Survival Assessment by Central Review vs. Local Investigator in Metastatic Melanoma: A Systematic Review and...

Background: Although blinded independent central review (BICR) can reduce assessment variability, it introduces additional financial and logistical burdens to trial operations. This study analyzed the discrepancy indexes (DIs) to evaluate differences between progression-free survival (PFS) assessments by local investigators (LIs) and BICR in randomized clinical trials (RCTs) of patients with metastatic melanoma. Methods: A comprehensive literature search was conducted on PubMed, Embase, and Cochrane databases up to 30 June 2024. The primary outcome was the DI, which was calculated for each trial as a ratio of the hazard ratios (HR)_BICR by HR_LI. The agreement between PFS HRs was also evaluated using the intraclass correlation coefficient (ICC) and Pearson's correlation coefficient (r). Results: Twelve studies comprising 4915 patients were included in this study. Of these, 10 (83%) were Phase III, 11 (92%) were cutaneous melanoma, one was uveal, and all identified PFS as the primary endpoint. Most (86%) of the PFS comparisons yielded the same statistical inference by both BICR and LIs. The overall combined DI was calculated at 1.08 (95% CI: 1.01-1.15), indicating a statistically significant, numerically small difference in PFS evaluations driven primarily by the uveal Phase III double-blinded study, while there was a strong overall correlation [(ICC: 0.87, p < 0.001); (r = 0.89, 95% CI 0.67-0.96, p < 0.0001)]. Cutaneous melanoma trials demonstrated strong agreement between BICR and local investigator assessments. Conclusions: In randomized trials of metastatic cutaneous melanoma, LI-assessed PFS closely aligns with BICR and provides equivalent trial-level conclusions in most cases. These findings support the use of LI-assessed PFS as a valid and practical primary endpoint, without routine requirement for BICR. Central review should be reserved for selected scenarios.