8
Responsible Research Involving Children

[T]hose who participate as subjects of research studies should share in the accolades usually accorded great scientists…. [They] deserve to be fully informed, treated with respect, listened to, and protected from foreseeable harm.

Institute of Medicine, 2003a, p. 29

A robust system for protecting human participants in research in general is a necessary but not sufficient foundation for protecting child research participants in particular. Meeting the special ethical and legal standards for protecting infants, children and adolescents who participate in research demands additional resources and attention beyond that required for protecting adults. Such additional commitments are particularly important given recent requirements or incentives to increase the amount of research involving children. Between 1997 and 2001, the number of industry-sponsored pediatric clinical trials and the number of child participants in such trials increased by an estimated three-fold (Dembner, 2001; Milne, 2002).

In some cases, the special ethical and regulatory protections for children may preclude potentially important clinical studies that would be approved for adult participation. This prospect can put pressure on those involved in developing or reviewing studies that include infants, children, or adolescents. A strong system of protections for adult and child partici-



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Ethical Conduct of Clinical Research Involving Children 8 Responsible Research Involving Children [T]hose who participate as subjects of research studies should share in the accolades usually accorded great scientists…. [They] deserve to be fully informed, treated with respect, listened to, and protected from foreseeable harm. Institute of Medicine, 2003a, p. 29 A robust system for protecting human participants in research in general is a necessary but not sufficient foundation for protecting child research participants in particular. Meeting the special ethical and legal standards for protecting infants, children and adolescents who participate in research demands additional resources and attention beyond that required for protecting adults. Such additional commitments are particularly important given recent requirements or incentives to increase the amount of research involving children. Between 1997 and 2001, the number of industry-sponsored pediatric clinical trials and the number of child participants in such trials increased by an estimated three-fold (Dembner, 2001; Milne, 2002). In some cases, the special ethical and regulatory protections for children may preclude potentially important clinical studies that would be approved for adult participation. This prospect can put pressure on those involved in developing or reviewing studies that include infants, children, or adolescents. A strong system of protections for adult and child partici-

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Ethical Conduct of Clinical Research Involving Children pants in research will provide support and guidance for all involved to help them fulfill their legal and ethical responsibilities in such situations. This chapter considers the final element in the committee’s statement of task, which relates to the unique roles and responsibilities of institutional review boards (IRBs) in reviewing research involving infants, children, and adolescents. Consistent with the report’s system perspective, the chapter also looks at the roles and responsibilities of other key parties, including investigators, research institutions, federal agencies, and public and private research sponsors. For a more comprehensive resource on ways to improve the structure and functioning of the national system for protecting human participants in research, readers may consult the analyses and recommendations in the 2003 Institute of Medicine (IOM) report Responsible Research (IOM, 2003a). Although this chapter focuses on those who conduct, review, fund, and regulate research, the committee recognizes the important role of parents. They 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. Chapter 5, in particular, has discussed how investigators, IRBs, and others can effectively and compassionately support parents in fulfilling their responsibilities and, thereby, help them to feel that they have done the right thing for their child, whatever their choices about the child’s participation in research. Once parents have agreed to their child’s participation in research, they—and older children and adolescents—may sometimes have crucial responsibilities for following the research protocol (e.g., administering medicines or bringing the child in for research appointments). Investigators need to make sure that parents and older children and adolescents understand any such responsibilities before they agree to research participation and that they have appropriate support in adhering to the protocol during the course of the research. As a general statement of concern about the responsible conduct of clinical research involving children, the committee notes that the regulations offering special protections to child participants in research do not cover all research. They apply only to clinical research that is conducted, supported, and regulated by the U.S. Department of Health and Human Services (DHHS) or that is covered by the policies of research institutions that extend these regulations to other studies conducted under their auspices. If other agencies undertake or support clinical research that includes children, they too should formally adopt these regulations, and private organizations not otherwise covered by the rules should likewise abide by them. Furthermore, institutions involved in significant innovation in clinical care for children should ensure that patients are protected by safeguards equivalent to those that federal regulations provide to research participants. The committee believes that all research that includes infants, children,

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Ethical Conduct of Clinical Research Involving Children and adolescents should occur under the oversight of a formal program for the protection of human research participants. In this, it follows the 2003 IOM report cited above and the 2001 report of the National Bioethics Advisory Commission (NBAC, 2001b). 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. The committee recognizes that legitimate questions exist about the federal government’s authority to require such oversight. Thus, it also encourages state governments to exercise their authority to regulate research—but to do so in ways that are consistent with federal policies and compatible with multicenter studies. ROLES AND RESPONSIBILITIES Because the relationship between the investigator and the research participant is so critical to participant protection, this section begins with a summary discussion of the roles and responsibilities of investigators who conduct research involving infants, children, or adolescents. The discussion then turns to the roles and responsibilities of IRBs and research institutions. Later sections consider the roles and responsibilities of federal agencies and research sponsors. Investigators and the Research Team [In addition to participants’ knowledge that they are participating in research], there is the more reliable safeguard provided by the presence of an intelligent, informed, conscientious, compassionate, responsible investigator. Henry Beecher, 1966, p. 1360 As observed by Edmund Pellegrino (1992), this statement by Henry Beecher serves as a definition of “the character traits of the morally responsible investigator” (p. 1). In clinical research, the investigator has the ultimate responsibility for ensuring the safety, rights, and welfare of individuals participating in research and for seeing that all members of the research team meet the requirements for valid, ethical research. This is the case whether the investigator has a major role in designing the research or uses a design developed by a research sponsor or others. Likewise, he or she is responsible for the safety and welfare of child participants in research, whether the study includes only children or also includes adults.

