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Despite some success in drug development for multiple sclerosis (MS), it is unclear how well drug testing in animal studies predicts successful bench-to-bedside translation. Understanding which experimental factors of MS animal research govern successful development of treatments would allow a more efficient drug discovery, while reducing the number of animals used in research. Objectives: To identify predictors of successful animal-to-human translation for MS, we systematically compared animal studies of approved MS disease-modifying therapies (DMTs) to those DMTs that failed in clinical trials for efficacy/safety reasons. Methods: Approved and failed DMTs for MS were identified through literature review. Animal studies for these DMTs were identified from searches in PubMed and EMBASE. Machine-learning methods were exploited for abstract screening and data extraction. A random effect meta-analysis was fitted to the data to compare outcome effect sizes for approved vs. failed DMTs. Results: We included 477 animal studies, covering 15 approved and 11 failed DMTs, tested in 29’991 animals. DMTs were tested in a small repertoire of experimental parameters, i.e., about 87% and 79% of studies used experimental autoimmune encephalomyelitis (EAE) and mice, respectively. Clinically pertinent outcomes of animal studies were not associated with successful translation. However, testing a DMT under more diverse experimental settings, e.g., across different labs or animal models, was associated with successful approval. Surprisingly, 90% of animal studies have been conducted after official FDA approval. Conclusions: Our systematic review underscores specific challenges in translating animal research to clinical practice. Notably, many animal studies lack translational validity, even with seemingly pertinent outcomes, and there is a limited range of experimental methods and a disconnect between preclinical and clinical studies. To optimize the value of animal research for patient care, we recommend introducing greater variability in experimental conditions and strengthening ties between preclinical and clinical researchers.
Project Lead
CRS Collaborators
External Collaborators
Ingrid Berg, Pia Härvelid, Wolfgang Emanuel Zürrer
Publications
