Adverse drug events in children: the US Food and Drug Administration perspective

Abstract

Background: Adverse events are unwelcome occurrences associated with drug use. Some of these events are predictable or preventable, whereas others are idiosyncratic. The “off-label” use of drugs in pediatric patients further complicates the assessment of adverse events because pediatric dosing based on recommended adult doses may not be appropriate. Adverse events often occur in pediatric patients in an environment of incomplete information about the drug's pharmacokinetics in the pediatric population, and the inherent metabolic differences between adults and children may not be detected with extrapolating maneuvers. Adverse event information may be acquired during the drug development process, including the preclinical, preapproval, and postapproval processes. However, the lack of clinical trials in pediatric patients indicates that such information is not available. Objective: This paper reviews the pharmacologic basis for the different types of adverse events in children and adults and provides examples of the differences between these 2 groups. Methods: Data from spontaneous reports of adverse events that support a trend may assist with initiating and identifying an early signal for an adverse event and an assessment of its occurrence. We summarized our experience with the exclusivity initiative aimed at improving the acquisition of knowledge about use of drugs in children. We also summarized the data available from some spontaneous adverse event reports as well as examined pertinent literature to provide state-of-knowledge information on the specific adverse events. Results: Of the first 16 products that were subsequently studied in children, 6 (37.5%) had significant changes in labeling that had an impact on safety or efficacy. Specifically, we were able to identify situations in which proposed dosing could have led to overdosing or underdosing. We also identified situations in which adverse events, previously undescribed, could be expected. Conclusions: This information provides a better understanding of potential reasons for adverse events and defines unique pediatric adverse events. The exclusivity initiative supports the need for formal studies in the pediatric population if the therapy is to be used in children.