Journal
CIRCULATION
Volume 138, Issue 10, Pages 1039-1053Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.118.034668
Keywords
biomarkers; clinical trial; drug discovery; endpoint determination; heart failure
Funding
- National Institutes of Health [5T32HL069749-14, U01HL125511-01A1, U10HL110312, R01AG045551-01A1, 5T32HL069749]
- Heart Failure Society of America/Emergency Medicine Foundation Acute Heart Failure Young Investigator Award - Novartis
- Amgen
- Novartis
- Akros
- AstraZeneca
- Bayer
- GlaxoSmithKline
- Gilead
- Luitpold
- Medtronic
- Merck
- Otsuka
- ResMed
- National Institutes of Health
- Patient-Centered Outcomes Research Institute
- European Union
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With few notable exceptions, drug development for heart failure (HF) has become progressively more challenging, and there remain no definitively proven therapies for patients with acute HF or HF with preserved ejection fraction. Inspection of temporal trends suggests an increasing rate of disagreement between early-phase and phase III trial end points. Preliminary results from phase II HF trials are frequently promising, but increasingly followed by disappointing phase III results. Given this potential disconnect, it is reasonable to carefully re-evaluate the purpose, design, and execution of phase II HF trials, with particular attention directed toward the surrogate end points commonly used by these studies. In this review, we offer a critical reappraisal of the role of phase II HF trials and surrogate end points, highlighting challenges in their use and interpretation, lessons learned from past experiences, and specific strengths and weaknesses of various surrogate outcomes. We conclude by proposing a series of approaches that should be considered for the goal of optimizing the efficiency of HF drug development. This review is based on discussions between scientists, clinical trialists, industry and government sponsors, and regulators that took place at the Cardiovascular Clinical Trialists Forum in Washington, DC, on December 2, 2016.
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