Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Harvard Center for Bioethics, Harvard Medical School, Boston, MA.
J Natl Cancer Inst. 2020 Apr 1;112(4):335-342. doi: 10.1093/jnci/djz211.
The US Food and Drug Administration's accelerated approval and later withdrawal of bevacizumab in patients with metastatic breast cancer (mBC) is a seminal case for ongoing debates about the validity of using progression-free survival (PFS) as a surrogate measure for overall survival (OS) in cancer drug approvals. We systematically reviewed and meta-analyzed the evidence around bevacizumab's regulatory approval and withdrawal in mBC.
We searched for all published phase II or III clinical trials testing bevacizumab as a first-line therapy for patients with mBC. Data were extracted on trial demographics, interventions, and outcomes. Descriptive analysis was stratified by whether the trial was initiated before, during, or after the accelerated approval. We used a cumulative random-effects meta-analysis to assess the evolution of evidence of the effect of bevacizumab on PFS and OS. We estimated the association between the trial-level PFS and OS effect using a nonlinear mixed-regression model.
Fifty-two studies were included. Trial activity dramatically dropped after the accelerated approval was withdrawn. Eight clinical trials reported hazard ratios (hazard ratios) and were meta-analyzed. The cumulative hazard ratio for PFS was 0.72 (95% CI = 0.65 to 0.79), and the cumulative hazard ratio for OS was 0.90 (95% CI = 0.80 to 1.01). The regression model showed a statistically nonsignificant association between PFS benefit and OS benefit (β = 0.43, SE = 0.81).
The US Food and Drug Administration's decision-making in this case was consistent with the evolving state of evidence. However, the fact that seven clinical trials are insufficient to conclude validity (or lack thereof) for a trial-level surrogate suggests that it would be more efficient to conduct trials using the more clinically meaningful endpoints.
美国食品和药物管理局（FDA）加速批准贝伐珠单抗用于转移性乳腺癌（mBC），并随后撤回该适应证，这是关于将无进展生存期（PFS）作为癌症药物批准中总生存期（OS）替代终点的有效性的持续争论中的一个重要案例。我们系统地回顾和荟萃分析了贝伐珠单抗在 mBC 中的监管批准和撤回的证据。
我们搜索了所有已发表的测试贝伐珠单抗作为 mBC 一线治疗的 II 期或 III 期临床试验。提取了试验人群统计学、干预措施和结果的数据。根据试验是在加速批准之前、期间还是之后启动，对数据进行了分层。我们使用累积随机效应荟萃分析来评估贝伐珠单抗对 PFS 和 OS 影响的证据演变。我们使用非线性混合回归模型来估计试验水平 PFS 和 OS 效应之间的关联。
共纳入 52 项研究。在加速批准被撤回后，试验活动急剧下降。有 8 项临床试验报告了风险比（hazard ratios），并进行了荟萃分析。PFS 的累积风险比为 0.72（95%CI=0.65 至 0.79），OS 的累积风险比为 0.90（95%CI=0.80 至 1.01）。回归模型显示 PFS 获益与 OS 获益之间存在统计学上无显著关联（β=0.43，SE=0.81）。
在这种情况下，美国 FDA 的决策与证据的发展状况一致。然而，有七个临床试验不足以得出试验水平替代终点的有效性（或缺乏有效性），这表明使用更具临床意义的终点进行试验效率更高。
