Overall/Regulatory
During the 19-year period, the FDA issued 40 WRs to study drug products for solid tumors and/or hematologic malignancies in the pediatric population. Of the studies included in 40 WRs, 27 were for pediatric solid tumors, 18 were for pediatric hematologic malignancy, and 5 of the WRs included studies for both solid tumor and hematologic malignancies. The WRs that were identified include pediatric oncology trials conducted in pediatric patients from the neonatal period up to the age of 17. A few of the clinical trials included young adults up to the age of 30. The list of drugs for which WRs were issued, the initial request dates, current status of each WR, the approved age range and sections related to WRs included in the labeling are shown in Table 1. The table includes the information that is either listed from https://www.fda.gov/drugs/development-resources/list-determinations-including-written-request or https://www.fda.gov/media/79154/download or additional websites are included as footnotes in the table.
Fifteen out of 27 WRs that included solid tumor studies and 11 out of 18 WRs that included hematologic malignancies studies have been completed (23 out of 40 WRs completed in total, and 3 of the WRs included studies for both solid tumor and hematologic malignancies). Ninety-two percent (21/23) of the completed WRs submitted reports to the FDA in accordance with the timeline required in written requests. Three oncology drugs for the treatment of solid tumor or hematologic malignancies resulted in approval of the product for pediatric use added in the US prescribing information (USPI) specifically for pediatric age groups.
Of the completed WRs, 14 out of 15 WRs that include studies for solid tumors and 5 out of 11 WRs that include studies for hematologic malignancies have been granted 6-month exclusivity. One WR was denied exclusivity because of insufficient patients enrolled to assess the efficacy or for insufficient ability to inform a description of pharmacokinetic (PK) parameters. One pediatric trial was terminated or released due to enrollment difficulty (1 WR). Two WRs were completed; however, the timeline to submit had passed. Finally, 1 drug has no remaining patent life. Therefore, there is no exclusivity to add. A summary of pediatric exclusivity status for the completed WRs is shown in Table 2.
Requests for amendments to the WRs were submitted to the FDA in 53% (21 WRs) of the 40 and 20% (8 WRs) were amended upon request from the sponsor more than twice. The reasons for requests to amend a Written Request include a change in age distribution reflecting accrual expectations in practice, a cancelation of planned studies, an updated timeline, an increase or decrease in disease cohorts, and adjustment to the study endpoints (e.g. adding/removing a safety or efficacy endpoint and replacing MTD with RP2D). Other less common reasons for requesting amendments include a change of dose levels, a change of therapy, a change of formulations, and a change of statistical evaluation method or criteria.
TABLE 1: List of Issued Written Requests (WRs) between Jan. 1, 2001 and Dec. 31, 2019 (selected with public information)
TABLE 2: Summary of pediatric exclusivity status for the completed WRs
FIGURE 1. The distribution of disease cohorts for WRs and the number of patients enrolled for completed pediatric trials. The upper left panel (1a) shows the number of disease cohorts in solid tumor studies, the upper right (1b) shows that for studies of hematologic malignancies. The x axis represents the number of disease cohorts, and the y axis shows the number of WRs.
Among the pediatric trials initiated since 2001 in 40 WRs, extrapolation from adult trials was planned or used to support efficacy in pediatrics for 5 drugs, given similar underlying pathobiology and mechanism of action in pediatric patients and adults.