Patient, Physician, and Assessor Blinding in Phase III Randomized Trials in Oncology: A Meta-Epidemiological Analysis.

BACKGROUND

Blinding mitigates bias in randomized trials and may be especially crucial for surrogate endpoints, such as progression-free survival (PFS). Here, we characterize utilization of and factors associated with blinding in Phase III oncology trials with PFS primary endpoints.

METHODS

Two-arm, superiority-design trials investigating systemic therapy were identified in May 2024 from ClinicalTrials.gov with no date limitation. Trials were required to have a PFS primary endpoint. The study outcomes were the presence of double-blind designs and blinded independent central review (BICR) for the primary endpoint. Ninety-five percent credible intervals for binary outcomes were estimated from beta distributions, and multivariable logistic regressions explored associations with trial-level features.

RESULTS

After screening, 237 trials were included, enrolling 127,518 patients. A double-blind design was used in 105 trials (44%, 95% CrI 38%-51%). BICR was used in 111 trials (47%, 95% CrI 41%-53%), including 39 double-blind trials (16%, 95% CrI 12%-22%). Trials with BICR had higher odds of meeting the primary endpoint (OR 1.84; 95% CI 1.06-3.18; p = 0.03). The PFS assessor identity (central vs. local) or blinding status was not reported in 50 trials (26%, 95% CrI 16%-27%). Trials that met prespecified significance criteria for PFS were more likely to report whether PFS assessors were blinded/unblinded and central/local (OR, 3.05; 95% Cl: 1.60-5.81; p = 0.0007).

CONCLUSIONS

Despite the importance of double blinding in combination with BICR for reducing bias, only a few trials blinded physicians, patients, and primary endpoint assessors. This meta-epidemiological study illuminates the prevalence of potential assessment biases affecting PFS in Phase III oncology and secondarily emphasizes the need for improved methodology reporting.