Summary

In recent decades, advancesin biomedical research have, each year, helped to save or lengthen the lives of tens of thousands of children around the world, prevent or reduce illness or disability in many more, and improve the quality of life for countless others. Beyond the infants, children, and adolescents directly affected, the benefits of research extend to the families, friends, and communities who love and care for them. Since the 1950s, for example, researchers have created vaccines against polio, measles, mumps, and a number of other childhood infections that have dramatically cut deaths, disability, and discomfort from these diseases. Children and their families have also benefited from research demonstrating the harm or ineffectiveness of what were once standard therapies, for instance, high-dose oxygen for premature infants.

Despite these advances, pediatricians and others have argued that infants, children, and adolescents have not shared equally with adults in advances in biomedicine. In particular, many drugs with potential pediatric uses have not been tested in studies that include children. These drugs may



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Ethical Conduct of Clinical Research Involving Children Summary In recent decades, advancesin biomedical research have, each year, helped to save or lengthen the lives of tens of thousands of children around the world, prevent or reduce illness or disability in many more, and improve the quality of life for countless others. Beyond the infants, children, and adolescents directly affected, the benefits of research extend to the families, friends, and communities who love and care for them. Since the 1950s, for example, researchers have created vaccines against polio, measles, mumps, and a number of other childhood infections that have dramatically cut deaths, disability, and discomfort from these diseases. Children and their families have also benefited from research demonstrating the harm or ineffectiveness of what were once standard therapies, for instance, high-dose oxygen for premature infants. Despite these advances, pediatricians and others have argued that infants, children, and adolescents have not shared equally with adults in advances in biomedicine. In particular, many drugs with potential pediatric uses have not been tested in studies that include children. These drugs may

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Ethical Conduct of Clinical Research Involving Children still be prescribed for children based on physicians’ judgment about how data from studies with adults might be extrapolated to children. Because children differ physiologically from adults in myriad ways that can affect how drugs work in the body, extrapolation based on adult drug doses and children’s weight or age can be dangerous and lead to underdosing, overdosing, or specific adverse effects not evident in adults. The U.S. Congress, the Food and Drug Administration (FDA), and the National Institutes of Health (NIH) have acted in recent years to expand research involving children. Notwithstanding the expected benefits of these efforts, some caution is appropriate. Unlike most adults, children usually lack the legal right and the intellectual and emotional maturity to consent to research participation on their own behalf. Their vulnerability demands special consideration from researchers and policymakers and additional protections beyond those provided to mentally competent adult participants in research. In the United States, research that is supported, conducted, or regulated by the U.S. Department of Health and Human Services (DHHS) is now subject to a (mostly) common set of regulations to protect adult and child participants in research. Nonetheless, deficiencies in the conduct of human research—most of which are fairly minor but some of which result in deaths or serious injuries—continue to be revealed. Concerns about the adequacy of the system for protecting child participants in research, combined with the public commitment to expanding clinical research involving children, provided the impetus for this Institute of Medicine (IOM) report, which was requested in the Best Pharmaceuticals for Children Act of 2002 (P.L. 107-109). The legislation charged the IOM with preparing a report that reviewed federal regulations, reports, and research and that made recommendations about desirable practices in clinical research involving children. Specifically designated topics were (1) the appropriateness of the regulations for children of various ages, (2) the interpretation of regulatory criteria for approving research, (3) the processes for securing parents’ and children’s agreement to a child’s participation in research, (4) the expectations and comprehension of children and parents about participating in research, (5) the appropriateness of payments related to the child’s participation in research, (6) compliance with and enforcement of federal regulations, and (7) the unique roles and responsibilities of institutional review boards (IRBs). The report, prepared by a 14-member committee of the Institute of Medicine, focuses primarily on clinical research involving preventive, diagnostic, treatment, or similar interventions and direct interactions with children. It stresses three broad themes:

