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1 Introduction D ecades of research have demonstrated that children do not respond to medications in the same way as adults. Although few would argue that children should receive medications that have not been adequately tested for safety and efficacy, the majority of drugs prescribed for children—50 to 75 percent—have not been tested in pediatric popula- tions (Budetti, 2003; Roberts et al., 2003; FDA, 2006). Without adequate data from such testing, prescribing drugs appropriately becomes chal- lenging for clinicians treating children, from infancy through adolescence. The Institute of Medicine’s Forum on Drug Discovery, Development, and Translation held a 1-day workshop, Addressing the Barriers to Pediatric Drug Development, on June 13, 2006, to identify barriers to the develop- ment and testing of drugs for pediatric populations, as well as to examine ways in which the system can be improved to facilitate better treatments for children. Participants included representatives from the U.S. Food and Drug Administration (FDA), the National Institutes of Health, the American Academy of Pediatrics, the pharmaceutical industry, academia, and several patient advocacy groups. Response to Drugs in Various Age Groups Differences between children and adults in the metabolism, renal clearance, other drug disposition mechanisms, and overall response to medications are due to profound anatomical, physiological, and develop- mental differences (Kearns et al., 2003; McKinney, 2003). Substantial varia- 

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 ADDRESSING THE BARRIERS TO PEDIATRIC DRUG DEVELOPMENT tion also exists among children of different ages in their ability to metabo- lize, absorb, excrete, and transform medications (ICH, 2000; Roberts et al., 2003). As noted above, however, minimal information is available on the safety and efficacy of drugs in pediatric patients, and the younger the age group, the more likely this is to be the case (Roberts et al., 2003). Recent studies of medications for pediatric patients have revealed several unsuspected differences in efficacy by age group. For example, a study by the Pediatric AIDS Clinical Trials Group compared combinations of drugs for treating children with HIV. Results indicated that a regi- men of two daily doses of nelfinavir (Viracept) was pharmacokinetically superior to three daily doses, particularly in smaller, younger children. These were unexpected and positive findings for clinicians attempting to increase medication adherence and reduce the development of drug resistance (Floren et al., 2003; McKinney, 2003). Product Labeling Because most drugs prescribed for children have not been tested in pediatric populations, important information on their risks and appro- priate use for these patients is not available on the product labels. These labels provide health care professionals with details on the use of the drugs, including information from carefully controlled clinical studies. Poor labeling is often an indicator of inadequate study. Off-label use occurs when drugs are prescribed for purposes other than those included under the terms of the FDA product approval (Roberts et al., 2003). Off- label use of drugs is common in adults but far more prevalent in children. While such use can be beneficial to the patient, it can also result in adverse reactions due to a lack of understanding of the drug’s pharmacokinetics in this population. Current laws employ both incentives and mandates to encourage drug makers to test their products in pediatric populations and to enhance the pediatric information provided on drug labels. The result has been a substantial increase in pediatric drug trials, with corresponding infor- mation being added to the labels for 115 drugs. Examples of drugs for which labeling changes have affected dosing and risk include loratadine ( ­ Claritin) and fluvoxamine maleate (Luvox). In a single-dose pharmaco­ kinetic study of pediatric subjects (age 2 to 5 years) it was found that children receiving a 5-mL dose of CLARITIN Syrup containing 5 mg of loratadine had comparable range of pharmacokinetic parameters (AUC and Cmax) to adults and older children who had received a tablet or syrup containing 10 mg of loratadine. Likewise, fluvoxamine maleate, used to treat ­obsessive-compulsive disorder, was found to be most effec- tive in adolescents at the recommended adult dose, but girls aged 8 to 11

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INTRODUCTION  were found to need a smaller dose (approximately half the values seen in the male patients) (Roberts et al., 2003). Despite increases in the testing of drugs in pediatric populations, a pressing need for more study remains. Although incentives exist to study new, on-patent drugs, some argue that additional incentives are needed, especially to encourage testing of older drugs that are off-patent. The two existing laws that address the need to study drugs in pediatric populations—the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA)—will sunset in October 2007 with- out congressional action. ORGANIZATION of THIS summary The following chapters summarize the presentations and discus- sions at the workshop. Chapter 2 reviews the regulatory framework for pediatric drug development and testing, summarizing BPCA and PREA and their impact. Chapter 3 addresses challenges to the development of drugs for children, including the barriers posed by ethical concerns, eco- nomic obstacles, and logistical and technical issues; the difficulty of devis- ing appropriate formulations; and issues of dosing, bioavailability, and drug response. Chapter 4 considers the potential adaptation of existing models—such as vaccine development, European regulatory models, and the approach used by St. Jude Children’s Research Hospital to develop oncology drugs—to enhance pediatric drug development. The final chap- ter summarizes participants’ suggestions for solutions and next steps. Fluvoxamine dosing was not based on body-weight. After the starting dose of 25 mg, the fluvoxamine dosing was titrated according to clinical response and tolerance, and the result- ing fluvoxamine dose was in a range of 50–200 mg/day (on a bid schedule) in a 10-week study. In a pharmacokinetic study, consistent with clinical observations, fluvoxamine expo- sure (AUC and Cmax at steady state) was significantly higher in younger female patients compared to those in the corresponding age group of male patients. Hence, the label says that therapeutic effects in female children may be achieved with lower doses. Subsequent to this workshop, both BPCA and PREA were reauthorized by Congress as part of the Food and Drug Administration Amendments Act of 2007, Public Law 110-85, which was signed by the President in September 2007.