A Systematic Review Comparing Experimental Design of Animal and Human Methotrexate Efficacy Studies for Rheumatoid Arthritis: Lessons for the Translational Value of Animal Studies

SIMPLE SUMMARY: If we want to use animal studies to predict what will happen if we give a drug to humans, it makes sense to perform the animal studies as similarly to human studies as possible. For example, if animal tests of a drug only look at the effect of injecting the drug in young healthy animals, we cannot expect the results to be similar in human tests giving tablets to older patients who may have other diseases besides the one for which they receive the drug. We did an in-depth analysis of how 147 animal and 512 human studies of the drug methotrexate for rheumatoid arthritis were performed. Important differences were present, for example, animal studies used more males, while rheumatoid arthritis occurs more in females. We calculated the human-equivalent age of the animals, and they were on average younger than humans. Many studies did not fully report the way the experiments were performed. In spite of these differences, the drug methotrexate works well against rheumatoid arthritis in animal models and humans. Further (literature) research is still needed; we do not yet understand when we can reliably predict human effects from animal studies. ABSTRACT: Increased awareness and understanding of current practices in translational research is required for informed decision making in drug development. This paper describes a systematic review of methotrexate for rheumatoid arthritis, comparing trial design between 147 animal and 512 human studies. Animal studies generally included fewer subjects than human studies, and less frequently reported randomisation and blinding. In relation to life span, study duration was comparable for animals and humans, but included animals were younger than included humans. Animal studies often comprised males only (61%), human studies always included females (98% included both sexes). Power calculations were poorly reported in both samples. Analyses of human studies more frequently comprised Chi-square tests, those of animal studies more frequently reported analyses of variance. Administration route was more variable, and more frequently reported in animal than human studies. Erythrocyte sedimentation rate and c-reactive protein were analysed more frequently in human than in animal studies. To conclude, experimental designs for animal and human studies are not optimally aligned. However, methotrexate is effective in treating rheumatoid arthritis in animal models and humans. Further evaluation of the available evidence in other research fields is needed to increase the understanding of translational success before we can optimise translational strategies.