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  • Review Article
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Strategies to improve drug development for sepsis

Key Points

  • Sepsis, a common and sometimes fatal systemic illness, is triggered by microbial infection and often leads to impaired function of the lungs, kidneys or other vital organs.

  • Since the early 1980s, a large number of therapeutic agents for the treatment of sepsis have been evaluated in randomized controlled clinical trials, but no specific therapeutic agent is currently approved for this indication.

  • Animal models that better mimic and predict outcomes in humans with sepsis would facilitate the development of effective therapeutic agents.

  • Use of the current standard definition of sepsis as an entry criterion for clinical trials leads to a heterogeneous population of enrolled patients, thereby diluting the relevant study population and raising the possibility of deleterious effects in patients who may not benefit.

  • Adaptive trial designs, particularly at the Phase II stage, should be considered for the development of new drugs for sepsis, in order to optimize the enrolment criteria, the timing and duration of treatment, and the dosing strategy.

  • Some promising drug targets are linked specifically to circulating molecules, which might be used as biomarkers in clinical trials for patient selection and/or adjustment of dosing regimens.

Abstract

Sepsis, a common and potentially fatal systemic illness, is triggered by microbial infection and often leads to impaired function of the lungs, kidneys or other vital organs. Since the early 1980s, a large number of therapeutic agents for the treatment of sepsis have been evaluated in randomized controlled clinical trials. With few exceptions, the results from these trials have been disappointing, and no specific therapeutic agent is currently approved for the treatment of sepsis. To improve upon this dismal record, investigators will need to identify more suitable therapeutic targets, improve their approaches for selecting candidate compounds for clinical development and adopt better designs for clinical trials.

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Figure 1: Simplified view of the 'standard model' for the pathogenesis of severe sepsis and septic shock.
Figure 2: Scheme for the development of therapeutic agents for sepsis, including key steps in the discovery process, the preclinical development process and the clinical evaluation process.

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Acknowledgements

H.S.W. was supported in part by the US Defense Advanced Research Projects Agency (DARPA) Grant W911NF-13-1-0070 and Grant 87200 from the Shriners Hospital for Crippled Children. The article represents the views of the authors alone and should not be construed to necessarily represent the views of the granting agencies.

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Summary of late phase (II or III) clinical trials of pharmacological interventions for the adjuvant treatment of sepsis, which have been reported since 1982. (PDF 210 kb)

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Fink, M., Warren, H. Strategies to improve drug development for sepsis. Nat Rev Drug Discov 13, 741–758 (2014). https://doi.org/10.1038/nrd4368

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