Oral antihypertensive trial design and analysis under the pediatric exclusivity provision

The Best Pharmaceuticals for Children Act provides a 6-year extension to the economic incentives offered to drug manufacturers under the Pediatric Exclusivity Provision, for providing requested information on drugs used in children, which includes >50 oral antihypertensive medications. Guidelines were published outlining specific requirements for the design and analysis of trials to provide the requested information.

We review the design and analysis requirements, along with recruitment and eligibility guidelines, for dose-ranging studies of oral antihypertensives in children in light of ethical and methodologic issues unique to pediatric research. We also discuss examples of trials conducted to date and the implications and limitations of legislative efforts.

Four possible trial types are outlined in the guidelines. Trial C, which uses a randomized withdrawal phase after treatment, has been used most often. Avoidance of a true placebo arm may enhance patient recruitment and minimize ethical concerns at the expense of a more complicated design and analysis. In addition, this trial involves little risk for manufacturers because patent extension does not depend on the outcome of the trial.

Studies being conducted under the Pediatric Exclusivity Provision will provide valuable information concerning dosing and efficacy for several antihypertensive medications used in children. New legislation may stimulate study of drugs without remaining patent life, but data on safety, long-term outcomes, and the youngest pediatric age groups are also needed for a full understanding of all issues pertinent to pediatric use.