3
Regulatory Framework for Protecting Child Participants in Research

The involvement of children in research raises particular ethical concerns because of their reduced autonomy and their incompetency to give informed consent…. The Commission has therefore sought to answer the following two questions: under what conditions is the participation of children in research ethically acceptable, and under what conditions may such participation be authorized by the subjects and their parents.

National Commission, 1977, p. xi

The federal regulations governing research that includes infants, children, and adolescents are very closely based on the recommendations of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in its 1977 report on that topic. The Belmont Report, issued by the Commission in 1978, served as the basis for the core regulations applicable to all federally supported, conducted, or regulated research involving humans (National Commission, 1978a).

Although thoughtfully designed government regulations can guide and promote responsible behavior-related regulations, they are only one part of the U.S. system for protecting child or adult participants in research. They cannot guarantee full and competent implementation by the public and private institutions that fund, administer, and oversee research. Neither regulations nor institutional programs can substitute for well-trained, well-motivated investigators who understand their obligations and the means of fulfilling them. Chapters 7 and 8 of this report consider compliance with



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Ethical Conduct of Clinical Research Involving Children 3 Regulatory Framework for Protecting Child Participants in Research The involvement of children in research raises particular ethical concerns because of their reduced autonomy and their incompetency to give informed consent…. The Commission has therefore sought to answer the following two questions: under what conditions is the participation of children in research ethically acceptable, and under what conditions may such participation be authorized by the subjects and their parents. National Commission, 1977, p. xi The federal regulations governing research that includes infants, children, and adolescents are very closely based on the recommendations of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in its 1977 report on that topic. The Belmont Report, issued by the Commission in 1978, served as the basis for the core regulations applicable to all federally supported, conducted, or regulated research involving humans (National Commission, 1978a). Although thoughtfully designed government regulations can guide and promote responsible behavior-related regulations, they are only one part of the U.S. system for protecting child or adult participants in research. They cannot guarantee full and competent implementation by the public and private institutions that fund, administer, and oversee research. Neither regulations nor institutional programs can substitute for well-trained, well-motivated investigators who understand their obligations and the means of fulfilling them. Chapters 7 and 8 of this report consider compliance with

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Ethical Conduct of Clinical Research Involving Children federal regulations and the roles and responsibilities of investigators, institutional review boards (IRBs), research institutions, research sponsors, and policymakers in implementing federal regulations and, more generally, sustaining an effective system of protections for human participants in research. This chapter presents an overview of current federal regulations. The overview is mainly descriptive, with more analysis as well as recommendations and other guidance offered in subsequent chapters. Later sections of this chapter briefly describe other policies for protecting the safety of participants in certain clinical studies and, in addition, policies relating to research conducted in other countries. Appendix B discusses state policies relevant to the conduct of research involving children. These policies include laws defining the age of majority (when minors become adults) and the circumstances when individuals under the age of majority can provide consent to medical care or research participation. Most states do not have specific policies and regulations on the protection of human participants in research. Appendix C summarizes conflict-of-interest and privacy policies (including the Health Insurance Portability and Accountability Act) that also contribute to the protection of research participants. Overall, the committee concluded that the federal regulations providing special protections for child participants in research are generally appropriate for children of different ages. They reasonably defer to state laws defining the age at which individuals become entitled to make decisions about their medical care and the special circumstances under which minors may make decisions in their own right. For the most part, the problems with the regulations relate to variability in the interpretation of criteria for approving research that include inherently subjective elements that the committee doubts would be substantially and predictably clarified by the time-consuming process of revising the regulations. As discussed in Chapter 5, one change the committee does recommend is that the Food and Drug Administration (FDA) make its policies on the waiver of parental permission consistent with the U.S. Department of Health and Human Services (DHHS) regulations that permit such waivers under certain circumstances. A number of commissions and committees have recommended that federal policymakers formally extend regulatory protections for human participants in research to all research, regardless of the source of funding or the regulatory status (see, e.g., NBAC, 2001b and IOM, 2003a). As discussed in Chapter 8, this committee agrees. It recognizes, however, that the federal government may not have the authority to do this, so it also encourages state governments to exercise their authority to regulate research in ways that are consistent with federal regulations and supportive of multistate studies.

