Why Clinical Trials Stop: The Role of Genetics

Many drug discovery projects are started, but few progress fully through clinical trials to approval. Previous work has shown that human genetics support for the therapeutic hypothesis increases the chance of trial progression. Here, we applied natural language processing to classify the freetext reasons for 28,842 clinical trials that stopped before their endpoints were met. We then evaluated these classes in the light of the underlying evidence for the therapeutic hypothesis and target properties. We show that trials are more likely to stop due to lack of efficacy in the absence of strong genetic evidence from human populations or genetically-modified animal models. Furthermore, trials are more likely to stop for safety reasons if the drug target gene is highly constrained in human populations and if the gene is not selectively expressed. These results support the growing use of human genetics to evaluate targets for drug discovery programmes.