al., ‘Infectious Hepatitis: Detection’.

(14.) Beecher is citing the ‘International Code of Medical Ethics’ passed by the General Assembly of the World Medical Association (WMA), London, 1949. Reprinted in Beecher, Research and the Individual, 236–7, hereinafter cited as ‘International Code of Medical Ethics’.

Of note, the Declaration of Helsinki provided ethical guidelines for clinical research. It was adopted by the WMA in 1964, although draft guidelines had existed since 1962. In both versions, the idea that medical research must benefit the patient was incorporated from the International Code of Medical Ethics with minimal modification. See WMA, Ethical Committee, ‘Draft Code of Ethics on Human Experimentation’, British Medical Journal, 2 (1962), 1119 [hereinafter cited as Draft Code]; and 18th WMA, ‘Declaration of Helsinki: Recommendations Guiding Doctors in Clinical Research’, adopted in Helsinki, Finland 1964 as reprinted in Beecher, Research and the Individual, 277–8 [hereinafter cited as 18th WMA, Declaration of Helsinki].

(15.) Beecher, ‘Ethics and Clinical Research’, 1358.

(16.) See, e.g., ‘Studies with Children Backed on Medical, Ethical Grounds’, The Medical Tribune, 20 February 1967, 1 & 23, 23; and Krugman, S. ‘The Willowbrook Hepatitis Studies Revisited: Ethical Aspects’, Reviews of Infectious Diseases, 8 (1986), 157–62.

(17.) Krugman, ‘Ethical Aspects’, 158–9.

(18.) Ibid. See also ‘Studies with Children’.

(19.) Stokes, J. Jr., and Neefe, J. R., ‘Prevention and Attenuation of Infectious Hepatitis by Gamma Globulin: Preliminary Note’, Journal of the American Medical Association, 127 (1945), 144 as cited by Beecher, Research and the Individual, 124.

(20.) Ward et al., ‘Infectious Hepatitis’.

(21.) Beecher, ‘Ethics and Clinical Research’, 1358.

(22.) Beecher, Research and the Individual, 125 commenting on the interview with Dr Joan Giles from ‘Studies with Children’ 23.

(23.) Beecher, Research and the Individual, 126.

(24.) Jack Hammond cited in ‘Studies with Children’, 23.

(25.) Ticktin, H. E., and Zimmerman, H. J., ‘Hepatic Dysfunction and Jaundice in Patients Receiving Triaceyloleandomycin’, New England Journal of Medicine, 267 (1962), 964–8. This is case study 4 in Beecher's ‘Ethics and Clinical Research’.

(26.) Beecher, ‘Ethics and Clinical Research’, 1360.

(27.) Zollinger, R. M., Lindem, M. C., Filler, R. M., Corson, J. M., and Wilson, R. E., ‘Effect of Thymectomy on Skin‐Homograft Survival in Children’, New England Journal of Medicine, 270 (1964), 707–10. This is case study 6 in Beecher's ‘Ethics and Clinical Research’.

(28.) Beecher, ‘Ethics and Clinical Research’, 1357.

(29.) Of note, Beecher was not the first to question the ethics of this study. In response to its publication in 1964, Dr Byron Waksman wrote a letter to the New England Journal of Medicine questioning whether the risks were sufficiently offset by the usefulness of the data that could be obtained, and whether ‘the long‐term hazards, unknown at present, were duly noted and called to the subjects' attention’, Waksman, B., ‘Thymus Experimentation’, New England Journal of Medicine, 270 (1964), 1018–19, 1019. Waksman's letter led to an editorial in the same issue which asked, ‘How far is it morally proper to go in using human beings for experimental purposes and under what conditions?’ The editors stated that ‘[t]he question is especially disturbing when it involves children…’, ‘The Ethics of Human Experimentation’, New England Journal of Medicine, 270 (1964), 1014–15, 1014.

