Rethinking Endpoints in Clinical Research Beyond Mortality

Clinical trials have long relied on "hard" endpoints such as mortality, kidney failure, and stroke, as the gold standard for measuring treatment benefit. But as therapies advance into earlier disease stages and preventive settings, these traditional endpoints increasingly fall short. Trials designed around them can require decades of follow-up, enormous investment, and populations too large to be practical, leaving patients waiting for treatments that may already show promise through other, earlier signals.

The October 2025 DCRI Think Tanks meeting, "From Survival to Significance: Evolving Endpoints Beyond Mortality and Related 'Hard' Outcomes Across Clinical Research," brought together experts from academia, industry, and regulatory agencies to examine how surrogate and alternative endpoints can be better selected, validated, and applied across the clinical trial continuum.

Key themes from the discussion included:

• Clarifying the surrogate endpoint validation pathway: The FDA distinguishes between surrogates that are "reasonably likely" and those that are fully "validated," but the road between them remains poorly defined — creating uncertainty for sponsors and slowing progress across therapeutic areas.
• Aligning stakeholders around patient-centered goals: Regulators, payers, clinicians, and patients each bring different timelines and incentives to endpoint selection. Bridging those differences requires a shared focus on what outcomes matter most to patients.
• Enabling prevention and low-risk trials: Demonstrating benefit in healthy or low-risk populations using traditional endpoints is often simply not feasible. Surrogate endpoints that capture early disease modification offer a potential path forward — but require extending the evidence base beyond populations where disease is already established.
• Rethinking composite endpoints: Conventional composites, such as major adverse cardiovascular events, treat all component events equally, obscuring differences in disease burden and severity. Novel frameworks, such as the Desirability of Outcome Ranking (DOOR), offer more nuanced tools for capturing net clinical benefit, including patient-reported outcomes alongside clinical events.
• Harnessing real-world data: Post-marketing surveillance remains an underused resource for refining surrogate endpoint validation. Realizing its potential will require investment in data standardization, interoperability, and long-term monitoring infrastructure.