Distinguishing between exploratory and confirmatory preclinical research will improve translation.
Preclinical researchers confront two overarching agendas related to drug development: selecting interventions amid a vast field of candidates, and producing rigorous evidence of clinical promise for a small number of interventions. We suggest that each challenge is best met by two different, complementary modes of investigation. In the first (exploratory investigation), researchers should aim at generating robust pathophysiological theories of disease. In the second (confirmatory investigation), researchers should aim at demonstrating strong and reproducible treatment effects in relevant animal models. Each mode entails different study designs, confronts different validity threats, and supports different kinds of inferences. Research policies should seek to disentangle the two modes and leverage their complementarity. In particular, policies should discourage the common use of exploratory studies to support confirmatory inferences, promote a greater volume of confirmatory investigation, and customize design and reporting guidelines for each mode.
Studies of Translation, Ethics, and Medicine (STREAM), Biomedical Ethics Unit, Experimental Medicine, McGill University, Montreal, Quebec, Canada.
Jonathan
J
Kimmelman
Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada.
Jeffrey S
JS
Mogil
Departments of Neurology and Experimental Neurology, Center for Stroke Research Berlin, and Excellence Cluster NeuroCure Charité - Universitätsmedizin Berlin, Berlin, Germany; German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany; Center for Cardiovascular Diseases (DZHK), partner site Berlin, Germany.
Ulrich
U
Dirnagl
D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D017410:Practice Guidelines as Topic; D012107:Research Design / Q000331:legislation & jurisprudence*; D057170:Translational Research, Biomedical / Q000379:methods* / Q000458:organization & administration