Tibau Ariadna, Cliff Edward R Scheffer, Romano Alejandra, Borrell Maria, Molto Consolacion, Kesselheim Aaron S
Program on Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Harvard Medical School, Boston, Massachusetts, USA.
EClinicalMedicine. 2025 May 31;84:103088. doi: 10.1016/j.eclinm.2025.103088. eCollection 2025 Jun.
The accelerated approval pathway allows the FDA to approve drugs for serious conditions based on promising surrogate measures, with confirmatory studies required later. If subsequent testing shows an unfavorable benefit-risk profile, the indication may be withdrawn. This study aimed to identify factors associated with the withdrawal of drug indications following accelerated approval.
In this retrospective cohort study, we identified FDA-approved drugs for solid and hematologic cancers from 1992 to 2022 and extracted factors present at the time of accelerated approval, including pivotal trial characteristics, outcomes, and confirmatory study initiation timing from drug labels and published reports. Clinical benefit was assessed using the European Society of Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS), with high benefit as A-B/4-5 and low as C/≤2. Multivariable logistic regression identified factors associated with drug indication withdrawal.
Among 167 accelerated approval indications for 113 anticancer drugs, by August 2024, 102 (61%) had been converted to regular approval, 31 (19%) were withdrawn, and the remaining 34 (20%) were ongoing accelerated approvals. Of the 133 indications that were either converted or withdrawn, 52 (39%) were approvals for hematologic cancer drugs, and 41 (31%) supported genome-targeted drug approvals. Among 83 eligible indications, 46 (55%) were granted Breakthrough Therapy designation. In the 133 pivotal trials, 112 (84%) used response rate as the primary endpoint, and 66% (86/130) offered low clinical benefit on the ESMO-MCBS. In multivariable analysis, Breakthrough Therapy designations (OR 0.26; 95% CI, 0.10-0.75; p = 0.01) and indications for genome-targeted therapies (OR 0.26; 95% CI, 0.08-0.80; p = 0.02) were associated with lower withdrawal rates. Higher withdrawal rates were associated with low ESMO-MCBS scores (OR, 4.63; 95% CI, 1.50-14.33; p = 0.008).
Accelerated approvals based on early data suggesting limited clinical benefit tend to have higher withdrawal rates, whereas therapies with Breakthrough Therapy designation and genome-targeted mechanisms are more likely to validate clinical benefits and achieve regular approval. Patients and healthcare providers should consider these factors when evaluating whether to use therapies granted accelerated approval.
Alfonso Martín Escudero Foundation (to AT) and Arnold Ventures, the Commonwealth Fund, and Kaiser Permanente Institute for Health Policy Research (to ASK).
加速批准途径允许美国食品药品监督管理局（FDA）基于有前景的替代指标批准用于严重病症的药物，随后需要进行确证性研究。如果后续测试显示获益风险比不佳，则该适应症可能会被撤销。本研究旨在确定与加速批准后药物适应症撤销相关的因素。
在这项回顾性队列研究中，我们确定了1992年至2022年期间FDA批准的用于实体癌和血液系统癌症的药物，并从药品标签和已发表报告中提取加速批准时存在的因素，包括关键试验特征、结果以及确证性研究启动时间。使用欧洲医学肿瘤学会临床获益程度量表（ESMO-MCBS）评估临床获益，高获益定义为A-B/4-5，低获益定义为C/≤2。多变量逻辑回归确定与药物适应症撤销相关的因素。
在113种抗癌药物的167个加速批准适应症中，截至2024年8月，102个（61%）已转为常规批准，31个（19%）被撤销，其余34个（20%）仍在进行加速批准。在133个已转为常规批准或被撤销的适应症中，52个（39%）是血液系统癌症药物的批准，41个（31%）支持基因组靶向药物的批准。在83个符合条件的适应症中，46个（55%）被授予突破性疗法认定。在133项关键试验中，112项（84%）使用缓解率作为主要终点，66%（86/130）在ESMO-MCBS上显示临床获益低。在多变量分析中，突破性疗法认定（比值比[OR]0.26；95%置信区间[CI]，0.10-0.75；p = 0.01）和基因组靶向疗法的适应症（OR 0.26；95% CI，0.08-0.80；p = 0.02）与较低的撤销率相关。较高的撤销率与ESMO-MCBS得分低相关（OR，4.63；95% CI，1.50-14.33；p = 0.008）。
基于早期数据显示临床获益有限的加速批准往往具有较高的撤销率，而具有突破性疗法认定和基因组靶向机制的疗法更有可能验证临床获益并获得常规批准。患者和医疗保健提供者在评估是否使用获得加速批准的疗法时应考虑这些因素。
阿方索·马丁·埃斯库德罗基金会（给AT）以及阿诺德风险投资公司、联邦基金和凯撒永久健康政策研究所（给ASK）。
