STUDY DATA

TECHNICAL CONFORMANCE GUIDE

Technical Specifications Document

This Document is incorporated by reference into the following

Guidance Document(s):

Guidance for Industry Providing Regulatory Submissions in Electronic

Format – Standardized Study Data

For questions regarding this technical specifications document, contact CBER at

[email protected] or CDER at [email protected]

U.S. Department of Health and Human Services

Food and Drug Administration
Center for Biologics Evaluation and Research (CBER)
Center for Drug Evaluation and Research (CDER)

March 2025
 STUDY DATA
TECHNICAL CONFORMANCE GUIDE

March 2025
 Revision History
Date Version Summary of Revisions
January 2014 1.0 Initial Version
Revisions based on the public comment period (February 2014 – May 2014); and CDER/CBER
December 2014 2.0 internal review May 2014 – December 2014
Revisions based on comments received to version 2.0. Updates to Sections 2.2 Study Data
Reviewer’s Guide (SDRG)
March 2015 2.1 SDRG, 2.3 Analysis Data Reviewer’s (ADRG), 3.3.1 SAS Transport Format, 3.3.2. Dataset
Size and a revision of Section 4.1.4.5 Data Definition File
Revisions based on comments received to version 2.1. Updates on Table of Contents; Sections
4.1, 4.1.1.2, 4.1.2.3. Updates to Trial Design. Added Exposure as Collected (EC Domain) and
Death Details (DD) subsections. Updates to 4.1.2.2, 4.1.2.3, 4.1.2.4, 4.1.2.5, 4.1.2.6, 4.1.2.8,
June 2015 2.2 4.1.2.9.1, 4.1.2.9.2, 4.1.4 (header and all sub-headers updated to specify which standards
apply), 4.1.4.5, and 4.1.4.6. Added 5.1 subsection; 6.7, 6.7.1, 6.7.1.1. Updates on Section 7,
8.2.2 and Glossary.
Updates to Section 1.3, Exposure as Collected (EC Domain) and Death Details (DD Domain).
October 2015 2.3 Reorganization of Section 4.1.2 and corresponding updates to appropriate sub-sections. Updates
to Sections 4.1.4.5 and 5.1. Added Sections 7.1 and 7.2.
Section 2.2 (Study Data Reviewer’s Guide) – Updated link for SDRG in Footnote 10
Section 3.3.2 (Dataset Size) – Increased Data Set Size
Section 4.1.1.2 (SDTM General Considerations) – Updated to reflect define.xml file and SDRG
reference.
Section 4.1.2.2 (Analysis Data Model – General Considerations) – Updated to reflect define.xml file
and SDRG reference.
Section 4.1.3.2 (Standard for Exchange of Nonclinical Data – General Considerations) – Updated to
reflect define.xml file and SDRG reference.
Section 4.1.4.5 (Data Definition Files for SDTM, SEND, and ADaM) – Updated to reflect define.xml
version 2.0 and data definition specification details
March 2016 3.0 Section 5.1 (Therapeutic Area Standards – General) – Updated to reflect more detailed information
related to Therapeutic Area Standards
Section 5.2 (Supported Therapeutic Area Standards) – Added information related to acceptance
testing on the standard
Section 5.2.1 (Chronic Hepatitis C) – Added Section for this information.
Section 5.2.2 (Dyslipidemia) – Added Section for this information.
Section 6.1.2.1 (Use of the specific controlled term “OTHER”) – Added information related to
controlled terminology and the mapping to “Other”
Section 8.3.1 (Study Data Traceability Overview) – Update to Study Data Traceability flow diagram
reference.
Section 2.1 (Study Data Standardization Plan) Updated to reflect acronym SDSP (Study Data
Standardization Plan) and added footnote 10.
Section 4.1.1.3 (SDTM Domain Specifications) – Updated Trial Design Model (TDM)
Section 4.1.3.3 (SEND Domain Specification) – Added Trial Design (TD)
Section 5.2.3 (Diabetes) – Added Section for this information.
Section 5.2.4 (QT Studies) – Added Section for this information.
July 2016 3.1 Section 5.2.5 (Tuberculosis) – Added Section for this information.
Section 8.2.1.1 (Conformance validation) – Created Section Header and expanded information.
Section 8.2.1.2 (Quality checks) – Created Section Header and updated to reflect study data standard.
Section 8.2.2 (Support on Data Validation Rules) – Expanded information.
Section 3.2 (Portable Document Format) & Glossary – Updated International Council for
Harmonisation (ICH) name

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 Revision History
Date Version Summary of Revisions
Section 2.2.1 (SDRG for Clinical Data) – Added naming convention
Section 2.2.2 (SDRG for Nonclinical Data) -Added naming convention
Section 2.3 (Analysis Data Reviewer’s Guide) – Provided additional information
Section 3.3.3 (Dataset Column Length) – Expanded Information
Section 4.1.1.2 (SDTM General Considerations) – Expanded Adjudication Data
Section 4.1.2.10 ( Software Programs) – Added more detail related to software programs
Section 4.1.3.2 (General Considerations) – Added VISITDY variable information
Section 4.1.3.3 (SEND Domain Specification) – Added Clinical Observations (CL) Domain and
Pharmacokinetic Concentrations (PC) Domain. Expanded Trial Arms and Trial Sets information.
Section 5.1 (General) – Expanded Information
October 2016 3.2 Section 5.2 (Supported Therapeutic Areas) – Expanded Information
Section 7.1 (ECTD File Directory Structure) – Referenced the Guidance to Industry Providing
Regulatory Submissions in Electronic Format: Certain Human Pharmaceutical Product Applications
and Related Submissions Using the Electronic Common Technical Document Specifications and
added footnote
Section 7.2 (ECTD Sample Submission) – Change header to align with detailed information.
Section 8.2.1 (Types of Data Validation Rules) – Expanded Information
Section 8.2.1.1 (Conformance validation) – Expanded Information
Section 8.2.1.2 (FDA Business Rules) – Added new Section
Section 8.2.2 (Support on Data Validation Rules) – updated to reflect conformance rules
Section 8.3.1 (Overview (Study Data Traceability) – added relate counts information
Section 8.2.2 (Support on Data Validation Rules) – Footnote 50 Added reference to the Standards
Webpage.
Section 4.1.3.3 (SEND Domain Specification) – Fixed Typo.
November 2016 3.2.1 Global (Updated naming convention for clinical Study Data Reviewer’s Guide (“csdrg.pdf”) and the
non-clinical Study Data Reviewer’s Guide (“nsdrg.pdf”) to reflect lower case instead of upper case.
eCTD requires lower case file names
Section 1.1 (Background) – Updated tense
Section 1.4 (Organization and Summary of the Guide) – Clarification on terminology section
Section 2.3 (Analysis Data Reviewer’s Guide) – Clarification on ADRG
Section 4.1.1.3 (SDTM Domain Specifications) – Clarification on DS Domain
Section 4.1.2.2 (General Considerations) – Added prior text for desired analysis views for reviews
Section 4.1.3.2 (General Considerations) – Clarification on VISITDY for MA, MI, OM in the DS
Domain
Section 4.1.3.3 (SEND Domain Specification) – Clarification on SUPPQUAL and MI Domain.
Expanded PC Domain, Custom Domain, and Trial Design Model information. Added footnote for
March 2017 3.3 SENDIG
Section 4.1.4.1 (Variables in SDTM and SEND: CDISC Required, Expected, and Permissible) –
Clarification on SEND datasets and Subject Visits in SDTM.
Section 5.1 (General) – Updated and clarified text
Section 5.2 (Supported Therapeutic Areas) – Updated and clarified text, added TA section
Section 8 (Study Validation and Traceability) –Updated and clarified text
Section 8.3.1 (Overview) – Expanded information on traceability
Section 8.3.2 (Legacy Study Data Conversion to Standardized Study Data) – Clarification on legacy
data conversions
Glossary – Additions

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 Revision History
Date Version Summary of Revisions
Section 1.5 (Relationship to Other Documents) – Updated references
Section 2.1 (Study Data Standardization Plan) – Clarification on SDSP and added footnotes
Section 2.2 (Study Data Reviewer’s Guides) – Clarification on Reviewer Guides
Section 4.1 (Clinical Data Interchange Standards Consortium) – Clarification on terms SDTM,
ADaM, and SEND
Section 4.1.1.2 (SDTM General Considerations) – Updated and clarified text
Section 4.1.1.3 (SDTM Domain Specifications) – Added QS Domain (Questionnaires)
Section 4.1.2.4 (Subject-Level Analysis Data) – Updated and clarified text on baseline characteristics
Section 4.1.2.10 (Software Programs) – Updated and clarified text
Section 4.1.3.1 (Definition) – Updated and clarified text
Section 4.1.3.2 (General Considerations) – Clarification on variable usage
October 2017 4.0 Section 4.1.3.3 (SEND Domain Specification) – Clarification and added text
Section 4.1.4.1 (Variables in SDTM and SEND: CDSIC Required, Expected, and Permissible) –
Added text
Section 4.1.4.6 (Annotated Case Report Form (aCRF) for SDTM) – Updated and clarified text. The
recommendation to use the SDTM Metadata Submission Guidelines was removed pending further
FDA review.
Section 5.2 (Supported Therapeutic Areas) –Added TA sections
Section 6.3.1.1 (General Considerations) – Updated and clarified text
Section 6.7.1.1 (General Considerations) – Added clarification text
Section 8.3.2 (Legacy Study Data Conversion to Standardized Study Data) – Added clarification text
Section 8.3.2.2 (Legacy Data Conversion Plan and Report) – Added clarification text
Section 2.1 (Study Data Standardization Plan) – Clarified text
Section 2.2 (Study Data Reviewer’s Guides) – Updated footnote text
Section 2.3 (Analysis Data Reviewer’s Guide) – Clarified text
Section 3.3.1 (SAS Transport Format) – Updated text
Section 3.3.6 (Variable and Dataset Names) – Updated text
Section 4.1.1.2 (SDTM General Considerations) – Updated and clarified text
Section 4.1.1.3 (SDTM Domain Specifications) – Updated and clarified text
Section 4.1.2.2 (General Considerations) – Clarified text
March 2018 4.1 Section 4.1.2.10 (Software Programs) – Updated and clarified text
Section 4.1.3.3 (SEND Domain Specification) – Clarified text
Section 4.1.4.1 (Variables in SDTM and SEND: CDISC Required, Expected, and Permissible) –
Updated and clarified text
Section 5.2 (Supported Therapeutic Areas) –Added TA sections
Section 6.1.2 (Use of Controlled Terminologies) – Updated and clarified text
Section 6.4.2.1 (General Considerations) – Clarified text
Section 6.6.1.1 (General Considerations) – Updated text
Section 3.3.5 (Special Characters: Variables and Datasets) – Added clarification text
Section 4.1.1.3 (SDTM Domain Specifications) – Additional text and table under DM and Trial
Design Model sections, added DV Domain section
Section 4.1.2.10 (Software Programs) – Clarified text
Section 4.1.3.2 (General Considerations) – Updated text
Section 4.1.3.3 (SEND Domain Specification) – Added Lab Test Results, Body Weight, and
Comments domains, updated Pharmacokinetics Concentrations Domain and Trial Design Model
October 2018 4.2 sections
Section 4.1.4.1 (Variables in SDTM and SEND: CDISC Required, Expected, and Permissible) –
Updated text
Section 5.2 (Supported Therapeutic Areas) –Added TA sections
Section 6.6.1.1 (General Considerations) – Updated text
Section 7.1 (eCTD Specifications) – Updated text
Section 8.2.2 (Support on Data Validation Rules) – Updated text
Appendix B, C, D, E, F, G – Added
Section 4.1.1.3 (SDTM Domain Specifications) – Updated text
December 2018 4.2.1 Section 4.1.3.3 (SEND Domain Specification) – Updated text
Appendix F, G – Removed

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 Revision History
Date Version Summary of Revisions
Section 2.3 (Analysis Data Reviewer’s Guide) – Clarified text
Section 4.1.1.3 (SDTM Domain Specifications) – Updated text
Section 4.1.3.2 (General Considerations) – Clarified text
Section 4.1.3.3 (SEND Domain Specification) – Added, updated, and clarified text
Section 4.1.4.5 (Data Definition Files for SDTM, SEND, and ADaM) – Clarified text
Section 5.2 (Supported Therapeutic Areas) – Added TA sections
March 2019 4.3 Section 6.4.1.1 (General Considerations) – Updated text
Section 6.4.2.1 (General Considerations) – Updated text
Section 6.5.1 (Medication – Reference Terminology) – Updated text
Section 6.5.1.1 (General Considerations) – Updated text
Section Appendix B – Updated text
Section Appendix C – Added, updated, and clarified text
Section 2.1 (Study Data Standardization Plan) – Added clarifying text
Section 2.2 (Study Data Reviewer’s Guide) – Added clarifying text
Section 2.3 (Analysis Data Reviewer’s Guide) – Added clarifying text
Section 4.1.1.2 (SDTM General Considerations) – Added clarifying text
Section 4.1.1.3 (SDTM Domain Specifications) – Added text
Section 4.1.3.3 (SEND Domain Specification) – Added text
October 2019 4.4 Section 4.1.2.6 (Key Efficacy and Safety Data) – Updated title and text
Section 5.2 (Supported Therapeutic Areas) – Re-ordered by inclusion date, added TA section
Section 6.1 (Use of Controlled Terminologies) – Added clarifying text
Section 6.7.1.1 (General Considerations) – Updated section
Section 7.1 (eCTD Specifications) – Added text
Section 8.2.2 (Support on Data Validation Rules) – Added text
Section 4.1.3.3 (SEND Domain Specification) – Updated and added clarifying text
March 2020 4.5 Section 5.2 (Supported Therapeutic Areas) – Added TA section
Section 5.2.18 (Vaccines Therapeutic Area User Guide v1.1) – Added text
July 2020 4.5.1 Appendix D – Added text
Section 1.2 (Purpose) – Added text
Section 4.1.1.2 (SDTM General Considerations) – Text clarified
Section 4.1.3.2 (General Considerations) – Updated and added clarifying text
Section 4.1.4.1 (Variables in SDTM and SEND: CDISC Required, Expected, and Permissible) – Text
November 2020 4.6 clarified
Section 5.2 (Supported Therapeutic Areas) – Added TA section
Section 6.1.3 (Maintenance of Controlled Terminologies) – Added clarifying text
Appendix C – Added text and notes
Appendix D – Updated text
Section 4.1.1.3 (SDTM Domain Specifications) – Provided clarification on the use of AE domains and
the use of laboratory data units.
Section 4.1.3.2 (General Considerations) – Specified when FOCID should be utilized
Section 4.1.3.3 (SEND Domain Specification) – Provided clarification on the use of BLQ vs BQL,
March 2021 4.7 and the use of custom domains
Section 7.1 (eCTD Specifications) – Provided clarification on the submission of toxicity study data for
nonclinical Weight of Evidence documents
Appendix C: Removed TS code for Interim Study Flag, updated the description for TS code Planned
Dose Frequency, and added new TS code titled Study Report Status
Section 4.1.4.7 (Requirements During Specific Public Health Emergencies Declared by the Secretary
June 2021 4.7.1 of HHS) – Provided clarification about when electronic standardized study data are required as part of
a submission during a declared public health emergency
Section 8.2.2 (Support on Data Validation Rules) – Provided clarification regarding the submission of
4.7.2
August 2021 clinical study data with the use of simplified ts.xpt and technical rejection criteria
Section 4.1.3.2 (General Considerations) – Correction made to indicate that SEND datasets will not be
4.7.2.1 required for CBER submissions until March 15, 2023
Section 4.1.3.4 (Scope of SEND), Section 4.1.3.4.1 (Scope of SEND for SENDIGs v3.0 and v3.1),
September 2021 4.8 Section 4.1.3.4.2 (Scope of SEND for SENDIG – Animal Rule v1.0) – Provided clarification on the
expectation of SEND for studies listed in the referenced SENDIGs.

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 Revision History
Date Version Summary of Revisions
October 2021 4.8.1 Footnotes were updated to fix web links and other typos and formatting issues.
Section 3.3.3 (Dataset Column Length) – Provided clarification
Section 3.3.7 (Variable and Dataset Labels) – Provided clarification
Section 4.1.1.2 (SDTM General Considerations) – Provided clarification
Section 4.1.1.3 (SDTM Domain Specifications) – Provided clarification
Section 4.1.3.2 (General Considerations) – Provided clarification
Section 5.3 – Added section “List of Technical Specifications Documents”;
Added technical rejection criteria for study data documentation information in the following:
March 2022 4.9 Section 7.1
Section 8.2.2
Appendix F
Appendix G
Section 7.2 (Electronic File Directory) – Added this section ‘to focus on recommended file folder
structure
Appendix B – Provided clarification
Appendix C – Updated table
Document first paragraph – Added link to Docket for entering comments on this document
Purpose – Added clarification to the use of the word ‘require’
Footnotes – Updated links in footnotes referring to FDA Guidance documents
Section 4.1.2.10 – Clarified language concerning acceptable file extensions that aligns with eCTD file
format specification
Section 4.1.3.3 – Under BG Domain (Body Weight Gain), removed ‘CDER’ as this applies to both
October 2022 5.0 CBER and CDER submissions
Section 4.1.4 – General Considerations: SDTM, SEND, and/or ADaM; clarified the use of the word
‘required’
Section 4.1.4.1 – Clarified headings
Section 6.5.1.1 – Updated the link to the document entitled Established Pharmacologic Class Text
Phrase
Appendix B and C – Clarified use of TS Parameters
Footnotes – Updated links in footnotes referring to FDA Guidance documents
Footnotes – Added footnotes relating to the expectation of SEND datasets for nonclinical EFD studies
Section 3.3.1 (v5 Transport Format) – Heading changed, content updated
Section 4.1.1.3 (SDTM Domain Specifications) – Addition of Immunogenicity Domain (IS)
Section 4.1.2.6 (Key Efficacy and Safety Data) – Language added regarding analysis of
immunogenicity
Section 4.1.3.1 (Definition) – SEND definition updated to match the SDTM definition under Section
4.1.1.1
Section 4.1.3.3 (SEND Domain Specification) – Language updated
Section 4.1.3.4.1 (Scope of SEND for SENDIGv3.0 and v3.1) – Language updated to match the Scope
March 2023 5.1 of SENDIG-DARTv.1.1
Section 4.1.3.4.3 (Scope of SEND for SENDIG-DARTv1.1 for CDER) – Provided clarification on the
expectation of SEND
Section 4.1.4.5 (Data Definition Files for SDTM, SEND, and ADaM) – Updated language for Define-
XML
Section 6.5.1.1 (General Considerations) – Updated for clarity
Appendix C – Updated link for MED-RT terminology
Appendix F – Table 6 updated for clarity
Glossary – Addition of MED-RT

Section 4.1.4.7.1 (SEND Requirements During the COVID-19 Public Health Emergency) – Updated
language due to the expiration of the COVID-19 PHE
May 2023 5.2 Appendix H: HHS Declared Public Health Emergencies and Modifications to Data Standards
Requirements – Added
May 2023 5.3 Section 4.1.4.5 (Data Definition Files for SDTM, SEND, and ADaM) – Updated language

June 2023 5.4 Section 4.1.1.3 (SDTM Domain Specification) – Updated language under LB Domain (Laboratory)

