Nonalcoholic Steatohepatitis Clinical Trials Research Articles

Clinical Utility of Change in Nonalcoholic Fatty Liver Disease Activity Score and Change in Fibrosis in NAFLD

The Nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) has been applied as a method for evaluating treatment response, and a ≥2-point improvement in NAS has been commonly used as an accepted end point in phase 2b clinical trials in nonalcoholic steatohepatitis.1,2 Although liver fibrosis is the strongest histologic predictor of liver-related outcome and all-cause mortality in NAFLD,3,4 the association between change in NAS and change in fibrosis stage has not been fully verified. Therefore, we aimed to examine the association between change in NAS and change in fibrosis stage in well-characterized patients with NAFLD who had a paired liver biopsy assessment.

Role of betaine in liver disease-worth revisiting or has the die been cast?

Nonalcoholic steatohepatitis (NASH) is an important indication for liver transplantation in many Western countries due to the epidemic of obesity and insulin resistance. Unfortunately, no medication is approved for NASH and risk factor modification is often advised. Over the last decade, several clinical trials on NASH have been conducted with several ongoing and the future looks promising. Although betaine (trimethyl glycine) was evaluated for NASH, results were mixed in the clinical trials in large part due to the quality of the studies. It seems reasonable to re-evaluate betaine in clinical trials for NASH and alcoholic liver disease due to its low cost, tolerability and mechanism of action.

A composite biomarker using multiparametric magnetic resonance imaging and blood analytes accurately identifies patients with non-alcoholic steatohepatitis and significant fibrosis

Non-alcoholic steatohepatitis (NASH) is major health burden lacking effective pharmacological therapies. Clinical trials enrol patients with histologically-defined NAFLD (non-alcoholic fatty liver disease) activity score (NAS) ≥ 4 and Kleiner-Brunt fibrosis stage (F) ≥ 2; however, screen failure rates are often high following biopsy. This study evaluated a non-invasive MRI biomarker, iron-corrected T1 mapping (cT1), as a diagnostic pre-screening biomarker for NASH. In a retrospective analysis of 86 biopsy confirmed NAFLD patients we explored the potential of blood and imaging biomarkers, both in isolation and in combination, to discriminate those who have NAS ≥ 4 and F ≥ 2 from those without. Stepwise logistic regression was performed to select the optimal combination of biomarkers, diagnostic accuracy was determined using area under the receiver operator curve and model validated confirmed with and fivefold cross-validation. Results showed that levels of cT1, AST, GGT and fasting glucose were all good predictors of NAS ≥ 4 and F ≥ 2, and the model identified the combination of cT1-AST-fasting glucose (cTAG) as far superior to any individual biomarker (AUC 0.90 [0.84–0.97]). This highlights the potential utility of the composite cTAG score for screening patients prior to biopsy to identify those suitable for NASH clinical trial enrolment.

Complex Innovative Design for NASH Clinical Trials

The prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing world-wide. The development of drug product for treating NASH is considered unmet medical need. Due to the increasing prevalence and the health burden, there is a high need to develop therapeutic strategies for patients with NASH. The primary objective of the treatment for NASH is to prevent liver-related morbidity and mortality, which generally takes a long time (e.g., more than 10-20 years) to develop. In practice, it is not feasible to conduct such clinical studies. Thus, regulatory agencies such as United States Food and Drug Administration (FDA) encourage to look at surrogate endpoints for review and approval. Seamless adaptive clinical trial designs in NASH provide an opportunity to shorten the overall path to registration for a new drug and offer continuity for patients enrolled in the study. In this article, Characteristics for applying various seamless adaptive designs to clinical trials in NASH are reviewed. Statistical, clinical, and strategic issues related to drug development of NASH are also discussed.

