Noncirrhotic Nonalcoholic 
Steatohepatitis With Liver 
Fibrosis:  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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 Evangela Covert 301-796-4075.  
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
December 2018 
Clinical/Medical 
37256dft.docx 
11/29/2018   
Noncirrhotic Nonalcoholic 
Steatohepatitis With Liver 
Fibrosis:  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) 
 
December 2018 
Clinical/Medical 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION..................................................................................................1 
II.  BACKGROUND ....................................................................................................2 
III.  GENERAL CONSIDERATIONS ........................................................................2 
IV.  CONSIDERATIONS FOR DRUG DEVELOPMENT PROGRAMS ..............3 
A.  General Considerations .................................................................................................... 3 
B.  Phase 2 Development Considerations .............................................................................. 3 
1. Early Phase 2 Trials ............................................................................................................ 3 
2. Late Phase 2 Trials .............................................................................................................. 4 
C.  Phase 3 Development Considerations .............................................................................. 5 
1. Patient Population/Main Enrollment Criteria .................................................................... 5 
a.  Patient inclusion criteria ............................................................................................... 5 
b.  Patient exclusion criteria .............................................................................................. 6 
2. Trial design and efficacy endpoints ..................................................................................... 7 
3. Safety Considerations .......................................................................................................... 8 
D.  Pediatric Considerations ................................................................................................... 9 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Noncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis: 
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 noncirrhotic nonalcoholic steatohepatitis (NASH) with liver fibrosis.  Specifically, 
19  this guidance describes the FDAs current thinking regarding the necessary components of a 
20  drug development program for noncirrhotic NASH with liver fibrosis and identifies knowledge 
21  gaps that represent important challenges in the development of drugs for the indication.   
22   
23  This guidance does not address the clinical development of drugs for the treatment of cirrhosis 
24  caused by NASH.  This guidance also does not address the clinical development of in vitro 
25  diagnostic (IVD) devices that may assist in drug development for NASH.2  
26   
27  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
28  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
29  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
30  the word should in Agency guidances means that something is suggested or recommended, but 
31  not required. 
32   
33   
                                                 
