CHAPTER 10
DIRECTIONS FOR RESEARCH

Awful as it was, I was given a gift of experience. If I can use it [in research] to help someone else, it makes [my daughter’s] life mean something still.

Bereaved parent (Contro, 2002, p.15)

Among the most common phrases in this report are “research is limited” and “systematic data are not available.” Clinicians and parents must often make decisions about the care of children with little guidance from clinical or health services research that documents the potential burdens as well as the potential benefits of medical interventions. For example, parents of infants born more than 14 weeks prematurely are faced with urgent decisions about the extent of life support that they wish for their infant. They frequently must confront unanswerable questions and make their best guesses about what to do with the help and support of neonatolgists and nurses who must often, in turn, rely on their own experience and judgment with limited scientific knowledge to guide them. Neonatologists generally lack validated predictors of very premature infants’ risk of death or long-term morbidity, although both outcomes are frequent.

The knowledge base for organizational and policy decisions is likewise limited. For example, organizations considering the creation of a pediatric palliative care program have little research on which to base decisions about services, staffing, outreach, budgets, and similar matters. What information is available relies heavily on descriptive case studies of adult programs. Funding for comparative health services research to test different approaches to organizing adult or pediatric palliative care is minuscule



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CHAPTER 10 DIRECTIONS FOR RESEARCH Awful as it was, I was given a gift of experience. If I can use it [in research] to help someone else, it makes [my daughter’s] life mean something still. Bereaved parent (Contro, 2002, p.15) Among the most common phrases in this report are “research is limited” and “systematic data are not available.” Clinicians and parents must often make decisions about the care of children with little guidance from clinical or health services research that documents the potential burdens as well as the potential benefits of medical interventions. For example, parents of infants born more than 14 weeks prematurely are faced with urgent decisions about the extent of life support that they wish for their infant. They frequently must confront unanswerable questions and make their best guesses about what to do with the help and support of neonatolgists and nurses who must often, in turn, rely on their own experience and judgment with limited scientific knowledge to guide them. Neonatologists generally lack validated predictors of very premature infants’ risk of death or long-term morbidity, although both outcomes are frequent. The knowledge base for organizational and policy decisions is likewise limited. For example, organizations considering the creation of a pediatric palliative care program have little research on which to base decisions about services, staffing, outreach, budgets, and similar matters. What information is available relies heavily on descriptive case studies of adult programs. Funding for comparative health services research to test different approaches to organizing adult or pediatric palliative care is minuscule

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compared to the funding available for clinical research. Even when hospices and hospitals undertake data-intensive internal studies (e.g., for quality improvement projects), they often lack the resources and motivation to produce analyses that meet peer-review standards for publication and wider dissemination. Researchers, clinicians, and policymakers have recognized shortfalls in clinical research involving palliative and end-of-life care for children and have taken steps to encourage and guide such research, some of which are described later in this chapter. The remainder of this chapter briefly reviews initiatives to encourage pediatric research in general and in palliative and end-of-life care specifically; describes directions for clinical, health services, and educational research to guide improvements in palliative, end-of-life, and bereavement care for children and their families; summarizes the practical challenges of undertaking pediatric research; and reviews ethical and legal questions raised by research involving children. Lessons learned from the kinds of research recommended here should help inform and improve the care of children who survive as well as children who die. It should likewise help all families who experience a child’s serious or fatal medical problem. INITIATIVES TO ENCOURAGE PEDIATRIC RESEARCH General Federal policymakers have taken steps to encourage certain kinds of pediatric research. In 1998, following directions from Congress in 1995, the National Institutes of Health (NIH) issued policies and guidelines for including children as research participants (NIH, 1998). Under the policy, children are to be included in all such research funded by the NIH unless their exclusion is justified on scientific or ethical grounds. Exclusion would, for example, be justified when a medical problem does not affect children. For some medical conditions, children’s developmental characteristics might suggest the need for a separate, child-only study. Legislative conference language accompanying the legislation encouraged but did not require the NIH to establish pediatric research priorities (NIH, 1998). The organization has not developed an overall set of priorities, although some individual institutes have developed priorities for certain clinical problems or services including kidney disease (NIDDK, 2001),