Zollinger et al. responded. They clarified their methodology stating that they ‘did not create thymectomized patients but merely chose patients who had total thymectomy as a necessary part of aortic exposure during cardiac surgery’. They noted that the skin‐homograft donors were chosen carefully to minimize the risk of hepatitis, and that none of the subjects had developed hepatitis, Zollinger, R. M. Jr., Lidem, M. C. Jr., Filler, R. M., Corson, J. M., and Wilson, R. E., ‘Ethics of Thymus Experimentation’, New England Journal of Medicine, 270 (1964), 1314.

Clearly their response is ethically inadequate. Although none of the subjects developed hepatitis, good results do not justify unethical means. In this vein, the effect of thymectomy on skin graft survival is also ethically irrelevant. The study found no difference in skin homograft survival between those children who underwent thymectomy and those who did not (Zollinger et al., ‘Effect of Thymectomy’). The researchers also did not address the consent issue raised by Waksman about whether the parents understood the additional risks that the research imposed. Consent is not mentioned in the original article nor in the authors' response.

(30.) Lich, R. Jr., Howerton, L. W. Jr., Goode, L. S., and Davis, L. A., ‘The Ureterovesical Junction of the Newborn’, Journal of Urology, 1964; 92: 436–8. This is case study 22 in Beecher's article, ‘Ethics and Clinical Research’.

(31.) Beecher, ‘Ethics and Clinical Research’, 1359.

(32.) Pappworth, Guinea Pigs. All page numbers refer to the Penguin Books publication (1969).

(33.) Pappworth, Guinea Pigs, ch. 1, ‘Experiments on Infants and Children’, 47–61.

(34.) Doxiadis, S. A., Goldfinch, M. K., and Holt, K. S., ‘Alkalosis in Infants: Treatment by Intravenous Infusion of Ammonium Chloride’, Lancet, ii (1953), 801–4.

(35.) Bickel, H., Gerrard, J., and Hickmans, E. M., ‘Preliminary Communication: Influence of Phenylalanine Intake on Phenylketonuria’, Lancet, ii (1953), 812–13.

(36.) Ibid.

(37.) Fisher, R. E. W., ‘Controls’, Lancet, ii (1953), 993.

(38.) Ibid.

(39.) Bickel, H., and Gerrard, J., ‘In reply: Controls’, Lancet, ii (1953), 993.

(40.) Holt, K. S., ‘In reply: Controls’, Lancet, ii (1953), 993. Italics in original.

(41.) Leys, D., ‘Ethical Standards in Clinical Research’, Lancet, ii (1953); 1044.

(42.) The selection of disabled children as controls was not, on my reading, invidious discrimination against disabled children per se, but rather a selection of convenience. Pappworth discusses the common practice of using hospitalized patients as controls for research on conditions unrelated to their hospitalization because of their accessibility. See Pappworth, Guinea Pigs. ch. 10, ‘Patients as Controls’, 127–57.

(43.) Bickel et al., ‘Preliminary Communication’, 812.

(44.) Pappworth, Guinea Pigs, 50–5.

(45.) Ibid., 59–61. The studies were all published in the Journal of Urology between 1953 and 1960.

(46.) See Lich et al., ‘Uretovesical’ cited as case 22 in Beecher's ‘Ethics and Clinical Research’.

(47.) Beecher, Research and the Individual.

(48.) Ibid.,10.

(49.) Ramsey, P., The Patient as Person. New Haven, CT: Yale University Press, 1970, xi.

(50.) Ibid., xiv.

(51.) Ibid., xvi–xv citing Scanlan, J. P., ‘The Morality of Deception in Experiments’, Bucknell Review, 13 (1965) at 26.

(52.) Ibid., 2.

(53.) Ibid.,10.

(54.) Ibid., 2.

(55.) Fletcher, J., Morals and Medicine. Princeton, NJ: Princeton University Press, 1954.

(56.) Rothman, Strangers, 107.

(57.) Ramsey, Patient as Person, 12–13.

(58.) Ibid., 13.

(59.) Ibid., 14.

(60.) Ibid., 14.

(61.) Ibid., 35 Kant's principle of respect for persons states: ‘Act in such a way that you treat humanity, whether in your own person or in the person of another, always at the same time as an end and never simply as a means’, Kant, I., Grounding for the Metaphysics of Morals (1785) translated by J. W. Ellington. Indianapolis, IN: Hackett Publishing Co., 1981, para. 429.