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 This guidance does not address the regulatory issues related to commercial development of an IVD device to 
identify a specific biomarker, which may require FDA clearance or approval of the IVD.  Manufacturers interested 
in pursuing the development of a specific assay for commercial use should consult the Office of In Vitro Diagnostics 
and Radiological Health in the Center for Devices and Radiological Health.  For further information on the process 
for obtaining an investigational device exemption for an IVD, see the guidance for sponsors, clinical investigators, 
institutional review boards, and FDA staff FDA Decisions for Investigational Device Exemption Clinical 
Investigations.  We update guidances periodically.  To make sure you have 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 
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34  II.  BACKGROUND 
35   
36  Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of histological changes that begin 
37  with simple fatty infiltration of the liver, also known as simple or isolated steatosis or 
38  nonalcoholic fatty liver (NAFL), which may gradually, sometimes over decades, progress to the 
39  development of chronic inflammation (steatohepatitis or NASH), fibrosis, and ultimately 
40  cirrhosis.  Only a subgroup of patients with NAFL will progress to NASH and subsequent 
41  cirrhosis.  Currently, there are no clear criteria to identify this group of patients.   
42   
43  NAFLD is the most common cause of chronic liver disease in North America.3  Currently, there 
44  are no approved drugs for the treatment of NASH.  Given the high prevalence of NASH, the 
45  associated morbidity, the growing burden of end-stage liver disease, and limited availability of 
46  livers for organ transplantation, FDA believes that identifying therapies that will slow the 
47  progress of, halt, or reverse NASH and NAFLD will address an unmet medical need.  
48   
49   
50  III.  GENERAL CONSIDERATIONS 
51   
52  Splitting NAFLD into three successive stages (NAFL, noncirrhotic NASH, and NASH with 
53  cirrhosis) can provide sponsors a convenient conceptual framework to identify areas of potential 
54  future drug development.  At this time, because patients NAFL can exist for many years and 
55  may not progress to NASH, it may be challenging to demonstrate a favorable benefit-risk profile 
56  of pharmacological treatment(s) in NAFL patients.  Therefore, NAFL treatment may be better 
57  addressed by interventions such as diet and exercise.  
58   
59  Of the histologic features of NASH, fibrosis is considered the strongest predictor of adverse 
60  clinical outcomes, including liver-related death.  Because of the significant prognostic 
61  differences between NAFL and NASH with fibrosis and the absence of clear clinical, 
62  biochemical, or histological criteria that can identify patients with NAFL who are at risk for 
63  progression to NASH, the FDA encourages sponsors to focus drug development on the area of 
64  greatest need and potential effect on health (i.e., noncirrhotic NASH with liver fibrosis).  
65   
66  At this time, reliable diagnosis and staging of NASH can only be made by histopathological 
67  examination of a liver biopsy specimen.  Liver biopsy, however, is an invasive procedure that is 
68  associated with occasional morbidity and, in rare circumstances, mortality.  The use of liver 
69  biopsies in clinical trials poses significant logistical challenges (e.g., cost, availability of 
70  pathologists with specific expertise in NASH); in addition, some patients are reluctant or 
71  unwilling to undergo biopsy.  Therefore, noninvasive biomarkers are needed (including imaging 
72  biomarkers) to supplant liver biopsy and provide a comparable or superior ability to accurately 
73  diagnose and assess various grades of NASH and stages of liver fibrosis.  Identification and 
74  validation of such biomarkers could significantly accelerate drug development in NAFLD.  FDA 
75  encourages sponsors to consider biomarker development.  
76   
77   
                                                 
