Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montreal, QC, Canada.
Clin Trials. 2020 Feb;17(1):18-29. doi: 10.1177/1740774519873883. Epub 2019 Oct 3.
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.
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.
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.
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.
药物研发者在获得批准后，通常会开展试验，尝试将新药与其他药物联合使用，以扩大其应用范围。然而，人们对这种研究的风险和获益知之甚少。
为了确定风险和获益的历史基准，我们检索了 Medline 和 Embase 中 2005 年至 2007 年间首次获批的 12 种抗癌“索引”药物获得食品药品监督管理局批准后 5 年内，针对抗癌药物联合用药的临床试验。风险评估基于 3 级或以上的药物相关不良事件；获益评估基于疗效结局和联合用药进入临床实践指南或获得食品药品监督管理局批准的情况。
我们共捕获了 323 项已发表的获批后试验，探索了联合用药，包括 266 种独特的联合用药指征组合，共纳入 29835 例患者。与对照组相比，随机分组至联合用药组和对照组的试验中，与研究药物相关的 3-4 级严重不良事件和因药物相关死亡的治疗风险比分别为 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汇总风险比分别为 0.99（0.92-1.05）和 0.85（0.79-0.93）。初始药物获批后推出的联合用药指征组合均未获得食品药品监督管理局批准，在最初试验后 5 年内，仅有 13 种组合（4.9%）被国家综合癌症网络推荐。在我们的样本中，5 年随访期内有 12.7%的患者参与了导致食品药品监督管理局批准或国家综合癌症网络指南推荐的试验，而在 8 年随访期内，这一比例为 22.3%。
在总生存期方面，接受联合治疗的患者与对照组患者同样可能获益，但在获批后联合治疗的试验中，他们更有可能出现治疗相关的严重不良事件。