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Ethical Conduct of Clinical Research Involving Children FEDERAL REGULATIONS TO PROTECT CHILD PARTICIPANTS IN RESEARCH The federal regulations that govern research involving children have two basic elements. One element is the Common Rule, codified by DHHS at Subpart A of Title 45, Part 46 of the Code of Federal Regulations (45 CFR 46). The Common Rule, which applies to 17 federal agencies, sets forth the general regulations for protecting participants in federally conducted, supported, or regulated research. (The label reflects the common application of rules initially adopted by DHHS as described in Chapter 1.) The second relevant element of the regulations consists of Subpart D, additional protections for children involved in research. These regulations have been adopted by DHHS, the Central Intelligence Agency, the Social Security Administration, and the U.S. Department of Education. FDA has separate regulations (21 CFR 50 and 56) that are similar but not identical, as explained further below. Because these regulations apply to studies conducted or supported by DHHS and to research regulated by FDA, they cover research conducted by investigators employed by the National Institutes of Health (NIH) or other DHHS agencies, outside researchers whose studies are funded by DHHS agencies, and investigators whose research must meet the requirements set forth by FDA, even if that research is privately funded. One provision of Subpart A reaches further. It requires research institutions to provide and have approved a written “assurance” that they will comply with the human research protection regulations. To have such an assurance approved, an institution must have a “statement of principles” that governs the institution in protecting human participants in research “regardless of whether the research is subject to Federal regulation” (45 CFR 46.103(b)(1)). In the spirit of this provision, many institutions require all research involving humans to go through the same basic review process, whether or not the research is explicitly covered by the regulations. The Common Rule or Subpart A: Basic Regulations As discussed earlier, in 1991 the federal government slightly revised and extended to 17 other federal agencies the regulations that formed Subpart A of the human research protection regulations that had been adopted in 1981 by DHHS. (The regulations that established this Common Rule also provided that each agency could adopt procedural modifications appropriate to its functions and responsibilities.) FDA did not adopt the Common Rule as such in 1991 but revised its regulations, which were already generally similar to those of DHHS, to bring them into greater

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Ethical Conduct of Clinical Research Involving Children conformity (FDA, 1991a).1 Following promulgation of the requirements of the Children’s Health Act of 2000, FDA issued interim rules that include additional protections found in Subpart D of the DHHS regulations (FDA, 2001b). Although FDA is part of DHHS, for convenience, this report refers to the regulations found in 45 CFR 46 as the DHHS regulations and the regulations found in 21 CFR 50 and 56 as the FDA regulations. Also, because this report focuses on clinical research that is conducted, funded, or otherwise regulated by DHHS, the rest of this chapter usually will refer to Subpart A rather than the Common Rule. Differences in the FDA regulations will be noted as appropriate. The summary below focuses on selected elements in Subpart A that are important to understand as context for the interpretation and application of the regulations covering children. Institutional Assurances and Responsibilities Institutions whose members or agents (e.g., contractors) undertake research involving human subjects that is conducted or supported by one of the 17 Common Rule departments or agencies must assure the government that they comply with relevant regulations (45 CFR 46.103; see also OHRP, 2002a). DHHS can approve a “federalwide assurance” for an institution that other federal agencies can then accept for research that they conduct or support. As part of ensuring their compliance with the applicable regulations, institutions are held to a number of requirements, including: the development of an acceptable statement of ethical principles for the protection of human participants in research, whether or not the research is covered by federal regulations; the designation of one or more IRBs and the provision of resources to those IRBs sufficient to meet their responsibilities; the provision and updating of a list of IRB members that includes information sufficient to indicate their expected contributions to the IRB and their relationship (if any) to the institution; the development of written procedures that IRBs should follow in conducting their reviews and fulfilling their other responsibilities; and 1   The FDA regulations are found in two parts of the Code of Federal Regulations, 21 CFR Parts 50 (Protection of Human Subjects) and 21 CFR 56 (Institutional Review Boards). 21 CFR 50 has two general subparts, Subpart A (scope of regulations and definitions) and Subpart B (informed consent), in addition to Subpart D, which covers children. Subpart C, which covers prisoners, has been stayed indefinitely. 21 CFR 56 has five subparts that present requirements for IRBs.

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Ethical Conduct of Clinical Research Involving Children a certification that the research projects covered have been reviewed and approved by an IRB and will be periodically reviewed as required by regulations. General Criteria for Approving Proposed Research Subpart A establishes several important criteria that must be met for proposed research to be approved. These criteria are listed in Box 3.1. Research involving children must meet these and additional criteria that are set forth in Subpart D. In combination with other regulations and government guidance documents, several of these criteria have given rise to additional policies or structures. For example, as discussed in a later section of this chapter, NIH may require the creation of a board that monitors the data from and safety of clinical trials. Requirements for Informed Consent Subpart A sets forth a number of requirements for the process of obtaining an individual’s informed consent to participate in research. These requirements, in addition to provisions of Subpart D, also apply when agreement to participate in research is being sought from a parent or other authorized representative for a person not legally competent to provide consent in his or her own right. Informed consent is not required for research that is exempt from review, and it can also be waived under certain conditions. Chapter 5 describes the general provisions for informed consent in more detail. Institutional Review Boards (IRB) Beyond the general institutional responsibilities of IRBs described above, the federal regulations specify additional requirements for IRBs. One set of requirements covers IRB membership (45 CFR 46.107; 21 CFR 56.107). Other requirements relate to IRB functions and operations, including both the initial review of projects and their continuing review. At a minimum, an IRB must have at least five members. At least one member must be concerned primarily with scientific topics, and at least one member must be concerned primarily with nonscientific topics. At least one must be community based, that is, not affiliated with the institution directly or through a family member. Taken together, the members must have sufficient expertise, experience, and diversity of backgrounds to promote competent review of the usual kinds of research conducted by the institution and to promote “respect for its advice and