3 Chalasani N et al., 2018, The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance 
From the American Association for the Study of Liver Diseases, Hepatology, 67(1):328357. 
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78  IV.  CONSIDERATIONS FOR DRUG DEVELOPMENT PROGRAMS 
79   
80  A.  General Considerations 
81   
82  Sponsors should consider the following during drug development for treatment of noncirrhotic 
83  NASH with liver fibrosis: 
84   
85    FDA encourages the sponsor to use animal models for NASH to screen and identify 
86  potential investigational drugs.  The sponsor should select a specific animal model based 
87  on the mechanism of action of the investigational drug. 
88   
89    If there is a potential for liver toxicity based on animal toxicology studies, the sponsor 
90  should institute an appropriate plan to monitor liver safety early in drug development.  
91  For such a plan, the sponsor should consider the challenges of effectively recognizing a 
92  liver signal in a chronic liver condition such as NASH.   
93   
94    Until a sponsor can characterize a drugs initial tolerability, preliminary safety, and 
95  pharmacokinetics, patients with evidence of abnormal liver synthetic function should be 
96  excluded from early phase trials (i.e., phase 1 and early proof-of-concept (POC) clinical 
97  trials).  In addition, the sponsor should study the effects of hepatic impairment on the 
98  drugs pharmacokinetics early during the drug development program in a dedicated 
99  hepatic study to support appropriate dosing and dose adjustment across the spectrum of 
100  NASH liver disease. 
101   
102  B.  Phase 2 Development Considerations 
103   
104  1.  Early Phase 2 Trials 
105   
106  Sponsors should consider the following during early phase 2 trials for drug development for 
107  treatment of noncirrhotic NASH with liver fibrosis: 
108   
109    FDA recognizes that, for sponsors, POC trials are desirable before embarking on 
110  extensive clinical development programs.  Sponsors should provide adequate rationale 
111  and justification for the design of POC trials, including enrollment criteria, duration of 
112  the trials, and the choice of endpoints.  Sponsors can seek proof of concept in respect to 
113  improvement on markers of steatohepatitis, fibrosis, or both.   
114   
115    Noninvasive, disease-specific biomarkers; standard measures of liver injury (aspartate 
116  aminotransferase (AST) and alanine aminotransferase (ALT)); and imaging modalities 
117  that assess liver stiffness or hepatic fat content are acceptable as POC study endpoints as 
118  long as the sponsor can scientifically justify them.  
119   
120    In these early trials, baseline histologic documentation of NASH may not always be 
121  needed, depending on the endpoints to be assessed.  Sponsors can enroll patients based on 
122  either a known histological diagnosis of NASH or a combination of biochemical criteria 
3  Contains Nonbinding Recommendations 
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123  and/or imaging evidence of steatosis/steatohepatitis/fibrosis in addition to known risk 
124  factors for NASH.   
125   
126    The sponsor should ensure that these early trials capture the same or similar patient 
127  populations as those planned for the phase 3 development program.  The sponsor can 
128  accomplish this via careful selection of inclusion and exclusion criteria.  
129   
130    Duration of the trial will depend on the known mechanism of action of the drug and the 
131  anticipated effect on the efficacy assessment of interest.  
132   
133    Evaluation of multiple dose levels is advisable at this early stage of development to 
134  inform dose selection for subsequent trials.   
135   
136    If an early trial uses a histological endpoint, the trial should be of long enough duration to 
137  ensure that an anticipated effect can be observed (see section IV. B. 2., Late Phase 2 
138  Trials). 
139   
140    Such early trials offer a good opportunity for concomitant evaluation of histological and 
141  biochemical markers to characterize noninvasive biomarkers. 
142   
143  2.  Late Phase 2 Trials 
144   
145  Sponsors should consider the following during late phase 2 trials for drug development for 
146  treatment of noncirrhotic NASH with liver fibrosis. 
147   
148    Once proof of pharmacological activity has been demonstrated in a NASH population of 
149  interest, the phase 2 program should explore the treatment effect on histological 
150  endpoints. 
151   
152    A successful phase 2 program that supports initiation of phase 3 trials should provide the 
153  following:  
154   
155    Evidence of efficacy on a histological endpoint (i.e., reduction of inflammatory 

156  changes, improvement in fibrosis, or both). 
157   
158    Adequate characterization of the treatment effect size and variability around the 

159  histological assessment of interest to support planning of statistical analyses and 
160  powering for phase 3 trials. 
161   
162    Adequate dose response information to support phase 3 program dose selection. 

163   
164    Time course of treatment response to inform an appropriate duration of the phase 3 

165  program.  Given that histological changes take time, the duration of phase 2 trials 
166  should be at least 1218 months.  Sponsors should provide clear scientific 
167  justification for trials of shorter durations.   
168   
4  Contains Nonbinding Recommendations 
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169    The sponsor should provide information supporting the proposed biomarker strategy for 
170  the late phase 2 program.  This can include, but is not limited to, the following: 
171   
172    Inclusion of biomarkers that can reliably predict the histopathological evidence of 

173  NASH with or without liver fibrosis and, as such, can increase the likelihood of a 
174  confirmatory liver biopsy, reduce the number of screening failures, and expedite the 
175  screening of eligible patients  
176   
177    Inclusion of diagnostic biomarkers that may provide evidence of progression to 

178  cirrhosis  
179   
180    Inclusion of prognostic biomarkers that may robustly predict liver-related 

