Transforming Drug Development in Heart Failure: Navigating the Regulatory Crossroads.

Abstract

Based on favorable hemodynamic data, flosequinan, an oral vasodilator, received marketing approval in Europe in September 1992 and in the United States in March 1993 for use in chronic heart failure (HF). Later, a phase III trial signaled increased mortality, prompting its withdrawal from the market. Oral milrinone was initially used for refractory HF but was later shown to increase adverse events when tested in late-phase trials. More recently, in 2002, the Food and Drug Administration (FDA) approved nesiritide for dyspnea improvement in patients with worsening HF,1 but a subsequent phase III trial showed that it did not influence mortality or readmission risk.2 These examples reinforce the enduring need for large, randomized trials with clinically meaningful end points and the role of regulatory authorities in protecting public health. Contradicting results between early-phase data and outcomes in registration trials in HF have raised the global regulatory bar for new drug approvals and have introduced regulatory uncertainty3 into the current drug development model. In 2016, candidate compounds are tested in sequential phases, terminating in trials in global, heterogeneous populations,4 mostly targeting neurohormonal pathways that may contribute to adverse remodeling. Surrogate end points are used in early-phase trials, whereas an adequate margin of safety (often assessed by risk of mortality or hospitalization) is required in registration trials.5 Placebo-controlled designs have been the standard, although active-controlled protocols have been used.6 Sponsors, few academic collaborators, and academic or contract research organizations guide the process and ultimately present the data to regulatory authorities. This paradigm has unfortunately been met with high operating costs of contemporary HF drug development programs, which has translated into fewer new drug applications and approvals by the FDA.3 This underscores the need for new approaches that will match increasingly scarce resources with high-yield trial propositions …