[Considerations on clinical trial issues related to new drug development for metabolic and alcohol-associated liver disease and fatty liver disease].

The global incidence of alcohol-associated liver disease(ALD) is rising. Beyond glucocorticoids, effective pharmacological therapies for severe ALD remain limited. With the introduction of the novel concept of "metabolic and alcohol-associated liver disease (MetALD) ", it has emerged as a distinct clinical condition characterized by synergistic liver injury resulting from the interplay between metabolic dysfunction and alcohol consumption. In contrast to the substantial progress in drug development for metabolic associated steatotic liver disease (MASLD), clinical research on ALD and MetALD has advanced slowly. Worldwide, only a limited number of clinical trials for ALD have been registered, and ongoing studies frequently encounter challenges such as patient recruitment difficulties and high attrition rates. Given its recent classification, MetALD currently lacks specific clinical trial guidance from regulatory agencies. These hurdles are compounded by additional challenges, including etiological heterogeneity, stigma related to alcohol use, and suboptimal treatment adherence, which collectively impede therapeutic development. Stratification of study populations according to cardiometabolic risk profiles and stages of liver fibrosis represents a critical strategy to optimize trial design and identify patient subgroups most likely to benefit. This article delineates key challenges in clinical trial design for novel ALD and MetALD therapeutics, summarizes the current research landscape and its core limitations, and proposes future directions focused on the selection of hard clinical endpoints, dual-pathway benefit assessment, and investigator-initiated trials.