An Improved qFibrosis Algorithm for Precise Screening and Enrollment into Non-Alcoholic Steatohepatitis (NASH) Clinical Trials

Background: Many clinical trials with potential drug treatment options for non-alcoholic fatty liver disease (NAFLD) are focused on patients with non-alcoholic steatohepatitis (NASH) stages 2 and 3 fibrosis. As the histological features differentiating stage 1 (F1) from stage 2 (F2) NASH fibrosis are subtle, some patients may be wrongly staged by the in-house pathologist and miss the opportunity for enrollment into clinical trials. We hypothesized that our refined artificial intelligence (AI)-based algorithm (qFibrosis) can identify these subtle differences and serve as an assistive tool for in-house pathologists. Methods: Liver tissue from 160 adult patients with biopsy-proven NASH from Singapore General Hospital (SGH) and Peking University People’s Hospital (PKUH) were used. A consensus read by two expert hepatopathologists was organized. The refined qFibrosis algorithm incorporated the creation of a periportal region that allowed for the increased detection of periportal fibrosis. Consequently, an additional 28 periportal parameters were added, and 28 pre-existing perisinusoidal parameters had altered definitions. Results: Twenty-eight parameters (20 periportal and 8 perisinusoidal) were significantly different between the F1 and F2 cases that prompted a change of stage after a careful consensus read. The discriminatory ability of these parameters was further demonstrated in a comparison between the true F1 and true F2 cases as 26 out of the 28 parameters showed significant differences. These 26 parameters constitute a novel sub-algorithm that could accurately stratify F1 and F2 cases. Conclusion: The refined qFibrosis algorithm incorporated 26 novel parameters that showed a good discriminatory ability for NASH fibrosis stage 1 and 2 cases, representing an invaluable assistive tool for in-house pathologists when screening patients for NASH clinical trials.

Current and Emerging Treatments for Non-alcoholic Steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) is highly prevalent globally, and its progressive form, non-alcoholic steatohepatitis (NASH), has become a leading cause of cirrhosis, hepatocellular carcinoma, and liver transplantation. Unfortunately, there remains an urgent unmet need for regulatory approved NASH treatments. This review focuses on the current NASH treatment recommendations and critically discusses investigational agents in clinical development. Most NASH clinical trials are currently in early phase. Many later phase drugs have already failed to meet key endpoints. Obeticholic acid, elafibranor, cenicriviroc, and resmetirom are currently furthest along in the phase 3 development phase. The pursuit to find a treatment for NASH is vital. If one or more agents in late-stage development prove effective, a commercially available medication will help augment the benefits of lifestyle interventions.

Glycerol-3-phosphate Acyltransferase1 Is a Model-Agnostic Node in Nonalcoholic Fatty Liver Disease: Implications for Drug Development and Precision Medicine

Left untreated nonalcoholic fatty liver disease (NAFLD) can progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The observed failure of clinical trials in NASH may suggest that current model systems do not fully recapitulate human disease, and/or hallmark pathological features of NASH may not be driven by the same pathway in every animal model let alone in each patient. Identification of a model-agnostic disease-associated node can spur the development of effective drugs for the treatment of liver disease. Glycerol-3-phosphate acyltransferase1 (GPAT1) plays a pivotal role in lipid accumulation by shunting fats away from oxidation. In the present study, hepatic GPAT1 expression was evaluated in three etiologically different models of NAFLD. Compared to the sham cohort, hepatic GPAT1 mRNA levels were elevated by ∼5-fold in steatosis and NASH with fibrosis with immunofluorescent staining revealing increased GPAT1 in the fatty liver. A significant and direct correlation (r = 0.88) was observed between hepatic GPAT1 mRNA expression and severity of the liver disease. Picrosirius red staining revealed a logarithmic relation between hepatic GPAT1 mRNA expression and scar. These data suggest that hepatic GPAT1 is an early disease-associated model-agnostic node in NAFLD and form the basis for the development of a potentially successful therapeutic against NASH.