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Ethical Conduct of Clinical Research Involving Children Box 8.1 summarizes some of the major responsibilities of clinical investigators who conduct research that includes infants, children, or adolescents. To varying degrees, research institutions, sponsors of research, and regulators understand—or should understand—that investigators’ success in fulfilling their responsibilities depends significantly on supportive administrative, financial, educational, and other systems, both local and national. The infrastructure provided by these systems should extend from the initial education of investigators through the eventual dissemination of research findings and likewise should encompass all relevant settings and types of practice. BOX 8.1 Key Responsibilities of Investigators for the Ethical Conduct of Clinical Research Involving Infants, Children, and Adolescents Achieve and maintain appropriate training, credentials, and skills to perform or supervise all clinical and research procedures required for a study that includes children. Achieve and maintain appropriate training and knowledge to meet the ethical and regulatory requirements for conducting research that includes children. Ensure that research protocols involving children conform to ethical and scientific standards for such research. Submit proposals and proposal amendments for scientific and ethical review and approval before beginning or modifying research and, as required, during the course of research. Conduct the study in accord with the approved protocol. Disclose potential conflicts of interest to appropriate parties. Ensure that the processes for securing parents’ permission and children’s assent to research participation meet ethical and regulatory standards and are effective and active through the duration of the study. Provide rationale and propose appropriate protections consistent with federal and state laws if a waiver of parent permission is sought. Communicate with children participating in research in developmentally appropriate ways and with guidance from their parents about what will happen to them throughout the course of the research. Support appropriate safety monitoring and reporting of adverse events. Report protocol violations, errors, and problems as required to research sponsors, regulators, or IRBs. Disclose research results to the scientific community and the public. Communicate research results, as appropriate, to research participants or participant communities. SOURCE: Adapted from IOM, Responsible Research: A Systems Approach to Protecting Research Participants. Washington, D.C.: National Academy Press, (2003a, Box 4.1).

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Ethical Conduct of Clinical Research Involving Children The committee commends recent efforts by research institutions, sponsors, and federal agencies to strengthen education in research ethics for investigators. Unless an educational program is narrowly tailored to investigators who will not study children, it should specifically cover ethical principles and standards for the conduct of research involving children. Pellegrino and others have argued that ethical values, behavior, and character can be taught to clinicians and researchers, although this can be challenging when the surrounding environment is, in some respects, not friendly to these values and virtues (see, e.g., Pellegrino, 1992; Ludmerer, 1999; and Siegler, 2002). Again, this challenge underscores the importance of having a supportive system to stand with and behind the ethical investigator. For example, given the special ethical responsibilities of pediatric investigators and the critical need for studies that contribute to generalizeable knowledge to improve children’s health, these investigators may face a serious ethical dilemma if research sponsors seek to prevent or limit publication of their findings. Consistent with the IOM report Responsible Research (2003a), research institutions should help investigators avoid such dilemmas by approving contracts with research sponsors only if they provide for public disclosure of the findings from properly conducted research. The next section of this report suggests other ways in which IRBs and research institutions, in particular, can make it easier for researchers who study children to know and to do what is ethically and scientifically responsible. As discussed in Chapter 2, it is also important to have sufficient numbers of pediatric investigators who have the necessary preparation to design and conduct valid and ethical research involving infants, children, and adolescents. The National Institutes of Health (NIH) and pediatric professional societies have taken steps to strengthen the education of pediatric investigators, and these efforts should be sustained. 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. Although professional societies are not normally considered to be part of the system for protecting human participants in research, they too have a role to play in developing ethical standards for human research and helping clinical investigators understand and uphold these standards in practice.

