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.