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Ethical Conduct of Clinical Research Involving Children BOX 3.1 General Criteria That Research Must Meet to Be Approved Under Federal Regulations (excluding criteria related to special protections for children and other identified groups) For research to be approved, all of the following requirements must be met: Risks to subjects are minimized: (i) by using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk, and (ii) whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes. Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result. In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies subjects would receive even if not participating in the research). The IRB should not consider possible long-range effects of applying knowledge gained in the research (for example, the possible effects of the research on public policy) as among those research risks that fall within the purview of its responsibility. Selection of subjects is equitable [taking into account] … the purposes of the research and the setting in which the research will be conducted and … special problems of research involving vulnerable populations, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons. Informed consent will be sought from each prospective subject or the subject’s legally authorized representative, in accordance with, and to the extent required by [other sections of the regulations]. Informed consent will be appropriately documented, in accordance with, and to the extent required by [other sections of the regulations]. When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects. When appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data. SOURCE: 45 CFR 46.111. counsel.” Diversity of backgrounds includes not only areas of scientific or professional expertise but also culture, race, and gender. IRBs that regularly review proposals that include children are not required to have a member or members who have expertise and experience with children, but they are advised to consider the inclusion of such individuals. The regulations provide that IRBs may seek assistance with the review of proposals from individuals who have expertise that is not represented on the IRB. (Chapter 8 of this report stresses the importance of pediatric expertise for IRBs that review research involving infants, children,

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Ethical Conduct of Clinical Research Involving Children and adolescents, and it recommends approaches that IRBs can use to secure this expertise.) DHHS guidance to institutions strongly recommends that institutions provide appropriate education and training for investigators, IRB members, and others to prepare them to fulfill their responsibilities to protect human subjects. Continuing Review IRBs are responsible not only for the initial review of research protocols but also for the continuing review of ongoing research (see, e.g., 45 CFR 46.109 and 21 CFR 56.109). The latter must occur at least annually with more frequent review required if the research protocol changes significantly or if the level of risk presented by the protocol warrants it. If the IRB detects that the research as conducted does not meet the requirements of the federal regulations and is not consistent with the IRB’s initial approval or if it finds unexpected and serious harm to participants in the research, the IRB may suspend or terminate its approval of the research. The IRB must give the reasons for such action and promptly notify the investigator, the institution, and the Office for Human Research Protections. As described by FDA, the IRB is to review the investigator’s written progress report. These reports are to include “the number of subjects entered into the research study; a summary description of subject experiences (benefits, adverse reactions); numbers of withdrawals from the research; reasons for withdrawals; the research results obtained thus far; a current risk-benefit assessment based on study results; and any new information since the IRB’s last review” (FDA, 1998a, unpaged). In its review, the IRB is to pay particular attention to identifying whether any unanticipated risks have emerged. (See discussion below of additional requirements for adverse event reports and data and safety monitoring bodies.) Exempt Research and Expedited Review Certain categories of research may be exempt from review under the provisions of Subpart A, although research institutions may independently require that research in these categories be reviewed. Exempt categories include much research that is conducted in educational settings (e.g., studies of educational techniques); involves a federally funded or approved research or demonstration project to evaluate a public benefit or service program; uses existing data, documents, records, pathological specimens, or

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Ethical Conduct of Clinical Research Involving Children diagnostic specimens that are either publicly available or not directly or indirectly linked to individuals; evaluates food quality or taste or consumer acceptance; or employs educational tests, survey procedures, interview procedures or observation of public behavior (unless individual subjects can be identified and disclosure of the information could damage the subject’s reputation, liberty, financial standing, or employability). When research involves children, the exemption for survey and interview procedures does not apply unless the procedures relate to educational techniques and involve no sensitive topics. Likewise, the exemption for research that uses observations of public behavior does not apply when children are involved if the investigator participates in the activities under observation. Some research, including research that involves children, may be eligible for expedited review. Eligible research is periodically identified by the Secretary of DHHS with a notice in the Federal Register. The most recent list of such research appeared in 1998 (DHHS, 1998). Examples of research eligible for expedited review include collection of biological specimens for research purposes by noninvasive means (e.g., by clipping fingernails or toenails or by cutting hair) or collection of data from voice or video recordings made for research purposes. A preliminary review must determine that the research presents no more than a minimal risk to participants or involves only minor changes in research approved during the preceding year. Chapter 4 discusses the concepts and interpretation of minimal risk and related terms. Subpart D: Special Protections for Children In 1983, DHHS adopted special protections for child participants in research, generally referred to as Subpart D because of their location in Subpart D of 45 CFR 46. In 2001, as required by the Children’s Health Act of 2000, FDA issued interim regulations to bring its rules into compliance with the DHHS regulations. The interim rule incorporated most elements of Subpart D (with a few changes) into the agency’s regulations at 21 CFR 50 and 56. As noted above, the U.S. Department of Education, the Central Intelligence Agency, and the Social Security Administration are the only other federal agencies to adopt these regulations. These special regulations include several important definitions, most of which have been adopted by FDA (Box 3.2).

