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Part II

Chapter 7


The Context for Nontherapeutic Research with Children

Risk of Harm and Nontherapeutic Research with Children

Beyond Risk: Other Dimensions of the Ethics of Nontherapeutic Research on Children

The Studies at the Fernald School


Chapter 7: The Context for Nontherapeutic Research with Children

Children as Mere Means

In both law and medical ethics, it has long been recognized that children may not authorize medical treatment for themselves, except in special circumstances.[4]Instead, authorization must be sought from the parent. Historically, the source of this respect for parental authority rested upon the view that children were the property of their parents, and thus parents had the right to determine how their "property" was to be treated. Today, we still speak of parental rights, although the justification for these rights no longer rests on an analysis of children as property. Instead, respect for the rights of parents is viewed as a mechanism for valuing and fostering the institution of the family and the freedom of adults to perpetuate family traditions and commitments. Another important line of justification for respecting the authority of parents relies not on a recognition of parental rights but on the view that the interests of the child are generally best served by ceding decisional authority to the parent. The parent is thought not only to be in the best position to determine what is in the interests of the child but is also thought to be generally motivated to act in the child's best interests.[5]

When research involving children offers a prospect of medical benefit to the child-subject, the application of the above analysis is straightforward. Parents are generally thought to have the authority to determine whether their children should be made subjects of such research. Certainly today, any use of a child in research would not be ethically acceptable or legally permissible without the parent's permission.[6] Where the research does not offer any prospect of benefit to the child, however, the legitimacy of the parent as authorizer is less clear.

Respect for the authority of parents to make decisions for their children and otherwise control their children's lives is not without bounds. The law recognizes several exceptions, designed primarily to protect the child from what society at large considers to be unacceptable or unjustifiable harm or risk of harm.[7] Laws against the physical abuse of children are perhaps the most obvious example of such limitations on parental authority. In the context of research, the question arises of whether a parent has the authority to permit a child to be put at risk of harm in an experiment from which the child could not possibly benefit medically. In this case, the child is to be used as a means to the ends of others. Children are not in a position to determine for themselves whether they wish to agree to such a use and thus cannot themselves render the use morally acceptable. Should parents have such authority? Should anyone?

This question was resolved as a matter of public policy in the 1970s through the work of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research and the subsequent adoption, in 1983, of federal regulations governing research involving children that were guided by the recommendations of the National Commission.[8] These regulations state that children can participate in federally funded research that poses greater than minimal risks to the subject if a local review committee (an institutional review board, or IRB) finds that the potential risk is "justified by the anticipated benefit to the subjects"; "the relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches"; and "adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians."[9] The word consent is purposely avoided in these regulations to distinguish parental permission and minor assent from the autonomous, legally valid consent of a competent adult.

Federal regulations do allow nontherapeutic research on children if an IRB determines that the research presents "no greater than minimal risk" to the children who would serve as subjects, although no clear definition of what constitutes minimal risk is provided.[10] As with therapeutic pediatric research, parents or guardians must grant "permission" and children who are deemed capable must offer "assent."

The regulations also allow for nontherapeutic research with children that does present more than minimal risk, again with parental permission and assent of the child (as appropriate), but only if the risk represents a minor increase over minimal risk, the procedures involved are commensurate with the general life experiences of subjects, and the research is likely to yield knowledge of "vital importance" about the subjects' disorder or condition.[11] Research with children that is not otherwise approvable may be permitted, but only under special, and presumably rare, circumstances. In addition to local IRB review, such research must withstand the special scrutiny of the secretary of the agency sponsoring the research, who is to be advised by a special IRB.[12] The secretary must also allow the opportunity for "public review and comment" on a proposed nontherapeutic research project that is not otherwise approvable.

The regulations thus draw a sharp distinction between therapeutic and nontherapeutic research. Nontherapeutic research, while severely restricted, is not banned. The decision to permit parents to authorize the use of their children in nontherapeutic research reflects both the recognition that some important advances in pediatrics could come only from research with children that was of no benefit to them and the recognition that we all--as parents, as potential future parents, and as members of society--share in the interest of advancing the health of the young. At the same time, however, parental authority to permit such use of a child is generally restricted to research judged to pose little risk; as important as it is to promote the welfare of children (as a class), this interest justifies only minor infringements of the principle not to use people as mere means to the ends of others.

These 1983 regulations, and the reasoning behind them, were the culmination of considerable public debate and scholarly analysis, much of which occurred in the 1970s. To situate properly the experiments of interest to the Committee, it is necessary to examine the social and professional roots of the issues and arguments that ultimately led to the federal regulations.