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HIV/AIDS (NIH, 2001a), and emergency medical services (NIH, 2001b). The priority-setting activity related to emergency services was stimulated in part by recognition that more needed to be done to implement the research recommendations in the 1993 Institute of Medicine (IOM) report on emergency medical services for children (IOM, 1993). In 2000, the Children’s Health Act (P.L. 106-310), among its other provisions, created a pediatric research initiative to increase NIH support for research on diseases, disorders, and other conditions in children. The legislation also supported the training of more pediatric researchers to conduct basic and clinical research. Earlier, the Food and Drug Administration Modernization Act of 1997 (P.L. 105-115) provided incentives for pharmaceutical companies to test drugs in children, and Congress renewed that legislation with slight modifications late in 2001 (Best Pharmaceuticals for Children Act, P.L.107-109). Companies that undertake studies on their products’ effects on children get six months of exclusive marketing rights for the drugs in return.1 (A later section of this chapter describes provisions in this and other legislation and regulation related to protection of child participants in such studies.) In addition to the pediatric exclusivity provision, the Food and Drug Administration (FDA) issued regulations in 1998 that allow it to require drug companies to undertake pediatric testing for certain drugs likely to be used in children (63 Fed. Reg. 66632, December 2, 1998, effective April 1, 1999).2 In May 2001, the FDA published an updated list of priorities for pediatric drug research that included more than 425 drugs or drug uses (FDA, 1   Federal regulations requiring pediatric studies of certain drug and biologic products were proposed in 1997 and issued in final form in 1998 (http://www.fda.gov/ohrms/dockets/98fr/120298c.txt). In 2002, the government announced that it would suspend these rules for two years pending study of the need for them (Connolly, 2002); a month later, it reversed that decision (Kaufman and Connolly, 2002; Landa, 2002). Unlike the legislation, the regulations also cover biologics (e.g., vaccines, blood products, gene therapy products, HIV and hepatitis tests, innovative therapies for diseases such as cancer and arthritis). 2   In a set of questions and answers about the rule, the FDA has stated (emphasis in the original deleted): “Under the rule, FDA has the authority to require pediatric studies on a drug product for the product’s approved indications if there is substantial use in the pediatric population or the product would provide a meaningful therapeutic benefit—and the absence of adequate labeling could pose significant risk (see 21 CFR 201.23(a)). At this time, however, FDA will not require studies of approved drugs except if approved by the Center Director. Instead, FDA will seek to have manufacturers voluntarily submit studies for marketed drugs under the incentives provided by [the legislation] (see 63 FR 66634 Sec II). For those drugs in which voluntary measures fail to obtain necessary pediatric studies, FDA will consider requiring studies” (http://www.fda.gov/cder/pediatric/faqs.htm#the“Rule”; last update: March 8, 2001).

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2001b). Of these, about two dozen uses might relate to symptoms of life-threatening illnesses. In a report on the pediatric exclusivity provisions, the General Accounting Office noted that when the legislation was passed, approximately 70 to 80 percent of drugs were not adequately labeled for use with children. Since then, pediatric drug research has increased substantially and has provided “new and useful information about whether and how drugs work in children” (USGAO, 2001b, p. 6). According to a recent FDA report to Congress, “the pediatric exclusivity has done more to generate clinical studies and useful prescribing information for the pediatric population than any other regulatory or legislative process to date” (FDA, 2001c, p. ii). The FDA report also noted continuing problems in some areas including the irrelevance of exclusivity provisions to certain old, “off-patent” antibiotics and other drugs and to drugs with low volumes of sales (“orphan drugs”). Another problem has been inadequate incentives for studies in neonates and very young children that must follow studies conducted on older children. In addition, following the completion of studies, manufacturers have sometimes been slow to change drug labeling to reflect the results. The 2001 legislation renewing “pediatric exclusivity” included provisions to encourage timely changes in drug labeling to reflect new research results. It also established an Office of Pediatric Therapeutics within the FDA to coordinate the agency’s activities related to children and pediatric practice and provided for the NIH-based Foundation for the National Institutes of Health (formerly the Foundation for Biomedical Research) to collect funds to support pediatric drug research. Pediatric Palliative and End-of-Life Care Research to support improvements in palliative, end-of-life, and bereavement care for children and their families constitutes only a tiny fraction of research involving children. Likewise, research involving children and their families occupies a small niche in the world of research on palliative and end-of-life care, which itself is small in comparison to other areas of clinical and health services research. Some units of the National Institutes of Health are supporting or show a potential willingness to support relevant research (NINR et al., 1997). For example, in soliciting research proposals on emergency medical services for children, the National Institute of Child Health and Development (NICHD) identified the need for research on the biobehavioral aspects of pain, stress, and coping with illness or injury in situations of emergency care (NIH, 2000b). The National Institute of Mental Health suggested research on aspects of emergency medical services delivery (e.g., medical staff communication style, follow-up care) that could potentially identify

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processes of emergency care that positively or negatively affect the experience of families whose children die. In addition, as discussed elsewhere in this report and in Appendix H, the Center for Medicare and Medicaid Services (CMS) is funding several demonstration projects that are intended to provide information about the development, operation, effectiveness, and costs of comprehensive programs of palliative care for children and families from the time of diagnosis through bereavement. Although the evaluation designs do not involve controlled comparisons, the evaluations should provide considerable descriptive and analytic detail about the structure of palliative care programs, populations served, and costs. Foundation-supported studies have been and continue to be particularly important in extending the knowledge base for adult and pediatric palliative, end-of-life, and bereavement care. Two pediatric programs are among 22 projects funded by the Robert Wood Johnson Foundation to test creative strategies for improving palliative care (Promoting Excellence, 2001). One, led by Children’s Hospital and Regional Medical Center of Seattle involves the state health department and regional Blue Cross Blue Shield plans in developing innovative ways to extend health plan coverage for palliative care during a child’s life-threatening illness. (See also Chapter 7.) The other, led by SSM Cardinal Glennon Children’s Hospital in St. Louis, involves support for a statewide network of health care providers ready to care for children at home. The hospital is developing a palliative care consult program to provide 24-hour consultative services, with a palliative care team to educate physicians, hospice providers, and community hospital staff. Another example of a privately funded initiative is the already-cited project supported by the Nathan Cummings Foundation and the Open Society Institute that is led by the Education Development Center of Boston (Solomon et al., 2001a). It involves eight children’s hospitals (Children’s Hospital/Dana-Farber Cancer Institute, Boston; Children’s Hospital of Philadelphia; Children’s Hospital and Health Center of San Diego; Johns Hopkins Children’s Center; Children’s Mercy Hospital, Kansas City; Lucile Packard Children’s Hospital, Stanford University Medical Center; University of California, San Francisco Children’s Hospital; and Vanderbilt Children’s Hospital). This project has examined clinicians’ and parents’ perspectives on palliative care and is developing quality improvement models and educational materials to support improvements in care for children with a range of life-threatening medical problems and their families. Another project involving support from multiple private foundations (including Soros and the Charitable Leadership Foundation) is the Pediatric Advanced Illness Coordinated Care (PAICC) initiative that was discussed in Chapter 6. This effort, being led by the Center for Advanced Illness Coor-