Suboptimal reliability of liver biopsy evaluation has implications for randomized clinical trials

Liver biopsies are a critical component of pivotal studies in non-alcoholic steatohepatitis (NASH), constituting inclusion criteria, risk stratification factors and endpoints. We evaluated the reliability of NASH Clinical Research Network scoring of liver biopsies in a NASH clinical trial. Digitized slides of 678 biopsies from 339 patients with paired biopsies randomized into the EMMINENCE study - examining a novel insulin sensitizer (MSDC-0602K) in NASH - were read independently by 3 hepatopathologists blinded to treatment code and scored using the NASH CRN histological scoring system. Various endpoints were computed from these scores. Inter-reader linearly weighted kappas were 0.609, 0.484, 0.328, and 0.517 for steatosis, fibrosis, lobular inflammation, and ballooning, respectively. Inter-reader unweighted kappas were 0.400 for the diagnosis of NASH, 0.396 for NASH resolution without worsening fibrosis, and 0.366 for fibrosis improvement without worsening NASH. In the current study, 46.3% of the patients included in the study based on 1 hepatopathologist's qualifying reading were deemed not to meet the study's histologic inclusion criteria by at least 1 of the 3 hepatopathologists. The MSDC-0602K treatment effect was lowest for those histologic features with lower inter-reader reliability. Simulations show that the lack of reliability of endpoints and inclusion criteria can drastically reduce study power - from >90% in a well-powered study to as low as 40%. The reliability of hepatopathologists' liver biopsy evaluation using currently accepted criteria is suboptimal. This lack of reliability may affect NASH pivotal studies by introducing patients who do not meet NASH study entry criteria, misclassifying fibrosis subgroups, and attenuating apparent treatment effects. Since liver biopsy analysis plays such an important role in clinical studies of non-alcoholic steatohepatitis, it is important to understand the reliability of hepato-pathologist readings. We examined both inter- and intra-reader variability in a large data set of paired liver biopsies froma clinical trial. We found very poor inter-reader and modest intra-reader variability. This result has important implications for entry criteria, fibrosis stratification, and the ability to measure a treatment effect in clinical trials.

Low real-world eligibility rates for nonalcoholic steatohepatitis patients for phase 3 clinical trial criteria application in a large academic health system.

Nonalcoholic steatohepatitis (NASH) is the most common liver disease in the USA. Clinical trials have stringent study criteria which may limit real-world generalizability. Thus, we studied whether a real-world, university-based cohort of patients could be eligible for a pivotal phase 3 NASH clinical trial. We queried Yale-New Haven Health System electronic medical records for patients with a diagnosis of NASH from 2013 to 2017. Of those who received liver biopsy, we extracted demographic, clinical, laboratory, and biopsy data. We compared patient characteristics to enrollment criteria of the Randomized Global Phase 3 Study to Evaluate the Impact on NASH with Fibrosis of Obeticholic Acid Treatment. Of 14 403 patients with NASH, 478 (3.3%) completed liver biopsy, of whom 237 (49.6%) had histological confirmation by a gastrointestinal pathologist. Histologically-confirmed NASH patients were 51.1 ± 13.2 years old, 56.5% female, 69.6% white race, and 24.6% had cirrhosis. In this group, 68 (28.7%) patients met all inclusion criteria, 87 (36.7%) had no exclusions, and 34 (14.4%) met all enrollment criteria. Other than cirrhosis, common reasons for ineligibility were presence of medical comorbidity (n = 83) or laboratory abnormalities (n = 47). Multiple logistic regression did not reveal significant predictors of eligibility. Within a university-based cohort of NASH patients, few met phase 3 clinical trial enrollment criteria, mostly due to low rates of liver biopsy. Of those with histologic confirmation, 14.4% met enrollment criteria. Validation of generalizability for safety and efficacy of NASH investigational agents in real-world populations is needed.

New Drugs for NASH and HIV Infection: Great Expectations for a Great Need.

In recent years, there has been an increasing number of clinical trials for the treatment of nonalcoholic steatohepatitis (NASH). People living with human immunodeficiency virus (PLWH) are commonly excluded from these studies, usually due to concerns over drug-drug interactions associated with antiretroviral therapy. The Steatohepatitis in HIV Emerging Research Network, a group of international experts in hepatology and infectious diseases, discusses our current understanding on the interaction between human immunodeficiency virus and NASH, and the issues related to the inclusion of PLWH in NASH clinical trials. Recent trials addressing NASH treatment in PLWH are discussed. The risk of drug-drug interactions between antiretroviral therapy and aramchol, cenicriviroc, elafibranor, obeticholic acid and resmetirom (MGL-3196), which are currently in phase 3 trials for the treatment of NASH, are reviewed. A model for trial design to include PLWH is proposed, strongly advocating for the scientific community to include this group as a subpopulation within studies.

