Technical Specifications for Submitting Clinical Trial Data Sets for Treatment of Noncirrhotic Nonalcoholic Steatohepatitis (NASH): Guidance for Industry Technical Specifications Document

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Technical Specifications for
Submitting Clinical Trial Data Sets
for Treatment of Noncirrhotic
Nonalcoholic Steatohepatitis
(NASH)
Guidance for Industry
Technical Specifications Document
For questions regarding this technical specification document, contact CDER
at cder-edata@fda.hhs.gov.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
December 2024
Technical Specifications Document

Revision History
Date Version Summary of Revisions
August 2021 1.0 Initial Version
January 2022 1.1
• Section 5.0 – Added language about CDISC
Controlled Terminology.
• Revisions made to Section 5.1.4 - Corrected test code
values for Ascites and Encephalopathy Grade.
December 2024 1.2
• Revisions made to Section 5.1.3 – Corrected
Microscopic Findings Test Results for NASH CRN
Fibrosis State and Ishak Fibrosis Score.
• Updated Table 5 in Section 5.1.5 on MELD related
scores to include MELD 3.0. and corrected
assignment of Child-Pugh test names to the respective
test codes.
• Updated Table 9 in Section 5.1.11 to include Hepatitis
D tests.
• Addition of language in Section 5.1.10 to reflect
custom LC domain structured identically to LB for
data in conventional units.
• Revisions made to Section 5.1.13 – Corrected
TSPARMCD variable name.
• Addition of language in Section 5.2.3.1 to reflect
custom ADLC data set structured identically to
ADLB for data in conventional units.

Contains Nonbinding Recommendations
Table of Contents
1.0 INTRODUCTION............................................................................................................. 1
2.0 RELEVANT ACRONYMS .............................................................................................. 2
3.0 FDA DATA STANDARDS CATALOG ......................................................................... 4
4.0 OVERVIEW OF DATA SETS ........................................................................................ 4
4.1 SDTM Domains .............................................................................................................................. 4
4.2 ADaM Data Sets ............................................................................................................................. 5
5.0 OVERVIEW OF DATA SET SPECIFICATIONS ....................................................... 7
5.1 SDTM Domains .............................................................................................................................. 8
5.1.1 Biospecimen Events (BE) Domain............................................................................................ 8
5.1.2 Biospecimen Findings (BS) Domain ........................................................................................ 8
5.1.3 Microscopic Findings (MI) Domain ......................................................................................... 8
5.1.4 Supplemental Microscopic Findings (SUPPMI) Domain ...................................................... 11
5.1.5 Disease Response and Clinical Classifications (RS) Domain ................................................ 12
5.1.6 Imaging Results (ZI) Domain ................................................................................................. 14
5.1.7 Adjudication (ZA) Domain ..................................................................................................... 14
5.1.8 Concomitant Medications (CM) Domain ............................................................................... 17
5.1.9 Medical History (MH) Domain .............................................................................................. 18
5.1.10 Laboratory (LB) Domain...................................................................................................... 18
5.1.11 Microbiology Specimens (MB) Domain ............................................................................... 19
5.1.12 Substance Use (SU) Domain ................................................................................................ 20
5.1.13 Trial Summary (TS) Domain ................................................................................................ 21
5.1.14 RELREC Domain ................................................................................................................. 21
5.1.15 Other SDTM Considerations ................................................................................................ 21
5.1.15.1 Gastroesophageal varices .............................................................................................. 21
5.1.15.2 All-cause mortality........................................................................................................ 22
5.2 ADaM Data Sets ........................................................................................................................... 22
5.2.1 Subject-Level Analysis Data Set (ADSL) ................................................................................ 22
5.2.2 Occurrence Data Structure (OCCDS) Data Sets ................................................................... 26
5.2.2.1 Adverse Event Analysis Data Set (ADAE) .................................................................... 27
5.2.3 Basic Data Structure (BDS) Data Sets ................................................................................... 28
5.2.3.1 Laboratory Analysis Data Set (ADLB) .......................................................................... 28
5.2.3.2 Drug Induced Liver Injury Analysis Data Set (ADDILI) .............................................. 30
5.2.3.3 Microscopic Findings Analysis Data Set (ADMI) ......................................................... 34
5.2.3.4 Non-Invasive Serum Biomarkers of Liver Fibrosis and NASH Analysis Data
Set (ADRS) ..................................................................................................................... 35
5.2.4 Time-to-Event Analysis Data Set (ADTTE) ........................................................................... 37
APPENDIX .................................................................................................................................. 39
Example ADLB and ADDILI Data Sets ............................................................................................. 39
Example MI and SUPPMI Domains ................................................................................................... 40

Contains Nonbinding Recommendations
1
Technical Specifications for Submitting Clinical Trial Data Sets for	1
Treatment of Nonalcoholic Steatohepatitis (NASH)	2
3
Guidance for Industry	4
Technical Specifications Document1
5
6
7
8
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on	9
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can	10
use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To	11
discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title	12
page.	13
14
15
16
1.0 INTRODUCTION	17
18
Nonalcoholic steatohepatitis (NASH) is a subcategory of nonalcoholic fatty liver disease	19
(NAFLD). NASH carries a significant disease burden as it can progress to cirrhosis and liver	20
failure and is associated with an increase incidence of liver cancer.	21
22
The Division of Hepatology and Nutrition (DHN) serves as the clinical review division in the	23
Office of New Drugs (OND) for the review of marketing applications for drug and biological	24
products2 for the treatment of liver fibrosis due to NASH. In December 2018, FDA issued a draft	25
guidance outlining recommendations for clinical development of drugs intended for treatment of	26
noncirrhotic NASH with liver fibrosis.3 The 2018 draft guidance acknowledges that subjects	27
with NASH fibrosis have unique clinical considerations (e.g., underlying hepatic dysfunction)	28
that may present challenges in demonstrating favorable benefit-risk profile. Furthermore,	29
evaluation of potential drug-induced liver injury (DILI) in this population is challenging because	30
the risk of DILI in subjects with underlying liver disease has not been fully characterized and it	31
can be difficult to differentiate between progression of liver disease and DILI.	32
1 This guidance has been prepared by the Division of Biomedical Informatics, Research, and Biomarker
Development and the Division of Hepatology and Nutrition in the Center for Drug Evaluation and Research at the
Food and Drug Administration. You may submit comments on this guidance at any time. Submit comments to
Docket No. FDA-2018-D-1216 (available at https://www.regulations.gov/docket?D=FDA-2018-D-1216) (see the
instructions for submitting comments in the docket).
2 For the purposes of this guidance, the term drug or drugs includes both human drug and therapeutic biological
products unless otherwise specified.
3 See the draft guidance for industry Noncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis: Developing
Drugs for Treatment (December 2018). When final, this guidance will represent the FDA’s current thinking on this
topic. For the most recent version of a guidance, check the FDA guidance web page at
https://www.fda.gov/regulatory-information/search-fda-guidance-documents.

Contains Nonbinding Recommendations
2
33
This document provides detailed information and specifications for the content of the tabulated	34
domains and analysis data sets submitted to FDA as part of the sponsor’s application for drugs	35
intended to treat noncirrhotic NASH. This guidance does not provide recommendations for	36
clinical development of drugs intended for the treatment of NASH, or assessment of potential	37
DILI.	38
39
Revised nomenclature for NAFLD and NASH was introduced in 2023.4 The proposed	40
nomenclature for NAFLD is metabolic dysfunction-associated steatotic liver disease (MASLD).	41
MASLD is diagnosed if a patient has hepatic steatosis (>5% hepatocytes) with at least one	42
cardiometabolic risk factor. Screening for other potential causes of steatotic liver disease is still	43
indicated. The new nomenclature for NASH is metabolic dysfunction-associated steatohepatitis	44
(MASH) with no change in histopathological criteria. FDA considers the terms NAFLD and	45
NASH interchangeable with MASLD and MASH, respectively, and has maintained the former	46
nomenclature for NASH in this guidance pending universal acceptance of the new nomenclature.	47
48
The recommendations outlined in the guidance pertain to submission of the sponsor’s tabulated	49
and analysis data sets in order to improve reviewability. These specifications also provide an	50
opportunity for dialogue between the sponsor and DHN to discuss issues related to trial design or	51
conduct that may affect the content of these data sets. These specifications are intended to	52
support the draft guidance for industry Noncirrhotic Nonalcoholic Steatohepatitis With Liver	53
Fibrosis: Developing Drugs for Treatment (NASH Guidance) and reflect the data standards and	54
processes described in the FDA Study Data Technical Conformance Guide.5	
55
56
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	57
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only	58
as recommendations, unless specific regulatory or statutory requirements are cited. The use of	59
the word should in Agency guidance means that something is suggested or recommended, but	60
not required.	61
62
2.0 RELEVANT ACRONYMS	63
64
Abbreviation Description
ADaM Analysis Data Model
ADRG Analysis Data Reviewers Guide
4 ME Rinella, JV Lazarus, V Ratziu, SM Francque, AJ Sanyal, F Kanwal, D Romero, MF Abdelmalek, QM Anstee,
JP Arab, M Arrese, R Bataller, U Beuers, J Boursier, E Bugianesi, CD Byrne, GE Castro Narro, A Chowdhury, H
Cortez-Pinto, DR Cryer, K Cusi, M El-Kassas, S Klein, W Eskridge, J Fan, S Gawrieh, CD Guy, SA Harrison, SU
Kim, BG Koot, M Korenjak, KV Kowdley, F Lacaille, R Loomba, R Mitchell-Thain, TR Morgan, EE Powell, M
Roden, M Romero-Gómez, M Silva, SP Singh, SC Sookoian, CW Spearman, D Tiniakos, L Valenti, MB Vos, VW
Wong, S Xanthakos, Y Yilmaz, Z Younossi, A Hobbs, M Villota-Rivas, and PN Newsome, 2023, A Multisociety
Delphi Consensus Statement on New Fatty Liver Disease Nomenclature, 78(6): 1966–1986.
5 Available at https://www.fda.gov/industry/fda-resources-data-standards/study-data-standards-resources.

Contains Nonbinding Recommendations
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Abbreviation Description
APRI Aspartate Aminotransferase-to-Platelet Ratio Index
BDS Basic Data Structure
CAC Cardiac Adjudication Committee
CDISC Clinical Data Interchange Standards Consortium
CK-18 Cytokeratin-18
CRN Clinical Research Network
DHN Division of Hepatology and Nutrition
DILI Drug-Induced Liver Injury
ELF Enhanced Liver Fibrosis
FDA Food and Drug Administration
HAC Hepatic Adjudication Committee
MACE Major Adverse Cardiac Events
MASH Metabolic Dysfunction-Associated Steatohepatitis
MASLD Metabolic Dysfunction-Associated Steatotic Liver Disease
MedDRA Medical Dictionary for Regulatory Activities
MELD Model for End-Stage Liver Disease
NAFLD Nonalcoholic Fatty Liver Disease
NAS NAFLD Activity Score
NASH Nonalcoholic Steatohepatitis
NCI EVS National Cancer Institute Enterprise Vocabulary Services
OCCDS Occurrence Data Structure
PRO-C3 N-terminal propeptide of type III collagen
RELREC Related Records Domain
SDRG Study Data Reviewers Guide
SDTM Study Data Tabulation Model

Contains Nonbinding Recommendations
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Abbreviation Description
SMQ Standardized MedDRA Query
TAUG Therapeutic Area User Guide
65
3.0 FDA DATA STANDARDS CATALOG	66
67
This technical specification has been drafted in accordance with the currently supported versions	68
of the Study Data Tabulation Model (SDTM) Implementation Guide and Analysis Data Model	69
(ADaM) Implementation Guide as noted in the FDA Data Standards Catalog.6 As new versions	70
of the respective implementation guides become available and supported by FDA, this technical	71
specification may change to align to the newly supported implementation guide(s).	72
73
Sponsors should review the FDA Data Standards Catalog to ensure data submissions follow	74
FDA-supported standards.	75
76
4.0 OVERVIEW OF DATA SETS	77
78
This technical specification contains guidance for 21 data sets (14 SDTM domains and 7 ADaM	79
data sets) relevant to noncirrhotic NASH development programs briefly described below. The	80
subsequent sections provide more detailed descriptions regarding the information to be collected	81
and stored in each domain and/or data set. Sponsors should submit all data sets in accordance	82
with the Study Data Technical Conformance Guide, including those not discussed in this	83
technical specification.7	
84
85
4.1 SDTM Domains	86
87
This technical specification provides guidance for providing 14 SDTM domains. Sponsors	88
should still provide standard SDTM domains in addition to those listed below, including but not	89
limited to Demographics (DM), Adverse Events (AE), Disposition (DS), Death Details (DD),	90
Subject Visits (SV), Exposure (EX), Comments (CO), etc.	91
92
Biospecimen Events (BE) domain: This domain contains information related to	93
collecting, handling, and processing biological specimens. It is an events domain	94
structured as one record per subject, per biospecimen event, per biospecimen identifier	95
and links to the Biospecimen Findings (BS) domains.	96
97
Biospecimen Findings (BS) domain: This findings domain contains information related	98
to observations of specimen quality and characteristics of collected and derived	99
biospecimens. This information is collected to assess the adequacy of the biopsies that are	100
6 Available at https://www.fda.gov/industry/fda-resources-data-standards/study-data-standards-resources.
7 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/study-data-technical-
conformance-guide-technical-specifications-document.

