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Grimes v. Kennedy Krieger Institute: Revisiting the Ethical Issues

The Grimes v. Kennedy Krieger Institute case (366 Md. 29, 782 A.2d 807) in 2001 reinvigorated the debate over core ethical issues raised by conducting research with children, especially children who are economically and educationally vulnerable. Many researchers and scholars criticized the decision as being inconsistent with the federal regulations and forbidding valuable research allowed under these regulations (Ross, 2002; Amici Curiae Association, 2000). Other scholars argued that with some modifications to research protocols, research on abatement of housing hazards could still be carried out under the more protective terms of the ruling (Kopelman, 2002; Nelson, 2005). Regardless of one’s position, the ruling illustrated the complexity of the ethical issues involved and the continuing need to debate and refine guidelines for conducting research involving children and families in the context of changing cultural norms and expectations and scientific developments.

This chapter provides a brief summary of Grimes v. Kennedy Krieger Institute with a focus on the core ethical issues raised by the court’s opinion; presents the reasoning reflected in the current federal regulations in light of issues raised by the court’s opinion; and introduces the current federal regulations governing research involving human participants (“subjects”).

Although the federal regulations refer to humans involved in research as research “subjects,” other recent National Academies reports and the National Bioethics Advisory Committee (NBAC) have adopted the term “participants.” NBAC rejected the traditional term in part because it connotes a power imbalance between volunteers and investigators, suggesting that the volunteer is “under the rule of (and being obedient to) the investi-



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Ethical Considerations for Research on Housing-Related Health Hazards Involving Children 3 Grimes v. Kennedy Krieger Institute: Revisiting the Ethical Issues The Grimes v. Kennedy Krieger Institute case (366 Md. 29, 782 A.2d 807) in 2001 reinvigorated the debate over core ethical issues raised by conducting research with children, especially children who are economically and educationally vulnerable. Many researchers and scholars criticized the decision as being inconsistent with the federal regulations and forbidding valuable research allowed under these regulations (Ross, 2002; Amici Curiae Association, 2000). Other scholars argued that with some modifications to research protocols, research on abatement of housing hazards could still be carried out under the more protective terms of the ruling (Kopelman, 2002; Nelson, 2005). Regardless of one’s position, the ruling illustrated the complexity of the ethical issues involved and the continuing need to debate and refine guidelines for conducting research involving children and families in the context of changing cultural norms and expectations and scientific developments. This chapter provides a brief summary of Grimes v. Kennedy Krieger Institute with a focus on the core ethical issues raised by the court’s opinion; presents the reasoning reflected in the current federal regulations in light of issues raised by the court’s opinion; and introduces the current federal regulations governing research involving human participants (“subjects”). Although the federal regulations refer to humans involved in research as research “subjects,” other recent National Academies reports and the National Bioethics Advisory Committee (NBAC) have adopted the term “participants.” NBAC rejected the traditional term in part because it connotes a power imbalance between volunteers and investigators, suggesting that the volunteer is “under the rule of (and being obedient to) the investi-

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Ethical Considerations for Research on Housing-Related Health Hazards Involving Children gator” (National Bioethics Advisory Committee, 2001, p. 33), which is inconsistent with a central tenet of research ethics: that volunteers are autonomous agents, free to choose whether to participate or to withdraw from a study. Adopting the term “participant” addresses this by suggesting that the volunteer is a willing partner in the research enterprise. However, as pointed out by some members of NBAC, many persons who are enrolled in studies are not free and equal participants, and the use of the term “participant” may send a false signal that less vigilance is needed to protect human research participants. Furthermore, the term “participant” does not accurately apply to children, particularly infants and very young children, who are too young even to assent to research. Overall, the term “participant” conveys the aspiration of reducing the power imbalance between researchers and the persons they study. The committee was mindful of these views in its deliberations and in its conclusions and recommendations. The committee has adopted the term participant when referring to general research protection issues, including the federal regulations, but we have retained the term subject when referring specifically to children given the inability of most children to be “free and equal participants.” As noted in Chapter 1, an analysis of the merits of the Grimes case or the court’s ruling is beyond the charge to this committee: the committee’s consideration of the study and ruling is limited to an analysis of the broad and complex ethical issues raised by the case that are pertinent to research on housing health hazards involving children. This chapter presents the committee’s rationale for embracing the balancing of risks and benefits reflected in the federal regulations and rejecting the suggestion that parents not be allowed to enroll children in research that does not offer the prospect of direct benefit (“nontherapeutic” research), core issues raised by the ruling. Other issues raised by the case, including research involving vulnerable populations, the informed consent process, and research oversight, form part of the basis for more detailed discussion in later chapters of the report. BACKGROUND Grimes v. Kennedy Krieger Institute has become a key case in the recent history of concern about ethical issues in research. The federal government began overseeing research that involves human participants in 1974, creating a framework for independent review of research protocols and requiring informed consent from participants to assure that research would be conducted in an ethically responsible manner. The regulations that the U.S. Department of Health and Human Services (DHHS) and other federal agencies adopted were based primarily on the recommendations of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The commission reviewed the available

