Section of Hematology/Oncology, Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada.
Department of Medical Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada.
JNCI Cancer Spectr. 2021 Jun 30;5(4). doi: 10.1093/jncics/pkab061. eCollection 2021 Aug.
The US Food and Drug Administration (FDA) introduced an Accelerated Approval (AA) pathway to expedite patient access to new drugs. AA accepts less rigorous trial designs, including single-arm studies (SAS), owing to perceived lack of feasibility of timely randomized controlled trials (RCTs).
We designed hypothetical RCTs with endpoints of overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) for FDA approvals based on SAS for solid tumors during 2010-2019. Existing standards of care served as controls. RCTs were designed to detect a difference with power of 0.80, α-error of 5% (2-sided), and 1:1 randomization. Accrual duration was estimated based on participation by less than 5% of eligible patients derived from cancer-specific incidence and mortality rates in the United States.
Of 172 (18.0%) approvals during the study period, 31 (18.0%) were based on SAS. Median sample size was 104 (range = 23-411), and 77.4% were AA. All studies reported ORR, 55% reported duration of response, 19.4% reported PFS, and 22.5% reported OS. Median sample sizes needed to conduct RCTs with endpoints of ORR, PFS, and OS were 206, 130, and 396, respectively. It would have been theoretically possible to conduct RCTs within duration comparable with that required by SAS for 84.6%, 94.1%, and 80.0% of approvals with endpoints of ORR, PFS, and OS, respectively.
An overwhelming majority of FDA approvals based on SAS should be feasible as RCTs within a reasonable time frame. Given the collateral harms to patients and to scientific rigor, drug approval based on SAS should only be permitted under exceptional circumstances.
美国食品和药物管理局（FDA）引入了加速批准（AA）途径，以加快新药物惠及患者。AA 接受了不太严格的试验设计，包括单臂研究（SAS），这是由于认为及时进行随机对照试验（RCT）不可行。
我们设计了假设的 RCT，终点为总缓解率（ORR）、无进展生存期（PFS）和总生存期（OS），基于 2010 年至 2019 年期间 FDA 对实体瘤的 SAS 批准。现有标准治疗作为对照。RCT 的设计目的是在双侧 5%的α错误率（2 侧）和 1:1 随机分组下，检测到 80%的效能差异。基于美国癌症特定发病率和死亡率，从合格患者中抽取不到 5%参与研究来估计入组时间。
在研究期间，有 172 项（18.0%）批准中有 31 项（18.0%）基于 SAS。中位样本量为 104（范围=23-411），77.4%为 AA。所有研究均报告了 ORR，55%报告了缓解持续时间，19.4%报告了 PFS，22.5%报告了 OS。需要进行 ORR、PFS 和 OS 终点的 RCT 样本量中位数分别为 206、130 和 396。理论上，在与 SAS 要求的时间相当的时间内，对 84.6%、94.1%和 80.0%的 ORR、PFS 和 OS 终点的批准进行 RCT 是可行的。
基于 SAS 的绝大多数 FDA 批准应该可以在合理的时间框架内作为 RCT 进行。鉴于对患者和科学严谨性的附带伤害，仅在特殊情况下才应允许基于 SAS 的药物批准。
