Pediatric gastroenterologists in the United States are routinely faced with the dilemma of treating children with therapies that have not been approved by the United States Food and Drug Administration (FDA). As a consequence, we may either deny our patients the benefit of potentially efficacious medications and therapeutic advances, or treat them guided by anecdotal experience or impressions extrapolated from adult studies. In both situations pediatric patients are placed at a potential disadvantage regarding their clinical care. In the past, children in the United States have not benefited from the regulatory mandates that required pharmaceutical companies to conduct well-controlled clinical trials to demonstrate safety and efficacy of new drugs and biologics in adults. Because of the lack of pediatric studies, more than three-quarters of the drugs approved in the United States are either not labeled, or are inadequately labeled, for use in pediatric patients (1). Fortunately, in the past decade changes have occurred that may reverse these inequities.
First, a culture shift has led to an appreciation that it is not only ethical, but also in the best interest of children to conduct well-designed and well-executed pediatric clinical trials. Second, the US Food and Drug Administration (FDA) has developed policies intended to promote pediatric clinical trials. In 1997, the Food and Drug Administration Modernization Act (FDAMA) was passed. This Act provided pharmaceutical companies the financial incentive of a 6-month extension of patent or marketing exclusivity if they conducted pediatric clinical trials for approved drugs that met the requirements of a written request (2). One year later, the FDA's Pediatric Rule mandated that manufacturers obtain data to support pediatric use before submitting new drug applications (3). Controversy surrounding the Pediatric Rule recently occurred when free-market advocacy groups filed a lawsuit challenging the FDA's authority and claiming that the rule would delay new drug approvals. In March 2002 the FDA reported that it would not fight the lawsuit and that it was suspending the Pediatric Rule. Following great criticism by the pediatric medical community and other child-health advocates the FDA reversed its decision one month later under pressure from its supervisory body, the Department of Health and Human Services (DHHS) (4).
As of May 2002, the FDA has issued 246 written requests for pediatric studies and companies are currently conducting over 400 pediatric clinical trials in response to these requests (2). In contrast, only 71 pediatric studies were filed with the FDA from 1991 to 1996, and of these, only 11 were completed. Unfortunately, less than 6% of the FDA's written requests since 1997 have targeted gastrointestinal products.
FDAMA's success in generating pediatric studies has been tempered by the fact that its incentives are only effective with products in which exclusivity has the greatest value. Additionally, once exclusivity is granted based on studies of older children, there is no incentive to study very young children in whom pharmacokinetics are most likely to differ from those of adults. In January 2001, the DHHS submitted a report to the U.S. Congress supporting FDAMA's renewal with modifications that would address some of its shortfalls (2). DHHS's recommendations led to the Best Pharmaceuticals for Children Act signed into law in January 2002. This new legislation renews the exclusivity incentives and delineates procedures to study off-patent drugs, adds neonates to the definition of the pediatric age group, and establishes a research fund for the study of drugs that no longer have exclusivity or patent protection (2).
Although we applaud the FDA's efforts to promote pediatric clinical trials, the policies have actually been a double-edged sword. While the number of studies involving children has indeed increased, many of them have been uncontrolled trials of a single treatment strategy. To augment the FDA's efforts and to advance the care of children with gastrointestinal diseases, pediatric gastroenterologists need to design and execute large, controlled pediatric clinical trials. Many of the opportunities and challenges involved in such trials were recently discussed in a course on Clinical Trials in Pediatric Gastroenterology, held in April 2002 in Baltimore, Maryland. This course, sponsored by The Johns Hopkins School of Medicine, brought together individuals with an interest in clinical trials in pediatric gastroenterology, hepatology, and nutrition from academia, the private sector, federal agencies, and industry. As the participants reviewed topics such as motility disorders, inflammatory bowel disease, peptic diseases, malabsorptive syndromes, hepatitis, cholestatic liver disease, and obesity, the lack of well-designed clinical trials involving children was appallingly evident.
It became clear that, regardless of the clinical problem, several key issues impeding research were common to all. Inadequate infrastructure, insufficient research education, lack of financial support for multicenter pediatric studies, and small patient populations with serious disorders are issues that require solutions in academic institutions, pharmaceutical companies, and funding agencies. Institutions with centralized clinical trials offices to oversee and support clinical research have experienced greater growth in the number of industry-sponsored trials than institutions that continue to leave the details of clinical research up to individuals or departments (5). It also became clear that the development of workable national and international collaboration was going to be essential to promote research in conditions with small populations of patients. To learn about collaborative group models we can turn to such successful models as the Children's Cancer Group and the Pediatric Oncology Group. The impact of these national collaborative research organizations on the outcome of childhood cancers has been dramatic (6). Individual efforts in promoting clinical trials in children can be augmented by our own pediatric gastroenterology societies, which should play key roles in educating the public and in advocating for increased federal support and funding.
The field of pediatric gastrointestinal disease has rapidly expanded in the past two decades and the future holds much promise for improving and refining the therapeutic options for children. If we are to continue to make advances in treating childhood gastrointestinal diseases, well-designed and well-executed studies of therapies and strategies are essential. We hope that future conferences will stimulate networking and cooperation in clinical research, and lead to the formation of collaborative research groups that will develop badly needed multicenter trials in pediatric gastroenterology. Only then will we be able to truly integrate scientific evidence into our clinical practice and thus provide the best care possible for children.
1. Committee on Drugs. Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Pediatrics 1995; 95:286–294.
3. Food and Drug Administration. Regulations requiring manufacturers to assess the safety and effectiveness of new drugs and biological products in pediatric patients; Final Rule. Fed Regist 1998; 63:66631–66672.
4. Marshall E. Challenge to FDA's authority may end up giving it more. Science 2002; 296:820–21.
5. Abzug MJ, Esterl EA. Establishment of a clinical trials office at a children's hospital. Pediatrics 2001; 108:1129–34.
6. Bleyer WA. The U.S. pediatric cancer clinical trials programmes: International implications and the way forward. Eur J Cancer 1997; 33:1439–47.