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Ethical Conduct of Clinical Research Involving Children Well-designed and well-executed clinical research involving children is essential to improve the health of future children—and future adults—in the United States and worldwide. Children should not be routinely excluded from clinical studies. No subgroups of children should be either unduly burdened as research participants or unduly excluded from involvement. A robust system for protecting human research participants in general is a necessary foundation for protecting child research participants in particular. An efficiently administered, effectively performing system with adequate resources must, however, commit additional resources and attention to meet ethical and legal standards for protecting infants, children, and adolescents who participate in research. Effective implementation of policies to protect child participants in research requires appropriate expertise in child health at all stages in the design, review, and conduct of such research. This expertise includes knowledge of infant, child, and adolescent physiology and development as well as awareness of the unique scientific, psychosocial, and ethical requirements and challenges of pediatric clinical care and research. REGULATORY CONTEXT In 1983, DHHS published the first regulations specifically governing federally supported or conducted research involving children (Subpart D of 45 CFR 46). This was 10 years after the first general departmental regulations on protecting human participants in research were published (now Subpart A of 45 CFR 46, also called the “Common Rule”). Similar but not identical regulations for research regulated by FDA are found at 21 CFR 50 and 56. (For simplicity in making comparisons, the regulations at 45 CFR 46 are termed DHHS regulations, even though the FDA is part of DHHS.) Subpart A of the regulations sets forth basic requirements for all covered research, including provisions that the risk to research participants be minimized, that the risks be reasonable in relation to the anticipated benefits, that the selection of research participants be equitable, and that informed consent be obtained from participants. Subpart D provides that parents must, under most circumstances, provide permission before children (usually those under age 18 as defined by state laws) can participate in research. It also provides that, when appropriate, children should affirmatively agree or assent to participate in research. In addition, Subpart D establishes four categories under which research involving children can be approved. Omitting reference to specific requirements for parents’ permission and children’s assent, these categories of approvable research are summarized in Box S.1. The committee concluded that the federal regulations providing special

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Ethical Conduct of Clinical Research Involving Children BOX S.1 Summary of Categories of Research Involving Children That Are Approvable Under Subpart D of 45 CFR 46 Section 46.404: Research that involves no greater than minimal risk to children Section 46.405: Research that involves greater than minimal risk but the risk is justified by the anticipated benefit to the participants and the relation of the anticipated benefit to the risk is at least as favorable as that presented by available alternative approaches. Section 46.406: Research that involves greater than minimal risk and no prospect of direct benefit to research participants but (a) the risk represents only a minor increase over minimal risk, (b) the research involves experience reasonably commensurate with those inherent in the child’s medical, dental, psychological, social, or educational situations, and (c) the research is likely to yield generalizable, vitally important knowledge about the child’s disorder or condition. Section 46.407: Research that is not otherwise approvable but that the IRB and the Secretary of DHHS determine presents an opportunity to understand, prevent, or alleviate a serious problem affecting children’s health or welfare and will be conducted in accordance with sound ethical principles. NOTE: The corresponding regulations for the FDA are found at 21 CFR 50.51 to 50.54. protections for child participants are, in general, appropriate for children of different ages. They reasonably defer to state laws that define both the age at which individuals become entitled to make medical care decisions and the special circumstances under which minors may make such decisions in their own right (e.g., for care related to sexually transmitted diseases). For the most part, the problems with the regulations relate to insufficient government guidance about their interpretation and implementation, shortfalls in data about implementation and compliance, and variability in investigator and IRB interpretations of the criteria for approving research involving children. Some of these criteria include inherently subjective elements that the committee doubts would be substantially and predictably clarified by revising the regulations. As discussed below, one change that the committee does recommend is that FDA make its policies consistent with those of DHHS that allow the waiver of parental permission for children’s, especially adolescents’, participation in research when permission is not a reasonable requirement to protect a child. Another recommendation is that all research that includes infants, children, and adolescents should occur under the umbrella of a formal program for the protection of human research participants (Recommendation 8.1). Because the federal

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Ethical Conduct of Clinical Research Involving Children government may not have the authority to require this, state governments should consider exercising their authority to regulate research in ways that are consistent with federal regulations and supportive of multistate studies. All federal agencies that support or conduct research involving children can, however, adopt the protections in Subpart D of 45 CFR 46. INTERPRETING RESEARCH RISK AND OTHER REGULATORY CONCEPTS Categorizing, evaluating, and weighing the risks of proposed research are among the most challenging and subjective tasks for those charged with reviewing research that includes infants, children, and adolescents. The committee was specifically asked to consider the regulatory definition of “minimal risk” in the context of research involving children. It also examined several other closely related concepts in the regulations. For purposes of approving human research, federal regulations define the term minimal risk as meaning “that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests” (45 CFR 46.102(i); 21 CFR 50.3(k)). That this standard invites variable interpretations has long been clear, especially for studies involving multiple sites and multiple IRBs. Consistent with the conclusions of a number of other groups, the committee rejected an interpretation of minimal risk that would allow greater research risk for children exposed to higher than average risk of harm in their personal lives (e.g., because they are ill or live in unsafe neighborhoods). This “relative” interpretation misinterprets the minimal risk standard and undercuts its moral and social purposes for pediatric studies, which are to guide judgments about when risks are low enough to safely and ethically enroll children in studies that are not designed to benefit them. The assessment of risk should be compared or indexed to the experiences of average, normal, healthy children. Recommendation 4.1: In evaluating the potential harms or discomfort posed by a research protocol that includes children, investigators, and reviewers of research protocols should interpret minimal risk in relation to the normal experiences of average, healthy, normal children; focus on the equivalence of potential harms or discomfort anticipated in research with the harms or discomfort that average, healthy, normal children may encounter in their daily lives or experience in routine physical or psychological examinations or tests;

