The US Food and Drug Administration's expedited approval programs: Evidentiary standards, regulatory trade-offs, and potential improvements
The US Food and Drug Administration's expedited approval programs: Evidentiary standards, regulatory trade-offs, and potential improvements
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DOI：
10.1177/1740774518770648
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发表时间：
2018-06-01
期刊：
影响因子：
2.7
通讯作者：
Naci, Huseyin
中科院分区：
文献类型：
--
作者：
Wallach, Joshua D.;Ross, Joseph S.;Naci, Huseyin
美国食品和药物管理局制定了多项监管计划和途径，以加快旨在治疗严重或危及生命的疾病的治疗药物的开发和批准。这些计划的一个共同特点是监管灵活性，允许采用定制的审批方法，在不太严格的证据的基础上进行市场授权，以换取要求上市后证据生成。近年来，美国食品和药物管理局批准的治疗药物中越来越多的份额与加速计划相关。在本文中，我们概述了食品和药物管理局的快速制定和审查计划所需的证据标准，总结了最近学术文献的研究结果，证明了这些计划的一些局限性，并概述了解决这些局限性的潜在机会。最近的证据表明，食品和药物管理局的快速计划中的治疗药物是在较少和较小的研究的基础上批准的，这些研究可能缺乏比较组和随机分配，而不是关注研究终点的临床结果，而是依赖于疾病的替代标志物。一旦上市，获得快速批准的药物通常会迅速纳入临床实践，而上市后产生的证据可能不一定能解决进入市场时的证据限制。此外，并非所有途径都需要额外的上市后研究。有证据表明，加速审批计划中的药物与食品和药物管理局在进入市场后采取安全行动的可能性更大有关。有多种机会可以提高接受快速批准的治疗药物的上市前和上市后研究的及时性、信息价值和有效性。当在进入市场之前无法避免使用非随机和非对照研究时，在上市后阶段应强制进行随机试验，除非有充分理由不进行此类研究。在上市前阶段，可以通过更严格地评估替代标志物与患者相关临床结果的相关性来提高替代标志物的有效性。减少上市后随机试验的持续时间、复杂性和成本的机会不应损害其有效性，而应纳入务实的现实世界设计元素。尽管最近人们热衷于在监管环境中广泛使用现实世界证据、适应性设计和实用试验，但在大规模实证评估证明其与更传统的试验设计相比的有效性之前，仍需谨慎。
The US Food and Drug Administration has several regulatory programs and pathways to expedite the development and approval of therapeutic agents aimed at treating serious or life-debilitating conditions. A common feature of these programs is the regulatory flexibility, which allows for a customized approval approach that enables market authorization on the basis of less rigorous evidence, in exchange for requiring postmarket evidence generation. An increasing share of therapeutic agents approved by the Food and Drug Administration in recent years are associated with expedited programs. In this article, we provide an overview of the evidentiary standards required by the Food and Drug Administration's expedited development and review programs, summarize the findings of the recent academic literature demonstrating some of the limitations of these programs, and outline potential opportunities to address these limitations. Recent evidence suggests that therapeutic agents in the Food and Drug Administration's expedited programs are approved on the basis of fewer and smaller studies that may lack comparator groups and random allocation, and rather than focusing on clinical outcomes for study endpoints, rely instead on surrogate markers of disease. Once on the market, agents receiving expedited approvals are often quickly incorporated into clinical practice, and evidence generated in the postmarket period may not necessarily address the evidentiary limitations at the time of market entry. Furthermore, not all pathways require additional postmarket studies. Evidence suggests that drugs in expedited approval programs are associated with a greater likelihood that the Food and Drug Administration will take a safety action following market entry. There are several opportunities to improve the timeliness, information value, and validity of the pre- and postmarket studies of therapeutic agents receiving expedited approvals. When use of nonrandomized and uncontrolled studies cannot be avoided prior to market entry, randomized trials should be mandatory in the postmarket period, unless there are strong justifications for not carrying out such studies. In the premarket period, validity of the surrogate markers can be improved by more rigorously evaluating their correlation with patient-relevant clinical outcomes. Opportunities to reduce the duration, complexity, and cost of postmarket randomized trials should not compromise their validity and instead incorporate pragmatic real-world design elements. Despite recent enthusiasm for widely using real-world evidence, adaptive designs, and pragmatic trials in the regulatory setting, caution is warranted until large-scale empirical evaluations demonstrate their validity compared to more traditional trial designs.