Methods for randomized, blinded, controlled evaluation of putative disease interventions in multilaboratory, preclinical assessment networks

Science faces a reproducibility crisis, and public trust in science declines when large clinical trials, which had been qualified by promising preclinical studies, fail. While some clinical trial designs may have been inadequate, preclinical assessments of disease interventions might have lacked key elements of rigor such as treatment concealment, randomization, blinded outcomes, prespecified and adequate sample sizes, and models including comorbidities. Here, to demonstrate feasibility and practicality of enhanced rigor in preclinical assessment, we designed a six-laboratory network that implemented rigorous study elements, using acute ischemic stroke for demonstration. This network enrolled 2,615 rodents in 5 different models and implemented a multistage, multiarm statistical design that sequentially eliminated candidate interventions during interim analyses. The methods included centralized intervention packaging, randomization, data quality assessment and data archiving. Blinded analysis of 9,274 video-recorded behavioral tasks and 3,652 magnetic resonance images were evaluated. All tools and protocols are presented and could be adapted to preclinical assessment in other disease areas.