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Ethical Conduct of Clinical Research Involving Children BOX 3.2 Definitions in Subpart D That Have Also Been Adopted by the FDA “Children” are persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted. “Assent” means a child’s affirmative agreement to participate in research. Mere failure to object should not, absent affirmative agreement, be construed as assent. “Permission” means the agreement of parent(s) or guardian to the participation of their child or ward in research.* “Parent” means a child’s biological or adoptive parent. “Guardian” means an individual who is authorized under applicable State or local law to consent on behalf of a child to general medical care.** “Legally authorized representative” means an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject’s participation in the procedures involved in the research. Definition added by FDA A “ward” is a child who is placed in the legal custody of the State or other agency, institution, or entity, consistent with applicable Federal, State, or local law. *   The FDA rules clarify “that permission applies to participation in clinical investigations involving FDA-regulated products” (FDA, 2001b, p. 20592). **   The FDA rules add that “for a guardian to be able to grant permission for a child to participate in research, the guardian must either have authority to consent to a child’s general medical care (where participation in clinical research falls within general medical care) or must have authority to consent to a child’s participation in research” (FDA, 2001b, p. 20592). SOURCE: 45 CFR 46.102 and 21 CFR 50.3 Assessment of Risks and (Potential) Benefits The regulatory criteria for IRB approval of research involving children are more restrictive than those for research involving adults and focus, in considerable measure, on the assessment of risks and benefits. (As discussed in Chapter 4, because risk involves potential harms, it is more appropriate to refer to “risks and potential benefits” or “potential harms and potential benefits.”) The general boundaries of research involving children that DHHS can conduct or support are laid out in four sections of Subpart D that largely correspond to the recommendations of the 1977 report on children by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (National Commission, 1977). The four sections are often referred to by their section numbers in the regula-

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Ethical Conduct of Clinical Research Involving Children BOX 3.3 Research Involving Children That DHHS Is Permitted to Conduct or Support * §46.404 Research not involving greater than minimal risk DHHS will conduct or fund research in which the IRB finds that no greater than minimal risk to children is presented, only if the IRB finds that adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians, as set forth in §46.408. §46.405 Research involving greater than minimal risk, but presenting the prospect of direct benefit to the individual subjects DHHS will conduct or fund research in which the IRB finds that more than minimal risk to children is presented by an intervention or procedure that holds out the prospect of direct benefit for the individual subject, or by a monitoring procedure that is likely to contribute to the subject’s well-being, only if the IRB finds that: the risk is justified by the anticipated benefit to the subjects; the relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches; and adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians, as set forth in §46.408. §46.406 Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject’s disorder or condition DHHS will conduct or fund research in which the IRB finds that more than minimal risk to children is presented by an intervention or procedure that does not hold out the prospect of direct benefit for the individual subject, or by a monitoring procedure which is not likely to contribute to the well-being of the subject, only if the IRB finds that: the risk represents a minor increase over minimal risk; the intervention or procedure presents experiences to subjects that are tions: 404, 405, 406, and 407. Box 3.3 presents the regulatory language for each section. FDA interim regulations (21 CFR 50.51 to 50.54) include the corresponding sections, except that they refer to research involving an FDA-regulated product rather than to research funded or supported by DHHS, and they provide that the FDA commissioner rather than the secretary of DHHS can approve certain research that does not meet the criteria for IRB approval. As discussed further in Chapter 4, the four regulatory categories involve an escalating set of assessments that need to be made and requirements that need to be met before a research proposal is approved. Several of the terms in these regulations (e.g., minimal risk and minor increase over