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dinated Care of Albany, New York, is now developing, evaluating, and refining a standardized model of communication and care coordination in five institutions (Himelstein et al., 2002; Hilden and Tobin, 2002). DIRECTIONS FOR FUTURE RESEARCH General Throughout its work, the committee has been hampered by the lack of basic descriptive information about death in childhood as well as scant research testing the effectiveness of clinical interventions and organizational processes and structures in providing palliative, end-of-life, and bereavement care that meets the needs of seriously ill or injured children and their families. Studies reviewed by the committee in Chapter 3 describe deficits in care received by children who die and their families. Unfortunately, available research leaves much that is unclear about the extent and causes of shortfalls in care, the number and kinds of children and families who could benefit from palliative and end-of-life care, and the effectiveness of specific strategies to improve the delivery and financing of this care. Recommendation: The National Center for Health Statistics, the National Institutes of Health, and other relevant public and private organizations, including philanthropic organizations, should collaborate to improve the collection of descriptive data—epidemiological, clinical, organizational, and financial—to guide the provision, funding, and evaluation of palliative, end-of-life, and bereavement care for children and families. In the 2001 report Improving Palliative Care for Cancer (IOM, 2001c), the IOM’s National Cancer Policy Board included two recommendations aimed at stimulating palliative care research in designated “centers of excellence” and encouraging such centers to take a lead role as agents of national policy in promoting palliative care. The Board also recommended that the National Cancer Institute (NCI) should add the requirement of research in palliative care and symptom control for an institution’s designation as a “comprehensive cancer center.” The research activities suggested for such centers included the following: formal testing and evaluation of new and existing practice guidelines for palliative and end-of-life care; pilot testing of “quality indicators” for assessing end-of-life care at the level of the patient and the institution; uncovering the determinants of disparities in access to care by

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minority populations and developing specific programs and initiatives to increase access; and providing clinical and research training fellowships in medical and surgical oncology in end-of-life care for adult and pediatric patients. This general strategy should also prove productive in stimulating palliative, end-of-life, and bereavement care research involving children and their families. While by no means discouraging research in other institutions, the committee encourages initiatives that build on federally funded pediatric centers, networks, and similar structures. Recommendation: Units of the National Institutes of Health and other organizations that fund pediatric oncology, neonatal, and similar clinical and research centers or networks should define priorities for research in pediatric palliative, end-of-life, and bereavement care. Research should focus on care for infants, children, adolescents, and their families, including siblings, and should cover care from the time of diagnosis through death and bereavement. Priorities for research include but are not limited to the effectiveness of clinical interventions including symptom management; methods for improving communication and decisionmaking; innovative arrangements for delivering, coordinating, and evaluating care, including interdisciplinary care teams and quality improvement strategies, and different approaches to bereavement care. By organizing multiple sites to investigate a common problem using a common methodology, this strategy should increase the number of children involved in studies and increase the credibility of the findings. It should also stimulate the development of investigator expertise in pediatric palliative care research, encourage the formulation and successful completion of more high-quality research projects, and promote attention to palliative care, end-of-life, and bereavement issues in both pediatric clinical trials and regular patient care. By involving designated institutional participants in collaborative research, a “centers” strategy should also encourage tests of organizational interventions (e.g., random assignment of institutions to test innovations in information systems, training, staffing, or conflict management). The results should benefit children who survive, children who die, and the families of both groups. The committee recognizes that the infrastructure for biomedical and clinical research varies considerably for different diseases, disorders, and other medical conditions affecting children. For example, the Children’s

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Oncology Group (COG), supported by the NCI, involves nearly 240 centers (COG, 2001), whereas the Neonatal Research Network funded by the National Institute of Child Health and Development (NICHD) includes approximately a dozen centers (NICHD, 2000; see also http://neonatal.rti.org). Given differences in the research infrastructure and in the conditions that bring death to children, the specific incentives and mechanisms for a center- or network-focused research strategy will have to be flexible and creative. Although the recommendation focuses on NIH-funded centers and networks, philanthropic foundations and other private organizations can also participate in supporting creative projects that are based on these networks but are not limited to NIH priorities. Flexibility and creativity on the part of both research sponsors and investigators will also be required to extend research earlier into the period following the diagnosis of a life-threatening problem and later into the period of bereavement experienced by the families of so many children with grave medical problems who participate in clinical research. If researchers focus on earlier stages in the trajectory of fatal and potentially fatal conditions, they may be able to increase the number of children participating in research on certain aspects of palliative care (e.g., effective symptom management). They may also be able to develop a fuller understanding of the symptoms and distress associated with serious illnesses (and their treatments) and the benefits and challenges of incorporating aspects of palliative care earlier in the course of a life-threatening condition. In proposing directions for research to improve pediatric palliative and end-of-life care, the committee tried to focus on the gaps in the knowledge base needed to put the principles set forth in Chapter 1 into practice and to implement the recommendations listed in subsequent chapters. The discussion below focuses on several specific areas for further research including quality of life, symptom measurement and management, bereavement, edu-cation, and models for delivering and financing palliative, end-of-life, and bereavement care. At a more general level, a comprehensive research agenda for pediatric palliative, end-of-life, and bereavement care should consider the needs of infants, children, and adolescents and developmentally appropriate care strategies; a range of causes and trajectories of death including sudden, unexpected deaths, deaths from progressive chronic conditions, and deaths from conditions diagnosed prenatally; the effects of uncertainty in diagnosis, prognosis, and treatment on communication with children and families, establishment of care goals and care plans, decisions about interventions, preparation for death, and family perspectives and emotions after death; the needs of parents, siblings, and other family members;

