Functional abdominal pain is part of the functional gastrointestinal disorders (FGIDs) that are chronic in nature and are prevalent in the pediatric population (1). It has been estimated that chronic abdominal pain occurs in 2 to 4% of all pediatric office visits. Hyams found that 13% of middle school–age and 17% of high school–age students experience abdominal pain weekly (2). Because these conditions affect an individual during a critical phase of growth and development, families are confronted with the need and the desire to obtain an explanation for the causes of abdominal pain in their children. These evaluations may be costly without demonstrable evidence of a pathological condition such as an anatomic, metabolic, infectious, inflammatory, or neoplastic disorder. In addition, the chronic nature of abdominal pain has a negative impact on the quality of life for these children (1,3).
During the last 2 decades, there has been an increasing recognition of the impact of functional gastrointestinal disorders in adults along with enhanced research effort to understand the physiological and psychosocial bases of these disorders. The research in functional gastrointestinal disorders in the pediatric age group has, however, lagged. Because collaboration in the field of functional abdominal pain in the pediatric age group is essential to advance research in this area, the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) cosponsored a 1-day symposium with the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) on new insights into functional abdominal pain and irritable bowel syndrome. The purpose of the symposium was fourfold: identify research targets for future studies of pediatric FGIDs, foster interaction and information sharing among national and international experts in a variety of relevant disciplines, define the state of the art in the evaluation and treatment of these disorders, and establish a consortium for multidisciplinary collaborative studies.
During the symposium, the role of the National Institutes of Health (NIH) and research opportunities were identified. Twenty-seven institutes and centers within the NIH carry out the NIH's mission to improve the health of the country. Although NIDDK is the lead NIH institute that conducts research on digestive diseases, there are 9 other institutes that conduct research on digestive diseases. Several institutes conduct research on mechanisms and treatment of functional abdominal pain: the National Institute of Child Health and Human Development (NICHD), National Center for Complementary and Alternative Medicine (NCCAM), the National Institute of Mental Health (NIMH), and National Institute of Neurological Disorders and Stroke (NINDS).
NIDDK, NICHD, NCCAM, NIMH, and NINDS have supported research through the NIH's primary mechanism of support, the regular research grant mechanism, the RO1. The use of the RO1 mechanism by investigators has allowed them to unravel the underlying mechanisms of FGIDs. For example, several NIH-supported investigators have provided insights into the link between brain–gut and serotonin interaction in modulating pain perception in abdominal pain (4). Thus, NIH encourages investigators to become aware of funding opportunities that are published weekly in the NIH Guide. These funding opportunities may be in the form of program announcements (PA) or Request for Applications (RFA). These funding opportunities highlight the areas that the NIH has defined as priority areas for research.
The Functional Bowel Disorders Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition meeting stated that there is an urgent need for clinical studies and clinical trials in the area of functional abdominal pain in the pediatric population (5). In addition, they recommended the development of therapeutic agents to modulate the abnormalities in the sensorimotor function of the enteric nervous system in functional disorders to relieve specific symptoms that affect these children (6). To support the working group's recommendations, the NIDDK recently released the NIDDK Multicenter Clinical Study Implementation Planning Grant (U34). This mechanism, which is a 2-phase process, should help accelerate research in functional abdominal pain in children and is designed to permit early peer review of the rationale for the proposed clinical study, permit assessment of the design/protocol of the proposed study, provide support for the development of a complete study protocol and associated documents including a manual of operations, and support the development of other essential elements required for the conduct of a clinical study. The completion of the required products of a U34 grant is a prerequisite for submission of a multicenter clinical study cooperative agreement (U01) application (the second part of the process), which will support the actual conduct of the study (7).
NIDDK will accept, send out for peer review, and consider for funding applications for investigator-initiated, multicenter clinical studies from U34 awardees only, except when an exemption from this requirement has been obtained from NIDDK. An applicant who can demonstrate that all of the work required for submission of a multicenter clinical study proposal has been completed may request an exemption from the prerequisite of holding an U34 award before submitting the U01 application (8).
The materials developed in the U34 phase will allow the applicant to initiate study staff training followed by study subject recruitment soon after an expedited peer review and final NIDDK approval of the clinical study application. In order not to delay the initiation of the study, the peer review and award of grant should be completed within 4 months of the receipt of the application, when possible.
INCLUSION OF CHILDREN IN BIOMEDICAL RESEARCH
Aware that research in the area of disorders of children lagged far behind that in adults, the NIH has developed a policy for the inclusion of children in research. This policy was put into place after a jointly sponsored workshop by the NICHD and the American Academy of Pediatrics. The group concluded that there is a need to enhance the inclusion of children in clinical research. This conclusion was based upon scientific evidence, information demonstrating human need, and considerations of justice for children in receiving adequately evaluated treatments. The need reaches across a broad spectrum of disorders for which clinical research is needed, including studies on pharmaceutical and therapeutic agents; behavioral, developmental, and life cycle issues including childhood antecedents of adult disease; and prevention and health services research.
It is NIH policy that children (ie, individuals younger than 21 years) must be included in all human subjects' research that is conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all NIH-conducted or -supported research involving human subjects, including research that is otherwise “exempt” in accord with Sections 101(b) and 401(b) of Title 45 of the Code of Federal Regulations, Part 46, Protection of Human Subjects. The inclusion of children as subjects in research must be in compliance with all applicable subparts of 45 CFR 46, as well as with other pertinent federal laws and regulations (9). Therefore, proposals for research involving human subjects must include a description of plans for including children. If children will be excluded from the research, then the application or proposal must present an acceptable justification for the exclusion.
These guidelines reaffirm the commitment of the NIH to the fundamental principles of inclusion of children in research. This policy should result in a variety of new research opportunities to address significant gaps in knowledge about health problems, especially the condition of functional abdominal pain and irritable bowel syndrome in the pediatric age group.
During the last 2 decades, the NIH has taken steps to accelerate research in the area of pediatric disorders, including functional abdominal disorders. The pediatric research community is encouraged to take advantage of the funding opportunities that are periodically advertised in the NIH Guide. Furthermore, the pediatric research community is encouraged to take advantage of the U34 mechanism that NIDDK has launched to promote collaborative research in FGIDs.
1. American Academy of Pediatrics, Subcommittee on Chronic Abdominal Pain, North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. Chronic abdominal pain in children. Pediatrics 2005;115:e370–e381.
2. Hyams JS. Recurrent abdominal pain and irritable bowel syndrome in children. J Pediatr Gastroenterol Nutr 1997; 25(Suppl 1):S16–S17.
3. Drossman DA, Camilleri M, Mayer EA, et al
. AGA technical review on irritable bowel syndrome. Gastroenterology 2002; 123:2108–2131.
4. Cooke HJ. Role of the “little brain” in the gut in water and electrolyte homeostasis. FASEB J 1989; 3:127–138.
5. Hyams J, Colletti R, Faure C, et al
. Functional gastrointestinal disorders: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr 2002; 35(Suppl 2):S110–S117.
6. Veldhuyzen van Zanten SJ, Talley NJ, Bytzer P, et al
. Design of treatment trials for functional gastrointestinal disorders. Gut 1999; 45(Suppl 2):II69–II77.
7. NIDDK Multi-Center Clinical Study Implementation Planning Grants (U34), NIDDK PAR-08-057. NIH Guide
, December 18, 2007.
8. NIDDK Multi-Center Clinical Study Cooperative Agreement (U01), PAR-08-058. NIH Guide
. December 19, 2007.
9. National Institutes of Health Revitalization Act. Pub L No. 103-43, 107 Stat 126 (1993).