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 Revision History
Date Version Summary of Revisions
Footnotes – Added links to the FDA Data Standards Catalog and SAS Help Center
Section 3.3.2 (Dataset Size) – Updated for clarity
Section 3.3.3 (Dataset Column Length) – Updated for clarity
Section 4.1.1.3 (SDTM Domain Specifications) – Added PC Domain (Pharmacokinetic Concentration) and
PP Domain (Pharmacokinetic Parameters)
Section 4.1.1.3 (SDTM Domain Specifications) – Added SV Domain (Subject Visits)
Section 4.1.3.2 (General Considerations) – Updated for clarity
Section 4.1.3.3 (SEND Domain Specifications) – PC Domain (Pharmacokinetic Concentration) updated for
clarity
Section 4.1.3.3 (SEND Domain Specifications) – Updated Custom Domains to include SENDIGv3.1.1
Section 4.1.3.4.1 (Scope of SEND for SENDIGs v3.0, v3.1 and v3.1.1) – Updated to include mentions of
SENDIGv3.1.1
Section 4.1.3.4.1 (Scope of SEND for SENDIGs v3.0, v3.1 and v3.1.1) – Section C updated for clarity.
Section 4.1.3.4.3 (Scope of SEND for SENDIG-DARTv1.1 for CDER) – Sections H, I, J, and K, updated
October 2023 5.5 for clarity
Section 4.1.4.1 (Variables in SDTM and SEND: CDISC Required, Expected, and Permissible) – Updated to
address baselines
Section 4.1.4.7.1 (SEND Requirements During the COVID-19 Public Health Emergency) – Language added
to address the end of the 180-day wind-down period for the modification to the SEND requirement
Section 6.1.3 (Maintenance of Controlled Terminologies) – Updated for clarity
Section 6.5.1.1 (General Considerations) – Language added to reflect CDER preferences
Appendix C – Added the following TSPARMCDs: PPTCNAM, PPTEGID, PPTEGSYM, PPTMDA
Appendix D – Updated list of SDO properties that align or do not align with current CBER and CDER
business needs
Appendix G – Updated for clarity
Appendix H – Language added to address the end of the 180-day wind-down period for the modification to
the SEND requirement
Glossary – Addition of PHE and SDO
Section 4.1.1.3 (SDTM Domain Specifications) – Updated to address LOINC
Section 4.1.3.4.2 (Scope of SEND for SENDIG-Animal Rule v1.0) – Updated for clarity
December 2023 5.6 Section 5.3 (List of FDA Technical Specification Documents) – Section updated
Section 6.7 (Laboratory Tests) – Updated for clarity
Section 4.1.1.3 (SDTM Domain Specifications) – Updates for LB and LC Domain
Section 4.1.3.2 (General Considerations) – Addressed ELTM and DOSDUR
Section 4.1.3.3 (SEND Domain Specifications) – Updates for LB Domain
Section 4.1.4.3 (Naming Conventions in SDTM and SEND) – Addressed naming for drugs and metabolites
March 2024 5.7 Section 8.2.2.3 (Technical Rejection Criteria and Use of a Simplified ts.xpt for Nonclinical Studies) –
Language updated
Appendix B – Added new TSPARMCD
Appendix C – Added reference to Section 4.1.3.2 for the DOSDUR TSPARMCD
Appendix D – Updated lists
Section 2 (Planning and Providing Standardized Study Data) – Addressed submissions in eCTDv4.0
Section 2.1.2 (SDRG for Nonclinical Data) – Addressed submissions in eCTDv4.0
Section 4.1.1.2 (SDTM General Considerations) – Added reference to Section 7.1
Section 4.1.3.2 (General Considerations) – Added referecnces to Section 7.1, addressed submissions in
eCTDv4.0
Section 4.1.4.5 (Data Definition Files for SDTM, SEND, and ADaM) – Addressed submissions in
eCTDv4.0
Section 7.1 (eCTD Specifications) – New Section, clarifying language
September 2024 5.8 Section 7.1.2 (eCTDv4.0 Specifications) – New Section, addressed submissions in eCTDv4.0
Section 7.1.3 (Weight of Evidence) – New Section
Section 8.1.2.1 (eCTD Technical Rejection Criteria for Study Data) – Addressed submissions in eCTDv4.0
Section 8.1.2.2 (Technical Rejection Criteria and Use of a Simplified ts.xpt for Clinical Studies) –
Addressed submissions in eCTDv4.0
Section 8.1.2.3 (Technical Rejection Criteria and Use of a Simplified ts.xpt for Nonclinical Studies) –
Addressed submissions in eCTDv4.0
Appendix F – Addressed submissions in eCTDv4.0
Appendix G – New STUDYID examples added to address submissions in eCTDv4.0

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 Revision History
Date Version Summary of Revisions
Section 4.1.1.3 (SDTM Domain Specifications) – Updated the LB Domain and added the MB Domain
Section 4.1.3.4.4 (Scope of SEND for SENDIG-Genetox-v1.0) – New Section, SENDIG-Genetox v1.0
Section 6.1.2 (Use of Controlled Terminologies) – Language updated
October 2024 5.9 Section 6.1.2.1 (Use of the Specific Controlled Term 'OTHER') – Language updated
Section 6.1.4.1 (General Considerations) – Language updated
Appendix B – Updated the FDA Notes for TSPARMCDs
Appendix D – Updated lists of SDO properties
Section 2 (Planning and Providing Standardized Study Data) – Language updated
Section 2.1.2 (SDRG for Clinical Data) – Language updated
Section 4.1.1.3 (SDTM Domain Specifications) – Language updated
March 2025 6.0 Section 4.1.2.11 (ADLB and ADLC) – New section
Section 4.1.4.1 (Variables in SDTM and SEND: CDISC Required, Expected, and Permissible) – Language
updated
Section 7.1.4 (File Tags) – New section

Table of Contents
1. INTRODUCTION............................................................................................................... 1
BACKGROUND ................................................................................................................................................ 1
PURPOSE ...................................................................................................................................................... 1
DOCUMENT REVISION AND CONTROL ................................................................................................................. 2
ORGANIZATION AND SUMMARY OF THE GUIDE ..................................................................................................... 2
RELATIONSHIP TO OTHER DOCUMENTS ............................................................................................................... 3
2. PLANNING AND PROVIDING STANDARDIZED STUDY DATA .............................................. 4
STUDY DATA STANDARDIZATION PLAN ................................................................................................................ 4
STUDY DATA REVIEWER’S GUIDES...................................................................................................................... 5
2.1.1 SDRG for Clinical Data ........................................................................................................ 5
2.1.2 SDRG for Nonclinical Data.................................................................................................. 5
ANALYSIS DATA REVIEWER’S GUIDE ................................................................................................................... 5
3. EXCHANGE FORMAT – ELECTRONIC SUBMISSIONS........................................................... 6
EXTENSIBLE MARK-UP LANGUAGE...................................................................................................................... 6
PORTABLE DOCUMENT FORMAT ........................................................................................................................ 6
FILE TRANSPORT FORMAT ................................................................................................................................ 7
3.1.1 v5 Transport Format .......................................................................................................... 7
3.1.2 Dataset Size........................................................................................................................ 7
3.1.3 Dataset Column Length...................................................................................................... 7
3.1.4 Variable and Dataset Descriptor Length ............................................................................ 7
3.1.5 Special Characters: Variables and Datasets ....................................................................... 8
3.1.6 Variable and Dataset Names ............................................................................................. 8
3.1.7 Variable and Dataset Labels .............................................................................................. 8
4. STUDY DATA SUBMISSION FORMAT – CLINICAL AND NONCLINICAL ................................. 9
CLINICAL DATA INTERCHANGE STANDARDS CONSORTIUM ....................................................................................... 9
4.1.1 Study Data Tabulation Model ............................................................................................ 9
Definition ..................................................................................................................................... 9
SDTM General Considerations ..................................................................................................... 9
SDTM Domain Specifications ..................................................................................................... 11
4.1.2 Analysis Data Model ........................................................................................................ 16
Definition ................................................................................................................................... 16

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 General Considerations .............................................................................................................. 16
Dataset Labels ............................................................................................................................ 16
Subject-Level Analysis Data........................................................................................................ 16
Core Variables ............................................................................................................................ 17
Key Efficacy and Safety Data ...................................................................................................... 17
Timing Variables ......................................................................................................................... 17
Numeric Date Variables ............................................................................................................. 18
Imputed Data ............................................................................................................................. 18
Software Programs..................................................................................................................... 18
ADLB and ADLC .......................................................................................................................... 18
4.1.3 Standard for Exchange of Nonclinical Data ..................................................................... 19
Definition ................................................................................................................................... 19
General Considerations .............................................................................................................. 19
SEND Domain Specification ........................................................................................................ 21
Scope of SEND ............................................................................................................................ 25
4.1.4 General Considerations: SDTM, SEND, and/or ADaM ...................................................... 32
Variables in SDTM and SEND: CDISC Required, Expected, and Permissible ............................... 32
Dates in SDTM and SEND ........................................................................................................... 33
Naming Conventions in SDTM and SEND ................................................................................... 33
SDTM and SEND Versions .......................................................................................................... 34
Data Definition Files for SDTM, SEND, and ADaM...................................................................... 34
Annotated Case Report Form (aCRF) for SDTM ......................................................................... 35
Modification of Requirements During Specific Public Health Emergencies Declared by the
Secretary of HHS ............................................................................................................................................. 35
5. THERAPEUTIC AREA TOPICS........................................................................................... 35
GENERAL .................................................................................................................................................... 35
SUPPORTED THERAPEUTIC AREAS .................................................................................................................... 36
5.1.1 Dyslipidemia Therapeutic Area User Guide v1 ................................................................. 36
5.1.2 Chronic Hepatitis C Therapeutic Area Data Standard User Guide v1 ............................... 36
5.1.3 QT Studies Therapeutic Area User Guide v1 .................................................................... 36
5.1.4 Diabetes Therapeutic Area User Guide v1.0 – Supplement for ADaM ............................. 36
5.1.5 Tuberculosis Therapeutic Area User Guide v2.0............................................................... 36
5.1.6 Diabetic Kidney Disease Therapeutic Area User Guide v1.0 ............................................ 36
5.1.7 Ebola Therapeutic Area User Guide v1.0.......................................................................... 36
5.1.8 Rheumatoid Arthritis Therapeutic Area User Guide v1.0 ................................................. 37
5.1.9 Malaria Therapeutic Area User Guide v1.0 ...................................................................... 37
5.1.10 Kidney Transplant Therapeutic Area User Guide v1.0...................................................... 37
5.1.11 TAUG-Influenza v1.1 ........................................................................................................ 37
5.1.12 Virology Therapeutic Area User Guide v2.1 ..................................................................... 37
5.1.13 Prostate Cancer Therapeutic Area User Guide v1.0 ......................................................... 37
5.1.14 Schizophrenia Therapeutic Area User Guide v1.1 ............................................................ 38
5.1.15 Major Depressive Disorder Therapeutic Area User Guide v1.0 ........................................ 38
5.1.16 Traumatic Brain Injury Therapeutic Area User Guide v1.0............................................... 38
5.1.17 Duchenne Muscular Dystrophy Therapeutic Area User Guide v1.0 ................................. 38
5.1.18 Vaccines Therapeutic Area User Guide v1.1..................................................................... 38
5.1.19 Chronic Obstructive Pulmonary Disease Therapeutic Area User Guide v1....................... 39
5.1.20 Colorectal Cancer Therapeutic Area User Guide v1.0 ...................................................... 39
5.1.21 Huntington’s Disease Therapeutic Area User Guide v1.0................................................. 39
5.1.22 Post Traumatic Stress Disorder Therapeutic Area User Guide v1.0 ................................. 39
5.1.23 Clostridium Difficile Associated Diarrhea Therapeutic Area User Guide v1.0 .................. 39
5.1.24 Acute Kidney Injury v1.0................................................................................................... 39
LIST OF FDA TECHNICAL SPECIFICATION DOCUMENTS.......................................................................................... 39
5.1.25 Submitting Nonclinical Datasets for Evaluation of Rodent Carcinogenicity Studies of
Pharmaceuticals, Guidance for Industry ............................................................................................. 40

viii
 5.1.26 Submitting Next Generation Sequencing Data to the Division of Antiviral Products ....... 40
5.1.27 Submitting Clinical Trial Datasets for Evaluation of QT/QTc Interval Prolongation and
Proarrhythmic Potential of Drugs ....................................................................................................... 40
5.1.28 Bioanalytical Methods Templates .................................................................................... 40
5.1.29 Submitting Select Clinical Trial Data Sets for Drugs Intended to Treat Human
Immunodeficiency Virus-1 Infection .................................................................................................... 40
5.1.30 Submitting Study Datasets for Vaccines to the Office of Vaccines Research and Review 40
5.1.31 Technical Specifications-Comparative Clinical Endpoint Bioequivalence Study Analysis
Datasets for Abbreviated New Drug Applications .............................................................................. 40
5.1.32 Technical Specifications for Submitting Clinical Trial Data Sets for Treatment of
Noncirrhotic Nonalcoholic Steatohepatitis (NASH) ............................................................................. 40
5.1.33 Submitting Patient-Reported Outcome Data in Cancer Clinical Trials ............................. 40
5.1.34 Submitting Clinical Trial Datasets and Documentation for Clinical Outcome Assessment
Using Item Response Theory ............................................................................................................... 40
6. TERMINOLOGY .............................................................................................................. 40
GENERAL .................................................................................................................................................... 40
6.1.1 Controlled Terminologies ................................................................................................. 41
6.1.2 Use of Controlled Terminologies ...................................................................................... 41
Use of the Specific Controlled Term ‘OTHER’............................................................................. 42
6.1.3 Maintenance of Controlled Terminologies ....................................................................... 42
CDISC CONTROLLED TERMINOLOGY ................................................................................................................ 43
ADVERSE EVENTS.......................................................................................................................................... 43
6.1.4 MedDRA ........................................................................................................................... 43
General Considerations .............................................................................................................. 43
MEDICATIONS .............................................................................................................................................. 43
6.1.5 FDA Unique Ingredient Identifier ..................................................................................... 43
General Considerations .............................................................................................................. 43
6.1.6 WHODrug Global ............................................................................................................. 44
General Considerations .............................................................................................................. 44
PHARMACOLOGIC CLASS ................................................................................................................................ 45
6.1.7 Medication Reference Terminology ................................................................................. 45
General Considerations .............................................................................................................. 45
INDICATION ................................................................................................................................................. 45
6.1.8 SNOMED CT...................................................................................................................... 45
General Considerations .............................................................................................................. 45
LABORATORY TESTS....................................................................................................................................... 46
6.1.9 LOINC ............................................................................................................................... 46
General Considerations .............................................................................................................. 46
7. ELECTRONIC SUBMISSION FORMAT ............................................................................... 46
7.1 eCTD Specifications .......................................................................................................... 46
7.1.1 eCTD v3.2.2 Specifications ............................................................................................... 46
7.1.2 eCTD v4.0 Specifications .................................................................................................. 47
7.1.3 Weight of Evidence .......................................................................................................... 48
ELECTRONIC FILE DIRECTORY........................................................................................................................... 48
ECTD SAMPLE SUBMISSION ............................................................................................................................ 51
7.1.4 File Tags ........................................................................................................................... 51
8. STUDY DATA VALIDATION AND TRACEABILITY ............................................................... 58
DEFINITION OF STUDY DATA VALIDATION .......................................................................................................... 58
TYPES OF STUDY DATA VALIDATION RULES ........................................................................................................ 58
8.1.1 FDA Business and Validator Rules .................................................................................... 58

ix
 8.1.2 Support on Data Validation Rules .................................................................................... 59
eCTD Technical Rejection Criteria for Study Data (See Appendix F for more details) ................ 59
Technical Rejection Criteria and Use of a Simplified ts.xpt for Clinical Studies.......................... 60
Technical Rejection Criteria and Use of a Simplified ts.xpt for Nonclinical Studies (eCTD
Modules 4.2.3.1, 4.2.3.2, and 4.2.3.4) ............................................................................................................ 61
STUDY DATA TRACEABILITY ............................................................................................................................. 64
8.1.3 Overview .......................................................................................................................... 64
8.1.4 Legacy Study Data Conversion to Standardized Study Data ............................................ 64
Traceability Issues with Legacy Data Conversion ....................................................................... 65
Legacy Data Conversion Plan and Report .................................................................................. 66
APPENDIX A: DATA STANDARDS AND INTEROPERABLE DATA EXCHANGE ............................................. 68
APPENDIX B: TRIAL SUMMARY (TS) PARAMETERS FOR SUBMISSION – CLINICAL .................................. 71
APPENDIX C: TRIAL SUMMARY (TS) PARAMETERS FOR SUBMISSION – NONCLINICAL ........................... 74
APPENDIX D: ADDITIONAL DOCUMENTS EVALUATED BY FDA............................................................... 77
APPENDIX E: EXAMPLE STUDY DATA FOLDER STRUCTURE .................................................................... 78
APPENDIX F: TECHNICAL REJECTION CRITERIA FOR STUDY DATA VALIDATION IMPORTANT
INFORMATION .................................................................................................................................... 80
APPENDIX G: EXAMPLES OF TS.XPT DATASETS ..................................................................................... 83
APPENDIX H: HHS DECLARED PUBLIC HEALTH EMERGENCIES AND MODIFICATIONS TO DATA
STANDARDS REQUIREMENTS............................................................................................................... 84
GLOSSARY 87

x
 Contains Nonbinding Recommendations

STUDY DATA
TECHNICAL CONFORMANCE GUIDE

This technical specifications document represents the Food and Drug Administration’s
(FDA’s) current thinking on this topic. It does not create or confer any rights for or on
any person and does not operate to bind FDA or the public. You can use an alternative
approach if the approach satisfies the requirements of the applicable statutes and
regulations. If you want to discuss an alternative approach, contact the FDA staff
responsible for implementing this guidance. If you cannot identify the appropriate FDA
staff, send an email to [email protected] or [email protected]. You can
submit comments to this document online at https://www.regulations.gov and searching
Docket No. FDA-2018-D-12160002.

1. Introduction
Background
This Study Data Technical Conformance Guide (Guide) provides specifications,
recommendations, and general considerations on how to submit standardized study data
using FDA-supported 1 data standards located in the FDA Data Standards Catalog
(Catalog). 2 The Guide supplements the guidance for industry Providing Regulatory
Submissions in Electronic Format — Standardized Study Data (eStudy Data). The eStudy
Data guidance implements the electronic submission requirements of section 745A(a) of
the Food, Drug, & Cosmetic (FD&C) Act with respect to standardized study data
contained in certain investigational new drug applications (INDs), new drug applications
(NDAs); abbreviated new drug applications (ANDAs); and certain biologics license
applications (BLAs) that are submitted to the Center for Drug Evaluation and Research
(CDER) or the Center for Biologics Evaluation and Research (CBER). 3

Purpose
This Guide provides technical recommendations to sponsors 4 for the submission of
animal and human study data and related information in a standardized electronic format
in INDs, NDAs, ANDAs, and BLAs. 5 The Guide is intended to complement and promote
interactions between sponsors and FDA review divisions. However, it is not intended to
replace the need for sponsors to communicate directly with review divisions regarding
implementation approaches or issues relating to data standards.

1
For the purposes of this document, “supported” means the receiving Center has established processes and
technology to support receiving, processing, reviewing, and archiving files in the specified file format.
2
Available at http://www.fda.gov/eStudyResources.
3
See Providing Regulatory Submissions in Electronic Format — Standardized Study Data (section II.A)
available at http://www.fda.gov/eStudyResources.
4
For the purposes of this document, the term “sponsor” refers to both “sponsors” and “applicants” who are
submitting study data to the Agency.
5
Docket No. FDA-2018-D-1216
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Because of the inherent variability across studies and applications, it is difficult to

identify all data needed by a review division prior to a scientific regulatory review. We
recommend that as early as the pre-IND meeting, sponsors should use the established
regulatory process to discuss with the review division the key data necessary to support a
submission, the data elements that should be included in each dataset, and the
organization of the data within the datasets.

