Drug development for NASH has become one of the hottest research areas in medicine. According to the US Food and Drug Administration and the European Medicines Agency, a drug can be conditionally registered for clinical use if it improves histological fibrosis without worsening of NASH or resolution of NASH without worsening of fibrosis. However, because these histological endpoints are not considered fully validated, even after conditional approval, the phase 3 studies need to continue for 5 years or more to demonstrate an improvement in long-term clinical outcomes including progression to cirrhosis and development of cirrhotic complications.
Among the histological features of NASH, liver fibrosis has the strongest correlation with clinical outcomes. However, although NASH is farther from the clinical outcomes, it is the driver for fibrosis progression. Other than correlation with outcomes, other practical considerations when choosing endpoints would include the biological plausibility, the time needed to show a change, and the reliability of the measurement. For example, while histological endpoints are now commonly used in phase 2b and phase 3 trials, the evaluation of liver biopsy specimens suffers from the issue of sampling, intra-observer and inter-observer variability. The use of artificial intelligence has been shown to improve the reproducibility of histological assessment, but further work has to be done for its adoption and acceptance by regulators.
Improvement in histological assessment should only be the first stage. After we have demonstrated the reliability of histological features as surrogate endpoints, the next goal should be to replace them with non-invasive tests. A number of non-invasive tests of fibrosis have already been extensively evaluated in cross-sectional studies. We need to evaluate their role as monitoring tools for fibrosis change and the correlation with clinical outcomes.