Tufts University School of Medicine, Boston, MA, USA.
Duke University Health System, Durham, NC, USA.
Clin Trials. 2021 Aug;18(4):488-499. doi: 10.1177/17407745211005044. Epub 2021 Apr 16.
BACKGROUND/AIMS: The US Food and Drug Administration outlines clinical studies as postmarketing requirements and commitments to be fulfilled following approval of new drugs and biologics ("therapeutics"). Regulators have increasingly emphasized lifecycle evaluation of approved therapeutics, and postmarketing studies are intended to advance our understanding of therapeutic safety and efficacy. However, little is known about the indications that clinical studies outlined in postmarketing requirements and commitments investigate, including whether they are intended to generate evidence for approved or other clinical indications. Therefore, we characterized US Food and Drug Administration postmarketing requirements and commitments for new therapeutics approved from 2009 to 2018.
We conducted a cross-sectional study of all novel therapeutics, including small-molecule drugs and biologics, receiving original US Food and Drug Administration approval from 2009 to 2018, using approval letters accessed through the Drug@FDA database. Outcomes included the number and characteristics of US Food and Drug Administration postmarketing requirements and commitments for new therapeutics at original approval, including the types of studies outlined, the indications to be investigated, and the clinical evidence to be generated.
From 2009 to 2018, the US Food and Drug Administration approved 343 new therapeutics with 1978 postmarketing requirements and commitments. Overall, 750 (37.9%) postmarketing requirements and commitments outlined clinical studies. For 71 of 343 (20.7%) therapeutics, no postmarketing requirements or commitments for clinical studies were outlined, while at least 1 was outlined for 272 (79.3%; median 2 (interquartile range: 1-4)). Among these 272 therapeutics, the number of postmarketing requirements and commitments for clinical studies per therapeutic did not change from 2009 (median: 2 (interquartile range: 1-4)) to 2018 (median: 2 (interquartile range: 1-3)). Among the 750 postmarketing requirements and commitments for clinical studies, 448 (59.7%) outlined new prospective cohort studies, registries, or clinical trials, while the remainder outlined retrospective studies, secondary analyses, or completion of ongoing studies. Although 455 (60.7%) clinical studies investigated only original approved therapeutic indications, 123 (16.4%) enrolled from an expansion of the approved disease population and 61 (8.1%) investigated diseases unrelated to approved indications.
The US Food and Drug Administration approves most new therapeutics with at least 1 postmarketing requirement or commitment for a clinical study, and outlines investigations of safety or efficacy for both approved and unapproved indications. The median number of 2 clinical studies outlined has remained relatively constant over the last decade. Given increasing emphasis by the US Food and Drug Administration on faster approval and lifecycle evaluation of therapeutics, these findings suggest that more postmarketing requirements and commitments may be necessary to address gaps in the clinical evidence available for therapeutics at approval.
背景/目的：美国食品和药物管理局将临床研究列为药品和生物制品批准后的上市后要求和承诺（“疗法”）。监管机构越来越强调对已批准疗法的生命周期评估，而上市后研究旨在增进我们对治疗安全性和疗效的理解。然而，对于上市后要求和承诺中概述的临床研究的适应症知之甚少，包括它们是否旨在为已批准或其他临床适应症生成证据。因此，我们对 2009 年至 2018 年批准的新疗法的美国食品和药物管理局上市后要求和承诺进行了特征描述。
我们对 2009 年至 2018 年期间所有获得美国食品和药物管理局原始批准的新型疗法（包括小分子药物和生物制剂）进行了横断面研究，使用通过 Drug@FDA 数据库访问的批准信。结果包括新疗法在原始批准时的美国食品和药物管理局上市后要求和承诺的数量和特征，包括概述的研究类型、要调查的适应症以及要生成的临床证据。
2009 年至 2018 年，美国食品和药物管理局批准了 343 种新疗法，其中有 1978 项上市后要求和承诺。总体而言，750 项（37.9%）上市后要求和承诺概述了临床研究。对于 343 种疗法中的 71 种，没有为临床研究制定上市后要求或承诺，而对于 272 种（79.3%；中位数 2（四分位距：1-4））则制定了至少 1 项。在这 272 种疗法中，每种疗法的上市后临床研究要求和承诺数量从 2009 年（中位数：2（四分位距：1-4））到 2018 年（中位数：2（四分位距：1-3））没有变化。在 750 项上市后临床研究要求和承诺中，448 项（59.7%）概述了新的前瞻性队列研究、登记处或临床试验，而其余的则概述了回顾性研究、二次分析或正在进行的研究的完成情况。尽管 455 项（60.7%）临床研究仅调查了原始批准的治疗适应症，但 123 项（16.4%）研究是从批准疾病人群的扩大范围招募的，61 项（8.1%）研究调查了与批准适应症无关的疾病。
美国食品和药物管理局批准的大多数新疗法都至少有 1 项上市后临床研究的要求或承诺，并概述了对已批准和未批准适应症的安全性或疗效的研究。过去十年中，概述的 2 项临床研究的中位数数量相对保持稳定。鉴于美国食品和药物管理局对更快批准和疗法生命周期评估的重视程度不断提高，这些发现表明，为了弥补批准时治疗方法可用临床证据的差距，可能需要制定更多的上市后要求和承诺。