Not every data element included in a standard’s underlying data model is fit for purpose
for every trial. The use of the word ‘required’ in this document generally indicates a
requirement by the Agency and not any external organization. Any use of the word
‘required’ that would have a different meaning will be explained in the text. For example,
the Study Data Tabulation Model Implementation Guide (SDTMIG) 6 classifies variables
as required, expected, or permissible. This use of the word ‘required’ by the Standards
Data Organization does not necessarily indicate an Agency requirement. What data are
collected and submitted is a decision that should be made based on scientific reasons,
regulation requirements, and discussions with the review division. However, all study-
specific data necessary to evaluate the safety and efficacy of the medical product should
be submitted in conformance with the standards currently supported by FDA and listed in
the Catalog.

This document applies to submissions to CDER and CBER, however some review offices
and multi-disciplinary review teams may have specific technical guidance which provides
additional details on preparing and submitting information that may differ from this
document. In those cases the specific technical guidance should be followed instead of
the information contained herein. If there is a question regarding a specific submission or
a particular data standard implementation, the sponsor should contact the review division
for specific submission questions or the appropriate contact for data standards issues
([email protected] or [email protected]).

This Guide supersedes all previous Study Data Specifications documents (Versions 1.0 –
2.0) and CDER Study Data Common Issues Documents (Versions 1.0 -1.1).

Document Revision and Control

FDA intends to post updated versions of the Guide to the Study Data Standards
Resources Web page (Standards Web page). 7 The plan is to publish updated versions in
March and October of each calendar year. However, the Guide will be posted sooner if
important issues arise. The revision history page of the Guide provides information on the
changes made to previous versions.

Organization and Summary of the Guide

This document is organized as follows:

6
See http://www.cdisc.org.
7
The Standards Web page can be accessed at http://www.fda.gov/eStudyResources.
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Section 1: Introduction – provides information on regulatory policy and guidance

background, purpose, and document control.
Section 2: Planning and Providing Standardized Study Data – recommends and
provides details on preparing an overall study data standardization plan, a
study data reviewer’s guide and an analysis data reviewer’s guide.

Section 3: Exchange Format: Electronic Submissions – presents the specifications,

considerations, and recommendations for the file formats currently supported
by FDA.
Section 4: Study Data Submission Format: Clinical and Nonclinical – presents
general considerations and specifications for sponsors using, for example, the
following standards for the submission of study data: Study Data Tabulation
Model (SDTM), Analysis Data Model (ADaM), and Standard for Exchange of
Nonclinical Data (SEND).
Section 5: Therapeutic Area Topics – presents supplemental considerations and specific
recommendations when sponsors submit study data using therapeutic area
extensions of FDA-supported standards.
Section 6: Terminology – presents general considerations and specific recommendations
when using controlled terminologies/vocabularies for clinical trial data or
nonclinical study data.
Section 7: Electronic Submission Format – provides specifications and
recommendations on submitting study data using the electronic Common
Technical Document (eCTD) format.
Section 8: Study Data Validation and Traceability – provides general
recommendations on conformance to standards, data validation rules, data
traceability expectations, and legacy data conversion.

Relationship to Other Documents

This Guide integrates and updates information discussed previously in the Study Data
Specifications and the CDER Common Data Standards Issues documents. As noted
above, this Guide supersedes all previous Study Data Specifications documents (Versions
1.0 – 2.0) and CDER Study Data Common Issues Documents (Versions 1.0 -1.1). The
examples of issues and concerns discussed in the Guide are intended as examples only of
common issues, and not an inclusive list of all possible issues.

This Guide is incorporated by reference into the Guidance to Industry Providing

Regulatory Submissions in Electronic Format: Standardized Study Data. In addition,
sponsors should reference the following:

• Study Data Standards Resources Web page (See section 1.3)

• FDA Data Standards Catalog (See section 1.1)

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• FDA Portable Document Format Specifications (See section 3.2)

• Specifications for File Format Types Using eCTD Specifications 8
• Guidance to Industry Providing Regulatory Submissions in Electronic Format:
Submissions Under Section 745A(a) of the Federal Food, Drug, and Cosmetic
Act 9
• Guidance to Industry Providing Regulatory Submissions in Electronic Format:
Certain Human Pharmaceutical Product Applications and Related Submissions
Using the Electronic Common Technical Document Specifications 10

2. Planning and Providing Standardized Study Data

Study Data Standardization Plan
For clinical and nonclinical studies, sponsors should include a plan (e.g., during the early
stages of product development conducted under the IND) describing the submission of
standardized study data to FDA. The Study Data Standardization Plan (SDSP) assists
FDA in identifying potential data standardization issues early in the development
program. Sponsors may also initiate discussions at the pre-IND stage. For INDs, NDAs,
and BLAs, the SDSP should be located in eCTD sections 1.13.9 General Investigational
Plan or 1.20 General Investigational Plan for Initial IND. Although a specific template is
not specified, an example SDSP is available. 11

The SDSP should be updated in subsequent communications with FDA as the

development program expands and additional studies are planned. Updates to the SDSP
should not be communicated each time a study is started. The cover letter accompanying
a study data submission should describe the extent to which the latest version of the
SDSP was executed. An SDSP should be provided with pre-NDA and pre-BLA meetings.

In addition, for clinical studies that will be submitted to CBER, the SDSP appendix
should be provided to the review office no later than the End-of-Phase 2 (EOP2) meeting.
The CBER SDSP appendix should include tables of proposed SDTM domain/variable
usage, supplemental domain usage and proposed analysis.

8
See https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/electronic-common-
technical-document-ectd
9
Available at
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
10
Available at
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
11
A specific template for a Study Data Standardization Plan is not specified. However, an example can be
found at https://phuse.global/Deliverables, The PhUSE SDSP template has been reviewed by FDA and
published in the Federal Register https://www.federalregister.gov/documents/2016/11/08/2016-
26913/intent-to-review-a-study-data-standardization-plan-template-notice-of-availability-establishment-of.
FDA prefers but does not require its use.
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Study Data Reviewer’s Guides

The preparation of the relevant Reviewer Guides (RG) 12 is recommended as an integral
part of a standards-compliant study data submission. An RG should describe any special
considerations or directions or conformance issues that may facilitate an FDA reviewer’s
use of the submitted data and may help the reviewer understand the relationships between
the study report and the data.

There are two study data reviewer guides (SDRG): clinical and nonclinical. The SDRG
for nonclinical studies (nSDRG) 13 and SDRG for clinical studies (cSDRG) 14 should be
placed with the study data in Module 4 and 5, respectively, in the eCTD. 15 When
submitting in eCTD v3.2.2, the SDRG should be file-tagged as ‘study-data-reviewers-
guide’, with a clear leaf title. When submitting in eCTD v4.0, the SDRG should utilize
document type keyword ‘study data reviewers guide’, with a clear document title.

2.1.1 SDRG for Clinical Data

An SDRG for clinical data should be named cSDRG (the prefix ‘c’ designates ‘clinical’)
and the document should be named ‘csdrg’ and provided as a PDF file upon submission
(csdrg.pdf).

2.1.2 SDRG for Nonclinical Data

An SDRG for nonclinical data should be named nsdrg (the prefix ‘n’ designates
‘nonclinical’) and the document should be named ‘nsdrg’ and provided as a PDF file
upon submission (nsdrg.pdf).

Analysis Data Reviewer’s Guide

The preparation of an Analysis Data Reviewer’s Guide (ADRG) 16 is recommended as an
important part of a standards-compliant analysis data submission for clinical trials. The
ADRG provides FDA reviewers with context for analysis datasets and terminology,
received as part of a regulatory product submission, additional to what is presented within

12
For the purposes of this document, the term ‘Reviewer Guide’ refers only to those located in the m4 or
m5 eCTD folders.
13
A specific template for a Study Data Reviewer’s Guide for nonclinical studies is not specified. However,
an example can be found at https://phuse.global/Deliverables. The PhUSE nSDRG template has been
reviewed by FDA and published in the Federal Register
https://www.federalregister.gov/documents/2015/07/23/2015-18027/intent-to-review-a-study-data-
reviewers-guide-template. FDA prefers but does not require its use.
14
A specific template for a Study Data Reviewer’s Guide for clinical studies is not specified. However, an
example can be found at https://phuse.global/Deliverables. The PhUSE cSDRG template has been reviewed
by FDA and published in the Federal Register
https://www.federalregister.gov/documents/2016/03/04/2016-04791/intent-to-review-a-nonclinical-study-
data-reviewers-guide-template. FDA prefers but does not require its use.
15
The Study Data Reviewer’s Guides are separate documents from an overall reviewer’s guide which is
placed in Module 1 of the eCTD.
16
A specific template for an Analysis Data Reviewer’s Guide is not specified. However, an example can be
found at https://phuse.global/Deliverables.
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the data folder (i.e., define.xml). The ADRG also provides a summary of ADaM
conformance findings. The ADRG purposefully duplicates limited information found in
other submission documentation (e.g., the protocol, statistical analysis plan (SAP),
clinical study report, define.xml) in order to provide FDA reviewers with a single point of
orientation to the analysis datasets. It should be noted that the submission of an ADRG
does not eliminate the requirement to submit a complete and informative define.xml file
corresponding to the analysis datasets.

• The ADRG for a clinical study should be placed with the analysis data in Module
5 of the eCTD.
o When submitting in eCTD v3.2.2, the ADRG should be file-tagged as
‘analysis-data-reviewers-guide’, with a clear leaf title.
o When submitting in eCTD v4.0, the ADRG should utilize document
type keyword ‘analysis data reviewers guide’, with a clear document
title.
• An ADRG for clinical data should be called an ADRG and the document should
be a PDF file ‘adrg.pdf’ upon submission.

3. Exchange Format – Electronic Submissions

Extensible Mark-up Language
Extensible Mark-up Language (XML), as defined by the World Wide Web Consortium
(W3C), specifies a set of rules for encoding documents in a format that is both human-
readable and machine-readable. 17,18 XML facilitates the sharing of structured data across
different information systems. An XML use case is CDISC’s define.xml file. All XML
files should use .xml as the file extension. Although XML files can be compressed, the
define.xml should not be compressed.
Portable Document Format
Portable Document Format (PDF) is an open file format used to represent documents in a
manner independent of application software, hardware, and operating systems. 19 A PDF
use case includes, e.g., the annotated CRF (aCRF / blank crf), and other documents that
align with the International Council for Harmonisation (ICH) M2. 20 FDA PDF
specifications are located on FDA’s eCTD Web site. 21 The Catalog lists the PDF
version(s) that are supported by FDA. All PDF files should use .pdf as the file extension.

17
See http://en.wikipedia.org/wiki/XML.
18
See http://www.w3.org/XML/.
19
Adobe Systems Incorporated, PDF Reference, sixth edition, version 1, Nov. 2006, p. 33.
20
See http://www.ich.org/products/electronic-standards.html.
21
Available at http://www.fda.gov/ectd.
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File Transport Format

3.1.1 v5 Transport Format

The Transport Format (XPORT) Version 5 is the file format for the submission of all
electronic datasets. 22 XPORT is an open file format published by SAS Institute for the
exchange of study data. Data can be translated to and from XPORT to other commonly
used formats without the use of programs from any specific vendor. There should be one
dataset per transport file, and the dataset in the transport file should be named the same as
the transport file (e.g., ‘ae’ and ae.xpt, ‘suppae’ and suppae.xpt, ‘lb1’ and lb1.xpt).

XPORT files can be created by the COPY Procedure in SAS Version 5 and higher of the
SAS Software. SAS Transport files processed by the SAS CPORT cannot be reviewed,
processed, or archived by FDA. Sponsors can find the record layout for SAS XPORT
transport files through SAS technical document TS-140. 23 All SAS XPORT transport
files should use .xpt as the file extension, and the files should not be compressed. Note
also that SAS custom formats should NOT be used in submissions to the FDA.

3.1.2 Dataset Size

Each dataset should be provided in a single transport file. The maximum size of an
individual dataset that FDA can process depends on many factors. Datasets greater than 5
gigabytes (GB) in size should be split into smaller datasets no larger than 5 GB. Sponsors
should submit these smaller datasets, in addition to the larger non-split datasets, to better
support regulatory reviewers. The split datasets should be placed in a separate sub-
directory labeled ‘split’ (See section 7.2). A clear explanation regarding how these
datasets were split needs to be presented within the relevant data RG.

3.1.3 Dataset Column Length

The allotted length for each column containing character (text) data should be set to the
maximum length of the variable used across all datasets in the study except for suppqual
datasets. For suppqual datasets, the allotted length for each column containing character
(text) data should be set to the maximum length of the variable used in the individual
dataset. This will significantly reduce file sizes. For example, if USUBJID has a
maximum length of 18, the USUBJID’s column size should be set to 18, not 200. If
datasets are split according to section 3.3.2, reduce variable length before datasets are
split. Care should be taken to avoid accidental truncation of data through dataset merges.

3.1.4 Variable and Dataset Descriptor Length

The length of variable names, descriptive labels, and dataset labels should not exceed the
maximum permissible number of characters described in Table 1.

22
See http://www.sas.com.
23
http://support.sas.com/techsup/technote/ts140.pdf.
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Table 1: Maximum Length of Variables and Dataset Elements

Element Maximum Length in Characters
Variable Name 8

Variable Descriptive Label 40

Dataset Label 40

3.1.5 Special Characters: Variables and Datasets

Variable names, as well as variable and dataset labels should include American Standard
Code for Information Interchange (ASCII) text codes only. Variable values are the most
broadly compatible with software and operating systems when they are restricted to
ASCII text codes (printable values below 128). Use UTF-8 for extending character sets;
however, the use of extended mappings is not recommended. Transcoding errors, variable
length errors, and lack of software support for multi byte UTF-8 encodings can result in
incorrect character display and variable value truncations. Ensure that LBSTRESC and
controlled terminology extensions in LBTEST do not contain byte values 160-191 as
some character mappings in that range may interfere with agency processes.

3.1.6 Variable and Dataset Names

Implement the SDO technical specifications when preparing your datasets for
submission. Datasets submitted in legacy formats should follow the conventions
described in other documents. 24

Use V7 as the valid variable name option (VALIDVARNAME) and extend for the valid
member name option (VALIDMEMNAME).

3.1.7 Variable and Dataset Labels

Do not submit study data with the following special characters in variable and dataset
labels:
1. Unbalanced apostrophe, e.g., “Parkinson’s”
2. Unbalanced single and double quotation marks
3. Unbalanced parentheses, braces or brackets, e.g.,‘(’, ‘{’ and ‘[’

24

https://documentation.sas.com/doc/en/lrcon/9.4/p18cdcs4v5wd2dn1q0x296d3qek6.htm#n0nfuxt1u6y9jin12
0gszztjh00o.
https://documentation.sas.com/doc/en/lesysoptsref/9.4/p124dqdk8zoqu3n1r4nsfqu5vx52.htm.
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4. Study Data Submission Format – Clinical and Nonclinical

Clinical Data Interchange Standards Consortium
Clinical Data Interchange Standards Consortium (CDISC) is an open, multidisciplinary,
neutral, nonprofit standards development organization (SDO) that has been working
through consensus-based collaborative teams to develop global data standards for clinical
and nonclinical research. 25

Data format specifications for the tabulation datasets of clinical and nonclinical
toxicology studies are provided by SDTM and SEND, respectively, while data format
specifications for the analysis datasets of clinical studies are provided by ADaM. It
should be noted that data format specifications for the analysis datasets of nonclinical
toxicology studies have not been developed. As noted in section 1.1, the Catalog provides
a listing of the currently supported data standards with links to reference materials. For
the purposes of this Guide, the terms SDTM, ADaM, and SEND apply to versions only
listed and supported by FDA in the Catalog.

Although the SDTM and SEND formats facilitate review of the data, they do not always
provide the data structured in a way that supports all analyses needed for review.
Analysis files are critical for FDA to understand, on a per subject basis, how the specific
analyses contained in the study report have been created. Therefore, sponsors should
supplement the SDTM with ADaM analysis datasets as described below.

There may be instances in which current implementation guides (e.g., SDTMIG,

SENDIG) do not provide specific instruction as to how certain study data should be
represented. In these instances, sponsors should discuss their proposed solution with the
review division and submit supporting documentation that describes these decisions or
solutions in the appropriate SDRG at the time of submission.

4.1.1 Study Data Tabulation Model

Definition
The Study Data Tabulation Model (SDTM) defines a standard structure for human
clinical trials tabulation datasets.
SDTM General Considerations
It is recommended that sponsors implement the SDTM standard for representation of
clinical trial tabulation data prior to the conduct of the study.

The SDTMIG should be followed unless otherwise indicated in this Guide or in the
Catalog. The conformance criteria listed in the SDTMIG should not be interpreted as the
sole determinant of the adequacy of submitted data. If there is uncertainty regarding
implementation, the sponsor should discuss application-specific questions with the
review division and general standards implementation questions with the specific center

25
See http://www.cdisc.org.
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resources identified elsewhere in this Guide (See section 1.2). Each submitted SDTM
dataset should have its contents described with complete metadata in the define.xml file
(See section 4.1.4.5) and within the cSDRG as appropriate (See section 2.2). When
updated datasets (e.g., ‘ae.xpt’, ‘lb.xpt’) are submitted, updated and complete define.xml
and cSDRG covering all datasets should be submitted replacing the original file (see
section 7.1. for more details).

Except for variables that are defined in the SDTMIG as being coded, numerically coded
variables typically are not submitted as part of the SDTM datasets. Numeric values
generated from validated scoring instruments or questionnaires do not represent codes,
and therefore have no relevance for this issue. There may be special instances when
codes are preferred, hence sponsors should refer to the review division for direction, if
there are any questions.

Subject Identifier (SUBJID)

The variable SUBJID uniquely identifies each subject that participates in a study. If a
single subject is screened and/or enrolled more than once in a study, then the subject’s
SUBJID should be different for each unique screening or enrollment. For a study with
multiple screenings and/or multiple enrollments per subject, SUBJID should be included
in other related domains besides DM even though it may cause validation errors. It is
recommended to include a table linking each SUBJID for a single subject to that subject’s
USUBJID with any additional necessary explanation included in the relevant RG.

Unique Subject Identifier (USUBJID)

The variable USUBJID is an identifier used to uniquely identify a subject across all
studies for all applications or submissions involving the product. 26 Each individual
subject should be assigned a single unique identifier across the entire application. This is
in addition to the subject ID (SUBJID) used to identify subjects in each study and its
corresponding study report. An individual subject should have the exact same unique
identifier across all datasets, including between SDTM and ADaM datasets. Subjects that
participate in more than one study should maintain the same USUBJID across all studies.
It is important to follow this convention to enable pooling of a single subject’s data
across studies (e.g., a randomized control trial and an extension study).

Sponsors should not add leading or trailing spaces to the USUBJID variable in any
dataset. For example, applications have been previously submitted in which the
USUBJID variable for each individual subject appeared to be the same across datasets;
however, in certain datasets, the actual entry had leading zeros added, or zeros added
elsewhere in the entry. This does not allow for machine-readable matching of individual
subject data across all datasets. Improper implementation of the USUBJID variable is a
common error with applications and often requires sponsors to re-submit their data.

Adjudication Data

26
CDISC, https://www.cdisc.org/standards/foundational.
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There are no existing standards or best practices for the representation of adjudication
data as part of a standard data submission. Until standards for adjudication data are
developed, it is advised that sponsors discuss their proposed approach with the review
division and also include details about the presence, implementation approach, and
location of adjudication data in the SDRG.

Whenever adjudication data are provided, they should be clearly identified so that the
reviewer can distinguish the results of adjudication from data as originally collected.
SDTM Domain Specifications
SUPPQUAL (Supplemental Qualifier)
A SUPPQUAL dataset is a special SDTM dataset that contains non-standard variables
which cannot be represented in the existing SDTM domains. SUPPQUAL should be used
only when key data cannot be represented in SDTM domains. In general, variables used
to support key analyses should not be represented in SUPPQUAL. Discussion with the
review division should occur if the sponsor intends to include important variables (e.g.,
that support key analyses) in SUPPQUAL datasets, and this should be reflected in the
SDRG.

