and children, but their pathophysiology, severity, course, and response to treatment may differ for infants, children, and adolescents. Treatments that are safe and effective for adults may be dangerous or ineffective for children. Many of the examples cited in this report involve drugs, but clinically significant differences between children and adults extend to other areas. Radiation therapy can, for example, disrupt normal tissue development in children.

Clinical research involving infants, children, and adolescents is, in some important respects, more challenging than research involving adults. As reviewed in this chapter, these challenges include the relatively small numbers of children with serious medical problems, the need for developmentally appropriate outcome measures for children of different ages, the complexities of parental involvement and family decision making, and the adaptations required in research procedures and settings to accommodate children’s physical, cognitive, and emotional development. Understanding and complying with the special ethical and regulatory protections for children constitutes another challenge. These various challenges underscore the need for those reviewing research protocols that include children to have adequate expertise in different areas of child health and research.

The next sections of this chapter provide additional historical context; discuss definitions used for the periods of infancy, childhood, and adolescence in different research arenas; and expand on the rationale and complex challenges of pediatric research. The last sections describe government policies adopted in recent years to encourage research involving children while protecting them from research risks.


The ideal laboratory species for accumulating data on human functions and reactions is human, and that “animal of necessity” has been widely utilized in research in the biomedical sciences in the second half of the twentieth century.

Faden and Beauchamp, 1986, p. 152

If adult humans have been the “animal of necessity” in clinical research, then children have often been “therapeutic orphans,” as characterized over 35 years ago by clinical pharmacologist Harry Shirkey (1968, p. 119). To a considerable degree, children retain this disadvantaged status, despite the recent creation of policy incentives for clinical research involving children.

As described in Chapter 1, a survey of the 1991 edition of the Physician’s Desk Reference found that approximately 80 percent of the listed medications had labels that provided no prescribing information for

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