Reassessing Phase II Heart Failure Clinical Trials: Consensus Recommendations

Abstract

The increasing burden and the continued suboptimal outcomes for patients with heart failure underlines the importance of continued research to develop novel therapeutics for this disorder. This can only be accomplished with successful translation of basic science discoveries into direct human application through effective clinical trial design and execution that results in a substantially improved clinical course and outcomes. In this respect, phase II clinical trials play a pivotal role in determining which of the multitude of potential basic science discoveries should move to the large and expansive registration trials in humans. A critical examination of the phase II trials in heart failure reveals multiple shortcomings in their concept, design, execution, and interpretation. To further a dialogue on the challenges and potential for improvement and the role of phase II trials in patients with heart failure, the Food and Drug Administration facilitated a meeting on October 17, 2016, represented by clinicians, researchers, industry members, and regulators. This document summarizes the discussion from this meeting and provides key recommendations for future directions.

Keywords: United States Food and Drug Administration; clinical trial; heart failure; mortality; safety.

Figure 1. Innovations in Phase II Trials

Innovation in phase II trials should include (1) identifying new surrogate markers, (2) comprehensive utilization of existing data, (3) novel statistical and analytical methods, and (4) developing guiding principles. * Including machine learning, data mining and sharing. † e.g. next generation genome sequencing. ‡ e.g. wearable and implantable devices, smart phone applications.

Figure 2. Therapeutic Targets in Phase II Trials

Targets of Phase II Trials should include increased filling pressures, congestion, cardiac remodeling, peripheral deconditioning, and neuroendocrine imbalance