Contains Nonbinding Recommendations
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used for analysis and is structured as one record per subject, per measurement, per	101
biospecimen identifier.	102
103
Microscopic Findings (MI) domain: This domain contains all information related to	104
histological characteristics of liver biopsies. This domain is structured as one record per	105
subject, per biopsy parameter, per evaluator, per collection.	106
107
Supplemental Microscopic Findings (SUPPMI) domain: This domain contains	108
supplemental information related to the biopsies, specifically the sponsors’ assessment of	109
slide adequacy. Justification should be provided in this domain for specimens deemed	110
inadequate.	111
112
Disease Response and Clinical Classifications (RS) domain: This domain contains	113
information related to disease response to therapy that includes clinical classification	114
based on published criteria and captures results of Model for End-Stage Liver Disease	115
(MELD) scoring8 and Child-Pugh Classification. This findings domain is structured as	116
one record per subject, per response or clinical classification assessment time point, per	117
medical evaluator.	118
119
Imaging Results (ZI) domain: This custom domain contains results of imaging	120
procedures done to assess liver steatosis, inflammation, and fibrosis. Sponsors may	121
choose the tests and data points to collect from imaging procedures, but this domain	122
provides guidance to ensure the data is submitted to FDA in a consistent manner.	123
124
Adjudication (ZA) domain: This custom domain contains results of assessments of	125
individual adjudicators as it pertains to potential DILI and other clinical events and	126
outcomes. This domain is structured similar to the MI domain, where the evaluator	127
information is stored in ZAEVAL and ZAEVALID to account for intra- and inter-	128
observer variability.	129
130
Additional information, instructions, and CDISC Controlled Terminology are included in	131
individual subsections pertaining to the Concomitant Medications (CM), Medical History (MH),	132
Laboratory (LB), Microbiology Specimens (MB), Substance Use (SU), and Trial Summary (TS)	133
domains.	134
135
4.2 ADaM Data Sets	136
137
ADaM data sets include variables that represent derived study days. It is assumed that the anchor	138
date for study day 1 is Date of First Exposure to Treatment (TRTSDT) and this date of first dose	139
is identical to Date of Randomization (RANDDT). If the Date of First Exposure to Treatment	140
and Date of Randomization differ, sponsors should provide an explanation for this discrepancy.	141
All ADaM data sets should be accompanied by informative metadata, as provided in a compliant	142
ADaM define.xml document and Analysis Data Reviewers Guide (ADRG) that describes the	143
8 Individual components of MELD scoring are captured elsewhere, but final calculation for MELD is placed in the
RS domain.

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source and derivation of the variables. In addition, programs used to create ADaM data sets	144
should be submitted.	145
146
Subject-Level Analysis Data Set (ADSL): This data set contains one record per subject.	147
This data set provides information about the subjects’ demographics, treatment arm, trial	148
start and end dates, and summary baseline characteristics. Many of the baseline	149
characteristic variables in this data set are calculated or derived values from other data	150
sets (e.g., baseline alanine aminotransferase (ALT)) and an associated categorization of	151
that value. The notes in the ADSL table provided within this document should be	152
considered a guide and a baseline instruction set; sponsors should submit additional	153
variables and derivations as they see fit. Specific sections of the ADSL should be carried	154
into other ADaM data sets for analysis purposes (e.g., Basic Demographic Variables,	155
Treatment Arms, etc.), and are noted in the full description of the ADaM data sets. All	156
derivations should be noted in the define.xml file, and additional notes about the data set	157
included in the ADRG.	158
159
Adverse Event Analysis Data Set (ADAE): This data set contains one record per	160
subject, per adverse event, per collection. All AEs reported for a subject during their	161
participation in the trial should be recorded. It also includes additional relevant variables	162
to the review, such as sponsor derived Standardized Medical Dictionary for Regulatory	163
Activities Query (MedDRA SMQ) flags and/or custom MedDRA queries for DILI.	164
165
Laboratory Analysis Data Set (ADLB): This data set contains one record per subject,	166
per lab test, per collection. The laboratory tests of most interest are noted below in the	167
full description for SDTM.LB, but this specification contains additional analysis	168
variables to be submitted in ADLB. However, it is acceptable for additional laboratory	169
tests to be included. If the submitted data set is greater than 5 GB, the data set should be	170
split according to laboratory panels of hematology, chemistry, urinalysis, and other (if	171
necessary, for miscellaneous tests). This data set is designed to be equivalent to an ADaM	172
compliant Basic Data Structure (BDS) laboratory data set with additional review division	173
specific variables. An additional custom data set ADLC structured identically to ADLB	174
containing conventional units should be submitted. It is ideal if both conventional and SI	175
units come directly from the lab vendor and should include all results from unscheduled	176
tests or visits, and local laboratories. Reference ranges used for specific populations	177
should be identified in the SDRG and ADRG.	178
179
Drug-Induced Liver Injury Analysis Data Set (ADDILI): This custom data set	180
contains one record per subject, per parameter, per collection, where each subject should	181
have a minimum of one parameter to evaluate potential DILI. Subjects deemed to have	182
potential DILI should have two additional parameters: one to list the action taken and	183
another to list the outcome. This data set also contains variables derived from pertinent	184
data from the ADLB data set, such as post-baseline maximum values for each of the liver	185
enzymes. In addition, this data set contains flags to indicate any additional work-up	186
conducted to evaluate potential DILI. Sponsors may create new variables to support the	187
analysis or additional parameters using the existing variables (or both) in consultation	188
with FDA.	189

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190
Microscopic Findings Analysis Data Set (ADMI): This data set contains one record per	191
subject, per biopsy parameter, per evaluator, per collection. If re-read of biopsies is	192
performed, this data set should include flags to indicate different readings for the same	193
biopsy. This data set is meant to capture all source biopsy records and evaluate subjects	194
with respect to the histological endpoints as designated by the study protocol. Each	195
histological endpoint is given its own parameter and evaluated in AVALC (e.g., ‘Y’ or	196
‘N’). Additional criteria and analysis flags should also be included as needed from the	197
sponsor. This data should be submitted when the histological data are collected and	198
reported to FDA.	199
200
Non-Invasive Serum Biomarkers of Liver Fibrosis and NASH Analysis Data Set	201
(ADRS): The ADRS data set contains the non-invasive NASH and fibrosis serum	202
biomarkers sponsors may wish to evaluate such as Cytokeratin-18 (CK-18), MELD	203
score, Enhanced Liver Fibrosis (ELF) score, Liver Fibrosis (FIB-4) score, Aspartate	204
Aminotransferase-to-Platelet Ratio Index (APRI), etc. Measurements may be derived as	205
calculations from data points in other data sets such as SDTM.LB or SDTM.RS. This	206
data set follows the same structure as the SDTM.RS domain but contains additional	207
parameters; each non-invasive endpoint (e.g., MELD Score from Baseline <12 to >=15	208
post-baseline) is given its own parameter and evaluated in AVALC (e.g., ‘Y’ or ‘N’).	209
Additional criteria and analysis flags should be included as the sponsor sees fit. This data	210
should be submitted when the non-invasive serum biomarkers are collected and reported	211
to FDA.	212
213
Analysis Time to Event Data Set (ADTTE): This data set is one record per subject, per	214
parameter, per time point. Sponsors should use this data set to evaluate time-to-event	215
endpoints for all subjects. This guidance contains sample parameters, but sponsors should	216
consult with FDA on the specific parameters relevant to their program.	217
218
5.0 OVERVIEW OF DATA SET SPECIFICATIONS	219
220
Each section below provides specifications and/or appropriate CDISC Controlled Terminology	221
that describes the desired content and structure of the data set. The variable names and associated	222
metadata are based on current CDISC SDTM and ADaM standards where possible. If any	223
variable is unclear, sponsors are encouraged to discuss the expectations with DHN.	224
225
Sponsors are strongly encouraged to seek DHN input for additional custom data sets and	226
variables to support determination of efficacy and/or safety. Though sponsors should consider	227
the data sets referenced in this guidance as FDA’s recommendation to support regulatory review,	228
some variables may not be appropriate for all clinical trials.	229
230
CDISC Controlled Terminology developed and maintained by CDISC and National Cancer	231
Institute Enterprise Vocabulary Services (NCI EVS)9 should be used where applicable, but	232
codelists may be extensible. If a submission used alternate controlled terminology or extended	233
any codelist, then sponsors should indicate this in the define.xml document as well as the SDRG	234
9 Available at https://evs.nci.nih.gov/ftp1/CDISC/SDTM/SDTM%20Terminology.pdf.

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and ADRG. The variable labels and the variable type noted in the specifications should be used.	235
As updates are made to CDISC Controlled Terminology, sponsors should use the current version	236
provided by CDISC and NCI EVS.	237
238
5.1 SDTM Domains	239
240
5.1.1 Biospecimen Events (BE) Domain	241
242
The BE domain should contain information regarding the collection of specimens that are used	243
for histological assessment within the Microscopic Findings (MI) domain, including the	244
anatomic location from which the specimen was collected. The collection event is linked to the	245
Biospecimen Findings (BS) domain that stores information regarding any measurements	246
performed on the specimens. For example, a tissue sample that is collected, extracted, frozen,	247
shipped, and thawed should have five records, each with a BEDECOD value of	248
‘COLLECTING’, ‘EXTRACTING’, ‘FREEZING’, ‘SHIPPING’ and ‘THAWING’ respectively.	249
250
5.1.2 Biospecimen Findings (BS) Domain	251
252
Sponsors should provide a complete listing of all characteristics of biospecimens and derived	253
samples used for analysis in the Microscopic Findings (MI) domain. These measurements are	254
used to assess the adequacy and integrity of the samples collected. Sponsors should collect and	255
submit information for the following Biospecimen Characteristics Test Name (BSTEST) values:	256
257
Table 1: Biospecimen Domain Test Values	258
259
BSTESTCD BSTEST BSORRES Notes
DIAMETER Diameter This test is extended from the BSTEST codelist.
LENGTH Length The result should be reported in millimeters (mm).
260
It is important to note that sponsors may submit additional tests to support the decision to include	261
or exclude the sample from analysis. In addition, sponsors may use the Related Records	262
(RELREC) domain to connect the specimens between the BS and MI domains.	263
264
5.1.3 Microscopic Findings (MI) Domain	265
266
Currently, the surrogate endpoints that are acceptable to DHN for a phase 3 trial to support	267
approval for treatment of noncirrhotic NASH with fibrosis are biopsy-based under 21 CFR 314	268
Subpart H - Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses. A	269
semi-quantitative scoring system that considers a core set of histological features known as the	270
NASH Clinical Research Network (CRN) Scoring System is used to assess NASH. Sponsors	271
may provide data for additional scoring systems conforming to CDISC standards.10 Details on	272
alternative scoring should be described in the SDRG and ADRG.	273
10 Available at https://www.cdisc.org/standards.

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274
Subjects should have an overall histological diagnosis of NASH with liver fibrosis before the	275
NASH CRN Score applies. The NASH CRN Scoring System consists of an evaluation of fibrosis	276
using the NASH CRN Fibrosis Stage and the NAFLD Activity Score (NAS), where NAS	277
combines scores of steatosis, lobular inflammation, and hepatocellular ballooning.11 For drug	278
development programs intended for treatment of noncirrhotic NASH with liver fibrosis, FDA has	279
accepted as critical inclusion criteria in NASH trials a NAS greater than or equal to 4 with at	280
least 1 point each in inflammation and ballooning along with a NASH CRN fibrosis score greater	281
than stage 1 fibrosis but less than stage 4 fibrosis.	282
283
Liver biopsy data can be tabulated using CDISC’s MI Domain. The MI domain is designed to	284
hold information generated from histological, pathological, and immunohistological images	285
obtained via microscopic evaluations of tissue samples. The MI domain provides a record for	286
each microscopic finding observed, where multiple microscopic tests on a specimen may be	287
conducted.	288
289
As the biopsy tissue may be processed into multiple slides prior to histopathological evaluation,	290
each individual slide may be assessed for individual NASH components. Sponsors should	291
determine whether or not the individual slides are adequate for assessment and record those	292
results in the Supplemental MI (SUPPMI) domain. Sponsors should also link records within the	293
MI, BS, and BE domains via a RELREC domain. Based on the specifications of the MI domain	294
and the CDISC Controlled Terminology approved thus far for liver fibrosis scoring, each specific	295
component of the NAS should be recorded using the Microscopic Findings Test Detail	296
(MITSTDTL) variable. Likewise, the total NAS score is represented with MITSTDTL of ‘Total	297
Score’ with the criteria (NAS) being held in Microscopic Findings Test Code (MITESTCD) and	298
Microscopic Findings Test (MITEST) variables, to group the individual components and total	299
score of NAS.	300
301
Given that histological assessments of NAFLD and NASH are subject to inter- and intra-	302
observer variability,12 sponsors should capture the observer details in the MI domain using the	303
Evaluator (MIEVAL) and Evaluator ID (MIEVALID) variables. The measure evaluator is stored	304
in MIEVAL and within the MIEVALID variable when distinction between multiple evaluators	305
with the same role is necessary. Where MIEVALID is populated, MIEVAL should exist and	306
have a non-null value. CDISC Controlled Terminology should be used to populate the values for	307
these variables. In cases where multiple evaluators provide assessments for a given time point	308
measurement or for an overall assessment, an independent assessor identifies one of multiple	309
measurements to be the accepted one and should be indicated through use of the Accepted	310
Record Flag variable (MIACPTFL). Values for this variable are not meant to be derived by the	311
sponsor.	312
313
11 DE Kleiner, EM Brunt, M Van Natta, C Behling, MJ Contos, OW Cummings, LD Ferrell, YC Liu, MS
Torbenson, A Unalp-Arida, M Yeh, AJ McCullough, and AJ Sanyal, 2005, Design and Validation of a Histological
Scoring System for Nonalcoholic Fatty Liver Disease, Hepatology, 41(6):1313–1321.
12 DE Kleiner and HR Makhlouf, 2016, Histology of Nonalcoholic Fatty Liver Disease and Nonalcoholic
Steatohepatitis in Adults and Children, Clin Liver Dis, 20(2):293–312.

