TABLE 1:

SOME KEY BARRIERS TO DRUG DEVELOPMENT FOR AH AND NASH AND POTENTIAL SOLUTIONS

Barrier	Alcoholic Hepatitis	NASH	Solution
General Barriers	• Social stigma • Lack of awareness • Lack of clear regulatory pathway	• Lack of awareness	Education
Populations	• Lack of consensus Related to definitions and nomenclature • Heterogeneity in terms of clinical-histological-molecular phenotypes • Lack of data linking well definited phenotypes to specific outcomes	• Heterogeneity of populations with respect to risk of progression and natural history of precirrhotic versus cirrhotic stages of the disease	• Alcoholic Hepatitis: collaborative efforts between NIAAA, academia and regulatory agencies.  • NASH: distinct trial design and endpoints for those with precirrhotic vs cirrhotic NASH
Endpoints	• Endpoints not cleanly linked to drivers of outcomes • Timing of outcome measurement affects assessment of drug interventions • Lack of validated endpoints other than mortality	• Need for a liver biopsy to assess short-term outcomes  • Lack of validated surrogate endpoints	• Multi-stakeholder collaboration to validate clinical endpoints and natural course of disease for specific populations of subjects with alcoholic liver disease or NASH
Safety	• DILI assessment is unclear • Lack of clarity on safety assessment related to intestinal microbiome	• DILI assessment is unclear  • Lack of clarity on safety assessment related to intestinal microbiome	• Collaborative multi-stakeholder effort to generate the evidence base to support guidance on safety assessment  • Ongoing FDA efforts to generate guidance
Biomarkers	• Gaps in knowledge related to distinct clinical-histological-molecular subpopulations	• Lack of point of care assessment tool  • Lack of validated PRO	• Large cohort and case control studies accompanied by biomarker assessment  • Assessment of novel biomarkers in circulation, urine, breath or stool