Benefit, burden, and impact for a cohort of post-approval cancer combination trials
Benefit, burden, and impact for a cohort of post-approval cancer combination trials
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DOI：
10.1177/1740774519873883
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发表时间：
2019-10-03
期刊：
影响因子：
2.7
通讯作者：
Kimmelman, Jonathan
中科院分区：
文献类型：
--
作者：
Carlisle, Benjamin Gregory;Doussau, Adelaide;Kimmelman, Jonathan
背景：在获得批准后，药物开发人员通常会进行旨在通过与其他药物结合来扩展新药使用的试验。人们对这种研究的风险和益处知之甚少。研究方法：为了建立风险和获益的历史基准，我们在Medline和Embase中检索了在食品和药物管理局批准的2005-2007年首次获得许可的12种抗癌“指标”药物的5年内联合使用抗癌药物的临床试验。基于3级或以上药物相关不良事件评估风险;基于疗效结局和联合用药进入临床实践指南或获得美国食品药品监督管理局批准的进展评估获益。结果如下：我们收集了323项已发表的探索联合用药的批准后试验，包括266项独特的联合用药适应症配对，招募了29，835例患者。在联合用药组和对照药物组之间随机分配的试验中，归因于研究药物的治疗相关3-4级严重不良事件和死亡的汇总风险比分别为1.54（1.33-1.79）和1.51（1.16-1.97）。总生存期和无进展生存期的合并风险比分别为0.99（0.92-1.05）和0.85（0.79-0.93）。在首次药物批准后推出的组合适应症配对中，没有一种获得食品和药物管理局的批准，13种配对（4.9%）在该配对中首次试验的5年内由国家综合癌症网络推荐。在我们的样本中，参与美国食品和药物管理局批准或国家综合癌症网络指南推荐的试验的患者比例为12.7%，随访5年，配对中有22.3%，随访8年。结论：在总生存期方面，治疗组患者与对照组患者一样可能受益，但在批准后的联合治疗试验中，他们更可能经历治疗相关的严重不良事件。
Background: After approval, drug developers often pursue trials aimed at extending the uses of a new drug by combining it with other drugs. Little is known about the risk and benefits associated with such research. Methods: To establish a historic benchmark of risk and benefit, we searched Medline and Embase for clinical trials testing anti-cancer drugs in combination within 5 years of approval by the Food and Drug Administration of 12 anti-cancer "index" drugs first licensed 2005-2007 inclusive. Risk was assessed based on grade 3 or above drug-related adverse events; benefit was assessed based on efficacy outcomes and advancement of combinations into clinical practice guidelines or approval by the Food and Drug Administration. Results: We captured 323 published post-approval trials exploring combinations, including 266 unique combination-indication pairings and enrolling 29,835 patients. The pooled risk ratios for treatment-related grade 3-4 severe adverse events and deaths attributed to the study drugs for trials randomized between a combination arm and a comparator were 1.54 (1.33-1.79) and 1.51 (1.16-1.97), respectively. The pooled hazard ratios for overall survival and progression-free survival were 0.99 (0.92-1.05) and 0.85 (0.79-0.93), respectively. None of the combination-indication pairings launched after initial drug approval received approval by the Food and Drug Administration, and 13 pairings (4.9%) were recommended by the National Comprehensive Cancer Network within 5 years of the first trial within that pairing. The proportion of patients in our sample who participated in trials leading to an approval by the Food and Drug Administration or a National Comprehensive Cancer Network guideline recommendation was 12.7% with 5 years of follow-up, and 22.3% among pairings for which there were 8 years of follow-up. Conclusion: Patients were just as likely to benefit in the treatment arm as the control arm in terms of overall survival, but they were more likely to experience a treatment-related severe adverse event in post-approval trials of combination therapy.