VOL. 62, No. 4, APRIL 2001

Labeling Antihypertensive Agents for Children

INTRODUCTION In the past several years, legislation has been enacted to generate more infor- mation concerning the dosing and safety of drugs in infants and children. As a result, the number of therapeutic entities undergoing evaluation in this vulner- able patient population has increased markedly. To date, well over 100 written requests have been proffered by the US Food and Drug Administration (FDA) to various drug manufacturers, directing the types of studies that will be required to obtain pediatric labeling for their products. More than 30 of these drugs have been granted pediatric exclusivity, resulting in extensions of patent protection for these agents. Among the written requests that have been granted pediatric exclusivity are more than a dozen for antihypertensive agents.

Certainly, primary hypertension is a significant cause of morbidity and, in some cases, mortality in adults. A tremendous amount of research has been conducted concerning the pathogenesis and pathophysiology of essential hy- pertension in adult patients. Armed with this information and decades of thera- peutic experience in the treatment of hypertension, the development of new drugs for this clinical indication proceeds in accordance with fairly standard protocols promulgated by the FDA with the support of the various pharmaceu- tical manufacturers.

When the time came to evaluate some of these drugs in infants and children in response to the FDA’s written requests, the paradigm began to unravel. At first there was great excitement on the part of pediatric nephrologists, pediatric cardiologists, and pediatric pharmacologists because a mandate would now foster the generation of the much-needed data that would permit the safe and effective use of the drugs that were currently available (and being used) in infants and children. However, when the protocols began to appear, they were indistinguishable from those used to evaluate these same drugs in adults with hypertension. Most of the initial protocols were written to evaluate these agents in children with essential hypertension, a rare entity. In contrast, most of the infants and children requiring antihypertensive treatment are patients with hypertension secondary to other clinical problems. These patients were excluded from the studies.

When this problem was discussed with pharmaceutical companies and their contract research organizations (CROs), the answer invariably was that the FDA dictated the process. The FDA, of course, remained open to input but had no venue through which to receive it. Several antihypertensive agents have been evaluated in pediatric patients. The development programs have been arduous, slow, and expensive, and, in the end, have provided little information concerning the use of these agents in the patients for whom dosing and safety data are so desperately needed. For all parties involved-the FDA, pharma-

281

CURRENT THERAPEUTIC RESEARCH@

ceutical manufacturers, CROs, and clinical investigators-this has been a learn- ing experience. We have learned a great deal already, and we hope to learn more as we move forward.

As a participant in some of these trials, I was struck by the paucity of infor- mation available to the FDA and drug manufacturers who were developing these trials. It seemed that there was a need to provide an overview of hyper- tension in children and some understanding of the current treatment ap- proaches. Certainly, a compendium of such information would have been useful to the “pioneers” at the various drug companies who struggled to design and complete these trials.

With this need in mind, I have prevailed on a number of experts in the fields of pediatric nephrology and pediatric clinical pharmacology to provide us with some of the fundamental information concerning the pathogenesis of hyper- tension in children and the current approaches to its treatment, and to identify the missing data required to use the currently available drugs safely and effec- tively. The following articles reflect the efforts of this dedicated group of clinician-scientists, who support the efforts of the FDA and the pharmaceutical industry to respond to the needs of children through the provision of dosing guidelines based on carefully conducted clinical trials. The articles are followed by some practical recommendations concerning protocol design, target popu- lations, and outcome measures.

It is hoped that, in the future, symposia like this one can be presented during the early phases of drug development to ensure that the proper drugs are being evaluated in the most appropriate patient groups, using optimal end points.

Jeffrey L. Blumer, PhD, MD Section Editor Trials in Pediatric Populations

282