(62.) Ramsey, Patient as Person, 20.

(63.) Ibid., 39.

(64.) Feinberg, J., Harm to Others: The Moral Limits of the Criminal Law. New York: Oxford University Press, 1984, 33–5.

(65.) Ramsey, Patient as Person, 13.

(66.) Alexander, D., ‘Foreword: Regulation of Research with Children: The Evolution from Exclusion to Inclusion’, Journal of Health Care Law and Policy, 6 (2002), 1–13, 2.

(67.) Ibid., 3 citing Nielsen v. Regents of the University of California et al., No 665–049 Civ. 8–9 (Super Ct. San Francisco, Cal., 23 Aug. 1973).

(68.) Ibid., 4.

(69.) Ramsey, P., ‘The Enforcement of Morals: Non‐Therapeutic Research on Children’, Hastings Center Report, 6 (August 1976), 21–30, 21 citing Ramsey P., ‘Medical Progress and Canons of Loyalty to Experimental Subjects’, Proceedings of Conference on Biological Revolution/Theological Impact sponsored by the Institute for Theological Encounter with Science and Technology, Fordyce House, St Louis, Missouri (6–8 April 1973), 51–77.

(70.) The National Commission's discussion can be found in: National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, Report and Recommendations: Research Involving Children. Washington DC: US Government Printing Office, 1977, DHEW Publication No. (OS) 77–0004, 94–121.

(71.) McCormick, R. A., ‘Proxy Consent in the Experimentation Situation’, Perspectives in Biology and Medicine, 18 (Autumn, 1974), 2–23, 11.

(72.) Ibid., 9.

(73.) Ibid., 12.

(74.) McCormick, R. A., ‘Experimentation in Children: Sharing in Sociality’, Hastings Center Report. 6 (December 1976), 41–6, 43.

(75.) Ramsey, P., ‘Children as Research Subject: A Reply’, Hastings Center Report 7 (April 1977), 40–1, 40.

(76.) See McCormick, ‘Sharing in Sociality’, 42.

(77.) Veatch, R. M., ‘Three Theories of Informed Consent: Philosophical Foundations and Policy Implications’ in the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, Appendix vol. II. Washington DC: US Government Printing Office, section 26, 26–41.

(78.) Ibid., 26–41.

(79.) Ibid., 26–41. Italics in the original.

(80.) Ibid., 26–42.

(81.) Ramsey, Patient as Person, xvi–xv.

(82.) Toulmin, S., ‘Fetal Experimentation: Moral Issues and Institutional Controls’, National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, Research on the Fetus, Appendix. Washington DC: US Government Printing Office, 1976, DHEW Publication No. (OS) 76–128, section 10, 10–7, 10–8.

(83.) Rawls, J., A Theory of Justice. Cambridge MA: Harvard University Press, 1972, 249 as cited by V. Worsfold, ‘A Philosophical Justification of Children's Rights’, Harvard Educational Review, 44 (1974), 142–57, 154–5.

(84.) National Commission, Research Involving Children, 107.

(85.) Ramsey, Patient as Person, 24.

(86.) Beecher, Research and the Individual, 63.

(87.) Bartholome, W. G., ‘Parents, Children, and the Moral Benefits of Research’. Hastings Center Report, 6 (December 1976), 44–5.

(88.) Curran, W. J., and Beecher, H. K., ‘Experimentation in Children: A Reexamination of Legal Ethical Principles’, Journal of the American Medical Association, 210 (1969), 77–83.

(89.) Bartholome, ‘Parents, Children’, 44–5.

(90.) Ackerman, T. F., ‘Fooling Ourselves with Child Autonomy and Assent in Nontherapeutic Clinical Research’, Clinical Research, 27 (1979), 345–8, 345.

(91.) Ibid., 345.

