Inefficiencies and Patient Burdens in the Development of the Targeted Cancer Drug Sorafenib: A Systematic Review.
Inefficiencies and Patient Burdens in the Development of the Targeted Cancer Drug Sorafenib: A Systematic Review.
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DOI：
10.1371/journal.pbio.2000487
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发表时间：
2017-02
期刊：
影响因子：
9.8
通讯作者：
Kimmelman J
中科院分区：
文献类型：
--
作者：
Mattina J;Carlisle B;Hachem Y;Fergusson D;Kimmelman J
癌症药物开发的失败给患者和研究系统带来了沉重的负担。为了调查癌症靶向药物开发的效率低下和负担，我们对抗癌药物索拉非尼（Bayer/Onyx Pharmaceuticals）的所有预许可试验进行了系统评价。我们于2014年10月14日检索了Embase和MEDLINE数据库，以获得索拉非尼抗癌的预许可临床试验。我们通过严重不良事件发生率来衡量风险，通过客观缓解率和生存率来衡量获益，通过达到预先设定的主要终点和可接受的毒性来衡量试验成功。索拉非尼的前两个临床有用的应用是在前两个疗效试验中发现的，在5例药物相关死亡（108例中的4.6%）和93例患者-年（3，928例中的2.4%）之后。此后，索拉非尼在26种适应症和67种药物组合中进行了测试，导致额外的许可证。药物开发人员在5项以上的试验中测试了5种适应症，其中包括56例药物相关死亡（占108例的51.8%）和1，155例患者-年（占3，928例的29.4%）的负担，这些患者-年试图发现对这些恶性肿瘤的效用。总体而言，32项II期试验（占II期活动的26%）是重复的，缺乏适当的随访，或由于累积失败而无法提供信息，共有1，773例患者（占11，355例患者的15.6%）参与了索拉非尼预许可试验。索拉非尼的临床效用在开发早期就已确立，对患者和资源的负担较低。然而，这些早期的成功之后是对各种恶性肿瘤和联合治疗方案的快速和详尽的测试，导致患者负担过重。我们对索拉非尼开发的评估表明，在癌症药物开发中有许多机会降低成本和不必要的患者负担。许多研究受试者在不成功的药物开发项目中暴露于不安全和/或无效的治疗。然而，即使是成功的药物开发计划也会给研究对象带来沉重的负担。在这份手稿中，我们测量了参与抗癌药物索拉非尼（2005年首次获得美国食品和药物管理局批准）成功开发的研究受试者的风险和获益。在发现对索拉非尼有反应的前两种癌症类型后，药物开发人员和研究人员测试了索拉非尼对许多其他癌症类型以及与许多其他药物的组合。我们发现，研究人员能够快速发现索拉非尼对前两种癌症类型的效用，并且患者负担很小。此后，尝试将索拉非尼的临床应用扩展到其他癌症和药物组合，涉及许多患者和不良事件，并且大多是徒劳的。我们还发现，索拉非尼首次获批后进行的许多研究返回的科学信息有限，因为它们重复或信息不足。我们的研究结果表明，即使是成功的药物开发项目也会给患者带来巨大的负担;他们还指出了监管机构、研究人员和政策制定者可以提高研究对象风险效益比的方法。
Failure in cancer drug development exacts heavy burdens on patients and research systems. To investigate inefficiencies and burdens in targeted drug development in cancer, we conducted a systematic review of all prelicensure trials for the anticancer drug, sorafenib (Bayer/Onyx Pharmaceuticals). We searched Embase and MEDLINE databases on October 14, 2014, for prelicensure clinical trials testing sorafenib against cancers. We measured risk by serious adverse event rates, benefit by objective response rates and survival, and trial success by prespecified primary endpoint attainment with acceptable toxicity. The first two clinically useful applications of sorafenib were discovered in the first 2 efficacy trials, after five drug-related deaths (4.6% of 108 total) and 93 total patient-years of involvement (2.4% of 3,928 total). Thereafter, sorafenib was tested in 26 indications and 67 drug combinations, leading to one additional licensure. Drug developers tested 5 indications in over 5 trials each, comprising 56 drug-related deaths (51.8% of 108 total) and 1,155 patient-years (29.4% of 3,928 total) of burden in unsuccessful attempts to discover utility against these malignancies. Overall, 32 Phase II trials (26% of Phase II activity) were duplicative, lacked appropriate follow-up, or were uninformative because of accrual failure, constituting 1,773 patients (15.6% of 11,355 total) participating in prelicensure sorafenib trials. The clinical utility of sorafenib was established early in development, with low burden on patients and resources. However, these early successes were followed by rapid and exhaustive testing against various malignancies and combination regimens, leading to excess patient burden. Our evaluation of sorafenib development suggests many opportunities for reducing costs and unnecessary patient burden in cancer drug development. Numerous research subjects are exposed to unsafe and/or ineffective treatments in unsuccessful drug development programs. Yet, even successful drug development programs can involve heavy burdens for research subjects. In this manuscript, we measure risks and benefits for research subjects participating in the successful development of the anticancer drug sorafenib (first approved by the United States Food and Drug Administration in 2005). After discovering the first two cancer types responding to sorafenib, drug developers and researchers tested sorafenib against many other cancer types and in combination with many other drugs. We find that researchers were able to discover the utility of sorafenib for the first two cancer types quickly and with very little patient burden. Thereafter, attempts to extend the clinical application of sorafenib to other cancers and drug combinations involved many patients and adverse events and were mostly fruitless. We also find that many studies pursued after the first approval of sorafenib returned limited scientific information because they were duplicative or insufficiently informative. Our findings suggest that even successful drug development programs can entail substantial patient burden; they also point to ways that regulators, researchers, and policymakers can improve the risk-benefit ratio for research subjects.
影响因子：
3.4
作者：
LoConte, Noelle K.;Holen, Kyle D.;Schelman, William R.;Mulkerin, Daniel L.;Deming, Dustin A.;Hernan, Hilary R.;Traynor, Anne M.;Goggins, Timothy;Groteluschen, David;Oettel, Kurt;Robinson, Emily;Lubner, Sam J.
通讯作者：
Lubner, Sam J.