Noninvasive Testing Using Magnetic Resonance Imaging Techniques as Outcomes in Nonalcoholic Steatohepatitis Clinical Trials: How Full Is the Glass?

Noninvasive Testing Using Magnetic Resonance Imaging Techniques as Outcomes in Nonalcoholic Steatohepatitis Clinical Trials: How Full Is the Glass?

Accounting for the Placebo Effect and Optimizing Outcomes in Clinical Trials of Nonalcoholic Steatohepatitis (NASH)

Understand the placebo effect and optimize the design of nonalcoholic fatty liver disease (NAFLD) clinical trials. The placebo effect on histologic outcomes and liver fat on MRI-based imaging has been assessed in a systematic review and meta-analysis, and three phase 3 studies have been reported. The placebo effect on improvement in the main histologic outcome was present in ~ 25% of the patients. The placebo effect on components of the NAFLD activity index in trials using the magnetic resonance imaging proton density fat fraction and magnetic resonance spectroscopy as outcomes also was reported. In this review, we discuss factors that led to placebo effects in the reported studies and suggest measures to ameliorate the effects in future NASH trials. The significant placebo response in NASH clinical trials is evidence that investigators should consider this effect in estimating sample size and designing future clinical trials.

Spontaneous Fluctuations in Liver Biochemistries in Patients with Compensated NASH Cirrhosis: Implications for Drug Hepatotoxicity Monitoring.

Patients with cirrhosis may have spontaneous fluctuations in liver enzymes, which may confound detection of drug-induced liver injury (DILI), but these fluctuations have not been described. We sought to quantify spontaneous liver enzyme abnormalities in patients with cirrhosis due to nonalcoholic steatohepatitis (NASH) enrolled in clinical trials. We examined the laboratory values of patients with compensated cirrhosis randomized to placebo in two clinical trials for NASH. Patients in one study were followed every 13 weeks up to week 57; patients in the other study were followed every 4 weeks up to week 120. In total, 53 and 85 patients were randomized to placebo in the trials. Baseline alanine aminotransferase (ALT) was greater than the laboratory upper limit of normal (ULN) in 53% and 49% of participants, aspartate aminotransferase (AST) was > ULN in 49% and 59%, alkaline phosphatase was > ULN in 36% and 27%, and bilirubin was >ULN in 13% and 19%. During follow-up, ALT increased to 2× baseline in 8% and 15%, AST increased to 2× baseline in 6% and 21%, and bilirubin increased to 2× baseline in 9% and 18%. Alkaline phosphatase did not increase to 2× baseline for any patient. The maximum ALT was 3× ULN in 9% and 12%. ALT increased to 3× baseline in three patients and to 5× ULN in two patients. No patients had elevations consistent with Hy's law. The maximum ALT for patients with abnormal baseline values was higher [median 48 U/L (range 34-299) and 56 U/L (47-85)] than for those with normal baseline values [median 26.5 U/L (range 18-33) and 29 U/L (25.5-30.5)] in both studies, respectively, with p < 0.001. Spontaneous liver enzyme abnormalities are common in patients with NASH cirrhosis in clinical trials, and these abnormalities rarely met criteria for DILI suspicion. Further work to better define these abnormalities and continued vigilance to detect DILI in this population is needed.

Defining Improvement in Nonalcoholic Steatohepatitis for Treatment Trial Endpoints: Recommendations From the Liver Forum.

Identifying effective therapies for nonalcoholic steatohepatitis (NASH) with fibrosis is a pressing challenge, with 1%-2% of the population in developed nations at risk of developing NASH cirrhosis and its complications. The design of NASH clinical therapeutic trials is hampered by the long period of minimally symptomatic disease that typically precedes the development of decompensated cirrhosis and the accompanying uncertainties regarding the best precirrhotic trial endpoints that reliably reflect a subsequent reduction in liver-related morbidity and mortality. The Liver Forum is a multistakeholder organization comprised of academic, industry, and regulatory experts working from a regulatory science perspective to identify barriers, prioritize research, and identify solutions to accelerate therapeutic development for NASH. Past work of The Liver Forum has focused on recommendations for disease definitions and baseline parameters to be implemented in clinical trials that are designed to assess disease status and prevent progression to cirrhosis, liver transplantation, hepatocellular carcinoma, and death. The purpose of this summary is to review currently available clinical data to identify parameters that change in parallel with liver histology and are likely to reflect clinically meaningful reductions in the risk of developing cirrhosis and its complications. We review available data on exploratory histological, blood-based, and imaging pharmacodynamic biomarkers that may reflect meaningful treatment responses and provide recommendations regarding measurements to be considered in phase 2 and 3 trials as well as during postmarketing monitoring trials.