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Ethical Considerations for Research on Housing-Related Health Hazards Involving Children literature and the complex debates over the ethical principles for human participants research, especially research with vulnerable populations. On several contentious issues the National Commission tried to strike compromises among conflicting interests and principles. The Case The case arose from a lead abatement study (repair and maintenance study) in Baltimore, Maryland, to compare and evaluate the effectiveness of low-cost lead control measures (Johns Hopkins University, 2001) by the Kennedy Krieger Institute of John Hopkins University. Almost all (95 percent) of the private low-income housing in Baltimore at the time had lead-based paint in the home (Johns Hopkins University, 2001). Both the blood lead levels of the enrolled children and environmental samples to measure lead levels inside and outside the homes were monitored during the study; see Box 3-1 for further details about the study. BOX 3-1 The Kennedy Krieger Study The goal of the repair and maintenance (lead abatement) study was to determine the efficacy of lead abatement methods in the home at reducing children’s exposure to residential paint and dust. The study had five test groups, each with 25 houses. The first three groups were the intervention groups and consisted of homes known to have lead present. The amount of repair and maintenance conducted in these homes increased from Group 1 to Group 2 to Group 3. The fourth group consisted of homes that had had lead present at one point, but had received previous lead abatement. The fifth group consisted of homes built after 1980 and presumably never had lead present (366 Md. at 34). The fourth and fifth groups served as the control groups for the study; there were no families living in homes with unattended lead hazards. After it was determined that a home met the criteria to be in an intervention group, it was randomly assigned to either Group 1, 2, or 3 (366 Md. 29 (2001)). Group 1 interventions included wet scraping of peeling and flaking paint on all interior surfaces; repainting treated areas; installation of window well caps; repainting exterior window trim and interior window sills; vacuuming of all horizontal surfaces and window components with a high-efficiency particulate vacuum; and wet cleaning all horizontal surfaces. Group 2 interventions included all the elements from Group 1 plus the use of sealants and paints to make floors smoother and more easily cleanable and in-place window and door treatments to reduce abrasion of lead-painted surfaces. Group 3 added window replacement and encapsulation of exterior door trim with aluminum, and the use of coverings on some floors and stars to make them smooth and more easily climbable.

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Ethical Considerations for Research on Housing-Related Health Hazards Involving Children Grimes v. Kennedy Krieger Institute, heard by the Maryland Court of Appeals, the highest court in the state, began as two separate lawsuits brought by the mothers of two children who were study subjects. The plaintiffs in both cases alleged that the researchers and the Kennedy Krieger Institute were negligent in the way they conducted the study and breached their duty of care to the children by failing to notify their parents of the risks of their children’s exposure to lead. The plaintiffs’ case was based on three basic contentions: (1) that the study design placed child subjects at an unacceptable level of risk; (2) that the institute did not adequately inform the mothers of the risks associated with the study; and (3) that the institute took too long to notify the mothers of elevated levels of lead (366 Md. 29). Court Rulings The trial court issued a summary judgment1 in favor of the defendants, ruling that the plaintiffs’ cases could not proceed because, as argued by the defendants, the researchers owed no legal duty of care to the research subjects. The Maryland Court of Appeals consolidated the two cases into one and overruled the trial court, holding that researchers do have a legal duty of care to research subjects and that both plaintiffs presented enough evidence to proceed to trial (366 Md. at 33). The appeals court ruled that the plaintiffs had presented enough evidence, when interpreted in a light most favorable to them, to support a potential finding of a legal duty and sent it back to the lower court for trial. In doing so, the court was not indicating that the plaintiffs would win at trial, only that there was enough evidence on the specific issue of a duty of care owed by the researchers to subjects for the case to go to trial. The ruling harshly criticized the design of the study and the research oversight process and raised legal and ethical issues related to the exploitation of vulnerable populations, institutional review and oversight of research, and the informed consent process. In addition, the appeals court ruled against allowing research which poses a risk of harm to child subjects in the study but does not offer them a prospect of direct therapeutic benefit. The next section discusses each of these issues. 1   A summary judgment is requested before a case goes to trial when a party in the case argues that there are no facts in dispute to necessitate a trial. In making the decision whether or not to grant summary judgment, the judge must “view the facts, including all inferences, in the light most favorable to the” party opposing the request for summary judgment (366 Md. at 72).

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Ethical Considerations for Research on Housing-Related Health Hazards Involving Children ISSUES RAISED BY THE APPEALS COURT RULING Duty of Care The court ruled that a researcher owes a research subject a legal duty of care, or is legally required to take reasonable actions to protect that person from foreseeable harms. The court described this duty of care as follows: This duty requires the protection of the research subjects from unreasonable harm and requires the researcher to completely and promptly inform the subjects of potential hazards existing from time to time because of the profound trust that participants place in investigators, institutions, and the research enterprise as a whole to protect them from harm [emphasis added] (366 Md. at 103). In this case, the court suggested that the researchers would have needed to provide more information about risks in the consent process and would have needed to provide certain environmental and biological sample test results sooner than they did in order to satisfy their duty to the child subjects (Wolf, 2004).2 However, there were insufficient facts presented in the summary judgment to determine exactly what information the Kennedy Krieger Institute would have needed to provide the plaintiffs to satisfy that duty and whether it had done so (Wolf, 2004). The court based its ruling in part on the “profound trust that participants place” in researchers. While the reliance on a researcher is a legally significant aspect of the relationship that supports the finding of a duty of care, there are also important ethical considerations based on the trust established between a researcher and a research subject’s parents. Parents might reasonably expect that their children will be protected from unreasonable harms and rely on researchers to fully inform them of hazards in their home and risks to their child’s health related to the topic of research. In fact, one plaintiff contended that the Kennedy Krieger Institute was negligent because it failed to inform her of the test results that indicated there were potentially dangerous levels of lead in her home, implying that her child’s involvement in the study and having her house examined by the investigators “gave her a false sense of security that there were no potential lead-based paint or dust hazards in her house” (366 Md. at 65). 2   The informed consent document stated that the Kennedy Krieger Institute would provide specific blood lead results and contract families to discuss a summary of the environmental results and possible steps to reduce any risks of exposure.

