Methods
Selection of Studies
The information that has been summarized in this paper was gathered from
public information about the WRs that were issued by the FDA between the
dates of January 1, 2001, and December 31, 2019 in response to Proposed
Pediatric Study Requests (PPSRs). When the trials were completed and
final clinical summary reports submitted in response to WRs and made
available
(https://www.fda.gov/drugs/development-resources/written-requests-issued,
https://www.fda.gov/drugs/development-resources/list-determinations-including-written-request
and https://www.fda.gov/media/79154/download), a comprehensive
survey was conducted on the trial results and corresponding FDA reviews,
as well as published papers related to the pediatric studies. We
excluded those pediatric WRs submitted to the National Institute of
Child Health and Human Development, National Institutes of Health (NIH)
for off patent drugs.
Technical Information
For each WR, key information included , but was not limited to specific
pediatric cancer indications, feasibility of extrapolation from adults
trials, number of studies requested, number of cohorts, designs, and
phases of the studies (phase 1/2 dose-escalation/dose-finding, signal of
activity seeking, proof of concept phase 2 studies or phase 3), study
drugs (monotherapy, combination), study designs (single-arm or with
control, any blinding, dose levels and more), age eligibility , study
endpoints, number and reasons for amendments. For the trials submitted
to fulfill the WR, key information was captured, including patient
accrual in trials included the WR, statistical methods used for efficacy
evaluation, primary results, dose levels, starting dose selection,
pharmacokinetics (PK) / pharmacodynamics (PD) sampling and analysis,
unique dose-limiting toxicity (DLT) observed in children and special
formulations developed for children. Finally, the current status of the
WR was summarized, and whether or not pediatric exclusivity was granted.
A single WR generally contains more than one trial and more than one
cohort/indication, since the WRs are expected to address all possible
pediatric indications for which the investigational drug might provide a
public health benefit be included in the assessment of the drug. Because
labeling updates and regulatory actions are taken for an individual
drug, therefore, the results were summarized for each WR rather than
individual trials in the WR. The number of patients included in each WR
was obtained by summing the numbers of trial subjects among all trials
and cohorts/indications included in the WR. If any one of the trials has
a control/comparator arm, the WR is categorized as controlled. If any
one of the trials in WR employed monotherapy, the WR is categorized as
monotherapy.
In the trials, the primary and secondary endpoints, were grouped into
the following types: objective response rate endpoints, including
overall response rate (ORR), complete response rate (CR), and complete
remission (CR), which are binary; time to event (TTE) endpoints,
including overall survival (OS), disease-free survival (DFS), Event-free
survival (EFS) and progression-free survival (PFS); dose finding
endpoints, including determination of maximum tolerated dose (MTD), and
recommended phase 2 dose (RP2D); PK/PD endpoints; safety endpoints; and
any other endpoints, including change from baseline and unspecified or
exploratory efficacy endpoints.
Completed WRs are those where complete study report from the WR studies
were submitted to the FDA in the form of product supplement or labeling
revision as a sNDA/BLA. The completed WRs were categorized as such if
any of the following were met: exclusivity granted, denied exclusivity,
under review, completed but fail to submit reports according to timeline
required in the written requests, and completed but no remaining
exclusivity. In contrast, WRs were considered as “not completed” if
any of the following were met: terminated, listed as
withdrawal/released, or categorized as ongoing.
Unique DLTs are defined as DLTs that are either only found or found with
increased incidence in pediatric patients.
Because children differ from adult including capacities for drug
administration, medicine-related toxicity and taste preference,
different formulations for children may be required and the WR may
include special formulation development. This includes extemporaneous
compounding of marketed adult formulations for investigational use or a
required marketable formulation.