7
Regulatory Compliance, Accreditation, and Quality Improvement

[T]o preserve public trust in research, the scientific community must go beyond a culture of compliance—it must strive for a culture of conscience—one in which we do the right thing not because we are required to, but because it is the right thing to do, a refrain now echoed frequently throughout the research community.

Greg Koski, 2002, p. 1

The late 1990s saw considerable public concern about the extent to which investigators and IRBs were following federal regulations to protect human participants in research. Chapter 1 summarized some of the consequences, which included the reorganizing and refocusing of federal government units responsible for regulatory oversight and the well-publicized, temporary suspensions of federally supported human research in a number of prominent universities for deficiencies in their programs for protecting research participants. By the time that Greg Koski (outgoing director of the Office for Human Research Protections) offered the challenge quoted above, the emphasis on compliance per se had expanded to recognize that a strong, broadly shared commitment to acting on the values underlying the regulations would be a far more powerful and consistent motivator of ethical performance than simply a commitment to compliance.

This chapter examines one element in the statement of task for this study: the compliance with and enforcement of the federal regulations. It



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Ethical Conduct of Clinical Research Involving Children 7 Regulatory Compliance, Accreditation, and Quality Improvement [T]o preserve public trust in research, the scientific community must go beyond a culture of compliance—it must strive for a culture of conscience—one in which we do the right thing not because we are required to, but because it is the right thing to do, a refrain now echoed frequently throughout the research community. Greg Koski, 2002, p. 1 The late 1990s saw considerable public concern about the extent to which investigators and IRBs were following federal regulations to protect human participants in research. Chapter 1 summarized some of the consequences, which included the reorganizing and refocusing of federal government units responsible for regulatory oversight and the well-publicized, temporary suspensions of federally supported human research in a number of prominent universities for deficiencies in their programs for protecting research participants. By the time that Greg Koski (outgoing director of the Office for Human Research Protections) offered the challenge quoted above, the emphasis on compliance per se had expanded to recognize that a strong, broadly shared commitment to acting on the values underlying the regulations would be a far more powerful and consistent motivator of ethical performance than simply a commitment to compliance. This chapter examines one element in the statement of task for this study: the compliance with and enforcement of the federal regulations. It

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Ethical Conduct of Clinical Research Involving Children also examines accreditation programs and quality improvement initiatives that promote voluntary efforts to exceed and not just to meet regulatory requirements. Technically, the federal regulations on protections for human participants in research apply only to federally conducted, supported, or regulated research. Many research institutions have gone further to establish the regulations as the standard for all human research. One of the recommendations in the final chapter of this report is that all clinical research involving children should occur under the umbrella of a formal human research protection program regardless of source of funding or regulation under the Federal Food, Drug, and Cosmetic Act. (Consistent with earlier chapters, 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.) Some of the failure to comply with the federal regulations is not due to obvious shortcomings on the part of investigators, members of institutional review boards (IRBs), or others. Rather, it reflects, in part, the ambiguity and lack of clarity in the regulations themselves. The federal government must bear some responsibility for the wide range of interpretations of important elements of the regulations. This report, particularly Chapter 4, attempts to clarify some key terms and concepts in the regulations. It also recommends that the government provide more interpretive guidance and provide examples of procedures and studies that illustrate permissible research involving infants, children, and adolescents. Such guidance should help investigators and IRBs better understand their responsibilities and the boundaries between acceptable and unacceptable practices, although differences in judgment will undoubtedly remain. Unfortunately, the committee found a particular dearth of information about compliance with the regulations as they relate to children. As a result, the group could not reach firm conclusions about compliance. One of the recommendations in this chapter is for government agencies and IRBs to collect and analyze information specific to children that will begin to allow assessment of the performance of investigators, IRBs, research institutions, research sponsors, and federal regulators. Having used its authority to establish regulations, the federal government has an obligation to collect information and take other actions to assess the extent to which they are being appropriately monitored and implemented. CONTINUED CONCERN ABOUT OVERSIGHT OF RESEARCH INVOLVING HUMANS As described in Chapter 1, policies and programs to protect human participants in research have evolved over several decades, often in re-