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Ethical Conduct of Clinical Research Involving Children reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations; the intervention or procedure is likely to yield generalizable knowledge about the subjects’ disorder or condition which is of vital importance for the understanding or amelioration of the subjects’ disorder or condition; and adequate provisions are made for soliciting assent of the children and permission of their parents or guardians, as set forth in §46.408. §46.407 Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children. DHHS will conduct or fund research that the IRB does not believe meets the requirements of §46.404, §46.405, or §46.406 only if: the IRB finds that the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; and the Secretary, after consultation with a panel of experts in pertinent disciplines (for example: science, medicine, education, ethics, law) and following opportunity for public review and comment, has determined either: that the research in fact satisfies the conditions of §46.404, §46.405, or §46.406, as applicable, or (2) the following: the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; the research will be conducted in accordance with sound ethical principles; adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians, as set forth in §46.408. *   The corresponding, slightly modified, FDA regulations are at 21 CFR 50.51 to 54. SOURCE: 45 CFR 46. minimal risk) involve subjective or ambiguous concepts that have caused and that continue to cause considerable uncertainty, confusion, and disagreement among IRB members, investigators, and others who encounter them. Agreement to Participate in Research Parental Permission Because children are not legally able to provide consent in their own right, the federal regulations generally require that parents or guardians provide permission before children can be enrolled in research. If the IRB determines that the research involves more than minimal

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Ethical Conduct of Clinical Research Involving Children risk but is not expected to benefit the child participant, the regulations require that investigators secure permission from both parents. If the IRB determines that research involves no more than minimal risk or that it holds out the prospect of direct benefit to the child, the IRB may decide that the permission of one parent is sufficient. Permission from one parent is also sufficient if that parent is legally responsible for the care and custody of the child or when the other parent has died or is unknown, incompetent, or not reasonably available. Chapter 5 describes circumstances in which the DHHS but not the FDA regulations provide for exceptions to the parental permission requirement. Child Assent Although children cannot legally consent to participation in research, the regulations provide for children’s agreement or assent to research participation. The regulations do not describe the information that must be provided to children but rely on IRBs to use their discretion in judging assent provisions. Researchers must seek a child’s assent unless the IRB determines that the children to be involved (as a group or individually) are not capable of providing assent, given their age, maturity, or mental state; the research has a prospect of an important direct benefit for the child that is possible only in the research context; or the research involves circumstances that would allow waiver of consent for adults. As noted previously in Box 3.2, federal regulations on human research protections define children in terms of state laws defining the legal age at which an individual can consent to the treatments or procedures involved in the research. The legal age of majority is now 18 in all states except Mississippi (age 21) and Nebraska and Alabama (both age 19).2 Chapter 5 and Appendix B discuss when those below the age of majority may agree to participate in research without permission from a parent or other authorized adults, for example, when they are accorded the status of emancipated or mature minors. They also consider special requirements related to research participation by children who are wards of the state. 2   In Mississippi, a person age 18 or over can consent to medical or surgical care. In Alabama, a statute permits minors to consent to medical or surgical treatment at age 14. See Appendix B.

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Ethical Conduct of Clinical Research Involving Children ADDITIONAL FEDERAL POLICIES FOR MONITORING SAFETY OF PARTICIPANTS IN CLINICAL RESEARCH Beyond the policies summarized above, both NIH and FDA have established additional policies and procedures for monitoring the safety of participants in clinical research. As discussed below, one set of policies relates generally to the reporting of adverse events, and another involves the creation of committees to monitor data on such events in certain clinical trials. An earlier IOM report included a constructive recommendation that “[f]ederal oversight agencies should harmonize their safety monitoring guidance for research organizations, including the development of standard practices for reporting adverse events” (IOM, 2003a, p. 148). The report also recommended that NIH provide additional guidance about the elements that should be included in data and safety monitoring plans for clinical trials and that NIH-funded clinical trials be monitored “with the same rigor and scrutiny as trials carried out” for products subject to FDA approval (IOM, 2003a, p. 151). Further, “any monitoring report for studies under a [research ethics review] board’s purview [should] be shared with that board” (p. 145). This recommendation extended to reports for studies that a sponsor ended without seeking FDA approval of a drug or other product. This committee supports these recommendations. The summary below focuses on the identification of unexpected and serious research-related problems and the monitoring of participant safety during clinical trials. Because most clinical trials are relatively limited in duration and in the size and diversity of study populations (e.g., by age, severity of illness, and diagnosis), they may fail to identify adverse events that are relatively uncommon, that are late effects that do not emerge for years after an intervention, or that occur as a result of long-term use of a drug or other intervention.3 For example, genetic studies, particularly those 3   As one response to concerns about patient or consumer safety problems that arise after drugs, devices, and other medical products have been approved for marketing, FDA has created various programs and procedures—under the rubric of postmarketing surveillance—that attempt to identify such problems. Surveillance may take several forms, including mandatory reporting of serious adverse events by manufacturers and health care providers, voluntary reporting by consumers and professionals, patient registries, surveys, and ad hoc investigations (e.g., laboratory or epidemiologic investigations). In addition, FDA may require further clinical studies as a condition of marketing approval. These studies—like other clinical research—require IRB review. In general, the postmarketing surveillance tools are limited in their ability to detect problems that arise after marketing begins. Also, the FDA requirements only cover FDA-regulated products and do not apply to certain kinds of surgical procedures or behavioral interventions. Reporting and analysis of adverse events are also important elements of voluntary efforts to improve the quality and safety of patient care (see, e.g.,