Public Attitudes, Professional Practices

Attitudes and Practices Prior to 1944

There was significant research interest in infants and children as early as the eighteenth century, as scientists began to experiment with vaccines and immunization. Children were particularly valuable subjects for this type of research because in general, they were less likely than adults to have been exposed to the disease being studied.[13] A child's response to immunizations was also of great interest because most immunizations are performed during childhood.

During the nineteenth century, the Industrial Revolution greatly increased the number of child laborers, and the public began to acknowledge the need for laws to protect children from abuse.[14] Physicians started to specialize in pediatrics, studying specifically the health problems and diseases that afflicted children. Simultaneously, as social reformers were creating a wide range of institutions for children, such as orphanages, schools, foundling homes, and hospitals, scientists recognized the value of research conducted in these types of institutions. In the late nineteenth and early twentieth centuries, Alfred F. Hess, the medical director of the Hebrew Infant Asylum in New York City, conducted pertussis vaccine trials and undertook extensive studies of the anatomy and physiology of digestion in infants at the asylum. According to Advisory Committee member and historian Susan Lederer, Hess sought to take advantage of the conditions in the asylum as they approximated those "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 infestation in man."[15]

Although many shared Hess's laudable goal of improving the health of asylum children, many people drew the line at the pediatrician's investigations of scurvy and rickets. In order to study the disease, Hess and his colleagues withheld orange juice from infants at the asylum until they developed lesions characteristic of scurvy. Responding to the public discussion of the ethics of using children in such nontherapeutic experiments, the editors of one American medical journal insisted that such investigations gave the children an opportunity to repay their debt to society, even as they conceded that experimentation on human beings should be limited to "children as may be utilized with parental consent."[16]

Hess's work was not the only case in which experiments involving children attracted negative public opinion. In 1896, for example, American antivivisectionists attacked a Boston pediatrician, Arthur Wentworth, who performed lumbar punctures on infants and children in order to establish the safety and utility of the procedure. The antivivisectionists were particularly alarmed because this procedure, which caused pain and discomfort, did not confer any benefits to the subjects. John B. Roberts, a physician from Philadelphia, labeled Wentworth's procedures "human vivisection," saying that "using the children in the hospital without explaining his plan to their mothers or gaining their permission intensified public fear of hospitals."[17]

The twentieth century brought new drugs and advanced technologies, which allowed for increased research on children. The conduct of this experimentation, however, was largely left to the individual investigator. When his experimental gelatin injections provoked "alarming symptoms of prostration and collapse in three normal children (including a 'feeble-minded' four-year-old girl), the physician Isaac Abt stopped his pediatric experiments and began experimenting on rabbits."[18] Meanwhile, legislation was being proposed throughout the country to protect children and pregnant women from experimenting physicians. Two proposals were introduced in the U.S. Senate in 1900 and 1902; proposals "'to prohibit such terrible experiments on children, insane persons and pregnant women . . . ,' and to ensure 'that no experiment should be performed on any other human being without his intelligent written consent' were introduced in the Illinois legislature" in 1905 and 1907; in 1914 and 1923, the New York legislature considered bills that prohibited experimentation with children.[19] Although these bills did not become law, it is clear that some unease concerning nontherapeutic research on children existed among the public and elected officials.

Reaction to the polio vaccine trials conducted during the 1930s further demonstrated the growing discomfort over pediatric experimentation as thousands of American children were involved in what some considered at the time to be premature human trials of the polio vaccine. Although it appears that parental consent was obtained for a number of these studies, the controversy over these trials stalled polio vaccine research for almost two decades and generally made investigators ambivalent about the use of human subjects.[20]

Although there are no legal cases that bear directly on nontherapeutic research with children during this period, an appellate court ruling in 1941, Bonner v. Moran, involving the performance of a nontherapeutic medical procedure on a child without parental consent, suggests how such a case might have been decided.[21] John Bonner, a fifteen-year-old African-American boy from Washington, D.C., had undergone an experimental skin graft for the benefit of Clara Howard, a cousin suffering from severe burns. When he discovered that John Bonner had the same blood type as the burn victim, Howard's plastic surgeon, Robert Moran, persuaded Bonner to allow him to fashion "a tube of flesh" by cutting from the boy's "arm pit to his waist line."[22] This procedure, however, was conducted without the consent of a parent, as "his mother, with whom he lived, was ill at the time and knew nothing about the arrangement."[23] Moran then attached the free end of Bonner's flesh tube to Clara Howard, hoping that the flesh-and-blood link would bring benefit to the burned girl. Due to poor circulation in the tube, the procedure did not help the burn patient and put the healthy boy, who was required to stay in the hospital for two months, at significant risk (and left him with permanent scars). Bonner's mother brought suit against Moran for assault and battery.

