The need for randomization in animal trials: an overview of systematic reviews
Open accessAbstract
BACKGROUND AND OBJECTIVES: Randomization, allocation concealment, and blind outcome assessment have been shown to reduce bias in human studies. Authors from the Collaborative Approach to Meta Analysis and Review of Animal Data from Experimental Studies (CAMARADES) collaboration recently found that these features protect against bias in animal stroke studies. We extended the scope the work from CAMARADES to include investigations of treatments for any condition. METHODS: We conducted an overview of systematic reviews. We searched Medline and Embase for systematic reviews of animal studies testing any intervention (against any control) and we included any disease area and outcome. We included reviews comparing randomized versus not randomized (but otherwise controlled), concealed versus unconcealed treatment allocation, or blinded versus unblinded outcome assessment. RESULTS: Thirty-one systematic reviews met our inclusion criteria: 20 investigated treatments for experimental stroke, 4 reviews investigated treatments for spinal cord diseases, while 1 review each investigated treatments for bone cancer, intracerebral hemorrhage, glioma, multiple sclerosis, Parkinson's disease, and treatments used in emergency medicine. In our sample 29% of studies reported randomization, 15% of studies reported allocation concealment, and 35% of studies reported blinded outcome assessment. We pooled the results in a meta-analysis, and in our primary analysis found that failure to randomize significantly increased effect sizes, whereas allocation concealment and blinding did not. In our secondary analyses we found that randomization, allocation concealment, and blinding reduced effect sizes, especially where outcomes were subjective. CONCLUSIONS: Our study demonstrates the need for randomization, allocation concealment, and blind outcome assessment in animal research across a wide range of outcomes and disease areas. Since human studies are often justified based on results from animal studies, our results suggest that unduly biased animal studies should not be allowed to constitute part of the rationale for human trials.
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Lack of bias-reducing measures such as randomisation and blinding can contribute to as much as 30%-45% inflation of effect sizes.
“There are, however, compelling data from systematic reviews showing that nonblinded outcome assessment leads to the treatment effects being overestimated, and the lack of bias-reducing measures such as randomisation and blinding can contribute to as much as 30%–45% inflation of effect sizes [67,68,85].”
From Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0 (2020) · cites this paper as [67]
The Introduction (Bias in Animal Studies; page unavailable) reports a 30% exaggeration of odds ratios in human trials lacking allocation concealment. The Conclusions report exaggerated effect sizes in animal studies lacking randomization, but the paper does not report 30%–45% inflation from lack of randomization and blinding; the Results (Blinding; page unavailable) found no significant overall difference in its primary analysis. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCompelling data from systematic reviews show that nonblinded outcome assessment leads to treatment effects being overestimated.
“There are, however, compelling data from systematic reviews showing that nonblinded outcome assessment leads to the treatment effects being overestimated, and the lack of bias-reducing measures such as randomisation and blinding can contribute to as much as 30%–45% inflation of effect sizes [67,68,85].”
From Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0 (2020) · cites this paper as [67]
The Introduction (Bias in Animal Studies) reports a human-trial study finding exaggerated odds ratios when outcome assessment was not blinded, and the Results (3. Blinding) find an effect for neurobehavioral outcomes. But this paper’s primary analysis found no significant overall difference between blinded and nonblinded animal studies, so it does not support the claim as an unqualified finding. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSystematic reviews have shown that animal experiments that do not report randomisation or other bias-reducing measures such as blinding are more likely to report exaggerated effects that meet conventional measures of statistical significance.
“Systematic reviews have shown that animal experiments that do not report randomisation or other bias-reducing measures such as blinding are more likely to report exaggerated effects that meet conventional measures of statistical significance [67–69].”
From Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0 (2020) · cites this paper as [67]
The Results (Randomization; page not available) report larger effect sizes in studies without randomization, and the Discussion says failure to randomize likely overestimates treatment benefits. But the Results (Blinding; page not available) find no overall difference for blinding in the primary analysis. The paper reports statistical significance for some pooled comparisons; it does not show that studies omitting these measures are more likely to report individually statistically significant effects. (LLM, conf=0.88)
Experimental — accuracy not yet measured
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- Authors
- Hirst, J. A., Howick, J., Aronson, J. K., Roberts, N., Perera, R., Koshiaris, C., & Heneghan, C.
- Affiliations
- University of Oxford (GB)
- Corresponding author
- Hirst, Jennifer A.
- Howick, Jeremy
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-06-06
- Volume
- 9
- Issue
- 6
- Pages
- e98856
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4048216
- OpenAlex
- W2037669635
- Cited by
- 294
- References
- 69
- Citations by year
- 2026: 18 · 2025: 25 · 2024: 20 · 2023: 25 · 2022: 28 · 2021: 38 · 2020: 30 · 2019: 21 · 2018: 20 · 2017: 19 · 2016: 32 · 2015: 16 · 2014: 1
- FWCI
- 6.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institute for Health and Care Research
- Topics
- Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Meta-analysis and systematic reviews
- Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Keywords
- randomization, allocation concealment, blinding, animal models, effect size
- MeSH terms
- Animals, Research Design, Review Literature as Topic, Bias, Animal Experimentation
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