A major pharmaceutical company has published* a thorough analysis of its R&D pipeline from 2005-2010 and summarized the primary reasons for successes and failures of its small-molecule drug projects. While R&D investment in the industry has reached record high levels and there has been a wealth of new technologies and new drug targets to explore, the rate of new drug launches has been steady and drug development costs have increased substantially. The conclusions of this article can be used to boost productivity of drug development efforts in hopes of increasing the number of successful drug launches.
An interesting point made in the paper is that volume-based metrics to boost portfolio projects and drug candidates have not necessarily yielded better performance. The authors state, "This volume-based approach damaged not only the quality and sustainability of R&D pipelines but, more importantly, also the health of the R&D organizations and their underlying scientific curiosity. This is because the focus of scientists and clinicians moved away from the more demanding goal of thoroughly understanding disease pathophysiology and the therapeutic opportunities, and instead moved towards meeting volume-based goals and identifying an unprecedented level of back-up and 'me too' drug candidates. In such an environment, 'truth-seeking' behaviours to understand disease biology may have been over-ridden by 'progression-driven' behaviours that rewarded scientists for meeting numerical volume-based goals." The authors suggest that volume-based metrics should be substituted with a more in depth understanding of drug targets, biologies, and patient selection metrics.
The company describes a comprehensive review undertaken for 142 drug discovery and development projects from candidate phase to Phase II. Data were gathered from more than 80% of these 142 projects and for 95% of projects in clinical phases. Of the projects analysed, 94 closed during the period assessed; 33 closed before clinical testing and a further 61 closed during clinical testing. The review was performed by submitting structured questionnaires to a cross-functional group of scientists and clinicians drawn from the project teams. The primary cause of failure for projects up to Phase II was unacceptale safety, which accounted for more than half of all project closures. The majority of these failures occurred before clinical testing (primarily during regulatory GLP toxicology testing), with safety issues being the reason for 82% of preclinical project closures. The analysis suggested a crucial need for teams to pay attention to preclinical safety signals.
Based on the analysis, the paper concludes that there 5 variable that predict success for an R&D portfolio:
(1) Right target - Strong link between target and disease; differentiated efficacy; available and predictive biomarkers
(2) Right tissue - Adequate bioavailability and tissue exposure; definition of PD biomarkers; clear understanding of preclinical and clinical PK/PD; understanding of drug-drug interactions
(3) Right safety - DIfferentiated and clear safety margins, understanding of secondary pharmcology risk, understanding of reactive metabolites, genotoxicity, drug-drug interactions, understanding of target liability
(4) Right patients - Identification of patient population for tailoring of molecules, definition of risk-benefit for a given population
(5) Right commercial potential - Differentiated value proposition versus future standard of care, focus on market access (payer, provider), personalized health care strategy (diagnostic, biomarkers)
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