Blueprint Translational Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada.
BMC Med. 2024 Oct 23;22(1):487. doi: 10.1186/s12916-024-03690-8.
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.
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.
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.
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.
与传统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，导致市场批准和临床采用的延迟。增加的监管反对意见通常与临床前证据有关，例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。需要综合和澄清证明治疗效果并推进早期临床试验所需的临床前证据，以帮助研究人员避免监管反对意见。
我们进行了范围界定审查，其中我们在国际协调理事会的存储库和所有国家成员组织（N=38）中搜索了与细胞治疗相关的临床前研究文件。纳入了与细胞治疗相关的主动指导文件，没有基于出版年份或语言的限制。数据提取由两人进行，通过共识讨论解决冲突。
从 1215 份确定的文件中，共纳入并分析了 182 份，其中 71%来自十个主要监管机构。解决的最常见的临床前项目是作用机制（n=161，占文件的 88%），强调了将临床前发现与临床应用联系起来的重要性。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，尽管关于疾病模型的具体建议较少（n=81，45%）。还经常推荐选择临床相关的干预参数（n=136，75%）和结果测量（n=121，66%），但选择相关的比较组似乎较少（n=35，19%）。此外，随机化和盲法等稳健的研究设计元素的推荐频率较低，仅出现在 31%的文件中（n=57）。与临床试验指南相比，临床前研究设计建议的严格性存在显著差距。
临床前疗效研究的监管指南通常强烈建议强调动物模型、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提高相关国家监管机构对临床前证据的可接受性，并可用作指南，以确保监管机构表示他们期望的所有证据都能有效地纳入新的临床试验申请中。