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Ethical Conduct of Clinical Research Involving Children sponse to public outcries over publicized instances of unethical or questionable research practices. The first stages of that evolution involved recognizing problems, placing them within an ethical framework, and developing standards and public policies for the ethical conduct of human research. Over time, policies became more formal as the government adopted regulations and expanded their scope, for example, by adding special protections for vulnerable populations, such as children and prisoners. In the last decade and a half, concern has increasingly focused on the implementation of the regulations at all levels—the investigator, IRB, research institution, and government levels—and on the adequacy of resources devoted to this task. A series of reports have noted progress in human research protections but have also described deficiencies in their implementation and have made recommendations for improvement. No report has, however, focused explicitly on problems in implementing the federal regulations protecting child participants in research. In the committee’s experience, however, the problems identified for human research protection programs generally extend to implementation of research protections for children. Indeed, the problems may be amplified in pediatric research for the reasons identified throughout this report. These reasons include the particular challenges of designing and conducting pediatric research, the limited amount of such research in many institutions, and the difficult or ambiguous concepts included in the regulations governing child participants in research. Government Reports on Human Research Protection Regulations and Programs A 1996 report by the General Accounting Office (GAO; an arm of the U.S. Congress) concluded that the regulatory oversight of biomedical and behavioral research had reduced the likelihood of abuses of human research participants. Nonetheless, it warned that no system of research protections can be foolproof and that limited resources and other constraints threatened the effectiveness of both local review boards and federal oversight (GAO, 1996). The report stressed the need for continued vigilance in protecting human participants in research and warned against overreliance on investigators’ voluntary compliance with regulatory requirements. A 2001 statement from the GAO noted several areas of progress since its earlier report but expressed continuing concern that the “pace of some actions is too slow” and “gaps remain” (Heinrich, 2001, p. 12). In addition to reiterating concerns about inadequate oversight resources at both the federal and local levels, it cited problems with insufficient guidance on informed consent and unclear requirements for adverse event reporting. That same year, another GAO report urged more forceful direction from the U.S. Depart-

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Ethical Conduct of Clinical Research Involving Children ment of Health and Human Services (DHHS) regarding the prevention and management of financial conflicts of interest that threatened the integrity of biomedical research (GAO, 2001). The DHHS Office of the Inspector General (OIG) has issued several critical reports on national and local oversight of human research. Taken together, three reports issued in 1998 characterized IRBs as being inundated with proposals, hurried in their reviews, beset by pressures on their independent judgment, and short of resources, including not only paid staff but also community (nonscientific) representation and clinical expertise from volunteers prepared to take time away from revenue-generating activities (OIG, 1998a, b, c). The OIG argued that the regulatory and oversight system often focused on less important issues while it ignored major ethical issues and concerns. The 1998 reports made a number of recommendations for federal action. Two years later, the OIG concluded that DHHS had increased its enforcement efforts and taken other promising steps but had not acted on most of the earlier recommendations (OIG, 2000a). The OIG acknowledged that some of the improvements that it had recommended would take legislative action. In a comprehensive report in 2001, the National Bioethics Advisory Commission (NBAC) argued (among other criticisms) that growth in the scope and scale of human research had outpaced the system for protecting participants in that research (NBAC, 2001b). For the entire system, “scarce [financial and human] resources limit the functioning of the oversight system at every level (NBAC, 2001b, p. 8). Noting that “any system of sanctions can only be as good as the monitoring and investigating processes that are used to determine their need,” the report observed that some agencies, such as DHHS, “conduct only ‘for cause’ investigations, generally because limited budgets do not permit more proactive monitoring” (NBAC, 2001b, pp. 12-13). (As discussed later in this chapter, the Office for Human Research Protections [OHRP] now undertakes occasional “not-for-cause” evaluations.) The 2001 NBAC report noted the failure of all federal agencies that conduct or fund research involving children to adopt the special protections application to children found in Subpart D of the DHHS regulations. As described in Chapter 3, only the Department of Education, the Central Intelligence Agency, and the Social Security Administration have adopted Subpart D. The NBAC report also pointed to the inconsistent interpretation of research protection regulations across federal agencies. As discussed in Chapters 1 and 3, an increasing amount of pediatric research funded by American companies is being conducted in other countries. In another report issued in 2001, NBAC examined ethical issues in international research. The report noted that DHHS has never “determined formally that guidelines or rules from any other countries afford protec-

