Methods
Selection of Studies
The information that has been summarized in this paper was gathered from
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 studies were completed and final clinical
summary reports submitted in response to WRs, a comprehensive survey was
conducted on the study 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
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, types and phases
of the studies (phase 1/2 dose-escalation/dose-finding, signal of
activity seeking or phase 3), study drugs (monotherapy, combination),
study designs (single-arm or with control, any blinding, dose levels and
more), age range, study endpoints, number and reasons for amendments.
For the studies submitted to fulfill WR, key information was captured,
including patient accrual in the trials supporting 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 written request generally contains more than one study and more
than one cohort/indication since the statutory language requires that
all possible pediatric indications for which the investigational drug
might provide clinical benefit be included in the assessment of the
drug. Because labeling updates and regulatory actions are taken for
individual drug, therefore, the results were summarized for each WR
rather than individual studies in WR. The number of patients included in
each WR was obtained by summing the numbers of study subjects among all
studies and cohorts/indications included in the WR. If any one of the
studies has a control/comparator arm, the WR is categorized as
controlled. If any one of the studies in WR employed monotherapy, the WR
is considered that the monotherapy activity was established.
In the study, the primary and secondary endpoints, were grouped into the
following types: 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 is defined as DLTs that are only found in pediatric
patients. This excludes those observed in adult DLTs or adult adverse
reactions.
Because children differ from adult including capacities for drug
administration, medicine-related toxicity and taste preference,
different formulation for children may be needed through requirement of
special formulation development. This includes different formulations
from marketed adult formulations, for example hazardous-substance-free
ingredients for children, different administrative solutions (such as
oral solution for small children that are unable to swallow tablets),
and special developments (such as different shapes and colors to
increase palatability.)