Nonalcoholic Steatohepatitis 
with Compensated Cirrhosis:  
Developing Drugs for 
Treatment 
Guidance for Industry 
 
 
 
DRAFT GUIDANCE 
 
This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD  20852.  All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact Frank Anania at 240-402-9725. 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
June 2019 
Clinical/Medical
24785284dft.docx 
3/6/2019   
Nonalcoholic Steatohepatitis 
with Compensated Cirrhosis:  
Developing Drugs for 
Treatment 
Guidance for Industry 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
June 2019 
Clinical/Medical 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  PHASE 3 PROGRAM CONSIDERATIONS ................................................................. 2 
A.  Patient Population/Enrollment Criteria ...................................................................................... 2 
B.  Trial Design/Efficacy Endpoints ................................................................................................... 4 
C.  Safety Considerations .................................................................................................................... 4 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Nonalcoholic Steatohepatitis with Compensated Cirrhosis:  
2  Developing Drugs for Treatment 
3  Guidance for Industry1 
4   
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
9  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
10  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
11  for this guidance as listed on the title page. 
12   
13   
14   
15  I.  INTRODUCTION 
16   
17  The purpose of this guidance is to assist sponsors in the clinical development of drugs for the 
18  treatment of nonalcoholic steatohepatitis (NASH) with compensated cirrhosis.  
19   
20  This guidance describes the Food and Drug Administrations (FDAs) current recommendations 
21  regarding the important components of a drug development program for compensated NASH 
22  cirrhosis.  This guidance focuses on the enrollment criteria, trial design, efficacy endpoints, and 
23  safety considerations for phase 3 trials.  This guidance also identifies knowledge gaps that 
24  represent important challenges in the development of drugs for this indication.  
25   
26  This guidance does not address the clinical development of drugs for the treatment of 
27  decompensated cirrhosis resulting from NASH.  This guidance also does not address drug 
28  development for patients with noncirrhotic NASH or provide general recommendations on early 
29  drug development in NASH, such as use of animal models and approaches to monitoring for 
30  potential liver toxicity.  These are both addressed in the draft guidance for industry Noncirrhotic 
31  Nonalcoholic Steatohepatitis with Liver Fibrosis:  Developing Drugs for Treatment (December 
32  2018).2 
33   
34  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
35  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
36  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
37  the word should in Agency guidances means that something is suggested or recommended, but 
38  not required. 
39   
40   
                                                 
1 This guidance has been prepared by the Division of Gastroenterology and Inborn Error Products in the Center for 
Drug Evaluation and Research at the Food and Drug Administration.  
 
2 When final, this guidance will represent the FDAs current thinking on this topic.  For the most recent version of a 
guidance, check the FDA guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.  
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
41  II.  BACKGROUND 
42   
43  Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of histological features that range 
44  from simple fatty infiltration of the liver to chronic liver inflammation with or without fibrosis 
45  and cirrhosis.  Cirrhosis is broadly divided into two main stages, compensated and 
46  decompensated.   
47   
48  Patients with compensated NASH cirrhosis have significant scar formation that is evident by 
49  histopathology, with hepatocytes clustered in nodules surrounded by dense extracellular matrix.  
50  Despite this, patients may appear clinically healthy.  However, patients with compensated NASH 
51  cirrhosis can progress to decompensated cirrhosis, defined primarily by complications related to 
52  portal hypertension and impaired synthetic function that results in end-stage liver disease, the 
53  primary manifestation of decompensated cirrhosis.3    
54   
55  The goals of treatment for compensated NASH cirrhosis are to halt or slow progression of 
56  fibrosis, prevent clinical decompensation, reduce the need for liver transplantation, and improve 
57  survival.  There are currently no FDA-approved drugs for compensated NASH cirrhosis.  
58   
59   
60  III.  PHASE 3 PROGRAM CONSIDERATIONS 
61   
62  A.  Patient Population/Enrollment Criteria 
63   
64  Sponsors of drugs to treat compensated NASH cirrhosis should consider the following when 
65  enrolling patients in phase 3 clinical trials: 
66   
67    Sponsors should be careful to enroll in clinical trials only patients whose cirrhosis is 
68  secondary to NASH and not caused by other etiologies.  Patients should have histological 
69  diagnoses of NASH, and other causes of chronic liver disease should be ruled out (e.g., 
70  alcoholic liver disease, viral hepatitis, primary biliary cholangitis, primary sclerosing 
71  cholangitis, autoimmune hepatitis, Wilsons disease, hemochromatosis, alpha-1-
72  antitrypsin deficiency, HIV).  
73   
74    The protocol should specify the following criteria used to establish a diagnosis of 
75  compensated cirrhosis:  
76   
77    A diagnosis of cirrhosis can be supported by histology (e.g., a NASH Clinical 
78  Research Network fibrosis score of 4); the sponsor can propose and discuss other 
79  histological criteria with the FDA. 
80   
81    Non-histologic criteria for the diagnosis of cirrhosis have not been established, but 
82  the sponsor can propose non-histologic criteria that could be acceptable, if 
                                                 
3 Agopian VG, Kaldas FM, Hong JC, Whittaker M, Holt C, Rana A, Zarrinpar A, et al., 2012, Liver Transplantation 
for Non-Alcoholic Steatohepatitis: The New Epidemic, Ann Surg, 256(4):624633.  
 
