Acute heart failure clinical drug development

From planning to proof of activity to phase III

Gad Cotter, Adriaan A. Voors, Beth Davison Weatherley, Peter Pang, John R. Teerlink, Gerasimos Filippatos, Piotr Ponikowski, Olga Milo-Cotter, Howard Dittrich, Sam L. Teichman, Kirkwood F. Adams, Mihai Gheorghiade, Marco Metra

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Over the last decades, attempts to develop new therapies for acute heart failure (AHF) have largely failed. Limitations in understanding the pathophysiology of AHF, its natural history, the effects of current therapies, the properties of new agents, and, importantly, study designs and execution have contributed to these disappointing results. We propose a novel approach for the development of new agents for AHF. Initial stages of development (proof of activity and phase IIa studies) should provide a granular understanding of the mechanism of the actions and pharmacodynamic properties of the new intervention, first in animal models of HF and then in small tightly designed human studies. This will facilitate the identification of patients who are more likely to show a favorable response. In phase II studies (proof of concept), the assessment of efficacy and final dose selection should not be based on surrogate endpoints but rather on clinically meaningful endpoints such as the relief of AHF symptoms, i.e. breathlessness, as well as consistent trends in the relief of other symptoms and clinical signs of recurrence (worsening HF either in hospital or after discharge) and short-term mortality. Lastly, other safety parameters, i.e. effects such as renal and myocardial damage, should be assessed. In some instances, the decision to move to phase III may be based on clear consistent trends rather than on 1 statistically significant endpoint. In studies that confirm clinical utility (phase III), efficacy will be judged relative to the magnitude of the benefit, i.e. improvements in symptoms (breathlessness), the prevention of symptom recurrence, and short-term mortality, balanced by the consideration of safety signals including an estimation of absolute mortality.

Original languageEnglish (US)
Pages (from-to)292-301
Number of pages10
JournalCardiology
Volume116
Issue number4
DOIs
StatePublished - Oct 2010
Externally publishedYes

Fingerprint

Heart Failure
Pharmaceutical Preparations
Dyspnea
Mortality
Safety
Recurrence
Natural History
Signs and Symptoms
Animal Models
Biomarkers
Kidney
Therapeutics

Keywords

  • Acute heart failure
  • Breathlessness
  • Drug development

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Pharmacology (medical)

Cite this

Cotter, G., Voors, A. A., Weatherley, B. D., Pang, P., Teerlink, J. R., Filippatos, G., ... Metra, M. (2010). Acute heart failure clinical drug development: From planning to proof of activity to phase III. Cardiology, 116(4), 292-301. https://doi.org/10.1159/000318048

Acute heart failure clinical drug development : From planning to proof of activity to phase III. / Cotter, Gad; Voors, Adriaan A.; Weatherley, Beth Davison; Pang, Peter; Teerlink, John R.; Filippatos, Gerasimos; Ponikowski, Piotr; Milo-Cotter, Olga; Dittrich, Howard; Teichman, Sam L.; Adams, Kirkwood F.; Gheorghiade, Mihai; Metra, Marco.

In: Cardiology, Vol. 116, No. 4, 10.2010, p. 292-301.

Research output: Contribution to journalArticle

Cotter, G, Voors, AA, Weatherley, BD, Pang, P, Teerlink, JR, Filippatos, G, Ponikowski, P, Milo-Cotter, O, Dittrich, H, Teichman, SL, Adams, KF, Gheorghiade, M & Metra, M 2010, 'Acute heart failure clinical drug development: From planning to proof of activity to phase III', Cardiology, vol. 116, no. 4, pp. 292-301. https://doi.org/10.1159/000318048
Cotter G, Voors AA, Weatherley BD, Pang P, Teerlink JR, Filippatos G et al. Acute heart failure clinical drug development: From planning to proof of activity to phase III. Cardiology. 2010 Oct;116(4):292-301. https://doi.org/10.1159/000318048
Cotter, Gad ; Voors, Adriaan A. ; Weatherley, Beth Davison ; Pang, Peter ; Teerlink, John R. ; Filippatos, Gerasimos ; Ponikowski, Piotr ; Milo-Cotter, Olga ; Dittrich, Howard ; Teichman, Sam L. ; Adams, Kirkwood F. ; Gheorghiade, Mihai ; Metra, Marco. / Acute heart failure clinical drug development : From planning to proof of activity to phase III. In: Cardiology. 2010 ; Vol. 116, No. 4. pp. 292-301.
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