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CDISC Controlled Terminology provides values of ‘Fibrosis’ within MITESTCD and MITEST.	314
While there is currently no specified terminology published by CDISC for the NASH CRN	315
Fibrosis Stage, CDISC does provide terminology for other liver fibrosis scoring criteria for use	316
with the Microscopic Findings Test Detail (MITSTDTL) variable. MITSTDTL is a qualifier	317
variable for MITESTCD and MITEST. Based on this, sponsors should specify NASH CRN	318
Fibrosis Stage in MITSTDTL, used in conjunction with MITESTCD and MITEST of ‘Fibrosis.’	319
Results from the biopsy can be specified using the Microscopic Findings Original Result	320
(MIORRES) variable.	321
322
Tables 2 (recommended) and 3 (permissible) below contain a representation of concepts for the	323
MI domain. Sponsors should discuss with the review division if any of the permissible tests are	324
required for an individual trial. Sponsors should store any comments about the biopsy or slide	325
readings in a Comments (CO) domain.	326
327
Table 2. Recommended Microscopic Findings Test Codes, Tests, Test Details and Results13	
328
329
MITESTCD MITEST MITSTDTL MIORRES
NASHIND
Histological Presence of
NASH with Fibrosis
Indicator
Yes, No
NAS NAFLD Activity Score STEATOSIS 0, 1, 2, 3
NAS NAFLD Activity Score LOBULAR
INFLAMMATION 0, 1, 2, 3
NAS NAFLD Activity Score BALLOONING 0, 1, 2
NAS NAFLD Activity Score TOTAL SCORE 0, 1, 2, 3, 4, 5, 6, 7, 8
STEAT Steatosis STEATOSIS GRADE <5%, 5-33%, >33-66%, >66%
STEAT Steatosis STEATOSIS LOCATION Zone 3, Zone 1, Azonal, Panacinar
STEAT Steatosis MICROVESICULAR
STEATOSIS Present, Absent
FIBROSIS Fibrosis NASH CRN FIBROSIS
STAGE 0, 1A, 1B, 1C, 2, 3, 4
INFLAM Inflammation LOBULAR
INFLAMMATION No foci, <2 foci, 2-4 foci, >4 foci
INFLAM Inflammation PORTAL
INFLAMMATION14 None to minimal, >Minimal
13 Note: The terminology listed in the table below is proposed terminology.
14 Portal Inflammation is recommended for pediatric trials and permissible for adult trials.

Contains Nonbinding Recommendations
11
MITESTCD MITEST MITSTDTL MIORRES
HCCINJ Hepatocellular Injury BALLOONING
DEGENERATION None, Few, Many
PTNUM Number of Portal Tracts
330
Table 3. Permissible Microscopic Findings Test Codes, Tests, Test Details and Results	331
332
MITESTCD MITEST MITSTDTL MIORRES
FIBROSIS Fibrosis ISHAK FIBROSIS SCORE 0-6
INFLAM Inflammation MICROGRANULOMAS Present, Absent
HCCINJ Hepatocellular Injury ACIDOPHIL BODIES None to rare, Many
HCCINJ Hepatocellular Injury MALLORY BODIES None to rare, Many
HCCINJ Hepatocellular Injury PIGMENTEED
MACROPHAGES None to rare, Many
HCCINJ Hepatocellular Injury MEGAMITOCHONDRIA None to rare, Many
333
5.1.4 Supplemental Microscopic Findings (SUPPMI) Domain	334
335
Sponsors should provide a Supplemental Microscopic Findings (SUPPMI) domain with a	336
parameter to assess the adequacy of biopsy sample(s) collected for analysis. Adequacy of the	337
slide(s) created for evaluating the histopathological features (e.g., steatosis, inflammation,	338
ballooning) should be established based on results collected in the BS and MI domains. Sponsors	339
should provide their rationale in the supplemental qualifier ‘Image Condition’ for slides	340
determined to be not adequate for analysis. If there are multiple reasons, ‘Image Condition’	341
should take a value of ‘MULTIPLE’ with the individual reasons listed in QVAL for ‘Image	342
Condition 1’ and ‘Image Condition 2.’ Sponsors may provide additional slide-level data points in	343
the SUPPMI domain as they see fit (e.g., evaluator name, container name). The table below	344
provides the variables and terminology to be used for assessing adequacy of the sample.	345
346

Contains Nonbinding Recommendations
12
Table 4. Terminology for SUPPMI Domain	347
348
RDOMAIN IDVAR IDVARVAL QNAM QLABEL QVAL
MI
Use these variables to
link back to MI domain
MIOIQ Overall Image
Quality
Expected Values: Adequate,
Not Adequate
MI MIIMCND Image Condition e.g., Blurry Image, Cracked
Slide, Multiple
MI MIIMCND1 Image Condition 1 List Condition 1 if Multiple
Conditions
MI MIIMCND2 Image Condition 2 List Condition 2 if Multiple
Conditions
349
5.1.5 Disease Response and Clinical Classifications (RS) Domain	350
CDISC provides specific guidance for characterizing and recording clinical indicators of hepatic	351
disease progression including MELD Scoring,15 West Haven Hepatic Encephalopathy Grade,16	
352
and Child-Pugh Classification17 in the RS domain.	353
• MELD Related Scores (e.g., MELD, MELD Sodium (MELD-Na), MELD 3.0): While	354
there are no current CDISC guidance for MELD-related scores, sponsors should follow a	355
similar modeling strategy as MELD scoring as shown in Table 5. Individual laboratory	356
test result values (e.g., Creatinine, Bilirubin, INR) and patient sex should be represented	357
in the LB domain and composite scoring in the RS domain where the linkage is	358
represented using the --LNKID variable. The relationship between the two domains is	359
stored in the RELREC domain.	360
361
• West Haven Hepatic Encephalopathy Grade: The measure evaluator is stored in	362
Evaluator (RSEVAL), and if distinction between multiple evaluators with the same role	363
is necessary, this information is stored within the Evaluator ID (RSEVALID) variable.	364
Where RSEVALID is populated, RSEVAL should exist and have a non-null value.	365
Results should be populated in the Original (RSORRES) and Standard Character	366
(RSSTRESC) Results variables and take values of ‘GRADE 0’, ‘GRADE 1’, ‘GRADE	367
2’, ‘GRADE 3’, or ‘GRADE 4’.	368
369
15 Available at https://www.cdisc.org/standards/foundational/qrs/model-end-stage-liver-disease.
16 Available on the https://www.cdisc.org/ website after login at
https://www.cdisc.org/system/files/members/standard/foundational/qrs/SDTM%20RS-
WH%20Hepatic%20Encephalopathy%20Grade%20v1%20Public%20Domain.pdf.
17 Available on the https://www.cdisc.org/ website after login at
https://www.cdisc.org/system/files/members/standard/foundational/qrs/SDTM%20RS-Child-
Pugh%20v1%20Public%20Domain.pdf.

Contains Nonbinding Recommendations
13
• Child-Pugh Classification: Guidance provided by CDISC provides a way to represent	370
the individual laboratory test result values in the LB domain collection of ascites	371
information in the CE domain, and composite scoring in the RS domain where the	372
linkage is represented using the --LNKID variable from each of the domains. For	373
example, a serum bilirubin result of 2.3 mg/dL would result in a RSORRES of ‘2 to 3’	374
and a RSSTRESN value of 2 where RSTEST = ‘CPS01-Serum Bilirubin.’ The	375
relationship between the two domains is represented in a RELREC domain. Since the	376
input to the Child-Pugh Encephalopathy Grade parameter originates from the West	377
Haven Hepatic Encephalopathy Grade that is also modeled in the RS domain (see above	378
section on ‘West Haven Hepatic Encephalopathy Grade’), the guidance further provides	379
linking of these two RS records through the use of the RSGRPID variable.	380
381
The table below provides CDISC Controlled Terminology that has been developed for RSCAT,	382
RSTESTCD and RSTEST. Refer to the current version of the NCI EVS to ensure no changes to	383
the terminology relevant to the RS domain.	384
385
Table 5. Terminology for Disease Response and Clinical Classifications (RS) Domain18	386
387
RSCAT RSTESTCD RSTEST CDISC Definition (if available)
MELD MELD0101 MELD-01 Score Model for End Stage Liver Disease–MELD
Score.
MELD-NA MELD0201 MELD-NA Score
MELD-3.0 MELD0301 MELD-03 Score
WEST HAVEN
HEPATIC
ENCEPHALOPATHY
GRADE
WHEG0101
WHEG01-WH
Hepatic
Encephalopathy
Grade
West Haven Hepatic Encephalopathy Grade
– Grade.
CHILD-PUGH
CLASSIFICATION
CPS0101
CPS01-
Encephalopathy
Grade
Child-Pugh Classification - Encephalopathy
Grade.
CPS0102 CPS01-Ascites Child-Pugh Classification - Ascites.
CPS0103 CPS01-Serum
Bilirubin
Child-Pugh Classification - Serum bilirubin,
mg/dL.
CPS0104 CPS01-Serum
Albumin
Child-Pugh Classification - Serum albumin,
g/dL.
CPS0105A CPS01-PT, Sec
Prolonged
Child-Pugh Classification - Prothrombin
time, sec prolonged.
18 Note: MELD-NA terminology is proposed terminology and not listed in the NCI EVS.

Contains Nonbinding Recommendations
14
RSCAT RSTESTCD RSTEST CDISC Definition (if available)
CPS0105B CPS01-PT, INR Child-Pugh Classification - Prothrombin
time, international normalized ratio (INR).
CPS0106 CPS01-Total Score Child-Pugh Classification - Child-Pugh total
score.
CPS0107 CPS01-Grade Child-Pugh Classification - Child-Pugh
grade.
388
5.1.6 Imaging Results (ZI) Domain19	
389
390
The custom ZI domain captures results of liver imaging procedures (e.g., MRI or CT scan).	391
392
Sponsors may choose to conduct imaging procedures to further investigate the liver during the	393
clinical trial, including measurements for liver steatosis, inflammation, and/or fibrosis. Imaging-	394
based biomarkers are currently not accepted by DHN to support primary efficacy assessments in	395
trials intending to support a marketing application; however, they can be used to assess	396
preliminary efficacy in early phase trials and as exploratory or secondary endpoints to provide	397
supportive evidence. It is therefore important for these data points to be submitted consistently.	398
The procedure itself should be recorded in the Procedures (PR) domain and results of the	399
procedure should be recorded in this custom Imaging Results (ZI) domain.	400
401
The ZI domain takes the structure of a findings domain and should contain variables such as	402
Imaging Results Test (ZITEST), Imaging Results Test Code (ZITESTCD), and Imaging Results	403
Original Result (ZIORRES). Sponsors may use their discretion regarding which data points to	404
collect and submit from the imaging procedure(s). Recording of the procedure in the PR domain	405
and results of that procedure in the ZI domain may be linked via the RELREC domain.	406
407
5.1.7 Adjudication (ZA) Domain	408
409
Sponsor protocols may specify for certain events and/or clinical outcomes to be adjudicated by	410
investigator(s) and/or committee(s). Sponsors should create a custom ZA domain to provide	411
assessments by individual adjudicators as it relates to certain events (e.g., DILI). Examples of	412
adjudicated events in NASH development programs may include DILI, Liver-Related Death,	413
Hepatic Decompensation Events, Major Adverse Cardiac Events (MACE), and Cardiac-Related	414
Death. All potential events sent for adjudication should be included in the data set regardless of	415
the adjudication outcome.	416
417
The ZA domain should follow the structure of a Findings About Events or Interventions (FA)	418
domain. An FA domain utilizes the SDTM findings class structure with the addition of an	419
19 Note: Future releases of the SDTMIG may contain a Gastrointestinal System Findings (GI) domain as discussed
in the Crohn’s Disease Therapeutic Area User Guide (TAUG). If and when the GI domain becomes available in a
future version of the SDTMIG and if FDA supports that new version, sponsors may choose to submit ZI findings
into the GI domain.

Contains Nonbinding Recommendations
15
‘Object’ (--OBJ) variable that serves to specialize the topic being measured within the --	420
TESTCD/--TEST variable.	421
422
Sponsors should specify in their protocol and in the ZA domain the event that is being	423
adjudicated, type of investigator assessing the event as well as the committee responsible for	424
resolving any discrepancies between individual adjudicators. For example, the custom ZA	425
domain may provide DILI assessments and/or Liver-Related Death/Clinical Outcomes by	426
individual hepatologists and a Hepatic Adjudication Committee (HAC), if applicable. MACE	427
and Cardiac-Related Death events may be adjudicated by a Cardiac Adjudication Committee	428
(CAC).	429
430
The date of the adjudicator’s assessment may be stored in ZADTC. The earliest date that the	431
assessor determines the subject to have met the criteria should be modeled as its own record with	432
ZATEST value of ‘EVALUATED EVENT ONSET DATE’ with the date value stored in	433
ZAORRES. The Object (ZAOBJ) variable should hold the name of the event being evaluated,	434
such as ‘DILI’ or ‘CARDIAC MACE.’ Each block of records resulting from assessment of a	435
single adjudication event should be grouped using a unique Repetition Number (ZAREPNUM)	436
variable. The Category (ZACAT) variable may be used to distinguish if the adjudication is a	437
‘FIRST ADJUDICATION’ or a ‘READJUDICATION.’	438
439
For assessing potential DILI, each adjudicator’s assessment should include a category of	440
likelihood that the investigational or study product caused DILI. We recommend the likelihood	441
categories used by the Drug-Induced Liver Injury Network’s numeric score of 1 to 6 (1 =	442
Definite, 2 = Highly Likely, 3 = Probable, 4 = Possible, 5 = Unlikely, or 6 = Indeterminate).20 If	443
a HAC was used, then consensus assignment of likelihood category should also be provided (and	444
noted in the ZAEVAL variable). If the adjudicator is reviewing lab data to determine whether the	445
subject meets potential DILI injury, the records from the LB domain and the record(s) in the ZA	446
domain may be linked using the RELREC domain.	447
448
For assessing whether a subject meets given criteria (e.g., cardiac-related death), sponsors should	449
include in their study protocol the specific criteria being used for the event being adjudicated.	450
The Test (ZATEST) variable may take a value such as ‘EVENT CRITERIA MET’ with the	451
event itself stored in the ZAOBJ variable. The result variable (ZAORRES) may take values of	452
‘Yes’ or ‘No.’ Any comments made by an adjudicator or an adjudication committee the sponsor	453
wishes to submit should be stored in the Comments (CO) domain, linked to the ZA domain by	454
means of the variables RDOMAIN (related domain), IDVAR (Identifying Variable), and	455
IDVARVAL (Identifying Variable Value) within the CO domain. Linking a comment to an	456
individual record in the ZA domain, use RDOMAIN = ‘ZA’, IDVAL = ‘ZASEQ’ and the	457
appropriate value of ZASEQ in IDVARVAL.	458
459
For assessing hepatic decompensation events requiring adjudication, the ZAOBJ variable could	460
take a value of ‘HEPATIC DECOMPENSATION EVENT.’ The adjudicator’s assessment of the	461
specific event causing the subject to reach the endpoint is stored in ZAORRES where ZATEST =	462
‘ADJUDICATION OUTCOME’ with the adjudicator’s assessment of when the subject reached	463
that endpoint stored in ZAORRES where ZATEST = ‘EVALUATED EVENT ONSET DATE.’	464
20 Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637941/pdf/nihms-444700.pdf.