181  complications  
182   
183    Sponsors could use innovative designs to combine phase 2 and phase 3 trials (e.g., a trial 
184  design with an initial dose response exploration phase followed by continuation at a 
185  selected dose or doses).  Before initiating the trials, the sponsor should discuss with the 
186  FDA specific trial design issues and statistical topics (e.g., multiplicity control, alpha 
187  spending). 
188   
189    Given the appreciable overlap of NASH and metabolic conditions (e.g., obesity, type 2 
190  diabetes mellitus (T2DM)), the proportion of patients with these comorbidities to be 
191  included in clinical trials should be reflective of the target population and should be 
192  discussed with the FDA before the sponsor initiates phase 2/3 trials.  
193   
194  C.  Phase 3 Development Considerations 
195   
196  This section addresses phase 3 drug development for treatment of noncirrhotic NASH with liver 
197  fibrosis, which includes clinical trials intended to support a marketing application. 
198   
199  1.  Patient Population/Main Enrollment Criteria 
200   
201  a.  Patient inclusion criteria 
202   
203  Sponsors should consider the following patient inclusion criteria for clinical trials in drug 
204  development for treatment of noncirrhotic NASH with liver fibrosis.  
205   
206    Patients should have a histological diagnosis of NASH with liver fibrosis made close to 
207  the time of trial enrollment (i.e., no more than 6 months before enrollment).  Because 
208  baseline histology is critical for efficacy evaluation, liver biopsies obtained more than 6 
209  months before enrollment may not represent an accurate status of the disease at the 
210  beginning of the trial.   
211   
212    FDA has accepted as critical inclusion criteria in NASH trials a NASH activity score 
213  (NAS) greater than or equal to 4 with at least 1 point each in inflammation and 
214  ballooning along with a NASH Clinical Research Network (CRN) fibrosis score greater 
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215  than stage 1 fibrosis but less than stage 4 fibrosis.  These two criteria ensure that patients 
216  have evidence of steatohepatitis and significant liver fibrosis without cirrhosis at 
217  enrollment.  Depending on the drugs mechanism of action and anticipated effect on 
218  inflammation and/or fibrosis, the sponsor can propose for discussion with the FDA 
219  alternatives to the NAS and NASH/CRN fibrosis score.  The sponsor should provide 
220  adequate scientific justification for the alternatives.  
221   
222    Patients with a baseline Model for End-Stage Liver Disease (MELD) score less than or 
223  equal to 12 can be enrolled.  
224   
225    Patients with a documented history of Gilberts syndrome can be enrolled if the direct 
226  bilirubin is within normal reference range.  
227   
228    Patients with T2DM can be enrolled if they have been on stable doses of antidiabetic 
229  medication for at least 3 months before enrollment and can demonstrate that the T2DM is 
230  at least moderately controlled.  If patients with diabetes are enrolled, the randomization 
231  should be stratified by the presence or absence of T2DM.  
232   
233    Because some NASH patients are treated with vitamin E or pioglitazone, enrollment of 
234  such patients in clinical trials may confound treatment effects.  Therefore, such NASH 
235  patients should either discontinue vitamin E or pioglitazone or be on stable doses for 6
236  12 months before enrollment.  Stratified randomization may be necessary to avoid 
237  imbalances between treatment arms for concurrent treatment with vitamin E or 
238  pioglitazone. 
239   
240    A patients standard of care, background therapy for other ongoing chronic conditions, 
241  and weight should be stable for at least 3 months before trial enrollment.  Stable weight is 
242  defined as no more than a 5 percent change.   
243   
244    Patients who have had a biopsy more than 3 months before trial enrollment should have 
245  stable weights between the time of the biopsy and trial initiation.   
246   
247  b.  Patient exclusion criteria 
248   
249  Sponsors should consider the following patient exclusion criteria for clinical trials in drug 
250  development for treatment of noncirrhotic NASH with liver fibrosis:  
251   
252    Sponsors should rule out other causes of chronic liver disease for trial patients, including 
253  alcoholic liver disease, viral hepatitis, primary biliary cirrhosis, primary sclerosing 
254  cholangitis, autoimmune hepatitis, Wilsons disease, hemochromatosis, alpha-1 
255  antitrypsin deficiency, human immunodeficiency virus, etc.  
256   
257    The protocol should clearly state the criteria for exclusion (e.g., biochemical, 
258  histopathological, clinical) of patients with cirrhosis.  Currently, the FDA recommends 
259  excluding patients with bilirubin greater than or equal to 1.3 milligrams per deciliter and 
260  an international normalized ratio (INR) greater than or equal to 1.3.  
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261   
262    Evidence of portal hypertension (e.g., low platelet counts, esophageal varices, ascites, 
263  history of hepatic encephalopathy, splenomegaly), elevated bilirubin, or prolonged INR 
264  should disqualify patients from trial enrollment. 
265   
266    Elevations of the liver enzymes such as ALT and AST are expected in NASH.  However, 
267  an ALT and AST elevation greater than five times the upper limit of normal (ULN) 
268  (approximately 250 units per liter (U/L)) would indicate the possibility of other 
269  concomitant liver diseases (e.g., alcohol-associated liver disease, autoimmune hepatitis).  
270  Therefore, such patients should not be enrolled.  Similarly, bilirubin levels should not 
271  exceed the ULN.  Alkaline phosphatase should be less than 2 ULN (less than 250300 
272  U/L). 
273   
274  2.  Trial design and efficacy endpoints 
275   
276  Sponsors should consider the following trial design and efficacy endpoints for clinical trials in 
277  drug development for treatment of noncirrhotic NASH with liver fibrosis:  
278   
279    Sponsors should evaluate drugs for the treatment of NASH in double-blind, placebo-
280  controlled clinical trials of sufficient duration and size.   
281   
282    The ultimate goal of NASH treatment is to slow the progress of, halt, or reverse disease 
283  progression and improve clinical outcomes (i.e., prevent progression to cirrhosis and 
284  cirrhosis complications, reduce the need for liver transplantation, and improve survival).  
285   
286    Because of the slow progression of NASH and the time required to conduct a trial that 
287  would evaluate clinical endpoints such as progression to cirrhosis or survival, the FDA 
288  recommends sponsors consider the following liver histological improvements as 
289  endpoints reasonably likely to predict clinical benefit to support accelerated approval 
290  under the regulations:4 
291   
292    Resolution of steatohepatitis on overall histopathological reading and no worsening 

