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A novel approach for establishing cardiovascular drug efficacy

Nature Reviews Drug Discovery volume 13, page 942 (2014)Cite this article

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Gaining an early understanding of the likely ultimate efficacy of drugs is crucial for the pharmaceutical industry, as lack of efficacy remains a major reason for attrition in the later stages of drug development (Phase II and Phase III attrition rates 2011–2012. Nature Rev. Drug Discov. 12, 569; 2013)1. Drug development for cardiovascular and/or renal diseases is currently often based on the modification of a single risk factor, such as blood pressure or lipid profiles, with the expectation that this will decrease the long-term risk of morbidity or mortality. Thus, the risk factor serves as a surrogate for the intended effect. To confirm that the drug effect on the risk factor indeed leads to the expected long-term efficacy and safety, short-term trials focused on effects on the risk factor are (or should be) followed by one or more (post-registration) trials evaluating clinically meaningful outcomes, such as reduction in cardiovascular events, which are typically large, complex and expensive. In parallel to this process to investigate efficacy, the safety of the drug is established by monitoring a mostly fixed set of parameters in all efficacy trials.

Current drug discovery and development for indications such as hypertension assumes two things; first, that the drug-induced change in an on-target risk factor, such as blood pressure, is the most important contributor to the anticipated reduction in cardiovascular/renal risk. Hence, the on-target drug effect should explain the drug effect on long-term outcome2. Second, it is assumed that the drug has no other effects that influence long-term outcome.

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Acknowledgements

This work was performed as part of the Escher project (project number T6-202) within the framework of the Dutch Top Institute Pharma. H.J.L.H. is supported by a VENI-Grant from the Netherlands Organisation for Scientific Research.

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Authors and Affiliations

  1. Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, Groningen, 9713 AV, the Netherlands

    Hiddo. J. Lambers Heerspink & Dick de Zeeuw

  2. Julius Center for Health Science and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands

    Diederick E. Grobbee

Authors
  1. Hiddo. J. Lambers Heerspink
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  2. Diederick E. Grobbee
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  3. Dick de Zeeuw
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Corresponding author

Correspondence to Hiddo. J. Lambers Heerspink.

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The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (table)

Outcome trials or post-marketing studies of drugs that failed to provide additional cardiovascular/renal protection despite favourable effects on the on-target risk marker (PDF 254 kb)

Supplementary information S2 (box)

Examples of failures in late-stage drug development or post-marketing studies (PDF 140 kb)

Supplementary information S3 (box)

PRE score: an integrated score to estimate drug efficacy (PDF 182 kb)

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Heerspink, H., Grobbee, D. & de Zeeuw, D. A novel approach for establishing cardiovascular drug efficacy. Nat Rev Drug Discov 13, 942 (2014). https://doi.org/10.1038/nrd4090-c2

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