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Ethical Conduct of Clinical Research Involving Children that identify inheritable genetic defects, may have consequences for research participants, family members, and family relationships that emerge or intensify after the study ends. Long-term consequences are also an important concern for many cancer treatments (see, e.g., the recent report on long-term survivors of childhood leukemia [Pui et al., 2003]). The identification of studies that warrant long-term follow-up and the design and sponsorship of such studies should be recognized as elements of a comprehensive system for protecting human participants in research. Adverse Event Reporting In a general sense, an adverse event is an occurrence that causes harm to a patient or research participant or that has the potential to do so. The focus is usually on serious, unexpected problems (e.g., not described in the research protocol) that appear to be associated with the research. The reporting of adverse events in clinical studies is a complex topic, and the role of IRBs in relation to adverse events is not well-defined, which causes considerable frustration and uncertainty. As observed in a popular handbook for IRB members, “guidance [to IRBs] from federal authorities has been both confusing and contradictory” (Amdur and Bankert, 2003, p. 64). Without mentioning adverse events as such, both DHHS and FDA regulations require that IRBs have written procedures for the prompt reporting to the IRB, appropriate institutional officials, and the relevant Department or Agency head of “any unanticipated problems involving risks” to human research participants or others (e.g., investigators) (45 CFR 46.103(b)(5); 21 CFR 56.108(b)(1)). The regulations also require prompt reporting to the investigator, appropriate institutional officials, and the Department or Agency head of any suspension or termination of an individual research protocol related to “unexpected serious harm” (45 CFR 46.113; 21 CFR 56.113). In separate regulations relating to investigational new drugs, FDA specifies additional requirements for investigators or research sponsors to report unanticipated or unexpected adverse experiences,     JCAHO, 2003). In the Best Pharmaceuticals Act of 2002 (P.L. 107-109), FDA was directed to review adverse events reports for the year after a drug was granted pediatric exclusivity (as described in Chapter 2). FDA staff have reported to the FDA Pediatric Advisory Subcommittee on several products. For some of the products, staff asked the subcommittee whether an additional year of follow-up was advisable, given the small number of reports (Iyasu, 2003). Staff also reported on the limitations of the current monitoring system. The limitations include the questionable quality of individual reports, biased or selective reporting and underreporting, and an inability to calculate problem rates because the system lacks denominator data (i.e., data identifying the number of individuals who are, for example, taking a particular drug).

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Ethical Conduct of Clinical Research Involving Children events, effects or problems (the terminology varies) associated with the use of the drug (21 CFR 312.32; 21 CFR 312.53; 21 CFR 312.64; 21 CFR 312.66). Sponsors are required to report to FDA and participating investigators adverse experiences that are “both serious and unexpected” (21 CFR 312.32). The FDA regulations also include requirements for reporting of adverse experiences or effects for medical devices and biological products. Since 1999, NIH has required that summary reports of adverse events be provided to the IRB at each trial site for multisite studies that have a data safety and monitoring board as described below. Serious adverse events or experiences include deaths (which usually must be reported even if mortality is an identified risk in a study), hospitalizations, persistent or significant disabilities, and birth defects. Unanticipated problems are those not described or foreseen as risks in the study protocol. They include harms that are more serious or frequent than expected. DHHS and FDA regulations require IRBs to have written procedures for ensuring effective communication regarding problems with or changes to research activity (45 CFR 46.103; 21 CFR 56.103). The regulations do not provide further direction, and the committee found no comprehensive overview of actual IRB procedures related to adverse event reports. Information from individual institutions and committee experience make it clear, however, that IRB policies and practices vary with respect to what, when, and how investigators should report problems and how the IRB should evaluate the reports received. For example, adverse event reporting forms created by institutions vary in the information required, the guidance provided, and the extent to which the form highlights a report involving a serious, unanticipated, research-related event. Some IRB policies specify that the chair or other qualified individual will do an initial screening of adverse event reports submitted to the IRB; others use a group. In certain emergency situations, the individual or group may act to suspend or modify a study subject to later review by the full IRB membership. Depending on the information received, the IRB may require modifications in the study (e.g., changes in the consent form and process), increase the frequency of continuing review, reconsider the approval of the study, halt the study, or decide that no action is needed. IRBs are required to notify investigators of any decisions in writing (45 CFR 46.109(d)). Data and Safety Monitoring Boards and Data Monitoring Committees The discussion below focuses primarily on federal policies for data and safety monitoring during clinical trials designed to test the safety and efficacy of drugs and other products. In addition, during their review of a research protocol, IRBs may determine that a data safety and monitoring

