FDA Publishes Draft Noncirrhotic Non-alcoholic Steatohepatitis (NASH) With Liver Fibrosis Guidance

January 18, 2019 Becky Hurt

By: Brad Gillespie, Principal Consultant, PAREXEL® Consulting

Nonalcoholic fatty liver disease (NAFLD) is diagnosed when the liver contains more than 5% fat (steatosis). NAFLD can progress to the inflammatory liver condition Non-Alcoholic Steatohepatitis (NASH), fibrosis, cirrhosis and in some cases, hepatocellular carcinoma. Worldwide, NASH-related-cirrhosis is the third most frequent cause of liver transplantation and is projected to become the most common in the next 10-20 years1.There are no FDA-approved drugs for the treatment of NASH. The Pharmaceutical Industry is aware of this: Clintrials.gov recently listed 658 NASH studies.

In December 2018 FDA issued a draft guidance document designed to accelerate the development of drug products (also applicable to biologics) useful for the treatment of NASH with or without liver fibrosis2. Key clinical development considerations are discussed, below.

  • The goal of NASH treatment should be to slow, halt or ultimately reverse its progression, improve outcomes, reduce the need for transplantation and increase survival.

  • Currently, definitive NASH diagnosis is by liver biopsy, an invasive procedure that is not without risk. Treatment periods of 12-18 months are required to assess efficacy using histopathologic endpoints. As a result, non-invasive, validated biomarkers are needed (to include imaging modalities) to streamline NASH drug development.

  • Proof of Concept studies may avoid the use of histopathologic endpoints, instead assessing the potential of the candidate drug on standard measures of liver injury such as ALT and AST or characterization of liver stiffness or fat content using imaging methods.Nonetheless, the sponsor should endeavour to enrol similar patient populations to that planned for confirmatory Phase 3 trials.

  • As in all clinical trials, it is critical to monitor liver safety. Further, sponsors are implored to characterize the impact of liver impairment on drug disposition early in development, as appropriate.

  • Phase 2 dose ranging trials must prove efficacy using a meaningful histopathological endpoint. Any biomarkers planned for Phase 3 should be collected and assessed versus histopathological-proven activity.

  • Phase 3 trials should enrol patients diagnosed within the past 6 months; baseline histology is critical. Critical inclusion criteria include a NASH Activity Score of at least 4, inflammation, ballooning and Stage 1-3 fibrosis.

  • While increased ALT and AST levels are expected in NASH patients, patients with elevations >5 x ULN may have concomitant liver pathology and should be excluded from late-stage trials.

  • Sponsors are encouraged to employ a combination of histological endpoints that are likely to predict clinical benefit, such as no worsening/resolution of steatohepatitis and/or liver fibrosis. The relationship between histological improvement and clinical outcomes have not been fully established. As a result, sponsors should propose and justify the degree of improvement required to establish efficacy.

  • Sponsors are encouraged to consider adaptive clinical trial designs to streamline the development process.

  • NASH drugs able to fulfil unmet medical needs may be eligible for accelerated approval the sponsor is able to develop a surrogate endpoint able to predict clinical benefit. Nonetheless, if the sponsor is able to secure accelerated approval designation, confirmatory trials assessing clinical benefit should be underway at the time of regulatory submission.

  • The pediatric pathology of NASH differs from adults. As a result, extrapolation of safety and efficacy from adults to children using pharmacokinetic and/or pharmacodynamic (PK/PD) approaches are not appropriate. Additional natural history of pediatric NASH disease information is needed to design proper trials. FDA acknowledges the complexity of pediatric NASH trials and suggest that sponsors initiate such studies after obtaining safety and efficacy information in adults. FDA is currently planning the issuance of a pediatric NASH guidance document.

  • PAREXEL encourages early FDA engagement prior to the initiation of any human trials.

PAREXEL is currently supporting several clients pursuing NASH therapies: both re-purposed molecules [505(b)(2) pathway] as well as new molecular entities [small molecules and biologics]. Based on our extensive experience in the development of drugs for unmet needs, we are well positioned to develop and execute efficient, molecule-specific NASH clinical development plans.


1 Zezos, P & Renner, EL. (2014). Liver transplantation and non-alcoholic fatty liver disease. World J Gastroenterol. 20(42): 15532–15538

2 FDA.gov: GuidanceComplianceRegulatoryInformation/Guidances/UCM627376.pdf

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