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the roles and relationships of different health care professionals and other personnel who are involved with children who may die or who have died and their families; the range of care settings and organizations that are involved with children who may die or have died and their families (e.g., emergency first-response units, emergency departments, intensive care units, other inpatient units, hospices, home health agencies, and medical examiners’ offices); the contribution of family, provider, and other factors to timely or delayed recognition that death is near and to differences in family and physician assessments of prognosis and care options; the reports of children and families about their specific experiences with care (preferably concurrent with care rather than after the child’s death), not just their global assessments of satisfaction with care; the experiences of children and families outside the health care system, including with schools; the psychological effects on professionals of caring for children who die and the consequences for their ability to care for children and parents; and methods and processes for improving communication and preventing or resolving conflicts among clinicians, patients, and family members. Much of the research suggested in this chapter is descriptive and qualitative. It involves epidemiological, methodological, behavioral, organizational, and policy studies as well as clinical research. Controlled research strategies, including randomized clinical trials and careful case-control studies, should be encouraged. Such approaches will, however, often be difficult given the small numbers of children who die and the charged emotional circumstances surrounding a child’s life threatening illness or injury. Even for relatively narrow clinical questions (e.g., comparison of one pain management regimen versus another), randomized trials are relatively uncommon. Qualitative studies have an important role to play in describing the experiences, perspectives, and values of patients, family members, and caregivers (see, e.g., Sackett and Wennberg, 1997). In devising suitable research strategies, researchers will need to combine creativity, flexibility, and sensitivity both to patient and family burdens and anxieties. Each research topic suggested here presents different methodological challenges. In general, researchers may encounter problems in defining and recruiting sufficient numbers of research participants, collecting information about subjective experiences from individuals who may be physically or emotionally limited in their ability or willingness to respond to questions, identifying necessary information in medical or other records, and defining measures relevant to patient and family experiences at different stages of life-threatening medical experiences. Epidemiologic and health

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services research may have to rely on data that is years old by the time it is released. Researchers may also encounter difficulties in getting research approved by Institutional Review Boards, a topic that warrants investigation in its own right. Research Directions: Quality of Life for Children and Families To identify practices that affect the quality of life experienced by a child with a life-threatening medical problem requires measurement tools that can reliably and validly reflect the child’s experience, particularly when the problem has reached an advanced stage and death is expected or possible in the foreseeable future. Appendix C identifies some of the limitations of current measurement tools (especially those intended for well children) and the complexities of developing better ones. Although improvements in measures relevant for pediatric palliative and end-of-life care can build in a general way on measurement strategies used for adults, much of the work needed will have to be specific to infants, children, and adolescents. Box 10.1 summarizes some important directions for such work. As discussed in Appendix C, existing pediatric quality-of-life instruments may be generic in nature or they may be disease and condition specific. Either way, such instruments are designed primarily for well or chronically ill children and adolescents. They include items that measure function, problems with physical activities, emotional concerns, cognitive abilities to concentrate on and complete school tasks, and concerns with certain symptoms. Many of these items may not be relevant for a child with advanced illness. The instruments may also overlook some issues, for example, spiritual or existential concerns. In addition, completing an instrument intended for healthier children may be unduly burdensome for a seriously ill child. BOX 10.1 Directions for Research on Quality-of-Life Measures for Children and Families Identify domains of quality of life relevant for children with advanced illness and for their family members. Investigate the importance of different domains of quality of life for children and for family members, including how their importance may vary over time. Assess the need to adapt measurement instruments to reflect differences in the ill child’s stage of development, the nature of the illness, and other child and family characteristics. Evaluate the degree and nature of agreement or disagreement between child self-reports and proxy reports by parents or others.

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Some instruments also exist to assess quality of life for parents of children who are seriously ill. These focus primarily on elements of caregiver burden and may only incompletely capture the quality of life of the parent of a dying child. The committee is aware of no instruments that assess quality of life for siblings of seriously ill children. One task for methodologists is to identify specific domains (e.g., physical, spiritual) of quality of life that are relevant for a child with advanced illness. Another task is to determine whether the importance of a domain changes over time as an illness progresses. Methodologists will also have to consider the influence of development stage, culture, and context (e.g., sites of care, nature of the illness, family circumstances) both in the design of instruments and in their application. For example, an instrument may require different formats for young children and adolescents. Interventions directed toward improving or at least maintaining a dying child’s quality of life could also improve the quality of life of family members who suffer with the child. Likewise, interventions to help parents, siblings, and other family members could benefit the ill child. Researchers designing interventions to protect and improve the quality of life of children with advanced illness and their families should consider how they might evaluate these “spillover” effects. When possible, obtaining the dying child’s own report of his or her quality of life is preferred. It may not, however, be possible to identify definitively when a child is dying until illness is far advanced. Also, given the uncertainties associated with predicting time of death, death may come earlier than expected. Thus, some dying children will not be capable of providing self-reports, and the report of a parent or other proxy or surrogate may be necessary. Studies comparing children’s self-reports with reports from parents or professionals tend to show low to moderate agreement in ratings of symptoms or other aspects of quality of life (see Appendix C). Comparisons have not been completed for dying children and their parents or health care providers. Another question may arise when dying children experience changes in health care setting (e.g., home to hospital, distant medical center to community hospital) or health care provider (e.g., pediatric oncologist to generalist pediatrician or hospice professional). How such changes might affect proxy reports, especially those of health care professionals, is unknown. Comparisons of child self-reports and proxy reports will be challenging in the context of a child’s advanced illness and will require great sensitivity. Nonetheless, it is important to get a better sense of the degree and nature of agreement or disagreement between the two and of the factors that might increase or diminish agreement (e.g., child’s development stage, family culture, location and continuity of end-of-life care). If parents or other proxies tend to overestimate, underestimate, or otherwise misperceive the quality of