(92.) Ibid., 346–7. Ackerman cites two empirical studies that support his arguments: Schwartz, A. H., ‘Children's Concepts of Research Hospitalization’, New England Journal of Medicine, 287 (1972), 589–92; and Abramovitch, R., Freedman, J. L., Thoden, K., and Nikolich, C., ‘Children's Capacity to Consent to Participation in Psychological Research: Empirical Findings’, Child Development, 62 (1991), 1100–9.

(93.) Ackerman, ‘Fooling Ourselves’.

(94.) Ross, L. F., Families, Children and Health Care Decision Making. Oxford: Clarendon Press, 1998, esp. ch. 5. I examine the issue of moral development in this book in Chap. 4, ‘Should We Provide Healthy Children with Greater Protection in Medical Research?’

(95.) Department of Health, Education, and Welfare, National Institutes of Health, ‘Protection of Human Subjects: Proposed Policy’, Federal Register 38 (9 Oct. 1973), 27882–5; and Department of Health, Education, and Welfare, National Institutes of Health, ‘Protection of Human Subjects: Policies and Procedures’, Federal Register, 38 (16 Nov. 1973), 31738–49.

(96.) Alexander, ‘Foreword’, 5.

(97.) National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Washington DC: US Government Printing Office, 1978, DHEW Publication No. (OS) 78–12. On the web at: http://ohsr.od.nih.gov/guidelines/belmont.html, hereinafter cited as Belmont Report.

(98.) National Commission, Research Involving Children.

(99.) Department of Health, Education, and Welfare (DHEW). (45 CFR Part 46), ‘Protection of Human Subjects: Proposed Regulations on Research Involving Children’, Federal Register, 43 (21 July 1978), 31786–94; and Department of Health, Education and Welfare (DHEW), ‘(45 CFR Part 46) Notice of Proposed Regulations Amending Basic HEW Policy for Protection of Human Research Subjects’, Federal Register, 44 (14 Aug. 1979), 47688–729.

(100.) Department of Health and Human Services (DHHS). (45 CFR Part 46, Subpart A), ‘Protection of Human Subjects: Final Regulations Amending Basic HHS Policy for the Protection of Human Research Subjects’, Federal Register, 46 (26 Jan. 1981), 8366–91; and Department of Health and Human Services, (45 CFR (p.38) Part 46, Subpart D), ‘Additional Protections for Children Involved as Subjects in Research’, Federal Register, 48 (8 March 1983), 9814–20.

(101.) Department of Agriculture, Department of Energy, National Aeronautics and Space Administration, Department of Commerce, Consumer Product Safety, Commission International Development Cooperation Agency, Agency for International Development, Department of Housing and Urban Development, Department of Justice, Department of Defense, Department of Education, Department of Veterans Affairs, Environmental Protection Agency, Department of Health and Human Services, National Science Foundation, and Department of Transportation Agencies: 7 CFR Part 1c; 10 CFR Part 745; 14 CFR Part 1230; 15 CFR Part 27; 16 CFR Part 1028; 22 CFR Part 225; 24 CFR Part 60; 28 CFR Part 46; 32 CFR Part 219; 34 CFR Part 97; 38 CFR Part 16; 40 CFR Part 26; 45 CFR Part 46; 45 CFR Part 690; 49 CFR Part 11. ‘Federal Policy for the Protection of Human Subjects, Final Rule’, Federal Register, 56 (18 June 1991), 28003–18, hereinafter cited as the Common Rule.

(102.) Department of Health and Human Services (DHHS). (45 CFR 46 Subpart D), ‘Additional Protections for Children Involved as Subjects in Research’, Federal Register, 56 (18 June 1991), 28032, hereinafter cited as Subpart D by CFR number.

(103.) National Commission, Research Involving Children, 2.

(104.) Ibid., 2–3.

