Statistical fragility of findings from randomized phase 3 trials in pediatric oncology.

e23003 Background: The fragility index (FI) and survival-inferred fragility index (SIFI) have been proposed as adjunctive metrics to facilitate interpretation of p-values in clinical trials. FI/SIFI is the number of patients on a positive (p < 0.05) trial’s experimental arm who would need to switch from “responder/non-event” to “non-responder/event” to cause p > 0.05. Fragility indices have been reported previously in medical oncology, with median values < 10 often seen in the literature. This metric has not been studied in pediatric oncology trials. Methods: PubMed was used to identify randomized phase 3 pediatric oncology trials published between 1980-2020. We report trial characteristics and calculate FI for trials with a binary outcome and SIFI for trials with a time-to-event outcome. We also report the fragility quotients (FQ and SFQ) to normalize FI and SIFI relative to trial size. Results: 113 trials included sufficient data for analysis. The median FI for trials with a binary outcome (n = 40) was 4.5 (range: 1-33). The median SIFI for trials with a time-to-event outcome (n = 73) was 13 (range: 0-61). The FI or SIFI was less than the number of patients lost to follow-up in 25% of 36 trials. Median FQ = 0.026 and SFQ = 0.03, indicating that revised outcome in 2.6% or 3% of trial participants would be sufficient to alter the trial conclusion. FQ and SFQ did not significantly vary according to trial characteristics. While sample sizes increased over time (mean 187, 1980s; mean 437, 2010s), FQ and SFQ remained stable between 2-3%. Conclusions: The statistical conclusions of pediatric oncology phase 3 trials hinge on a relatively small number and proportion of patients. Despite sample size limitations of low prevalence diseases, pediatric cancer trials appear similarly or less fragile than adult oncology trials. Fragility was similar for large versus small trials and remained constant over four decades. [Table: see text]