Biomedical Ethics, McGill University, Montreal, Quebec, Canada.
Biomedical Ethics Unit / SSOM, McGill University, Montreal, Quebec, Canada
BMJ Open. 2020 Feb 17;10(2):e034306. doi: 10.1136/bmjopen-2019-034306.
After regulatory approval, drug companies, public funding agencies and academic researchers often pursue trials aimed at extending the uses of a new drug by testing it in new non-approved indications. Patient burden and clinical impact of such research are not well understood.
We conducted a retrospective cohort study of postapproval clinical trials launched within 5 years after the drug's first approval, testing anticancer drugs in monotherapy in indications that were first pursued after a drug's first Food and Drug Administration (FDA) license, for all 12 anticancer drugs approved between 2005 and 2007. FDA, Medline and Embase search date 2019 February 12.
Our primary objective was to measure burden and clinical impact for patients enrolling in these trials. Each trial was sorted into a 'trajectory' defined by the drug and cancer indication. The risk was operationalised by proportions of grade 3-4 severe adverse events and deaths. The clinical impact was measured by estimating the proportion of patients participating in trajectories that resulted in FDA approval, uptake into National Comprehensive Cancer Network (NCCN) clinical practice guidelines or advancement to randomised controlled trials within 8 years.
Our search captured 104 published trials exploring monotherapy, including 69 unique trajectories. In total, trials in our sample enrolled 4699 patients. Grade 3-4 adverse events were experienced by 19.6% of patients; grade 5 events were experienced by 2.8% of patients. None of the trajectories launched after initial drug approval received FDA approval. Five trajectories were recommended by the NCCN within 8 years of the first trial within that trajectory. Eleven trajectories were advanced to randomised controlled testing.
The challenges associated with unlocking new applications for drugs that first received approval from 2005 to 2007 were similar to those for developing new drugs altogether. Our findings can help inform priority setting in research and provide a basis for calibrating expectations when considering enrolment in label-extending trials.
监管部门批准后，制药公司、公共资助机构和学术研究人员通常会开展旨在通过在新的未经批准的适应证中测试新药来扩大新药用途的试验。人们对这类研究对患者的负担和临床影响知之甚少。
我们对药物首次批准后 5 年内启动的上市后临床试验进行了回顾性队列研究，在所有 2005 年至 2007 年间批准的 12 种抗癌药物中，研究了单药治疗在药物首次获得美国食品药品监督管理局（FDA）批准后首次探索的适应证中的抗癌药物。FDA、Medline 和 Embase 搜索日期为 2019 年 2 月 12 日。
我们的主要目标是衡量入组这些试验的患者的负担和临床影响。每个试验都被归入由药物和癌症适应证定义的“轨迹”。风险通过 3-4 级严重不良事件和死亡的比例来确定。临床影响通过估计在 8 年内导致 FDA 批准、纳入国家综合癌症网络（NCCN）临床实践指南或推进至随机对照试验的轨迹中参与的患者比例来衡量。
我们的搜索共捕获了 104 项探索单药治疗的已发表试验，包括 69 个独特的轨迹。在我们的样本中，试验共纳入了 4699 名患者。19.6%的患者出现 3-4 级不良事件；2.8%的患者出现 5 级不良事件。最初药物批准后启动的任何轨迹均未获得 FDA 批准。在该轨迹内首次试验后的 8 年内，有 5 个轨迹被 NCCN 推荐。11 个轨迹被推进到随机对照测试。
与开发全新药物相比，解锁 2005 年至 2007 年首次获得批准的药物的新应用所面临的挑战类似。我们的发现可以帮助为研究设定优先顺序，并为考虑参加扩大标签试验时调整期望提供依据。
