Patient-Reported Outcomes in Pediatric Cancer Registration Trials: A US Food and Drug Administration Perspective

Abstract

Pediatric patient-reported outcome (PRO) data can help inform the U.S. Food and Drug Administration’s (FDA) benefit-risk assessment of cancer therapeutics by quantifying symptom and functional outcomes from the patient’s perspective. This study assessed use of PROs in commercial pediatric oncology trials submitted to FDA for regulatory review. FDA databases were searched to identify pediatric oncology product applications approved between 1997 and 2020. Sponsor-submitted documents were reviewed to determine whether PRO data were collected, which instruments were used, and the quality of collected data (sample size, completion rates, and use of fit-for-purpose instruments). The role of PROs in each trial (endpoint hierarchy) was also recorded, along with whether any PRO endpoints were included in product labeling. Seventeen pediatric oncology applications were reviewed, 4 included PRO data: Denosumab, Tisagenlecleucel, Larotrectinib, and Selumetinib. In these 4 instances, PROs served as exploratory endpoints and were not incorporated in product labeling. Trials collecting PRO data were Phase II or Phase I/II single-arm studies with sample sizes of 28 to 88 patients. Symptomatic Adverse Events were characterized using clinician-reported Common Terminology Criteria for Adverse Events (CTCAE) without additional patient self-report. PROs were infrequently utilized in pediatric cancer registration trials. When used, PRO data were limited by lack of a clear research objective and corresponding prospective statistical analysis plan. Contemporary PRO symptom libraries such as the National Cancer Institute’s Pediatric PRO-CTCAE may provide an opportunity to better evaluate the occurrence and impact of symptomatic Adverse Events, from the patient’s perspective, in pediatric oncology trials.

Longitudinal use of patient reported outcomes in pediatric leukemia and lymphoma reveals clinically relevant symptomatic adverse events

“…Evidence for the validity of the self-report version of the Ped-PRO-CTCAE has been previously documented, [11][12][13] and the 62 item Ped-PRO-CTCAE library of symptomatic AEs has now been endorsed by the US Food and Drug Administration for inclusion in pediatric oncology trials. 14 Prior studies have shown that children with LL are at increased risk for many symptomatic AEs and impaired HRQOL. [14][15][16][17][18] However, these findings have been limited by small sample sizes and a focus on broad areas of HRQOL rather than specific symptoms, and thus may not have captured the full symptom profile.…”

“…14 Prior studies have shown that children with LL are at increased risk for many symptomatic AEs and impaired HRQOL. [14][15][16][17][18] However, these findings have been limited by small sample sizes and a focus on broad areas of HRQOL rather than specific symptoms, and thus may not have captured the full symptom profile. A more detailed symptom profile is needed to help guide choice of PROs for clinical trials as well as to better understand the child's experience.…”

Clinical and humanistic burden among pediatric patients with neurofibromatosis type 1 and plexiform neurofibroma in the USA

“…To mitigate this limitation, questions on patients’ length of hospitalizations related to debulking surgeries were restricted to the three most recent hospitalizations. Additionally, the acute version of the PedsQL was used due to its shorter recall period (relative to the standard version), which reduces measurement error [ 35 ]. Second, among the 32 patients with debulking surgeries, 17 were reported by their caregivers to have received only partial resections.…”

Use of Daily Patient-Reported Outcome Measurements in Pediatric Cancer Care

“…In fact, less than 1% of pediatric clinical trials submitted to ClinicalTrials.gov and EudraCT (European Union Drug Regulating Authorities Clinical Trials) use PROMs as a primary end point. 6,7 Several shortfalls in pediatrics may be explained in part by (1) insecurity regarding the choice of the appropriate PROM questionnaire, (2) skepticism regarding PROM data collection, (3) inappropriate timing of assessment, and (4) inadequate statistical analysis and outcome interpretation. 8 The biggest hurdle to overcome in pediatrics, however, is the fact that the professional team needs to interact not only with the children, but also with their proxies.…”

“…JAMA Network Open. 2022;5(7):e2223701. doi:10.1001/jamanetworkopen.2022.23701 (Reprinted) July 26, 2022 10/10 Downloaded From: https://jamanetwork.com/ on 08/01/2022…”