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Ethical Conduct of Clinical Research Involving Children board or committee should be established if not already provided for or required. Building on guidelines dating back to the 1970s, NIH has issued rules requiring the creation of data and safety monitoring boards (DSMBs) for multisite clinical trials that are supported or conducted by NIH and that involve potentially risky interventions (NIH, 1998b). The National Cancer Institute (NCI) has issued more detailed policies and guidance about the level and kind of monitoring appropriate for the phase 1, 2, and 3 clinical trials that it supports or conducts (NCI, 1999). The NCI policy provides that phase 1 and 2 trials may be monitored by the principal investigator or project manager or by NCI staff (or some other designated person) or jointly. Phase 3 randomized clinical trials must have a DSMB. As noted above, NIH requires that summary reports of adverse events be provided to relevant IRBs for multisite trials. Commercially sponsored research regulated by FDA is covered by draft guidance on the establishment and operation of what the agency calls data monitoring committees (FDA, 2001c). Except for certain research conducted in emergency situations, FDA does not require such committees. It does, however, have additional requirements for the reporting of adverse events both before and after the approval of products over which it has jurisdiction (see below). As discussed further in chapter 7, FDA has an extensive monitoring system that also includes inspections of investigators and IRBs (and sometimes research sponsors) to assess compliance with guidelines. Large trials are more likely to prompt inspections than smaller trials (IOM, 2003a). Institutions that routinely engage in clinical trials may establish a standing monitoring committee, unless a trial has an externally appointed body. Many clinical trials testing drugs for the treatment for cancer operate under the umbrella of some kind of cooperative research group and have their own DSMB. For example, protocols sponsored by the Children’s Oncology Group are monitored under the procedures established by that group. The NCI website has links to several examples of approved data monitoring plans (NCI, 2002a). Box 3.4 summarizes the general responsibilities of monitoring boards or committees, however they are appointed and wherever they are located. DSMBs have the power to stop studies early when the results reveal a clear benefit or a clear harm. For example, the 076-AZT trial, which tested a drug regimen to prevent mother-to-fetus transmission of HIV, was stopped early by the DSMB because of the obvious efficacy of the regimen (Mofenson, 2000). Recently, a placebo-controlled randomized trial of inhaled tobramycin in young children with cystic fibrosis was stopped early based on the basis of evidence that the drug had a significant effect on

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Ethical Conduct of Clinical Research Involving Children BOX 3.4 General Responsibilities of Data and Safety Monitoring Boards and Data Monitoring Committees Reviewing research protocols (initial and major revisions), including the descriptions of potential harms and benefits and the plans for data and safety monitoring. Evaluating the progress of trials and periodically assessing the quality and timeliness of the reported data, the recruitment and retention of participants, the performances at the various trial sites, and other factors. Identifying external factors (e.g., publication of results from other studies involving the same condition) relevant to the safety of participants or the ethical status of studies. Recommending revisions in protocols when indicated by the review of data and procedures. Determining when circumstances warrant suspension or early conclusion of a trial. Pseudomonas aeruginosa infection, a common cause of morbidity and mortality in these children (Gibson et al., 2003). The primary responsibility of data and safety monitoring bodies, whatever their label, is to protect the safety of human participants in research (Ellenberg and Braun, 2002). A second major responsibility is to help protect the integrity of clinical trials so that the results will be trustworthy and useful. To that end, monitoring committees should be independent of the studies being monitored. Independence from the institutions involved may also be desirable. The appropriate composition of a monitoring group depends on the nature of the study or studies being monitored. Usually, the membership will include individuals who are experts on the medical condition or intervention under study and statisticians who are familiar with the kinds of data that a trial will generate. Depending on the trial, the monitoring group may also include experts in clinical trials methodology, ethicists, epidemiologists, representatives of the patient community being studied, and others. When the research in question involves infants, children, or adolescents, then the monitoring group should also include pediatric expertise appropriate for the condition and population under study. For long-term genetic studies involving children or family members, monitoring boards may include individuals familiar with the short- and long-term impact of genetic information on the psychological status of children. In general, even if it is not required by sponsors, IRBs should require that some form of data and safety monitoring be incorporated into pediatric research protocols that involve more than minimal risk and that this

