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

## TL;DR

This paper introduces a rigorous, multi-lab preclinical trial framework to improve reproducibility and trust in disease interventions using stroke models as an example.

## Contribution

The paper introduces a feasible, multi-laboratory framework with rigorous methods for preclinical evaluation of disease interventions.

## Key findings

- A six-laboratory network assessed 2,615 rodents using rigorous statistical and blinded methods.
- Tools and protocols were developed for centralized packaging, randomization, and data archiving.
- Blinded analysis of behavioral tasks and MRI scans was successfully implemented across multiple sites.

## Abstract

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.

This Article details the methods used for rigorous assessment of disease interventions in a multicenter preclinical trial. Using stroke models as proof of concept, it offers adaptable protocols for any field requiring robust preclinical validation.