Abstract
Animal models of osteoarthritis are extensively used for investigating disease pathways and for preclinical testing of novel therapies. Their predictive utility, however, has often been questioned, mainly because preclinical efficacy of novel therapeutics is poorly translated in clinical trials. In the current narrative review, we consider the preclinical models that were used to support undertaking clinical trials for disease-modifying osteoarthritis drugs, and compare outcomes between clinical and preclinical studies. We discuss this in light of the 1999 Food and Drug Administration draft guidelines for industry for use in the development of drugs, devices, and biological products intended for the treatment of osteoarthritis, which raised five considerations on the usefulness of osteoarthritis models. We systematically discuss what has been learnt regarding these five points since 1999, with emphasis on replicating distinct risk factors and subtypes of human osteoarthritis, and on comprehensive evaluation of the disease in animals, including pathology of all joint tissues, biomarker analysis, and assessment of pain and joint function. Finally, we discuss lessons learnt and propose some recommendations for how the evidence from preclinical research might be strengthened with a view to improving success in clinical translation.
Highlights
The current practice of translational biomedical research is failing its end-users, with as much as 90 % of ‘highly promising basic science discoveries failing to enter routine clinical use within 20 years’ [1]
In 1999, the US Food and Drug Administration (FDA) provided draft guidelines for industry for use in the development of drugs, devices, and biological products intended for the treatment of osteoarthritis (OA) [9]
Suggestions for improvements that will enable translation in OA research are similar in other diseases [132] and include: 1. Better aligning of preclinical models and the clinical trial population - including OA disease phenotype, stage, age, sex and confounding co-morbidities
Summary
The current practice of translational biomedical research is failing its end-users, with as much as 90 % of ‘highly promising basic science discoveries failing to enter routine clinical use within 20 years’ [1]. In 1999, the US Food and Drug Administration (FDA) provided draft guidelines for industry for use in the development of drugs, devices, and biological products intended for the treatment of osteoarthritis (OA) [9]. This nine-page document contains a paragraph on the use of preclinical models in OA, which surprisingly is lacking in the equivalent European guidelines [10]. The brief section (excerpt in Box 1) in the FDA document raises a number of specific issues that speak largely to how well any proposed animal model of OA mimics the human disease, and will be predictive of therapeutic outcome in clinical trials and medical practice. When evaluating the possible usefulness of an animal model, the following questions should be considered: 1. How accurately does the model replicate human OA?
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