(105.) Institutional Review Boards (IRBs) serve the primary purpose of protecting the rights and welfare of human research subjects. The first federal document to propose committee review of research procedures was dated 17 November 1953 and applied only to intramural research at the newly opened clinical center at the NIH. See Subcommittee on Health of the Committee on Labor and Public Welfare, United States Senate, Federal Regulation of Human Experimentation. Washington DC: US Government Printing Office, 1975, Publication No. 45–273–0 as cited by R. J. Levine, Ethics and Regulation of Clinical Research, 2nd edn. New Haven CT: Yale University Press, 1986, 322. The first federal policy was not issued for another decade. On 8 February 1966, the Surgeon General issued a memorandum requiring prior review of all research involving human subjects funded by US Public Health Service Grants. See Steward, W. H., ‘Clinical Investigations Using Human Subjects’, Memorandum dated 8 February 1966 cited by Levine, Ethics and Regulation, 323.

Initially most IRB committees were composed of scientists and physicians. Revisions in US Public Health Service policy and DHEW and DHHS regulations have evolved to require a more diverse composition. The duties of the IRBs have also expanded. The history of IRBs is given in Levine, Ethics and Regulations, ch. 14.

(106.) Gross, C. P., Anderson, G. F., and Powe, N. R., ‘The Relation between Funding by the National Institutes of Health and the Burden of Disease’, New England Journal of Medicine, 340 (1999), 1881–7.

(107.) American Academy of Pediatrics (AAP) Committee on Drugs, ‘Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations’, Pediatrics, 60 (1977), 91–101, 99. This same concern is expressed in the Committee's revised statement in 1995. American Academy of Pediatrics (AAP) (p.39) Committee on Drugs, ‘Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations’, Pediatrics, 95 (1995), 286–94, 286.

(108.) Begley, S., Hager, M., and Wilson, L., ‘Desperation Drugs. Frustrated AIDS Patients are Spurring the FDA to Relax the Rules of the Game’, Newsweek, 114 (7 August 1989), 48–9 & 51; Gould, S. J., ‘AIDS and FDA Drug‐Approval Policy: An Evolving Controversy’, Journal of Health & Social Policy, 2 (1990), 39–46; and Shilts, R., And the Band Played On: Politics, People, and the AIDS Epidemic. New York: St. Martin's Press, 1987.

(109.) Department of Health and Human Services, Food and Drug Administration, ‘New Drug, Antibiotic, and Biological Drug Product Regulations, Accelerated Approval’, Federal Register, 57 (11 December 1992), 58942–60.

(110.) The persistent lag time is discussed in the final rule regarding drug testing in children. See Department of Health and Human Services (DHHS) Public Health Service (PHS) Food and Drug Administration (FDA), 21 CFR Parts 201, 312, 314, and 601, ‘Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients, Part II, Final Rule’, Federal Register, 63 (2 December 1998), 66632–72, 66632–3.

(111.) Department of Health and Human Services (DHHS), Public Health Service (PHS), and Food and Drug Administration (FDA), 21 CFR Part 201, ‘Specific Requirements on Content and Format of Labeling for Human Prescription Drugs; Revision of “Pediatric Use” Subsection In the Labeling, Part II’, Federal Register, 59 (13 December 1994): 64240–50.

(112.) FDA, ‘Regulations Requiring Manufacturers’, 66632.

(113.) Department of Health and Human Services (DHHS), Public Health Service (PHS), and Food and Drug Administration (FDA), ‘Labeling and Prescription Drug Advertising; Content and Format for Labeling for Human Prescription Drugs’, Federal Register, 44 (26 June 1979), 37434–67, 37453.

(114.) Ibid., 37465.

(115.) FDA, ‘Specific Requirements’, 64240–1.

(116.) Ibid., 64242.

(117.) ‘Proceedings of Workshop, Inclusion of Children in Clinical Research’ (5 September 1996), unpublished, on file with author, supplied by Mona Rowe, Deputy Director, Office of Science Policy, Analysis and Communication, National Institute of Child Health and Human Development.

(118.) American Academy of Pediatrics (AAP), Council on Pediatric Research, ‘Meeting the Research Needs of Children and Youth: Research along the Life Cycle’, unpublished, undated manuscript that served as a background piece for the meeting, on file with author.

(119.) Shirkey, ‘Therapeutic Orphan’.

(120.) AAP Committee on Drugs (1995), ‘Ethical Conduct’, 286.

