Editorial: changes of health‐related quality of life associated with hepatic disease severity and its improvement after treatment in NAFLD—authorsʼ reply

We appreciate the editorial comments by Drs. Sun and Fan about our study assessing the associations of patient- reported outcomes (PROs) and non- invasive tests (NITs) in patients with non- alcoholic fatty liver disease (NAFLD) and non- alcoholic steatohepatitis (NASH). 1,2 In their editorial, the authors correctly highlight that improvements of liver histology in terms of hepatic fat reduc-tion, NASH remission, NAFLD activity score decline, and fibrosis regression in clinical trials are associated with improvement of PRO scores. 2 Despite advances in our understanding of the pathophysiology and pathogenesis of NAFLD, no specific drug has been approved for NASH. 3,4 In recent years, several double- blind, placebo- controlled trials relying on sequential liver biopsies failed to show statistically significant improvements over time in traditional primary endpoints 3,4 ( i.e ., improvement of liver fibrosis with-out worsening of NASH or resolution of NASH with no worsening of liver fibrosis). 5 Although these endpoints are typically deter-mined for regulatory purposes, we believe that attempts to estab-lish disease modification in NAFLD should be encouraged by all stakeholders involved in drug development. These attempts should take into account not only the surrogates of clinical outcomes ( e.g ., histologic or NIT stage of fibrosis) but also PRO scores, which are the surrogates for patient experience. Although traditional phase III study designs may suffice to show the impact of treatment regi-mens on PROs, studies with alternative designs should also be considered. In this context, PRO assessment may require alternative designs and/or a longer study duration than traditional phase III clinical