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Ethical Conduct of Clinical Research Involving Children tions equal to those provided by U.S. human regulations” (NBAC, 2001a, p. 14). It also detailed criticisms from foreign investigators and others about the excessive burdens imposed by the United States’ research protection regulations. NBAC commended OHRP for recent efforts to make certain rules applying to foreign research less burdensome (e.g., permitting foreign institutions to abide by other ethical standards or guidelines identified in this report). It also recommended that an independent body evaluate the new policies after a suitable period. Such an evaluation should examine research involving children. In the same year as the Commission’s report, the DHHS OIG issued a critical report stating that the Food and Drug Administration (FDA) “receives minimal information on the performance of foreign institutional review boards … [and] has an inadequate database on the people and entities involved in foreign research” (OIG, 2001, p. ii). It argued that it is not sufficient to depend on foreign investigators’ statements that will they comply with protections for human research participants. Other Reports and Attention Several reports from the Institute of Medicine (IOM) have offered recommendations for improving the ethical conduct and oversight of research involving human participants. One of the strongest statements about the difficulties of assessing system performance came in the report Responsible Research (IOM, 2003a). It noted that a lack of information on current protection activities and results had “repeatedly confounded” analysis but went on to say that “the evidence is abundant regarding the significant strains and weaknesses of the current system” and that “major reforms are in order” (IOM, 2003a, p. 4). Congress has twice included provisions in legislation calling for reports that would, among other topics, discuss the appropriateness of the regulations on protecting child participants in research and the monitoring and enforcement of compliance with them. This report responds to the most recent legislation (the Best Pharmaceuticals for Children Act of 2002). In a report called for in earlier legislation, the Children’s Health Act of 2000 (P.L. 106-310), DHHS concluded that the federal regulations are “sound, effective, and well-crafted, and when implemented properly by IRBs and investigators, provide adequate and appropriate protections for children of all ages and maturity levels” (DHHS, 2001, p. iii). The DHHS report did not include explicit findings on IRB or investigator implementation of or compliance with the regulations but observed that “problems and concerns related to research involving children generally have resulted from a failure to implement the existing regulations appropriately and consistently, not from fundamental deficiencies of the regulations” (DHHS, 2001, p. iii).

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Ethical Conduct of Clinical Research Involving Children (The body of the report, which had to be finished on a short, 6-month timetable, was 22 pages in length, excluding the summary.) In addition to sometimes critical reports on the system for protecting human participants in research, the system has also come under public scrutiny and criticism after the deaths of several research participants. For example, a story in the New York Times about the death of Ellen Roche, a healthy volunteer at Johns Hopkins University, reported that information about the research “sketch[ed] a picture of an experiment that went amiss” (Altman, 2001, p. A16). The story also described the difficulties in obtaining information about the circumstances surrounding the death. The September 1999 death of Jesse Gelsinger in a gene therapy trial likewise prompted many critical stories (see, e.g., Halim, 2000 and Stolberg, 1999). As noted above, federal officials have temporarily suspended or restricted federally funded or regulated research at several major academic institutions (see Exhibit 3.1 of NBAC, 2001b, pp. 54–56). Although some criticized these actions as being too extreme, they dramatically underscored a new commitment by officials to identify and correct deficiencies in the protection of human participants in research and recognized this protection as “an absolutely critical foundation” of research involving humans (Koski, 2001, p. 1). Federal officials have also undertaken a number of more positive actions to improve the protection of human participants in research, as discussed below. GOVERNMENT OVERSIGHT OF REGULATIONS PROTECTING CHILD PARTICIPANTS IN RESEARCH The committee that prepared the IOM report Responsible Research (IOM, 2003a) found that government data on compliance with policies on protection of human research participants were very limited. The present committee found that data specific to clinical research involving children were even more limited. Most of what follows describes the government’s compliance monitoring and enforcement activities in general. OHRP was able to provide some data on compliance problems related to clinical research involving children, but FDA could not. As described in Chapter 1, both DHHS and FDA have reorganized their human research protection programs following the above-cited criticisms of the oversight of human research protections and the widely publicized instances of questionable or deficient research conduct. In June 2000, the Office for Protection from Research Risks became the more explicitly named Office for Human Research Protections (OHRP), and DHHS moved the unit from the National Institutes of Health (NIH) to the Office of the Secretary of DHHS (DHHS, 2000). In March 2001, the FDA established the Good Clinical Practices Program within the Office of Science and Health