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Ethical Conduct of Clinical Research Involving Children consider the risk of harms or discomfort in relation to the ages of the children to be studied; and assess the duration as well as the probability and magnitude of potential harms or discomfort in determining the level of risk. In Section 406 of 45 CFR 46, federal regulations permit research that involves a minor increase over minimal risk without the prospect of direct benefit if the research involves children with a disorder or condition, is likely to yield vital knowledge about that disorder or condition, and entails research experiences that are reasonably similar to those that such children encounter in certain other situations. Consistent with the interpretation of minimal risk, the interpretation of this level of research risk should not allow a higher threshold of risk for children who are exposed to more risk in other aspects of their lives (Recommendation 4.2). Also, consistent with the language of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, which defined this standard in 1977, the risk allowed under this category can be only slightly above minimal risk. In the context of IRB determinations about whether a study can be approved under Section 406 of 45 CFR 46, the term condition is also ambiguous. If a characteristic of a group of children is to be designated as a condition that allows children to be exposed to a higher level of risk without a prospect of benefit, the link between the characteristic and a deficit in children’s health or well-being should be supported by scientific evidence or clinical knowledge. Recommendation 4.3: In determining whether proposed research involving a minor increase over minimal risk and no direct benefit can be approved, the term condition should be interpreted as referring to a specific (or a set of specific) physical, psychological, neurodevelopmental, or social characteristic(s) that an established body of scientific evidence or clinical knowledge has shown to negatively affect children’s health and well-being or to increase their risk of developing a health problem in the future. The committee further recommends that IRBs make (and record in their minutes) explicit determinations about each of the regulatory criteria that must be met for the approval of research involving children (Recommendation 4.4). To assist investigators and IRBs, the committee recommends that the DHHS Office for Human Research Protections (OHRP) develop explicit guidance and examples for IRBs and investigators based on the findings presented in this IOM report and the work that it cites (Recommendation 4.5). In addition, the Secretary’s Advisory Committee on Human Research Protection is encouraged to continue work to develop con-

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Ethical Conduct of Clinical Research Involving Children sensus assessments about the risk of common research procedures, including rationales for the categorization of procedures judged to involve either minimal risk or a minor increase over minimal risk (Recommendation 4.5). UNDERSTANDING AND AGREEING TO CHILDREN’S PARTICIPATION IN RESEARCH Informed consent is widely regarded as a cornerstone of ethical research. Because children (except for adolescents under certain conditions) do not have the legal capacity to provide informed consent, the concepts of parental permission and child assent have been developed as standards for ethical research involving children. (The term parent is used here to include guardians as well.) Parents asked for permission for a child’s participation in clinical research are often making decisions under great stress and time pressure. Some prefer to trust the physician’s assessment rather than make their own, and investigators must be acutely sensitive to the influence that they wield in discussions with parents of ill or injured children. As is also the case for adults considering their own participation in research, a significant minority of parents may misunderstand the purpose of the research, especially when the research tests a therapy for a serious medical condition. Nonetheless, the goal of informed agreement by parents remains an important protection for children, both when participation in research is initially sought and throughout the course of a study. The capacity to make voluntary, informed decisions clearly evolves from birth through adolescence and into adulthood. It also clearly varies among individuals of the same age. The committee found some disagreement and mixed evidence about the age at which children can be meaningfully involved in discussions and decisions about their research participation given various research contexts. Again, despite this uncertainty, the goal should be to involve children in discussions and decisions about research participation as appropriate given their cognitive and emotional maturity and psychological state. Involving children in discussions and decision making respects their emerging maturity, helps them prepare for participation in research, gives them an opportunity to express their concerns and objections and, possibly, allows them to influence what happens to them. As many others have argued, informed consent—and, by extension, permission and assent—should be viewed as a process and not a form. This goal remains less a reality than an aspiration. IRBs should focus more of their attention on the adequacy of the process for securing permission and assent in proposed research protocols. Discussions with parents and, as appropriate, children should allow sufficient time for questions and, if

