Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland.
Department of Epidemiology and Biostatistics, University of California, San Francisco.
JAMA Intern Med. 2023 May 1;183(5):435-441. doi: 10.1001/jamainternmed.2023.0190.
Idelalisib is a first-in-class phosphatidylinositol 3-kinase inhibitor that received US Food and Drug Administration accelerated approval in July 2014 as a single-agent treatment for relapsed follicular lymphoma (FL) and small lymphocytic lymphoma (SLL). Serious adverse effects were reported in 2016 leading to termination of postmarketing registry trials. However, idelalisib remained on the market until 2022 when Gilead voluntarily withdrew the drug for the accelerated approval indication.
Evaluate the regulatory oversight of the accelerated approval pathway and evidence generation for idelalisib during premarketing (2008-2014), postmarketing (2014-2016), and premarketing withdrawal periods (2016-2022).
ClinicalTrials.gov, FDA.gov, PubMed database.
Clinical trials investigating the safety and effectiveness of idelalisib.
Study characteristics and relative risk (RR) of safety outcomes were abstracted. Data were pooled using random effects meta-analysis. The analysis was performed in October of 2022.
Trial status, recruitment status, publication status, serious adverse events (SAEs), fatal adverse events (FAEs), and all-cause mortality.
Overall, 31 idelalisib trials met selection criteria. In total, 20 of 30 (65%) included SLL and/or FL; 13 (42%) trials were completed, 13 (42%) had published results, and 7 (23%) were randomized clinical trials (RCTs). Overall, 6 RCTs of idelalisib had publicly available data on safety outcomes. By the initial postmarketing period (2016), the cumulative RR for SAEs was 1.86 (95% CI, 1.63-2.11), for FAEs was 3.30 (95% CI, 1.56-7.00), and for death was 1.35 (95% CI, 0.85-2.12). In the premarketing withdrawal period, only a single phase 3 trial was enrolling patients for FL and was terminated. However, idelalisib was not withdrawn from the market until 2022. Gilead reported cumulative sales revenue of $842 million during market authorization (2014-2022) and annual sales had a steady decline from $168 million to $62 million during the premarketing withdrawal period (2016-2021).
Findings of this systematic review and meta-analysis show that serious risks of SAE, FAE, and death with idelalisib treatment were evident by 2016. However, idelalisib remained on the market for another 6 years, with minimal evidence generation. It was voluntarily withdrawn for FL and SLL accelerated approval indications coinciding with decreasing revenue generation. Closer attention for safety and effectiveness of drugs reaching market by accelerated approval is needed.
伊德拉利昔布是一种首创的磷脂酰肌醇 3-激酶抑制剂，于 2014 年 7 月获得美国食品和药物管理局加速批准，作为复发性滤泡性淋巴瘤 (FL) 和小淋巴细胞性淋巴瘤 (SLL) 的单一药物治疗方法。2016 年报告了严重的不良反应，导致上市后注册试验终止。然而，伊德拉利昔布仍在市场上销售，直到 2022 年吉利德公司自愿撤回该药的加速批准适应症。
评估伊德拉利昔布在上市前 (2008-2014 年)、上市后 (2014-2016 年) 和上市前撤回期间 (2016-2022 年) 的加速批准途径的监管监督和证据生成情况。
ClinicalTrials.gov、FDA.gov、PubMed 数据库。
研究伊德拉利昔布安全性和有效性的临床试验。
提取研究特征和安全性结果的相对风险 (RR)。使用随机效应荟萃分析对数据进行汇总。分析于 2022 年 10 月进行。
试验状态、招募状态、出版状态、严重不良事件 (SAE)、致命不良事件 (FAE) 和全因死亡率。
总体而言，31 项伊德拉利昔布试验符合入选标准。其中 20 项 (65%) 包括 SLL 和/或 FL；13 项 (42%) 试验完成，13 项 (42%) 有出版结果，7 项 (23%) 为随机临床试验 (RCT)。总体而言，6 项伊德拉利昔布 RCT 有公开的安全性结果数据。到最初的上市后时期 (2016 年)，SAE 的累积 RR 为 1.86 (95%CI，1.63-2.11)，FAE 为 3.30 (95%CI，1.56-7.00)，死亡为 1.35 (95%CI，0.85-2.12)。在上市前撤回期间，只有一项针对 FL 的 III 期试验正在招募患者，并已终止。然而，伊德拉利昔布直到 2022 年才从市场上撤出。吉利德报告称，在市场授权期间 (2014-2022 年) 的累计销售收入为 8.42 亿美元，在上市前撤回期间 (2016-2021 年) 的年销售额从 1.68 亿美元稳步下降至 6200 万美元。
本系统评价和荟萃分析的结果表明，到 2016 年，伊德拉利昔布治疗的 SAE、FAE 和死亡的严重风险已经明显。然而，伊德拉利昔布在市场上又销售了 6 年，几乎没有产生任何证据。它自愿撤回了 FL 和 SLL 的加速批准适应症，恰逢收入下降。需要更加关注通过加速批准进入市场的药物的安全性和有效性。
