Mapping strategies towards improved external validity in preclinical translational research

Translation is about successfully bringing findings from preclinical contexts into the clinic. This transfer is challenging as clinical trials frequently fail despite positive preclinical results. Limited robustness of preclinical research has been marked as one of the drivers of such failures. One suggested solution is to improve the external validity of <i>in vitro</i> and <i>in vivo</i> experiments via a suite of complementary strategies. In this review, the authors summarize the literature available on different strategies to improve external validity in <i>in vivo</i>, <i>in vitro</i>, or <i>ex vivo</i> experiments; systematic heterogenization; generalizability tests; and multi-batch and multicenter experiments. Articles that tested or discussed sources of variability in systematically heterogenized experiments were identified, and the most prevalent sources of variability are reviewed further. Special considerations in sample size planning, analysis options, and practical feasibility associated with each strategy are also reviewed. The strategies reviewed differentially influence variation in experiments. Different research projects, with their unique goals, can leverage the strengths and limitations of each strategy. Applying a combination of these approaches in confirmatory stages of preclinical research putatively increases the chances of success in clinical studies.

临床转化旨在将临床前研究成果成功推向临床应用。这一转化过程极具挑战：即便临床前研究结果呈阳性，临床试验仍常以失败告终。临床前研究稳健性不足被认为是此类试验失败的关键诱因之一。有研究提出可通过一系列互补策略提升体外（in vitro）与体内（in vivo）实验的外部有效性。本综述中，作者系统梳理了可提升体内（in vivo）、体外（in vitro）及离体（ex vivo）实验外部有效性的各类策略，包括系统性异质化、泛化性测试、多批次与多中心实验等。研究团队筛选出针对系统性异质化实验中变异来源开展测试或讨论的相关文献，并对其中最常见的变异来源进行了深入综述。此外，本文还针对每种策略在样本量规划、分析方案选择及实际可行性方面的特殊考量进行了综述。本次综述涉及的各类策略对实验变异的影响各不相同。不同研究项目可结合自身独特目标，灵活利用各策略的优势与局限。在临床前研究的验证阶段综合运用这些策略，有望提升临床试验的成功概率。