Brown Gabrielle, Msaouel Pavlos, Miller Avital M, Kouzy Ramez, Lin Timothy A, Abi Jaoude Joseph, Ludmir Ethan B, Sherry Alexander D
Division of Radiation Oncology, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Cancer Med. 2025 Aug;14(15):e71097. doi: 10.1002/cam4.71097.
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.
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.
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).
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.
盲法可减轻随机试验中的偏倚，对于无进展生存期（PFS）等替代终点可能尤为关键。在此，我们描述了以PFS为主要终点的III期肿瘤试验中盲法的使用情况及相关因素。
2024年5月从ClinicalTrials.gov中识别出调查全身治疗的双臂优效性设计试验，无日期限制。试验要求有PFS主要终点。研究结果为双盲设计的存在情况以及主要终点的盲态独立中央审查（BICR）情况。二元结果的95%可信区间由贝塔分布估计得出，多变量逻辑回归探讨与试验水平特征的关联。
筛选后，纳入237项试验，共招募127,518名患者。105项试验采用了双盲设计（44%，95% CrI 38%-51%）。111项试验采用了BICR（47%，95% CrI 41%-53%），其中包括39项双盲试验（16%，95% CrI 12%-22%）。采用BICR的试验达到主要终点的几率更高（OR 1.84；95% CI 1.06-3.18；p = 0.03）。50项试验（26%，95% CrI 16%-27%）未报告PFS评估者身份（中央 vs. 本地）或盲法状态。达到PFS预设显著性标准的试验更有可能报告PFS评估者是否处于盲态/非盲态以及是中央/本地评估者（OR，3.05；95% Cl：1.60-5.81；p = 0.0007）。
尽管双盲结合BICR对于减少偏倚很重要，但只有少数试验对医生、患者和主要终点评估者进行了盲法处理。这项元流行病学研究揭示了影响III期肿瘤试验中PFS的潜在评估偏倚的普遍性，并进而强调了改进方法报告的必要性。