(121.) Department of Health and Human Services, Food and Drug Administration (FDA), 21 CFR Parts 201, 312, 314, and 601, ‘Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients, Part V’, Federal Register, 62 (15 August 1997), 43900–16, 43902.

(122.) Department of Health and Human Services (DHHS), Public Health Service (PHS), and Food and Drug Administration (FDA), 21 CFR Parts 201, 312, 314, and 601, ‘Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients, Part II, Final Rule’, Federal Register, 63 (2 December 1998), 66632–72.

(123.) Food and Drug Administration Modernization Act (FDAMA) of 1997, Public Law 105–15, 111 Stat. 2296 (1997).

(124.) Best Pharmaceuticals for Children Act, Public Law 107–9, 115 Stat. 1408 (2002).

(125.) See Ch. 13, section 9, ‘Further Anecdotal Support’ where I give an example. In response to a written request from the FDA, GlaxoSmithKline (GSK) performed two clinical trials of Flovent (an anti‐inflammatory inhalational medication) for asthma in young children. The data were uninterpretable with respect to both safety and efficacy, and yet GSK was granted six months of additional exclusivity.

(126.) Department of Health and Human Services (DHHS), and US Food and Drug Administration (FDA), ‘The Pediatric Exclusivity Provision, January 2001 Status Report to Congress’. On the web at http://www.fda.gov/cder/pediatric/ reportcong01.pdf. Note a recent article in JAMA discusses the benefits of FDAMA. See Roberts, R., Rodriquez, W., Murphy, D., and Crescenzi, T., ‘Pediatric Drug Labeling: Improving the Safety and Efficacy of Pediatric Therapies’, JAMA, 290 (2003), 905–11.

(127.) Association of American Physicians & Surgeons, Inc. v. FDA, 226 F.Supp.2d 204 (D.D.C. 2002).

(128.) Associated Press, ‘Reversal on “Pediatric Rule” ’, New York Times (20 April 2002), A13. Two of the bills introduced by Congress were S.2394, which would amend the Federal Food, Drug, and Cosmetic Act to require labeling containing information applicable to pediatric patients, introduced in the Senate 29 April 2002, and H.R. 4730, introduced in the House 14 May 2002.

(129.) American Physicians and Surgeons, 222.

(130.) Pediatric Research Equity Act of 2003 (Public Law 108–55).

(131.) Department of Health and Human Services (DHHS), ‘HHS Identifies Drugs for Pediatric Testing and Announces FY 2003 and FY 2004 Funding’, Press Release, 21 Jan. 2003. On the web at: http:/ /www.hhs.gov/news/press/2003pres/ 20030121.html.

(132.) ‘NIH Policy and Guidelines for the Inclusion of Children as Participants in Research Involving Human Subjects’, 6 March 1998. On the web at: http:/ / grants1.nih.gov/grants/guide/notice‐files/not98–024.html.

(133.) National Institutes of Health Office of Extramural Research, ‘Questions and Answers about the NIH Policy and Guidelines on the Inclusion of Children as Participants in Research involving Human Subjects’ (March 1999). On the web at: http:/ /grants.nih.gov/grants/funding/children/pol_children_qa.htm.

(134.) See, e.g., Hilts, P. J., ‘VA [Veteran's Administration] Hospital Is Told to Halt All Research’, New York Times (29 March 1999), A25; Guerrero, L. M., and Herguth, R. C., ‘Human Tests Halted; UIC Projects Suspended after Probe’, Chicago Sun‐Times (28 August 1999), 1; Hilts, P. J., ‘US Halts Human Research (p.41) at Alabama’, New York Times, National edition (22 January 2000), A.10; Stolberg, S. G., ‘Gene Therapy Ordered Halted at University’, New York Times, National edition (22 January 2000), A.1; Hilts, P. J., ‘Safety Concerns Halts Oklahoma Research’, New York Times, National edition (11 July 2000), D.10; and Hubler, E., ‘FDA Move Halts Local Research; Thousands of Projects Suspended at Six CU [Colorado University]‐Affiliated Institutions’, Denver Post (24 September 1999), A.01; Kolata, G., ‘Johns Hopkins Death Brings Halt to US‐Financed Human Studies’, New York Times, National edition (20 July 2001), A1; and Hopper, L., ‘Prisoner Enrollment Halted in Studies; Feds Cite Safety Lapses in Projects at UTMB [University of Texas at Medical Branch at Galveston]’, Houston Chronicle (1 September 2000), A31 (Metfront).