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Ethical Considerations for Research on Housing-Related Health Hazards Involving Children Exploitation of Vulnerable Populations Reflecting the apparent outrage of the court, the ruling compared the study to several egregiously unethical research studies. Most notable among these was the Tuskegee syphilis study, in which researchers followed a group of black men infected with syphilis for more than 30 years without informing them of their disease or of the availability of treatment with penicillin when it became available, in order to observe the natural history and long-term effects of the illness (Institute of Medicine, 2004). Although the court explicitly states that the Kennedy Krieger Institute study “differs in large degree from” studies such as Tuskegee (366 Md. at 43), it was clearly concerned that landlords, in its view, were at a minimum encouraged and possibly required to rent to families with children as a condition of receiving abatement resources. The court pointed out that each of the unethical studies involved persons who are members of vulnerable populations: “uneducated African-American men, debilitated patients in a charity hospital, prisoners of war, inmates of concentration camps and others falling within the custody or control of the agencies conducting…the experiments. In the present case, children, especially young children living in lower economic circumstances, albeit not as vulnerable as the other examples, are nonetheless, vulnerable as well” (366 Md. at 45). Using this analogy, the court concluded that in-house processes to review research are inappropriate and ineffective to ensure the ethical treatment of humans enrolled in research, especially members of vulnerable populations (366 Md. 29). Institutional Review Process The court heavily criticized the John Hopkins University Joint Committee on Clinical Investigation, the institutional review board (IRB) that reviewed and approved the Kennedy Krieger Institute repair and maintenance study, regarding suggestions made to the researchers about amending the protocol so that it would comply with federal regulations and therefore qualify for federal funding. Although the Kennedy Krieger Institute initially presented the study to its IRB as having no prospect of direct benefit, the IRB recommended changing the category of research to providing a prospect of direct benefit, thereby lowering the criteria for review. In its critique of the suggestions made, the court pointed out that “[o]ne of the most important objectives of such [IRB] review is the review of the potential safety and the health hazard impact of a research project on the human subjects of the experiment, especially on vulnerable subjects such as children” and emphasized that an IRB’s “function is not to help researchers seek funding for research projects” [emphasis in original] (366 Md. at 39).

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Ethical Considerations for Research on Housing-Related Health Hazards Involving Children The court stated that the Johns Hopkins IRB had “abdicated that responsibility” in the interest of securing funding for the study and instead “encouraged the researchers to misrepresent the purpose of the research in order to bring the study under the label of “therapeutic” and thus under a lower safety standards of regulation” (366 Md. at 39). More generally, the court stated that IRBs “are, primarily, in-house organs. In our view, they are not designed, generally, to be sufficiently objective in the sense that they are as sufficiently concerned with the ethicality of the experiments they review as they are with the success of the experiments” (366 Md. at 45). The decision overall expresses great mistrust of not only the specific research project but also of the system of research oversight. Informed Consent The court examined at length the adequacy of the forms provided to parents to provide consent for their children to participate in the research. It seriously questioned whether or not the Kennedy Krieger Institute had provided sufficient information to the mothers about the study design and goals and the risks to their children associated with enrolling in the study so as to obtain truly free and informed consent. Related to the issue of parents’ expectations that their children would be protected from foreseeable harms, as discussed above, the court concluded that the “informed consent was not valid because full material information was not furnished to the subjects or their parents,” with this line of argument: [a] reasonable parent would expect to be clearly informed that it was at least contemplated that her child would ingest lead particles, and that the degree to which lead dust contaminated the child’s blood would be used as one of the ways in which the success of the experiment would be measured…. Whether assessed by a subjective or an objective standards, the children, or their surrogates, should have been additionally informed that the researchers anticipated that, as a result of the experiment, it was possible that there might be some accumulation of lead in the blood of the children (366 Md. at 90). This statement points out the critical nature of informed consent and the vital importance of ensuring that parents of potential subjects understand the research study and the risks associated with enrollment. The ruling challenges researchers, sponsors, and IRBs to rethink important ethical issues concerning research on housing health hazards involving children (Glantz, 2002; Nelson, 2005). It suggests stricter limits on risks to vulnerable child subjects, broader informed consent discussions, and stronger IRB review.

