From preclinical promise to regulatory reality: translation of small rodent acute injury therapies to human approval and safety outcomes: A systematic review.

BACKGROUND: Preclinical animal studies are considered essential for therapeutic development, yet translation to human benefit remains poor. The commonly cited translation rate of approximately 20% conflates trial entry with regulatory approval and may substantially overestimate the predictive validity of animal models for specific therapeutic indications. OBJECTIVES: To determine, for preclinical acute injury studies in small animal models: (a) the proportion progressing to human clinical trials; (b) the proportion achieving regulatory approval for the tested indication; (c) whether approvals represented novel translations or repurposed/class-effect approvals; and (d) post-market safety outcomes for translational successes. METHODS: Systematic review following PRISMA 2020 and SYRCLE guidance. We included controlled preclinical studies in small animal models (rats, mice, guinea pigs, hamsters, rabbits) of acute injury that tested a therapeutic intervention not already in routine clinical use, published 1990-2010. MEDLINE (via PubMed) was searched on 22 March 2022; full strategy in S1 File, Section S3. Five reviewers independently screened records in duplicate. Risk of bias was assessed with the SYRCLE tool. Therapies were grouped by active ingredient and classified against pre-specified regulatory categories by two reviewers blinded to post-market safety, with a third adjudicating. Post-market safety used five pre-defined criteria. Translation rates were synthesised descriptively as proportions with 95% Wilson score confidence intervals; no meta-analysis was performed. The review was registered on OSF (https://osf.io/w97fd). RESULTS: Of 3,847 records identified, 1,257 studies met inclusion criteria, yielding 100 distinct therapies with sufficient clinical outcome data (83 drugs, 17 devices/physical interventions). Translation-to-trial was 20.0% (251/1,257; 95% CI 17.9-22.4%). Among 83 drug therapies, only 3 (3.6%; 95% CI 1.2-10.1%) achieved first-in-class regulatory approval for the tested indication; 15 (18.1%) definitively failed in clinical trials. In an exploratory post-market analysis, 86% of drugs meeting any definition of translational success subsequently demonstrated major safety concerns; only beractant (Survanta®) remains in routine clinical use for the tested indication without major caveats, and this was not a novel first-in-class translation. CONCLUSIONS: Within acute injury research, the true regulatory success rate for novel preclinical therapies is 3.6%, likely an upper bound given publication bias. Most approved drugs subsequently experienced serious post-market safety concerns. Small rodent models have limited demonstrated predictive validity for human therapeutic outcomes in this domain. REGISTRATION: Open Science Framework, https://osf.io/w97fd.