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
83  scientifically supported.  The FDA encourages sponsors to identify biochemical or 
84  imaging noninvasive biomarkers that can replace liver biopsies.   
85   
86    The protocol should specify criteria to exclude patients with decompensated cirrhosis.  
87  The criteria can include, but are not limited to, the following:  
88   
89    Evidence of portal hypertension (e.g., low platelet counts, esophageal varices, ascites, 
90  history of hepatic encephalopathy, splenomegaly) 
91   
92    Elevated bilirubin  
93   
94    Elevated international normalized ratio or prolonged prothrombin time. 
95   
96    Patients who develop manifestations of hepatic decompensation between screening and 
97  enrollment should not be randomized.   
98   
99    Sponsors can enroll patients with documented history of Gilberts syndrome if the direct 
100  bilirubin is within normal reference range.  
101   
102    Sponsors can enroll patients with type 2 diabetes mellitus (T2DM) if they are adequately 
103  controlled on a stable dose or doses of antidiabetic medication(s) for at least 3 months 
104  before trial enrollment.   
105   
106    Some patients with compensated NASH cirrhosis can be treated with vitamin E or 
107  pioglitazone.  Such patients should either (1) discontinue vitamin E or pioglitazone or (2) 
108  be on a stable dose for 6 months before trial enrollment, and the dose should be held 
109  constant during the trial.  
110   
111    Elevations of liver enzymes such as alanine aminotransferase (ALT) and aspartate 
112  aminotransferase (AST) can be expected in NASH.  However, ALT or AST elevation 
113  greater than 5 times the upper limit of normal (ULN) would indicate the possibility of 
114  concomitant liver disease(s) (e.g., alcohol-associated liver disease, autoimmune 
115  hepatitis).  Therefore, sponsors should not enroll patients with evidence of such 
116  transaminase elevations.  Similarly, bilirubin levels should not exceed ULN.  Alkaline 
117  phosphate should be less than 1.5 times the ULN. 
118   
119    Sponsors should exclude the following patients from trial enrollment: 
120   
121    Patients listed for living-related or orthotopic liver transplantation.  
122   
123    Patients with a baseline Model for End-Stage Liver Disease (MELD) score greater 
124  than 12.    
125   
126    Patients with a history of hepatocellular carcinoma (HCC) or history of HCC 
127  treatment.  
128   
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
129  B.  Trial Design/Efficacy Endpoints 
130   
131  Sponsors of drugs to treat compensated NASH cirrhosis should consider the following for trial 
132  design and efficacy endpoints: 
133   
134    Drugs for the treatment of compensated NASH cirrhosis should be evaluated in 
135  randomized, placebo-controlled, double-blind clinical trials.  Sponsors can propose 
136  stratification factors (e.g., T2DM, vitamin E, pioglitazone) and discuss with the FDA 
137  before initiating phase 3 trials.  
138   
139    The drug development program should evaluate the effect of the investigational drug 
140  relative to placebo on the composite endpoint of time from randomization to the first of 
141  any one of the following outcome events: 
142   
143    Complication of ascites including any of the following: spontaneous bacterial 
144  peritonitis, diuretic-resistant ascites (refractory ascites), hepato-pleural effusion, etc.  
145   
146    Variceal hemorrhage  
147   
148    Hepatic encephalopathy  
149   
150    Worsening in the MELD score to greater than or equal to 15 (this endpoint 
151  approximates listing for liver transplant) 
152   
153    Liver transplantation 
154   
155    Death from any cause 
156   
157    The FDA strongly recommends clinical outcome trials to support a marketing 
158  application.  Histological improvements in fibrosis can be proposed and justified; 
159  however, at present the relationship between histological changes in cirrhosis and clinical 
160  outcomes has not been characterized, and further, reversal of cirrhosis (e.g., fibrosis stage 
161  F4) may not be feasible.  Because currently there is insufficient evidence to support the 
162  use of histological improvements as a surrogate endpoint that is reasonably likely to 
163  predict clinical benefit to support accelerated approval, in general, the FDA expects to 
164  evaluate drugs for the treatment of compensated NASH cirrhosis under the traditional 
165  approval pathway. 
166   
167  C.  Safety Considerations 
168   
169  Assessment of potential drug-related liver toxicity can be challenging in patients with chronic 
170  liver disease.  The FDA encourages the sponsor to develop a specific approach (e.g., an 
171  algorithm) for monitoring liver function in patients with abnormal liver function at baseline, 
172  including criteria for drug discontinuation for individual patients and trial stopping rules 
173  (temporary or permanent).  The protocol should specify guidelines for monitoring liver function.  
174  The sponsor should establish an expert committee to adjudicate cases that meet protocol-defined 
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
175  criteria for drug-induced liver injury.  Given the growing evidence for an association between 
176  NAFLD and cardiovascular disease, cardiovascular safety should be adequately monitored 
177  during the clinical trial. 
5