Contains Nonbinding Recommendations
16
465
Table 6 contains the variables and subsequent comments, and Table 7 contains example	466
terminology for adjudicated events and outcomes.	467
468
Table 6. ZA Variables	469
470
Variable
Name Variable Label Type Comments
Adjudication Test and Results
ZATESTCD Adjudication Test
Code
Char See Table 7.
ZATEST Adjudication Test Char See Table 7.
Sponsors may include additional tests beyond what is listed
in Table 7. Additional tests can apply to all objects or some
objects (i.e., sponsors are permitted to submit an object-
specific test).
ZAOBJ Object of Interest Char See Table 7.
The category of event that is being adjudicated, e.g., ‘DILI’,
‘CARDIAC MACE’.
If the trial protocol calls for additional events or outcomes
to be adjudicated, sponsors may extend the codelist beyond
what is listed in Table 7.
ZACAT Category Char Used to define if the adjudication is a first adjudication or
re-adjudication.
ZAORRES Original Result Char The adjudicator’s assessment of ZATEST.
ZASTRESC Standard Character
Result
Char Standardized Result of the adjudicator’s assessment of
ZATEST.
Adjudicator Information
ZAEVAL Evaluator Char Role of the person who provided the evaluation. Used only
for results that are subjective (e.g., assigned by a person or a
group). Should be null for records that contain collected or
derived data. Examples: INVESTIGATOR,
ADJUDICATION COMMITTEE, VENDOR.
ZAEVALID Evaluator Identifier Char Used to distinguish multiple evaluators with the same role
recorded in ZAEVAL. Examples: ‘Hepatologist 1’,
‘Hepatologist 2’. ZAEVAL should be populated when
ZAEVALID is populated.
Other Flags
ZAACPTFL Accepted Record Flag Char The Acceptance Flag identifies those records that have been
determined to be the accepted assessment by an independent
assessor. This flag would be provided by an independent
assessor and when multiple evaluators (e.g., ‘Hepatologist
1’, ‘Hepatologist 2’, and ‘Hepatic Adjudication
Committee’) provide assessment or evaluations at the same
time point or an overall evaluation.
471

Contains Nonbinding Recommendations
17
Table 7. Example Terminology for Adjudicated Events and Outcomes	472
473
ZAOBJ ZATESTC
D ZATEST ZAORRES
DILI
ADJDILI DILI ADJUDICATION
SCORE 1-6
ADJDATE EVALUATED EVENT
ONSET DATE
Adjudicator’s assessment of when the
subject met event criteria
CARDIAC MACE
ADJCRIT EVENT CRITERIA MET Yes, No
ADJDATE EVALUATED EVENT
ONSET DATE
Adjudicator’s assessment of when the
subject met event criteria
CARDIAC DEATH
ADJCRIT EVENT CRITERIA MET Yes, No
ADJDATE EVALUATED EVENT
ONSET DATE Date of Death
LIVER-RELATED
DEATH
ADJCRIT EVENT CRITERIA MET Yes, No
ADJDATE EVALUATED EVENT
ONSET DATE Date of Death
CAUSE OF
DEATH
ADJOUT ADJUDICATION
OUTCOME
Adjudicator’s assessment of cause of
death
ADJDATE EVALUATED EVENT
ONSET DATE Date of Death
HEPATIC
DECOMPENSATI
ON EVENT
ADJOUT ADJUDICATION
OUTCOME
HEPATIC ENCEPHALOPATHY,
ASCITES, VARICEAL BLEED,
SPONTANEOUS BACTERIAL
PERITONITIS
ADJDATE EVALUATED EVENT
ONSET DATE
Adjudicator’s assessment of when the
subject met event criteria
474
5.1.8 Concomitant Medications (CM) Domain	475
476
Sponsors should provide a complete list of concomitant medications for all subjects in	477
accordance with supported CDISC standards. In addition to prescription medications, sponsors	478
should include any over-the-counter medications (e.g., weight-loss medication, dietary and	479
herbal medications). Of particular interest are lipid-lowering agents, statins, antihypertensive,	480
antidiabetic, thiazolidinediones, vitamin E, and anticoagulants and antiplatelets. Data relating to	481
concomitant medications should be captured and recorded during scheduled visits as reflected in	482
the trial protocol and when the subject is undergoing evaluation for potential DILI.	483
484

Contains Nonbinding Recommendations
18
5.1.9 Medical History (MH) Domain	485
486
Sponsors should provide complete medical history data for all subjects in accordance with	487
supported CDISC standards. Of particular interest are preexisting medical conditions that may	488
impact NASH disease progression and/or DILI assessment (e.g., diabetes, primary liver cancers,	489
alcohol/substance use disorder, gallstone disease, heart failure, etc.). Sponsors should refer to the	490
draft NASH Guidance regarding recommendations for trial enrollment depending on the phase of	491
drug development. Additionally, sponsors should include a record in the MH domain for any	492
condition that precludes a subject from participating in the study, in addition to their record in	493
the Inclusion/Exclusion (IE) domain.	494
495
496
5.1.10 Laboratory (LB) Domain	497
498
Sponsors should provide the complete tabulated data for all lab measurements recorded,	499
including central and local labs (denoted using LBNAM variable) as well as scheduled and	500
unscheduled visits. All lab data should be provided in accordance with supported CDISC	501
Standards and Controlled Terminology and the Study Data Technical Conformance Guide.	502
Sponsors should discuss specific laboratory parameters to be collected with DHN.	503
Recommended parameters are listed below:	504
505
• Hematology parameters (e.g., white blood cell, hemoglobin, platelets)	506
507
• Metabolic parameters (e.g., electrolytes, hemoglobin A1C, creatine kinase, lactate	508
dehydrogenase)	509
510
• Liver parameters including bilirubin fractions21 (e.g., direct and indirect or conjugated	511
and unconjugated)	512
513
• Renal parameters (e.g., creatinine, estimated glomerular filtration rate)	514
515
• Lipid parameters	516
517
• Coagulation parameters (e.g., prothrombin time/international normalized ratio)	518
519
• Autoimmune parameters (e.g., Antinuclear antibody (ANA), anti-smooth muscle	520
antibody (ASMA), Total IgG levels)	521
522
In addition to the above tests, sponsors may wish to include other serum biomarkers that may be	523
relevant to understanding NASH, fibrosis, and/or DILI (e.g., ELF,22 CK-18, APRI, FIB-4, N-	524
21 Sponsors should use appropriate terminology to clearly reflect the method used to assess bilirubin fractions (i.e.,
conjugated vs. direct).
22 If the ELF Score is calculated histologically, the result should be stored in the MI domain for MI.MIORRES
under MI.MITSTDTL = ‘ENHANCED LIVER FIBROSIS SCORE’ and MI.MITESTCD = ‘FIBROSIS’.

Contains Nonbinding Recommendations
19
terminal propeptide of type III collagen (PRO-C3), Phosphatidylethanol (PEth)). Note that	525
individual components of calculated serum biomarkers should have their own record(s) in the LB	526
domain. Any biomarker that is derived from individual components should store the analytical	527
method used for calculation stored in the Analysis Method variable (LB.LBANMETH).	528
Terminology for the components of and results for the aforementioned example serum	529
biomarkers are provided below in Table 8Table 8. All lab parameters submitted to FDA should	530
follow supported CDISC Controlled Terminology.	531
532
An additional custom domain called LC structured identically to the LB domain should contain	533
conventional units in --STRESU for the results in conventional units in the --STRESC and --	534
STRESN variables. It is ideal if both conventional and SI units come directly from the lab	535
vendor. Submit the results of all tests obtained on subjects, including the results from	536
unscheduled tests or visits, and results obtained from local laboratories. Identify all reference	537
ranges used for specific populations in the SDRG.	538
539
Table 8. Terminology for Example Liver Serum Biomarkers in LB Domain23	
540
541
LBTESTCD LBTEST NCI Code CDISC Definition (if available)
ELF Components
TIMP1 Tissue Inhibitor of
Metalloproteinase 1 C82036 A measurement of the tissue inhibitor of
metalloproteinase 1 in a biological specimen.
P1NP Procollagen 1 N-Terminal
Propeptide C96625 A measurement of the procollagen 1 N-terminal
propeptide in a biological specimen.
HYALUAC Hyaluronic Acid C112319 A measurement of hyaluronic acid in a biological
specimen.
Example Liver Serum Biomarkers
ELF Enhanced Liver Fibrosis
APRI AST to Platelet Ratio Index C156512
A calculation that indicates the likely presence of liver
cirrhosis and fibrosis, measured as the relative
measurement of aspartate aminotransferase (AST) to
AST upper limit of normal, divided by the platelet
count, and multiplied by 100.
CYFRA18 Cytokeratin 18 Fragment C130160 A measurement of the cytokeratin 18 fragment in a
biological specimen.
LVFBRSC Liver Fibrosis Score C147385
A scoring system that evaluates liver pathology
through the assessment of multiple blood test
parameters, taking into account additional
demographic factors such as the age and/or sex of the
subject.
P3NP Procollagen 3 N-Terminal
Propeptide C128973 A measurement of the procollagen 3 N-terminal
propeptide in a biological specimen.
542
5.1.11 Microbiology Specimens (MB) Domain	543
544
Sponsors should use the MB domain to provide serologic test results for hepatitis (hepatitis A, B,	545
C, and E) serology tests collected as part of the trial entry evaluation and during potential DILI	546
23 The line item for Enhanced Liver Fibrosis is proposed terminology in the LB domain as a calculation from the
individual components (TIMP1, P1NP, HYALUAC).

Contains Nonbinding Recommendations
20
assessments, if applicable. CDISC Controlled Terminology for the hepatitis tests are provided in	547
Table 9 below. Please use the terms from SDTM Controlled Terminology (CT) Q3 2023 (2023-	548
09-29) even if the terms may not be listed in subsequent SDTM CT versions.	549
550
Table 9. Terminology for Hepatitis Serology in Microbiology Specimens Domain	551
552
MBTESTCD MBTEST NCI Code CDISC Definition (if available)
HAAB* Hepatitis A Virus Antibody C92534 A measurement of the hepatitis A virus antibody in a
biological specimen.
HAIGMAB* Hepatitis A Virus IgM
Antibody C92271 A measurement of hepatitis A virus IgM antibody in a
biological specimen.
HBSAG Hepatitis B Virus Surface
Antigen C64850 A measurement of the surface antigen reaction of a
biological specimen to the hepatitis B virus.
HBCAB* Hepatitis B Virus Core IgM
Antibody C96660 A measurement of the hepatitis B virus core antibody
in a biological specimen.
HCAB* Hepatitis C Virus Antibody C92535 A measurement of the hepatitis C virus antibody in a
biological specimen.
HCRNA Hepatitis C Virus RNA C142330 A measurement of the hepatitis C virus RNA in a
biological specimen.
HDRNA Hepatitis D Virus RNA C186156 A measurement of the hepatitis D virus RNA in a
biological specimen
HDAB*
Hepatitis D Virus
Antibody; Hepatitis Delta
Antibody
C96664 A measurement of the hepatitis D virus antibody in a
biological specimen.
HDIGGAB* Hepatitis D Virus IgG
Antibody C119281 A measurement of the hepatitis D virus IgG antibody
in a biological specimen.
HDIGMAB* Hepatitis D Virus IgM
Antibody C119282 A measurement of the hepatitis D virus IgM antibody
in a biological specimen.
HEIGGAB* Hepatitis E Virus IgG
Antibody C106526 A measurement of IgG antibody to the hepatitis E
virus in a biological specimen.
HEIGMAB* Hepatitis E Virus IgM
Antibody C96665 A measurement of IgM antibody to the hepatitis E
virus in a biological specimen.
HERNA Hepatitis E Virus RNA C142331 A measurement of the hepatitis E virus RNA in a
biological specimen.
* These terms exist in the SDTM Controlled Terminology (CT) Q3 2023 (2023-09-29) but may not be listed	553 subsequent versions.	554
555
5.1.12 Substance Use (SU) Domain	556
557
Data related to substance use (e.g., alcohol use) should be collected as part of the NASH clinical	558
trial and DILI evaluation. The extent of prior alcohol use should be assessed at baseline, during	559
protocol-defined scheduled visits, and in suspected cases of DILI. Data collected should be	560
recorded in the SU domain and included in the Inclusion/Exclusion (IE) domain as appropriate.	561
For example, a subject who consumes one 12-ounce beer per day may contain the following data	562
point:	563
564
• SUTRT: BEER	565
• SUCAT: ALCOHOL	566
• SUDOSE: 12	567