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Ethical Conduct of Clinical Research Involving Children Coordination in the Office of the Commissioner. The program essentially has the lead for policy issues related to human subject protection, although individual centers (e.g., the Center for Drug Evaluation Research) still maintain their own medical policy and bioresearch monitoring units relevant to their jurisdictions (David Lepay, M.D., Ph.D., Food and Drug Administration, personal communication, October 4, 2003). As described below, OHRP and FDA use different strategies to monitor compliance with regulations for the protection of human participants in research. Oversight by the Office for Human Research Protections Even when regulators necessarily rely on voluntary compliance with regulations and adopt a quality improvement perspective that encourages excellence and not merely compliance, regulators must still have methods suitable for monitoring and enforcing adherence to the regulations for which they are responsible. The OHRP strategy for compliance oversight relies primarily on the investigation of allegations of institutional noncompliance or other problems (Koski, 2000). Since 1990, the agency has conducted more than 750 investigations of such allegations (Carome, 2003). In 1998 and 1999, the office’s actions against institutions holding an OHRP-approved assurance increased significantly, particularly for academic medical centers which saw one action in 1997 and 14 in 1999 (Burman et al., 2001). (An assurance states an institution’s formal commitment to protect human research participants.) In 2002, OHRP announced the expansion of “not-for-cause” evaluations, in part to obtain a more representative picture of institutional performance. Since 2001, the agency has undertaken eight such evaluations (Carome, 2003). If OHRP staff determine that the office has jurisdiction to act on an allegation or an indication of a compliance problem at an institution, the usual first step in evaluating the problem involves sending a letter to the institution that explains the office’s concerns and its investigation process. The letter asks the institution to investigate the situation and submit its findings along with relevant documentation such as IRB policies and meeting minutes. OHRP staff may subsequently request additional information and documents. They may also interview institutional officers, IRB members, investigators, or others. Sometimes they conduct an on-site evaluation. Once its assessment is complete, OHRP issues a “determination letter” that describes the agency’s conclusions, which may include findings of noncompliance and a list of corrective steps to be taken. If the institution investigated responds that it has already taken action on the basis of its own evaluation, the letter will note whether the actions are satisfactory. If an

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Ethical Conduct of Clinical Research Involving Children institution is in compliance, the agency may still suggest improvements in policies and practices. If OHRP finds an institution to be in serious noncompliance, the institution’s authorization to conduct federally funded research may be restricted or even suspended. For very serious misconduct, investigators or institutions may be debarred from participating in federally funded research. To date, OHRP has not recommended this sanction (Carome, 2003). OHRP can also recommend that NIH or other peer review groups be notified of an institution’s or an investigator’s noncompliance before the review of new federal funding awards or requests for applications for awards from that institution or investigator. Each determination letter is posted on the OHRP website. The office has also compiled information on common findings of noncompliance in several areas, including (1) initial, continuing, and expedited reviews; (2) informed consent; (3) IRB membership, expertise, workload, and resources; and (4) documentation of IRB activities and findings. In a presentation to the committee, OHRP staff reported an analysis of noncompliance findings from 269 determination letters sent to 155 institutions (including some units of NIH) between October 1, 1998, and June 30, 2002 (Carome, 2003). The letters contained 1,120 citations of noncompliance or deficiencies. More than 90 percent of the institutions investigated were found to have at least one finding of noncompliance or deficiency. The median number was 4, with a range of 0 to 53. Of the 155 institutions receiving letters of determination, more than 80 percent conducted research involving children. One-fifth of the institutions were cited for an IRB’s failure to make the required findings for research involving children (e.g., whether the research involved minimal risk or a prospect of direct benefit) (Carome, 2003). Of the total of 1,120 citations, 3.5 percent involved a failure to document findings related to proposed pediatric studies. More than three-quarters of the 18 institutions that OHRP visited on-site had such deficiencies. Oversight by the Food and Drug Administration FDA monitors compliance with a substantial array of regulations to ensure the safety and effectiveness of a wide range of medical products, including drugs, medical devices, and biologic products (e.g., vaccines, products derived from blood or human cells, and tissues for transplantation). As noted in Chapter 3, the FDA regulations on human research protections are nearly identical to the DHHS regulations. In addition to regulations, FDA issues guidance documents, E6 Good Clinical Practice: Consolidated Practice (FDA, 1996a) and E11 Clinical Investigation of Medicinal Products in the Pediatric Population (FDA, 2000b), both of which were developed by

