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 free-text reasons for 28,561 clinical trials that stopped before their endpoints were met. We then evaluated these classes in light of the underlying evidence for the therapeutic hypothesis and target properties. We found that trials are more likely to stop because of a lack of efficacy in the absence of strong genetic evidence from human populations or genetically modified animal models. Furthermore, certain 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 broadly expressed across tissues. These results support the growing use of human genetics to evaluate targets for drug discovery programs.

许多药物发现项目已经启动，但很少有项目能够完全通过临床试验直至获得批准。先前的研究表明，人类遗传学对治疗假设的支持增加了试验进展的机会。在这里，我们应用自然语言处理对 28,561 项在达到终点之前停止的临床试验的自由文本原因进行分类。然后，我们根据治疗假设和目标特性的潜在证据评估这些类别。我们发现，在缺乏来自人群或转基因动物模型的强有力的遗传证据的情况下，试验更有可能因为缺乏疗效而停止。此外，如果药物靶基因在人群中受到高度限制并且该基因在组织中广泛表达，则某些试验更有可能出于安全原因而停止。这些结果支持越来越多地使用人类遗传学来评估药物发现计划的目标。