DM Domain (Demographics)
In the DM domain, each subject should have only one single record per study.

Screen failures, when provided, should be included as a record in DM with the ARM,
ARMCD, ACTARM, and ACTARMCD field left blank. For subjects who are
randomized in treatment group but not treated, the planned arm variables (ARM and
ARMCD) should be populated, but actual treatment arm variables (ACTARM and
ACTARMCD) should be left blank. 27

For subjects with multiple enrollments within a single study, the primary enrollment
should be submitted in DM. Additional enrollments should be included in a custom
domain with a similar structure to DM. Clarifying statements in the RG would be helpful.

For subjects with multiple screenings and no subsequent enrollment, include the primary
screening in DM with additional screenings in a custom domain with a structure similar
to DM.

For subjects with multiple screenings and subsequent enrollment, include the enrollment
in DM with screenings in a custom domain with a structure similar to DM.

DS Domain (Disposition)
When there is more than one disposition event, the EPOCH or DSSCAT variable should
be used to aid in distinguishing between them. This will allow identification of the
EPOCH in which each event occurred or DSSCAT to differentiate if the disposition is for
treatment or study. If a death of any type occurs, it should be the last record and should

27
Although this convention is inconsistent with the SDTMIG, FDA recommends its use so that ‘Screen
Failure’, ‘Not assigned’, and ‘Not treated’ are not specified as a treatment arm.
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include its associated EPOCH. It is expected that EPOCH variable values will be
determined based on the trial design and thus should be defined clearly and documented
in the define.xml.

SE Domain (Subject Elements)

The Subject Elements domain should be included to aid in the association of subject data
(e.g., findings, events, and interventions) with the study element in which they occurred.

AE Domain (Adverse Events)

The AE domain should include all adverse events, unless otherwise specified in
Technical Specification Document(s) 28 appropriate for the indication. The definition of
treatment emergent adverse events should be agreed upon with the review division and
specified in the protocol (e.g., any AE after first dose of investigational product
administration, or any AE after first dose of investigational product administration until
X days after the last dose).

The entry of a ‘Y’ for the serious adverse event variable, AESER, should have the
assessment indicated (e.g., as a death, hospitalization, or disability/permanent damage).
Frequently, sponsors omit the assessment information, even when it has been collected on
the CRF. The criteria that led to the determination should be provided. This information
is critical during FDA review to support the characterization of serious Aes.

Custom Domains
The SDTMIG permits the creation of custom domains if the data do not fit into an
existing domain. Prior to creating a custom domain, sponsors should confirm that the data
do not fit into an existing domain. If it is necessary to create custom domains, sponsors
should follow the recommendations in the SDTMIG. In addition, sponsors should present
their implementation approach in the cSDRG. To provide study data that do not fit into
an existing SDTM domain or draft SDTM domain, consider creating a custom dataset
aligned with the Study Data Tabulation Model (SDTM). Questions about custom
domains should be addressed in pre-submission meetings and documented in the SDSP.

PC Domain (Pharmacokinetic Concentration)

All planned samples should have a record in this domain. If a sample analysis was
planned but no result is available, a reason for why the test was not done should be
included in PCREASND. Values for the lower limit of quantitation should be included in
PCLLOQ and correspond to those units in PCSTRESU. Naming for all timepoints and
visits should be consistent with the data provided in the clinical study report. Naming for
all analytes should be consistent with the data represented in the pharmacokinetic
parameters (PP) domain. If data for an analyte per subject is present in PP, there should
be information for that analyte per subject per sample in PC.

PP Domain (Pharmacokinetic Parameters)

Technical Specification Document(s) can be found on the FDA Study Data Standards Resources
28

webpage, https://www.fda.gov/industry/fda-resources-data-standards/study-data-standards-resources.
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Naming for all visits should be consistent with the data provided in the clinical study
report. Naming for all analytes should be consistent with the data represented in the
pharmacokinetic concentrations (PC) domain.

LB Domain (Laboratory)
The size of the LB domain dataset submitted by sponsors is often too large to process
(See section 3.3.2). This issue can be addressed by splitting a large LB dataset into
smaller datasets according to LBCAT and LBSCAT, using LBCAT for initial splitting. If
the size is still too large, then use LBSCAT for further splitting. For example, use the
dataset name lb1 (file name ‘lb1.xpt’) for chemistry, dataset name lb2 (file name
‘lb2.xpt’) for hematology, and dataset name lb3 (file name ‘lb3.xpt’) for urinalysis.
Splitting the dataset in other ways (e.g., by subject or file size) makes the data less
useable. Sponsors should submit these smaller files in addition to the larger non-split
standard LB domain file. Sponsors should submit the split files in a separate sub-
directory/split that is clearly documented in addition to the non-split standard LB domain
file in the SDTM datasets directory (See section 7).

In general, associated reference ranges for each lab result should be provided. For
subpopulations (e.g., pediatric) the appropriate reference range for that subpopulation
should be provided.

For clinical studies, submit two separate domains for lab results. The LB domain should
contain SI units in LBSTRESU for the SI results in the LBSTRESC and LBSTRESN
fields. An additional custom domain called LC structured identically to LB should
contain conventional units in –STRESU for the results in conventional units in the –
STRESC and –STRESN variables. It is ideal if both conventional and SI units come
directly from the lab vendor. Submit the results of all tests obtained on subjects, including
the results from unscheduled tests or visits, and results obtained from local laboratories.
Identify all reference ranges used for specific populations in the SDRG and ADRG.

There is no expectation to submit the new LB variables found in SDTMv2.0 and

SDTMIGv3.4, which may support individual parts of a LOINC. These new variables
should only be submitted in LB datasets when it is medically or scientifically appropriate
to do so.

Immunogenicity Domain (IS)

The IS domain should be submitted for all individual studies where immunogenicity data
was collected. Titer results should be included in the IS domain and not as part of
supplemental domains.

Trial Design Model (TDM)

Unless a simplified ts.xpt is indicated (see below), all TDM datasets should be included
with each SDTM study submission to describe the planned conduct of a clinical study.

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When submitting a full ts.xpt, refer to the appendix section for a list of study parameters
that should be submitted where relevant for clinical studies. Additional parameters may
be included beyond those listed in the appendix. For clinical studies, study start date
(SSTDTC) is the earliest date of informed consent among any subject that enrolled in the
study. 29

In addition to the study parameters indicated in the appendix section, if the study data
submitted follows a Therapeutic Area User Guide (TAUG) or an FDA Technical
Specification, 30 use the values for TSPARM/TSPARMCD and TSVAL from the table
below in the TS domain. Use of these parameters in TS will allow for tracking and
reporting on the submission rates of study data following a particular TAUG or technical
specification. At this time, it is also helpful to include the version of the CDISC
implementation guide (IG) and model used using the parameters indicated in the table
below.

TSPARMCD TSPARM TSVAL value

value value
CTAUG CDISC Should be the exact listing in section 5.2 of the TCG for
Therapeutic TAUGs
Area User Ex. Chronic Hepatitis C Therapeutic Area User Guide v1.0
Guide
FDATCHSP FDA Tech Should be the exact listing on the study data standards
Spec resources website for technical specification documents
Ex. Vaccines Technical Specification Guidance v1.0
SDTIGVER SDTM IG Should be the exact term listed in column F of the FDA Data
Version Standards Catalog, Submission Data Exchange Stds tab. If
multiple SDTM IG Versions are used for a study, then each
version used should have a unique value for TSPARM.
Ex. 3.2
SDTMVER SDTM Should be the exact term listed in column E of the FDA Data
Version Standards Catalog, Submission Data Exchange Stds tab. If
multiple SDTM Versions are used for a study, then each
version used should have a unique value for TSPARM.
Ex. 1.4

EC Domain (Exposure as Collected)

The Exposure as Collected domain provides for protocol-specified study treatment
administrations, as-collected. The EC domain may address some challenges in providing
a subject’s exposure to study medication.

DD Domain (Death Details)

The Death Details domain provides for supplemental data that are typically collected
when a death occurs, such as the official cause of death. The AE domain variables,

29
Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/providing-
regulatory-submissions-electronic-format-standardized-study-data.
30
https://www.fda.gov/forindustry/datastandards/studydatastandards/default.htm.
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AEOUT, AESDTH and AEENDTC/AEENDY should be populated and consistent with

the death details.

QS Domain (Questionnaires)
Some items in an instrument may be logically skipped per the instrument’s instructions.
Responses for logically skipped items should be (1) recorded and/or scored according to
the instructions provided in the instrument’s user manual, scoring manual, or other
documentation provided by the instrument developer and (2) included in the submission
dataset.

If instructions on how to record and/or score responses to items not done due to
conditional branching are available from the instrument developer, then records for items
with conditional branching should be included in the submission dataset with the
following:
• QSCBRFL = “Y”
• QSORRES, QSSTRESC, and QSSTRESN would be assigned according to the
instrument’s instructions

If instructions on how to record and/or score responses to items not done due to
conditional branching are not available from the instrument developer, then records for
items with conditional branching should be included in the submission dataset with the
following:
• QSSTAT = “NOT DONE”,
• QSCBRFL = “Y” and,
• QSORRES, QSSTRESC, and QSSTRESN all set to null.
• QSREASND = missing or the sponsor-provided reason (e.g., “LOGICALLY
SKIPPED ITEM”)

DV Domain (Protocol Deviations)

The DV domain should be included in your submission. It will be used by reviewers to
examine protocol deviation trends of various study sites in order to facilitate the
Bioresearch Monitoring Program (BIMO) clinical investigator site selection process, and
once FDA tools are developed to extract and format needed data from SDTM, to populate
line listings used by the Office of Regulatory Affairs (ORA) investigators during
inspections. The following variables besides CDISC required variables should be
included in the DV domain when submitting DV data: DVSPID, DVTERM, DVDECOD,
DVCAT, DVSCAT, DVSTDTC, DVENDTC and EPOCH.

SV Domain (Subject Visits)

It is the current preference of the Agency that for all clinical studies, subject visit data for
scheduled (whether or not they occurred), and unscheduled visits be submitted in one
single dataset structured as the current CDISC Subject Visits (SV) domain. It is also
Agency preference that three non-standard variables (NSVs) for missed visits, --
REASOC (Reason for Occur Value), --EPCHGI (Epi/Pandemic Related Change
Indicator), and –CNTMOD (Contact Mode), outlined in the CDISC property “Guidance
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for Ongoing Studies Disrupted by COVID-19 Pandemic” be included within the SV

domain and not within the supplemental SUPPSV domain or in other SDTM datasets.
Submitting subject visits information in one single structured dataset allows both the
human and technology consumer of this information to operate efficiently and with
confidence that all visit data are considered during regulatory review.

MB Domain (Microbiology)
Viral load results should be placed in the MB domain.

4.1.2 Analysis Data Model

Definition
Specifications for analysis datasets for human drug product clinical studies are provided
by the Analysis Data Model (ADaM) and its implementation by the Analysis Data Model
Implementation Guide (ADaMIG). ADaM datasets should be used to create and to
support the results in clinical study reports (CSRs), Integrated Summaries of Safety (ISS),
and Integrated Summaries of Efficacy (ISE), as well as other analyses required for a
thorough regulatory review. ADaM datasets can contain imputed data or data derived
from SDTM datasets.
General Considerations
Generally, ADaM assists FDA review. However, it does not always provide data
structured in a way that supports all of the analyses that should be submitted for review.
For example, ADaM structures do not support simultaneous analysis of multiple
dependent variables or correlation analysis across several response variables. Therefore,
sponsors should, as needed, supplement their ADaM datasets after discussions with the
specific review division.

One of the expected benefits of analysis datasets that conform to ADaM is that they
simplify the programming steps necessary for performing an analysis. As noted above,
ADaM datasets should be derived from the data contained in the SDTM datasets. There
are features built into the ADaM standard that promote traceability from analysis results
to ADaM datasets and from ADaM datasets to SDTM datasets. To ensure traceability, all
SDTM variables utilized for variable derivations in ADaM should be included in the
ADaM datasets when practical. Each submitted ADaM dataset should have its contents
described with complete metadata in the define.xml file (See section 4.1.4.5) and within
the ADRG as appropriate (See section 2.3).
Dataset Labels
Each dataset should be described by an internal label that is shown in the define.xml file.
The label names of ADaM datasets should be different from those of the SDTM datasets.
For example, the SDTM adverse event dataset (i.e., AE) and the ADaM adverse event
dataset (i.e., ADAE) should not share the exact same dataset label, such as “Adverse
Events.”
Subject-Level Analysis Data
Subject-Level Analysis Data (ADSL) is the subject-level analysis dataset for ADaM. All
submissions containing standard analysis data should contain an ADSL file for each
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study. In addition to the variables specified for ADSL in the ADaMIG, such as those
listed below in the core variables section (See section 4.1.2.5), the sponsor should include
multiple additional variables representing various important baseline subject
characteristics / covariates presented in the study protocol. Some examples of baseline
characteristics / covariates for drug studies include, but are not limited to, disease severity
scores such as Acute Physiology and Chronic Health Evaluation (APACHE) scores, 31
baseline organ function measurements such as calculated creatinine clearance or Forced
Expiratory Volume in 1 second (FEV1), range categories for continuous variables, and
numeric date variables in non-International Standards Organization (ISO) formats. Some
examples of baseline characteristics for vaccine studies include, but are not limited to,
past medical history (e.g., prior infection history), immunosuppressive conditions, prior
vaccination history and concomitant medications/vaccines.
Core Variables
Core variables, which include covariates presented in the study protocol that are
necessary to analyze data, should be included in each ADaM dataset, and are typically
already included in the ADSL dataset (See section 4.1.2.4). The core variables included
in an ADaM dataset should be necessary for the analysis need in that dataset. Examples
of core variables include study/protocol number, center/site number, geographic region,
country, treatment assignment information, sex, age, race, analysis population flags (e.g.,
Intent-to-Treat (ITTFL), Full Analysis Set (FASFL), Safety (SAFFL), and Per-Protocol
(PPROTFL)), and other important baseline demographic variables. Note that all variables
that contain coded data should be accompanied by a variable that provides the decoded
information.

In addition, it is important to note that SDTM datasets do not have core variables (such as
demographic and population variables) repeated across the different domains. The
duplication of core variables across various domains can be fulfilled through their
inclusion in the corresponding analysis datasets. For example, the SDTM AE dataset does
not allow for the inclusion of variables such as treatment arm, sex, age, or race. These
and other variables should be included in the adverse event ADaM dataset (i.e., ADAE).
Key Efficacy and Safety Data
Sponsors should submit ADaM datasets to support efficacy and safety analyses
(including analysis of immunogenicity). At least one dataset should be referenced in the
data definition file as containing the primary efficacy variables. Further, variables and
parameters pertaining to the primary and secondary endpoints of a study, along with their
derivations (as applicable), should be provided as well as documented appropriately (i.e.,
variable-level metadata or parameter value-level metadata) in the data definition file.
Timing Variables
A variable for relative day of measurement or event, along with timing variables for visit,
should be included when an ADaM dataset contains multiple records per subject (i.e.,
repeated measures data).

31
Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985). “APACHE II: a severity of disease
classification system.” Critical Care Medicine, 13 (10): 818–829.29.
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Numeric Date Variables

Numeric date variables are needed for analysis and review purposes. Apply formats to all
numeric date variables using a format that is understandable by SAS XPORT Version 5
files as per section 3.3.1 above. The software specific (as opposed to study specific) date
of reference used to calculate numeric dates should be specified within the ADRG. In the
event of partial dates, imputation should be performed only for dates required for analysis
according to the SAP, and appropriate corresponding ADaM imputation flags should be
utilized. When numeric time or date time variables are needed, all considerations apply as
previously discussed for numeric dates.

For traceability purposes, SDTM character dates formatted as ISO 8601 should also be
included in the ADaM datasets.
Imputed Data
When data imputation is utilized in ADaM, sponsors should submit the relevant
supporting documentation (i.e., define.xml and ADRG) explaining the imputation
methods.
Software Programs
Sponsors should provide the source code used to create all ADaM datasets, tables, and
figures associated with primary and secondary efficacy analyses. Sponsors should submit
source code in single byte ASCII text format. Files with MS Windows executable
extensions (.cmd, .com, and .exe) should NOT be submitted. For a list of acceptable file
extensions, refer to the document entitled Specifications for File Format Types Using
eCTD Specifications. 32

Furthermore, sponsors should submit the source code used to generate additional
information included in Section 14 CLINICAL STUDIES of the Prescribing
Information, 33 if applicable. The specific software utilized (version and operating system)
should be specified in the ADRG.

ADLB and ADLC

For clinical studies, submit two separate ADaM datasets for lab results. The ADLB
domain should contain results in SI units. An additional domain called ADLC structured
identically to ADLB should contain conventional units. It is ideal if both conventional
and SI units come directly from the lab vendor. Submit the results of all tests obtained on
subjects, including the results from unscheduled tests or visits, and results obtained from
local laboratories. Identify all reference ranges used for specific populations in the
ADRG.

32
Available at https://www.fda.gov/media/85816/download.
33
Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/labeling-
human-prescription-drug-and-biological-products-implementing-plr-content-and-format.
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4.1.3 Standard for Exchange of Nonclinical Data

Definition
The Standard for Exchange of Nonclinical Data (SEND) provides the organization,
structure, and format of standard nonclinical tabulation datasets for regulatory
submission.
General Considerations
The SENDIG provides specific domain models, assumptions, and examples for preparing
standard tabulation datasets that are based on the SDTM model. If there is uncertainty
regarding SEND implementation, the sponsor should discuss the issue with the review
division.

The ideal time to implement SEND is prior to the conduct of the study as it is very
important that the results presented in the accompanying study report be traceable back to
the original data collected. Each submitted SEND dataset should have its contents
described with complete metadata in the define.xml file (See section 4.1.4.5) and within
the nSDRG as appropriate (See section 2.2).

For nonclinical studies, the define.xml StudyName element value should contain the
sponsor’s study identifier, consistent with:

• the study identifier [study-id] used in the eCTD study tagging file (STF)
referenced under the appropriate subsection of Module 4 when submitting in
eCTD v3.2.2; refer to Section 7.1.1 for additional information.
• the study identifier [Study Id] used in the eCTD Study Id Study Title keyword
referenced under the appropriate subsection of Module 4 when submitting in
eCTD v4.0; refer to Section 7.1.2 for additional information.

For studies outsourced to a contract test facility, the alternate study identifier assigned to
the study by the testing facility, which is typically included in the STUDYID field of the
SEND datasets, should be included in the ProtocolName element value in define.xml.

For submissions to CBER and CDER, SEND datasets are required when submitting a
draft study report as these data form the basis of regulatory decisions regarding
nonclinical support for clinical development in accordance with the dates specified in the
Catalog. 34 If there are changes to the SEND datasets requiring resubmission with the final
study report, submit the new datasets replacing the previous datasets. Information about
replacing datasets can be found in Section 7.1. SEND datasets would not need to be
resubmitted with the final report if there were no changes to the dataset from the draft
report. Even when SEND datasets do not need to be resubmitted, it is recommended that
an updated nSDRG is submitted with the final study report. This updated nSDRG should
include the current study report version (Section 1.1), any date (or administrative)
changes, and a notation that no changes to SEND datasets were made or needed other

34
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/data-standards-catalog.
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than the notation of the version change (e.g., STRPSTAT change) after the draft report
was submitted.

Sponsor should use the VISITDY or --NOMDY variable appropriate to the selected
SENDIG version to group observations for summary analysis. This includes grouping
animal data collected over multiple days for a single planned event.