The appellate court based its ruling against Moran on what it perceived as a disturbing combination of a lack of direct benefit for John Bonner and a lack of permission from the boy's mother:

[H]ere we have a case of a surgical operation not for the benefit of the person operated on but for another. . . . We are constrained, therefore, to feel . . . that the consent of the parent was necessary.[24]

The court did not refer to the episode as an instance of experimentation, but the parallels between this novel procedure performed for the benefit of another and a nontherapeutic medical experiment are quite powerful.[25]

Attitudes and Practices 1944-1974

As best the Committee can establish, there were no written rules of professional ethics for the conduct of research on children prior to 1964. Taken literally, the Nuremberg Code, which requires that all subjects of research "have legal capacity to give consent," precludes all research with children.[26] There is no reason to believe, however, that the judges at Nuremberg meant to impose such a prohibition, and the Nuremberg Code did not result in a ban on research with children.

Pediatric research flourished after World War II, as did biomedical research in general. What is less clear is how this research was conducted, and on whom. One source of evidence about legal thinking on pediatric research, if not actual practice, is the writings of Irving Ladimer, a lawyer who, in 1958, was completing a doctoral degree in juridical science at the same time he was employed as an administrator at the National Institutes of Health. Ladimer concluded his doctoral dissertation, "Legal and Ethical Implications of Medical Research on Human Beings," with an appendix devoted to the issues surrounding "Experimentation on Persons Not Competent to Provide Personal Consent," whom he defined broadly as minors and mental incompetents.[27] Ladimer argued that it was "permissible to employ minors and incompetents as subjects of medical investigations . . . where there is informed consent by a parent or guardian (including the state) for procedures which also significantly benefit or may be expected to benefit the individual."[28] Ladimer was less sanguine, however, about nontherapeutic research with these populations. He expressed particular concern about the use of institutionalized children--even with proxy permission--in research that did not hold the possibility of personal benefit: "Permission given by parents or the state to utilize institutionalized children, without any suggestion of benefit to the children, may well be beyond the ambit of parental or guardianship rights."[29]

Ladimer did, however, leave open a window for the use of legally incompetent subjects in nontherapeutic research, but he clearly harbored great discomfort with his own suggestion:

[T]he availability of certain persons, not able to consent personally, may constitute a strategic resource in terms of time or location not otherwise obtainable. It must be remembered, however, that the Nazis hid behind this rationalization in explaining certain highly questionable or clandestine medical experiments. Such justification should not even be considered except in dire circumstances. If ever employed, it should not be assimilated into the concept of personal benefit, else there may be no legal or ethical control for the protection of both prospective subject and investigator and their individual integrity.[30]

As part of the Committee's Ethics Oral History Project, we interviewed two pediatricians who were beginning their careers in academic medicine in the late 1940s. One of these respondents, Dr. Henry Seidel, had some research experience with institutionalized children. He noted that "we got access [to the children] very easily," and although his research was merely observational, it was "not hard to imagine" that experimental research with these children could have been conducted.[31] When asked about the studies conducted by Dr. Saul Krugman on institutionalized children at the Willowbrook State School (discussed later in this chapter), Seidel observed, "I didn't have any problem imagining that possibility. In retrospect, I'm sure it could happen, you know. There was something about those reports that rang true. . . ."[32] William Silverman, the other pediatrician interviewed, had clear recollections of how research was conducted in pediatrics at that time. He recalled that, in the 1950s, many pediatricians, including himself, believed that it was not necessary to obtain the permission of parents before using a pediatric patient as a subject in research--even if the research was nontherapeutic (he has since become a strong proponent of the parental permission requirement in pediatric research).[33] He also asserted that performing nontherapeutic experiments on children without authorization from parents was part of a broader "ethos of the time" in which "everyone was a draftee" in a national war on disease.[34] Dr. Silverman's account squares with the picture that emerged in chapter 2 of practices in research with adults, in which it was not uncommon to use adult patients as subjects of research without their knowledge or consent.

