Abstract

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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Acknowledgements

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.

Author information

Author notes

    • Paul Morgan
    •  & Dean G. Brown

    P.M. and D.G.B. contributed equally to this work.

Affiliations

  1. Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, 1 Francis Crick Avenue, Cambridge CB2 0RE, UK.

    • Paul Morgan
    • , Mark J. Anderton
    •  & Stefan Platz
  2. Discovery Sciences, IMED Biotech Unit, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, USA.

    • Dean G. Brown
  3. IMED Biotech Unit, AstraZeneca, 1 Francis Crick Avenue, Cambridge CB2 0RE, UK.

    • Simon Lennard
    •  & Menelas N. Pangalos
  4. Oncology, IMED Biotech Unit, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, USA.

    • J. Carl Barrett
  5. Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gothenburg, Pepparedsleden 1, SE-431 83, Sweden.

    • Ulf Eriksson
    •  & Bengt Hamrén
  6. Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, 1 Francis Crick Avenue, Cambridge CB2 0RE, UK.

    • Mark Fidock
    •  & Ruth E. March
  7. Early Clinical Development, IMED Biotech Unit, AstraZeneca, 1 Francis Crick Avenue, Cambridge CB2 0RE, UK.

    • Anthony Johnson
    •  & James Matcham
  8. Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, USA.

    • Jerome Mettetal
  9. Discovery Sciences, IMED Biotech Unit, AstraZeneca, 1 Francis Crick Avenue, Cambridge CB2 0RE, UK.

    • David J. Nicholls
    • , Steve Rees
    •  & Michael A. Snowden

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  1. 1.

    Supplementary information S1 (table)

    Example structures from lead generation approaches

  2. 2.

    Supplementary information S2 (figure)

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

  3. 3.

    Supplementary information S3 (figure)

    Comparison of interspecies gastrointestinal toxicity with BRD4 inhibitors.

  4. 4.

    Supplementary information S4 (figure)

    Decision plot for combination of AZD8186 and AZD2014.

  5. 5.

    Supplementary information S5 (table)

    EGFR-m versus insulin receptor affinity for a series of EGFR-m inhibitors

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https://doi.org/10.1038/nrd.2017.244