For animals necropsied over multiple grace days for a single scheduled interim, terminal
or recovery termination event, the DS dataset VISITDY or DSNOMDY variables should
contain a single scheduled day for the event. Postmortem findings in DD, MA, MI, OM,
and TF for each planned termination event can then be analyzed together based on the DS
dataset VISITDY or DSNOMDY. When in-life observations such as terminal body
weight or clinical pathology sample collection are scheduled at the time of necropsy, the
VISITDY or --NOMDY associated with those observations should also contain the single
planned day for the termination event.

For other in-life observations, when the defined schedule for an observation covers
multiple days or the schedule is for a specific day but grace days allowed, and animals
are observed/tested over multiple days, VISITY or --NOMDY should contain a single
day under which the data should be grouped for analysis. Some examples:

• ECGs are scheduled for week 1, and some animals are tested on day 1, some
animals are tested on day 2, and some animals are tested on day 3, all animal ECG
results for week 1 should have a common VISITDY or EGNOMDY.
• Urinalysis is scheduled for day 15, but no urine was collected from one animal on
that day so the collection attempted again on day 16 and was successful. In the
Study Report, the data collected for the day 16 urine sample would be analyzed
with the day 15 sample results, so VISITDY or LBNOMDY for day 15 and 16
should be 15.
• Due to the number of animals on study, the protocol allows 1 grace day for
physical exams with vital signs scheduled for day 1. Some animals are examined
on day 1 and some on day 2. All physical exam and vital sign data should be
reported under VISTIDY or --NOMDY day 1.
For tests or observations scheduled relative to dose and having --TPTREF and --
RFTDTC should be filled to describe the dosing event, and --TPT, --TPTNUM and --
ELTM filled to describe the time relative to dose. VISITDY or --NOMDY should always
contain the dose day, not the day of the test or observation. VISITDY should be empty
for records with unscheduled tests or observations. In SENDIGv3.0, an empty VISITDY
identifies data collected for an unplanned event.

Whenever used, FOCID should be consistently represented across domains for the same
focus within a study.

Population of ELTM is preferred for pre-dose collections for our nonclinical visualization
tools. If there is only one pre-dose collection period, ELTM is PT0H to indicate that the

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end of the period is immediately prior to dose. If there is more than one period prior to
dose, then two different ELTM values would be used to identify each of them separately.

DOSDUR should be used to indicate the longest planned duration of time between the
first day of dosing and the terminal sacrifice, regardless of the number of doses
administered subsequent to the first dose. For example, DOSDUR would be P28D
whether dosing occurred daily beginning on Day 1, only on Day 1, or biweekly on Days
1 and 15 when the terminal sacrifice is Day 29 (see the latter example in Fig. 1 below).
DOSDUR should not include the recovery phase, defined as the non-dosing period that
follows the main dosing phase of a study. For safety pharmacology studies, DOSDUR
would include the time after the dose was administered to the end of the planned
observation period if the animals are not sacrificed.

Figure 1: Example of DOSDUR Population

SEND Domain Specification

SUPPQUAL (Supplemental Qualifier)
A SUPPQUAL dataset is a special SEND dataset that contains non-standard variables
which cannot be represented in the existing SEND domains. Discussion with the review
division should occur if the sponsor intends to include important variables (i.e., that
support key analyses) in SUPPQUAL datasets and this should be reflected in the nSDRG.

Currently, SUPPMA, SUPPMI, and SUPPTF should be used to capture some collected
information (e.g., pathology modifiers) as detailed in the SENDIG.

MI Domain (Microscopic Findings)

Sponsors should ensure that the transformation of findings from MIORRES to
MISTRESC closely adheres to the instructions in the SENDIG. When controlled
terminology is not required for MISTRESC, non-neoplastic findings should be
standardized and limited to only the base pathological process to ensure that data can be
tabulated. For suggestions as to what constitutes a base pathological process, refer to the
CDISC NONNEO Controlled Terminology list. Result qualifiers for which there are
variables available (e.g. MISEV, MIDTHREL, MICHRON) should be placed
appropriately and not duplicated in MISTRESC or SUPPMI.

When using a CDISC CT version dated before 2018 and histopathology severity data are
collected on a severity scale that cannot be represented using the CDISC MISEV codelist

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without a loss of scientific accuracy (e.g. data were collected on 3 levels or 4 levels but
MISEV specifies 5 levels), severity scores may be represented in MISEV as ‘1 OF 4’ ‘2
OF 4’ or ‘1 OF 3’as appropriate, where the first number is the score and the second is the
number of available severities in the scale. A score of 1 should be the least severe
finding. Extend the non-extensible MISEV codelist with the necessary terms to describe
the alternative severity scores, include these extended values in the define.xml and
nSDRG, and explain any resulting validation error(s) in the nSDRG.

CL Domain (Clinical Observations)

Only Findings should be provided in CL; ensure that Events and Interventions are not
included. Sponsors should ensure that the standardization of findings in CLSTRESC
closely adheres to the SENDIG. The information in CLTEST and CLSTRESC, along
with CLLOC and CLSEV when appropriate, should be structured to permit grouping of
similar findings and thus support the creation of scientifically interpretable incidence
tables. Differences between the representation in CL and the presentation of Clinical
Observations in the Study Report which impact traceability to the extent that terms or
counts in incidence tables created from CL cannot be easily reconciled to those in the
Study Report should be mentioned in the nSDRG.

LB Domain (Laboratory Test Results)

Categorical, noncontinuous results reported as incidence counts rather than summary
statistics (i.e. mean and standard deviation) should be placed in LBSTRESC, and even if
the categories are numbers, LBSTRESN should be null. Specifically, this includes
urinalysis tests where the results are values on a scale. For example, if the allowable
values for a urine glucose dipstick test are: ‘NEGATIVE’, ‘100’, ‘250’, ‘500’, ‘1000’,
‘>2000’, results should only be placed in LBSTRESC. Placing categorical results in
LBSTRESC allows straightforward creation of incidence tables on LBSTRESC. The full
scale used for laboratory tests with categorical results should be included in the nSDRG.

When a laboratory test result is either above or below the limit of quantification (LOQ)
for the measurement method and this result was used in calculation of group means in the
study report, the value used for calculation should be submitted using the supplemental
qualifier variable LBCALCN.

If an animal is fasted prior to collection of a sample for laboratory testing, all results from
testing of the collected sample should have LBFAST = ‘Y’.

When reporting results for tests that do not have published controlled terminology, it is
important that the test code values defined for LBTESTCD strictly adhere to the
specifications in the SENDIG: It cannot be longer than eight characters, it cannot start
with a number and it cannot contain characters other than letters, numbers and
underscores.

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PC Domain (Pharmacokinetics Concentrations)

The PC domain should support creation of time series graphs and automatic calculation
of pharmacokinetic parameters from sets of related plasma concentrations. Three
elements are necessary:

• Nominal timings relative to the dose in ISO 8601 duration format

• Grouping of each different set of time series measurements used to calculate a
related pharmacokinetic parameter
• Identification of the start of each time series relative to the start of exposure
If the nominal times are provided in PCELTM, nulls should be avoided for plasma
concentrations used to calculate a profile. PCDTC and PCDY variables should be
populated with actual/collected information when it available; however, for single dose,
repeat dose, or carcinogenicity studies where actual/collected information are not readily
available to be incorporated into the dataset, these variables may be left null or populated
with calculated or nominal dates/times. The use of calculated or nominal dates and times
should be mentioned in the nSDRG.

When actual dose dates or date/time values are available for PCRFTDTC/PPRFTDTC,
they can be included.

When a test result is below a lower limit of quantitation (LLOQ), it should be submitted
using the following instructions:

• PCORRES should not contain a specific value. For example, the value in
PCORRES may be ‘<LLOQ’, where LLOQ is the numerical value.
• ‘BLQ’ 35 should be in PCSTRESC to signify that the result is below the LLOQ.
• PCSTRESN should be blank.
• Standardized units for LOQ should be in PCSTRESU.
• PCLLOQ should be populated with the lower limit of quantitation for the analyte.
• When a numeric value has been assigned to a result that is below the LLOQ for
the purpose of group summary statistics, that value should be submitted in
SUPPPC as QNAM = ‘PCCALCN’ to allow the group statistics presented in the
study report to be reproduced. When a value that is below the LLOQ is excluded
from group statistics, no PCCALCN entry is needed.

Custom Domains
To provide study data that does not fit into an existing SENDIG domain, draft SENDIG
domain, or published SDTMIG domain, consider creating a custom dataset aligned with
the SDTM model version associated with the SENDIG version used for submission.
Questions about custom domains should be addressed in pre-submission meetings and
documented in the SDSP.

35
According to the FDA’s Bioanalytical Method Validation Guidance for Industry (May 2018), study
samples with concentrations listed below the LLOQ should be reported as ‘BQL’; however, ‘BLQ’, as
specified in FDA-supported SENDIG versions, is appropriate to use in SEND datasets to report this data.
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When immune response data are collected in toxicology studies intended for submission
to CBER, these data ideally should be submitted in a dataset(s); however, these data
currently may be submitted as part of the study report. For data submitted using
SENDIGv3.1 or 3.1.1, use of LB domain or a custom IS domain is acceptable. In these
cases, when a numeric value has been assigned for calculation purpose to a result of
below limit of quantification, the value should be provided in SUPPLB, as QNAM =
‘LBCALCN’; or in SUPPIS, as QNAM = ‘ISCALCN’.

Trial Design Model (TDM)

All TDM datasets should be included in SEND submissions as a way to describe the
planned conduct of a nonclinical study.

Ensure that Trial Arms and Trial Sets represented in TA and TX closely follow the
SENDIG examples of study designs with recovery and/or toxicokinetic animals.
Recovery and/or toxicokinetic animals should be presented in separate Trial Sets from the
main animals. Trial Sets should be defined to contain animals of both sexes if all other
experimental parameters are the same.

The Trial Sets domain (TX) should be submitted for each study. Every set in the TX
domain should have only one record with each of the following TXPARMCD values:
SPGRPCD (sponsor group code associated with the set), GRPLBL (sponsor group label
associated with the set), PLANMSUB (planned number of males in set), and PLANFSUB
(planned number of females in set). There should be a one-to-one correspondence
between GRPLBL and SPGRPCD entries in the TX domain.

See the appendix section for a list of parameters that should be included in the full Trial
Summary (TS) dataset where relevant for nonclinical studies. Additional parameters can
be included beyond those listed in the appendix. If information for a parameter listed in
the appendix of a full TS.xpt file is not available, the parameter should not be included
for datasets modeled in SENDIGv3.0. If information for a parameter listed in the
appendix of a full TS.xpt file is not available, it can be included with TSVAL blank and
TSVALNF filled for datasets modeled in SENDIGv3.1. For nonclinical studies, study
start date (TSPARMCD= STSTDTC) is the date on which the study protocol or plan is
approved (signed) by the Study Director, also known as the study initiation date. 36

Tumor Dataset
Carcinogenicity studies should include an electronic dataset of tumor findings to allow
for a complete review. At this time, sponsors should continue to include the tumor.xpt
and associated define.pdf files regardless of whether the study is in SEND format. When
both tumor.xpt and SEND are submitted, the sponsor should ensure that data are
consistent and traceable between tumor.xpt and the SEND datasets, with the information
specified in the FDA Business Rules. Any information needed to establish traceability
should be presented in the nSDRG. The Tumor Findings dataset (tf.xpt) is necessary if

36
Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/providing-
regulatory-submissions-electronic-format-standardized-study-data.
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the SEND datasets are the basis for creation of the tumor.xpt dataset. If sponsors choose
to not submit Tumor Finding dataset (tf.xpt) with the SEND submission, the algorithm
used to calculate 'Time in days to detection of tumor' should be included in the nSDRG.

BG Domain (Body Weight Gain)

It is not necessary to include a BG domain in submissions.

CO Domain (Comments)
Comments submitted in the CO domain should be relevant to study interpretation. To
reduce ambiguity, abbreviations in any free text field should be avoided or outlined in the
nSDRG.

Scope of SEND

4.1.3.4.1 Scope of SEND for SENDIGs v3.0, v3.1 and v3.1.1

The following is the Agency’s current thinking of the scope of SEND for studies listed in
the SENDIGv3.0, SENDIGv3.1 and SENDIGv3.1.1, as supported in the FDA Data
Standards Catalog. The intent is to provide clarification on the expectation of SEND for
studies listed in these SENDIGs, specifically addressing the following language:

“SENDIG is designed to support data typically found in single-dose

general toxicology, repeat-dose general toxicology, and carcinogenicity
studies, as well as respiratory and cardiovascular testing done during
safety pharmacology studies.” 37

It is acknowledged that some of these study types can encompass a broad range of study
designs (e.g., number of animals per group, number of endpoints tested) and have
different drug development purposes (e.g., exploratory or tolerability studies versus
standard toxicity studies designed to assess clinical safety). Given the variability of study
design and intent of a nonclinical study, the Agency is providing clarification on what
studies are subject to the SEND requirement. Study types outlined in the FDA-supported
SENDIGs that are out of scope for this discussion include those described in the
SENDIG-ARv1.0 (the scope of SEND for nonclinical natural history and efficacy studies
in Animal Rule submissions are discussed in 4.1.3.4.2). The Agency’s current
interpretation of the scope of SEND is subject to change based on the availability of new
information. This document will be updated to reflect any needed change.

Overall, the expectation of SEND datasets for nonclinical studies is linked to the
pharmacological and toxicological information required to provide FDA with the data
needed to assess and support the safety of the proposed clinical investigations. 38 These
data form the basis of the rationale on how the sponsor concluded that it is reasonably

37
See CDISC SENDIGv3.1 (Section 1.1) available at www.cdisc.org.
38
21 CFR 312.23(a)(8).
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safe to conduct the proposed clinical trial. If the nonclinical pharmacology or toxicology
study is required to support a regulatory decision by the Agency, such that the absence of
this study would result in a determination that there is insufficient information to assess
the risks to human subjects, then the nonclinical study would require SEND.
Additionally, SEND datasets are required to be submitted at the same time as the
nonclinical PDF study report for a commercial IND or NDA/BLA. Further clarification
on specific topics is outlined below.

A. SEND is required 39 for single-dose and repeat-dose general toxicology studies

that are submitted by the sponsor to support the safety of a proposed clinical
trial under commercial IND development or for the support of marketing
authorization and/or labeling. These nonclinical studies generally identify
potential safety concerns, support the dose and duration of human clinical
trials, and characterize the toxicologic profile of the test article and proposed
clinical product. Study design incorporates endpoints that can sufficiently
inform the potential for clinical adverse events by identifying any nonclinical
target organ toxicity and dose or exposure dependency. These studies may be
conducted at any point in development ranging from support of an initial safe
starting dose for a first-in-human trial to those that support longer duration
clinical trials. Submission of these studies may occur at any time during
development even if the proposed clinical investigation protocol, that the
study supports, has not yet been submitted.
B. When general toxicity studies incorporate other study types (e.g.,
cardiovascular safety pharmacology, genetic toxicity), SEND datasets for
these additional study types would also be expected only when they can be
modeled in an FDA-supported SENDIG. For example, if a cardiovascular
safety pharmacology study was incorporated into a repeat-dose toxicity study,
then SEND would be required for both study types.
C. The age of the animal at study start does not impact whether the SEND
requirement applies. Dedicated juvenile animal studies that typically include
multiple phases and are multi-generational cannot currently be modelled in
FDA-supported SENDIGs and therefore would not require SEND. However,
when general toxicology studies (single- or repeat-dose) are conducted with
juvenile animals (e.g., young, post-weaning animals), SEND is required as
outlined above.
D. Carcinogenicity studies and repeat-dose toxicity studies that support a
carcinogenicity Special Protocol Assessment (SPA) require SEND when they
are initiated after an FDA-supported SENDIG requirement date as described
in the Data Standards Catalog. These studies are used to inform regulatory
decisions related to the risk to human subjects and ultimately impact labeling.
E. The requirement for SEND is not limited to the drug substance. Nonclinical
studies that are modeled in an FDA-supported SENDIG version (e.g., repeat-

39
See the Data Standards Catalog for the latest version of SEND required and the relevant requirement
dates for specific submission types. Please note all references to SEND being required in this Guide refer to
this standardized format being required for an electronic submission of clinical or nonclinical study data
under section 745A(a) of the FD&C Act.
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dose toxicology) and are conducted to assess the safety of any component or
metabolite of the proposed clinical therapeutic product, require SEND.
Examples of such components include but are not limited to the active moiety
(API), impurities, excipients, leachables, extractables, pro-drugs, combination
products, vaccine adjuvants, and drug/device combinations.
F. The study report status or the finalization of the study report (i.e., draft,
interim or final) does not impact whether the SEND requirement applies.
G. The requirement for SEND is not limited to GLP studies. As both GLP and
non-GLP toxicity studies may be submitted to the FDA to support clinical
safety, the decision for inclusion of SEND is independent of GLP status. In
cases where non-GLP toxicity studies are submitted to support a
determination of safety, as outlined above, such studies must include SEND.
H. SEND is not required for study types that are not listed in an FDA-supported
SENDIG (e.g., primary pharmacology) even if one or more endpoints are able
to be modeled in SEND.
I. If SEND datasets are generated by the sponsor for nonclinical studies that are
not intended to support clinical safety, the Agency would accept these;
however, submission of these datasets would not be required.

Technical Specifications
A. Sponsors are encouraged to use the Study Data Standardization Plan (SDSP)
to communicate the intent to submit SEND datasets during product
development, and to allow for discussion with the review division when there
is any ambiguity on the SEND requirement for a study (See sections 8.2.2 and
2.1 of the Guide).
B. When SEND is not submitted for reasons outlined under Section 4.1.3.4.1
(Scope of SEND for SENDIGv3.0, SENDIGv3.1 and SENDIGv3.1.1), use of
a simplified ts.xpt file may be needed where the value “NA” (Not Applicable)
should be populated in the TSVALNF field (See section 8.2.2 of the Guide).
C. For further information on nonclinical Weight of Evidence documents, refer
to Section 7.1 of the Guide.

4.1.3.4.2 Scope of SEND for SENDIG-Animal Rule v1.0

SEND datasets will be required for any nonclinical natural history or efficacy study
initiated after March 15, 2022, for NDAs, ANDAs, and BLAs and any nonclinical natural
history or efficacy study initiated after March 15, 2023, for certain INDs 40 that are
submitted to CDER and for which the CDER review division expects a full tabulation of
data (i.e., line listings of the results for each individual animal) to support detailed

40
On March 11, 2020, FDA published a Federal Register notice (85 FR 14205) announcing the dates that
FDA’s support began and requirements become effective for specific Animal Rule data standards. That
document omitted the 36-month implementation period for certain INDs as required by FDA’s guidance for
industry Providing Regulatory Submissions in Electronic Format--Standardized Study Data. On June 10,
2021, FDA published a Federal Register notice (86 FR 30960) that corrected that error.
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review. Although not required, FDA also recommends that sponsors submit SEND
datasets for such studies that are initiated before March 15, 2022, and March 15, 2023, as
applicable. In addition, SEND datasets are recommended for such studies that are
submitted to pre-INDs and FDA’s Animal Model Qualification Program.

Application-specific questions about which natural history and efficacy studies should
include full tabulations of data and datasets should be discussed with the CDER review
division as early as possible during product development. Similarly, questions about
natural history studies that will be submitted to an animal model qualification package
should be discussed with the Animal Model Qualification Program
([email protected]).

Although not currently required by CBER, CBER recommends sponsors submit datasets
modeled with SDTMv1.8 and SENDIG-ARv1.0 for nonclinical natural history or
efficacy studies. CBER also recommends including the immunogenicity (IS) domain
(described in SDTMv1.4 and SDTMIGv3.2 and later versions) to represent
immunogenicity data obtained in animal studies.

