NEW REGULATIONS FOR PEDIATRIC LABELING OF PRESCRIPTION DRUGS

Table 1. Pediatric Information for New Molecular Entities Approved by the Food and Drug Adrninistration The term "pediatric patients" would include those from birth to 16 years of age. As a guide, the FDA provides age breakdowns as follows: birth-I month, I month-2 years, 2-12 years, and 12-16 years. Although these breakdowns were considered "inevitably arbitrary," each of these age groups can be heterogenous. For example, the age range of I month-2 years may be too broad. The total body clearance of theophylline increases with age up to 12 months,3 while that of midazolam increases up to 3 months.4 In addition, although the pharmacokinetics of ibuprofen were similar in two age groups of children «I y vs. >5 y), the antipyretic response was not.5 Although the FDA requires a description of risks associated with inactive ingredients in the dosage form, such risks may be unknown at the time of drug approval. Finally, it may not be possible in some cases to extrapolate data from adults to predict therapeutic outcomes in pediatric patients. Uniform enforcement of the new regulations will be difficult. For example, how will it be decided (1) whether the disease and the drug effects are sufficiently similar in adults and pediatric patients; or (2) whether the drug is widely used, represents a safety hazard, or is therapeutically important in the pediatric population? If the FDA has concluded the latter to be true, the agency "may require that the sponsor develop and/or submit pediatric use information."· If the sponsor fails to provide pediatric use information, the FDA may consider the drug to be misbranded or falsely labeled and constitute an unapproved or unlicensed product. However, how accurate would be the labeling statements prepared from various studies that had used different designs and methodologies? If previous studies were done with extemporaneous formulations, would the sponsor be required to market a liquid or intravenous formulation suitable for use in pediatric patients? Although the rule states, "Because this final rule does not impose additional requirements for sponsors to conduct EFFECTIVE JANUARY 12, 1995 the Food and Drug Administration (FDA) implemented revised regulations for labeling of prescription drugs for pediatric patients. Under the previous requirements issued in 1979, pediatric labeling normally required "substantial evidence derived from adequate and well-controlled studies in the pediatric population."· Although the creation of a "Pediatric use" subsection was intended to encourage drug labeling in this population, only 19% of the new molecular entities contained pediatric use information in the labeling at the time of approval during 1991-1995 (Table 1). Too often a statement such as, "Safety and effectiveness in children have not been established," appears in the labeling for many drugs frequently used in pediatric patients. This may either discourage the use of important drugs or lead to suboptimal therapy in infants, children, and adolescents. Under the new rule, the sponsors (i.e., the pharmaceutical industry) "must reexamine existing data to determine whether the Pediatric use subsection of the labeling can be modified based on adequate and well-controlled studies in adults, and other information supporting pediatric use, and if appropriate, submit a supplemental application to comply with new rule by December 13, 1996."· Furthermore, the sponsor is expected to "develop and/or submit" data if the drug is widely used, represents a safety hazard, or is therapeutically important in pediatric patients. The new regulations would allow labeling of drugs for pediatric use based on adequate and well-controlled studies in adults and additional supporting studies dealing with pharmacokinetics, pharmacodynamics, and safety in pediatric patients, "provided that the course of the disease and the drug effects are sufficiently similar in the pediatric and adult populations."· The rule clearly states, "Pediatric use subsection of the labeling must include any limitations on the pediatric indication, need for specific monitoring, specific hazards of the drug, differences between pediatric and adult responses to the drug, and other information related to the safe and effective use of the drug in pediatric patients."· The new regulations appear to be a step in the right direction to encourage labeling of more drugs for pediatric patients. However, certain issues need to be clarified.