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Ethical Conduct of Clinical Research Involving Children necessary, further explanations. Such discussions should precede the presentation of a permission or assent form. Recommendation 5.1: To focus attention on the process of requesting parents’ permission and children’s assent to research participation, investigators should provide and IRBs should review protocol descriptions of who will request permission and assent; how and when permission and assent will be requested; who should be contacted if parents have questions or concerns about the research; and for studies that extend over considerable periods of time, when and how permission and assent may be requested again, for example, as children reach important developmental milestones. Although the research literature is limited and not entirely consistent, it supports a gradual expansion of the involvement of children in discussions and decisions about their participation in research. For younger children, the emphasis should be on providing basic information about what will happen, responding to their questions and concerns, and—particularly when the research does not offer the prospect of direct benefit—recognizing when children do not want to participate. As children mature, they can participate more fully in discussions and decisions about their participation in research. Older adolescents may not have the legal capacity to make decisions in their own right, but research generally suggests that the substance of the assent process can be similar to the substance of the consent process for adults if that process is properly designed to accommodate people of various educational, social, and cultural backgrounds. Recommendation 5.6: In designing and reviewing procedures for seeking a child’s assent to participation in research, investigators and institutional review boards should aim to create assent processes that consider and respect the child and the family as a unit as well as individually. The process for requesting assent should be developmentally appropriate given the ages and other characteristics of the children to be approached; provide opportunities for children to express and discuss their willingness or unwillingness to participate; clarify for parents and children (as appropriate) the degree of control that each will have over the participation decision; and when appropriate, describe to children and parents the kinds of information about the child that will or will not be shared with the parents.

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Ethical Conduct of Clinical Research Involving Children One particularly sensitive issue is when adolescents should be free to consent to research participation without parental permission. Certain studies that are important to adolescent health and well-being will not be feasible without such a waiver. The research reviewed here suggests that the DHHS regulations appropriately provide for waivers, including a requirement that a suitable mechanism is provided to protect children when parental permission is waived. FDA should revise its rule on the waiver of parental permission to be consistent with DHHS rules (Recommendation 5.4). PAYMENT RELATED TO RESEARCH PARTICIPATION Ethical standards for participation in research require that the agreement to participate be freely given; that is, it should not be either coerced or unduly influenced by psychological, financial, or other pressure. The major concern about payments related to research participation is that they may unduly influence and distort decisions about research participation made by individuals in their own right or by parents on behalf of their child. Survey and other information available to the committee suggested that many IRBs and research institutions do not have written policies to guide reviews of research payment practices. By developing written policies on payments to parents and children, IRBs can consider ethical issues outside of the context of an individual protocol. Such deliberation will help achieve a fairer and more consistent approach to making decisions on appropriate payments. In general, these policies should provide that payment be discussed during the process of seeking parents’ permission and the child’s assent to participation in research. Recommendation 6.1: Institutional review boards, research institutions, and sponsors of research that includes children and adolescents should adopt explicit written policies on acceptable and unacceptable types and amounts of payments related to research participation. These policies should specify that investigators disclose the amount, the recipient, the timing, and the purpose (e.g., an expense reimbursement or a token of appreciation to a child) of any payments as part of the process of seeking parents’ permission and, as appropriate, children’s assent to research participation; avoid emphasis on payments or descriptions of payments as benefits of participating in research during the permission or assent process; and obtain institutional review board approval for the disclosure of information about payments in advertisements and in permission and assent forms and procedures.

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Ethical Conduct of Clinical Research Involving Children Certain types of payments to parents or adolescents are usually, if not always acceptable, for example, reimbursement for reasonable expenses that are necessary for participation in research. Other payments are never appropriate, for example, paying parents for permitting their child to be exposed to a greater research risk. Compensation to parents for lost wages or time may be appropriate under carefully scrutinized circumstances. One objective of IRB and institutional policies on payments related to children’s participation in research should be to encourage equal access to study participation, regardless of a family’s economic status, while avoiding practices that risk exerting undue influence over the parents’ and children’s consideration of the child’s participation in research (Recommendation 6.2). To respond to the diverse barriers to children’s participation in research, nonfinancial alternatives that equalize participation opportunities should also be considered, for example, adjusting the times or places for research visits for parents who cannot take time off from work. REGULATORY COMPLIANCE, QUALITY IMPROVEMENT, AND ACCCREDITATION The dearth of information about human research protection programs in general and about protections for child research participants in particular makes it impossible to describe adequately the implementation and enforcement of federal regulations and, likewise, hinders evaluation and improvement efforts. As one of its recommendations for strengthening the system for protecting human participants in research, the 2003 IOM report Responsible Research proposed that DHHS commission studies to gather basic information about the current system as needed to identify problems and track improvements. This committee agrees. Recommendation 7.1: To help identify what further guidance, education, or other steps may be needed to protect child participants in research, the U.S. Department of Health and Human Services—with direction from the U.S. Congress, if necessary—should develop and implement a plan for gathering and reporting data on research involving children, including the categorization of studies by the relevant section of federal regulations (45 CFR 46.404 to 407 and 21 CFR 50.51 to 54), and implementation of the regulations that govern research involving children, including data from the Office for Human Research Protections and the Food and Drug Administration on their inquiries, investigations, and sanctions related to such research.