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Ethical Conduct of Clinical Research Involving Children plan be reviewed by the IRB as part of the approval process. The type of data and safety monitoring plan will depend on specifics such as the degree and the nature of the risks associated with the trials. IRBs should examine the plan to assess the independence of the strategy from individuals and organizations with conflicting interests. IRBs should then be provided with periodic reports regarding data and safety monitoring activities and findings. IRBs should also have the opportunity to refer concerns for data and safety monitoring. FEDERAL RULES FOR RESEARCH CONDUCTED IN OTHER COUNTRIES As discussed in Chapter 1, research and protections for participants in research must increasingly be viewed in an international context. Many multicenter studies involving adults or children include sites in both the United States and foreign countries, and some research that is submitted to FDA as part of the process of securing approval to market drugs, devices, or other products may be conducted entirely outside the United States. About one-quarter of the new drug applications submitted to FDA include important data from foreign sites, and almost all of these submissions involve commercial sponsors (Lepay, 2003). Examples include applications for the drugs lamivudine and didanosine. Both DHHS and FDA rules include provisions on foreign research. The DHHS rules note that procedures for protecting human research participants may differ in other countries and that these procedures may be substituted if the department or agency head determines that the procedures provide protections equivalent to those provided for under DHHS rules (45 CFR 46.101(h)). When such a substitution is approved, the agency is usually supposed to publish a notice of the action. For foreign institutions, the DHHS requirements for an assurance of compliance provide that institutions will be guided by ethical principles, such as the World Medical Association’s Declaration of Helsinki (WMA, 2002 [see Chapter 1]) or the Belmont Report (National Commission, 1978a). They must also comply with the guidelines outlined in 45 CFR 46 or other recognized guidelines and procedures for research involving human subjects.4 Recognized guidelines include the Guideline for Good Clini- 4   In addition to requiring that institutions provide adequate resources and written policies for the review of research, the terms of an assurance for a foreign institution include agreement to requirements that informed consent be obtained and documented consistent with 45 CFR 46.116 and 117.

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Ethical Conduct of Clinical Research Involving Children cal Practice: E6 (ICH, 1996) from the International Conference on Harmonisation (ICH) and the International Ethical Guidelines for Biomedical Research Involving Human Subjects (CIOMS, 2002). The 1996 ICH guideline, which was also published as guidance by the FDA, does not provide explicit special protections for children (except as part of provisions related to informed consent). Children are, however, discussed in a separate ICH statement, Clinical Investigation of Medicinal Products in the Pediatric Population: E11 (ICH, 2000b). This ICH guideline was also published as guidance by FDA, which described it as not binding but as representing the agency’s “current thinking” (FDA, 2000b, p. 1). This guidance covers a variety of technical and practical issues in pediatric research in addition to ethical issues. In addition to the ICH efforts, FDA has also been working with the European Agency for the Evaluation of Medicinal Products on issues related to international pediatric oncology research (Stephen Hirschfeld, M.D., Center for Biologics Evaluation and Research, Food and Drug Administration, personal communication, November 21, 2003). For drug companies or other firms seeking to have foreign studies considered in FDA decisions, FDA provides two options (FDA, 2001a; OIG, 2001). The first (applicable to all U.S. studies) requires the submission of an Investigational New Drug Application, under which studies are to be conducted consistent with the research protections described earlier in this chapter. The second option does not require prior approval or explicit conformity with the rules applicable to U.S. research. Rather, the conduct of foreign research must be consistent with international guidelines, such as the Declaration of Helsinki, or the host country’s laws and regulations.5 5   FDA regulations (21 CFR 312.120 (c)) require that sponsors of studies using the second option “explain how the research conformed to the ethical principles contained in the Declaration of Helsinki or the foreign country’s standards, whichever were used. If the foreign country’s standards were used, the sponsor shall explain in detail how those standards differ from the Declaration of Helsinki and how they offer greater protection.” In addition, sponsors must provide information that allows the FDA to judge whether the studies are scientifically sound. The regulations governing approval of drug applications specify the 1989 version of the Declaration of Helsinki, whereas the regulations governing medical devices specify the 1983 version. Unlike the 1989 document, the 1983 version does not require that review be independent of the investigator or sponsor of the research. The most recent update of the Declaration of Helsinki occurred in 2000, with a clarification in 2001 (WMA, 2002). In March 2001, FDA issued guidance to industry under the title “Acceptance of Foreign Clinical Studies.” This guidance notes that FDA did not incorporate the 2000 amendments to the Declaration. The guidance also indicated that the agency was reviewing the regulations related to foreign studies.

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Ethical Conduct of Clinical Research Involving Children CONCLUSION This largely descriptive chapter has provided an overview of federal regulations intended to protect adults and children involved in research. It has noted several issues that are considered further in the remainder of the report. These issues include the uncertainty and confusion over the interpretation of key concepts in the regulations; the adequacy of pediatric expertise in IRB review of research involving children; and the lack of regulatory protections for adults and children participating in research that is not federally conducted, funded, or regulated. The following chapters highlight a number of additional concerns, including the lack of data on the performance of the system of research protections for children. Without such data, it is impossible to judge how effectively and efficiently the system is working overall and where it may be failing those whom it is supposed to protect.