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Ethical Conduct of Clinical Research Involving Children the International Conference on Harmonisation (ICH) (ICH, 1996, 2000b). Compliance with the guidance documents is not required if a regulated firm or institution can show that it follows satisfactory alternative practices. Overall, about 70 percent of FDA-regulated research is commercially funded, and more than half of the regulated research is conducted outside academic institutions. These sites include nonacademic hospitals, clinics, and physicians’ offices that may not have their own IRB. Many protocols are reviewed by independent, commercial IRBs that are not affiliated with academic or other institutions and that are distant from the research sites. FDA has prepared specific guidance for such IRB reviews (FDA, 1998c). It has also provided guidance for IRB reviews of “cooperative” research studies that involve multiple sites and delegation of IRB review to a single lead site (FDA, 1998b). FDA has a more intensive and direct process for monitoring regulatory compliance than does OHRP. It reviews information submitted to it and conducts on-site inspections. This review and monitoring program covers much more than compliance with protections for human research participants. Notably, it covers compliance with scientific and quality standards to ensure that drugs and other products are safe and effective. Depending on the specific product and its characteristics, FDA reviews may occur at several stages, for example, when a company seeks permission to study a drug in clinical trials with humans, while it is conducting the study, when the company seeks permission to market the drug, when the agency requires further studies once a drug is approved for marketing, and following reports of adverse events. Given the complexity of FDA reviews, review teams typically include physicians, pharmacologists, statisticians, and others. They review new research protocols, revisions in protocols, safety reports, and other data (e.g., from animal or laboratory studies). FDA reviewers can recommend that study protocols be revised or suspended or that additional laboratory or other data be collected. FDA also conducts approximately 1,100 on-site inspections yearly (Lepay, 2003). About two-thirds of these inspections involve clinical investigators, and approximately one-quarter involve IRBs. Most of the inspections involve routine surveillance, but some are prompted by complaints or problems identified during the review of written information. Depending on what prompted the inspection, FDA staff may review written procedures and data, conduct interviews, and undertake forensic studies. As with OHRP, most problems identified are resolved through voluntary actions, without penalties or sanctions. FDA could not readily provide information on inspection findings or problems found during the review of written materials that involved pediatric studies, its rules on pediatric trials, or ICH guidelines on pediatric studies. However, FDA is currently establishing a mechanism whereby the

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Ethical Conduct of Clinical Research Involving Children Division of Scientific Investigations in FDA’s Center for Drug Evaluation and Research will be notified of all studies done under the pediatric exclusivity provision (David Lepay, M.D., Ph.D., Food and Drug Administration, personal communication, December 15, 2003). Given the government’s application of incentives to increase the numbers of pediatric clinical trials, the committee believes that special attention by FDA’s new Office of Pediatric Therapeutics to inspection and other findings related to pediatric studies is warranted. Institutional and Sponsor Oversight of Compliance Research institutions have the responsibility for ensuring institutional compliance with a wide range of federal regulations involving not only the protection of human research participants but also a number of other research concerns, including conflicts of interest; research misconduct; and research involving animals, biohazards, or radioactive materials. These responsibilities are important and complex enough that institutions have usually created compliance offices to monitor such research-related regulations. Except in institutions that focus exclusively or nearly exclusively on pediatric research, compliance with regulations for pediatric studies does not appear to be a particular focus. Research sponsors, particularly commercial companies that have a large economic stake in ensuring that their clinical trials meet all FDA standards, typically have active programs for monitoring trials for both safety and compliance with FDA regulations and guidance documents. Sponsors have increasingly relied on contract research organizations to undertake some or most activities related to clinical trials, including ensuring compliance with federal regulations. In response to the competition for clinical trials business from such organizations, academic children’s medical centers have been developing more extensive infrastructures for supporting commercially sponsored clinical trials, again, including the monitoring of compliance with FDA regulations and guidelines. Improving Data on Federal Oversight of Pediatric Research, Regulatory Protections, and Safety in Clinical Trials The dearth of information about human research and human research protections in general and about pediatric research and research protections for children in particular makes it impossible to describe adequately the application of these regulations, much less evaluate compliance. As one of its recommendations for strengthening the system for protecting human participants in research, the IOM report Responsible Research proposed

