Successful drug discovery is like finding oases of safety and efficacy in chemical and biological deserts. Screens in disease models, and other decision tools used in drug research and development (R&D), point towards oases when they score therapeutic candidates in a way that correlates with clinical utility in humans. Otherwise, they probably lead in the wrong direction. This line of thought can be quantified by using decision theory, in which 'predictive validity' is the correlation coefficient between the output of a decision tool and clinical utility across therapeutic candidates. Analyses based on this approach reveal that the detectability of good candidates is extremely sensitive to predictive validity, because the deserts are big and oases small. Both history and decision theory suggest that predictive validity is under-managed in drug R&D, not least because it is so hard to measure before projects succeed or fail later in the process. This article explains the influence of predictive validity on R&D productivity and discusses methods to evaluate and improve it, with the aim of supporting the application of more effective decision tools and catalysing investment in their creation.

Suppression of the myostatin (GDF‐8) pathway has emerged as an important therapeutic paradigm for muscle‐wasting disorders. In this study, we conducted a translational pharmacokinetic/pharmacodynamic (PK/PD) analysis of MYO‐029, an anti‐myostatin monoclonal antibody, using PK data in mice, rats, monkeys, humans, mouse tissue distribution data with 125I‐labeled MYO‐029, muscle weight increase in SCID mice, and muscle circumference changes in monkeys. This analysis revealed significant in vivo potency shift between mice and monkeys (72 nM vs. 1.3 μM for 50% effect on quadriceps). Estimated central clearance of MYO‐029 (0.38 mL/h/kg) in humans was greater than twofold higher than typical IgG mAbs. Peak and trough steady‐state exposures of MYO‐029 in patients at biweekly intravenous doses of 10 mg/kg MYO‐029 are predicted to achieve only 50% and 10% of the maximum effect seen in monkeys, respectively. These retrospective analyses results suggest that the MYO‐029 exposures in this trial had a low probability of producing robust efficacy.

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