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DRGs or the RBRVS properly categorize and weigh palliative and end-of-life services for children. Such research could also identify possible adjustments in these systems to correct any problems identified. Chapter 7 made general suggestions about establishing children’s eligibility for certain types of palliative services using diagnosis and severity-of-illness criteria. Analytic work is needed to identify reliable and valid approaches for establishing such criteria for payment purposes and to assess their feasibility, cost implications, and likely consequences for child and family access to palliative care. Hospice As discussed in Chapter 7, studies of hospice care for adults have identified serious limitations in Medicare’s per diem payments for that care. For example, studies have documented hospice access problems for adult patients with particularly high-cost needs (e.g., those requiring expensive pain medications or other palliative therapies). Research is needed to document the extent of hospice access problems for pediatric patients, examine hospice referral patterns, and identify characteristics of patients who are denied access. To explore these issues, prospective studies using existing clinical networks (e.g., the Children’s Oncology Group) for patient identification should be conducted. In order to implement a payment outlier system for hospices (recommended by the committee in Chapter 7) and to facilitate research on utilization and costs of hospice care for adult and pediatric patients, a Medicaid hospice cost-reporting system should be created. Since many hospices do not currently maintain detailed data on number of hours or types of services provided by staff, Medicaid could begin by creating a cost-reporting system based on high-cost items that hospices are more likely to track (e.g., expensive medications, durable medical equipment). Prospective Payment for Home Health Care Because Medicare policies often influence state and private policies, studies are needed to examine how new Medicare prospective payments systems for home health care and other services have diffused to state Medicaid programs and private health plans and how these systems are affecting care for children with life-threatening medical conditions. A first phase of research would involve surveying Medicaid and private plans to assess their adoption of Medicare reimbursement methods. A second phase would investigate the impact of these payment approaches on family burden and quality of care for Medicaid-covered children.

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Cost Implications of Family Choices For reasons discussed earlier in this report, families should have choices about the site of death for children with fatal medical problems. To assess the cost implications of these choices, prospective studies are needed to identify and compare the costs of different home and inpatient care options for children expected to die from congenital anomalies, cancers, progressive neurological disorders, and other serious conditions. Existing studies based on Medicare beneficiaries’ use of hospice care cannot be generalized to children and are, in any case, flawed by retrospective research designs that cannot control for selection bias (i.e., differences in preferences and other characteristics of those who choose hospice care). Although the committee expects that the financing changes recommended in Chapter 7 will involve limited additional costs for the benefits expected, a simulation model would assist in estimating the cost and utilization effects of implementing different options. For example, the cost of eliminating the six-month prognosis requirement could be estimated. Finally, as noted elsewhere in this chapter, long-term prospective research is needed to evaluate the effectiveness of bereavement interventions for parents and siblings. The estimated costs and long-term cost-effectiveness of alternative interventions should also be investigated if such studies are undertaken. Research Directions: Educating Health Professionals Despite several decades of research on methods for educating health care professionals, much uncertainty remains about methods that can be consistently applied to produce changes in knowledge and practice, especially changes that endure beyond the classroom or the continuing education program. One challenge for educators is that the knowledge, values, and actions they teach are not uniformly rewarded or reinforced in day-to-day practice. Educational research is not always valued within academic departments or by research funders. Long-term follow-up of educational outcomes, in particular, tends to be expensive and logistically complicated. Nonetheless, given the huge investments in preparing health professionals for practice, research is essential to identify the effectiveness of different educational techniques and emphases in creating desired changes in knowledge, skills, attitudes, and especially, behaviors. The committee expects that much research involving education in pediatric care, adult palliative care, and generally relevant attitudes or skills (e.g., empathy, interviewing patients) would be generalizable to education in pediatric palliative care. Nonetheless, in developing curricula or inter-