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Ethical Conduct of Clinical Research Involving Children Thus, it is important for organizations such as the American Academy of Pediatrics, the Society for Pediatric Research, and the Society for Adolescent Medicine to remain attentive not only to the need for research but to the need for continued vigilance in protecting infant, child, and adolescent participants in research. Institutional Review Boards and Research Institutions IRBs are the cornerstone of a system in which other entities, such as research sponsors, also have obligations to protect research participants. Institute of Medicine, 2003a, p. 70 Much of the administrative infrastructure and activity that contribute to competent and ethical IRB and research institution performance will support equally the protection of adult and child participants in research. Beyond this foundation, however, both the research institutions that conduct research involving children and the local, central, or independent IRBs that review such research have further ethical and legal responsibilities that demand special attention. Box 8.2 summarizes these responsibilities, which begin with educating IRB members, investigators, and others about their ethical and legal responsibilities for protecting child participants in research. The effective performance of IRB responsibilities can be threatened by the accretion of additional responsibilities for activities such as managing institutional risk related to research activities, assessing potential investigator or institutional conflicts of interest, and overseeing institutional compliance with a range of other research-related policies. Given the magnitude of the tasks involved in effectively overseeing the ethical aspects of human research, research institutions will best promote the objectives of this oversight by assigning other tasks to units other than the IRB as recommended in Responsible Research (IOM, 2003a). That report also argued for keeping IRBs (what it termed research ethics review boards) focused on the ethical dimensions of human research through the development of “distinct mechanisms” to provide separate, prior reviews of protocols for scientific merit and financial conflicts of interest. The results of these two separate reviews would then inform the final determinations made by the IRB. Expertise in Child Health and Research A critical obligation of IRBs is to bring appropriate expertise to the review of research involving infants, children, and adolescents. The federal regulations on children do not, however, explicitly require that IRBs in-

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Ethical Conduct of Clinical Research Involving Children BOX 8.2 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 websites 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). clude a member with such expertise. IRBs with publicly accessible web sites that list members of biomedical IRBs generally show at least one pediatrician member or, less often, a pediatric nurse or other child health expert. The sites usually provide little indication of any formal provisions for securing additional expertise. In the committee’s experience, these provisions are highly variable. As more children participate in clinical trials and other research, the need is growing for both investigator and IRB expertise in the biological, medical, behavioral, and emotional dimensions of research involving infants, children, and adolescents. Given concerns cited earlier about the adequate supply of trained and experienced pediatric investigators, this can pose an additional challenge for IRBs and research institutions. In some cases, research institutions may have to reach beyond their own boundaries to fulfill their responsibilities, for example, by using outside consultants or referring protocols to IRBs that have the requisite expertise. IRBs that review research involving children are not the only entities that need expertise in child health and research. As noted in Chapter 3, when a data safety and monitoring board or a data monitoring committee is established to monitor research that involves infants, children, or adolescents, it should include pediatric expertise appropriate for the condition

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Ethical Conduct of Clinical Research Involving Children and population included. For certain long-term genetic studies, monitoring bodies may include individuals familiar with the impact of genetic information on the long-term psychological status of children and family members involved in such studies. In addition, as proposed in Chapter 7, agencies that accredit IRBs will require expertise in child health and research to establish standards for IRB review of research that includes children. The following recommendation focuses specifically on IRBs. It applies to independent, central, and other IRBs as well as local IRBs affiliated with biomedical research institutions. 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, and community members who can provide relevant family or community perspectives. Although IRBs that review research protocols involving children can and should rely on consultants to provide additional expertise relevant to particular studies, their own membership should include core expertise in general pediatrics; child development (cognitive, emotional, and social); and the ethical, regulatory, methodologic, and psychosocial dimensions of research involving infants, children, and adolescents. The committee expects that an IRB will require at least three members or alternates with broad pediatric expertise to cover these core areas. Some IRBs may find this difficult and may choose to refer proposals for research involving to children to IRBs that do have the appropriate expertise. A referring IRB should still review proposals for issues related to local conditions and concerns. An earlier IOM committee recommended allocating one-quarter of the membership of review boards to individuals who are not scientists, not affiliated with the research institution, and able to represent the perspectives of research participants or the community (IOM, 2003a). This committee agrees and further advises that standing pediatric advisory committees and pediatric IRBs include at least one nonscientist, unaffiliated member who can represent explicitly the perspectives of parents and children. (The presence of IRB members who also happen to be parents as well as scientists, ethicists, or clinicians does not suffice.)

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Ethical Conduct of Clinical Research Involving Children Depending on the focus of individual protocols, IRBs may also consult with parents and children affected by the condition proposed for study to obtain additional insights and guidance. These community and family perspectives are important for such tasks as comprehensively assessing a study’s potential harms and benefits (including effects on the relevant ethnic and other communities); considering the adequacy of personnel and sites for working with children; and evaluating the provisions for informing families before, during, and after the completion of research (Dresser, 2001). All members of IRBs and advisory committees should be prepared to consider relevant community interests in research that includes children, especially research involving sensitive issues such as genetic predisposition to a disease. Given the great range of clinical studies involving infants, children, and adolescents, even IRBs that specialize in the review of such studies will need to use consultants because some protocols will present issues outside the expertise of the group’s members. Depending on a study’s focus and setting, consultants may include various kinds of pediatric medical subspecialists, child and adolescent psychologists, child life specialists, pediatric nurses and nurse researchers, and others experienced in the care and study of infants, children, and adolescents with the condition covered by the protocol. Except for certain studies involving older adolescents (e.g., some antihuman immunodeficiency virus [HIV] drug trials), adult subspecialists usually cannot provide appropriate pediatric expertise. The rosters of pediatric consultants will need to be large enough to provide timely reviews of protocols, consistent with the IRB and institutional workload. The consultants may support multiple IRBs that review all types of biomedical research for institutions operating on that model. Although many children’s hospitals are part of academic medical centers and have IRBs that focus almost entirely on pediatric studies, some IRBs are associated with general children’s hospitals or medical groups that are not part of academic medical centers and whose personnel have limited direct experience with the design and conduct of pediatric clinical trials or other complex studies involving children. For these IRBs, expertise in trial design and methods may need to be obtained through consultants or the referral of protocols to appropriately constituted IRBs. That is, expertise is required in pediatric research as well as in pediatric medical conditions and clinical care. Noting the scarcity of expertise in pediatric research in their statement to the committee, the Society for Pediatric Research and American Pediatric Society recommended creating ways to pool pediatric research resources, for example, through regional pediatric advisory committees or review bodies that could assist local IRBs (SPR and APS, 2003). This could be particularly helpful for rural and other institutions that are not part of