Contains Nonbinding Recommendations
21
• SUDOSU: OUNCES	568
• SUDOSFRQ: QD	569
570
Other substances such as tobacco or caffeine usage should also be recorded in the SU domain.	571
572
5.1.13 Trial Summary (TS) Domain	573
574
Data related to the trial summary should be collected and stored in the TS domain. Of particular	575
interest to FDA is the frequency that this technical specification is used in creating and	576
submitting trial data. Per the FDA Study Data Technical Conformance Guide, sponsors may	577
include an additional parameter in their TS domain to note that this technical specification was	578
used for the study. The parameter and associated value sponsors should use is noted below:	579
580
• TSPARMCD = FDATCHSP	581
• TSPARAM = FDA Tech Spec	582
• TSVAL = NASH Technical Specification Guidance version x.x	583
584
5.1.14 RELREC Domain	585
586
As discussed in previous sections, sponsors should use a RELREC domain to describe the	587
relationship between records captured in separate domains together. A common use case for the	588
RELREC domain is connecting AE and CM records. As it relates to this technical specification,	589
the RELREC domain may connect the needle size captured in the BS domain with the biopsy	590
slide measurements evaluated in the MI domain. Another example may be connecting the record	591
of an MRI procedure in the PR domain with the results of that MRI in the ZI domain. Where	592
relationships between records in different domains should be established, the RELREC domain	593
should store those relationships.	594
595
The full instructions for creating the RELREC domain, including the required variables, are	596
located in the SDTM Implementation Guide.	597
598
5.1.15 Other SDTM Considerations	599
600
5.1.15.1 Gastroesophageal varices	601
602
Subjects who progress to cirrhosis during the trial may undergo screening for gastroesophageal	603
varices on esophagogastroduodenoscopy (EGD). Information on the EGD can be modeled in	604
SDTM using the PR domain. The PR domain falls within the Interventions Class of domains and	605
is intended to capture information on interventional activity that are to have diagnostic,	606
preventive, therapeutic, or palliative effects. The name of the procedure, EGD, can be captured	607
within the Reported Name of Procedure (PRTRT) variable.	608
609
Currently, CDISC does not have any guidance on modeling the results of the EGD procedure	610
related to varices (e.g., number of varices, size of varices, presence of red wale marks). Given	611
that CDISC has a draft domain for Gastrointestinal System Findings (GI) that may be under	612
development, the current recommendation is to model the results of the EGD procedure in the	613

Contains Nonbinding Recommendations
22
custom Imaging Results (ZI) domain that follows the structure of a CDISC findings domain.	614
Occurrence of varices, size of varices, red wale marks, and variceal bleeding can be modeled	615
under using ZITESTCD and ZITEST Test Codes and Test Names. Sponsors may submit	616
additional data points about the results of the endoscopy in the ZI domain.	617
618
When gastroesophageal variceal hemorrhage is captured as an AE, it should be captured in the	619
AE domain, with verbatim term indicating gastroesophageal variceal hemorrhage captured in the	620
topic variable of AE.AETERM. The record in the AE domain should be linked to that of the ZI	621
domain using the --LNKID variable, with relationships captured using the RELREC domain.	622
623
5.1.15.2 All-cause mortality	624
625
All-cause mortality or death is a component of several composite endpoints currently accepted	626
by DHN to demonstrate clinical benefit in NASH clinical trials. If a subject dies during the	627
study, information regarding the subject’s death is tabulated in several SDTM domains,	628
including the Death Details (DD) domain, which should store all death information. Additional	629
domains that should include death information are the Disposition (DS) domain that records the	630
death as a disposition event, Adverse Events (AE), Demographics (DM) to populate the Death	631
Date (DTHDTC), and Death Flag (DTHFL) variables that are referenced within this domain. The	632
records within the AE, DS, and DD domains should be linked using the --LNKID variable, with	633
the relationship represented in the RELREC domain. Sponsors should consult CDISC Controlled	634
Terminology as well as the SDTM Implementation Guide in using these domains.	635
636
5.2 ADaM Data Sets	637
638
This section contains three parts: Analysis Data Set Subject Level (ADSL), Occurrence Data	639
Structure (OCCDS) data sets, and Basic Data Structure (BDS) data sets. At a minimum, sponsors	640
should provide the data sets and variables listed throughout these sections. Sponsors can and	641
should submit additional data sets and variables beyond what is listed below in accordance with	642
FDA-supported ADaM Implementation Guide (ADaMIG)24 in the FDA Data Standards Catalog.	643
644
Sponsors should also include appropriate Sequence Number variables in their ADaM data sets	645
for easy traceability back to the SDTM domains. Specific instructions are located in the ADaM	646
Implementation Guide.	647
648
5.2.1 Subject-Level Analysis Data Set (ADSL)	649
650
The ADSL data set contains one record per subject and derives information from other data sets	651
for analysis purposes. Sponsors should include all required variables in the ADSL, including	652
basic demographic information, assigned treatment, actual treatment received, treatment start and	653
end dates, whether the subject discontinued treatment or study early, treatment duration, and	654
study start and end dates.	655
656
Table 10 provides a list of variables that should be included in the ADSL data set. The baseline	657
variables should be used when those tests are collected and provided in the data submission. For	658
24 Available at https://www.cdisc.org.

Contains Nonbinding Recommendations
23
example, if ELF score is not collected and reported, the ELFBL variable is not required for this	659
data set. Sponsors may add additional flags to this data set as appropriate (e.g., special subject	660
populations of interest for subgroup analyses or relevant concomitant medications).	661
662
The comments column of Table 10 contains recommended derivations for the baseline variables.	663
Sponsors should include their derivations in the ADaM define.xml file.	664
665
Table 10. ADSL Variables	666
667
Variable
Name Variable Label Type Comments
Baseline Vital Signs Characteristics Variables
WEIGHTBL Weight at Baseline
(kg) Num VS.VSSTRESN where VSTEST = ‘WEIGHT’ and VSBLFL
= ‘Y’
HEIGHTBL Height at Baseline
(cm) Num VS.VSSTRESN where VSTEST = ‘HEIGHT’ and VSBLFL
= ‘Y’
BMIBL Body Mass Index
at Baseline (kg/m2) Num VS.VSSTRESN where VSTEST = ‘BMI’ and VSBLFL =
‘Y’
SYSBL
Systolic Blood
Pressure at
Baseline (mmHg)
Num VS.VSSTRESN where VSTEST = ‘Systolic Blood Pressure’
and VSBLFL = ‘Y’
DIABL
Diastolic Blood
Pressure at
Baseline (mmHg)
Num VS.VSSTRESN where VSTEST = ‘Diastolic Blood
Pressure’ and VSBLFL = ‘Y’
HRBL
Heart Rate at
Baseline
(beats/min)
Num VS.VSSTRESN where VSTEST = ‘Heart Rate’ and
VSBLFL = ‘Y’
RESPBL
Respiratory Rate at
Baseline
(breaths/min)
Num VS.VSSTRESN where VSTEST = ‘Respiratory Rate’ and
VSBLFL = ‘Y’
WHBL Waist to Hip Ratio
at Baseline Num VS.VSSTRESN where VSTEST = ‘Waist to Hip Ratio’ and
VSBLFL = ‘Y’
Baseline Lab Characteristics
ALTBL Baseline ALT Num ADLB.AVAL where ADLB.PARAMCD = ‘ALT’ and
ADLB.DILIBLFL = ‘Y’
ALTCAT Baseline ALT
Category Text
Divide ADSL.ALTBL by LB.LBSTNRHI for the last pre-
treatment record for ALT and set the category to one of the
following:
• If result is <=1: <= ULN
• If result is >1 to <=3: > ULN to <=3x ULN
• If result is >3 to <=5: >3x ULN to <=5x ULN
• If result is >5: >5x ULN
ALTCATN Baseline ALT
Category (N) Integer
Numeric Representation of ALTCAT. ‘1’ = ‘<=ULN’, ‘2’ =
‘>ULN to <=3x ULN’, ‘3’ = ‘>3x ULN to <=5x ULN’, ‘4’ =
‘>5x ULN’

Contains Nonbinding Recommendations
24
Variable
Name Variable Label Type Comments
ASTBL Baseline AST Num ADLB.AVAL where ADLB.PARAMCD = ‘AST’ and
ADLB.DILIBLFL = ‘Y’
ASTCAT Baseline AST
Category Text
Divide ADSL.ASTBL by LB.LBSTNRHI for the last pre-
treatment record for AST and set the category to one of the
following:
• If result is <=1: <= ULN
• If result is >1 to <=3: >ULN to <=3x ULN
• If result is >3 to <=5: >3x ULN to <=5x ULN
• If result is >5: >5x ULN
ASTCATN Baseline AST
Category (N) Integer
Numeric Representation of ASTCAT. ‘1’ = ‘<=ULN’, ‘2’ =
‘>ULN to <=3x ULN’, ‘3’ = ‘>3x ULN to <=5x ULN’, ‘4’ =
‘>5x ULN’
ALPBL Baseline ALP Num ADLB.AVAL where ADLB.PARAMCD = ‘ALP’ and
ADLB.DILIBLFL = ‘Y’
ALPCAT Baseline ALP
Category Text
Divide ADSL.ALPBL by LB.LBSTNRHI for the last pre-
treatment record for ALP and set the category to one of the
following:
• If result is <=1: <= ULN
• If result is >1 to <=2: > ULN to <=2x ULN
• If result is >2: >2x ULN
ALPCATN Baseline ALP
Category (N) Integer Numeric Representation of ALPCAT. ‘1’ = ‘<=ULN’, ‘2’ =
‘>ULN to <=2x ULN’, ‘3’ = ‘>2x ULN’
TBILIBL Baseline Total
Bilirubin Num ADLB.AVAL where ADLB.PARAMCD = ‘BILI’ and
ADLB.DILIBLFL = ‘Y’
TBILCAT Baseline Tot.
Bilirubin Category Text
Set to ‘<=ULN’ if ADSL.TBILIBL <= LBSTNRHI (for the
last pre-treatment record in SDTM.LB where LBTESTCD =
‘BILI’); else set to ‘>ULN’ if ADSL.TBILIBL > LBSTNRHI
TBILCATN
Baseline Tot.
Bilirubin Category
(N)
Integer Numeric representation of ADSL.TBILCAT.
‘1’ = ‘<=ULN’, ‘2’ = ‘>ULN’
CBILIBL
Baseline
Conjugated
Bilirubin
Num ADLB.AVAL where ADLB.PARAMCD = ‘BILIDIR’ and
ADLB.DILIBLFL = ‘Y’
CBILCAT Baseline Conj.
Bilirubin Category Text
Set to ‘<=ULN’ if ADSL.CBILIBL <= LBSTNRHI (for the
last pre-treatment record in SDTM.LB where LBTESTCD =
‘BILDIR’); else set to ‘>ULN’ if ADSL.CBILIBL >
LBSTNRHI
CBILCATN
Baseline Conj.
Bilirubin Category
(N)
Integer Numeric representation of ADSL.CBILCAT.
‘1’ = ‘<=ULN’, ‘2’ = ‘>ULN’
CPKCAT Baseline CPK
Category Text
Set to ‘Normal’ if LB.LBSTRESN <= LB.LBSTNRHI for
LB.LBTESTCD = ‘CPK’ and LB.LBBLFL = ‘Y’; Set to
‘HIGH’ if LB.LBSTRESN > LB.LBSTNRHI for
LB.LBTESTCD = ‘CPK’ and LB.LBBLFL = ‘Y’

Contains Nonbinding Recommendations
25
Variable
Name Variable Label Type Comments
LDHCAT Baseline LDH
Category Text
Set to ‘Normal’ if LB.LBSTRESN <= LB.LBSTNRHI for
LB.LBTESTCD = ‘LDH’ and LB.LBBLFL = ‘Y’; Set to
‘HIGH’ if LB.LBSTRESN > LB.LBSTNRHI for
LB.LBTESTCD = ‘LDH’ and LB.LBBLFL = ‘Y’
PLATCAT Baseline Platelets
Category Text
Set to ‘Normal’ if LB.LBSTRESN >= LB.LBSTNRLO for
LB.LBTESTCD = ‘PLAT’ and LB.LBBLFL = ‘Y’; Set to
‘LOW’ if LB.LBSTRESN < LB.LBSTNRLO for
LB.LBTESTCD = ‘PLAT’ and LB.LBBLFL = ‘Y’
EGFRBL Baseline eGFR Num Baseline eGFR value
EGFRCAT Baseline eGFR
Category Text
Set to ‘Normal’ if Baseline eGFR >= 90, ‘Mild Renal
Impairment’ if 60 =< Baseline eGFR < 90, ‘Moderate Renal
Impairment’ if 30 =< Baseline eGFR < 60 and ‘Severe Renal
Impairment’ if 30 > Baseline eGFR
EGFRCATN Baseline eGFR
Category (N) Integer
Numeric representation of ADSL.EGFRCAT.
‘1’ if ‘Normal’, ‘2’ if ‘Mild Renal Impairment’, ‘3’ if
‘Moderate Renal Impairment’, ‘4’ if ‘Severe Renal
Impairment’
Baseline Medical History Characteristics
CHRONFL Chronic Liver
Disease Flag Char
Expected Values: ‘Y’ or ‘N’
Subjects with evidence of other causes of chronic liver
disease at baseline should be flagged as ‘Y’. Else, ‘N’
DIABFL Diabetes Flag Char Expected values: ‘Y’ or ‘N’
‘Y’ if the subject is diabetic at baseline. Else, ‘N’.
GALLFL Gallstones Flag Char
Expected values: ‘Y’ or ‘N’
‘Y’ if the subject has a history of gallstones at baseline. Else,
‘N’.
PCOSFL Polycystic ovary
syndrome Flag Char
Expected values: ‘Y’ or ‘N’
‘Y’ if the subject has a history of Polycystic ovary syndrome
at baseline. Else, ‘N’.
Baseline Biopsy Characteristics
FIBSCBL Baseline Fibrosis
Score Char
MI.MIORRES where MIBLFL = ‘Y’, MITESTCD =
‘FIBROSIS’ and MITSTDTL = ‘NASH CRN FIBROSIS
STAGE’
ISHAKBL Baseline Modified
ISHAK Score Num
MI.MORRES where MIBLFL = ‘Y’, MITESTCD =
‘FIBROSIS’ and MITSTDTL = ‘ISHAK FIBROSIS
SCORE’
STEOBL Baseline Steatosis
Score Integer MI.MIORRES where MIBLFL = ‘Y’, MITESTCD = ‘NAS’
and MITSTDTL = ‘Steatosis’
HBALLBL Baseline Hep.
Ballooning Score Integer MI.MIORRES where MIBLFL = ‘Y’, MITESTCD = ‘NAS’
and MITSTDTL = ‘Ballooning’
LOBINBL Baseline Lobular
Inflammation Score Integer MI.MIORRES where MIBLFL = ‘Y’, MITESTCD = ‘NAS’
and MITSTDTL = ‘Lobular Inflammation’
PORTFL Baseline Portal
Inflammation Text MI.MIORRES where MIBLFL = ‘Y’, MITESTCD =
‘INFLAM’ and MITSTDTL = ‘Portal Inflammation’
NASBL Baseline NAS Integer Sum of ADSL.STEOBL, ADSL.HBALLBL,
ADSL.LOBINFL