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Ethical Considerations for Research on Housing-Related Health Hazards Involving Children Research Risks to Children The court held that a parent or guardian cannot consent to a child’s enrollment in “nontherapeutic” research in which there is any risk of harm to the child that “parents, whether improperly enticed by trinkets, food stamps, money or other items, have no more right to intentionally and unnecessarily place children in potentially hazardous nontherapeutic research surroundings, than do researchers. In such cases, parental consent, no matter how informed, is insufficient” (366 Md. at 41). The ruling suggested that there might be sufficient evidence for a jury to determine that the study design itself placed the children at an unacceptable level of risk. Johns Hopkins University, together with the Association of American Medical Colleges and the Association of American Universities, asked the Appeals Court to reconsider since the ruling would have prohibited research otherwise allowable under federal regulations (Amici Curiae Association, 2000). The court denied the motion for reconsideration, but issued a clarification of the opinion, stating that by “any risk” it meant, “any articulable risk beyond the minimal kind of risk that is inherent in any endeavor” (366 Md. at 120). It appeared that this clarification would bring the holding in line with the federal regulatory definition of minimal risk research (45 CFR 46.404; see below). However, because the court did not explicitly refer to the federal regulations, it is unclear if that was the intention of the court (Wolf, 2004). The clarification also seems to preclude—at least in Maryland—other types of research that are allowable under the federal regulations, as discussed below. The legal decision related to “nontherapeutic” research and the court’s clarification reflect the perspective that children should not be enrolled in a study with more than minimal risk that does not offer the prospect of direct benefit to the individual child because children are unable to consent for themselves and parents cannot consent on their child’s behalf because they are bound to make decisions that are in the best interest of the child. The court concluded that “[I]t is…not in the best interest of any healthy child to be intentionally put in a nontherapeutic situation where his or her health may be impaired, in order to test methods that may ultimately benefit all children” (366 Md. at 105). The National Commission discussed similar issues from an ethical perspective: it recommended a balancing of risks and benefits and rejected the notion that nontherapeutic research with children is ethically unacceptable. ETHICAL ARGUMENTS IN NATIONAL COMMISSION REPORTS After the shocking revelations of the unethical treatment of human research participants in the Tuskegee syphilis study, Congress passed the

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Ethical Considerations for Research on Housing-Related Health Hazards Involving Children National Research Act of 1974. The act called for two major actions: (1) the creation of IRBs at all institutions that conducted biomedical or behavioral research with human participants under federal funding to ensure that studies comply with ethical standards; and (2) the creation of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (hereafter, National Commission) to identify the ethical principles for research involving humans, especially principles regarding the protection of vulnerable populations and to recommend ways to ensure that future research is consistent with those ethical principles. During its tenure, the National Commission produced 17 reports, two of which are directly relevant to this report. The first report and the one best known, the Belmont Report (1978), dealt with the ethical principles of research with human participants. It introduced the principles of respect for persons, beneficence, and justice as the pillars of ethical research and formed the basis for the federal regulations (Subpart A of 45 CFR 46) to protect human participants in research (see below). The Belmont Report (National Commission, 1978) declares that beneficence is a basic ethical principle for research involving humans. It argues that an absolute prohibition on exposing research participants to risk would preclude “learning what is harmful” or “learning what will in fact benefit” people. The report states: “The problem posed by these imperatives is to decide when it is justifiable to seek certain benefits despite the risks involved, and when the benefits should be foregone because of the risks” (National Commission, 1978, p. 5). The Belmont Report, while highlighting the difficult issues involved, did not take a specific position on whether it should be permissible to expose children to greater than minimal risk when there is no prospect of direct benefit. The second relevant report, Research Involving Children (1977), reviewed the debates surrounding the ethical appropriateness of research with child subjects and recommended specific measures to protect children based on the level of risk and prospect for direct benefit. Research Involving Children focused on the “Ramsey-McCormick debate,” in which two eminent bioethics scholars, Paul Ramsey and Richard McCormick, took fundamentally different views on the ethics of research with children that did not offer any prospect of benefit to the child. Key elements of the debate, similar to those raised in the Kennedy Krieger case, include the authority of parents to consent to enroll their children in research and the core question of whether or not it is ethically permissible to allow children to be enrolled in research that offers no prospect of individual direct benefit (“nontherapeutic” research). The National Commission concluded that research might be ethically justified on the basis of “direct benefit” when there is a reasonable prospect that the subjects will actually benefit from the procedure or intervention under study

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Ethical Considerations for Research on Housing-Related Health Hazards Involving Children (National Commission, 1977). For research in which the studied procedure or intervention does not present a prospect of direct benefit to the subjects, the National Commission carried out a detailed analysis of complex ethical issues about the protection of children and the authority of parents (National Commission, 1977). Parental Consent and the Best Interest of the Child Ramsey argued that research that does not directly benefit children is ethically impermissible, basing his arguments on the distinction between “nontherapeutic” and “therapeutic” or “beneficial” research. First, he argued that nontherapeutic research could be carried out only with the informed consent of the participant. Because children cannot give consent, he contended that enrolling them in such research would violate the principle of respect for persons, by treating the child merely as a means to carry out the ends of the research (National Commission, 1977). Second, Ramsey argued that parents cannot give permission for children to enroll in nontherapeutic research because they have a fiduciary duty to care for and protect the child, by making decisions in the best interests of their individual child. McCormick, on the other side, argued that parental consent for children to enroll in nontherapeutic research may be morally valid, at least for research that poses only a minimal risk of harm to individual subjects. He contended that children, like all people, have a moral obligation to help fellow human beings when there is little risk to themselves. He argued that it is reasonable to presume that children ought to consent to such research and that parental permission is acceptable. The parent is simply choosing what the child ought to choose for himself or herself, were he or she able to do so. He declared: “There are things we ought to do for others simply because we are members of the human community” (National Commission, 1977, p. 55). The National Commission disagreed with McCormick’s claim that consent may validly be presumed on the basis of an underlying ethical obligation, pointing out that there are many things that adults ought to do, but to which many persons would not consent. Indeed, the idea of respect for persons requires that we respect their right to make their own choices, including “their right not to perform certain actions which other persons believe, with some justification, that they ought to perform” (National Commission, 1977, p. 56). The National Commission expressed more sympathy with a possible modification of McCormick’s position, namely that children have a “presumed duty” to participate in minimal risk research (National Commission, 1977, p. 57). Other National Commission scholars took the somewhat different view