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Ethical Conduct of Clinical Research Involving Children academic medical centers. Such arrangements could also help institutions cooperate to increase the efficiency of reviews for multicenter studies. Moves in this direction would be assisted by the development of model affiliation or contractual arrangements that deal with liability concerns, costs, and similar practical matters. IRB Attention to Special Protections for Children Again, no systematic documentation exists on the extent to which IRB members understand and fulfill their responsibilities in reviewing studies that include children. In considering IRBs’ unique roles and responsibilities, the committee—beyond reference to ethical and regulatory standards—had to rely largely on its members’ judgment and experience, including their participation in such activities as regional and national meetings on human research protection, on-site or telephone consultations with IRB members and administrators, accreditation activities, and discussions of IRB reviews of multisite research projects. The committee also checked research institution websites to see what they included about research involving children. (Some IRBs restrict access to their web sites to investigators, IRB members, and others affiliated with the institution. No comprehensive listing of relevant, publicly accessible sites is available to allow a systematic sampling.) In an informal review of publicly accessible websites of institutions that conduct research involving children, the committee found that several sites displayed little information or guidance about special requirements related to such research. In some cases, useful institutional information or guidance on research involving children was available but was not easily located or clearly identifiable, for example, in website indexes that provide links to IRB policies, guidance, and other resources. As noted in Chapter 1, the 1978 Belmont Report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research is widely available on websites, but the committee could not find any site with the Commission’s 1977 report Research Involving Children. It, too, should be accessible through local IRB websites as well as through the websites of the Office for Human Research Protections (OHRP) and the Food and Drug Administration (FDA). Website design is a topic beyond the scope of this study, but the committee encourages IRBs and research institutions to design these sites and other resources so that investigators and IRB members will find it easy to locate policies and guidance related to research involving children. For example, the table of contents of the manual of IRB policies and procedures should identify a section on children. That section either should include all relevant policies and information related to child research or should provide clear cross-references to other sections that contain relevant informa-

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Ethical Conduct of Clinical Research Involving Children BOX 8.3 Suggested Elements of IRB and Research Institution Guidance on Clinical Research Involving Infants, Children, and Adolescents Easily identified references and Internet links to DHHS and FDA regulations and guidance specific to children Easily identified descriptions of state policies (including known but not written policies of administrative agencies) relevant to the conduct of research involving children and to minors’ ability to participate in research without parental permission Age of majority statutes Emancipated or mature minor policies and judicial decisions Policies involving wards of the state and foster children Other Clearly labeled checklist of information and requirements for research involving children, including identification of the applicable category of research under 45 CFR 46 Subpart D and 21 CFR 50 and 56 Institutional policies or guidance on the qualifications of investigators or other members of the research team Experience with child health care and/or research Role of child health experts in the different components of research Guidance for the scientific rationale sections of protocols involving children Necessity for the research to include infants, children, or adolescents Data from relevant laboratory, animal, and adult studies Data from studies with adolescents or older children prior to studies with infants or younger children tion. State policies on emancipated and mature minors should be cited in the sections of IRB manuals that discuss parental permission and children’s assent. To underscore the special ethical character of parents’ permission and children’s assent, policy manuals and other resources should use those terms rather than the term informed consent. Box 8.3 lists information specific to the responsible conduct of research involving children that should be easily identifiable among the resources for investigators and IRB members provide by research institution and IRBs. More generally, institutions and IRBs may also wish to check the recently updated guidelines from the Council for International Organizations of Medical Sciences (CIOMS, 2002) discussed in Chapters 1 and 3. The guidelines include a particularly detailed appendix that lists information and explanations that should be included in a human research protocol (or associated documents). Such lists and other tools should help increase the

