Ethical Conduct of Clinical Research Involving Children (2004) / Chapter Skim
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Summary I n recent decades, advances in 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.
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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.
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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)
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. 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.
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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.
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Recommendation 4.3: In determining whether proposed research in volving 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, neurodevelop mental, or social characteristic(s)
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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.
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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 seek ing a child's assent to participation in research, investigators and insti tutional review boards should aim to create assent processes that consider and respect the child and the family as a unit as well as individually.
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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 institu tions, 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.
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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.
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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)
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Box S.3 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.
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· Ensure that research protocols involving children conform to ethical and scientific standards for such research. · Submit proposals and proposal amendments for scientific and ethical re view and approval before beginning or modifying research and, as required, during the course of research.
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· 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.
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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)
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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 docu ment or set of linked documents -- comprehensive, consistent, periodi cally 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.
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; · 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)
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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)
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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)
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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.
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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.
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, 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.
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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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