(135.) Koski, G., ‘National Human Research Protections Advisory Commission Transcript, 29 January 2002’. On the web at: http:/ /www.hhs.gov/ohrp/nhrpac/mtg01–02/0129NHR.txt.

(136.) Subpart D, CFR §46.407.

(137.) Nelson, R. M., ‘A Brief History of Protocol Reviews Under 45 CR §46.407’. Presentation at the American Society of Bioethics and Humanities, Montreal, October 2003; and Office for Human Research Protections (OHRP), ‘Children Involved in Research 45 CFR part 46, subpart D’, n.d. On the web at: http:/ / ohrp.osophs.dhhs.gov/cpanl.htm. Another panel was convened in September 2004. The process and evolution of 407 panels are discussed in Chs. 14 and 15.

(138.) Children's Health Act of 2000, Public Law 106–310 (2000).

(139.) National Association of Children's Hospitals, Press Release: ‘Children's Hospitals Herald White House Signing of “Children's Health Act of 2000” ’ (18 Oct. 2000), available at http:/ / www.childrenshospitals.net/nach/news/pr_healthact 2000.asp.

(140.) Children's Health Act, §1003.

(141.) Department of Health and Human Services (DHHS), and Food and Drug Administration (FDA). 21 CFR Parts 50 and 56, ‘Additional Safeguards for Children in Clinical Investigations of FDA‐Regulated Products’, Federal Register, 66 (24 April 2001), 20589–600.

(142.) Children's Health Act, §1003.

(143.) Department of Health and Human Services (DHHS), ‘Protections for Children in Research: A Report to Congress’, May 2001. On the web at: http:// www.hhs.gov/ohrp/reports/ohrp502.pdf

(144.) Ibid., 18.

(145.) Ibid., 22.

(146.) Best Pharmaceuticals for Children Act.

(147.) Field, M. J., Behrman, R. E. (eds.), Committee on Clinical Research Involving Children, the Institute of Medicine (IOM), The Ethical Conduct of Clinical Research Involving Children. Washington DC: National Academies Press, 2004; hereinafter this reference is cited as the IOM, Ethical Conduct.

(148.) Ibid., 13.

(149.) Committee on Assessing the System for Protecting Human Research Subjects, Board on Health Sciences Policy, Institute of Medicine, Preserving Public Trust: (p.42) Accreditation and Human Research Participant Protection Programs. Washington DC: National Academy Press, 2001.

(150.) About the World Medical Association. On the web at: http://www.wma.net/e/about.html.

(151.) 2nd General Assembly of the World Medical Association (WMA], Declaration of Geneva, Geneva Switzerland 1948 reprinted in Beecher, Research and the Individual, 235.

(152.) ‘International Code of Medical Ethics’.

(153.) ‘Draft Code’.

(154.) 18th WMA Declaration of Helsinki.

(155.) The WMA, ‘Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects’ was adopted by the 18th WMA, Helsinki, Finland, 1964; and amended multiple times at WMA meetings: the first revision occurred at the 29th WMA, Tokyo, Japan, 1975. The principle cited is principle III.4. The 1975 version is reprinted in Levine, Ethics and Regulation, 427–9.

(156.) ‘Draft Code’.

(157.) Ibid.

(158.) 18th WMA Declaration of Helsinki.

(159.) Principle 24 of the 2000 and 2002 versions of the Declaration of Helsinki. After the 1975 revisions of Tokyo, Japan, the Declaration of Helsinki has been amended at the 35th WMA, Venice, Italy, 1983, the 41st WMA Hong Kong, China, 1989, the 48th WMA Somerset West, Republic of South Africa, 1996, the 52nd WMA, Edinburgh, Scotland, 2000. Note of clarification on para. 29 added by the WMA General Assembly, Washington 2002. The 2002 version can be found on the web at http://www.wma.net/e/policy/17‐c_e.html.

