Alexander G Caleb, Ogasawara Ken, Wiegand Dana, Lin Dora, Breder Christopher D
Center for Drug Safety and Effectiveness, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Ther Innov Regul Sci. 2019 Nov;53(6):752-758. doi: 10.1177/2168479018812058. Epub 2018 Dec 3.
Biological therapies are increasingly common in the United States. Although their clinical development may deviate significantly from the classic paradigm used for small molecule drugs, there has been little systematic analysis of these programs. We describe the development programs and factors associated with approval in the first review cycle for biologics approved by the US Food and Drug Administration's Center for Drug Evaluation and Research (FDA CDER) between 2003 and 2016.
We conducted a retrospective analysis of publicly available approval packages including clinical pharmacology/biopharmaceutics, medical and summary reviews, and approval letters for biologics approved by FDA CDER. We evaluated characteristics of the development program (eg, use of expedited pathways, clinical pharmacology studies, number and type of pivotal trials) and the prevalence and correlates of first cycle approval, a key indicator of successful product development.
We assessed 81 development programs for 75 unique therapies. Most programs (67%) made use of at least 1 expedited designation and about half (49%) were designated as orphan products. The clinical pharmacology programs were highly variable and one in four (25%) did not include an ascending dose study, where the tolerability of the therapeutic is typically determined before pivotal trials. Since 2003, an increasing proportion of biologics have been approved on first cycle approval and with fewer than 2 pivotal clinical trials ( < .001 for trend). Of the approximately three-fourths (76%) of products that were approved on the first review cycle, the likelihood of such approval was greater among development programs that performed an ascending dose study (84% vs 55%, = .01) or held an End of Phase 2 meeting (85% vs 57%, = .01).
Considerable regulatory flexibility, with respect to the number of pivotal trials and data supporting dosing, coincides with a growing number of biologics approved on an annual basis.
生物疗法在美国越来越普遍。尽管其临床开发可能与用于小分子药物的经典模式有很大偏差，但对这些项目的系统分析却很少。我们描述了2003年至2016年间美国食品药品监督管理局药品评价和研究中心（FDA CDER）批准的生物制品在首个审评周期中的开发项目及与获批相关的因素。
我们对公开可得的批准文件包进行了回顾性分析，这些文件包包括临床药理学/生物药剂学、医学和总结审评，以及FDA CDER批准的生物制品的批准函。我们评估了开发项目的特征（如加速审批途径的使用、临床药理学研究、关键试验的数量和类型）以及首个周期获批的普遍性和相关性，首个周期获批是产品开发成功的关键指标。
我们评估了75种独特疗法的81个开发项目。大多数项目（67%）至少使用了1种加速认定，约一半（49%）被指定为孤儿产品。临床药理学项目差异很大，四分之一（25%）的项目没有进行剂量递增研究，而剂量递增研究通常在关键试验之前确定治疗的耐受性。自2003年以来，越来越多的生物制品在首个周期获批，且关键临床试验少于2项（趋势P<0.001）。在首个审评周期获批的约四分之三（76%）产品中，进行了剂量递增研究的开发项目获批可能性更大（84%对55%，P=0.01），或召开了2期结束会议的开发项目获批可能性更大（85%对57%，P=0.01）。
在关键试验数量和支持给药的数据方面，相当大的监管灵活性与每年获批的生物制品数量增加相吻合。