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Ethical Considerations for Research on Housing-Related Health Hazards Involving Children that parents have a moral “obligation to inculcate into their children attitudes of unselfish service” (National Commission, 1977, p. 59). Enrolling children in research that will not benefit them personally but will potentially help other children is one way to foster altruism. These writers believed that children benefit from being enrolled in such research because their moral development is enhanced. Parents should encourage such involvement, but the child should also “be a willing participant” (National Commission, 1977, p. 60). After a detailed review of different perspectives on these issues, the National Commission concluded: “What seems in need of development is an explanation of the proper balance to be struck between the competing obligations to respect persons and to benefit those in need of help” (National Commission, 1977, p. 63). Balancing Risks and Benefits In Research Involving Children (1977), the National Commission rejected the distinction between therapeutic and nontherapeutic research and proposed instead an assessment of risks and benefits for three reasons. First, it said that the term “therapeutic research” is logically inconsistent because research “is intended to develop general knowledge,” while therapy is “for the benefit of an individual and therefore does not involve any generalizeable component” (National Commission, 1977, p. 54). Second, it expressed concern that “simply because a benefit (therapy) is included in a “therapeutic” research protocol,” all sorts of additional interventions not germane to the therapeutic intervention but useful for general knowledge can be regarded as justified” (National Commission, 1977, p. 54) and that these additional interventions might be approved with a lower threshold of allowable risk. Finally, it rejected Ramsey’s argument that children should not participate in research that he termed nontherapeutic, pointing out that Ramsey “neglects discussion of the low level of risk involved in most research involving children” (National Commission, 1977, p. 54). Although agreeing that a line must be drawn between permissible and impermissible risk, it characterized his “absolute prohibition” as “too restrictive” (National Commission, 1977, p. 54) since it would block the gaining of important knowledge when only a minimal risk of harm is present. The commission noted that it was “impressed by reported examples of diagnostic, therapeutic and preventive measures that might well have been derived from research involving risk that, while minor, would be considered more than minimal” (National Commission, 1977, p. 67). In its policy recommendations, the National Commission tried to strike a middle ground, balancing the competing values of respecting children who cannot give consent for themselves and benefiting children through

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Ethical Considerations for Research on Housing-Related Health Hazards Involving Children relevant research. The National Commission determined that under certain conditions it was ethically permissible to enroll children in research that offered them no prospect of direct benefit, provided that the risk was no more than a minor increase over minimal risk and other conditions applied. These recommendations eventually formed the basis of the provisions of Subpart D of the federal regulations governing research with human participants (“subjects”), discussed below. CURRENT FEDERAL REGULATIONS In 1978 the U.S. Department of Health, Education, and Welfare (HEW, the predecessor of DHHS) adopted the National Commission’s recommendations as agency regulations to govern oversight of research involving humans conducted or funded by HEW. In 1986 the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research3 recommended that the DHHS regulatory protections for human research participants be extended to apply to all research involving humans conducted by federal agencies or supported with federal funds. Several years later, in 1991, 17 federal agencies and departments adopted the DHHS general human research protection regulations. These regulations, Subpart A of 45 CFR 46, or the “Common Rule,” contain the basic requirements that must be met for a research protocol involving humans to qualify for federal funding from most federal agencies or departments.4 In 1983, several years after the release of Research Involving Children, DHHS became the first agency to adopt the National Commission’s recommendations designed to address the unique issues when involving children in research. The Central Intelligence Agency, the Social Security Administration, and the Department of Education have also adopted these additional protections which are specified in Subpart D (of 45 CFR 46).5 The Department of Housing and Urban Development and the Environmental Protection Agency, two of the main federal sponsors of housing health hazards research, have not formally adopted Subpart D. Therefore, while all of the agencies likely to fund housing health hazard research are subject 3   This congressionally mandated group was formed in 1978, succeeding the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. It worked independently from January 1980 to March 1983 (for details, see http://www.bioethics.gov/reports/past_commissions/ [November 15, 2004]). 4   The Common Rule also applies to research conducted by an organization that has proved an assurance to the federal government that all of its research will comply (45 CFR 46.103). 5   The Food and Drug Administration has regulations largely similar to Subpart D (at 21 CFR 50).

