Ethical Conduct of Clinical Research Involving Children (2004) / Chapter Skim
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8 Responsible Research Involving Children
8 Responsible Research Involving Children
Pages 246-276
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From page 246... ...
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.
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From page 247... ...
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.
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From page 248... ...
. Recommendation 8.1: Federal law should require that all clinical re search involving infants, children, and adolescents be conducted under the oversight of a formal program for protecting human participants in research.
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From page 249... ...
· Achieve and maintain appropriate training and knowledge to meet the eth ical and regulatory requirements for conducting research that includes children. · Ensure that research protocols involving children conform to ethical and scientific standards for such research.
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From page 250... ...
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)
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From page 251... ...
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.
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From page 252... ...
· 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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From page 253... ...
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.
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From page 254... ...
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.
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From page 255... ...
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.
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From page 256... ...
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)
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From page 257... ...
on · Payments to children or parents related to research participation · Advertising of studies that include children · Payments to physicians for enrolling children in studies · Appropriate expertise on data and safety monitoring boards or data moni toring committees for studies involving children and policies on establishment of such boards or committees, even when not required, for studies involving more than minimal risk · Guidance on data access and publication provisions in contracts with com mercial research sponsors of research that includes children efficiency of the review process by helping investigators submit protocols that do not have be returned because they lack essential information and explanations (e.g., why a protocol providing a waiver of parental permission is justified)
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From page 258... ...
Although deficiencies in IRB minutes may reflect poor documentation rather than inadequate analysis, it may also signal inattention by the IRB and research institution both to their responsibilities for assessing research involving children and to the specific regulatory requirements for the approval of such research.1 Protocol checklists or approval application forms that include items or attachments specific to research involving children help highlight -- for reviewers as well as investigators -- the ethical and regulatory standards for approving and conducting such research. Recommendation 8.4: For their policy manuals, websites, and other resources, institutional review boards (IRBs)
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From page 259... ...
Please describe: What are the processes for obtaining parental permission and children's assent? ___Greater than Minimal Risk research that holds out the prospect of direct benefit to the child.
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From page 260... ...
Other special considerations or requirements in research involving children. Please check as appropriate.
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From page 261... ...
Review of Multicenter Protocols As discussed in Chapter 2, multicenter clinical trials have a particularly important role in pediatric studies given the low prevalence of many serious medical conditions in children. Investigators and research sponsors involved in such studies have expressed considerable frustration with the time required to secure approval from IRBs at each study site, especially in view of the considerable variation among IRBs in the time from submission of a protocol to the time of approval of that protocol.
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From page 262... ...
For a second protocol for a randomized, double-blind, placebo-controlled study to investigate the safety, tolerability, and pharmacokinetics of an anti-inflammatory agent in adult and child patients, four of seven IRBs gave full approval whereas three approved the research for adult participants only. Of the IRBs giving full approval, three categorized the research as involving a minor increase over minimal risk and no direct benefit, but one categorized it as involving more than minimal risk with the prospect of direct benefit.
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From page 263... ...
RESPONSIBLE RESEARCH INVOLVING CHILDREN 263 TABLE 8.1 Example 1 -- Variability in IRB Approval of a Multicenter Research Protocol That Includes Children IRB Approval Full Modified Site Time (wks) Approval Approval Comments or Issues A 7 X B 3 X Approval under Section 406 C 3 X D 9 18 yrs onlya The IRB was unable to determine if this research fit into any of the required categories because information about the study drug was not sufficient to determine the risk to the subjects.
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From page 264... ...
until more information about the effects of the study drug on children becomes available. I X Greater than minimal risk but direct benefit (under 45 CFR 46.405)
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From page 265... ...
Alternatively, quick approval may sometimes result from a cursory review that does not adequately consider the criteria for approving research involving children, including the risks posed to children. Such an approval may be a relief to investigators and research sponsors but represents a departure from ethical and regulatory standards.
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From page 266... ...
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.
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From page 267... ...
. 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)
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From page 268... ...
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.
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From page 269... ...
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 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.
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From page 270... ...
. 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.
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From page 271... ...
SOURCE: Kopelman and Murphy, (in press) and Office for Human Research Protections (through January 2004)
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From page 272... ...
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 acces sible review process for considering research protocols referred by insti tutional 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 unneces sary 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.
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From page 273... ...
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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From page 274... ...
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.
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From page 275... ...
. 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.
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From page 276... ...
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.
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