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Ethical Conduct of Clinical Research Involving Children The committee recognizes that such data collection responsibilities will require a considerable investment of resources by OHRP and, particularly, FDA, given the latter’s more extensive oversight activities. Nonetheless, in calling for the present IOM study, the U.S. Congress has already recognized the concerns presented by research involving children and the regulations applicable to that research. If necessary, it should be prepared to direct and fund the collection of data on research involving children. For most public policies, including those related to the protection of child participants in research, the path to desired results depends in large measure on the voluntary actions of private individuals and organizations. Within the arena of human research protections, voluntary quality improvement efforts should, if successful and sustained, strengthen the overall system of human research protections within which the policies for children are embedded. Consistent with recommendations in earlier IOM reports, the committee supports the further development and systematic evaluation of accreditation for human research participant protection programs. For accrediting organizations to assess programs that encompass research involving children, these organizations themselves need expertise in child health and research involving children (Recommendation 7.2). ROLES AND RESPONSIBILITIES IN PROTECTING CHILDREN INVOLVED IN RESEARCH The benefits to the health of children collectively from involving more children individually in clinical research are compelling. Also compelling are the moral and legal obligations of all involved in research to specially protect children who are not able to provide informed, reasoned, and voluntary consent to their participation in research in their own right. This report focuses on those who conduct, review, regulate, and fund research, but the central role of parents must be recognized and respected. Parents have a most intimate and profound duty and desire to protect and promote their child’s safety and well-being in research, as in all realms of life. By improving the initial and continuing process for securing parental agreement to a child’s participation in research, investigators, IRBs, research institutions, and others can support parents in fulfilling their responsibilities and, thereby, help them feel that they have done the right thing for their child, whatever their decisions about research participation. Box S.2 summarizes some questions that parents may want to ask about their child’s participation in research.

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Ethical Conduct of Clinical Research Involving Children BOX S.4 Key Ethical and Legal Responsibilities of IRBs and Research Institutions Involved with Clinical Research That Includes Infants, Children, and Adolescents Educate IRB members and, as needed, IRB pediatric consultants about the ethical, legal, and scientific standards for approving research involving children and their appropriate interpretation. Educate investigators who conduct research that includes infants, children, or adolescents about their special ethical, legal, and scientific responsibilities. Apply ethical and regulatory standards for the initial and continuing review and approval of research protocols involving children, including careful evaluation and categorization of research risks. Provide for adequate expertise in child health and research in the review of protocols that include children, including assessment of whether those conducting the studies have adequate pediatric expertise. Make available reference materials and resources on research involving children, including information on research ethics, as part of IRB or research administration web sites and educational programs. Conduct ongoing assessments to guide improvements in IRB performance in reviewing and monitoring research involving children. Develop explicit policies or guidelines on important topics for which additional guidance to IRB members or investigators is needed (see Box 8.3). A critical obligation of IRBs is to bring appropriate expertise to the review of research involving infants, children, and adolescents. As more children participate in clinical trials and other research, the need grows for both investigator and IRB expertise in the biological, medical, behavioral, and emotional development and needs of children. The following recommendation applies to independent, central, and other IRBs as well as to those affiliated with biomedical and social science research institutions and children’s hospitals: Recommendation 8.3: Institutional review boards (IRBs) that review protocols for clinical research involving infants, children, and adolescents should have adequate expertise in child health care and research. They should have at least three individuals with such expertise present as members or alternates during meetings in which a research protocol involving children is reviewed. Among them, these individuals—who may be generalists or specialists—should have expertise in pediatric clinical care and research, the psychosocial dimensions of child and adolescent health care and research, and the ethics of research involving children. As appropriate for specific studies, IRBs should consult with other child health experts and with parents, children, adolescents,

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Ethical Conduct of Clinical Research Involving Children and community members who can provide relevant family or community perspectives. Publicly accessible information about IRB procedures and guidance related to the design and review of protocols that include children is limited and highly variable, which makes it difficult to judge this dimension of IRB and institutional performance. Some publicly accessible IRB websites display little readily identifiable information or guidance for investigators or IRB members related to research that includes children. For example, some websites have protocol checklists or application forms that include no items or an incomplete list of items that highlight requirements for research involving children (and no obvious alternative document with the relevant items). Federal agencies have found deficiencies in IRB practices related to the review of research involving children, particularly in the description of the bases for IRB decisions in the meeting minutes. More complete and specific protocol checklists or application forms would help highlight the ethical and regulatory standards for approving and conducting research involving children and should improve compliance with those standards. Recommendation 8.4: For their policy manuals, websites, and other resources, institutional review boards (IRBs) and research institutions should provide easily understood and easily located information that directs investigator and IRB member attention to the ethical principles and special regulatory requirements that apply to the conduct and review of research that includes infants, children, and adolescents. Federal Policymakers and Regulators For approximately a half-century, federal agencies responsible for conducting and sponsoring biomedical research and for regulating medical products have—sometimes directed by Congress—played a major role in developing policies to protect human participants in research. In recent years, they have paid increasing attention to the application of those policies by investigators, IRBs, and research institutions and to the education of these parties about their responsibilities. The guidance and other resources that OHRP and FDA have made available strongly shape if not dominate local IRB policy manuals and resource links. Although investigators and IRB members at research institutions should have good local support as recommended above, they and others—including policymakers and others interested in ethical and regulatory standards for clinical research—should also find it easy to locate guidance and information on government websites. FDA, which now has an Office of Pediatric Therapeutics within the Center for Drug Evaluation and Research, has a web page dedicated to pediatric research with links to a