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Ethical Conduct of Clinical Research Involving Children Regardless of the model, central or regional review could be counter-productive for research involving infants, children, or adolescents unless the review organization possesses expertise sufficient to its responsibilities in assessing such research. A critical goal of any streamlined review process should be not only to reduce inefficiency and unproductive redundancy but also to reduce the inexpert review of research involving children and, thereby, improve the quality of reviews. A different strategy for improving consistency and efficiency in IRB review was taken in an NIH grant-funded project to establish a voluntary national IRB database and information system by use of a secure Internet site (IRBnet, 2003). The primary goals were to (1) support communication among IRBs and investigators and (2) provide standardized guidance for investigators in developing protocols, including protocols involving children. The project will allow the centralized distribution and review of protocols and consent, assent, and permission forms from multiple centers. It will also support the sharing and updating of information about IRB decisions and other developments. 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. Again, any streamlining strategy that extends to research involving children should be attentive to the special ethical and regulatory requirements for such research. It should provide for expertise in child health and research that is consistent with Recommendation 8.3 and the accompanying discussion. It should also be attentive to the qualifications and characteristics of local investigators and research sites as discussed in Chapter 4. One argument for retaining a meaningful role in protocol review for local IRBs is that a local process seems more likely to engage and educate investigators in the ethical conduct of clinical research, for example, through service as an IRB member or presentation of protocols at an IRB meeting. Furthermore, the process for reviewing multicenter protocols should become more efficient if, as suggested earlier in this chapter, research institutions and IRBs provide investigators with more specific and easily located guidance on the standards for research involving children. As an anonymous reviewer of this report wrote, “[i]f the local [investigator] is not provided with the tools to make a good and thoughtful IRB application, he will only do so if he’s extremely process-savvy. It’s not the least bit surprising that IRB responses are all over the proverbial map [for multicenter studies], if the quality of applications [for IRB review] is all over the map.”

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Ethical Conduct of Clinical Research Involving Children Sharing Information About IRB Decisions Although reports are mainly anecdotal, research sponsors are said on some occasions to engage in IRB “shopping.” This practice may involve choosing research sites on the basis of expectations about the rigor of IRB review. It may also mean submission of a protocol disapproved by one IRB to another IRB without disclosure of the previous decision. A 1998 study by the DHHS Office of the Inspector General raised concerns about this practice based on interviews involving six university-based IRBs (OIG, 1998b). Citing similar concerns, the FDA issued an advance notice of proposed rulemaking in 2002 to obtain information on IRB practices for the purposes of determining whether investigators and research sponsors should be responsible for disclosing to an IRB the results of any IRB decisions made previously (FDA, 2002b). It also asked for information to help it assess how extensive the problem of IRB shopping was. As of the end of 2003, no final rule had been issued. This committee believes that the sharing of information about IRB decisions—especially the specific rationales for decisions—would be helpful to IRBs involved in the review of multisite protocols. The NIH project to create a national IRB database (cited earlier) has information sharing as one feature. A narrower approach would involve the posting of information on a sponsor’s website listing IRBs that had reviewed or would be reviewing a protocol, the results of the review, the decision outcome, the date, and a contact person at each IRB (Nelson, 2002). IRBs reviewing the same protocol could then query other IRBs to learn, for example, their rationales for negative decisions or modifications. The committee encourages a test of this strategy with a set of NIH-supported or FDA-regulated studies that include children. In addition, the committee encourages the FDA to share the results of its audits of investigators and research sites with the relevant IRBs. Federal Agencies For approximately a half century, the federal agencies responsible for conducting and sponsoring biomedical research and for regulating medical products have—sometimes directed by the U.S. 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. Federal agencies have also taken some steps to collect better information to guide the evaluation and improvement of system performance. Box 8.5 summarizes some of the key responsibilities of federal agencies. Although this report has focused primarily on the activities of OHRP and

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Ethical Conduct of Clinical Research Involving Children BOX 8.5 Key Responsibilities of Federal Agencies for the Ethical Conduct of Clinical Research Involving Infants, Children, and Adolescents Provide and promote educational programs for investigators, IRBs, research institutions, and research sponsors on regulations related to research involving children Develop additional policy guidance for investigators, IRBs, research institutions, and research sponsors about the application of regulations related to research involving children Monitor and enforce compliance with regulations Define and collect the data needed to oversee, evaluate, and improve performance nationally and locally and to develop or revise policies Report on system goals and performance to policymakers and the public Support innovative projects to improve efficiency, reduce inappropriate variability in practices and decisions, and evaluate the effectiveness of policies to protect child participants in research Promote cooperation among the government agencies responsible for conducting, funding, and overseeing human research to provide consistent incentives for ethical research conduct and reduce duplicate or conflicting requirements or policies related to research involving children FDA, other agencies, notably NIH, also have roles to play in promoting the protection of human research participant. NIH, for example, has funded research on decision making about children’s participation in research. Furthermore, NIH and other agencies also have important responsibilities for other aspects of ethical research conduct related to research participant safety, privacy, and conflict of interest. Education and Guidance for IRBs and Investigators Beyond the regulations themselves, the resources made available by OHRP and FDA strongly shape if not dominate local IRB policy manuals and resource links. Although the 1993 IRB Manual and other resources provide some information and guidance about research involving children, the OHRP website does not make it easy to locate resources related to research involving children. For example, under the heading “Policy Guidance,” the list of topics does not specifically mention children. The OHRP home page recently added a link to the regulations governing children’s participation in research (http://ohrp.osophs.dhhs.gov). OHRP’s list of guidance materials includes neither the 1977 report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral

