Reassessing the Role of Surrogate End Points in Drug Development for Heart Failure

Abstract

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.

Keywords: biomarkers; clinical trial; drug discovery; endpoint determination; heart failure.

Figure 1.

Proportion of cardiovascular trials with positive outcomes by the type of primary endpoint over time. Cardiovascular trials using intermediate or surrogate endpoints had similar proportions of positive outcomes over time, whereas trials including clinical endpoints had less positive outcomes over time. Analyses of temporal trends across trial time frames were performed using nonparametric tests for trend. Adapted with permission from Patel RB et al.

Figure 2.

Cumulative event rates for cardiovascular death or heart failure re-hospitalization within 12 months (A) and the change in NT-proBNP over follow-up (B) from the ASTRONAUT trial. Adapted from Gheorghiade M et al. Late Breaking Clinical Trial Presentation at ACC 2013 Meeting, March 11, 2013.

Figure 3.

Influence of aliskiren on longitudinal NT-proBNP level in the ASTRONAUT trial by atrial fibrillation/flutter status. The y-axis represents the estimated NT-proBNP level in pg/mL, derived from exponentiation of the log-transformed NT-proBNP level at each time point. NTproBNP, N-terminal pro-B-type natriuretic peptide. Adapted with permission from Greene SJ et al.

Figure 4.

Potential framework for re-appraising the future design, purpose, and execution of phase II studies in HF drug development. Recognizing that there are no reliable surrogate outcomes for phase III approval endpoints, we propose that the central goal of phase II should not be to predict phase III results but to optimize phase III execution and to clarify the drug mechanism and drug-patient interaction. Adaptive trial design may allow for a more efficient drug development process and may more directly allow information gained from phase II to shape the phase III trial.

Figure 5.

Conceptual framework of adaptive trial design. Trial would start with a planned end. Interim analysis in the statistical “promising” zone would prompt sample size re-estimation with addition of further patients and extension of the trial beyond the planned end, increasing chances of trial finding definitive result. Interim analysis in the “favorable” or “unfavorable” zone would not prompt extension of the trial, as the initial planned end would have reasonable probability of arriving at a definitive result. Interim analysis in the “efficacy” or “futility” zones would prompt the trial being stopped early before the planned end.