Increasing research and development (R&D) productivity is a major challenge facing the pharmaceutical industry. With this in mind, Swinney and Anthony investigate which drug discovery approaches have been most successful, by analyzing the discovery strategies and molecular mechanism of action (MMOA) for 259 new drugs that were approved by the US Food and Drug Administration between 1999 and 2008. They reveal that the contribution of phenotypic screening to first-in-class small-molecule drug discovery exceeded that of target-based approaches, thus concluding that greater use of translational phenotypic assays and consideration of diverse MMOAs when using a target-based strategy could decrease attrition in drug development. The treatment of heart failure remains a major challenge and the attrition rate of new drugs in Phase III trials remains high. In their Review, Tamargo and López-Sendón examine new therapeutic targets for heart failure and novel drugs that are under development. Possible explanations for the high failure rate of agents in Phase III trials — including a poor pathophysiological understanding of heart failure, disease and patient heterogeneity, and inadequate clinical trial design — are discussed. Drugs that show efficacy in Phase III trials may not always perform as well in everyday clinical practice. In their Perspective, Bloechl-Daum and colleagues explore the reasons behind this discrepancy, arguing that it is largely due to variability in drug responses and summarizing strategies to reduce the efficacy–effectiveness gap. In a final Review, Mitragotri and colleagues present recent advances in the design of drug carriers that are based on natural particulates, such as pathogens and mammalian cells, highlighting the various applications, challenges and limitations of each approach.
