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A s is true for many pediatric illnesses, the treatment of hypertension in childhood has been hampered by a paucity of data regarding antihypertensive drug pharmacokinetics and efficacy in children. Although nearly all antihypertensive agents have been used to treat hypertensive children, until recently only a few of these agents had been systematically studied in children, and few drug manufacturers included pediatric dosing recommendations in their published prescribing information. If a physician wishes to use a new drug or a drug without a manufacturer’s pediatric dose recommendation, he or she must adapt adult doses, a practice that is fraught with numerous potential problems. Hypertensive children in need of pharmacologic treatment could truly be considered “therapeutic orphans,” with each prescription written an experiment with a single subject. Fortunately, two recent developments have produced large quantities of new data that should rectify this situation and improve the treatment of hypertensive children. The first of these has been the publication of several relatively large single-center experiences with the use of newer antihypertensive agents in children. Although such studies suffer from important design flaws, including selection bias and lack of control groups, these “real-life” experiences add important information that may be lacking in industry-sponsored trials, especially use of a greater variety of doses and long-term tolerability. It may be necessary to combine the results of these studies with those of industry-sponsored trials to gain full understanding of how a particular antihypertensive should be used in children. The second development is the passage of the Food and Drug Modernization Act of 1997 (FDAMA) in the US, which amended the Federal Food, Drug and Cosmetic Act. Section 111 of FDAMA created incentives for pharmaceutical companies to conduct clinical trials in children. The mechanism established by FDAMA and later extended by the Best Pharmaceuticals for Children Act (BPCA) calls on the Food and Drug Administration (FDA) to determine whether a drug has potential health benefits in children, then issue a written request to that drug’s manufacturer to conduct a pediatric trial. In return for completing the trial and fulfilling the requirements set out in the written request, an additional 6 months of market exclusivity would be granted by the FDA. This mechanism applies both to drugs already on the market at the time of passage of FDAMA, and to drugs developed later. Although pediatric clinical trials are notoriously difficult and expensive to conduct due to the relative rarity of conditions such as hypertension in children compared to adults, the economic rewards of an additional half-year of market exclusivity makes this an extremely powerful incentive for manufacturers to sponsor pediatric trials. (A second provision of FDAMA, the so-called Pediatric Rule, would have made it mandatory for all new drugs to be studied in children as part of the drug approval process. This provision was struck down in October 2002 in US District Court on the grounds that the FDA lacks the legal authority to impose requirements for pediatric testing on drug manufacturers.) Early results indicate that FDAMA is proving to be a success. Over 260 written requests have been issued for compounds believed to have potential health benefits in children, and pharmaceutical companies in response to these requests have sponsored dozens of clinical trials. With respect to antihypertensive compounds, nearly two dozen written requests have been issued by the FDA, and pediatric clinical trials have been completed or are underway in response to nearly 75% of these requests (Table 1). Furthermore, nearly every completed study has resulted in granting of additional market exclusivity. More important, dissemination of the results of these studies by publications in scientific journals should provide valuable guidance to physicians who prescribe these medications to children. However, the FDAMA process will not necessarily produce the types of data that pediatricians require, nor will it answer all of the scientific questions of interest. For example, although manufacturers are required to conduct pediatric studies, they are not required to develop ageappropriate drug formulations, meaning that some drugs will be proven effective in the context of a trial but impossible to administer in practice. Drug doses and

Successes and shortcomings of the food and drug modernization act