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Ethical Considerations for Research on Housing-Related Health Hazards Involving Children to the Common Rule, some research that involves children may not be governed by the additional protections designed to protect children’s unique vulnerabilities. Elements of the Common Rule: Subpart A The federal regulations define a human research participant (“subject”) as a “living individual about whom an investigator conducting research obtains: (1) data through intervention or interaction with the individual; or (2) identifiable private information” (45 CFR 46.102(f)). Several provisions of the Common Rule are important to understand as context for housing health hazards research involving children.6 The Common Rule establishes several general requirements for all research involving human participants to be approved. The first of those requirements is that an institution that conducts a research study that will involve human participants submit an “assurance of compliance” to the Office of Human Research Protection (in DHHS) that demonstrates the steps the institution has taken to ensure compliance with the regulations and ethical principles overall (45 CFR 46.103). As part of this assurance, many institutions agree to ensure that their research adheres to the Common Rule, even it is not funded by a federal agency. Second, an institution is also required to establish an IRB that will review each research protocol involving human participants (45 CFR 46.107-109). Before approving a research protocol, the IRB must determine that it satisfies the regulatory criteria designed to protect human participants (45 CFR 46.111). In the case of research involving only minimal risk to participants, the IRB can provide expedited review by a less than full committee (45 CFR 46.110). For all other types of research, the protocol must demonstrate the following criteria to the IRB in order to be approved: minimization of risks: The risks to the participants have been minimized. reasonable risks in relation to the benefits: The risks posed to participants are reasonable in relation to the anticipated benefits to the participants and the importance of the knowledge that is reasonably expected to be gained from the research. This finding is limited to considering benefits that would accrue to the individual and not to long-term benefits, such as the possible effects of the research findings on public policy. equitable selection of participants: The selection of the participants 6   For a more detailed discussion of the regulations, see Institute of Medicine (2004, Chapters 3 and 4). Sections of that report are quoted here.

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Ethical Considerations for Research on Housing-Related Health Hazards Involving Children will be equitable. The IRB is directed to take into account considerations such as the purpose of the research and the setting in which the research will be conducted. The IRB is also specifically directed to be “particularly cognizant of the special problems of research involving vulnerable populations, such as children, … or economically or educationally disadvantaged persons” (45 CFR 46.111(a)(3)). informed consent: Informed consent has been obtained in accordance with 45 CFR 46.116 and is appropriately documented in accordance with 45 CFR 46.117 (see below for more details). measures to protect privacy: If needed, provisions have been made to protect the privacy of the participants and to maintain the confidentiality of data. additional safeguards for vulnerable populations: Lastly, if some or all of the participants are susceptible to being vulnerable to coercion or undue influence, such as children…or economically or educationally disadvantaged persons, that the research protocol has included additional safeguards to “protect the rights and welfare” of these participants (45 CFR 46.111(b)). Additional Protections for Research Involving Children: Subpart D Regulatory provisions that provide specific protections for child subjects in research were formally adopted by DHHS in 1983 as Subpart D.7 Subpart D specifies three categories of research that can be approved by local IRBs: research that does not involve greater than minimal risk (45 CFR 46.404 or “Section 404”); research that does involve greater than minimal risk, but for which research participation provides a prospect of individual benefit sufficient to offset that risk (45 CFR 46.405 or “Section 405”); research that involves greater than minimal risk without individual benefit sufficient to offset the risk—but for which the risk is only a minor increase over minimal risk, the excess risk is commensurate with ordinary experiences of the children under study, and the knowledge to be gained from the research is “… of vital importance for the understanding or 7   By 1978, the HEW regulations on research involving humans were located in 45 CFR 46 and contained three subparts: (1) Subpart A, the general regulations on human subject research protections; (2) Subpart B, the regulations specific for pregnant women, fetuses, and in vitro fertilization; and (3) Subpart C, the regulations relating to prisoners (see Institute of Medicine, 2004).

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Ethical Considerations for Research on Housing-Related Health Hazards Involving Children amelioration of the subjects’ disorder or condition…” (45 CFR 46.406 or “Section 406”). (See Chapter 8 for discussion of this category of research.) There is a great deal of variability across IRBs in their application of terms in the federal regulations, such as “minimal risk” and “minor increase over minimal risk,” and therefore which of the three above categories of research they consider applicable (Shah et al., 2004). A fourth category of research is set forth in Subpart D (45 CFR 46.407 or “Section 407”): research that presents a greater than minor increase over minimal risk with no prospect of direct benefit, but has the potential to provide knowledge to understand or ameliorate the health condition; see Box 3-2 for the regulatory language for research involving children permitted under Section 406. Such projects may not be approved by a local IRB; they must be reviewed by a national panel and approved by the Secretary of DHHS. In broad terms, this subpart requires researchers and IRBs to take a more cautious view of allowable risk for research involving children, to seek parental permission under most circumstances,8 and to seek the assent of the child whenever appropriate. The additional protections required under Subpart D focus to a significant degree on the assessment of risks and benefits. The stricter and more protective criteria established in Subpart D are directly related to the level of risk posed to potential child subjects in research. The relationship between the level of risk presented and the stringency of the procedural requirements is essentially a sliding scale: the greater the level of risk, the more requirements the research protocol must incorporate and satisfy. SUBSEQUENT ANALYSIS OF ETHICAL ARGUMENTS The National Commission identified fundamental ethical issues in research with children, which are still salient today. Recent scholars have analyzed issues embedded in the National Commission’s debate and come to similar conclusions about the fundamental issues. Assessing Risks and Benefits Physician-ethicist Robert Levine pointed out that in any given research study, some aspects may be carried out for therapeutic purposes, while 8   In some cases, such as research that presents no more than minimal risk of harm and involves no procedures that would normally require consent, the informed consent requirements may be waived by an IRB (45 CFR 46.408(c)).

