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Impact of a five-dimensional framework on R&D productivity at AstraZeneca


In 2011, AstraZeneca embarked on a major revision of its research and development (R&D) strategy with the aim of improving R&D productivity, which was below industry averages in 2005–2010. A cornerstone of the revised strategy was to focus decision-making on five technical determinants (the right target, right tissue, right safety, right patient and right commercial potential). In this article, we describe the progress made using this '5R framework' in the hope that our experience could be useful to other companies tackling R&D productivity issues. We focus on the evolution of our approach to target validation, hit and lead optimization, pharmacokinetic/pharmacodynamic modelling and drug safety testing, which have helped improve the quality of candidate drug nomination, as well as the development of the right culture, where 'truth seeking' is encouraged by more rigorous and quantitative decision-making. We also discuss where the approach has failed and the lessons learned. Overall, the continued evolution and application of the 5R framework are beginning to have an impact, with success rates from candidate drug nomination to phase III completion improving from 4% in 2005–2010 to 19% in 2012–2016.

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Figure 1: The 5R framework.
Figure 2: Number and phase of active preclinical projects in the portfolio from 2005 to 2016 and their target class composition.
Figure 3: Metrics for preclinical projects reaching the lead optimization phase.
Figure 4: Human pharmacokinetics prediction accuracy and impact of proof of mechanism on project success rate.
Figure 5: Project success rates and reasons for failure.
Figure 6: Impact of personalized health care on the portfolio.
Figure 7: Metrics for project costs, cycle times, publications and investor sentiment.


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The authors sincerely thank the following collaborators at AstraZeneca for their significant contribution to this manuscript: M. Davies, S. Delaney, K. Grime, D. Hayes, O. Jones, A. Kohlmann, R. Krestin, S. McGinty, D. McGinnity, C. Priestley, G. Schiavon, D. Stanski, M. Wagoner and J. Yates.

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Correspondence to Dean G. Brown or Menelas N. Pangalos.

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All authors are employees and shareholders of AstraZeneca.

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Example structures from lead generation approaches (PDF 367 kb)

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Target engagement and tolerability of AZD8848 (TLR7 agonist) and AZD1419 (TLR9 agonist) in healthy volunteers. (PDF 498 kb)

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Comparison of interspecies gastrointestinal toxicity with BRD4 inhibitors. (PDF 1022 kb)

Supplementary information S4 (figure)

Decision plot for combination of AZD8186 and AZD2014. (PDF 378 kb)

Supplementary information S5 (table)

EGFR-m versus insulin receptor affinity for a series of EGFR-m inhibitors (PDF 198 kb)

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Morgan, P., Brown, D., Lennard, S. et al. Impact of a five-dimensional framework on R&D productivity at AstraZeneca. Nat Rev Drug Discov 17, 167–181 (2018).

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