Contains Nonbinding Recommendations
26
Variable
Name Variable Label Type Comments
NASCAT Baseline NAS
Category Text Example NAS category: Set to ‘NAS <6’ if
ADSL.NASBL<6; Set to ‘NAS >=6’ if ADSL.NASBL>=6
NASCATN Baseline NAS
Category (N) Integer Numeric representation of NASCAT. ‘1’ = ‘NAS <6’, ‘2’ =
‘NAS >=6’
NASFIBFL
Overall
Histological
Diagnosis of
NASH with
Fibrosis Flag
Char
Expected Values: ‘Y’ or ‘N’
If MI.MIORRES = ‘Yes’ where MI.MITESTCD =
‘NASHIND’, then ‘Y’. Else, ‘N’
Non-Invasive Baseline Characteristics
MELDBL Baseline MELD
Score Num RS.RSSTRESN when RS.RSBLFL = ‘Y’ and RSTEST =
‘MELD01-Score’
FIB4BL Baseline FIB4 Float
Calculated using lab baseline values and age from
Demographics as: Age (years) x AST (U/L)/[Platelet Count
(x10^9/L) x ALT^(1/2) (U/L)]
ELFBL Baseline ELF Float
MI.MIORRES where MIBLFL = ‘Y’, MITESTCD =
‘Fibrosis’ and MITSTDTL = ‘Enhanced Liver Fibrosis
Score’
APRIBL Baseline APRI Float LB.LBSTRESN where LB.LBBLFL = ‘Y’ and LBTESTCD
= ‘APRI’
Concomitant Medications Characteristics
LIPCAT Lipid-Lowering
Agents Category Char
Expected values: ‘No Concomitant Use’, ‘Prior and
Concomitant Use’, ‘New Concomitant Use’
Any lipid-lowering agents, including statins
STATCAT Statins Category Char
Expected values: ‘No Concomitant Use’, ‘Prior and
Concomitant Use’, ‘New Concomitant Use’
Statins only
ANHYPCAT Antihypertensive
Category Char
Expected values: ‘No Concomitant Use’, ‘Prior and
Concomitant Use’, ‘New Concomitant Use’
Antihypertensive medications
ANDIACAT
Antidiabetic
Medications
Category
Char
Expected values: ‘No Concomitant Use’, ‘Prior and
Concomitant Use’, ‘New Concomitant Use’
Any antidiabetic medications, including Thiazolidinediones
TZDCAT Thiazolidinediones
Category Char
Expected values: ‘No Concomitant Use’, ‘Prior and
Concomitant Use’, ‘New Concomitant Use’
Thiazolidinediones only
VITECAT Vitamin E
Category Char
Expected values: ‘No Concomitant Use’, ‘Prior and
Concomitant Use’, ‘New Concomitant Use’
Vitamin E
ANCPCAT
Anticoagulants and
Antiplatelets
Category
Char
Expected values: ‘No Concomitant Use’, ‘Prior and
Concomitant Use’, ‘New Concomitant Use’
Anticoagulants and Antiplatelets
668
5.2.2 Occurrence Data Structure (OCCDS) Data Sets	669
670
Occurrence Data Structure data sets (OCCDSv1.0) are used for the counting of subjects with a	671
given record or term and often include a coding dictionary (e.g., MedDRA for adverse events,	672
WHODrug for concomitant medications). In creating ADaM OCCDS data sets, sponsors should	673

Contains Nonbinding Recommendations
27
follow the guidance as specified by the ADaM Structure for Occurrence Data in the FDA Study	674
Data Technical Conformance Guide, including sections on dictionary coding and categorization	675
variables, timing variables, and flag and indicator variables.	676
677
5.2.2.1 Adverse Event Analysis Data Set (ADAE)	678
679
Sponsors should include all records from SDTM.AE. If a sponsor uses the approach of recording	680
multiple records in AE each time the event changes in severity, relationship, etc. then this should	681
be noted in the SDRG and ADRG. Also note that the specification includes a flag variable that	682
indicates which record had the worst severity grade for a given adverse event (MedDRA	683
preferred term) when there are multiple occurrences (records) of the same adverse event for the	684
same subject. Sponsors may select a grading scale of their choice, which should be prespecified	685
in the study protocol, SDRG, and ADRG. In addition, sponsors should consult the FDA Data	686
Standards Catalog for guidance on the appropriate MedDRA version to use.	687
688
To aid evaluation of potential DILI, this specification also includes a Hepatic Injury Flag to flag	689
AEs occurring within defined grouped queries (e.g., Custom MedDRA Queries) and	690
accompanying flags to identify the earliest record within each hepatic injury flag. Sponsors	691
should discuss the exact derivations of the hepatic injury flags with FDA. Any deviations from	692
the specifications below should be clearly communicated to the review division.	693
694
Table 11. ADAE Variables	695
696
Variable
Name Variable Label Type Comments
TRTEMFL
Treatment-
Emergent Analysis
Flag
Char
Expected Values: ‘Y’ or null
A value of ‘Y’ on a record should indicate a new or worsening
AE after the first dose of study treatment. Metadata should be
clear on the reference dates that are used to define the period
during which an adverse event is considered treatment
emergent.
AOCCPIFL
1st Max Sev./Int.
Occur Within PT
Flag
Char
Expected Values: ‘Y’ or null
Character indicator for the first occurrence of the maximum
severity/intensity within the subject and preferred term.
HPxxFL Hepatic Injury xx
Flag Char
Expected values: ‘Y’ or null
Sponsors should create Hepatic Injury Flag(s) to capture
specific preferred terms within the MedDRA hierarchy.
Sponsors should consult FDA regarding how many flags are
required and how exactly to derive each flag.
HPFxxFL First Hepatic Injury
xx Flag Char
Expected values: ‘Y’ or null
Create one additional flag for each HPxxFL flag created and
flag the earliest (min ASTDY) on treatment (ASTDY >= 1) for
each subject and record that fits the criteria. Otherwise, null
DILIFL Potential DILI
Event Flag Char
Expected values: ‘Y’ or null
Flag the following Adverse Events as ‘Y’: Fatigue, Nausea,
Vomiting, Abdominal pain or tenderness, Fever, Rash,
Pruritus, Jaundice/icterus, Altered mental status
DILIPFL
Potential DILI
Event Flag (30-
days prior)
Char
Expected values: ‘Y’, ‘N’ or null
Null for records where DILIFL is null. For records with
DILIFL = ‘Y’: if the event occurs in the 30 days before a lab-

Contains Nonbinding Recommendations
28
Variable
Name Variable Label Type Comments
identified DILI threshold met in the ADDILI data set, then
‘Y’. Else, ‘N’
DILIAFL
Potential DILI
Event Flag (30-
days after)
Char
Expected values: ‘Y’,’N’ or null
Null for records where DILIFL is null. For records identified
with DILIFL = ‘Y’: if the event occurs in the 30 days after a
lab-identified DILI threshold met in the ADDILI data set, then
‘Y’. Else, ‘N’
697
698
5.2.3 Basic Data Structure (BDS) Data Sets	699
700
The following guidance should be used to create data sets that fall within the BDS structure (e.g.,	701
ADLB to display laboratory data). Specific guidelines are included for several BDS data sets. All	702
BDS data sets should use the guidelines provided below, which have been written in accordance	703
with the ADaM Implementation Guide.	704
705
All BDS data sets should contain the identifier variables, record-level treatment and dose	706
variables, and timing variables as specified in the ADaM Implementation Guide, specifically the	707
section as it relates to the ADaM Basic Data Structure.	708
709
5.2.3.1 Laboratory Analysis Data Set (ADLB)	710
711
The following issues are considerations for the creation and content of the laboratory analysis	712
data set. Sponsors should follow the ADaM BDS model when creating this data set. Visit	713
windowing and/or inclusion of unscheduled visits should be included in this analysis data set	714
(liver-related lab results should be included for all scheduled and unscheduled visits). When	715
records are imputed or derived in any manner, the standard ADaM variable, DTYPE should be	716
used. All tests and records included in the SDTM.LB domain should be carried into the ADLB	717
data set, and sponsors should also include a derived parameter for the calculated R value.	718
Sponsors should provide a clear derivation method for their calculation of the R value.	719
720
It is acceptable for a sponsor’s ADLB data set to contain additional parameters beyond those	721
noted above. Similarly, variables in addition to those described below may be included.	722
723
As with the LB domain, submit two separate data sets for lab results. The ADLB data set should	724
contain SI units. An additional custom data set called ADLC structured identically to ADLB	725
should contain conventional units. It is ideal if both conventional and SI units come directly from	726
the lab vendor. Submit the results of all tests obtained on subjects, including the results from	727
unscheduled tests or visits, and results obtained from local laboratories. Identify all reference	728
ranges used for specific populations in the ADRG. For more information on CDER/CBER	729
current thinking on conventional units, please see the FDA Study Data Technical Conformance	730
Guide available on the FDA Study Data Standards Resources web page.	731
732
The ADLB specifications listed below include four important variables for the analysis of drug-	733
induced liver injury: DILIBLFL, PEAKFL, REDUCEFL, and ONSETFL. These flags look for	734
DILI records at their baseline, peak (maximum post-baseline), washout (e.g., 50% reduction after	735

Contains Nonbinding Recommendations
29
reaching maximum post-baseline), and onset (first sign of potential DILI). There are many	736
different ways to define the onset of liver injury; sponsors should refer to the existing guidance	737
for industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation (July 2009)25 and	738
seek agreement with the FDA review division on how to specify the onset of DILI injury for	739
their study.	740
741
Table 12. ADLB Variables	742
743
Variable
Name Variable Label Type Comments
DILIFL Drug-Induced
Liver Injury Flag Char
Expected Value: ‘Y’ or null
This flag should have ‘Y’ for the following records:
• ALT, AST, ALP, GGT, Total Bilirubin, Direct Bilirubin,
INR records
AND
• The evaluable record for each test at each visit. If more
than one record is collected at each visit, a derived
record should be created with DTYPE = ‘AVERAGE’.
The average record should be flagged, and the individual
records used to create the average record should not be
flagged. Unscheduled visits may also be flagged as ‘Y’.
Else, null
ABLFL Analysis Baseline
Flag Char
Expected Value: ‘Y’ or null
Character indicator to identify the baseline record for each subject
and parameter. Sponsors should confirm with the FDA review
division on an appropriate definition for baseline. Examples may
include flagging the last record prior to treatment or deriving a
new baseline record as the average of all pre-treatment records for
a given subject and parameter.
DILIBLFL DILI Baseline
Flag Char
Expected Value: ‘Y’ or null
For each subject and liver biochemistry parameter, flag the
baseline record used for DILI analysis as ‘Y’. This flag is similar
to ABLFL, however, in subjects with elevated transaminase
levels at enrollment who show improvements in their
transaminase levels and in essence, establish a new lower baseline
during the trial, sponsors should use the new lower transaminase
values in subsequent assessment for potential DILI (and
subsequently using this flag to identify the record used in baseline
calculations for DILI analyses). Sponsors should seek review
division agreement and provide clear guidance in their ADRG or
define.xml file on derivations for alternate baseline calculations
and provide a flag in the ADSL to indicate if any subjects have
discrepancies between ABLFL and DILIBLFL for any liver
biochemistry parameter.
DTYPE Derivation Type Char
For the case where there are multiple observations and an average
or a geometric mean will be used for the observation for the visit
window in the analysis instead of a single selected real
observation. If this is the case, a new record should be created,
and the records identified by having some values for these records
25 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page
at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.