Silverman was among the researchers invited by Boston University's Law-Medicine Research Institute (LMRI) to participate in a conference on "Social Responsibility in Pediatric Research" held in May 1961.[35] This meeting was one in a series of closed-door conferences organized by LMRI to investigate actual practices among clinical researchers. The transcripts of the conference provide an important window onto practices and attitudes of the time; in large measure, they confirm Silverman's recollection of his own position some thirty-five years ago. Early in the meeting, Silverman asserted that "there is an unwritten consent by being a living person at this time to participate in this kind of advancement of knowledge [that is, nontherapeutic pediatric research]."[36] Some of the other participants employed the same analogy to the military draft that Silverman recently used to relate his recollections.

However, there was by no means unanimity about the appropriateness of this view:

Dr. A: [Dr. B] says that this [research without consent] is like military conscription.

Dr. C: Not comparable. We voted to do military conscription.[37]

The proceedings of the conference suggest that while it may not have been uncommon for pediatric patients to be used as subjects of nontherapeutic research without the permission of their parents, at least some physician-investigators, including investigators who followed this practice, thought it was morally wrong to do so. Consider, for example, a story relayed by one pediatrician-investigator at the conference who seemed to embrace with particular earnestness the desire of the conference organizers to learn the unvarnished reality of clinical research. In the opening minutes of the meeting, this researcher reminded his colleagues that "the question for us to discuss here today is how we operate on a daily basis."[38] He offered for discussion a provocative case from his personal experience in which he and his associates "wanted [to do] lumbar punctures on newborns."[39] He explicitly noted that "this study [was] not of benefit to the individual; it was an attempt to learn about normal physiology."[40] One of the other conferees asked, "Did you ask [parental] permission?" The researcher responded, "No. We were afraid we would not get volunteers."[41] The case prompted a great deal of discussion at the conference, but perhaps most tellingly this researcher frankly acknowledged toward the end of the discussion--in a meeting that had begun with an assurance of confidentiality from the organizers--that he had "sinned" in carrying out these lumbar punctures in "normal infants" without parental permission.[42]

The proceedings of the conference also suggest that at least some pediatrician investigators routinely obtained the permission of parents before embarking on research with their children. It is perhaps significant that the pediatric researcher who articulated this position at the conference was from Canada--and the conference transcript seems to suggest that he was providing a general characterization of practices in his country:

Dr. A: Let's ask [Dr. B] from Canada.

Dr. B: We have been quite sticky on consent. If we want a biopsy or a radioactive exposure and the parent says "no" then we don't do it. . . . The question of morals is too valuable.[43]

If this statement represents the sensitivity of Canadian pediatrician-investigators to issues of parental permission (which this single quotation does not prove), there is no obvious explanation as to why many of their colleagues in the United States behaved differently.

The LMRI conference is noteworthy not only for what it reveals about the range of views and practices concerning parental permission for nontherapeutic research, but also for the unanimity expressed about the importance of obligations to prevent or minimize harm to pediatric subjects of research. Minimizing risk was recognized by those at the conference as the most important (and, for some participants, the only) moral duty of pediatric investigators.[44]

Three years after the LMRI conference, in the summer of 1964, the World Medical Association ratified a code of ethics for human experimentation at a meeting in Helsinki. Unlike the Nuremberg Code, this statement, known as the Declaration of Helsinki, recognizes that research may be conducted on people with "legal incapacity to consent."[45] The Declaration distinguishes between two kinds of research: "Clinical Research Combined with Professional Care" and "Non-therapeutic Clinical Research."[46] It permits the use of people with legal incapacity to consent as subjects in both kinds of research, provided that the consent of the subject's legal guardian is procured.

Subjects of the first kind of research are referred to as patients; disclosure to and consent from patient-subjects are required by the Declaration, "consistent with patient psychology."[47] The Declaration does not specify whether considerations of "patient psychology" also could justify not obtaining the consent of the guardian where the subject does not have the legal capacity to consent.

The subjects of "non-therapeutic clinical research" are not referred to as patients but as human beings who must be "fully informed" and whose "free consent" must be obtained.[48] The Declaration also requires that nontherapeutic research be discontinued if in the judgment of the investigators to proceed would "be harmful to the individual."[49] Thus, although the Declaration permits parents to authorize the use of their children as subjects in nontherapeutic research, such research is not intended to be "harmful" to the subjects.

The language and reasoning of the Declaration was unclear and confusing with regard to clinical research, both therapeutic and nontherapeutic, on legally incapacitated individuals. It was revised in 1975, at a time when the ethics of research with human subjects was receiving considerable public attention in the United States (see chapter 3).