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Ethical Conduct of Clinical Research Involving Children variety of resources, including FDA regulations and guidelines for such research. The OHRP website has limited resources relevant to research involving children and they can be difficult to locate. Recommendation 8.6: The Office for Human Research Protections, the Food and Drug Administration, the National Institutes of Health, and other agencies with relevant responsibilities that include research involving children should each provide—in an easily identifiable document or set of linked documents—comprehensive, consistent, periodically updated guidance to investigators, institutional review boards, and others on the interpretation and application of federal regulations for the protection of child participants in research. DHHS has moved to significantly improve the process for reviewing proposals for research involving children that IRBs have referred to the Secretary for approval under the provisions of 45 CFR 46.407. That effort, with support from the Secretary’s Advisory Committee on Human Research Protections, should continue with the objective of establishing an open and publicly accessible process for reviewing referred protocols (Recommendation 8.7). DHHS should also develop guidance to help IRBs determine when it is appropriate to refer protocols for review. The referral of proposed research for “national” review should be reserved for “exceptional situations” and research of “major significance” and protocols should only be approved if they are expected to produce vitally important knowledge. The committee encourages the continued investment by OHRP in its quality improvement initiative, with attention to the special requirements and challenges of research involving children. OHRP, FDA, and other agencies should also continue to cooperate in the development of educational programs for use by government agencies, IRBs, research institutions, pediatric academic societies, and other groups. In addition, agencies should fund research and demonstration projects to expand the knowledge base for improving the performance of the system for protecting child participants in research. They can, for example, test strategies to improve the quality and consistency of reviews for multisite research projects and reduce unnecessary burdens and frustrations for their investigators and sponsors. Such improvements will not eliminate tensions between the goal of protecting today’s children from research harms and the goal of advancing research that improves the health and well-being of tomorrow’s children. They can, however, help all parties feel more confident that policymakers and IRBS are trying to identify and remove needless burdens on researchers. The full list of committee recommendations follows.

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Ethical Conduct of Clinical Research Involving Children Ethical Conduct of Clinical Research Involving Children: Complete List of Recommendations Recommendation 4.1 In evaluating the potential harms or discomfort posed by a research protocol that includes children, investigators, and reviewers of research protocols should interpret minimal risk in relation to the normal experiences of average, healthy, normal children; focus on the equivalence of potential harms or discomfort anticipated in research with the harms or discomfort that average, healthy, normal children may encounter in their daily lives or experience in routine physical or psychological examinations or tests; consider the risk of harms or discomfort in relation to the ages of the children to be studied; and assess the duration as well as the probability and magnitude of potential harms or discomfort in determining the level of risk. Recommendation 4.2 In evaluating the potential harms or discomfort posed by a research protocol that includes children who have a disorder or condition but no prospect of benefiting from participation, investigators and reviewers of research protocols should interpret minor increase over minimal risk to mean a slight increase in the potential for harms or discomfort beyond minimal risk (as defined in relation to the normal experiences of average, healthy, normal children); assess whether the research procedures or interventions present experiences that are commensurate with, that is, reasonably comparable to experiences already familiar to the children being studied on the basis of their past tests or treatments or their knowledge and understanding of the treatments that they might undergo in the future; consider risks of harms or discomfort in relation to the ages of the children to be studied; and assess the duration as well as the probability and magnitude of potential harms or discomfort in determining the level of risk. Recommendation 4.3 In determining whether proposed research involving a minor increase over minimal risk and no direct benefit can be approved, the term condition should be interpreted as referring to a specific (or a set of specific) physical, psychological, neurodevelopmental, or social characteristic(s) that an established body of scientific evidence or clinical knowledge has shown to negatively affect children’s health and well-being or to increase their risk of developing a health problem in the future. Recommendation 4.4 For purposes of determining whether proposed research involving a minor increase over minimal risk and no direct benefit

