| Sumario: | Metabolic and alcohol-related liver disease (MetALD) is a newly defined entity within the spectrum of steatotic liver disease, characterized by the interplay of cardiometabolic risk factors and alcohol consumption. The evolving epidemiology and complex pathophysiology of MetALD present unique challenges and opportunities for clinical trial design. Inclusion criteria should require simultaneous evidence of metabolic dysfunction (at least two cardiometabolic features) and verified quantifiable alcohol exposure recorded over the preceding 3–6 months. Traditional histological end points are limited by invasiveness, sampling error and interpretative variability. Thus, imaging modalities, serum-based fibrosis biomarkers and quantitative measures of alcohol intake are gaining relevance as non-invasive, reproducible and patient-centric end points aiming to improve trial feasibility. Furthermore, incorporating alcohol biomarkers, stratifying patients by metabolic risk factor burden, and using adaptive designs of trials might enhance the precision and generalizability of MetALD clinical trials. Although uncertainties remain regarding optimal patient selection criteria, event rates and the dynamic interplay between metabolic dysfunction and alcohol intake, ongoing research efforts aim to refine diagnostic criteria, standardize methodologies and validate novel end points. These advances will ultimately accelerate drug development, improve trial efficiency and foster interventions to treat MetALD. Metabolic and alcohol-related liver disease presents challenges in clinical trials due to complex pathophysiology. This Review discusses noninvasive imaging, serum biomarkers and adaptive designs as modalities to enhance patient-centric end points, aiming to refine diagnostics and improve drug development. Key points: Metabolic and alcohol-related liver disease (MetALD) combines metabolic dysfunction and alcohol use, with accelerated liver fibrosis progression compared with metabolic dysfunction-associated steatotic liver disease. MetALD diagnosis relies on self-reported alcohol use, which is prone to under-reporting, underestimation and recall bias. Advanced biomarkers, such as phosphatidylethanol, offer promise for enhancing diagnostic accuracy in MetALD and for providing a reliable quantification of alcohol consumption during clinical trials. Inclusion criteria for MetALD trials should integrate dynamic alcohol use and cardiometabolic profiles, and active alcohol use should be defined as intake within the last 6 months. Surrogate end points, such as fibrosis improvement and alcohol biomarkers, might enhance trial efficiency; noninvasive tests, including liver elastography-based techniques and serum biomarkers, can facilitate patient stratification and end point evaluation. Further research and regulatory–academic collaboration are essential to refine MetALD diagnostics, validate surrogate end points and standardize clinical trial frameworks.
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