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ventions for pediatric specialists in training or for established pediatric specialists, revisions or adjustments will have to be considered and evaluated to take into account the special emotional and other dimensions of caring for dying children and their families. For example, as discussed in Chapter 8, the use of standardized patients is now a common educational tool, but using child actors or volunteers to depict dying children might encounter practical and ethical obstacles. Standardized families can be used, and systematic research into the effectiveness of this strategy—and of different variants—would be helpful. The projects by Williams and colleagues (2001b, 2002) and Greenberg and colleagues (1993) discussed in Chapter 9 offer examples of how such standardized families might be used to improve skills in communicating bad news and informing family decisionmaking. Box 10.8 lists several directions for educational research. The involvement of bereaved parents in educational programs should be investigated, both for its impact on trainees and for the consequences for the parents. Conversations with bereaved parents suggest that some have found consolation and strength in presenting their experiences and perspectives, answering questions, and otherwise helping to educate both clinicians-in-training and established clinicians. Self-selection of the most confident or educated parents is, however, a potential concern and should be taken into account in any research about the role of parents as educators. Because it will take years for newly educated health professionals to dominate health care systems by numbers or other influence, it is important BOX 10.8 Directions for Research on Educating Health Care Professionals Investigate the participation of bereaved parents in educational programs at all levels. Identify characteristics of pediatric care systems (e.g., inpatient hospice programs, links to hospice agencies) that promote and reinforce lessons learned about palliative and end-of-life care in all educational contexts, including continuing education. Establish priorities and strategies for research on the short-term and long-term effects of education to prepare health care professionals to work in interdisciplinary teams. Assess strategies to improve symptom management and increase professionals’ awareness of how well their assessments and performance match the experiences and expectations of patients and family members. Assess educational strategies to improve physician comfort and skill in compassionately providing patients and families with accurate and complete information about diagnosis, prognosis, and treatment options (including palliative care).

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to examine continuing education in pediatric palliative care for established clinicians. Further, research is needed to identify characteristics of pediatric care systems that promote and reinforce lessons learned about palliative and end-of-life care in all educational contexts. As noted above, without reinforcement, educational interventions may manage to create desired short-term results but fail to produce durable changes. Research questions include whether education programs are more effective when institutions have formal relationships with hospices, formal pediatric palliative care consultation programs, formal adult inpatient palliative care services (for institutions serving adults and children), or identified palliative care role models and educators. This report has stressed the importance of team care to bring multiple clinical perspectives and skills to bear on the complex physical, emotional, spiritual, and practical needs of seriously ill or injured children and families. In addition to research on the performance of pediatric teams in different environments and contexts (including providing palliative, end-of-life, and bereavement care in hospitals or at home), research also should assess methods for successfully educating physicians, nurses, social workers, and others to function as effective members of health care teams. Also stressed in this report is the importance of adequate and timely information for patients and families. As reviewed in Chapters 3 and 4, studies have suggested that clinicians may be reluctant to provide such information when the diagnosis and prognosis are grim. One study (Lamont and Christakis, 2001) suggested that clinicians may provide patients and families with misleadingly optimistic assessments and that younger adult patients were more likely to receive such misleading assessments than older adults. Another study involving physicians caring for adults found that they dreaded explicit discussion of patient prognosis, usually were not specific, and often waited until parents or families raised the issue (Christakis and Iwashyna, 1998). Other studies of adult and pediatric palliative care have identified discrepancies between physician assessments of care and the assessments of patients or family members (see, e.g., Wolfe et al., 2000b). A variety of educational interventions—for example, role playing, standardized patients who provide feedback, and parents as teachers—could potentially promote greater clinician self-awareness and more explicit concern for the actual experiences and expectations of patients and family members. Studies of efforts to teach empathy that were conducted in the 1970s suggest strategies to assess and compare such educational interventions (Fine and Therrien, 1977; see also Spiro, 1992; Reiser, 1996; Halpern, 2001). Finally, the development and evaluation of educational techniques to improve the use of proven symptom management strategies are important if their benefits are to reach children in need. In particular, although cognitive

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and behavioral strategies have demonstrated effectiveness in reducing pain and improving coping, teaching of these techniques to clinicians generally appears to lack the rigor and uniformity that characterize other clinical domains. CHALLENGES OF RESEARCH ON PALLIATIVE AND END-OF-LIFE CARE FOR CHILDREN AND THEIR FAMILES The paucity of information about palliative and end-of-life care for children and their families has several explanations. Although over 50,000 children die each year, many of these deaths result from severe injuries or sudden infant death syndrome (SIDS). The medical care actually provided to or consciously experienced by these children is limited compared to that of children with chronic medical conditions. For surviving family members, interactions with emergency medical personnel (particularly first responders) or ICU personnel are often relatively brief and poorly documented, which makes it difficult for researchers to use medical records retrospectively to assess the extent and quality of the information and emotional support provided to survivors. Particularly for deaths involving infants and very young children, a considerable fraction of deaths result from an array of relatively or very uncommon congenital conditions. Even over several years and across multiple medical centers, it may be difficult to identify enough cases for each condition to allow productive prospective or retrospective analyses of the patterns and quality of palliative and end-of-life care for these children and their families. Combining information about children with different conditions may sometimes be a plausible strategy if the symptoms and other characteristics of each condition and the consequences for the children and families are similar. Nonetheless, accumulating enough cases for analysis may still take years. Even when numbers are sufficient for study, however, retrospective analyses of medical records may be constrained by failures to document relevant aspects of care, for example, whether or not pain and other symptoms were explicitly assessed. Such lack of documentation, in itself, is an important finding with implications for day-to-day clinical practice and quality improvement efforts. Another constraint is that although Medicare-related databases offer much comprehensive information about the types and costs of care provided to elderly adults, no comparable information is available for younger individuals covered by the 50-plus state Medicaid programs and thousands of private insurance plans. Other information sources, such as government surveys of home health and hospice agencies, may not include enough children to allow meaningful analyses.

