Fragility index of positive phase II and III randomised clinical trials of treatments for hepatocellular carcinoma (2002-2022)

Background & aims: The fragility index (FI), i.e., theminimum number of best survivors reassigned to the control group required to revert the statistically significant result of a clinical trial to non-significant, is a metric to evaluate the robustness of randomized controlled trials (RCTs). We aimed to assess the FI in the field of HCC.

Methods: This is a retrospective analysis of phase 2 and 3 RCTs for the treatment of HCC published between 2002 and 2022. We included two-arm studies with 1:1 randomization and significant positive results for a primary time-to-event endpoint for the FI calculation, which involves the iterative addition of a best survivor from the experimental group to the control group, until positive significance (p <0,05, Log-rank test) is lost.

Results: We identified 51 phase 2 and 3 positive RCTs, of which 29 (57%) were eligible for fragility index calculation. After reconstruction of the Kaplan-Meier curves, 25/29 studies remained significant, among which the analysis was performed. The median (interquartile range (IQR)) FI was 5 (2-10) and Fragility Quotient (FQ) was 3% (1%-6%). Ten trials (40%) had a FI of 2 or less. FI was positively correlated to the blind assessment of the primary endpoint (median FI 9 with blind assessment versus 2 without, p = 0.01), the number of reported events in the control arm (RS = 0.45, p = 0.02) and to impact factor (RS = 0.58, p = 0.003).

Conclusions: Several phases 2 and 3 RCTs in HCC have a low fragility index, underlying the limited robustness on the conclusion of their superiority over control treatments. The fragility index might provide an additional tool to assess the robustness of clinical trial data in HCC.

Impact and implications: The fragility index is a method to assess robustness of a clinical trial and is defined the minimum number of best survivors reassigned to the control group required to revert the statistically significant result of a clinical trial to non-significant. Among 25 randomised controlled trials in HCC, the median fragility index was 5, and 10 trials among 25 (40%) had a fragility index of 2 or less, indicating an important fragility.