综合临床前疗效展示和将有前景的细胞疗法转化为早期临床试验的监管指南:范围界定综述。

IF 7 1区 医学 Q1 MEDICINE, GENERAL & INTERNAL
Matthew S Jeffers, Cheng En Xi, Raj Bapuji, Hannah Wotherspoon, Jonathan Kimmelman, Patrick Bedford, Daniel I McIsaac, Manoj M Lalu, Dean A Fergusson
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引用次数: 0

摘要

背景:与传统的小分子或生物药物相比,细胞疗法的监管申请面临更多的反对意见,导致市场审批和临床应用的延迟。越来越多的监管反对意见往往与临床前证据问题有关,如动物研究的实验设计、动物模型的选择、终点和作用机制的确定。为了帮助研究人员避免监管部门的反对意见,需要对证明疗效和进入早期临床试验所需的临床前证据进行综合和澄清:我们进行了一次范围界定审查,搜索了国际协调理事会和所有国家成员组织(N = 38)的资料库中与细胞疗法临床前研究相关的文件。我们纳入了与细胞疗法相关的有效指导文件,对出版年份或语言没有任何限制。数据提取工作一式两份,有冲突时通过讨论达成共识:从 1215 份已确定的文件中,共纳入并分析了 182 份,其中 71% 来自 10 个主要监管机构。临床前研究中最常见的项目是作用机理(n = 161,占文件总数的 88%),凸显了临床前研究结果与临床应用之间的重要联系。大多数文件(n = 140,77%)强调了使用临床相关临床前模型的重要性,但有关疾病模型的具体建议并不常见(n = 81,45%)。选择与临床相关的干预参数(n = 136,75%)和结果测量(n = 121,66%)也是经常被推荐的,但选择相关的比较组则较少(n = 35,19%)。此外,随机化和盲法等稳健的研究设计要素也较少被推荐,仅出现在 31% 的文件中(n = 57)。与临床试验指南相比,临床前研究在研究设计建议的严谨性方面存在明显差距:结论:临床前药效研究的监管指南通常建议大力强调动物模型、干预参数、结果和作用机制的临床相关性。将这些建议纳入早期临床前研究应能提高临床前证据的可接受性,以获得相关国家监管机构的批准,并可作为一种指南,确保监管机构所期望的所有证据都能有效地汇集到新的临床试验申请中。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Synthesizing regulatory guidance for demonstrating preclinical efficacy and translating promising cell therapies to early phase clinical trials: a scoping review.

Background: Regulatory applications for cell therapy face more objections compared to conventional small molecule or biological drugs, leading to delays in market approval and clinical adoption. Increased regulatory objections frequently relate to issues regarding preclinical evidence, such as experimental design of animal studies, selection of animal models, endpoints, and determination of mechanism of action. Synthesis and clarification of the preclinical evidence necessary to demonstrate treatment efficacy and advance into early-phase clinical trials is needed to help researchers avoid regulatory objections.

Methods: We conducted a scoping review in which we searched repositories of the International Council for Harmonisation and all national member organizations (N = 38) for documents related to preclinical studies of cell therapies. Active guidance documents related to cell therapy were included, with no restrictions based on the year or language of publication. Data extraction was conducted in duplicate with conflicts resolved through consensus discussion.

Results: From 1215 identified documents, a total of 182 were included and analyzed, with 71% originating from ten major regulatory agencies. The most prevalent preclinical item addressed was the mechanism of action (n = 161, 88% of documents), underscoring its importance in bridging preclinical findings to clinical application. Most documents (n = 140, 77%) emphasized the importance of using clinically relevant preclinical models, though specific recommendations on models of disease were less common (n = 81, 45%). Selection of clinically relevant intervention parameters (n = 136, 75%) and outcome measures (n = 121, 66%) were also frequently recommended, but selection of relevant comparator groups appeared less frequently (n = 35, 19%). Furthermore, robust study design elements such as randomization and blinding were less frequently recommended, appearing in 31% of documents (n = 57). Comparison with clinical trial guidance revealed a significant gap in the rigor of study design recommendations for preclinical research.

Conclusions: Regulatory guidance for preclinical efficacy studies often recommends a strong emphasis on the clinical relevance of animal models, intervention parameters, outcomes, and mechanism of action. Incorporating these recommendations into early preclinical studies should improve the acceptability of preclinical evidence for approval by the relevant national regulators and can be used as a guide to ensure that all evidence that regulators say they expect is efficiently assembled into new clinical trial applications.

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来源期刊
BMC Medicine
BMC Medicine 医学-医学:内科
CiteScore
13.10
自引率
1.10%
发文量
435
审稿时长
4-8 weeks
期刊介绍: BMC Medicine is an open access, transparent peer-reviewed general medical journal. It is the flagship journal of the BMC series and publishes outstanding and influential research in various areas including clinical practice, translational medicine, medical and health advances, public health, global health, policy, and general topics of interest to the biomedical and sociomedical professional communities. In addition to research articles, the journal also publishes stimulating debates, reviews, unique forum articles, and concise tutorials. All articles published in BMC Medicine are included in various databases such as Biological Abstracts, BIOSIS, CAS, Citebase, Current contents, DOAJ, Embase, MEDLINE, PubMed, Science Citation Index Expanded, OAIster, SCImago, Scopus, SOCOLAR, and Zetoc.
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