Historically, submissions to the Food and Drug Administration (FDA) have been based on safety and efficacy data obtained from clinical trials conducted in adults with limited or no data from children. As a result, pediatricians and other health care professionals have relied on empiric therapeutic strategies, largely the consequence of treatment on a trial-and-error basis. In essence, the absence of information in the product label forces pediatricians to choose between avoiding the use of a medication that may be beneficial and using a medication “off-label” in the absence of evidence-based safety and efficacy data with the accompanying potential for ineffective and harmful outcomes.

During the past fifteen years, new federal laws and regulations have increased the level of scientific and clinical rigor of investigations aimed at ensuring that the use of medications by children is, indeed, safe and effective. Interested readers are referred to a detailed chronology of events occurring between 1994 and 2002 (1), and a contemporary discussion of the issues surrounding more recent legislative activities, such as the Pediatric Research Equity Act (PREA) of January 2003 (2). In general, it is recognized that growth and development are accompanied by changes in the physiological and biochemical processes determining drug disposition and response, for example, drug absorption, distribution, metabolism, excretion, and targets of drug response (3). However, the acquisition of information that can inform safe and efficacious use of medications in children of different ages or developmental stages has been a relatively recent development, increasing dramatically in recent years as a consequence of the various legislative initiatives. It is now apparent that extrapolation of adult data to pediatric populations is quite inappropriate because drug clearance may be greater than or, in some cases, less than that observed in adults (4). Thus, even though weight-based dosing strategies are becoming more sophisticated and have improved abilities to use adult data to infer drug clearance in children (5), they are unlikely to provide consistent dosing guidelines across all pediatric age groups or chemical classes. This is largely due to the variability in the developmental patterns of expression of the various drug-metabolizing enzymes and transporters involved in the disposition of individual compounds. Furthermore, evidence that the response to some medications may be different in children relative to adults despite comparable drug exposure is beginning to accrue (e.g., buspirone [4]), implying that age-related differences in drug targets and downstream signal transduction pathways may also be present.