Report on the AASLD/EASL Joint Workshop on Clinical Trial Endpoints in NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is a global public health concern. Its natural history, the development of nonalcoholic steatohepatitis (NASH) and fibrosis, is highly variable, prone to endogenous (e.g., genetics, microbiota) and exogenous (e.g., nutrition, alcohol, physical activity) disease modifiers, and can fluctuate over time. The complexity of its pathophysiology is reflected by the multitude of pharmacological targets in development. NASH clinical trials have provided valuable insight that is applicable to future trial design. Endpoints for NASH have evolved over the past decade and will continue to be refined. Currently accepted endpoints for conditional approval include resolution of NASH without worsening of fibrosis and/or improvement in fibrosis without worsening of NASH by standardized evaluation of paired liver histology. In pediatric NASH, practical obstacles, pubertal hormonal changes, and stringent safety requirements mandate adaptations in trial design. In adult patients with NASH-related cirrhosis, clinical events (e.g. decompensation, hepatocellular carcinoma, transplantation, death) are more prevalent and thereby are viable primary endpoints. Consideration of the natural fluctuation of disease, the clinical implication of the chosen primary endpoint, and factors that may affect placebo response will facilitate an accurate determination of efficacy of emerging therapeutics for NASH. Conclusion: The June 2018 American Association for the Study of Liver Diseases and European Association for the Study of the Liver joint workshop on NAFLD endpoints summarized important findings from ongoing and completed trials, defined the scientific evidence supporting distinct endpoints, and provided guidance for future trial design.

Challenges in developing an off-the-shelf cell therapy for ACLF and NASH

Background & Aim Promethera is a biopharma company focused on the research, development and commercialization of stem cell-based therapies and technologies for acute and chronic liver diseases. Our lead clinical program, an allogenic human liver derived mesenchymal stem cell product derived from our patented cell technology platform HepaStem, is currently being used in Phase IIa clinical trials for ACLF (acute on chronic liver failure) with the company also preparing clinical trials for NASH. Non-alcoholic steatohepatitis (NASH), a severe form of non-alcoholic liver diseases (NAFLD), is one of the prominent liver diseases worldwide. There is currently no approved drug for its treatment and liver transplantation is the only therapeutic approach for advanced NASH. Mesenchymal stem cells (MSCs) are promising candidates to modulate the pro-inflammatory and pro-fibrogenic environment of chronic liver because of their immunomodulatory properties. Recent data obtained in preclinical models of early and advanced stage NASH provided significant evidences to open new phase I/II clinical studies in NASH. Methods, Results & Conclusion The dosing for this indication is likely to be in the order of 100 million cells per infusion. Large numbers of cells thus need to be manufactured and using standard cell culture techniques would make it too expensive and labour intensive. A standard expansion protocol in flasks or cell factories is an open process, and therefore run in expensive clean rooms to avoid the risk of contamination. We have explored several state-of-the art-bioreactor systems, and various types of microcarriers in stirred tanks from different manufacturers. We have tested these systems to optimize the complete workflow of HepaStem culture, including stem cell isolation from livers and expansion up to the scale of many clinical doses. Quality control and comparability studies were performed to verify that the characteristics of HepaStem cells harvested from the different procedures were maintained. We have built a production platform, almost entirely in closed system, that can provide the large numbers of clinical doses that would be needed for the treatment of NASH. This platform functions with a strong reduction of human labour and it also modular and flexible to anticipate growing demand. In parallel we have developed serum-free and xenofree culture methods to be able to abandon the use of animal-derived products, for the related risks and because animal sera become scarce and expensive.

