Over the past decade, the field of heart failure (HF) has witnessed remarkable progress in drug development, resulting in the approval of numerous groundbreaking drugs by the U.S. Food and Drug Administration. To address some of these challenges, the U.S. Food and Drug Administration has issued guidance documents that have been critical in contemporary HF drug development; however, there are still many challenges in need of investigation. This paper leverages efforts of the Heart Failure Collaboratory and the scientific community to discuss the critical need for innovative trial designs, important concepts in clinical trials in the modern era, and the utilization of big data to accelerate HF drug development. At this inflection point in HF drug development, it is imperative that, as a global scientific community, we foster increased collaboration among researchers, clinicians, patients, and regulatory bodies. Only through such unified efforts can we navigate the complexities of HF, accelerate the development process, and ultimately deliver effective therapies that transform patient outcomes.
Over the past decade, the field of heart failure (HF) has witnessed remarkable progress in drug development, resulting in the approval of numerous groundbreaking drugs by the U.S. Food and Drug Administration (FDA). In a recent publication, we proposed a comprehensive roadmap for optimizing medical therapy within the context of contemporary HF trials. However, the evolving landscape of new therapies has brought forth novel challenges in development and implementation. In this context, the Heart Failure Collaboratory (HFC), a consortium of stakeholders dedicated to enhancing the efficiency and conduct of clinical trials, has played a critical role in fostering collaborative discussions, synthesizing diverse perspectives, and shaping actionable recommendations that aim to navigate contemporary clinical trial challenges and advance the field of HF drug development.
Historically, HF drug development programs focused on clinical outcomes such as hospitalization and mortality, particularly after the introduction of certain drugs in the 1980s that showed favorable effects on symptoms and function but raised concerns regarding survival (eg, milrinone, flosequinan). This history led to future cardiovascular outcome studies to be designed large enough to not overlook an increase in adverse outcomes. Subsequently, outcome studies across various drug classes, including beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, mineralocorticoid receptor antagonists, isosorbide/ hydralazine, angiotensin receptor neprilysin inhibitors, and sodium-glucose cotransporter 2 inhibitors, have shown important reductions in morbidity and mortality and defined a strategy for combination drug therapy to treat HF that is embraced in consensus guidelines from the American College of Cardiology/American Heart Association. However, the path of sizeable and longer megatrials focused on morbidity and mortality may be difficult to sustain because of escalating costs, increasing operational complexity, prolonged timelines, and a diminishing ability to distinctly show improvements, especially when juxtaposed with the efficacy of existing HF therapies.
To address some of these challenges, the FDA issued guidance documents for contemporary clinical trials, including adaptive clinical trial design and endpoints in HF; however, there are still challenges that need investigation. Looking forward, the adoption of innovative trial designs, endpoints, and advanced statistical methods for outcome interpretation is crucial to enhance trial efficiency and expedite HF drug development. As we delve deeper into the realm of big data and advanced analytics, a well-defined strategy for interpreting and acting on these findings, particularly within specific patient subgroups, becomes indispensable. Furthermore, with HF studies conducted worldwide, a standardized approach to trial design, endpoints, and data interpretation is imperative. Building upon these considerations, the aim of the present paper was to focus on addressing relevant concepts and challenges in drug development. Drawing from the collective insights of the HFC consortium and broader scientific community, the overarching goal of this paper was to summarize the current efforts of HFC and highlight important concepts in the contemporary landscape of HF drug development.