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E
Written Requests for Studies of
Pediatric Hypertension: Longitudinal
Changes in FDA Specifications
Jennifer Li*
T
he analysis presented here examines written requests for clinical
studies issued by the Food and Drug Administration (FDA) to inves-
tigate potential drug treatments for pediatric hypertension. It begins
with a summary of key elements in the written requests issued in the first
30 months after pediatric exclusivity provisions became effective in July
1998. The subsequent summaries describe key elements that either modified
specifications (e.g., by more precisely describing safety follow-up) or added
to them (e.g., by creating requirements for interim analyses). Some changes
were required by legislation (e.g., registration of trials at ClinicalTrials.gov
or documentation of a failed attempt to develop a new formulation).
FDA began with a basic template for the written requests for clinical
studies to investigate drug treatments for pediatric hypertension. In general,
the changes in elements of the template for both new and amended requests
tended to have a few common purposes. They might
• add precision (e.g., by specifying a 1-year period for safety follow-
up or by specifying minimum percentages of individuals of particu-
lar age or racial subgroups enrolled in trials);
• require more rigor in trial designs (e.g., by dropping the option for
a trial with no placebo and only alternative doses of the test drug
or by increasing the statistical power of trials to detect a clinically
meaningful effect);
* Jennifer Li, M.D., is a member of the study committee.
381
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382 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN
• 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 ap-
proved adult dose to slightly greater than the highest approved
adult dose. After 2 weeks of treatment, the trial would be ana-
lyzed 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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383
APPENDIX E
A Type A Design B Type B Design
High High
Medium
Medium
Low
Placebo Low
Placebo
Lead In Lead In Double Blind
Controlled Phase
Type C Design Type D Design
C D
High
High
Placebo
Lower Doses
Medium
Medium
Placebo
Placebo
Low
Low Titration to Placebo
Placebo Maximum Dose Controlled Phase
Placebo
Lead In Double Blind
Controlled Phase
FIGURE E-1 Trial design options for pediatric hypertension trials provided for by
FDA written requests. High, medium, and low refer to dose levels.
Figure E-1.eps
SOURCE: Reproduced with permission from Smith et al. (2008). See also Benjamin
et al. (2008).
ings, Design C consists of Design B modified to include a ran-
domized withdrawal phase. Patients would be recruited and
treated like those in the trial with Design B. At the end of a
2-week treatment period, patients would be rerandomized in a
blinded fashion to continue to their assigned treatments or be
withdrawn to placebo. A slope analysis would be used for the
first phase and then, if the dose-response curve is flat, an analysis
of the second phase would determine whether a blood pressure
effect existed. The result would be considered interpretable no
matter what the outcome, so long as the sample size for the
withdrawal phase was adequate.
– Trial Design D: Design D uses randomized withdrawal. Patients
would be force-titrated to maximal tolerated doses and then
randomly withdrawn to lower doses, including placebo.
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384 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN
Ages: Adolescents and at least 50 percent of subjects 6 to 12 years
•
of age or ≤Tanner 3
Statistical considerations: 80 percent power to detect a treatment
•
effect of conventional statistical significance (p = 0.05)
PKs from infants and toddlers, preschool-age children, school-age
•
children, and adolescents: Traditional or sparse sampling can be
chosen, and for the parent drug and each metabolite, estimate
bioavailability (area under the concentration-time curve), half-life,
maximum concentration of drug in plasma (Cmax), and time to
Cmax in the various age groups.
Labeling change: Appropriate sections of the label may be changed
•
to incorporate the findings of the studies.
CHANGES ADDED OR ELEMENTS MODIFIED IN SOME OR ALL
NEW REQUESTS OR AMENDMENTS FROM 2001 TO 2003
Safety data: One-year follow-up is specified, with all available
•
information (published and unpublished) to include information
on adverse events, growth (change in head circumference, weight,
length, or height), and development (milestones, school perfor-
mance, neurocognitive testing) at baseline and 1 year.
Age groups: 25 percent of participants should be infants to pre-
•
school age.
Race: Black enrollment is specified to be 40 to 60 percent of total
•
enrollment.
Age-appropriate formulation: An age-appropriate formulation or
•
documentation of an attempt to obtain an age-appropriate formu-
lation, if the attempt was unsuccessful, is required.
Statistical considerations: The ability to detect a 3-mm-Hg blood
•
pressure change with 90 percent power is required.
Efficacy endpoints: For the trial designs other than randomized
•
withdrawal from active drug (see above), the primary efficacy
measurement should be the change in blood pressure from baseline
to the end of the treatment period plus the interdosing interval
(trough). For randomized withdrawal trial designs, the primary
efficacy measurement should be the change in blood pressure from
the last on-treatment visit to the end of the withdrawal period.
CHANGES ADDED OR ELEMENTS MODIFIED, 2006
Interim analyses allowed to assess variability according to a pre-
•
specified rule to adjust the sample size to achieve the specified
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385
APPENDIX E
target power: This interim analysis must be performed with >90
percent of the initially planned enrollment. Options for estimating
variability are (1) a blinded, pooled analysis of all groups, (2) a
blinded analysis of one group, or (3) a partially unblinded analysis
within each group (performed by an independent third party).
Dissemination of information: Summaries of medical and clinical
•
pharmacology reviews are posted on the FDA website.
CHANGES ADDED OR ELEMENTS MODIFIED, 2009
Trial design: Two types
•
– Type A: randomized, double-blind parallel, placebo and two
doses
– Type B: two active doses with randomized withdrawal (same as
Trial Design C described above but with two doses)
Statistical considerations: The primary endpoint must be either
•
absolute or the percent change in systolic or diastolic pressure. The
statistical approach used will depend on the specific trial design;
but broadly, the sponsor can allocate alpha to each active arm in
the placebo-controlled comparison or to some combination of
treatment arms (highest, two doses), or the sponsor can look for a
positive slope in the dose-response relationship.
Sample size: The trial program must have a total of no less than
•
200 patients in the 6- to 16-year-old age groups and no less than
50 patients in the 1- to 5-year-old age groups.
Formulation: If reasonable attempts to develop a commercially
•
marketable formulation have failed, the sponsor must develop and
test an age-appropriate formulation that can be compounded by
a licensed pharmacist, in a licensed pharmacy, from commercially
available ingredients. The sponsor must document attempts and
reasons that attempts failed. If the reasons are accepted and studies
are conducted with the compounded formulation product, the label
must include detailed compounding information.
Dissemination of information: The written request and medical,
•
statistical, and clinical pharmacology reviews will be posted on the
FDA website, and the trial will be registered at ClinicalTrials.gov.
Labeling: Regardless of whether the studies demonstrate that the
•
drug is safe and effective or whether the results of such studies with
the pediatric population are inconclusive, the sponsor must submit
labeling to include information about the results of the studies.
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386 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN
REFERENCES
Benjamin, D. K., Jr., P. B. Smith, P. Jadhav, J. V. Gobburu, D. Murphy, V. Hasselblad, C. Baker-
Smith, R. M. Califf, and J. S. Li. 2008. Pediatric Antihypertensive Trial Failures: Analysis
of End Points and Dose Range. Hypertension 51(4):834-840. http://hyper.ahajournals.
org/content/51/4/834.full.pdf+html (accessed December 7, 2011).
Smith, P. B., J. S. Li, D. Murphy, R. M. Califf, and D. K. Benjamin, Jr. 2008. Safety of pla-
cebo controls in pediatric hypertension trials. Hypertension 51(4):829-833. http://hyper.
ahajournals.org/cgi/reprint/51/4/829 (accessed December 7, 2011).
