Building a bridge between animal studies and human randomized trials

Animal experiments are widely used in biomedical research to develop new therapies for human disease. Such experiments are conducted under the assumption that animal models mirror human disease with a high degree of fidelity and that findings of efficacy in animal models will generally translate into effective human interventions. Yet experience shows that many agents which prevent or treat disease in animal models fail to replicate when the results are tested in subsequent human clinical trials. The problem is evident in many domains but is especially apparent in cardiovascular medicine. This dissertation formulates a comprehensive strategy based on health services research to evaluate the results of animal studies before clinical trials are undertaken. The strategy is applied to address three areas in vascular medicine where promising animal data support therapeutic efficacy. The results suggest this approach yields a number of advantages over the current pathway of taking animal data directly into clinical trials. First, by imposing an intermediate phase between animal experimentation and randomized trials, health services research can be used to vet animal findings for human applicability and relevance; such work can act as a stage of sober, second thought. Second, health services studies can generate information on effect size and other vital variables for planning successful clinical trials. Third, health services studies can shed light on many elements not often seen in animal data, such as toxicity, cost-effectiveness, the impact of comorbidity, and evaluation of class effects and non-compliance. Fourth, the approach can be adapted to translating animal evidence on etiology and pathogenesis to human beings. Ultimately, the most significant implication of this approach is to enhance the process by which animal data is transformed into advances in the prevention and treatment of human disease.