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Ethical Considerations for Research on Housing-Related Health Hazards Involving Children BOX 3-2 Research Involving Children Permitted Under Subpart D: 45 CFR 46 Section 46.404 Research not involving greater than minimal risk. DHHS will conduct or fund research in which the IRB finds that no greater than minimal risk to children is presented, only if the IRB finds that adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians, as set forth in 46.408. Section 46.405 Research involving greater than minimal risk, but presenting the prospect of direct benefit to the individual subjects. DHHS will conduct or fund research in which the IRB finds that more than minimal risk to children is presented by an intervention or procedure that holds out the prospect of direct benefit for the individual subject, or by a monitoring procedure that is likely to contribute to the subject’s well-being, only if the IRB finds that: the 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, as set forth in 46.408. Section 46.406 Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject’s disorder or condition. DHHS will conduct or fund research in which the IRB finds that more than minimal risk to children is presented by an intervention or procedure that does not hold out the prospect of direct benefit for the individual subject, or by a monitoring procedure which is not likely to contribute to the well-being of the subject, only if the IRB finds that: the risk represents a minor increase over minimal risk; other parts of the protocol are carried out only to answer scientific questions (Weijer, 2000). For example, consider a housing research study that tests the effectiveness of a set of interventions to reduce cockroach allergens in the homes of children who have asthma. The interventions are intended to provide the prospect of direct benefit to child subjects. However, other parts of the study may be carried out solely to answer the research questions, such as administering skin tests for various allergens, taking measurements of the levels of various antigens in the home, and administering questionnaires about the child’s activities and limitations to activities. Although these latter activities might provide some benefit to the child (as in alerting parents to other possible allergies), they are included in the protocol solely for scientific reasons. The philosopher Charles Weijer (2000) extended Levine’s attention to

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Ethical Considerations for Research on Housing-Related Health Hazards Involving Children the intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations; the intervention or procedure is likely to yield generalizable knowledge about the subjects’ disorder or condition which is of vital importance for the understanding or amelioration of the subjects’ disorder or condition; and adequate provisions are made for soliciting assent of the children and permission of their parents or guardians, as set forth in section 46.408. Section 46.407 Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children. DHHS will conduct or fund research that the IRB does not believe meets the requirements of 46.404, 46.405, or 46.406 only if: the IRB finds that the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; and the Secretary, after consultation with a panel of experts in pertinent disciplines (for example: science, medicine, education, ethics, law) and following opportunity for public review and comment, has determined either: that the research in fact satisfies the conditions of 46.404, 46.405, or 46.406, as applicable, or the following: the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; the research will be conducted in accordance with sound ethical principles; adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians, as set forth in 46.408. the different components of a research study. Weijer also pointed out that the use of the term “therapeutic research” may undermine the protection of humans. When the protocol as a whole is classified as therapeutic because some interventions are administered with therapeutic intent, other interventions in the protocol that are administered solely to answer scientific questions may be accepted even though they are inappropriately risky. Weijer proposed a “component analysis” in which the risks and benefits of those components of the study that are carried out with therapeutic intent are analyzed separately from those components that are carried out solely for scientific purposes. NBAC (2001) agreed that a clinical research study often involves some procedures that offer the prospect of direct benefit to participants and other procedures that serve only research aims and thus offer no prospect of

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Ethical Considerations for Research on Housing-Related Health Hazards Involving Children direct benefit. It therefore also concluded that it makes little sense to classify an entire research project as therapeutic or nontherapeutic when most projects contain elements of each. Thus, the National Commission’s reasons for proposing a more nuanced system of balancing risks and benefits has withstood the test of time. More recent analyses have presented reasons for more refined assessment of risks and benefits in part to ensure that projects do not present unacceptable risks to participants. Best Interests of the Child One of the ethical issues in research involving children cited in Grimes v. Kennedy Krieger Institute is what is in the best interests of the child. As discussed above, Ramsey would have concurred with the court that parents cannot give permission for their children to enroll in nontherapeutic research because they are obligated to act in their children’s best interests. In fact, parents’ decisions regarding the welfare of their children have traditionally been granted great deference in the United States. Because parents are presumed to act in the best interest of their children, they are considered the most reliable and effective judges of what is best for them, with the family unit protected from government intrusions in a zone of privacy, which includes parental autonomy over childrearing decisions (Barnes, 2004). However, the doctrine of parens patriae (literally, the state is the parent of the nation) grew out of a twentieth-century idea that parental autonomy is not unlimited but is instead contingent on parents’ behaving in ways that are socially responsible and not neglectful or abusive. Parens patriae justifies a government intrusion in parental autonomy because of the state’s interest to protect children (Holder, 1985). When invoking this power, the government is said to be acting in the best interest of the child in place of the parent who has deviated from the accepted norm of care. The philosopher Ruth Macklin (1982, p. 301) commented on the best interests standard: “It is possible to accord a great deal of respect to family autonomy, and to hold a deep commitment to family integrity, and at the same time to recognize that close and loving family units are in no great danger of being destroyed by an occasional outside intervention aimed at serving the interests of a child.” In clinical settings, the principle of the best interests of the child has been used to impose standards of responsible action and obligate parents to accept life-saving medical treatments for children (Lo, 2005; Holder and Lo, 2003; Fleischman et al., 1994). Clinicians are obligated to oppose parental refusal of treatments that are known to be effective when such refusal places the child in imminent harm of death or disability (American Academy of Pediatrics Committee on Bioethics, 1997). For example, a state can override a parent’s refusal of life-saving blood transfusions or antibiotics for a child even if the parents base their

