Introduction: 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 in vitro and in vivo experiments via a suite of complementary strategies.
Areas covered: In this review, the authors summarize the literature available on different strategies to improve external validity in in vivo, in vitro, or ex vivo 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.
Expert opinion: 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.
Keywords: Experimental design; external validity; preclinical research; systematic heterogenization; translational success.