Clinical Trial Evidence Supporting FDA Approval of Novel Therapeutic Agents, 2005-2012
Clinical Trial Evidence Supporting FDA Approval of Novel Therapeutic Agents, 2005-2012
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DOI：
10.1001/jama.2013.282034
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发表时间：
2014-01-22
影响因子：
120.7
通讯作者：
Ross, Joseph S.
中科院分区：
文献类型：
--
作者：
Downing, Nicholas S.;Aminawung, Jenerius A.;Ross, Joseph S.
重要性许多患者和医生认为，新批准的治疗药物的安全性和有效性是很好的理解;但是，在此情况下，支持美国食品和药物管理局（FDA）批准决定的临床试验证据的强度尚未得到评估。（作为FDA批准的基础的临床试验）的新批准的新型治疗剂。使用公开的FDA文件对2005年至2012年期间批准的所有新型治疗药物进行部分分析。主要结果和指标根据以下设计特征对药物疗效试验进行分类：随机化、设盲、对照和试验终点。替代结局定义为使用预期可预测临床获益的生物标志物的任何终点。患者数量、试验持续时间和试验完成率也被确定。结果在2005年至2012年期间，FDA在448项关键疗效试验的基础上批准了188种用于206种适应症的新型治疗药物。每个适应症的关键性试验的中位数为2（四分位数范围，1-2.5），尽管74个适应症（36.8%）是基于单个关键性试验获得批准的。几乎所有试验均为随机（89.3% [95% CI，86.4%-92.2%]）、双盲（79.5% [95% CI，75.7%-83.2%]），并使用活性或安慰剂对照（87.1% [95% CI，83.9%-90.2%]）。在所有关键性试验中，每种适应症入组的患者中位数为760例（四分位距，270-1550）。至少1项持续时间为6个月或更长的关键性试验支持68项适应症获批（33.8% [95% CI，27.2%-40.4%]）。使用替代终点作为主要结局的临床试验形成了91个适应症（45.3% [95%CI，38.3%-52.2%]）、67个临床结局（33.3% [95%CI，26.8%-39.9%]）和36个临床量表（17.9% [95%CI，12.6%-23.3%]）的唯一批准基础。试验功能不同的治疗和适应症的特点，如治疗领域，预期的治疗时间，孤儿状态，并加速approvation.CONCLUSIONS和RELEVANCE的质量由FDA使用的临床试验证据的基础上，最近批准的新的治疗药物变化很大的适应症。这种变化对患者和医生在决定使用新批准的治疗药物时具有重要意义。
IMPORTANCE Many patients and physicians assume that the safety and effectiveness of newly approved therapeutic agents is well understood; however, the strength of the clinical trial evidence supporting approval decisions by the US Food and Drug Administration (FDA) has not been evaluated.OBJECTIVES To characterize pivotal efficacy trials (clinical trials that serve as the basis of FDA approval) for newly approved novel therapeutic agents.DESIGN AND SETTING Cross-sectional analysis using publicly available FDA documents for all novel therapeutic agents approved between 2005 and 2012.MAIN OUTCOMES AND MEASURES Pivotal efficacy trials were classified according to the following design features: randomization, blinding, comparator, and trial end point. Surrogate outcomes were defined as any end point using a biomarker expected to predict clinical benefit. The number of patients, trial duration, and trial completion rates were also determined.RESULTS Between 2005 and 2012, the FDA approved 188 novel therapeutic agents for 206 indications on the basis of 448 pivotal efficacy trials. The median number of pivotal trials per indication was 2 (interquartile range, 1-2.5), although 74 indications (36.8%) were approved on the basis of a single pivotal trial. Nearly all trials were randomized (89.3% [95% CI, 86.4%-92.2%]), double-blinded (79.5% [95% CI, 75.7%-83.2%]), and used either an active or placebo comparator (87.1% [95% CI, 83.9%-90.2%]). The median number of patients enrolled per indication among all pivotal trials was 760 (interquartile range, 270-1550). At least 1 pivotal trial with a duration of 6 months or greater supported the approval of 68 indications (33.8% [95% CI, 27.2%-40.4%]). Pivotal trials using surrogate end points as their primary outcome formed the exclusive basis of approval for 91 indications (45.3% [95% CI, 38.3%-52.2%]), clinical outcomes for 67 (33.3% [95% CI, 26.8%-39.9%]), and clinical scales for 36 (17.9% [95% CI, 12.6%-23.3%]). Trial features differed by therapeutic and indication characteristics, such as therapeutic area, expected length of treatment, orphan status, and accelerated approval.CONCLUSIONS AND RELEVANCE The quality of clinical trial evidence used by the FDA as the basis for recent approvals of novel therapeutic agents varied widely across indications. This variation has important implications for patients and physicians as they make decisions about the use of newly approved therapeutic agents.