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Ethical Considerations for Research on Housing-Related Health Hazards Involving Children refusal on religious beliefs (Barnes, 2004). In these clinical situations in which society inserts itself in family decision making, the risk to the child is very serious and likely, and medical interventions are very effective and have only minor side effects (Wadlington, 1994). In situations in which the medical condition is less grave and the treatment is less effective or more burdensome, parents have discretion to make decisions about their children’s medical care. The essential dilemma is determining when the danger posed to the child is sufficiently serious and likely to warrant an intrusion into the home, a violation of the zone of privacy, or an abrogation of parental authority (Barnes, 2004). Parents often make decisions that conflict with one child’s best interests because they promote the parent’s interests or the interests of another member of the family. For example, society also allows parents to require their children to help other people who are unrelated to them, even when doing so poses some risks to the child (Wendler and Emanuel, 2004). For example, parents may require that their children help neighbors by shoveling snow from their sidewalks or mowing their lawns. Charities, such as the Red Cross and Habit for Humanity, have established volunteer programs for children (Wendler and Emanuel, 2004). Habit for Humanity, for instance, allows children to help build homes for the poor, subject to strict guidelines: starting at age 5, children may help with fund raising; at age 10 they are allowed to help clear debris from construction sites; by age 16 they can help with actual construction (Habitat for Humanity, 2005). None of these activities are risk free. In deciding what counts as good or bad for a child, judges have looked to outcomes beyond physical well-being. For example, in custody disputes, judges are asked to consider the importance of continuity with a primary caretaker (Barnes, 2004). Mnookin concludes that often the best interests of a child are “indeterminate and speculative” (Mnookin, 1984, p. 679). Parental decisions about participation in research might reasonably be made in the context of family circumstances and values. The federal regulations (see below) are designed to ensure that the level of risk is balanced with the prospect for direct or societal benefit and that children won’t be exposed to known life-threatening interventions. Some observers who have criticized research that observes children in poor-quality housing without intervening have also invoked the principle of “the best interests of the child” to argue that research scientists have obligations to “rescue” children from harm and provide better living conditions for these unfortunate children (Sherav, 2003). Clinicians have an obligation to act in the best interests of their patients, but this obligation refers to the clinical care they provide, not to personally or directly ameliorating the patient’s living conditions. Under the Common Rule (see above), the researcher’s duty of beneficence requires that the risks of research

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Ethical Considerations for Research on Housing-Related Health Hazards Involving Children interventions be proportionate to the prospective benefits of research and that these risks be minimized. However, researchers have neither the authority nor the resources to provide better housing to all families participating in a research project or to eliminate all housing-related health risks. Although some research may provide the prospect of direct benefit to those involved, a researcher’s primary role is to produce new, generalizable knowledge. The intent is that this knowledge will ultimately help alleviate suffering and promote health by leading to changes in public policies and clinical practice. In addition, beneficence directs researchers who observe serious harms to child subjects to take steps to try to prevent harms. However, the researcher’s duty is not to personally and directly prevent harm by removing the child from the harmful environment. If the harm is imminent and serious, the researcher must report to child protective services (see discussion in Chapter 7). It is unrealistic and unfair to hold individual research investigators responsible for ameliorating the social circumstances that they study. Individuals can only be held responsible for actions, decisions, and conditions that are under their control. Researchers are not responsible for the housing of children in research, except in some intervention studies that assign subjects to housing conditions. However, as discussed in Chapter 5, researchers should consider how they can work with the community to ensure that their results are thoroughly disseminated and available to inform policy discussions. CONCLUSIONS The federal regulations, particularly the additional protections articulated in Subpart D, provide a solid foundation for research involving children. Grimes v. Kennedy Krieger Institute raised many issues that were debated during the development of the regulations and resolved with appropriate protections for child subjects in research. A nuanced balancing of the benefits and risks of research was a significant contribution of the federal regulations and an approach that this committee and recent analyses conclude is sound. Although the court in Grimes vs. Kennedy Krieger Institute questioned whether parents should be allowed to enroll their children in research that does not offer a prospect of direct benefit, the committee concludes that it is reasonable to defer such decisions to parents, provided that they are fully informed about the risks and benefits involved, that they understand the essential features of the study, that the level of risk is acceptable, and that payments do not represent an undue inducement. Later chapters of this report outline strategies for ensuring that the risks and benefits of research are truly understood by the parents of potential child subjects in research and that payments are reasonable.

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Ethical Considerations for Research on Housing-Related Health Hazards Involving Children Grimes v. Kennedy Krieger Institute, however, provides a useful context in which to consider the particular issues raised in housing health hazards research and highlights the particular sensitivities that occur when conducting research with socially and economically disadvantaged populations. Subsequent chapters of this report address many of the issues discussed in the court’s decision.