Translational Pharmacology

The challenge for Translational Pharmacology is to improve the predictive value of the tools that are used to qualify the efficacy of a drug candidate. We should briefly consider the range of these tools and provide conjecture as to where the limitations may be and how these may be addressed. As this section of Frontiers develops, we will specifically welcome manuscripts that address ways of improving drug candidate qualification. There is a crisis in science that extends to medical science and to translational pharmacology. The best publicized aspect of this complex crisis is in the widely acknowledged lack of reproducibility of research findings (Baker, 2016). Several authors have written about specific systematic attempts by Pharma (e.g., Amgen) to reproduce preclinical findings, with very low success rates being reported (Begley and Ellis, 2012). These failures are attributed to a variety of factors, including poorly specified methods, variable context-dependent behavior of tools and cell lines, inadequate experimental power, post hoc analyses, and other forms of significance finding (now commonly known as P hacking; Begley, 2013). The research community, including the editorial board of the Frontiers series, is actively addressing the concerns raised by these observations and the ensuing debate. More recently a damning view of clinical research as a whole, has highlighted that many studies are redundant or non-feasible, creating waste, and unnecessary risk to patients/volunteers (Ioannidis, 2016). Closer to home we have some challenging failures in translational pharmacology. There have been several systematic analyses of the causes of major pharma pipeline attrition up to phase 2 of development. These studies consistently identify lack of efficacy as the cause of failure in approximately 50% of drug candidates (Cook et al., 2014). In this case, a " failure to fail " can be identified. Where can improvements in the process be found that will reduce the number of inefficacious candidates moving through to the later stages of clinical investigation? We have written an extensive commentary on one aspect of the drug candidate qualification process, namely the importance of cellular mechanics. We introduced the term " mechanopharmacology " to deal not only with the effects of drugs on mechanics, but also the effects of mechanics on drug actions (Krishnan et al., 2016), recognizing that the mechanical environment of the cells used in preclinical cellular pharmacology studies is often non-(patho)physiological. At a molecular level, the term also has utility in describing the impact of shear …