Both in the 1960s and early 1970s, public controversies erupted about several cases of research involving human subjects, controversies that led to the establishment of the National Commission and publication of the federal regulations (see chapter 3). One of the most well known of these cases involved research on institutionalized children. During the 1950s and 1960s, Dr. Saul Krugman of New York University conducted studies of hepatitis at the Willowbrook State School, an institution for the severely mentally retarded.[50] To study the natural history, effects, and progression of the disease, Krugman and his staff systematically infected newly arrived children with strains of the virus. Although the investigators did obtain the permission of the parents to involve their children in the research, critics of the Willowbrook experiments maintained that the parents were manipulated into consenting because, at least in the later years of the research, the institution was overcrowded and the long waits for admittance were allegedly shorter for children who were entering the research unit. Henry Beecher, a Harvard anesthesiologist whose impact on the history of research ethics is detailed in chapter 3, condemned Krugman and his staff for not properly informing the parents about the risks involved in the experiment.[51] Beecher also challenged the legal status of parental consent when no therapeutic benefit for the child was anticipated. A New York state senator, Seymour R. Thaler, criticized the Willowbrook research on the pages of the New York Times in 1967, only to come to its defense later in 1971. Also in the early 1970s Willowbrook became the subject of a heated debate in the medical literature.[52]

Interestingly, Dr. Krugman was one of the participants at the LMRI "Social Responsibility in Pediatric Research" conference where he expressed pride that he routinely obtained permission from the parents of the children in his studies. In that group in 1961, Krugman was thus among those pediatric investigators most sympathetic to the position that children could not be used as mere means to the ends of the researcher without the authorization of the parent.

AEC Requirements for Radiation Research With Children

Although in the 1940s and 1950s there were apparently no written rules of professional ethics for pediatric research in general, there were guidelines for the investigational use of radioisotopes in children. In 1949, the Subcommittee on Human Applications of the Atomic Energy Commission's Isotope Division established a set of rules to judge proposals submitted by researchers for the use of radioisotopes in medical experiments with human subjects, including "normal children."[53] These standards appeared in the fall 1949 supplement to the AEC's isotope catalogue and price list. Under the heading "Normal Children" the isotope catalogue offered the following statement:

In general the use of radioisotopes in normal children is discouraged. However, the Subcommittee on Human Applications will consider proposals for such use in important researches, provided the problem cannot be studied properly by other methods and provided the radiation dosage level in any tissue is low enough to be considered harmless. It should be noted that in general the amount of radioactive material per kilogram of body weight must be smaller in children than that required for similar studies in the adult.[54]

These guidelines did not mention consent--of parents, guardians, or children.[55] Instead, this statement simply discouraged nontherapeutic experiments with children. The guidelines did not, however, suggest that the practice was completely inappropriate; the subcommittee asserted that "important" research using "harmless" levels of radiation dosage with children was acceptable. The crucial terms important and harmless were left undefined.

It seems reasonable to expect that "important" pediatric research would address a significant medical problem affecting children or would explore key aspects of normal human physiology--relevant to health promotion or disease prevention--for which research on children is indispensable. By these standards, the twenty-one nontherapeutic radiation experiments with children whose risks we review in the next section of this chapter could all be said to address important questions relevant to pediatric health care. This judgment is not based on a determination of whether a given study proved important in the subsequent development of a particular field. Such retrospective analysis would place an unreasonable burden on investigators of the past, as research is an inherently speculative enterprise. Many experiments that prove to be of little value in the advance of medical knowledge are, at the time they are implemented, well designed and appropriate attempts to address important research questions.

It is easier to infer what the members of the AEC Subcommittee on Human Applications would have considered "important" research than what the subcommittee would have considered "harmless" radioisotope research. Acute toxicity is not seen following administration of nontherapeutic (tracer) doses of radioisotopes. Thus, the principal potential harm from radiation exposure at lower doses is the subsequent development of cancer. In the 1940s and 1950s, some in the field apparently discounted the risk, while others were wary of a prevailing uncertainty. Dr. John Lawrence, an early radioisotope researcher at the University of California, described how some researchers conducted public demonstrations of tracers, using an “unsuspecting physician out of the audience to act as the guinea pig,” presumably to reassure the audience that tracers were innocuous.[56] By contrast, other investigators focused on the tragedy of the radium dial painters, concerned that this might be repeated with man-made radionuclides.

Evidence of how well the AEC enforced its 1949 guidelines with respect to research on children is elusive (see chapter 6). AEC correspondence with researchers at the Fernald School suggests that in at least one case there was oversight of research in which children were administered radioisotopes.[57]

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