Tibau Ariadna, Romano Alejandra, Liu Ian T T, Han Jihye, Scheffer Cliff Edward R, Kesselheim Aaron S
Program On Regulation, Therapeutics, And Law (PORTAL), Division Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Harvard Medical School, Boston, Massachusetts, USA.
J Natl Cancer Inst. 2025 Jul 21. doi: 10.1093/jnci/djaf195.
The FDA's accelerated approval pathway expedites cancer drug approvals based on surrogate measures, while clinical benefit is assessed in post-approval confirmatory trials. Many confirmatory trials also rely on surrogate measures rather than overall survival (OS) or quality of life (QoL). We evaluated how often accelerated approvals demonstrate clinical benefits at the time of conversion to regular approval, and if not, how often OS, QoL, or substantial clinical benefit emerge post-conversion.
This retrospective cohort study reviewed FDA cancer drug accelerated approvals converted to regular approval (1992-2021), with follow-up through December 2024. We assessed confirmatory trial endpoints (OS and QoL) at conversion, and searched for updated evidence post-conversion. Clinical relevance was assessed using the ESMO-MCBS.
Of 77 confirmatory trials, 25 (32%) showed OS benefit at conversion; 52 (68%) relied on surrogate measures. After a median 5-year follow-up, OS benefit emerged for 7 (9%) additional indications. QoL benefit was shown in 9 (12%) confirmatory trials at conversion and in 4 (5%) post-conversion. Among 73 (95%) confirmatory trials scoreable by ESMO-MCBS, 34 (47%) met the substantial clinical benefit threshold at conversion. Of the 31 (97%) trials with a survival benefit evaluable by ESMO-MCBS, 19 of 24 (79%) met the threshold at conversion, and 5 of 7 (71%) post-conversion.
Once oncology drugs are converted from accelerated to full approval, new evidence of OS or QoL gains remain rare, underscoring the need to ensure such evidence is available at conversion. Patients should be informed of evidence variability, and the ESMO-MCBS can provide valuable guidance.
美国食品药品监督管理局（FDA）的加速批准途径基于替代指标加速癌症药物批准，而临床获益则在批准后的验证性试验中进行评估。许多验证性试验也依赖替代指标而非总生存期（OS）或生活质量（QoL）。我们评估了加速批准在转换为常规批准时显示临床获益的频率，若未显示临床获益，则评估转换后OS、QoL或显著临床获益出现的频率。
这项回顾性队列研究回顾了1992年至2021年期间从加速批准转换为常规批准的FDA癌症药物，并随访至2024年12月。我们在转换时评估验证性试验终点（OS和QoL），并在转换后搜索更新的证据。使用欧洲肿瘤内科学会临床获益量表（ESMO-MCBS）评估临床相关性。
在77项验证性试验中，25项（32%）在转换时显示OS获益；52项（68%）依赖替代指标。经过中位5年的随访，又有7项（9%）适应症出现OS获益。9项（12%）验证性试验在转换时显示QoL获益，并在转换后有4项（5%）显示QoL获益。在73项（95%）可通过ESMO-MCBS评分的验证性试验中，34项（47%）在转换时达到显著临床获益阈值；在31项（97%）可通过ESMO-MCBS评估生存获益的试验中，24项中的19项（79%）在转换时达到阈值，7项中的5项（71%）在转换后达到阈值。
一旦肿瘤药物从加速批准转换为完全批准，OS或QoL改善的新证据仍然很少，这凸显出在转换时确保有此类证据的必要性。应告知患者证据的变异性，ESMO-MCBS可提供有价值的指导。