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Despite many differences, researchers studying end-of-life care and researchers studying children share a common challenge: their subjects are often unable to report directly on the care they have received or on their physical or emotional distress or well-being. Even for children old enough to report reliably, the effects of a life-threatening medical problem or its treatment may render them unconscious, confused, drowsy, fatigued, or otherwise not able to answer questions. As a result, researchers frequently rely on surrogates—usually the parents—to describe their perceptions of the patient’s experience and quality of life (see Appendix C). Also, because the time of death is often unpredictable, researchers may be unable to assess patients’ status at comparable points before death and may have to rely on the recollections of surrogates about a patient’s status during the days, weeks, or months prior to death (see, e.g., Wolfe et al., 2000a,b). Nonetheless, surrogate reports and retrospective reports raise serious questions of validity and reliability, and researchers and research funders should consider alternatives whenever possible. Another challenge is that research funders, who are accustomed to more stable research situations, measurement tools, clinical end points (e.g., remission, five-year survival), and already-conducted pilot testing, may be reluctant to support research that does not fit these patterns. In the committee’s experience, they are also reluctant to fund the kinds of pilot studies that provide an essential base for more rigorous research. This puts researchers in this new and difficult arena in a classic “Catch-22” situation. In addition, the conduct of medical or health services research involving children faces more stringent ethical and legal constraints than apply to research involving most adults. These are discussed below. ETHICAL AND LEGAL ISSUES IN RESEARCH INVOLVING CHILDREN Policymakers, researchers, and ethicists have been working for decades to develop protections for people participating in research, especially “vulnerable” populations including children, prisoners, and those with serious cognitive or emotional problems. The first widely recognized principles for ethical research were the Nuremberg Code’s directives for human experimentation, which were developed in 1947 by judges presiding over the trials of Nazi physicians accused of research atrocities (Shuster, 1997). These judges developed 10 principles for research, the first of which stated that it is absolutely essential that human subjects voluntarily consent to participation. The statement did not consider the involvement of children in research. The 1964 Declaration of Helsinki from the World Medical Association called for parents of child participants in research to give their consent and

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for children’s “assent” to be obtained when possible (WMA, 1964). In the United States, a national commission on protection of human subjects in research likewise proposed in 1977 that parental permission be required as well as assent in some form from children age 7 and over (USDHEW, 1977). Subsequent books, articles, and conferences have continued to explore ethical issues involved in research on children, the boundaries of permissible research, and strategies for protecting child research subjects (see, e.g., Stanley and Sieber, 1992; Grodin and Glantz, 1994; AAP, 1995a; Levine, 1995; Rosato, 2000). If conducting research presents ethical questions, so does the failure to conduct research. As noted by the American Academy of Pediatrics in a statement on drug research, the “lack of studies in children presents the treating physician with an ethical dilemma. The physician must frequently either not treat children with potentially beneficial medications or treat them with medications based on adult studies or anecdotal empirical experience in children” (AAP, 1995a, p. 286). Federally Funded Research As set forth in Box 10.9, federal regulations adopted in 1983 and revised in 1991 set forth requirements related to children’s participation as subjects of federally funded research (45 CFR 46; USDHSS, 1993). The regulations also provided for institutional review boards (IRBs) to be established by each research institution to review federally funded research that involves human subjects and determine whether proposed research meets federal standards. Although the regulations and accompanying federal guidance encourage respect for a child’s views about participating in research, they make clear that a research project may be approved without requiring that each child provide assent before enrollment (45 CFR 46.408[a]). The IRB must conclude in such cases that the research has the potential to produce an important direct benefit to the child, that such benefit is possible only in the research context, and that provisions are adequate for obtaining informed permission from the child’s parents for the research. The regulations also require that research conform to state laws and judicial decisions including those related to the age of consent for medical treatment. If an adolescent is considered legally competent under state law to consent to treatment, he or she can usually consent to research presenting equivalent risk. In some situations (e.g., for research on children who have been abused), researchers and the IRB may seek alternatives to or reviews of parental permission for a child’s participation in research. If a child is a ward of the state, additional limitations are imposed on his or her participation in

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BOX 10.9 Categories of Research Involving Children That May Be Approved for Federal Funding Research Involving No Greater Than Minimal Risk (46.404) “The Institutional Review Board (IRB) must find that the research involves no greater than minimal risk to children and that adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians.” Research Involving Greater Than Minimal Risk That Has Potential to Benefit the Research Subjects Directly (46.405) “The IRB must find that more than minimal risk to children is presented by an intervention and then must also find that (a) the research may directly benefit the individual research subjects, (b) the anticipated benefit is sufficient to justify the risk, (c) the relation of the benefit to the risk is equally or more favorable as that presented by available nonresearch alternatives, and (d) adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians.” Research Involving Greater Than Minimal Risk That Has No Prospect of Direct Benefit to Individual Subjects but Is Likely to Yield Generalizable Knowledge (46.406) “The IRB must find that more than minimal risk to children is presented by an intervention that is not expected to benefit the individual subject directly but that (a) the increased risk is minor, (b) the experiences associated with the intervention are reasonably similar to those inherent in the subject’s actual or expected medical situation, (c) the intervention is likely to yield generalizable knowledge about the subject’s condition that is vitally important to understand or ameliorate the condition, and (d) adequate provisions are made for soliciting assent of the children and the permission of their parents or guardians.” Research That Is Not Otherwise Approvable (46.407) “The IRB must conclude that the research does not meet the above requirements but does present a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children. The research must then be judged by the Secretary of the Department of Health and Human Services (after consultation with appropriate experts and opportunity for public review and comment) to fit one of the categories described above or to meet the following conditions of (a) presenting a reasonable opportunity for better understanding, preventing, or alleviating a serious problem affecting the health or welfare of children, (b) following sound ethical principles for research, and (c) including adequate provisions for soliciting the assent of children and the permission of their parents or guardians.” SOURCE: 45 CFR 46 Protection of Human Subjects, Additional Protections for Children Involved as Subjects in Research, Subpart D, Sections 401–409. 56 FR 28032, June 18, 1991 (http://www.med.umich.edu/irbmed/FederalDocuments/hhs/HHS45CFR46.html).

