Developing safety criteria for introducing new agents into neoadjuvant trials.
Developing safety criteria for introducing new agents into neoadjuvant trials.
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DOI：
10.1158/1078-0432.ccr-12-2620
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发表时间：
2013-06-01
期刊：
影响因子：
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通讯作者：
Esserman L
中科院分区：
文献类型：
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作者：
DeMichele A;Berry DA;Zujewski J;Hunsberger S;Rubinstein L;Tomaszewski JE;Kelloff G;Perlmutter J;Buxton M;Lyandres J;Albain KS;Benz C;Chien AJ;Haluska P;Leyland-Jones B;Liu MC;Munster P;Olopade O;Park JW;Parker BA;Pusztai L;Tripathy D;Rugo H;Yee D;Esserman L
迫切需要新的药物开发方法来减少识别和优化活性药物所需的时间、成本和资源。加速药物开发的策略包括在疾病过程的早期测试药物，例如新辅助治疗。美国食品和药物管理局 (FDA) 发布了指导意见，旨在通过使用新辅助研究来加速药物审批，其中替代短期终点（病理反应）可用于识别活性药物，并缩短有效药物和生物标志物的批准时间，以识别最有可能产生反应的患者。然而，这种方法有独特的挑战。特别是，考虑到潜在可治愈患者接触安全经验有限的研究药物，患者安全问题至关重要。新辅助治疗中安全药物开发的关键组成部分包括定义一个使用标准治疗预后足够差的研究人群，以证明接触研究药物的合理性，定义第一阶段安全数据的范围和充分性，检测研究治疗和标准治疗之间潜在有害的相互作用，改进研究设计，例如限制患者接触无效药物的适应性策略，以及在试验过程中加强安全监测。 I-SPY2 试验是乳腺癌新药 II 期新辅助试验的一个例子，其中这些问题在试验的设计和实施中都得到了解决。 II 期设计的这些调整可以减少筛选新疗法活性的时间和成本，从而在不影响安全性的情况下加速药物开发。
New approaches to drug development are critically needed to lessen the time, cost, and resources necessary to identify and optimize active agents. Strategies to accelerate drug development include testing drugs earlier in the disease process, such as the neoadjuvant setting. The U.S. Food and Drug Administration (FDA) has issued guidance designed to accelerate drug approval through the use of neoadjuvant studies in which the surrogate short-term endpoint, pathologic response, can be used to identify active agents and shorten the time to approval of both efficacious drugs and biomarkers identifying patients most likely to respond. However, this approach has unique challenges. In particular, issues of patient safety are paramount, given the exposure of potentially curable patients to investigational agents with limited safety experience. Key components to safe drug development in the neoadjuvant setting include defining a study population at sufficiently poor prognosis with standard therapy to justify exposure to investigational agents, defining the extent and adequacy of safety data from phase I, detecting potentially harmful interactions between investigational and standard therapies, improving study designs, such as adaptive strategies, that limit patient exposure to ineffective agents, and intensifying safety monitoring in the course of the trial. The I-SPY2 trial is an example of a phase II neoadjuvant trial of novel agents for breast cancer in which these issues have been addressed, both in the design and conduct of the trial. These adaptations of phase II design enable acceleration of drug development by reducing time and cost to screen novel therapies for activity without compromising safety.