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Ethical Conduct of Clinical Research Involving Children that the DHHS commission studies “to gather baseline data on the current system … and to assess whether the system is improving over time” (IOM, 2003a, p. 164). The report noted that such information could not be compiled immediately and that some data could be collected through special studies and sample surveys rather than ongoing data collection mechanisms. This committee agrees that this kind of information is needed and emphasizes that it should cover studies involving children and compliance with the regulations governing such studies. Recommendation 7.1: To help identify what further guidance, education, or other steps may be needed to protect child participants in research, the U.S. Department of Health and Human Services—with direction from the U.S. Congress, if necessary—should develop and implement a plan for gathering and reporting data on research involving children, including the categorization of studies by the relevant section of federal regulations (45 CFR 46.404 to 407 and 21 CFR 50.51 to 54), and implementation of the regulations that govern research involving children, including data from the Office for Human Research Protections and the Food and Drug Administration on their inquiries, investigations, and sanctions related to such research. The categories of possible information suggested for a federal database are listed in Box 7.1 (which also includes annotations related to pediatric research). These categories include data on the types of research with humans being conducted as well as information on FDA and OHRP activities. The committee understands that such data collection responsibilities will require a considerable investment of resources by OHRP and, particularly, FDA, given the latter’s more extensive oversight activities. It also may require legislation to give DHHS the authority to collect this information without approval from the Office of Management and Budget. Nonetheless, in calling for this study, Congress has already recognized the particular concerns presented by research involving children and the regulations applicable to this research. If necessary, it should be prepared to direct the collection of baseline data on research that includes children and the implementation of research protections for children. COMPLIANCE IN THE CONTEXT OF VOLUNTARY ACTION, QUALITY IMPROVEMENT, AND ACCREDITATION “Remember … when things go bad, you’ll wish you did a better job. And so will we!” Elizabeth Hohmann, IRB chair

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Ethical Conduct of Clinical Research Involving Children BOX 7.1 Potential Data for a Federal Database on the System for Protecting Adult and Child Participants in Research A taxonomy of research institutions: the number of institutions conducting human research, including research involving infants, children, and adolescents, and the number and different types of studies (e.g., studies that include children) reviewed and approved or disapproved by IRBs. A taxonomy of review boards: the number of existing IRBs and the fraction of them that are primarily devoted to studies of particular types (e.g., studies involving children). A taxonomy of studies with adults and children: the numbers and distributions of investigations by type of study, for example, clinical trials of various stages, health services research, epidemiological and statistical investigations, cross-sectional and longitudinal surveys, and behavioral and social science experiments. The numbers of infant, child, and adolescent participants involved in research and, among them, how many are involved in research by category of research identified in Sections 404, 405, 406, or 407 of 45 CFR 46 and how many are enrolled in studies not under IRB review or any other form of review. The fraction of studies that involve children and present more than minimal risk for which formal safety monitoring boards have been established. The types and numbers of inquiries, investigations, and sanctions by the FDA and OHRP for studies that include children. A taxonomy of research harms and injuries applicable to infants, children, and adolescents, including physical, psychological, and social domains. The types and numbers of serious and unanticipated adverse events attributable to studies involving children and the types and numbers of research injuries attributable to such studies or to failures of participant protection by age of the child. SOURCE: Adapted from IOM (2003a, Box 6.1) A truism of public policy is that “policies don’t implement themselves.” Passing legislation or issuing regulations is only one step along the path from policy objectives to desired results. Formal enforcement mechanisms are, likewise, only one dimension of implementation. For most public policies, including those concerned with the protection of child participants in research, the path to desired results depends in large measure on voluntary actions by private individuals and organizations. These actions may have a mix of motivations, including ethical beliefs, commitment to scientific integrity, professionalism, self-interest, peer pressure, and a socialized willingness to follow the law. Various strategies exist to promote voluntary action on behalf of ethical and policy goals. The