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Ethical Conduct of Clinical Research Involving Children can be approved, institutional review boards should make a determination that the children to be included in the research have a disorder or condition; the research is likely to generate vital knowledge about the children’s disorder or condition; the research procedures or interventions present experiences that are commensurate with, that is, reasonably comparable to, experiences already familiar to the children being studied on the basis of their past tests or treatments or on their knowledge and understanding of the treatments that they might undergo in the future; and the research does not unjustly single out or burden any group of children for increased exposure to research risk on the basis of their social circumstances. Recommendation 4.5 The Secretary’s Advisory Committee on Human Research Protections (U.S. Department of Health and Human Services) should continue the work of its predecessor committee by developing additional consensus descriptions of procedures or interventions that present minimal risk or no more than a minor increase over minimal risk. In addition, the Office for Human Research Protections and the Food and Drug Administration should cooperate to develop and disseminate guidance and examples for investigators and institutional review boards to clarify important regulatory concepts and definitions (including definitions of minimal risk, minor increase over minimal risk, condition, and prospect of direct benefit). Recommendation 4.6 Institutional review boards should assess the potential harms and benefits of each intervention or procedure in a pediatric protocol to determine whether each conforms to the regulatory criteria for approving research involving children. When some procedures present the prospect of direct benefit and others do not, the potential benefits from one component of the research should not be held to offset or justify the risks presented by another. Recommendation 5.1 To focus attention on the process of requesting parents’ permission and children’s assent to research participation, investigators should provide and IRBs should review protocol descriptions of who will request permission and assent; how and when permission and assent will be requested; who should be contacted if parents have questions or concerns about the research; and for studies that extend over considerable periods of time, when and

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Ethical Conduct of Clinical Research Involving Children how permission and assent may be requested again; for example, as children reach important developmental milestones. Recommendation 5.2 When appropriate for research involving children with acute illnesses or injuries, investigators and institutional review boards should provide for ongoing processes for permission and assent that will accommodate a family’s evolving understanding of the child’s condition, the child’s emotional state and decision-making capacity, and the child’s changing medical and psychological status. These processes are not matters of signing or updating forms but, rather, of continuing communication based on appreciation of the difficult and even overwhelming circumstances in which parents may be asked to make grave decisions about their child’s future. Recommendation 5.3 Investigators—with assistance and oversight from institutional review boards, research institutions, and research sponsors—should design procedures for seeking parental permission for a child’s participation in research that are sensitive to educational, cultural, and other differences among families and include provisions for educating—not merely presenting information to—parents about issues critical to informed decision making and, as appropriate, assessing the degree to which these critical issues are understood; writing consent and permission materials in the simplest language that still conveys essential information about the study; and providing competent, trained translators and interpreters, when needed, and otherwise assisting parents with limited English-language proficiency with making informed decisions. Recommendation 5.4 Institutional review boards should consider granting waivers of parental permission for adolescent participation in research when the research is important to the health and well-being of adolescents and it cannot reasonably or practically be carried out without the waiver (consistent with 45 CFR 46.116(d) and 45 CFR 408(c)) or the research involves treatments that state laws permit adolescents to receive without parental permission (consistent with the definition of children at 46 CFR 402(a)) and when the investigator has presented evidence that the adolescents are capable of understanding the research and their rights as research participants and the research protocol includes appropriate safeguards to protect the interests of the adolescent consistent with the risk presented by the research.

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Ethical Conduct of Clinical Research Involving Children Recommendation 5.5 The Food and Drug Administration should adopt policies consistent with federal regulations at 45 CFR 46.408(c) that allow institutional review boards with appropriate expertise to waive requirements for parental permission in research, provided that additional, appropriate safeguards are in place to protect the child’s or the adolescent’s welfare. Recommendation 5.6 In designing and reviewing procedures for seeking a child’s assent to participation in research, investigators and institutional review boards should aim to create assent processes that consider and respect the child and the family as a unit as well as individually. The process for requesting assent should be developmentally appropriate given the ages and other characteristics of the children to be approached; provide opportunities for children to express and discuss their willingness or unwillingness to participate; clarify for parents and children (as appropriate) the degree of control that each will have over the participation decision; and when appropriate, describe to children and parents the kinds of information about the child that will or will not be shared with the parents. Recommendation 5.7 Guidance and education for investigators and members of institutional review boards should make clear that federal regulations allow discretion—based on children’s developmental maturity—about the way in which information is presented to children and the manner in which assent is documented. Investigators and institutional review board members should apply that knowledge in determining what procedures will best serve the goals of assent for particular research protocols and populations. Recommendation 5.8 To increase investigator competence in communicating with children and parents about research participation, educational programs for investigators and research staff who expect to do research involving children should include training and evaluation in developmentally appropriate and family-sensitive processes for seeking permission and assent. Recommendation 5.9 Federal agencies, private foundations, and advocacy groups should encourage and support research on existing and innovative permission and assent processes and information materials to support improvements in these processes and guide the education of investigators and institutional review board members.