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research when the research involves more than minimal risk with no prospect of direct benefit to the child. The research must either be related to children’s status as wards or be conducted in settings such as hospitals or schools where the majority of child research participants are not wards of the state (45 CFR 46.409). Also, a special advocate (other than the guardian) must be appointed for a child participating in such research. The committee understands that some states refuse to permit wards of the state to participate in research, even if no alternative treatment exists for the child’s life-threatening illness. Explanations of the proposed research are to be appropriate for the specific child’s age, maturity, experience, and medical condition. The National Cancer Institute provides guidance for parents and guardians, including advice that parents not withhold information about the discomforts or risks involved in research and that they monitor whether the child really seems to understand the explanations being provided (NCI, 2001c). Based on members’ experiences and their conversations with other researchers, the committee believes that many IRBs, as presently constituted, may lack the expertise and background to evaluate proposals for research on pediatric palliative and end-of-life care. They may have unwarranted concerns about the potential of such research to cause harm to children and families. As described below, Congress has asked for a study that will investigate the competence of IRBs to assess research involving children. Some research should soon be available to document positive responses by families to studies investigating their experiences and perspectives (Wolfe, 2001). As noted in a recent report on family perspectives on the quality of pediatric palliative care, “The families who participated in our assessment unanimously expressed gratitude for the opportunity to ‘tell their stories’ ” (Contro et al., 2002, p. 18). Researchers in that study reported, however, that 20 of 63 families they reached declined to participate because it would be too painful. Privately Funded Research The regulations described in the preceding section apply to federally funded research involving children. Pediatric drug research promoted by the Food and Drug Administration is generally funded by pharmaceutical companies. As directed by Congress in the Children’s Health Act of 2000, the FDA must apply Department of Health and Human Services requirements for federally funded research that involves children to privately funded studies of products regulated by the FDA. (The agency had long required IRB review of drug research submitted to it by private companies [Levine, 1988].)

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In April 1, 2001, the FDA issued an interim rule to change its regulations accordingly (21 CFR 50 and 56; FDA, 2001a). The agency invited comment on several issues including children’s participation in placebocontrolled trials, the definition of what constitutes a “minor increase over minimal risk” (and ways of measuring minor risk and determining when a minimal risk becomes a major risk), and ways to provide age-appropriate explanations of research to children. The interim rule differs from the regulations governing federally funded research in certain respects. For research in the “not otherwise approvable” category (see Box 10.8) that is referred to the commissioner of the FDA for consideration, the agency may not be able to offer public review and comment if the research sponsor is unwilling to make public necessary information that is privileged under other FDA requirements. Research that is neither federally funded nor conducted under the FDA provisions described earlier may be covered by state regulations and institutional policies requiring review of all research undertaken by its employees or students. In general, IRBs apply the same criteria to research proposals without reference to the source of funding. Continuing Concerns about Children’s Participation in Research Policies about children’s participation in research continue to prompt debate. The major issues involve the appropriateness of current regulations for children of different ages or intellectual and emotional maturity, the ethics of including children and other vulnerable subjects in research that is not expected to benefit these subjects directly, the definition of minimal risk, the extent of children’s and adolescents’ comprehension of information about the risks and benefits of treatments and participation in research, the potential for conflict between parent and child and the meaningfulness of “assent” or discussions about assent with a child when parents can override the child’s wishes, and the performance of IRBs in evaluating research involving children. The legislation reauthorizing the incentives for pediatric drug testing provided for an Institute of Medicine study to examine such issues and review federal regulations relating to research involving children. The results of this report are to be given to Congress by the close of 2003.

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CONCLUSION This chapter has proposed a range of research efforts to strengthen the very limited base of knowledge now available to guide those providing, organizing, financing, and monitoring palliative, end-of-life, and bereavement care for children and families. It has recommended strategies to promote relevant research in federally funded pediatric centers, networks, and similar structures. The intent is to increase the numbers of children and families involved in studies, encourage the development and use of common research methods, and increase the credibility and acceptance of the research findings. The research directions proposed here focus on children who have conditions that are certain or likely to prove fatal, but investigation of some of the suggested research questions may involve participation by children who survive and their families. In some cases, such participation will reflect the unpredictability of certain life-threatening conditions and the requirements of prospective research designs. In other cases, it will reflect a focus on questions that affect the well being of children and families facing a life-threatening problem, whether or not that problem actually ends in death. In either case, when it is appropriate, including a larger group of children usually has methodological advantages. Much of the research proposed here thus should provide knowledge that will inform and improve the care of children who survive as well as those who do not—and likewise will help every family that suffers with a seriously ill or injured child. Indeed, all of the recommendations in this report, if implemented, should help create a care system that all children and families can trust to provide capable, compassionate, and reliable care when they are in need.