4.1.3.4.3 Scope of SEND for SENDIG-DARTv1.1 for CDER

The following is CDER’s current thinking of the scope of SEND for studies listed in the
SENDIG-DARTv1.1 (Developmental and Reproductive Toxicology), as supported in the
FDA Data Standards Catalog. The intent is to provide clarification on the expectation of
SEND for the Embryo-Fetal Development (EFD) studies as modeled in SENDIG-
DARTv1.1:

“Version 1.1 of this document is intended to support the creation of

domain datasets for Embryo-Fetal Development (EFD) study data.
Subsequent versions of the SENDIG-DART will introduce additional
DART concepts and study types (e.g., Fertility, Postnatal Development
and Multi-generational).”

Per the ICH S5(R3) guidance for industry, Detection of Reproductive and Developmental
Toxicity for Human Pharmaceuticals, “The EFD toxicity study is designed to assess
maternal toxicity relative to that in nonpregnant females, and to evaluate potential effects
on embryo-fetal survival, intrauterine growth, and morphological development.” For
further information on EFD study design and regulatory context, refer to ICH S5(R3).

EFD studies can vary by study design (e.g., combination study) or have different drug
development purposes (e.g., dose range, definitive). Given this variability, the Agency is
providing clarification on what EFD studies are subject to the SEND requirement under
SENDIG-DARTv1.1. The Agency’s current interpretation of the scope of SEND is
subject to change based on the availability of new information. This document will be
updated to reflect any needed change.

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Similar to the Scope of SEND for SENDIGv3.0, SENDIGv3.1 and SENDIGv3.1.1, the
expectation of SEND datasets for nonclinical EFD studies is linked to the toxicological
information required to provide FDA with the data needed to assess and support the
safety of the proposed clinical investigations. 41 These data form the basis of the rationale
on how the sponsor concluded that it is reasonably safe to conduct the proposed clinical
trial.

A. SEND is required 42 for EFD studies that are submitted by the sponsor to support
the safety of a proposed clinical trial under commercial IND development or for
the support of marketing authorization and/or labeling. SEND datasets are
required to be submitted at the same time as the nonclinical PDF study report for
a commercial IND or NDA/BLA. These nonclinical studies generally identify
potential safety concerns, support the dose and population in human clinical trials,
and characterize the toxicologic profile of the test article and proposed clinical
product.
B. The requirement for SEND is not limited to the drug substance. Reproductive and
developmental studies may be conducted for the API and its metabolites when
appropriate, as well as for novel excipients. Nonclinical EFD studies conducted to
address any of these would require SEND if the purpose of that study was to
assess and inform clinical safety.
C. The study report status or the finalization of the study report (i.e., draft or final)
does not impact whether the SEND requirement applies.
D. The requirement for SEND is not limited to GLP studies. As both GLP and non-
GLP toxicity studies may be submitted to the FDA to support clinical safety, the
decision for inclusion of SEND is independent of GLP status. In cases where non-
GLP toxicity studies are submitted to support a determination of safety, as
outlined above, such studies must include SEND. Refer to ICH S5(R3) about the
appropriateness of GLP status for EFD study design.
E. As stated in ICH S5(R3), preliminary EFD toxicity studies have a similar design
to the definitive EFD toxicity study with evaluation of at least six pregnant
females per group (versus 16 per group for a definitive study). In cases where a
preliminary EFD study is being used to assess clinical safety, in lieu of a
definitive EFD study, then SEND is required.
F. Studies that are conducted in pregnant or non-pregnant animals only to establish
doses or dose schedules for an EFD study (e.g., dose range finding, tolerability,
pilot study) are not designed to inform clinical safety and therefore, do not require
SEND.
G. Fertility and Early Embryonic Development (FEED) studies and studies
conducted specifically to support dose selection for a fertility study are presently
not modeled in an FDA supported SENDIG, including SENDIG-DARTv1.1, and
therefore do not require SEND at this time. FEED studies are different from the

41
21 CFR 312.23(a)(8).
42
See the Data Standards Catalog for the latest version of SEND required and the relevant requirement
dates for specific submission types. Please note all references to SEND being required in this Guide refer to
this standardized format being required for an electronic submission of clinical or nonclinical study data
under section 745A(a) of the FD&C Act.
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assessment of certain endpoints of fertility (e.g., histopathology of the

reproductive tract) as assessed in a repeat-dose toxicology study. Such endpoints
of fertility in the repeat-dose toxicity studies are modeled in a supported
SENDIG, and therefore require SEND when assessed in those studies.
H. For combination FEED/EFD studies, only EFD study-related endpoints collected
from animals assigned to the EFD portion of the combination study, and modeled
in SENDIG-DARTv1.1 would require SEND. Fertility related endpoints assessed
in a FEED/EFD combination study would not require SEND.
I. For combination EFD and pre- and postnatal development studies (EFD/PPND),
only EFD study-related endpoints collected from animals assigned to the EFD
portion of the combination study, and modeled in SENDIG-DARTv1.1 would
require SEND. These combination studies, which differ from enhanced pre- and
postnatal developmental (ePPND) toxicity studies, are designed with specific
groups that would be assigned for cesarean section to assess EFD related
endpoints, with other groups allowed to continue to the postnatal phase. PPND
related endpoints assessed in an EFD/PPND combination study would not require
SEND.
J. Although enhanced pre- and postnatal developmental (ePPND) toxicity studies
combine the endpoints from both EFD and PPND studies, SEND is not required
for ePPND studies under SENDIG-DARTv1.1; however, many maternal and fetal
EFD endpoints measured during the gestation phase of an ePPND study can be
modeled under SENDIG-DARTv1.1. If any SEND datasets are created for EFD
study endpoints (as modeled in SENDIG-DARTv1.1) when assessed in an
ePPND study, voluntary submission of these datasets is encouraged.
K. Dedicated juvenile animal studies that typically include multiple phases and are
multi-generational are not currently modeled in FDA-supported SENDIGs
(including the SENDIG-DARTv1.1) and therefore would not require SEND.
However, when general toxicology studies (single- or repeat-dose) are conducted
with juvenile animals (e.g., young, post-weaning animals), SEND is required as
outlined under the Scope of SEND for SENDIGv3.0 and v3.1 (Section 4.1.3.4.1).

Technical Specifications

A. Sponsors are encouraged to use the Study Data Standardization Plan (SDSP) to
communicate the intent to submit SEND datasets during product development,
and to allow for discussion with the review division when there is any ambiguity
on the SEND requirement for a study (See sections 8.2.2 and 2.1 of the Guide).
B. If the Technical Rejection Criteria (TRC) is not implemented for an eCTD
Module, use of a simplified ts.xpt file is not needed when SEND is not required
for a study; however, submission of a simplified ts.xpt file to an eCTD Module
without TRC implementation will not interfere with electronic validations.
C. For preparation of complete SEND datasets for EFD studies, CDER’s preference
is that SENDIG-DARTv1.1 should be used in conjunction with the most recently
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updated and required SENDIG for nonclinical studies, as listed in the FDA Data
Standards Catalog.

4.1.3.4.4 Scope of SEND for SENDIG-Genetox-v1.0

The following is CDER and CBER’s current thinking of the scope of SEND for studies
listed in the SENDIG-Genetox-v1.0 (Genetic Toxicology), as supported in the FDA Data
Standards Catalog. The intent is to provide clarification on the expectation of SEND for
nonclinical in vivo comet and micronucleus tests, as modeled in SENDIG-Genetox-v1.0:

“SENDIG-Genetox describes the domain models, assumptions, business rules,

and examples for preparing standard nonclinical tabulation datasets based on the
SDTM. It is designed to support data typically found in comet and micronucleus
in vivo tests.” 43

The ICH S2(R1) guidance for industry, Genotoxicity Testing and Data Interpretation for
Pharmaceuticals Intended for Human Use 44, provides further information on the
recommendations for the use and design of in vivo genetic toxicity tests.

In vivo micronucleus and comet tests can vary by study design (e.g., integrated study
design versus stand-alone study) or have different drug development purposes (e.g., dose
range, definitive). Given this variability, the Agency is providing clarification on what
genetic toxicology studies are subject to the SEND requirement under SENDIG-Genetox-
v1.0. The Agency’s current interpretation of the scope of SEND is subject to change
based on the availability of new information.

Similar to the scope of SEND for SENDIGv3.0, SENDIGv3.1 and SENDIGv3.1.1, the
requirement for SEND datasets for nonclinical in vivo comet and micronucleus tests is
linked to the toxicological information required to provide FDA with the data needed to
assess and support the safety of the proposed clinical investigations. 45 These data form
the basis of the rationale on how the sponsor concluded that it is reasonably safe to
conduct the proposed clinical trial.

A. SEND is required 46 for in vivo comet and micronucleus genotoxicity studies that
are submitted by the sponsor to support the safety of a proposed clinical trial
under commercial IND development or for the support of marketing authorization
and/or labeling. SEND datasets are required to be submitted at the same time as
the nonclinical PDF study report for a commercial IND or NDA/BLA.

43
See http://www.cdisc.org.
44
See https://www.fda.gov/regulatory-information/search-fda-guidance-documents/s2r1-genotoxicity-
testing-and-data-interpretation-pharmaceuticals-intended-human-use.
45
See 21 CFR 312.23(a)(8).
46
See the Data Standards Catalog for the latest version of SEND required and the relevant requirement
dates for specific submission types. Please note all references to SEND being required in this Guide refer to
this standardized format being required for an electronic submission of clinical or nonclinical study data
under section 745A(a) of the FD&C Act.
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B. The SEND requirement is not limited to the drug substance. In vivo comet and
micronucleus tests may be conducted for the API, impurities, metabolites, and for
novel excipients. Nonclinical in vivo comet and micronucleus tests conducted to
assess the potential of any of these substances to cause genetic damage, would
require SEND if the purpose of that study was to assess and inform clinical safety.
C. The study report status or the finalization of the study report (i.e., draft or final)
does not impact whether the SEND requirement applies.
D. The SEND requirement is not limited to GLP studies. As both GLP and non-GLP
toxicity studies may be submitted to the FDA to support clinical safety, the
decision for inclusion of SEND is independent of GLP status. In cases where non-
GLP toxicity studies are submitted to support a determination of safety, as
outlined above, such studies must include SEND.
E. In vivo comet and micronucleus tests that are conducted only to establish doses or
dose schedules (e.g., exploratory, dose range finding, tolerability, pilot study) for
a follow-up study are not designed to inform clinical safety and therefore, do not
require SEND.
F. SEND is required for in vivo comet and micronucleus tests, whether they are
integrated into a general toxicology study or submitted as stand-alone studies.
G. In vitro assays and in vivo genetic toxicology tests other than in vivo
micronucleus and comet tests, are out of scope for SENDIG-Genetox-v1.0 and do
not have a SEND requirement.

Technical Specifications

A. Sponsors are encouraged to use the Study Data Standardization Plan (SDSP) to
communicate the intent to submit SEND datasets during product development,
and to allow for discussion with the review division when there is any ambiguity
on the SEND requirement for a study (See sections 8.2.2 and 2.1 of the Guide).
B. If the Technical Rejection Criteria (TRC) are not implemented for an eCTD
Module, use of a simplified ts.xpt file is not needed when SEND is not required
for a study; however, submission of a simplified ts.xpt file to an eCTD Module
without TRC implementation will not interfere with electronic validations.
C. SENDIGv3.1.1 should be used in conjunction with SENDIG-Genetox-v1.0 for
complete dataset generation of all domains needed for a genetic toxicity study.

4.1.4 General Considerations: SDTM, SEND, and/or ADaM

Variables in SDTM and SEND: CDISC Required, Expected, and

Permissible
CDISC uses the word “required” to describe variables in their data models (SEND,
SDTM, ADaM). This use does not indicate a requirement by the Agency.

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For the purposes of SDTM and SEND submissions, all CDISC required, expected, and
permissible variables that were collected, plus any variables that are used to compute
derivations, should be submitted. 47

FDA recognizes that SDTM contains certain operationally derived variables that have
standard derivations across all studies (e.g., --STDY, EPOCH). If the data needed to
derive these variables are missing, then these variables cannot be derived and the values
should be null. The following are examples of some of the permissible and expected
variables in SDTM and SEND that should be included, if available:
1. Clinical baseline flags (e.g., last non-missing value prior to first dose) for
laboratory results, vital signs, ECG, pharmacokinetic concentrations, and
microbiology results. Nonclinical baseline flags (e.g., last non-missing value prior
to first dose in parallel design studies) for laboratory results, vital signs, body
weight, cardiovascular test results, respiratory test results, and ECG results.
Currently for SDTM and SEND, baseline flags should be submitted if the data
were collected or can be derived.

2. EPOCH designators in SDTM. Follow CDISC guidance for terminology. 48 The

variable EPOCH should be included for clinical subject-level observation (e.g.,
adverse events, laboratory, concomitant medications, exposure, and vital signs).
This will allow the reviewer to easily determine during which phase of the study
the observation occurred (e.g., screening, on-therapy, follow-up), as well as the
actual intervention the subject experienced during that phase.

3. Whenever --DTC, --STDTC or --ENDTC, which have the role of timing

variables, are included in a general observation class domain, the matching study
day variables (--DY, --STDY, or --ENDY, respectively) should be submitted. For
example, in most findings domains, --DTC is expected, which means that --DY
should also be submitted. In the SDTM subject visits domain, SVSTDTC is
required and SVENDTC is expected; therefore, both SVSTDY and SVENDY
should be submitted.

As mentioned in section 4.1.3.3, in certain GLP nonclinical studies submitted in SEND,

PCDTC and PCDY may be imputed.
Dates in SDTM and SEND
Dates in SDTM and SEND domains should conform to the ISO 8601 format. Examples
of how to implement dates are included in the SDTMIGs and SENDIGs. 49
Naming Conventions in SDTM and SEND
Naming conventions (variable name and label) and variable formats should be followed
as specified in the SDTMIGs and SENDIGs.

47
See CDISC SDTM Implementation Guides and the SEND Implementation Guides at www.cdisc.org for
additional information on variables referenced throughout this Guide.
48
See http://www.cancer.gov/cancertopics/terminologyresources/page6.
49
See http://www.cdisc.org.
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To the extent possible, naming for drugs and metabolites should be consistent across
different clinical and nonclinical studies and across domains within a study. This
includes, but it is not limited to, the TS, EX, PC, and PP domains.
SDTM and SEND Versions
When submitting clinical or nonclinical data, sponsors should not mix versions within a
study. As noted above, the Catalog lists the versions that are supported by FDA.
Data Definition Files for SDTM, SEND, and ADaM
The data definition file describes the metadata of the submitted electronic datasets, and is
considered arguably the most important part of the electronic dataset submission for
regulatory review. This data definition specification for submitted datasets defines the
metadata structures that should be used to describe the datasets, variables, possible values
of variables when appropriate, and controlled terminologies and codes. An insufficiently
documented data definition file is a common deficiency that reviewers have noted.
Consequently, the sponsor needs to provide complete detail in this file, especially for the
specifications pertaining to derived variables. In addition, sponsors should also make
certain that the code list and origin for each variable are clearly and easily accessible
from the data definition file. The version of any external dictionary should be clearly
stated both in the data definition file and in the full TS domain when it is submitted. The
internal dataset label should also clearly describe the contents of the dataset. For
example, the dataset label for an efficacy dataset might be ‘Time to Relapse (Efficacy).’

Separate data definition files should be included for each type of electronic dataset
submission, i.e., a separate data definition file for the SDTM datasets of a given clinical
study, a separate data definition file for the SEND datasets of a given nonclinical study,
and a separate data definition file for the ADaM datasets of a given clinical study. The
data definition file should be submitted in XML format, i.e., a properly functioning
define.xml. 50 In addition to the define.xml, a printable define.pdf should be provided if
the define.xml cannot be printed. 51 To confirm that a define.xml is printable within the
CDER IT environment, it is recommended that the sponsor submit a test version to cder-
[email protected] prior to application submission. The Catalog lists the currently
supported version(s) of Define-XML. It should be noted that Define-XML version 2.0 or
later is strongly preferred. Sponsors should include a reference to the style sheet as
defined in the specification (as listed in the Catalog) and place the corresponding style
sheet in the same submission folder as the define.xml file. Within the eCTD v3.2.2 study
tagging file (STF), valid file-tags for define.xml are ‘data-tabulation-data-definition’ for
SEND or SDTM datasets or ‘analysis-data-definition’ for ADaM datasets. For studies
submitted within eCTD v4.0, valid document type keywords for define.xml are ‘data
tabulation data definition’ for SEND or SDTM datasets or ‘analysis data definition’ for
ADaM datasets.

50
See https://www.cdisc.org/standards/data-exchange/define-xml.
51
Detailed FDA PDF specifications are located on FDA’s Electronic Common Technical Document Web
site, http://www.fda.gov/ectd.
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Annotated Case Report Form (aCRF) for SDTM

An annotated case report form (aCRF) is a PDF document that maps the clinical data
collection fields used to capture subject data (electronic or paper) to the corresponding
variables or discrete variable values contained within the SDTM datasets. Regardless of
whether the clinical database is in a format supported by the Catalog, an aCRF should be
submitted preferably at the time a protocol is submitted. The aCRF should be provided as
a PDF with the file name ‘acrf.pdf.’ 52

The aCRF should include treatment assignment forms, when applicable, and should map
each variable on the CRF to the corresponding variables in the datasets (or database). The
aCRF should include the variable names and coding for each CRF item.

When data are recorded on the CRF but are not submitted, the CRF should be annotated
with the text ‘NOT SUBMITTED.’ There should be an explanation in the relevant RG
stating why these data have not been submitted.

Modification of Requirements During Specific Public Health

Emergencies Declared by the Secretary of HHS
4.1.4.7.1 SEND Requirements During the COVID-19 Public Health Emergency

As of November 8, 2023, SEND is required for commercial IND applications with a

proposed indication to diagnose, cure, mitigate, treat, or prevent COVID-19 (COVID-19
specific indications). 53 Information about the specific modifications to the SEND
requirement for COVID-19 related commercial IND applications that were permitted by
CDER during the COVID-19 PHE and the 180-day wind-down period can be found in
Appendix H.

5. Therapeutic Area Topics

General
Generally, when a data standard is released by a Standards Development Organization for
public use, it is not supported by FDA until it completes a testing and acceptance process
and is announced in the Federal Register. Testing and acceptance is conducted to assess
the impact of the new standard on FDA medical science review and the consistency and
usability of the standard with FDA review tools.

Therapeutic area (TA) standards are not data standards, but rather extend the CDISC
foundational standards (e.g., SDTM and ADaM) to represent data that pertain to specific

52
Previously acrf.pdf was called blankcrf.pdf.
53 As was the case during the COVID-19 PHE, SEND is required at the time of submission of a marketing
application for products with COVID-19 specific indications, even if SEND was not submitted under the
commercial IND, and cross-referencing nonclinical studies submitted to a commercial IND for a COVID-
19 indication does not obviate the requirement of SEND for a commercial IND for a non-COVID-19
indication.
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disease areas. CDISC publishes a TA User Guide (TAUG) for each therapeutic area
which includes the extensions as disease-specific metadata, examples and
recommendations for use (https://www.cdisc.org/standards/therapeutic-areas). The
CDISC TAUGs should not be interpreted as FDA guidance.

Questionnaires, Ratings and Scales are often used as outcome measures in clinical
studies. The instruments listed in the TAUGs should not be viewed as FDA
recommended instruments. Sponsors should consult with the appropriate FDA review
division on the best approach for each specific study.

Supported Therapeutic Areas

Sponsors may use new TA extensions of a CDISC standard, but are not required to until
the extensions have been incorporated into a SDTMIG version supported by FDA (the
supported SDTMIGs are listed in the Catalog). Sponsors should explain the rationale in
the cSDRG for using TA extensions that are not currently listed in this document.