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Ethical Conduct of Clinical Research Involving Children discussion here focuses on two: quality improvement initiatives and accreditation. Quality Improvement To encourage voluntary action and to promote not just compliance but excellence, health care policymakers and institutional leaders have increasingly recognized the precepts of quality improvement pioneered in industry (see, e.g., Berwick, 1989; IOM, 1990, 2001; and Nelson et al., 1998). Rather than focusing primarily on penalizing errors or regulatory noncompliance, policymakers and managers have paid greater attention, first, to identifying and correcting the system-level factors that contribute to problems and, second, to creating environments that make the desired actions easier or more rewarding to perform or both. As noted in Chapter 1, OHRP created a quality improvement initiative in 2002, in part, in response to criticisms from DHHS and congressional investigators (OHRP, 2002b). Although the office has reorganized the administrative placement of responsibilities for the activity, the initiative is to continue (OHRP, 2003).1 The office has developed, as a first step, a voluntary self-assessment instrument for research institutions and independent IRBs (OHRP, 2002d). The instrument, which has not yet been approved by the Office of Management and Budget, includes three questions (of 97) that ask about research involving children. Question 51: Does your IRB include awareness of, through consultation or representation on the IRB as appropriate, the additional concerns or issues of research involving vulnerable populations (such as, children, prisoners, women who are pregnant, persons with mental disabilities, or persons who are economically or educationally disadvantaged)? Question 55: When some or all of the subjects are likely to be vulnerable to coercion or undue influence (such as, children, prisoners, women who are pregnant, persons with mental disabilities, or persons who are economically or educationally disadvantaged), does your IRB consider and require that additional safeguards be included in the study to protect the rights and welfare of the subjects? 1   The Division of Assurances and Quality Improvement has been abolished and the responsibilities for quality improvement have been added to the Division of Education and Development.

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Ethical Conduct of Clinical Research Involving Children Question 74: For research involving children, do the minutes document IRB findings in accordance with Subpart D of 45 CFR 46? (OHRP, 2002d). Later stages of the quality improvement project are to include OHRP consultation with IRBs on improvements in institutional performance (with performance data held confidential) and the sharing of “best practices” among IRBs (OHRP, 2002d). Internally, OHRP has taken steps to ease bureaucratic hassles (e.g., by simplifying the process for obtaining the “assurances” described in Chapter 3), improve its information base (e.g., by developing a registration mechanism for IRBs), and increase investigator and IRB awareness of research participant protection policies through educational programs. OHRP has also promoted voluntary quality improvement in IRB performance by encouraging accreditation (see the next section). Local and national quality improvement efforts should, if successful, strengthen the overall system of human research protections within which the policies for children are embedded. The committee commends OHRP’s quality improvement initiative and encourages DHHS to provide the resources and leadership to follow through in the directions identified. As part of this process, explicit provisions for improving the design, conduct, and review of research involving children should be included. Quality improvement efforts are hindered by a lack of data, just as are regulatory compliance and oversight activities. The report Responsible Research (IOM, 2003a) recommended that research sponsors initiate and fund research to develop criteria for evaluating and improving the performance of human research protection programs. It noted that there is little experience in quality improvement initiatives that directly relates to such programs and that most efforts to date have focused on process criteria rather than outcome measures. The report identified several categories of data that might be included in a database to support quality assurance and improvement in human research protections programs. These are listed in Box 7.2 with annotations relevant to pediatric studies. When organizations that sponsor or conduct pediatric studies develop quality improvement plans for programs to protect human research participants, they should identify priorities related to research involving infants, children, and adolescents. Organizations that are not involved with significant amounts of pediatric research should still include such research in their quality improvement plans even if such research would not be otherwise identified by priority-setting exercises aimed at high-volume or high-risk studies.

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Ethical Conduct of Clinical Research Involving Children BOX 7.2 Examples of What Might Be Included in a Quality Assurance Database Related to Studies Involving Infants, Children, and Adolescents Resources allocated to the human research protection program (e.g., budget, full-time equivalent employees, and space) and resources dedicated to pediatric issues specifically Number and percentage of ongoing protocols that include children Target sample size for each protocol that includes children and the number of participants of different ages actually enrolled Types of studies being conducted (e.g., a clinical trial, observational study, or survey) Numbers and types of adverse events involving children and any related protocol modifications Sentinel events (not only deaths but also injuries and serious procedural errors) that raise safety concerns Duration of studies Dates of protocol submission, approval, and continuing review for each study Expertise in child health represented on the IRB(s) or sought through consultation by the IRB(s) for studies involving children Dates of data safety monitoring board or data monitoring committee actions, as relevant Principal investigators and collaborators Research staff profiles and delegated responsibilities Documentation of training in research ethics and regulations related to research involving children SOURCE: Adapted from IOM (2003a, Box 6.3) Compliance and Voluntary Accreditation In 2001, the IOM report Preserving Public Trust recommended the implementation of pilot projects to test programs of nongovernmental accreditation for programs to protect human participants in research (IOM, 2001). The rationale was to promote voluntary quality assurance and improvement efforts; direct greater attention to outcome measures; and encourage an evolving and cooperative process of identifying deficiencies, providing feedback on performance, and recognizing excellent performance. Since publication of that report, efforts to develop and implement accreditation programs have moved well along, and some organizations have won accreditation.

