• require more accommodation of the developmental variability of children (e.g., by requiring sponsors to try to develop age-appropriate formulations, if needed); or

• increase transparency (e.g., by requiring that sponsors submit New Drug Application supplements to add to the label information—whether negative or positive—from clinical trials).

KEY ELEMENTS SPECIFIED IN WRITTEN REQUESTS/
AMENDMENTS ISSUED FROM 1998 TO 2000

Requested trials:

– Dose-ranging trial with hypertensive pediatric patients

– Trial of pharmacokinetics (PKs) in children in four pediatric age groups (infants and toddlers, preschool-age children, school-age children, and adolescents)

– Safety data from a controlled trial with an open treatment phase following the trial or from some other comparable database with a summary of all available information on the safety of the drug in pediatric patients

Race: Ensure a mixture of black and nonblack patients.

Formulation: If no suspension/solution is available, a solid dosage form suspended in food could be used, if it has been shown to have acceptable bioavailability in adults.

Trial design: Randomized, double-blinded observation of parallel dose groups (it need not be successful, but it must be interpretable).

Four design options: A, B, C, and D (Figure E-1)

Trial Design A: Each patient is randomized to placebo or to one of three doses ranging from slightly less than the lowest approved adult dose to slightly greater than the highest approved adult dose. After 2 weeks of treatment, the trial would be analyzed by looking for a significantly positive slope of the placebo-corrected change in blood pressure from baseline as a function of dose. If the slope of this line is not differentiable from 0, the trial would be unsuccessful but it would be interpretable.

Trial Design B: Design B is similar to Design A, but without a placebo arm. If analysis revealed a significantly positive slope to the dose-response line, the trial would be successful. If, however, no dose-response is detected, the trial will be considered not interpretable and not responsive to the written request.

Trial Design C: To avoid the possibility of uninterpretable find-



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