Overall/Regulatory
During the 19-year, the Food and Drug Administration (FDA) issued 42 written requests to study drug products for solid tumors and/or hematologic malignancies in the pediatric population. Of these studies included in 42 WRs, 29 were on pediatric solid tumors, 18 were on pediatric hematologic malignancies, and 5 of these WRs covered 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 issued in the WRs, the initial request dates, current status of each WR, the approved age range and languages related to WRs included in the labeling are shown in Table 1.
For the current status of the WRs, 15 out of 29 solid tumor WRs and 11 out of 18 hematologic malignancies WRs have completed (23 out of 42 WRs completed in total with 3 completed in 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. Four oncology drugs for the treatment of pediatric 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, 13 out of 16 solid tumor WRs and 5 out of 13 hematologic malignancy WRs 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. Two pediatric trials were terminated or released due to safety concerns (1 WRs) or enrollment difficulty (1 WR). Two WRs were completed; however, the timeline to submit had passed. Finally, 2 drugs have no remaining patent life. Therefore, there is no exclusivity to add.
Requests for amendments to the WRs were submitted to the FDA in 50% (21 WRs) of the 42 and 19% (8 WRs) were amended more than twice. Majority of the reasons for amending 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 submitting 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: Lists of Issued Written Requests (WRs) between Jan. 1, 2001 and Dec. 31, 2019
Under BPCA, WRs typically require studies to be conducted in more than one indication. FIGURE 1 shows the number of disease indication distributions for WRs on solid tumor and hematologic malignancies (1a and 1b). Numbers of disease cohorts in these WRs range from 1 to 6 disease cohorts.
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 on solid tumors, the upper right (1b) shows that on hematological malignancies. The x axis represents the number of disease cohorts, and the y axis shows the number of WRs. For number of patients enrolled, the bottom left panel (1c) shows the number of patients enrolled for trials on solid tumors, the bottom right panel (1d) shows that for trials on hematological malignancies. The x axis represents the number of patients, the y axis shows the drug names. White bars represent number of patients required in written requests, black bars represent number of patients that actually enrolled in clinical trials. The white bars for a few drugs are missing because patient accrual information in those written requests are not specified.
Among the pediatric trials initiated since 2001 in 42 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. These drugs are Dabrafenib (Tafinlar), Trametinib (Mekinist) for treatment of solid tumors; and Ruxolitinib, Midostaurin (Rydapt), Nilotinib (Tasigna) for treatment of hematologic malignancies (TABLE 2).
TABLE 2: Drugs and Conditions where the Study Design or Approval was based on Extrapolation from adult trials