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Ethical Conduct of Clinical Research Involving Children During public meetings, this IOM committee heard from two organizations working to develop and implement such accreditation programs. One is the Association for the Accreditation of Human Research Protection Programs (AAHRPP).2 The other organization is the Partnership for Human Research Protection, Inc. (PHRP), which is a collaboration between the Joint Commission on Accreditation of Healthcare Organizations and the National Committee for Quality Assurance. Most of the standards adopted by these organizations focus on human research generally, but both have some statements that concern research involving children. In its statement to the committee, AAHRPP said that 52 of its 100 standards and elements are relevant to research involving children and are specifically evaluated when an institution conducts research involving children (AAHRPP, 2003). For example, the standards and elements require a meaningful consent process based on the type of research, the age of the children, the circumstances or risks under which the research will be conducted, and explicit IRB policies and procedures for obtaining parental permission (or waiving it) and for obtaining children’s assent (or waiving it). AAHRPP also requires investigators, the research staff conducting research involving children, and the reviewers of such research to have the expertise appropriate for these roles. Two policies of PHRP focus on pediatric research specifically (PHRP, 2003). They require evaluation of compliance with regulations on the involvement of children in research, including the review of both organizational policies and actual protocols. Policies on the review of research involving vulnerable populations specify that children be treated as members of vulnerable populations in the IRB’s review of research. In addition, the commentary on policies that relate to special IRB expertise notes that IRBs that do not routinely review pediatric studies may need a consultant if they receive a pediatric protocol for review. (The organization does not directly assess the expertise required to review research involving children.) Consistent with the 2001 IOM report, this committee supports the further development and systematic evaluation of accreditation for human research participant protection programs. The utility of these new programs, which add to the workloads of research institutions and which consume scarce resources, should be assessed and not assumed. In discussing roles and responsibilities for protecting child participants 2   AAHRPP consists of seven nonprofit founding member organizations: Association of American Medical Colleges, Consortium of Social Science Associations, Federation of American Societies of Experimental Biology, National Association of State Universities and Land Grant Colleges, National Health Council, Public Responsibility in Medicine and Research, and Association of American Universities.

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Ethical Conduct of Clinical Research Involving Children in research, Chapter 8 includes a recommendation about appropriate pediatric expertise for IRBs that review research involving children. For accrediting organizations to assess human research protection programs that encompass pediatric research, accrediting organizations themselves need pediatric expertise. 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. In addition, if they are not already doing so, accreditation organizations should examine samples of approved pediatric protocols and protocols that include both adults and children as part of their process of assessing organizations that review pediatric studies. CONCLUSION Given available data, little that is definitive can be said about investigator and IRB compliance with the federal regulations on research involving children. Nonetheless, survey information cited in this and other chapters, findings from government investigations and site visits, and discussions involving investigators and IRB members suggest reason for concern that some elements of the regulations may be overlooked and others may be so variably interpreted as to go beyond acceptable differences in judgment. Recent efforts to educate investigators and IRB members about regulatory requirements should help improve compliance. Better guidance about the interpretation of key concepts in the regulations—as recommended throughout this report—should likewise be useful. If federal quality improvement initiatives progress as initially proposed, they may not only help investigators and IRBs better understand their responsibilities but reduce certain procedural burdens that contribute little to meeting the goals of the regulations. Voluntary accreditation has the potential to provide further guidance and feedback to IRBs, improve knowledge of IRB practices and results, and encourage excellence. In addition, federal officials need better baseline data on clinical research involving children and implementation of research protections for children to help identify what further guidance, monitoring, or other steps may be needed to meet policy objectives.