(160.) This guideline was implemented as principle 11 in the 1983 and 1996 versions of the Declaration of Helsinki. It is moved to principle 25 in the 2000 and 2002 versions. The 2002 version can be found on the web as cited in endnote 159.

(161.) MRC, (1962–3) ‘Responsibility’.

(162.) Ibid.

(163.) The correspondence is described in Curran and Beecher, ‘Experimentation: A Reexamination’, 81.

(164.) Ibid., 83.

(165.) Royal College of Physicians. Supervision of the Ethics of Clinical Research Investigations in Institutions. London, UK: Royal College of Physicians,1973; Department of Health and Social Security, Supervision of the Ethics of Clinical Research Investigations and Fetal Research. London: Department of Health and Social Services, HSC (IS) 153, 1975; and British Paediatric Association (BPA), ‘Guidelines to Aid Ethical Committees Considering Research Involving Children’, Archives of Diseases of Childhood, 55 (1980), 75–7.

(166.) BPA, (1980) ‘Guidelines’, 77.

(167.) Nicholson, Medical Research.

(168.) Ibid., 234.

(169.) MRC (1962–3), ‘Responsibility’.

(170.) Nicholson, Medical Research, 231.

(171.) Ibid., 150–1.

(172.) Ibid., 151.

(173.) Ibid., 151.

(174.) Ibid., 233. Of note, the BPA used the terms negligible, minimal, and more than minimal risk in its 1980 document. See BPA (1980), ‘Guidelines’. The working group on ethics recommended that the British guidelines use the same terminology as the American guidelines (Nicholson, Medical Research, 105ff.). In 1992, the BPA revised its terminology to read minimal, low, and high risks which is NOT consistent with the American terminology. See British Paediatric Association, Guidelines for the Ethical Conduct of Medical Research Involving Children. London: British Paediatric Association, 1992.

(175.) Medical Research Council (MRC), ‘The Ethical Conduct of Research on Children, 1991’, reprinted in the Bulletin of Medical Ethics, 76 (1992), 8–10.

(176.) BPA (1992), ‘Guidelines’.

(177.) Royal College of Paediatrics and Child Health (RCPCH), Ethics Advisory Committee, ‘Guidelines for the Ethical Conduct of Medical Research Involving Children’, Archives of Disease in Childhood, 82 (2000), 177–82

(178.) BPA (1992), ‘Guidelines’, 3; RCPCH, ‘Guidelines’, 177.

(179.) MRC (1992), ‘Ethical Conduct’ Principle 3.2 at 9. The Medical Health Council of Australia has a similar requirement: ‘consent cannot be given for, research that is contrary to the child's or young person's best interests’. See National Health and Medical Research Council Act 1992. http://www.health.gov.au/ nhmrc/publications/pdf/e35.pdf.

(180.) BPA, ‘Guidelines’, 13; RCPCH, ‘Guidelines’, 180. Payment is not mentioned in the US federal regulations, although it is supported by the recent IOM report. See also IOM, Ethical Conduct. This topic is discussed further in Ch. 8, ‘Payment in Pediatric Research’.

(181.) Alderson, P., ‘Did Children Change, or the Guidelines?’ Bulletin of the Institute of Medical Ethics, 150 (1999), 38–44, 43.

(182.) DHHS and FDA, ‘Pediatric Exclusivity Provision’; and Roberts et al., ‘Pediatric Drug Labeling’.

(183.) Rothman, Strangers.

(184.) Belmont Report.

(185.) This is actually a requirement of all research, not just pediatric research. It is a principle espoused in virtually all national and international guidelines. It is discussed in greater detail in Ch. 10, ‘Minimizing Risks: Diabetes Research in Newborns’.

(186.) Ramsey, Patient as Person, 26; Jonas, H., ‘Philosophical Reflections on Experimenting with Human Subjects’ in P. A. Freund (ed.), Experimentation with Human Subjects. New York: Braziller, 1970, 1–31, 28–9.