To address the first question there is limited systematic public data on exactly why and how frequently novel agents fail in late-stage development (even in CI resources). However, historical studies and anecdotal reports (although mostly from the CDEV sector) imply that new drug applications (NDAs) most commonly fail from deficiencies in efficacy or safety. A useful orthogonal study (i.e. using non-US data and not major pharma) has looked at the classification of objections raised against human medicine marketing authorisation applications from by SMEs to the European Medicines Agency (EMA) between 2011 and 2015 and their impact on the outcome of applications (PMID 29953957). One of the informative charts in this report is shown in Fig. . There are useful general points exemplified and case study details in this Pfizer exposition on their way of doing things back then. However, not only was there no disclosed quantitative data on subsequent improved outcomes but the Citeline Annual Review figures imply this actually went into reverse. In 2013 Pfizer was 5 th in the global rankings with a pipeline of 202 drugs but by 2019 they had fallen to 9 th with 163. It has to be said that there are many factors that affect the rankings arrived at by Citeline, including differences in therapeutic area coverage between companies (i. As would be expected, failures still persist but there is an informative breakdown as to how the reasons for these have shifted as a consequence in Fig. . Significantly, as an independent endorsement of the real-world success of '5Rs', Dr Mene Pangolos, head of AZ R&D, was recently awarded the Prix Galien. Despite this, not all the development challenges are covered by the '5Rs'. In particular, the longitudinal statistics indicate that CDEV productivity peaked several decades ago, paradoxically when fewer molecular targets were resolved and less known about their pathways. It has thus been argued that disease-state phenotypic pharmacology was the major contribution to this historical success rate and that, against prevailing expectations, this actually declined in parallel with increasing post-genomic target-centricity. While the list of variables affecting even just drug < > receptor interaction is dauntingly large, this type of direct pathology-relevant screening can eliminate many of them (see 'Resolution of controversies in drug/receptor interactions by protein structure. Limitations and pharmacological solutions . However, as reported by one major pharma company, swinging the pendulum back towards phenotypic screening turned out not to be a panacea (see 'How Phenotypic Screening Influenced Drug Discovery: Lessons from Five Years of Practice', 2017, PMID 28800248).