293  of liver fibrosis on NASH CRN fibrosis score.  Resolution of steatohepatitis is 
294  defined as absent fatty liver disease or isolated or simple steatosis without 
295  steatohepatitis and a NAS score of 01 for inflammation, 0 for ballooning, and any 
296  value for steatosis;  
297   
298  OR 
299   
300    Improvement in liver fibrosis greater than or equal to one stage (NASH CRN fibrosis 

301  score) and no worsening of steatohepatitis (defined as no increase in NAS for 
302  ballooning, inflammation, or steatosis);  
                                                 
4 21 CFR 314.500 et seq. for new drugs and 21 CFR 601.40 et seq. for biological products.  See the guidance for 
Industry Expedited Programs for Serious Conditions  Drugs and Biologics. 
 
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303   
304  OR  
305   
306    Both resolution of steatohepatitis and improvement in fibrosis (as defined above).   

307   
308    Because the relationship between liver histological improvement and clinical outcomes 
309  has not been characterized, sponsors can propose and justify specific degrees of 
310  histological improvement anticipated to be beneficial based on the mechanism of action 
311  of the specific drug under development (i.e., drugs that predominantly address the 
312  inflammatory process, treat the fibrosis, or both).   
313   
314    For NASH drugs approved on the basis of liver histology under the accelerated approval 
315  pathway, randomized, double-blind, placebo-controlled clinical trials designed to 
316  describe and verify the drugs clinical benefit should be underway at the time of 
317  submission of the marketing application.  Clinical benefit can be verified by 
318  demonstrating superiority to placebo in delaying disease progression measured by a 
319  composite endpoint that includes the following: 
320   
321    Progression to cirrhosis on histopathology. 