If the study data submitted follows a Therapeutic Area User Guide (TAUG), include the
values for TSPARM/TSPARMCD and TSVAL indicated in the table from section 4.1.1.3
in the TS domain.

The TA extensions that are currently incorporated into FDA supported CDISC
foundational standards include:

5.1.1 Dyslipidemia Therapeutic Area User Guide v1

5.1.2 Chronic Hepatitis C Therapeutic Area Data Standard User Guide v1

5.1.3 QT Studies Therapeutic Area User Guide v1

5.1.4 Diabetes Therapeutic Area User Guide v1.0 – Supplement for ADaM

5.1.5 Tuberculosis Therapeutic Area User Guide v2.0

5.1.6 Diabetic Kidney Disease Therapeutic Area User Guide v1.0

5.1.7 Ebola Therapeutic Area User Guide v1.0

The Ebola Virus Disease (EVD) TAUG identified the ISARIC 54 EVD CORE Clinical
Dataset as input; however, only one of the two sets of source data is represented in the
TAUG. The Survivor forms are not included because they contain primarily standard
data seen in many studies. Sponsors should be aware of both components of the
ISARIC CORE Dataset when conducting EVD clinical trials.

54
International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC).
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5.1.8 Rheumatoid Arthritis Therapeutic Area User Guide v1.0

Standardization for Radiologic Score variables is not available in the Rheumatoid

Arthritis TAUG. Sponsors should refer to Radiographic Scoring methods as outcome
measures in rheumatoid arthritis for additional guidance. Additionally, while the
Controlled Terminology for the HAQ-DI Questionnaire is being finalized by CDISC,
sponsors should refer to the Stanford HAQ-DI instrument. It is advised to consult with
the review division for further guidance regarding a specific study.

5.1.9 Malaria Therapeutic Area User Guide v1.0

For Transmission Intensity:

Description and implementation examples demonstrating how malaria transmission
intensity is calculated at the site are currently not available in the TAUG. Sponsors
should consult with the appropriate FDA review division on the best approach for each
specific study.

For Meal Data:

Implementation examples demonstrating how the types of meals (i.e., fatty meals or
drinks) are currently not available in the TAUG. Sponsors should consult with the
appropriate FDA review division on the best approach for each specific study.

5.1.10 Kidney Transplant Therapeutic Area User Guide v1.0

The Kidney Transplant TAUG does not address two important data elements. First, the
date of the request for a biopsy is important for review, not just the date the biopsy
was performed. Second, evidence of C4d staining status in renal allografts (+ or -) is
important in the Banff classification criteria for the diagnosis of acute and chronic
antibody-mediate rejection. Sponsors should discuss these two data elements with the
appropriate review division.

5.1.11 TAUG-Influenza v1.1

5.1.12 Virology Therapeutic Area User Guide v2.1

5.1.13 Prostate Cancer Therapeutic Area User Guide v1.0

The TAUG v1.0 does not include a guidance on where to capture “Reason Not Done”
information for the tumor lesions that were inevaluable (this is a known issue). In
addition, the Agency considers it more accurate use the phrase ‘tumor lesions’ rather
than ‘tumors’.

Based on datasets previously submitted to the Agency, about 10% of scans are not
readable in identifying bone lesions. FDA recommends capturing Image Readability
flag for all scans, but the current TAUG does not address this. Sponsors should consult
with the appropriate FDA review division on the best approach for each specific study.

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For the Disease Assessments and Response for Metastatic Disease, in the proposed
Non-Standard Variables (NSV) comparison reference variable CMPREF, FDA
recommends providing a value of ‘First Post Treatment Scan’ instead of ‘Flare’ to
make it more inclusive, as not all subjects will have a flare in the 12 week scans.

FDA recommends submitting patient-level aggregated data if an Independent Review

Committee is part of a study and should include the overall assessment of disease
status (e.g., disease progression) on bone scans and soft tissue scans (CT or MRI).
Sponsors should consult with the appropriate FDA review division on the best
approach for each specific study.

5.1.14 Schizophrenia Therapeutic Area User Guide v1.1

The Schizophrenia TAUG does not address two important data elements. First, the
subjects daily living situation for the past 12 months. Second, when a protocol
violation prompts study termination, sponsors should use the existing Disposition
domain as appropriate and provide a referential link to any detailed information
regarding the protocol violation. Sponsors should consult with the appropriate FDA
review division on the best approach for each specific study.

5.1.15 Major Depressive Disorder Therapeutic Area User Guide v1.0

When reviewing the Major Depressive Disorder TAUG, also reference the FDA’s
Guidance for Industry document for MDD. Additionally, consult the Division of
Psychiatry Products when planning the submission.

5.1.16 Traumatic Brain Injury Therapeutic Area User Guide v1.0

5.1.17 Duchenne Muscular Dystrophy Therapeutic Area User Guide v1.0

5.1.18 Vaccines Therapeutic Area User Guide v1.1

The Vaccine TAUG should be used in conjunction with the FDA Guidance for
Industry “Submitting Study Datasets for Vaccines to the Office of Vaccines Research
and Review.” Investigator determined reactogenicity reporting should follow the
“Interim User Guide for COVID-19” examples on page 32 with the following
revisions:
• inclusion of the Investigator date/time of collection of the event in CE;
• inclusion of additional language in example 2 description first sentence to read
“In the study in this example, subjects kept a diary for 3 days assessing the
severity of symptoms.”;
• change of date/day of investigator assessment in FACE to 2020-04-02 (day 2)
• addition of rows in FACE to report data obtained from the subject’s diary from
study day 2 (moderate vomiting) and 3 (no vomiting).

The Vaccine TAUG represents the concept of maximum in the NSV, COLSRT
(Collected Summary Result Type). We assume that a daily value/result will be a
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maximum value for the day. The protocol should clarify that a maximum value should
be recorded for each day. If you will be reporting more than one value per day, consult
with your review team on how the data should be reported.

5.1.19 Chronic Obstructive Pulmonary Disease Therapeutic Area User Guide v1

5.1.20 Colorectal Cancer Therapeutic Area User Guide v1.0

Issue about Primary Tumor: The TAUG V1.0 does not provide guidance about the
identification, location, or laterality of the primary tumor. Even though this is noted as a
Known Issue, the importance of primary tumor for colorectal cancer is well established
and impacts interpretation of trial results. The FDA recommends that data related to the
primary tumor be provided.

Issue about Prior Therapies: The TAUG does not provide guidance about the importance
of documenting prior therapies and this is considered an oversight given the importance
of these data. The FDA recommends that data related to prior therapies be included in
clinical trial data.

Issue about Non-Target Lesions: The TAUG does not discuss the importance of
providing data to document the change in size of non-target lesions. This information is
required when using certain criteria (e.g., iRECIST). If these data are not provided in the
clinical data base, then the response criteria cannot be confirmed by the Agency.
Therefore, these data on non-target lesions are necessary if criteria, like iRECIST, is used
for trials in colorectal cancer.

5.1.21 Huntington’s Disease Therapeutic Area User Guide v1.0

5.1.22 Post Traumatic Stress Disorder Therapeutic Area User Guide v1.0

5.1.23 Clostridium Difficile Associated Diarrhea Therapeutic Area User Guide

v1.0

5.1.24 Acute Kidney Injury v1.0

List of FDA Technical Specification Documents

Technical specification documents provide detailed information for content on specific
topics, where applicable, submitted to FDA for an application. Sponsors should consult
with the review division early in the process to discuss issues with trial design or conduct
that may affect the content of the study data being submitted. Technical specifications
can be found here. 55

55
Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/providing-
regulatory-submissions-electronic-format-standardized-study-data.
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5.1.25 Submitting Nonclinical Datasets for Evaluation of Rodent Carcinogenicity

Studies of Pharmaceuticals, Guidance for Industry

5.1.26 Submitting Next Generation Sequencing Data to the Division of Antiviral

Products

5.1.27 Submitting Clinical Trial Datasets for Evaluation of QT/QTc Interval

Prolongation and Proarrhythmic Potential of Drugs

5.1.28 Bioanalytical Methods Templates

5.1.29 Submitting Select Clinical Trial Data Sets for Drugs Intended to Treat
Human Immunodeficiency Virus-1 Infection

5.1.30 Submitting Study Datasets for Vaccines to the Office of Vaccines Research
and Review

5.1.31 Technical Specifications-Comparative Clinical Endpoint Bioequivalence

Study Analysis Datasets for Abbreviated New Drug Applications

5.1.32 Technical Specifications for Submitting Clinical Trial Data Sets for
Treatment of Noncirrhotic Nonalcoholic Steatohepatitis (NASH)

5.1.33 Submitting Patient-Reported Outcome Data in Cancer Clinical Trials

5.1.34 Submitting Clinical Trial Datasets and Documentation for Clinical

Outcome Assessment Using Item Response Theory

6. Terminology
General
Common dictionaries should be used across all clinical studies and throughout the
submission for each of the following: adverse events, concomitant medications,
procedures, indications, study drug names, and medical history. FDA requires that
sponsors use, where appropriate, the terminologies supported and listed in the Catalog 56.
It is important that coding standards, if they exist, be followed (e.g., ICH Medical
Dictionary for Regulatory Activities (MedDRA) Term Selection: Points-to-Consider
document). Frequently, sponsors submit data that do not conform to terminology
standards, for example, misspelling of MedDRA or WHODrug Global terms, lack of
conformance to upper / lower case, or the use of hyphens. All controlled terms submitted
in datasets should conform to the exact case and spelling used by the terminology
maintenance organization (e.g., MedDRA, CDISC controlled terminology). These
conformance issues make it difficult to use or develop automated review and analysis
tools. The use of a dictionary that is sponsor-defined or an extension of a standard
dictionary should be avoided if possible, but, if essential, its use should be documented in
the define.xml file and the relevant RGs.

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6.1.1 Controlled Terminologies

Controlled terminology standards are an important component of study data

standardization and are a critical component of achieving semantically interoperable data
exchange (See Appendix A). Generally, controlled terminology standards specify the key
concepts that are represented as definitions, preferred terms, synonyms, codes, and code
system.

The analysis of study data is greatly facilitated by the use of controlled terms for clinical
or scientific concepts that have standard, predefined meanings and representations. In
electronic study data submissions, sponsors should provide the actual verbatim terms that
were collected (e.g., on the CRF), as well as the coded term.

Controlled terminology is also useful when consistently applied across studies to

facilitate integrated analyses (that are stratified by study) and cross-study comparative
analyses (e.g., when greater statistical power is needed to detect important safety signals).
Cross-study comparisons and pooled integrated analyses occasionally provide critical
information for regulatory decisions, such as statistical results that support
effectiveness, 57 as well as important information on exposure-response relationships 58
and population pharmacokinetics. 59

6.1.2 Use of Controlled Terminologies

FDA recognizes that studies are conducted over many years, during which time versions
of a terminology may change. Sponsors should use the most recent version of the
dictionary available at the start of a clinical or nonclinical study. If a new version
becomes available after the start of the study, sponsors may use the most current version
of the dictionary for that clinical or nonclinical study. It is common to have different
studies use different versions of the same dictionary within the same application (e.g.,
NDA, BLA). A submission of study data should describe (e.g., in the SDSP or relevant
RG) the impact, if any, of the use of different versions on the study results. For example,
if the sponsor anticipates pooling coded data across multiple studies, then it may be
desirable to use a single version across those studies to facilitate pooling. If a sponsor
selects this approach, then the approach and the justification should be documented in the
Standardization Plan, or in an update to the plan.

56
See https://www.fda.gov/regulatory-information/search-fda-guidance-documents/providing-regulatory-
submissions-electronic-format-standardized-study-data.
57
See the guidance for industry Providing Clinical Evidence of Effectiveness for Human Drugs and
Biological Products, available at https://www.fda.gov/drugs/guidance-compliance-regulatory-
information/guidances-drugs. We update guidance periodically. To make sure you have the most recent
version of guidance, check the FDA Drugs guidance Web page at https://www.fda.gov/drugs/guidance-
compliance-regulatory-information/guidances-drugs.
58
See the guidance for industry Exposure-Response Relationships — Study Design, Data Analysis, and
Regulatory Applications, https://www.fda.gov/drugs/guidance-compliance-regulatory-
information/guidances-drugs.
59
See the guidance for industry Population Pharmacokinetics, available at
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs.
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Regardless of the specific versions used for individual studies, pooled analyses (e.g., for
an ISS) should be conducted using a single version of a terminology. The current version
should be used at the time that data across studies are pooled. It is also acceptable to use
the most recent major version of a terminology if it describes the data well. This will
ensure a consistent and coherent comparison of clinical and scientific concepts across
multiple studies. Sponsors should specify the terminologies and versions used in the
study in the relevant RG.

Use of the Specific Controlled Term ‘OTHER’

The expansion of controlled terminology may lag behind scientific advancement, and
there may not be a relevant term within a controlled terminology’s value set to describe a
clinical trial event, finding, or observation. Mapping an undocumented term to ‘OTHER’
may be indicated in such cases. However, it is not recommended to map a collected value
to ‘OTHER’ when there is a controlled term available to match the collected value – even
when the terminology allows for sponsor expansion. Each unique value in a --TERM
field mapped to a --DECODE value of ‘OTHER’ should have a clear rationale outlined in
the relevant RGs.

6.1.3 Maintenance of Controlled Terminologies

The use of supported controlled terminologies is recommended wherever available. If a
sponsor identifies a concept for which no standard term exists, FDA recommends that the
sponsor submit the concept to the appropriate terminology maintenance organization as
early as possible to have a new term added to the standard dictionary. FDA considers this
good terminology management practice. The creation of custom terms for a submission is
discouraged. Furthermore, the use of custom or extensible code lists should not be
interpreted to mean that sponsors may substitute their own nonstandard terms in place of
existing equivalent standardized terms. Sponsors should allow sufficient time for a
proposed term to be reviewed and included in the terminology, as it is desirable to have
the term incorporated into the standard terminology before the data are submitted. If
custom terms cannot be avoided, the submitter should clearly identify and define them
within the submission, reference them in the relevant RGs, and use them consistently
throughout the application.

If a sponsor identifies an entire information domain 60 for which FDA has not accepted a
specific standard terminology, the sponsor may select a standard terminology to use, if
one exists. FDA recommends that sponsors include this selection in the Standardization
Plan (See section 2.1) or in an update to the existing plan, and reference it in the relevant
RG. If no controlled terminology exists, the sponsor may define custom terms. For
clinical studies, the non-FDA supported terms (whether from a non-supported standard
terminology or sponsor-defined custom terms) should then be used consistently
throughout all relevant studies within the application. Although the consistent use of non-

60
By information domain, we mean a logical grouping of clinical or scientific concepts that are amenable
to standardization (e.g., adverse event data, laboratory data, and histopathology data, imaging data).
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FDA supported terms across all nonclinical studies within an application is

recommended, it is understood that that this may not always be possible.
CDISC Controlled Terminology
Sponsors should use the terminologies and code lists in the CDISC Controlled
Terminology, which can be found at the NCI (National Cancer Institute) Enterprise
Vocabulary Services. 61 For variables for which no standard terms exists, or if the
available terminology is insufficient, the sponsor should propose its own terms. The
sponsor should provide this information in the define.xml file and in the relevant RGs.
Adverse Events

6.1.4 MedDRA

General Considerations
MedDRA is used for coding adverse events. 62 Generally, the studies included in an
application are conducted over many years and may have used different MedDRA
versions. The expectation is that sponsors or applicants will use the most current version
of MedDRA at the time of study start. However, there is no requirement to recode earlier
studies.

The spelling and capitalization of MedDRA terms should match the way the terms are
presented in the MedDRA dictionary (e.g., spelling and case). Common errors that have
been observed include the incorrect spelling of a System Organ Class (SOC) and other
MedDRA terms.

To avoid potential confusion or incorrect results, the preparation of the adverse event
dataset for the ISS should include MedDRA terms from the most current version of
MedDRAat the time that data across studies are pooled. It is also acceptable to use the
most recent major version of MedDRA if it describes the data well. The reason for an
ISS based on a single version of MedDRA is that reviewers often analyze adverse events
across studies, including the use of Standardized MedDRA Queries. 63 In addition,
sponsors should use the MedDRA-specified hierarchy of terms. The SDTM variables for
the different hierarchy levels should represent MedDRA-specified primary SOC-coded
terms.
Medications

6.1.5 FDA Unique Ingredient Identifier

General Considerations
The Unique Ingredient Identifier (UNII) 64 should be used to identify active ingredients
(specifically, active moieties) that are administered to investigational subjects in a study

61
See http://www.cancer.gov/cancertopics/terminologyresources/page6.
62
See https://www.meddra.org/.
63
See http://www.meddra.org/standardised-meddra-queries.
64
See http://www.fda.gov/ForIndustry/DataStandards/SubstanceRegistrationSystem-
UniqueIngredientIdentifierUNII/.
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(either clinical or nonclinical). This information should be provided in the SDTM TS

domain. UNIIs should be included for all active moieties of investigational products
(TSPARMCD= TRT or TRTUNII), active comparators (TSPARMCD= COMPTRT), and
any protocol-specified background treatments (TSPARMCD= CURTRT).

If a medicinal product has more than one active moiety, then multiple records in the full
TS should be provided, one for each active moiety. For example, if the investigational
product is Bactrim (a combination of sulfamethoxazole and trimethoprim), then TS will
contain two records for TSPARMCD= TRT: one for sulfamethoxazole and one for
trimethoprim.

The preferred substance names and UNII codes can be found by searching FDA’s
Substance Registration System, hosted by the National Library of Medicine. 65 We
recognize that unapproved substances may not yet have registered UNII codes. We
recommend that sponsors obtain UNII codes for unapproved substances as early in drug
development as possible, so that relevant information, such as study data, can be
unambiguously linked to those substances.

6.1.6 WHODrug Global

General Considerations
World Health Organization (WHO) Drug Global 66 is a dictionary maintained and updated
by Uppsala Monitoring Centre. WHODrug Global contains unique product codes for
identifying drug names and listing of medicinal product information, including active
ingredients and therapeutic uses.

Typically, WHODrug Global is used to code concomitant medications. The variable --

DECOD should be populated with the active substances from the WHODrug Global
Dictionary, and --CLAS populated with the drug class.

When using WHODrug Global, --CLAS is recommended to be populated with the

Anatomic Therapeutic Chemical (ATC) class most suitable per intended use, and the
remainder of the ATC classes, if any, placed in SUPPCM. Alternately, the use of the
SUPPCM or FACM domains to populate all ATC Classes associated with the --DECOD
value is acceptable. ATC classes should be submitted at the fourth level or most specific
available as defined within WHODrug Global.

Generally, studies included in a submission are conducted over many years and may have
used different WHODrug Global versions to code concomitant medications. The
expectation is the most current B3-format annual version of WHODrug Global at the
time of study start will be used to code concomitant medications. There is no requirement
to recode earlier studies to align with the WHODrug Global version of later studies.

65
The Substance Registration System can be accessed at https://precision.fda.gov/uniisearch.
66
See http://www.who-umc.org/.
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Pharmacologic Class

6.1.7 Medication Reference Terminology

General Considerations
The Veterans Administration’s Medication Reference Terminology (MED-RT) 67 should
be used to identify the pharmacologic class(es) of all active investigational substances
that are used in a study (either clinical or nonclinical). This information should be
provided in the SDTM TS domain when a full TS is indicated. The information should be
provided as one or more records in TS, where TSPARM = “Pharmacologic Class”.