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Ethical Conduct of Clinical Research Involving Children Research on research involving children nor any other identifiable document on this topic. The agency’s website should include links to both that report and the reports of the National Human Research Protection Advisory Committee. It should make all resources related to research involving children easy to identify and locate. In contrast to the dearth of easily located OHRP resources related to research involving children, the FDA provides considerable information and guidance through the website for its Division of Pediatric Drug Development (http://www.fda.gov/cder/pediatric).4 The site lists and has links to the FDA’s interim regulations on safeguards for children in clinical investigations. It likewise lists and has links to the agency’s official guidance on pediatric drug research (i.e., the ethical and scientific guidelines for pediatric research developed by the International Conference on Harmonisation [FDA, 2000b; ICH, 2000b]).5 In addition to OHRP and FDA, other agencies that fund or oversee research that includes children should examine their guidance for the ease with which special considerations in the design, conduct, and oversight of such research can be identified. These other agencies include, for example, the Recombinant DNA Advisory Committee (RAC) at the National Institutes of Health. For requirements and topics that they have in common, agencies should also cooperate to provide guidance that is consistent in content. 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. The recent efforts by the federal government to strengthen education in research ethics are an important positive step. These efforts include some workshops and programs devoted specifically to research involving children. OHRP, the FDA, and other agencies should cooperate in the contin- 4   The division is part of the Office of Counter-terrorism and Pediatric Drug Development within the Center for Drug Evaluation and Research. The FDA also has an Office of Pediatric Therapeutics within the Office of the Commissioner. 5   Guidance from other FDA centers is not so easy to locate. For example, the draft guidance on premarket approval of pediatric medical devices from the Center for Devices and Radiologic Health can be found using the “A to Z Index” for the Center’s website, but the agency’s home page and links do not mention children.

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Ethical Conduct of Clinical Research Involving Children ued development of such educational programs at the national level for use at all levels by government agencies, research institutions, pediatric academic societies, and other groups. For example, in its statement to the committee, the Society for Pediatric Research noted its eagerness to play a role in disseminating such educational programs (SPR and APS, 2003). In addition to formal educational programs for investigators and IRBs and the development of up-to-date and easily located guidance for investigators, the committee encourages OHRP to continue to invest in its quality improvement initiative, with attention to the special requirements and challenges of research involving children. For IRBs and research institutions seeking to improve their programs for protecting child research participants, the availability of consultation and other support from OHRP can be valuable both to the local institution and to agency staff in enlarging their appreciation of the various environments in which these programs operate. Protocols Referred to the Secretary of DHHS As described in Chapters 3 and 4, under Section 407 of 45 CFR 46, IRBs can refer research proposals to the Secretary of DHHS for review and approval when they find that the proposals are ineligible for approval under other sections of the regulations (Sections 404, 405, and 406) and also appear to offer a “reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children.” Section 54 of 21 CFR 50 similarly provides for the referral of protocols for review by the Commissioner of the FDA. In Chapter 4, the committee recommended that those reviewing protocols referred to the Secretary or the Commissioner for review should apply the criterion of “vital importance” in judging the potential contribution to knowledge that could result from the proposed research. It argued that the standard for approving these otherwise-not-approvable protocols should not be weaker than the standard applied to protocols that present more than a minor increase over minimal risk, offer no prospect of direct benefit, and involve children with a disorder or condition. Box 8.6 lists examples of protocols that have been referred for Section 407 reviews (and, in one case involving a smallpox vaccine, for joint DHHS and FDA review under 21 CFR 50.54). OHRP has returned some protocols on the basis of staff determinations that they clearly do not fit the criteria for referral under Section 407. Issues related to at least two protocols referred to the FDA were resolved before the protocols proceeded to a review panel (David Lepay, M.D., Ph.D., Food and Drug Administration, personal communication, December 15, 2003). Recently, DHHS has moved to improve significantly the process for reviewing research proposals that IRBs have referred to the Secretary under