322   
323    Reduction in hepatic decompensation events (e.g., hepatic encephalopathy, variceal 

324  bleeding, ascites).  These events should be adjudicated by a committee of experts. 
325   
326    Change in MELD score from less than or equal to 12 to more than 15.  (This endpoint 

327  approximates listing for liver transplant.) 
328   
329    Liver transplant. 

330   
331    All-cause mortality. 

332   
333    FDA encourages sponsors to identify biochemical or noninvasive imaging biomarkers 
334  that could eventually replace liver biopsies.  Sponsors could use such biomarkers, once 
335  characterized and agreed upon by the FDA, either for patient selection or for assessing 
336  efficacy in clinical trials.   
337   
338    Sponsors have multiple ways to design and implement phase 3 and postapproval 
339  confirmatory clinical trials.  Sponsors should discuss these designs and implementations 
340  with the FDA before initiating trials.   
341   
342  3.  Safety Considerations 
343   
344  FDA recommends the following safety considerations for clinical trials in drug development for 
345  treatment of noncirrhotic NASH with liver fibrosis:  
346   
347    The specific number of patients for each drug development program will require an 
348  individualized approach and should be discussed with the FDA.  Regardless of the 
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349  approach, the safety database for approval should include patients who have been 
350  exposed to the drug in multiple-dose trials at the relevant dose(s).  
351   
352    NASH is associated with elevation of liver enzymes, and assessment of potential drug-
353  related liver toxicity can be very challenging given the patients background of chronic 
354  liver disease.  FDA encourages sponsors to develop a specific approach (e.g., an 
355  algorithm) for liver monitoring in patients with abnormal liver function at baseline, 
356  including criteria for drug discontinuation for individual patients and trial stopping rules 
357  (temporary or permanent).  The protocol should specify a plan for diagnostic evaluation 
358  for such liver enzyme elevations.  Sponsors should establish an expert committee to 
359  adjudicate cases that meet protocol-defined criteria for hepatic decompensation events 
360  and possible cases of drug-induced liver injury.   
361   
362    Given the growing evidence of a link between NAFLD and cardiovascular disease, 
363  cardiovascular safety should be adequately monitored in clinical trials.  FDA encourages 
364  sponsors to establish an expert committee to adjudicate cases that meet protocol-defined 
365  criteria for major adverse cardiac events.  
366   
367  D.  Pediatric Considerations 
368   
369  Pediatric NASH appears to have different histological characteristics as well as a different 
370  natural history when compared to adult NASH.  For reasons that are currently unknown, disease 
371  characteristics and progression in pediatric patients may be different.  In addition, the common 
372  histologic findings of ballooning degeneration, classic zone-3 fibrosis, and parenchymal 
373  inflammation observed in adult NASH are less common in children with NASH.  Therefore, 
374  applying the adult scoring system to children with NASH may be challenging.  Sponsors of 
375  drugs for the treatment of noncirrhotic NASH with liver fibrosis should consider the following 
376  for pediatric studies: 
377   
378    Given all the differences mentioned, extrapolation of efficacy from adults to pediatric 
379  patients solely on pharmacokinetic or pharmacodynamic information is not appropriate at 
380  this time.  However, gathering robust exposure-response information during adult trials 
381  can be critical to inform the ability to extrapolate in the future. 
382   
383    Longitudinal natural history data in pediatric patients are needed to better characterize the 
384  disease course, identify inclusion/exclusion criteria for future clinical studies, and support 
385  choice of endpoints for pediatric studies.  
386   
387    The risk/benefit of each drug will determine the overall timing of the pediatric studies in 
388  relation to the adult clinical trials.  Sponsors should consider initiating pediatric studies 
389  once sufficient information about dosing, safety, and efficacy in adults is obtained. 
390   
391    Pediatric studies in noncirrhotic NASH pose additional challenges.  FDA plans to provide 
392  recommendations addressing drug development for pediatric noncirrhotic NASH in a 
393  future guidance. 
9