Relationship between three commonly used non‐invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non‐alcoholic steatohepatitis

Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement. In the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25mg OCA or placebo once daily for 72weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72weeks. In patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P=0.015) and FIB-4 (P=0.036), but not NFS (P=0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P=0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P<0.0001); NFS (P<0.05)]. Readily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.

End-points for drug treatment in NASH.

Non-alcoholic steatohepatitis (NASH) is an increasingly common cause of cirrhosis, hepatocellular carcinoma, and liver-related death (LRD). Consequently, there is a critical need for effective drug therapy that improves clinically relevant end-points. Hepatic steatosis assessed by magnetic resonance imaging-proton density fat fraction is increasingly used in the early phase trials examining drugs with anti-steatotic effects. However, the prognostic significance of a reduction in steatosis is unknown, and thus, phase 3 trials require a histological end-point of NASH resolution without fibrosis progression. Nonetheless, it is not clear whether this end-point which requires a liver biopsy reflects a better prognosis. Thus, conditional drug approval currently requires long-term follow-up to demonstrate reduction in 'harder' end-points of cirrhosis, liver transplantation, and LRD. Currently, there is an essential need to develop accurate non-invasive markers that are dynamic to drug-induced changes in underlying disease severity and prognosis to utilize as surrogate end-points for clinical trials in NASH.

Non-alcoholic Steatohepatitis (NASH) Drug Discovery - Building a Consensus on ADME Screening Tools and Clinical Pharmacology Strategies to Aid Candidate Development.

Number of drugs with different mechanisms of actions is undergoing clinical trials for non-alcoholic steatohepatitis (NASH). Given the complexity of the disease with respect to pathophysiology in the liver and associated changes in the renal function, it becomes apparent that a clear ADME (absorption, distribution, metabolism and excretion) strategy needs to be put in place for a successful nomination of a drug candidate for NASH. This review discusses using in vitro and in vivo ADME screens to understand the properties of drugs and to establish whether or not the chosen drug(s) can overcome the challenges related hepatic and renal transporters covering both uptake and efflux mechanisms imposed by NASH. A complete panel of in vivo preclinical experiments including a 14C-labeled study are proposed in NASH animal models to delineate the problematic areas for early drug development. Furthermore, a framework is provided with respect to the clinical pharmacology studies early in clinical development to characterise in an unbiased manner, the altered pharmacokinetics of drug in NASH patients for optimizing the dose selection for late phase clinical development. Because NASH patients have other co-morbid conditions and are prescribed co-medications for treating blood pressure, type 2 diabetes mellitus, obesity, dyslipidemia and many more disorders, it is also suggested to examine the drug-drug interaction potential by performing a cocktail probe study to cover a broad range of cytochrome P450 (CYP) enzymes and transporters.

Case definitions for inclusion and analysis of endpoints in clinical trials for nonalcoholic steatohepatitis through the lens of regulatory science.

Nonalcoholic steatohepatitis (NASH) is an important cause of liver‐related morbidity and mortality. There are no approved therapies, and the results of clinical trials have been difficult to compare due to inconsistent definitions of relevant disease parameters in patients with NASH. The natural course of the disease has not been rigorously characterized, particularly with respect to the contributions of underlying obesity, type 2 diabetes, and other comorbidities and the treatments provided for these comorbidities. Efforts to perform analyses of pooled data are limited by heterogeneous case definitions used across studies to define disease states. There remains a major unmet need in the field to develop standardized definitions for populations for interventional trials. Such definitions are expected to impact how endpoints for clinical trials are constructed. The Liver Forum is a multistakeholder effort including US and European regulatory agencies, academic investigators, professional and patient representative organizations, and industry to catalyze therapeutic development for NASH by developing potential solutions to barriers to development. The Case Definitions Working Group was established by The Liver Forum to evaluate the validity of case definitions for populations to be included in clinical trials for NASH from a regulatory science perspective. Based on such analyses, specific recommendations are provided noting the strengths and weaknesses of the case definitions along with knowledge gaps that require additional study. (Hepatology 2018;67:2001‐2012)