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Ethical Conduct of Clinical Research Involving Children BOX 8.6 Examples of Protocols Referred for Review by the Secretary of DHHS Under 45 CFR 46.407, by Year of Referral and Institution 1991 The New England Medical Center Hospital: Study of myoblast transfer in Duchenne muscular dystrophy. Not approved but few details are publicly available. (56 FR 49189) 1993 Children’s Hospital of Pittsburgh: Proposed study of cognitive function and hypoglycemia (generated through the use of an insulin clamp) in children with insulindependent diabetes mellitus. Approved. (58 FR 40819) 2001 University of Washington: Study of precursors to diabetes in Japanese-American youth. Public comment on departmental recommendation for approval initially requested August 7, 2002 (67 FR 51283-51284). Reopened for public comment in December, 2002 (67 FR 77495). No final decision from the Secretary of DHHS. (http://ohrp.osophs.dhhs.gov/pdjay/pdjayindex.htm) 2002 Harbor-UCLA Medical Center: Test of dilute smallpox vaccine in children ages 2 to 5. Disapproved by the Secretary of DHHS and the Commissioner of FDA for reasons related to expected lack of availability of the vaccine and not to Subpart D requirements. (67 FR 66403; http://ohrp.osophs.dhhs.gov/dpanel/dpindex.htm) 2003 University of California, Los Angles: Longitudinal study of prolonged HIV infection, antiretroviral therapy, and thymus performance involving comparisons between infected and noninfected children. No final decision from the Secretary of DHHS. (68 FR 42061; http://ohrp.osophs.dhhs.gov/panels/407-04pnl/pindex.htm) University of North Carolina: Longitudinal study of newborn infants with cystic fibrosis involving flexible fiber-optic bronchoscopy and procedural sedation. No final decision from the Secretary of DHHS. (68 FR 35414; http://ohrp.osophs.dhhs.gov/panels/407-02pnl/pindex.htm) Albert Einstein College of Medicine: Study of the role of metabolism in sleep mechanisms in adolescents. No final decision from the Secretary of DHHS. (68 FR 35415; http://ohrp.osophs.dhhs.gov/panels/407-03pnl/pindex.htm) Rhode Island Hospital: Study of the effects of small to moderate amounts of alcohol on sleep, waking performance, and circadian phase. No final decision from the Secretary of DHHS. (68 FR 17950; http://ohrp.osophs.dhhs.gov/panels/407-01pnl/pindex.htm) SOURCE: Kopelman and Murphy, (in press) and Office for Human Research Protections (through January 2004).

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Ethical Conduct of Clinical Research Involving Children the Section 407 process. By using its website (as well as publication in the Federal Register) to post information and solicit comments about protocols that are under review, the agency has made the process more open to the public and to interested investigators, IRBs, and others. The names and comments of expert reviewers can be read as can other key documents, which may include the initial application for IRB review of the protocol, excerpts from the minutes of the reviewing IRB(s), and relevant correspondence. Previously, it was very difficult to get information even with a Freedom of Information Act request. The committee commends OHRP for the steps that it has taken to improve the efficiency, effectiveness, and openness of the Section 407 process. It also encourages further reforms. The current process solicits comments from experts but does not provide for the experts to discuss and refine their views, consider and perhaps resolve disagreements, or present their views coherently as a group. A better alternative would be to create a standing Section 407 panel that would meet as needed to consider referred proposals (using topic-specific consultants as appropriate). Although ad hoc panels can provide expert reviews, they do not accumulate experience and insight in the way that a continuing panel would be able to do. The committee was encouraged that the new Secretary’s Advisory Committee on Human Research Protections has identified as one of its priorities the development of recommendations for improving the Section 407 process. The group will consider whether it should constitute a subgroup of the full committee to serve as a standing Section 407 advisory panel. 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. A further concern about the current process is that it is unclear to what extent and for what reasons the agency is declining to consider referred protocols and sending them back to the originating IRB. Committee members are aware of instances of this practice, but the lack of public information deprives IRBs of important insights into agency views and deprives the larger community of interest of the opportunity to evaluate agency deci-

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Ethical Conduct of Clinical Research Involving Children sions. The committee urges OHRP to provide more information about returned proposals and its criteria or reasons for returning them. An open process for reviews under Section 407 combined with more guidance about the interpretation of the regulations, as recommended in Chapter 4, should help reduce referrals by IRBs of protocols that do not fit the criteria for such review. It should also encourage IRBs to refer protocols when truly appropriately rather than avoid referrals by using overly broad interpretations of the terms such as direct benefit, condition, minimal risk, or minor increase over minimal risk. Policy Development, Guidance, Data Collection, and Research The most comprehensive policy recommendation in this report calls for all research involving children to be conducted under the oversight of a formal human research participant protection program. A uniform federal policy is preferable but in the absence of federal action, corresponding state action is encouraged. As encouraged earlier in this chapter, all federal agencies that support or conduct research involving children should adopt the provisions in Subpart D of 45 CFR 46. Most committee recommendations do not call for new or revised regulations. One that does is the recommendation that FDA make its regulations on the waiver of parental permission for a child’s participation in research consistent with those of DHHS. In general, the recommendations for federal agencies focus on the development of additional guidance for investigators, IRBs, research sponsors, and agency personnel and the collection of additional information to guide the further improvement of policies and programs. In addition to the recommendations in this chapter, the report includes recommendations or suggestions that OHRP, FDA, and NIH—as appropriate given their respective roles and responsibilities— develop procedures for identifying, collecting, and reporting basic data on research involving children to provide one foundation for designing further guidance or education for investigators and IRBs; create a centralized national registry of research trials involving children (including healthy children); provide official guidance for investigators and IRBs based on this committee’s interpretation of minimal risk and other key concepts in the regulations on research involving children; continue work through the Secretary’s Advisory Committee on Human Research Protections to develop consensus assessments of the risk presented by procedures or interventions commonly used in clinical research involving children;

