Table 3.

Endpoints (markers of outcomes) for early stage disease

Endpoint	Comment
Development of cirrhosis	Clearly defines a worsening of health status and adversely affects how a patient feels, functions or survives May serve as a primary endpoint for full approval May be measured by biopsy or other modalities for the diagnosis of advanced fibrosis/cirrhosis (e.g., liver stiffness measurements)
Reversal of steatohepatitis without progression to advanced fibrosis (stage 3–4)	Can be demonstrated within a 12–24 month time-frame Is a surrogate for prevention of cirrhosis May be suitable for subpart H approval process but will require long-term post-approval follow up to demonstrate that treatment prevents cirrhosis Advanced fibrosis/cirrhosis may be measured by biopsy or other modalities for the diagnosis of advanced fibrosis/cirrhosis (e.g., liver stiffness measurements)
NAFLD Activity Score (NAS)	Needs validation to demonstrate that a decrease reflects reduced risk of advanced fibrosis/cirrhosis. Relative impact of improvement of steatosis vs. inflammation vs. ballooning is not clear
Reduction of hepatic steatosis by imaging studies along with decrease in ALT and/or CK18	MR quantification of steatosis is now a community-accepted validated tool: requires FDA acceptance of the tool for validation and use in clinical trials used for registration* ALT usually, but not always, improves with improvement in histology Decreased CK18 has been shown to correlate with histological improvement in trials of subjects with stage 0–3 disease Best suited for early phase proof of concept (phase 1/2a) studies

^*It is recommended that sponsors planning to use this tool as an endpoint discuss their plans with FDA in accordance with FDA mechanisms for pre-trial consultation.