To secure approval, NASH drug candidates must prevent or delay disease progression, an ability measured via histopathological assessments of liver biopsies. Indeed, liver histopathology is a compulsory primary endpoint in NASH clinical trials and is thus a prerequisite for drug approval. Despite this, a number of endpoint-associated challenges to NASH trial development remain inadequately addressed.
This review aimed to investigate the challenges associated with NASH clinical trials’ design, analysis and interpretation. It further proposed solutions to overcome these trial-related hurdles.
Challenges limiting the progress of NASH trials include short and ineffective trial durations, baseline comorbidities, and unexpected placebo responses. However, the biggest obstacle to NASH drug development is the variability underpinning trials’ primary histological endpoints. Liver biopsy is hindered by its innate invasiveness, which limits patient enrollment. However, biopsies’ interpretations are also subject to inconsistency due to suboptimal intra- and inter-reader reliability, as evidenced by hepatocellular ballooning’s subjective identification amongst pathologists. The lack of stringent guidelines on the biopsy-reading process also reduces standardisation across NASH trials. Ultimately, research into NASH must focus on developing adaptive study designs and improving non-invasive tools (NITs), shifting the focus towards blood-based markers as well as ultrasound-based and enhanced liver fibrosis tests. Defining the best NIT combinations for later trial phases is paramount to improving and expediting NASH drug development.