Institute for Management and Innovation, Master of Biotechnology Program, University of Toronto Mississauga, Mississauga, Ontario, Canada.
Department of Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, USA.
Hematol Oncol. 2021 Feb;39(1):105-113. doi: 10.1002/hon.2818. Epub 2020 Oct 28.
This study analyzed the risk of clinical trial failure for leukemia drug development between January 1999 and January 2020. The specific leukemia subtypes of interest were acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). Drug development was investigated using data obtained from https://www.clinicaltrials.gov and other publicly available databases. Drug compounds were excluded if they began phase I testing for the indication of interest before January 1999, if they were not industry sponsored, or if they treated secondary complications of the disease. Further analysis was conducted on biomarker usage, drug mechanisms of action, and line of treatment. Drugs were identified following our inclusion criteria for ALL (72), CLL (106), AML (159), and CML (47). The likelihood (cumulative pass rate), a drug would pass all phases of clinical testing and obtain Food and Drug Administration approval, was 18% (ALL), 10% (CLL), 7% (AML), and 12% (CML). Biomarker targeted therapies improved the success rates by three- and sevenfold, for ALL and AML, respectively. Enzyme inhibitors doubled the cumulative success rate for AML. First-line therapy and kinase inhibitors both independently doubled the cumulative success rate for CLL. Oncologists enrolling patients in clinical trials can increase success rates by up to sevenfold by prioritizing participation in trials involving biomarker usage, while consideration of factors such as drug mechanism of action and line of therapy can further double the clinical trial success rate.
本研究分析了 1999 年 1 月至 2020 年 1 月期间白血病药物开发临床试验失败的风险。关注的具体白血病亚型为急性淋巴细胞白血病（ALL）、慢性淋巴细胞白血病（CLL）、急性髓细胞白血病（AML）和慢性髓细胞白血病（CML）。使用从 https://www.clinicaltrials.gov 和其他公开可用数据库中获得的数据来研究药物开发。如果化合物在 1999 年 1 月之前开始针对目标适应证的 I 期试验、不是由行业赞助的或治疗疾病的次要并发症，则将其排除在药物开发之外。进一步分析了生物标志物的使用、药物作用机制和治疗线。在我们纳入 ALL（72）、CLL（106）、AML（159）和 CML（47）的标准下，对药物进行了鉴定。药物通过所有临床测试阶段并获得食品和药物管理局批准的可能性（累积通过率）为 18%（ALL）、10%（CLL）、7%（AML）和 12%（CML）。生物标志物靶向治疗使 ALL 和 AML 的成功率分别提高了三倍和七倍。酶抑制剂使 AML 的累积成功率提高了一倍。一线治疗和激酶抑制剂都使 CLL 的累积成功率独立提高了一倍。肿瘤学家通过优先参与涉及生物标志物使用的临床试验，可以将成功率提高多达七倍，而考虑药物作用机制和治疗线等因素可以进一步将临床试验成功率提高一倍。