Contains Nonbinding Recommendations
30
Variable
Name Variable Label Type Comments
in DTYPE variable. The possible value could be ‘AVERAGE’, or
‘GEOMETRIC’, or other meaningful values. This should be
explained in the define file or SAP.
R2ANRHI
Ratio to Analysis
Range Upper
Limit
Num Ratio to the upper limit of the analysis range. Equal to AVAL /
ANRHI.
R2BASE Ratio to Baseline
Value Num
Ratio to the baseline value. Equal to AVAL / BASE. If used for a
given PARAM, should be populated for all post-baseline records
of that PARAM regardless of whether that record is used for
analysis.
ANL01FL Analysis Record
Flag 01 Char
Expected Values: ‘Y’ or null
Flag the records to be used in analysis. If multiple records are
recorded for a parameter at the same visit, use this flag to indicate
which record should be used. Derived records (if it was
appropriate to take an average of two records) may be flagged as
‘Y’. Sponsors should provide a clear derivation for how they
choose to derive this flag.
ANL02FL Analysis Record
Flag 02 Char
Expected Values: ‘Y’ or null
Flag the maximum post-baseline record for each subject and
parameter as ‘Y’
ANL03FL Analysis Record
Flag 03 Char
Expected Values: ‘Y’ or null
Flag the minimum post-baseline record for each subject and
parameter as ‘Y’
PEAKFL DILI Peak Flag Char
Expected Values: ‘Y’, ‘N’ or null
Null for all pre-treatment records and records where DILIFL =
‘N’. If ANL02FL = ‘Y’ and DILIFL = ‘Y’, then ‘Y’. Otherwise,
‘N’
REDUCEFL DILI Reduction
Flag Char
Expected Values: ‘Y’, ‘N’ or null
Null for all pre-treatment records and records where DILIFL =
‘N’. Flag the first record after PEAKFL for each subject and
parameter in which AVAL is equal to or less than 50% of the
value of AVAL where PEAKFL = ‘Y’
ONSETFL DILI Lab Onset
Flag Char
Expected Values: ‘Y’ or null
Sponsors should discuss an appropriate definition of DILI onset
with DHN. The agreed upon definition should be prespecified in
the study protocol. Based on the agreed upon definition, flag all
DILI records as ‘Y’ at a given visit when the onset trigger has
been met.
For example, if ONSET is determined as the first time a subject’s
ALT or AST value reaches >= 3x ULN with concurrent TB >= 2x
ULN within 30 days of the ALT or AST elevation, when a subject
does reach that threshold, all DILI records (ALT, AST, ALP, TB,
DB, GGT) from that visit should be flagged as ‘Y’.
LASTFL Last Record Per
Parameter Flag Char
Expected Values: ‘Y’ or null
Flag the last record (max ADY) for each subject and parameter.
NOTE: this is not limited to last on-treatment record; this may
include follow-up records.
744
5.2.3.2 Drug Induced Liver Injury Analysis Data Set (ADDILI)	745
746
This custom data set will be used to analyze subjects for potential DILI. Sponsors should seek	747
agreement with the FDA review division on the appropriate parameters to use for DILI	748

Contains Nonbinding Recommendations
31
assessments. This data set contains variables that seek a maximum value within ‘xx’ days.	749
Sponsors should discuss with FDA the appropriate time window (e.g., 30 days) to use.	750
751
For any subject meeting the sponsor-established criteria for potential DILI, two additional	752
parameters should be created – one to provide the outcome and another to provide the action	753
taken as a result of potential DILI.	754
755
Sponsors may include additional parameters as they see fit and should consult with FDA	756
regarding the acceptability of the additional parameters. Additionally, this data set includes a set	757
of flag variables that identifies any procedure(s) and/or workups performed to evaluate a subject	758
for potential DILI. These flag variables may be derived from the SDTM.PR (Procedures),	759
SDTM.LB, or SDTM.MB domains (or other domains as determined by the sponsor).	760
761
The ADDILI data set should include the basic demographic information, treatment variables,	762
start and end date variables, and baseline lab characteristics variables from the ADSL data set.	763
764
Table 13. ADDILI Variables	765
766
Variable
Name Variable Label Type Comments
PARAM Parameter Char Expected values: ‘Potential DILI’ and ‘Outcome of
Potential DILI’, ‘Action Taken from Potential DILI’
PARAMCD Parameter Code Char
• For PARAM = Potential DILI: ‘DILI’
• For PARAM = Outcome of Potential DILI –
Outcome: ‘OUTDILI’
• For PARAM = Action Taken from Potential DILI=
‘ACNDILI’
AVAL Analysis Value Num
Expected Values: 1 or 0
Note: The criteria below are example criteria for
evaluation of DILI. Sponsors may consult FDA for
appropriate criteria for their study.
Example 1: PARAMCD = ‘DILI’:
• If ALTULNMX >= 3 and TBALTMX >= 2 and
ALPALTMX < 2, then 1 OR
• If ASTULNMX >= 3 and TBASTMX >= 2 and
ALPASTMX < 2, then 1
• Else 0
Example 2: PARAMCD = ‘DILI’:
• If ALPULNMX >= 2 and TBALPMX >= 2, then 1
• Else 0
AVALC Analysis Value (C) Char
If AVAL = 1, then ‘Y’; if AVAL = 0, then ‘N’
For PARAMCD = ‘OUTDILI’
• Expected values: ‘FATAL’, ‘NOT
RECOVERED/NOT RESOLVED’.

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32
Variable
Name Variable Label Type Comments
‘RECOVERED/RESOLVED’,
‘RECOVERED/RESOLVED WITH SEQUELAE’,
‘RECOVERING/RESOLVING’, ‘UNKNOWN’
For PARAMCD = ‘ACNDILI’:
• Expected values: ‘DOSE INCREASED’, ‘DOSE
NOT CHANGED’, ‘DOSE RATE REDUCED’,
‘DOSE REDUCED’, ‘DRUG INTERRUPTED’,
‘DRUG WITHDRAWN’, ‘NOT APPLICABLE’,
‘UNKNOWN’
ALTULNMX
Post-Baseline
Maximum Ratio
ALT/ULN
Num For each subject, ADLB.R2ANRHI where
ADLB.PEAKFL = ‘Y’ and ADLB.PARAMCD = ‘ALT’
ALTBLMX
Post-Baseline
Maximum Ratio
ALT/BL
Num
For each subject, ADLB.AVAL where ADLB.PEAKFL =
‘Y’ and ADLB.PARAMCD = ‘ALT’ / ADLB.AVAL
where ADLB.DILIBL = ‘Y’ and ADLB.PARAMCD =
‘ALT’
ASTULNMX
Post-Baseline
Maximum Ratio
AST/ULN
Num For each subject, ADLB.R2ANRHI where
ADLB.PEAKFL = ‘Y’ and ADLB.PARAMCD = ‘AST’
ASTBLMX
Post-Baseline
Maximum Ratio
AST/BL
Num
For each subject, ADLB.AVAL where ADLB.PEAKFL =
‘Y’ and ADLB.PARAMCD = ‘AST’ / ADLB.AVAL
where ADLB.DILIBL = ‘Y’ and ADLB.PARAMCD =
‘AST’
ALPULNMX
Post-Baseline
Maximum Ratio
ALP/ULN
Num For each subject, ADLB.R2ANRHI where
ADLB.PEAKFL = ‘Y’ and ADLB.PARAMCD = ‘ALP’
ALPBLMX
Post-Baseline
Maximum Ratio
ALP/BL
Num
For each subject, ADLB.AVAL where ADLB.PEAKFL =
‘Y’ and ADLB.PARAMCD = ‘ALP’ / ADLB.AVAL
where ADLB.DILIBL = ‘Y’ and ADLB.PARAMCD =
‘ALP’
TBALTMX
Post-Baseline
Maximum Ratio
TB/ULN following
ALTULNMX
Num
For each subject, max value of ADLB.R2ANRHI where
ADLB.PARAMCD = ‘TB’ within xx days after post-
baseline maximum ALT value.
TBASTMX
Post-Baseline
Maximum Ratio
TB/ULN following
ASTULNMX
Num
For each subject, max value of ADLB.R2ANRHI where
ADLB.PARAMCD = ‘TB’ within xx days after post-
baseline maximum AST value.
TBALPMX
Post-Baseline
Maximum Ratio
TB/ULN following
ALPULNMX
Num
For each subject, max value of ADLB.R2ANRHI where
ADLB.PARAMCD = ‘TB’ within xx days after post-
baseline maximum ALP value.
ALPALTMX
Max ALP/ULN Ratio
after Max ALT/ULN
Ratio
Num
For each subject, max value of ADLB.R2ANRHI where
ADLB.PARAMCD = ‘ALP’ within xx days after post-
baseline maximum ALT value.
ALPASTMX
Max ALP/ULN Ratio
after Max AST/ULN
Ratio
Num
For each subject, max value of ADLB.R2ANRHI where
ADLB.PARAMCD = ‘ALP’ within xx days after post-
baseline maximum AST value.
RVAL R Value Num ADLB.AVAL where ADLB.PARAMCD = ‘R’
DILI Workup Flags

Contains Nonbinding Recommendations
33
Variable
Name Variable Label Type Comments
ALCHFL Alcohol Assessment
Flag Char
Expected Values: ‘Y’, ‘N’, or null
If Alcohol information was collected and reported in the
SDTM.SU domain as a result of potential DILI injury,
then ‘Y’. If alcohol information was not collected as a
result of potential DILI injury, then ‘N’. If unknown, null
HEPFL Hepatitis Serology Flag Char
Expected Values: ‘Y’, ‘N’, or null
If Hepatitis Serology information was collected and
reported in the SDTM.MB domain as a result of potential
DILI injury, then ‘Y’. If Hepatitis Serology information
was not collected as a result of potential DILI injury, then
‘N’. If unknown, null
AUTOIFL Auto-Immune Serology
Flag Char
Expected Values: ‘Y’, ‘N’, or null
If Auto-Immune Serology information was collected and
reported in the SDTM.LB domain as a result of potential
DILI injury, then ‘Y’. If Auto-Immune Serology was not
performed as a result of potential DILI injury, then ‘N’. If
unknown, null
ULTRAFL Ultrasound Flag Char
Expected Values: ‘Y’, ‘N’, or null
If an ultrasound was performed and reported in the
SDTM.PR as a result of potential DILI injury, then ‘Y’. If
an ultrasound was not performed as a result of potential
DILI injury, then ‘N’. If unknown, null
CTFL CT Scan Flag Char
Expected Values: ‘Y’, ‘N’, or null
If a CT scan was performed and reported in the SDTM.PR
as a result of potential DILI injury, then ‘Y’. If a CT scan
was not performed as a result of potential DILI injury,
then ‘N’. If unknown, null
MRIFL MRI Flag Char
Expected Values: ‘Y’, ‘N’, or null
If an MRI was performed and reported in the SDTM.PR
as a result of potential DILI injury, then ‘Y’. If an MRI
was not performed as a result of potential DILI injury,
then ‘N’. If unknown, null
BIOPFL Biopsy Flag Char
Expected Values: ‘Y’, ‘N’, or null
If a biopsy was conducted and reported in the SDTM.PR
as a result of potential DILI injury, then ‘Y’. If a biopsy
was not performed as a result of potential DILI injury,
then ‘N’. If unknown, null
ERCPFL ERCP Flag Char
Expected Values: ‘Y’, ‘N’, or null
If an ERCP was performed and reported in the SDTM.PR
as a result of potential DILI injury, then ‘Y’. If an ERCP
was not performed as a result of potential DILI injury,
then ‘N’. If unknown, null
MRCPFL MRCP Flag Char
Expected Values: ‘Y’, ‘N’, or null
If a MRCP was performed and reported in the SDTM.PR
as a result of potential DILI injury, then ‘Y’. If a MRCP
was not performed as a result of potential DILI injury,
then ‘N’. If unknown, null
LVTRNSFL Liver Transplant Flag Char
Expected Values: ‘Y’, ‘N’, or null
If a liver transplant was performed and reported in the
SDTM.PR as a result of potential DILI injury, then ‘Y’. If
a liver transplant was not performed as a result of
potential DILI injury, then ‘N’. If unknown, null
OTHPRFL Other Procedure Flag Char Expected Values: ‘Y’, ‘N’, or null

Contains Nonbinding Recommendations
34
Variable
Name Variable Label Type Comments
If another procedure was performed as the result of
potential DILI injury, then ‘Y’. If no other procedure was
performed as the result of potential DILI injury, then ‘N’.
If unknown, null
767
5.2.3.3 Microscopic Findings Analysis Data Set (ADMI)	768
769
The ADMI data set contains histological data used to support accepted efficacy determination in	770
noncirrhotic NASH development programs. AVALC is the primary variable used to support the	771
analysis. This data set should be derived primarily from the Microscopic Findings (SDTM.MI)	772
data set and should contain additional parameters discussed with FDA during the pre-NDA	773
process to assess all histological endpoints. This data set follows the ADaM BDS.	774
775
The ADMI data set should include the basic demographic variables (e.g., assigned treatment,	776
treatment start and end dates, baseline biopsy characteristics) from the ADSL data set.	777
778
Table 14. ADMI Variables	779
780
Variable
Name Variable Label Type Comments
Biopsy Parameter Information
PARAM Parameter Text
The ADMI data set should contain all records from the SDTM.MI
domain. In addition, the sponsor should create records with
parameters to evaluate the histological endpoints, with results
captured in the appropriate AVAL/AVALC variable.
PARAMCD Parameter Code Text
Short Code for PARAM. Sponsors may choose an appropriate
parameter code for the derived parameters that evaluate the
histological endpoints.
MITSTDTL Microscopic
Examination Detail Text MI.MITSTDTL
PARCAT1 Parameter Category
1 Text
MI.MICAT for records coming from MI data set. For derived
parameters evaluating histological endpoints, create an appropriate
category (i.e., ‘Primary histological endpoint’, ‘Secondary efficacy
endpoint’, etc.)
Analysis Information
AVAL Analysis Value Num Transferred from either MI.MISTRESN or MI.MIORRES
AVALC Analysis Value I Text Transferred from MI.MISTRESC for character tests (i.e., Definite
NASH)
AVALCAT1 Analysis Category 1 Text
It may be appropriate to categorize results of certain tests. For
example, the sponsor may decide it is important to separate Lobular
Inflammation results of 0 and 1 from results greater than one. In
that case, for records with PARAM = Lobular Inflammation,
AVALCAT would take values of either ‘Lobular Inflammation
score 0 to 1’ or ‘Lobular Inflammation greater than 1’. Additional

Contains Nonbinding Recommendations
35
Variable
Name Variable Label Type Comments
variables may be created (AVALCAT2, AVALCAT3, etc.) as
necessary.
Criteria Evaluation
CRIT1 Analysis Criterion 1 Text
NOTE: This is an example of a criterion that may be used for
analysis. Specific criterion to include in this data set should be
discussed with FDA, as this may change on a study-by-study basis.
Should more than one criterion be required, used CRIT2/CRIT2FL,
CRIT3/CRIT3FL, etc.
Where PARAMCD is ‘HCYTBALL’, ‘LOBINF’, ‘MODISHAK’,
‘NASHCRN’, ‘NASHHBLN’, ‘NLOBI’, ‘SAFACT’, ‘STEATOS’
indicates criteria of interest as ‘Improvement of histological
feature by at least 1 point/stage’
CRIT1FL
Criterion 1
Evaluation Result
Flag
Text Set to ‘Y’ if CRIT1 satisfied; else set to ‘N’
Other Flags
ABLFL Analysis Baseline
Flag Text Set to ‘Y’ for last non-missing record for each value of PARAMCD
prior to TRTSDT
ANL01FL Analysis Record
Flag 01 Text
Set to ‘Y’ for the baseline record and the records closest to the
target day within the visit target interval as defined by the study
metadata.
781
5.2.3.4 Non-Invasive Serum Biomarkers of Liver Fibrosis and NASH	782
Analysis Data Set (ADRS)	783
784
The ADRS data set contains information to support additional secondary efficacy endpoints	785
based on non-invasive serum biomarkers of liver fibrosis and NASH (e.g., MELD, FIB-4, ELF,	786
APRI). The MELD score should be provided for noncirrhotic NASH trials. Sponsors should	787
consult with FDA regarding additional tests that may be required for submission.	788
789
AVAL is the primary variable used to support the analysis. This data set should be derived	790
primarily from the Clinical Classifications and Disease Response (SDTM.RS) data set, though	791
many of the tests are calculations based on measurements collected in the Laboratory	792
(SDTM.LB) domain. This data set also contains flags based on the results of derived parameters	793
in the ADMI data set. This data set follows the ADaM Basic Data Structure (BDS).	794
795
The ADRS data set should include the basic demographic variables (e.g., assigned treatment,	796
treatment start and end dates, baseline biopsy characteristic, non-invasive baseline	797
characteristics) from the ADSL data set.	798
799