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Ethical Conduct of Clinical Research Involving Children cooperate to provide more explicit guidance on both the factors that should be considered in decisions about waiver of parent permission and the safeguards that are appropriate for different situations when parental permission is waived; join with private foundations and advocacy groups to support research on permission and assent processes and information materials; solicit ideas for research that could illuminate the ethical and practical implications of different kinds of payments related to children’s participation in research; harmonize guidance on safety monitoring for research organizations, including the standardization of requirements and practices for reporting adverse events; require that safety monitoring reports be shared with the relevant IRBs to alert them to potential problems with a study under their jurisdictions; prepare additional guidance about the elements that should be included in data and safety monitoring plans and provide that all clinical trials—including those supported by NIH—be monitored with the same degree of rigor and scrutiny; and require that protocols that include children and that involve more than minimal risk have a plan (not necessarily a board or committee) for monitoring the safety of child research participants and also provide that reports based on this plan be made available to relevant IRBs on a timely basis. Research Sponsors Research sponsors—both public and private—have crucial ethical and legal responsibilities for the protection of adult and child participants in research. The conditions that they impose or attempt to impose on the recipients of research funding can either support or undermine the ethical conduct of research and the safety of research participants. Large commercial sponsors of clinical research typically have well-developed policies and programs for designing, implementing, and monitoring human research consistent with federal regulations and, often, international standards. In fact, in the committee’s experience, their monitoring typically exceeds that required or undertaken by government sponsors of research and can serve, in some respects, as a guide to extending oversight by public funders of high-risk clinical studies. Earlier in this chapter, the committee advised research institutions to approve contracts with research sponsors only if they provide for public disclosure of findings. Research sponsors should likewise refrain from entering into contracts that limit such disclosure. In addition, the committee

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Ethical Conduct of Clinical Research Involving Children suggested ways in which the sharing of information about IRB decisions and concerns could be improved, for example, by the posting of information about IRB reviews on sponsors’ websites. The results of the FDA investigation of “IRB shopping” by research sponsors may suggest the need for new steps to safeguard the integrity of the system for protecting human research participants. An important, continuing question about the system for protecting human participants in research involves the costs associated with developing, reviewing, implementing, and monitoring protocols to meet ethical and regulatory standards. As described in another IOM report, “no satisfactory agreement has been reached regarding how the increasing costs of protecting participants should be distributed” (IOM, 2003a, p. 57). That report also notes that recent tragedies and administrative penalties for noncompliance with regulations have prompted significant increases in the resources that research institutions devote to their programs for protecting human research participants. The report commended NIH for providing one-time grants to fund information system and infrastructure improvements. It argued, however, that government agencies should—like private research sponsors—pay directly for initial and continuing IRB review. This committee agrees. One concern mentioned in Chapter 3 involved monitoring for long-term problems (e.g., the late effects of cancer chemotherapy or irradiation) that arise after research studies are completed. The discussion mentioned the limitations of FDA’s postmarket surveillance strategies, which, in any case, apply only to products approved for marketing by the agency. Research sponsors as well as investigators, IRBs, and relevant government agencies should consider potential late adverse effects of investigational therapies and assess what monitoring, end points, and evaluation plans might be advisable for studies with the potential for such harm. Reflecting a different concern about research-related harms, the committee recommended in Chapter 6 that research organizations and sponsors should pay medical and rehabilitation costs for children injured as a direct result of research participation, without regard to fault. On another point, the committee recommended that research sponsors not cover finder’s fees to physicians based on the referral of a child for enrollment in a study. CONCLUSION Policies and procedures for protecting adult and child participants in research have evolved over several decades, often prompted by public reports of unethical or questionable research practices. That evolution continues as policymakers, IRBs, research institutions, and investigators find shortfalls in their performance and devise strategies to improve the

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Ethical Conduct of Clinical Research Involving Children effectiveness and efficiency of the system for protecting human research participants. Investigators play a central role in the system for protecting child participants in research. Ensuring that they understand their obligations is a high priority as is further work to build an administrative, financial, and information infrastructure that makes it easier for investigators to know and fulfill their responsibilities. IRBs and research institutions can clearly improve their guidance and tools to help investigators design and implement ethically and scientifically sound clinical studies. Similar improvements by government agencies will, in turn, assist IRBs and research institutions as well as investigators. Government policymakers can also fund research and demonstration projects to expand the knowledge base for strengthening the performance of the system for protecting child participants in research, for example, by testing 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 the system for protecting child research participants is trying to identify and remove needless burdens on those who undertake these critical investigations.