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Ethical Conduct of Clinical Research Involving Children Recommendation 6.1 Institutional review boards, research institutions, and sponsors of research that includes children and adolescents should adopt explicit written policies on acceptable and unacceptable types and amounts of payments related to research participation. These policies should specify that investigators disclose the amount, the recipient, the timing, and the purpose (e.g., an expense reimbursement or a token of appreciation to a child) of any payments as part of the process of seeking parents’ permission and, as appropriate, children’s assent to research participation; avoid emphasis on payments or descriptions of payments as benefits of participating in research during the permission or assent process; and obtain institutional review board approval for the disclosure of information about payments in advertisements and in permission and assent forms and procedures. Recommendation 6.2 In addition to offering small gifts or payments to parents and children as gestures of appreciation, investigators may also—if they minimize the potential for undue influence—act ethically to reduce certain barriers to research participation when they reimburse reasonable expenses directly related to a child’s participation in research; provide reasonable, age-appropriate compensation for children based on the time involved in research that does not offer the prospect of direct benefit; and offer evening or weekend hours, on-site child care, and other reasonable accommodations for parental work and family commitments. Recommendation 6.3 Research organizations and sponsors should pay the medical and rehabilitation costs for children injured as a direct result of research participation, without regard to fault. Consent and permission documents should disclose to parents (and adolescents, if appropriate) the child’s right to compensation and the mechanisms for seeking such compensation. Recommendation 6.4 Investigators and their staffs may appropriately be reimbursed for the costs associated with conducting research. Payments in the form of finder’s fees or bonuses for enrolling a specific number of children or adolescents are unethical and should not be permitted. Recommendation 7.1 To help identify what further guidance, education, or other steps may be needed to protect child participants in research, the U.S. Department of Health and Human Services—with direction from the

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Ethical Conduct of Clinical Research Involving Children U.S. Congress, if necessary—should develop and implement a plan for gathering and reporting data on research involving children, including the categorization of studies by the relevant section of federal regulations (45 CFR 46.404 to 407 and 21 CFR 50.51 to 54), and implementation of the regulations that govern research involving children, including data from the Office for Human Research Protections and the Food and Drug Administration on their inquiries, investigations, and sanctions related to such research. Recommendation 7.2 Organizations that accredit human research protection programs should provide for expertise in child health in their own activities; develop explicit provisions for evaluating whether institutional review boards are appropriately constituted and are prepared to review research involving children; and involve parents, children, and adolescents who have experience with pediatric clinical research in discussions to identify their concerns with the conduct of research. Recommendation 8.1 Federal law should require that all clinical research involving infants, children, and adolescents be conducted under the oversight of a formal program for protecting human participants in research. Recommendation 8.2 To strengthen the base of qualified pediatric clinical investigators, federal and state policymakers and research institutions should support education in the fundamentals of pediatric clinical research, including research ethics, in all educational programs for pediatric subspecialists and additional advanced education in pediatric clinical research, including research ethics, for those who seek careers in this field of research. Recommendation 8.3 Institutional review boards (IRBs) that review protocols for clinical research involving infants, children, and adolescents should have adequate expertise in child health care and research. They should have at least three individuals with such expertise present as members or alternates during meetings in which a research protocol involving children is reviewed. Among them, these individuals—who may be generalists or specialists—should have expertise in pediatric clinical care and research, the psychosocial dimensions of child and adolescent health care and research, and the ethics of research involving children. As appropriate for specific studies, IRBs should consult with other child health experts and with par-

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Ethical Conduct of Clinical Research Involving Children ents, children, adolescents, and community members who can provide relevant family or community perspectives. Recommendation 8.4 For their policy manuals, websites, and other resources, institutional review boards (IRBs) and research institutions should provide easily understood and easily located information that directs investigator and IRB member attention to the ethical principles and special regulatory requirements that apply to the conduct and review of research that includes infants, children, and adolescents. Recommendation 8.5 The federal government, research institutions, research sponsors, and groups of institutional review boards should continue to test and evaluate means to improve the efficiency as well as the quality and consistency of reviews of multicenter studies, including those involving infants, children, and adolescents. Recommendation 8.6 The Office for Human Research Protections, the Food and Drug Administration, the National Institutes of Health, and other agencies with relevant responsibilities that include research involving children should each provide—in an easily identifiable document or set of linked documents—comprehensive, consistent, periodically updated guidance to investigators, institutional review boards, and others on the interpretation and application of federal regulations for the protection of child participants in research. Recommendation 8.7 The Office for Human Research Protections and the Food and Drug Administration should continue their activities to establish an open and publicly accessible review process for considering research protocols referred by institutional review boards for review under 45 CFR 46.407 and 21 CFR 50.54; create a standing panel that would meet as needed to consider such proposals; and provide detailed guidance on the interpretation of the federal regulations governing research involving children to reduce unnecessary referrals of protocols.

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