Contains Nonbinding Recommendations
36
Table 15. ADRS Variables	800
801
Variable
Name Variable Label Type Comments
Parameter Information
PARAM Parameter Text
The ADRS data set should contain all records from the
SDTM.RS and SDTM.LB domains for the following
example tests:
• MELD Score
• FIB-4 Score
• ELF Score
• APRI Score
In addition, the sponsor should create records with
parameters to evaluate the study’s endpoints, with results
captured in the appropriate AVAL/AVALC variable.
An example parameter may be: ‘MELD Score from
Baseline =<12 to >15’. In this case, sponsors should
consider a subjects’ baseline MELD score and their
maximum post-baseline record. If their baseline record
was less than 12 and their maximum post-baseline record
was greater than or equal to 15, AVALC would return a
value of ‘Y’ for this parameter. This is purely an example
parameter – sponsors should create their own parameters
in consultation with the FDA review division and the
endpoints of their study.
PARAMCD Parameter Code Text Short Code for PARAM
Analysis Information
AVAL Analysis Value Num
Transferred from either LB.LBSTRESN or
RS.RSSTRESN. For derived parameters that evaluate a
specific endpoint, ‘1’ if the endpoint criteria are met or ‘0’
if the endpoint criteria are not met.
AVALC Analysis Value (C) Text
Character value of AVAL. For derived parameters that
evaluate a specific endpoint, AVALC is ‘Y’ if the
endpoint criteria are met. Otherwise, null.
Other Flags
DTYPE Derivation Type Text
If multiple readings are taken at a given visit, create a new
record if appropriate that takes the average measurements
of the other records for that parameter at that visit.
DTYPE in this case would take a value of ‘AVERAGE’.
ABLFL Analysis Baseline
Flag Text Set to ‘Y’ for last non-missing record for each value of
PARAMCD prior to TRTSDT
ANL01FL Analysis Record
Flag 01 Text
Flag records used for analysis. Note: This may differ from
study-to-study, but one example definition may be: ‘Flag
baseline record and post-baseline records closest to the
target day within the visit target interval listed in the study
metadata.’

Contains Nonbinding Recommendations
37
Variable
Name Variable Label Type Comments
Criteria Evaluation
CRIT1 Analysis Criterion 1 Text
Use this flag to support any derived parameters for this
data set. For the example parameter listed under PARAM,
the corresponding CRIT1 may take a value of ‘MELD <
12’ where PARAM = ‘MELD01-Score’
CRIT1FL
Criterion 1
Evaluation Result
Flag
Text Set to ‘Y’ if CRIT1 satisfied; else set to ‘N’
CRIT2 Analysis Criterion 2 Text
Use this flag to support any derived parameters for this
data set. For the example parameter listed under PARAM,
the corresponding CRIT2 may take a value of ‘MELD >
15’ where PARAM = ‘MELD01-Score’
CRIT2FL
Criterion 2
Evaluation Result
Flag
Text Set to ‘Y’ if CRIT2 satisfied; else set to ‘N’
802
5.2.4 Time-to-Event Analysis Data Set (ADTTE)	803
804
The ADTTE data set contains all records needed to support time-to-event analysis for	805
noncirrhotic NASH endpoints and DILI. AVAL is the primary variable used to support the	806
analysis. Sponsors should follow the ADaM Basic Data Structure for Time-to-Event Analyses	807
when creating this data set. The description of the analysis parameter (PARAM) contains the unit	808
of measurement where results are captured in AVAL.	809
810
The time-to-event data set should include records for all subjects, including subjects who did not	811
experience an event defined by PARAM. For a subject who did not experience a specific type of	812
event, the subject’s time to event is considered ‘right-censored,’ where the value of AVAL	813
represents the length of time between the starting point and the end of the observation period	814
(e.g., the duration of the study for that subject). The numeric Censor (CNSR) variable is used to	815
distinguish whether a subject experienced an event between the defined starting point and the	816
end of the observation period.	817
818
When supporting analyses as listed in the examples below, ADTTE may be sourced from	819
ADAE, ADMI, ADDILI and ADSL (or elsewhere). Sponsors should consult FDA to determine	820
the appropriate parameters and their corresponding derivations to be collected and submitted in	821
this data set.	822
823
Sponsors should provide clear explanations in the ADaM define.xml for how AVAL is derived	824
for each parameter. In some cases, such as Time to Death, it may look at ASTDY for one record.	825
For other parameters where multiple records should be evaluated to determine if the subject has	826
met the endpoint, the derivation for AVAL may be more complicated. For example, a Time to	827
Peak Lab Washout for DILI parameter needs to consider both when the subject’s labs ‘peak’ as	828
well as when those peaks reach a ‘washout’ state—in this case, sponsors could use values of	829
ADY when ADLB.PEAKFL and ADLB.REDUCEFL = ‘Y’ to calculate AVAL in ADTTE.	830
831

Contains Nonbinding Recommendations
38
Examples of applicable analyses to support safety and efficacy analyses may include:	832
833
Table 16. Example Time to Event Parameters	834
835
PARAMCD PARAM26,27 AVAL
HPCIRRH Time to Histological Progression to Cirrhosis (days)
Propose derivations
for each parameter
HEPDCE Time to Hepatic Decompensation Event (days)
ASCREQTR Time to Ascites requiring treatment (days)
HEPENC Time to Hepatic Encephalopathy at least West Haven grade 2 or
above requiring hospitalization (days)
VARHEM Time to Variceal hemorrhage requiring hospitalization (days)
OTHCDE Time to Other Clinical Decompensation Event (e.g., Spontaneous
Bacterial Peritonitis) (days)
LVRTRNS Time to Liver Transplant (days)
DEATH Time to Death (days)
ONSETDIL Time to Onset Potential DILI Injury (days)
WASHOUT Time to Peak Lab Washout for DILI (days)
836
26 Per the ADaM Basic Data Structure for Time-to-Event Analyses, PARAM in the ADTTE may be longer than 40
characters (maximum 200). See https://www.cdisc.org/standards/foundational/adam/adam-basic-data-structure-bds-
time-event-tte-analyses-v1-0.
27 The examples listed below are measured in days. Sponsors should use their judgement in determining the
appropriate unit of measurement.

Contains Nonbinding Recommendations
39
APPENDIX	837
838
Example ADLB and ADDILI Data Sets	839
840
Consider the sample Laboratory Analysis Data Set (ADLB) and Drug-Induced Liver Injury Analysis Data Set (ADDILI) tables below	841
for Subject ABC-123. This example only shows one subject’s alanine aminotransferase (ALT) values; however, for the purposes of	842
this example, assume the subject’s aspartate aminotransferase (AST) and/or total bilirubin (TB) values indicate the subject is a	843
potential drug-induced liver injury (DILI) candidate as identified by pre-established criteria between the sponsor and the U.S. Food	844
and Drug Administration (FDA) (example criteria noted in the ADDILI section of this document). As a reminder, these criteria are	845
sample criteria. Sponsors should consult with FDA to establish appropriate criteria to evaluate DILI. Below is a list of other	846
considerations for this sample data set:	847
848
• In this example, the subject has two pre-baseline lab readings. These lab reading are averaged to create a new baseline record	849
for each parameter.	850
851
• Onset DILI (ONSETFL = ‘Y’) is defined in this example as the first visit in which a subjects’ ALT > 3x ULN. This happens	852
on study day 14 (assume ANRHI = 55.0). Sponsors may use their own definition for Onset DILI after consultation with FDA	853
review division.	854
855
• Reduced Flag (REDUCEFL = ‘Y’) may only occur after a subject has reached their peak (PEAKFL = ‘Y’) for a given subject	856
and parameter.	857
858
• The example ADDILI data set only contains the variables pertinent to ALT; sponsors should follow the guidance provided in	859
the ADDILI section of this document for the full list of variables to be provided.	860
861
• For the example ADDILI data set, ALTULNMX is calculated as the maximum post-baseline ALT value divided by the upper	862
limit of normal (197.0 / 55.0 = 3.58). ALTBLMX is calculated as the maximum post-baseline ALT value divided by the DILI	863
baseline value (197.0 / 52.5 = 3.75).	864
865

Contains Nonbinding Recommendations
40
Table A. Subset of Sample ADLB*	866
867
PARAMCD AVAL BASE ADY ABLFL ANL02FL ANL03FL PEAKFL REDUCEFL ONSETFL LASTFL
ALT 51.0 52.5 -14 N N N N N N N
ALT 54.0 52.5 -7 N N N N N N N
ALT 52.5 1 Y N N N N N N
ALT 95.0 52.5 7 N N N N N N N
ALT 197.0 52.5 14 N Y N Y N Y N
ALT 191.0 52.5 21 N N N N N N N
ALT 92.0 52.5 28 N N N N Y N N
ALT 73.0 52.5 35 N N Y N N N Y
* It is acknowledged that ‘N’ may not be indicated for flag variables.	868
869
Table B. Subset of Sample ADDILI	870
871
PARAM AVALC ALTULNMX ALTBLMX
Potential DILI Y 3.58 3.75
Outcome of Potential DILI RECOVERED/RESOLVED 3.58 3.75
Action Taken from Potential DILI DOSE REDUCED 3.58 3.75
872
Example MI and SUPPMI Domains	873
874
Consider the sample Microscopic Findings (MI) and Supplemental Microscopic Findings (SUPPMI) domains below for Subject ABC-	875
123. This subject has two biopsies, one at baseline and one at end of treatment, each with two pathologists reviewing. Any disagreement	876
between the histopathological assessment between the pathologists’ results in an adjudication committee making a final determination	877

Contains Nonbinding Recommendations
41
(as shown with Microscopic Findings Test (MITEST) = ‘FIBROSIS’ during the first biopsy). The data set should also include standard	878
variables such as STUDYID, DOMAIN, MIDTC, and MIDY as noted in the SDTM Implementation Guide. The sample below contains	879
only a few measurements; sponsors should refer to the MI section of this document for the complete list of recommended and permissible	880
parameters to be collected from the biopsy.	881
882
This example domain uses MIREFID as the identifier for the slide being analyzed, but sponsors should use identifier variables	883
available from the SDTMIG to label biopsies and slides cut from the biopsy. The linkage between the identifier variables should be	884
made clear in the define.xml and/or Study Data Reviewers Guide (SDRG) files. Linkages between individual biopsies and/or slides	885
and other domains such as Biospecimen Findings (BS) or Biospecimen Events (BE) should be connected via a Related Records	886
(RELREC) domain.	887
888
The SUPPMI domain shows the adequacy of the slides. The slide evaluated during the baseline biopsy was deemed adequate, and the	889
end of treatment biopsy was deemed not adequate due to both a blurred image and a cracked slide. As such, the MIACPTFL variable	890
is null for the end of treatment biopsy as these records were not accepted for the analysis due to the inadequate slide.	891
892
Table C. Subset of Sample MI Domain	893
894
MIREFID MITEST MITSTDTL MIORRES MIACPTFL MIEVAL MIEVALID VISIT
SPEC001 NAFLD Activity Score TOTAL SCORE 5 PATHOLOGIST PATHOLOGIST 1 BASELINE
SPEC001 Fibrosis NASH CRN FIBROSIS
STAGE 1B PATHOLOGIST PATHOLOGIST 1 BASELINE
SPEC001 NAFLD Activity Score TOTAL SCORE 5 PATHOLOGIST PATHOLOGIST 2 BASELINE
SPEC001 Fibrosis NASH CRN FIBROSIS
STAGE 3 PATHOLOGIST PATHOLOGIST 2 BASELINE
SPEC001 NAFLD Activity Score TOTAL SCORE 5 Y ADJUDICATION
COMMITTEE ADJUDICATOR BASELINE
SPEC001 Fibrosis NASH CRN FIBROSIS
STAGE 3 Y ADJUDICATION
COMMITTEE ADJUDICATOR BASELINE

Contains Nonbinding Recommendations
42
MIREFID MITEST MITSTDTL MIORRES MIACPTFL MIEVAL MIEVALID VISIT
SPEC002 NAFLD Activity Score TOTAL SCORE 5 PATHOLOGIST PATHOLOGIST 1 END OF
TREATMENT
SPEC002 Fibrosis NASH CRN FIBROSIS
STAGE 3 PATHOLOGIST PATHOLOGIST 1 END OF
TREATMENT
SPEC002 NAFLD Activity Score TOTAL SCORE 5 PATHOLOGIST PATHOLOGIST 2 END OF
TREATMENT
SPEC002 Fibrosis NASH CRN FIBROSIS
STAGE 3 PATHOLOGIST PATHOLOGIST 2 END OF
TREATMENT
895
Table D. Subset of Sample SUPPMI Domain	896
897
IDVAR IDVARVAL QLABEL QVAL
MIREFID SPEC001 Overall Image Quality Adequate
MIREFID SPEC002 Overall Image Quality Not Adequate
MIREFID SPEC002 Image Condition MULTIPLE
MIREFID SPEC002 Image Condition 1 CRACKED SLIDE
MIREFID SPEC002 Image Condition 2 BLURRY IMAGE
898