Pharmacologic class is a complex concept that is made up of one or more component

concepts: mechanism of action (MOA), physiologic effect (PE), and chemical structure
(CS). 68 The established pharmacologic class is generally the MOA, PE, or CS term that is
considered the most scientifically valid and clinically meaningful. Sponsors should
include in TS (the full TS) the established pharmacologic class of all active moieties of
investigational products used in a study. FDA maintains a list of established
pharmacologic classes of approved moieties. 69 If the established pharmacologic class is
not available for an active moiety, then the sponsor should discuss the appropriate MOA,
PE, and CS terms with the review division. For unapproved investigational active
moieties where the pharmacologic class is unknown, the “Pharmacologic Class” record
may not be available. FDA does not recommend the use of general terms such as “small
molecule,” “large molecule” and “peptide” to indicate the pharmacologic class.
Indication

6.1.8 SNOMED CT

General Considerations
The International Health Terminology Standards Organization’s (IHTSDO) Systematized
Nomenclature of Medicine – Clinical Terms (SNOMED CT) 70 should be used to identify
the medical condition or problem that the investigational product in a study is intended to
affect (treat, diagnose or prevent, i.e., the indication). This information should be
provided in the SDTM TS domain (the full TS) as a record where TSPARMCD= INDIC
and TSPARMCD= TDIGRP. SNOMED CT was chosen to harmonize with Indication
information in Structured Product Labeling (SPL). 71 Because the granted indication may
include important qualifiers to fulfill the need for adequate directions for use (e.g.,
descriptors of the population to be treated, adjunctive or concomitant therapy, or specific

67
See MED-RT Documentation (nih.gov).
68
See the guidance for industry and review staff Labeling for Human Prescription Drug and Biologic
Products —Determining Established Pharmacologic Class for Use in the Highlights of Prescribing
Information, available at https://www.fda.gov/drugs/guidance-compliance-regulatory-
information/guidances-drugs.
69
The FDA Listing of Established Pharmacologic Class (EPC) Text Phrases is available within Highlights
of Prescribing Information on https://www.fda.gov/drugs/fdas-labeling-resources-human-prescription-
drugs/prescribing-information-resources.
70
Available at http://www.ihtsdo.org/snomed-ct/.
71
See https://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.
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tests needed for patient selection), the indication section in a label may not be fully
represented by available SNOMED CT codes.

Laboratory Tests

6.1.9 LOINC

General Considerations
The Logical Observation Identifiers Names and Codes (LOINC) is a clinical terminology
housed by the Regenstrief Institute. LOINC codes are universal identifiers for laboratory
and other clinical observations that enable semantically interoperable clinical data
exchange. The laboratory portion of the LOINC database contains the categories of
chemistry, hematology, serology, toxicology, and more. The SDTM standard supports
LOINC codes using the LB.LOINC variable. LOINC codes should not be added to
SEND datasets.

When submitting LOINC codes you should:

1) Continue submitting laboratory data in the CDISC SDTM format using CDISC
laboratory terminology alongside the LOINC code for a given laboratory test.
2) Enter LOINC codes in the LB.LOINC field of the SDTM LB domain and
populate LB.METHOD when available. When LOINC codes are unavailable,
leave the field blank.
3) Submit LOINC codes only when they are available from the clinical laboratories
as a pass-through, i.e., reporting the codes as received from the laboratories with
no modifications. FDA understands that there may be inconsistencies in the
specification and interpretation of LOINC codes submitted across tests, studies,
and subjects.
4) Provide in-vitro diagnostic (IVD) device information in the SDTM Device
Identifiers (DI) domain, when available. This information will help inform further
FDA guidance on the consistency of LOINC codes associated with laboratory
devices.

7. Electronic Submission Format

7.1 eCTD Specifications

Based on the requirements as specified in the Data Standards Catalog, sponsors are
required to submit regulatory applications using eCTD format. Refer to the Data
Standards Catalog for more information on which version should be used.

7.1.1 eCTD v3.2.2 Specifications

For information on how to incorporate datasets into the eCTD v3.2.2, refer to the
Guidance to Industry Providing Regulatory Submissions in Electronic Format: Certain
Human Pharmaceutical Product Applications and Related Submissions Using the
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Electronic Common Technical Document Specifications. 72 Information on eCTD

Validations, including those referenced in the “Technical Rejection Criteria for Study
Data Important Information” (Appendix F), can be found in the Specifications for eCTD
Validation Criteria. 73 Details on the expectations for validations applying to study data
can be found in Section 8.2.2 (Support on Data Validation Rules) and Appendix F
(Technical Rejection Criteria for Study Data Important Information) of this Technical
Conformance Guide.

The study identifier (STUDYID) in trial summary (TS) and [study-id] in the study
tagging file (STF) should be identical wherever possible. 74 For studies where alignment
of the study identifier across TS and STF is not feasible, the value for [study-id] used in
the STF should be included in TS using the parameter SPREFID. Though SPREFID is
not in the SDTM controlled terminology for TSPARMCD, use SPREFID to reconcile
study identifiers where necessary for SEND or SDTM studies. FDA will use SPREFID to
match study identifiers across STF and TS to establish the study start date where
necessary for evaluation against the eCTD validation criteria.

Do not use the eCTD ‘append’ lifecycle operator when submitting updated or changed
content within study data files that were previously submitted. Updated files should be
submitted as replaced and not submitted as new.

7.1.2 eCTD v4.0 Specifications

For information on how to incorporate datasets into the eCTD v4.0, refer to the Guidance
to Industry Providing Regulatory Submissions in Electronic Format: Certain Human
Pharmaceutical Product Applications and Related Submissions Using the Electronic
Common Technical Document Specifications. 75 Information on eCTD Validations,
including those referenced in the “Technical Rejection Criteria for Study Data Important
Information” (Appendix F), can be found in the Specifications for eCTD v4.0 Validation
Criteria. 76 Details on the expectations for validations applying to study data can be found
in Section 8.2.2 (Support on Data Validation Rules) and Appendix F (Technical
Rejection Criteria for Study Data Important Information) of this Technical Conformance
Guide.

72
See “eCTD Technical Conformance Guide” for further details about submitting in eCTD v3.2.2.
Available at https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/ectd-resources.
See “eCTD v4.0 Technical Conformance Guide” for further details about submitting in eCTD v4.0.
Available at https://www.fda.gov/media/179700/download?attachment.
73
Specifications for eCTD Validation Criteria for eCTD v3.2.2 available at
https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/ectd-submission-standards-ectd-
v322-and-regional-m1. Specifications for eCTD v4.0 Validation Criteria for eCTD v4.0 available at
https://www.fda.gov/media/179723/download?attachment.
74
ICH M2 EWG: The eCTD Backbone File Specification for Study Tagging Files (June 2008)
https://www.ich.org/page/study-tagging-file-specification-and-related-files and CDISC Submission
Metadata Model SDTM Metadata Submission Guidelines v2.0 | CDISC.
75
See “eCTD v4.0 Technical Conformance Guide” for further details about submitting in eCTD v4.0.
Available at https://www.fda.gov/media/179700/download?attachment.
76
Available at https://www.fda.gov/media/179723/download?attachment.
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The study identifier (STUDYID) in trial summary (TS) and studyID in the Study Id Study
Title keyword should be identical wherever possible. 77 For studies where alignment of
the study identifier across TS and Study Id Study Title keyword is not feasible, the value
for studyID used in the Study Id Study Title keyword should be included in TS using the
parameter SPREFID. Though SPREFID is not in the SDTM controlled terminology for
TSPARMCD, use SPREFID to reconcile study identifiers where necessary for SEND or
SDTM studies. FDA will use SPREFID to match study identifiers across the Study Id
Study Title keyword and TS to establish the study start date where necessary for
evaluation against the eCTD validation criteria.

Updated files should be submitted as replaced and not submitted as new.

7.1.3 Weight of Evidence

When nonclinical Weight of Evidence (WOE) documents are submitted to the Agency as
assessments for particular topics or as justification of why a toxicity study is not needed,
these toxicity risk assessments should be submitted to the nonclinical eCTD Modules
relevant to the topic. Examples are listed below:

Rodent Carcinogenicity: Module 4.2.3.4

Reproductive and Developmental Toxicity: Module 4.2.3.5
Juvenile Animal Toxicity: Module 4.2.3.5

Cross-reference to these WOE documents may also be included within eCTD Module 2.4
(Nonclinical Overview summaries). Supporting literature references submitted with any
WOE document should be submitted to eCTD Module 4.3 (Literature References). When
a WOE document is submitted to an eCTD module that is subject to the Technical
Rejection Criteria (e.g., carcinogenicity risk assessment submitted to Module 4.2.3.4), a
simplified ts.xpt file must accompany this document. The TSVALNF field of the
simplified ts.xpt file should be populated with the null value “NA” (Not Applicable) as
further described under Section 8.1.2 (Support on Data Validation Rules) of this
Technical Conformance Guide.
Electronic File Directory
Study datasets and their supportive files should be organized into a specific file directory
structure when submitted in the eCTD 78 format (See Figure 2 and Table 2 below). Note
that this structure is distinct from the eCTD headings and hierarchy folder structure, and
does not affect it. Submission of files within the appropriate folders allows automated
systems to detect and prepare datasets for review, and minimizes the need for manual
processing.

77
ICH M8 Expert Working Group ICH Electronic Common Technical Document (eCTD) v4.0
Implementation Guide and CDISC Submission Metadata Model SDTM Metadata Submission Guidelines
v2.0 | CDISC.
78
See http://www.ich.org/products/ctd.html.
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If you need to split a file that exceeds file size limits (See section 3.3.2), you should
submit the smaller split files in the ‘split’ sub-folder in addition to the larger non-split file
in the original data folder. There is no need for a second define.xml file to be submitted
within the split subfolder.

For rodent carcinogenicity studies submitted in 4.2.3.4, the tumor.xpt file and its
associated define.pdf should be placed in analysis\legacy\datasets subfolder under the
study datasets folder.

The file folder structure for study datasets is summarized in Figure 2. Table 2 provides
the study dataset and file folder structure and associated description. For more detailed
examples of file folder structures for clinical and non-clinical datasets in both
standardized and legacy formats, see Appendix E: Example Study Data Folder Structure.

Figure 2: Folder Structure for Study Datasets

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Table 2: Study Dataset and File Folder Structure and Description

Folder Name Folder Level Description/Contents
Refers to the eCTD module in which study data are being
1 submitted. Name this folder m4 for nonclinical data and
[module]
m5 for clinical data. Do not place files at this level.
Resides within the module folder as the top-level folder
for study data (nonclinical or clinical) being submitted for
2
datasets the specified module (m4 or m5). Do not place files at
this level.
Name this folder with the study identifier or analysis type
3 performed (e.g., study123, iss, ise). Do not place files at
[study]
this level.
Contains folders for analysis datasets and software
4 programs; arrange in designated level 6 subfolders. Do
analysis
not place files at this level.
Contains subfolders for ADaM datasets and
5 corresponding software programs. Do not place files at
adam
this level.
6 Place ADaM datasets in this subfolder.
datasets

split 7 Place any split ADaM datasets in this subfolder.

Place software programs for ADaM datasets, tables and
programs 6
figures in this subfolder.
Contains legacy formatted analysis datasets and
5 corresponding software programs. Do not place files at
legacy
this level.
Place legacy analysis datasets in this subfolder. In m4
6 place tumor.xpt and its associated define.pdf in this
datasets
folder.

split 7 Place split legacy analysis datasets in this subfolder.

Place software programs for legacy analysis datasets,
programs 6
tables and figures in this subfolder.
Place miscellaneous datasets that don’t qualify as
misc 4 analysis, profile, or tabulation datasets in this subfolder.
This subfolder was formerly named “listings”.

profiles 4 Place patient profiles in this subfolder.

Contains subfolders for tabulation datasets. Do not place
4
tabulations files at this level.
Place legacy (non-standardized) tabulation datasets in this
5
legacy folder.

Place any split legacy tabulations datasets in this

split 6
subfolder.

sdtm Place SDTM tabulation datasets in this subfolder. Should

5
only be used in m5 for clinical data.

split 6 Place any split SDTM files in this subfolder.

Place SEND tabulation datasets in this subfolder. Should

send 5
only be used in m4 for animal data.

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eCTD Sample Submission

The FDA would like to work closely with people who plan to provide a submission using
the eCTD specifications and offer to help smooth the process. The Agency also offers a
process for submitting sample standardized datasets for validation. Sample submissions
are tests only and not considered official submissions. They are not reviewed by FDA
reviewers at any time. The Submit Using eCTD page provides more information
regarding the test submission process. 79

7.1.4 File Tags

Nonclinical
The following table lists nonclinical file tags that should be used for certain study reports
or documents submitted to eCTD Module 4. These file tags were created to facilitate
identification of specific studies or documents; therefore, further instruction and intent of
their use is outlined below. These file tags are additions to the already established list of
file tags as outlined in the eCTD Comprehensive Table of Contents Headings and
Hierarchy, the ICH valid-values (eCTD v3.2.2) and the ICH eCTD v4.0 Controlled
Vocabulary Package. This table is subject to modification based on the availability of
new information and will be updated to reflect any needed change.

File Tag Intended Use Detailed Description of Use

Name*
animal-rule- Use to tag nonclinical Efficacy studies conducted in animal
efficacy efficacy studies models of the disease or condition of
conducted for products interest for products being developed
regulated under the under the regulations commonly known
Animal Rule as the Animal Rule (21 CFR part 314,
subpart I for drugs; 21 CFR part 601,
subpart H for biologics)

Suggested eCTD Module/Folder use:

4.2.1.1

animal-rule- Use to tag nonclinical Natural history studies conducted in

natural-history natural history studies animals that are used to develop the
that are conducted with animal models in which the efficacy of
chemical, biological, investigational products is tested for
radiological, or nuclear products being developed under the
agents and used for regulations commonly known as the
animal model Animal Rule (21 CFR part 314, subpart I
development for for drugs; 21 CFR part 601, subpart H for
products regulated under biologics)
the Animal Rule

79
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File Tag Intended Use Detailed Description of Use

Name*
Suggested eCTD Module/Folder use:
4.2.1.1

weight-of- Use to tag nonclinical Nonclinical Weight of Evidence (WoE)

evidence weight-of-evidence or based risk assessment documents
risk assessment submitted to the FDA could include
documents justification of why a specific toxicity
study is not needed or relevant. Examples
of these types of documents could include
rat carcinogenicity WoE documents or a
WoE assessment for nonclinical
reproductive and developmental toxicity
studies.

Do not use for submission of:

• in vivo or in vitro study reports

Suggested eCTD Module/Folder use:

Refer to Section 7.1 of the sdTCG for
eCTD placement specifications for WoE
documents

nonstandard- Use to tag nonclinical Nonclinical studies conducted that may

safety-study studies conducted to replace animal studies or provide
provide complementary complementary or supportive safety
safety information to information to standard pharmacology
standard pharmacology and toxicology studies. These studies are
and toxicology studies not routinely conducted but the overall
intent would be to provide supplemental
information to inform and support safety
of any component of the therapeutic
product. These may include in vitro, in
silico, in chemico, ex vivo, or in vivo
toxicology or pharmacology studies
(including safety pharmacology).
Examples include but are not limited to:
• New Approach Methodologies
(NAMs)
• an ex-vivo or non-traditional in
vivo (e.g., zebrafish) study to
assess the teratogenic potential of
a compound

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File Tag Intended Use Detailed Description of Use

Name*
• an in vitro cell culture model to
assess spermatogenesis or
folliculogenesis
• Computational methods (e.g., in
silico, quantitative structure
activity (QSAR))
• Microphysiological Systems
(MPS) (e.g., microfluidic systems)
• Complex in vitro method (CIVM)
• 3D model (e.g., organoid,
spheroid, organ chip, organotypic)
• Stem cells (e.g., induced
pluripotent stem cells (iPSCs) or
human-induced pluripotent stem
cells (hi-iPSC)
• co-culture or tri-culture
• Engineered tissue (e.g.,
reconstructed human epidermis,
bioprinted tissue, micropattern)
• Multi Electrode Array (MEA)

Do not use for submission of:

• standard pharmacology and
toxicology study types typically
conducted as part of product
development

Suggested eCTD Module/Folder use:

4.2.1 or 4.2.3.7

PD-invivo- Use to tag in vivo Nonclinical in vivo studies that focus on

study nonclinical mechanism providing additional information about
of action or proof of the mechanism of action or pharmacology
concept studies that of a product. Use this file tag for studies
supplement standard that are conducted to provide
primary and secondary supplemental information on the
pharmacology studies pharmacological action of the product.
These studies are not traditionally
conducted as part of standard product
development and may be considered
“alternative” assays. Examples include
but are not limited to:

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File Tag Intended Use Detailed Description of Use

Name*
• humanized animal models (e.g.,
transgenic rodents, engrafted
rodents)
• zebrafish models

Do not use for submission of:

• standard nonclinical
pharmacology or proof-of-concept
studies that demonstrate efficacy
of the product in nonclinical
species
• standard primary in vivo PD
studies intended to investigate the
mode of action and/or effects of a
substance in relation to its desired
therapeutic target
• toxicology studies or standard
safety pharmacology studies

Suggested eCTD Module/Folder use:

4.2.1

PD-invitro- Use to tag in vitro Nonclinical in vitro studies that focus on

study nonclinical mechanism providing additional information about
of action or proof of the mechanism of action or pharmacology
concept studies that of a product. Use this file tag for in vitro,
supplement standard in silico, or ex vivo studies that are
primary and secondary conducted to provide supplemental
pharmacology studies information on the pharmacological
action of the product. These studies are
not traditionally conducted as part of
standard product development and may be
considered “alternative” assays. Examples
include but are not limited to:
• Microphysiological Systems
(MPS) (e.g., microfluidic systems)
• Complex in vitro method (CIVM)
• 3D model (e.g., organoid,
spheroid, organ chip, organotypic)
• Stem cells (e.g., induced
pluripotent stem cells (iPSCs) or
human-induced pluripotent stem
cells (hi-iPSC)

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File Tag Intended Use Detailed Description of Use

Name*
• co-culture or tri-culture
• Engineered tissue (e.g.,
reconstructed human epidermis,
bioprinted tissue, micropattern)
• Multi Electrode Array (MEA)

Do not use for submission of:

• standard in vitro nonclinical
primary or secondary
pharmacology studies that
demonstrate efficacy or binding
• standard ADME studies
• toxicology studies or standard
safety pharmacology studies
• genetic toxicity studies

Suggested eCTD Module/Folder use:

4.2.1
study-data- Use to tag SDRG for See Section 2 of Study Data Technical
reviewers- nonclincial data Conformance Guide: Planning and
guide Providing Standardized Study Data

Clinical
The following table lists clinical file tags that should be used for certain study reports or
documents submitted to eCTD Module 5. These file tags were created to facilitate
identification of specific studies or documents; therefore, further instruction and intent of
their use is outlined below. These file tags are additions to the already established list of
file tags as outlined in the eCTD Comprehensive Table of Contents Headings and
Hierarchy, the ICH valid-values (eCTD v3.2.2) and the ICH eCTD v4.0 Controlled
Vocabulary Package. This table is subject to modification based on the availability of
new information and will be updated to reflect any needed change.

File Tag Name* Intended Use Detailed Description

of Use
csr_other Use to tag clinical study report
submitted as multiple files and that do
not apply to ICH E3 reference
headings
hepatic-impairment- Use to tag hepatic impairment studies Clinical study to
study conducted to assess the influence of assess the influence
hepatic impairment on of hepatic
pharmacokinetics and, where impairment on the
pharmacokinetics

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File Tag Name* Intended Use Detailed Description

of Use
appropriate, pharmacodynamics of a and, where
drug appropriate, the
pharmacodynamics
of a drug

Suggested eCTD
Module/Folder use:
5.3.3
renal-impairment- Use to tag renal impairment studies Clinical study to
study conducted to assess the influence of assess the influence
renal impairment on pharmacokinetics of renal impairment
and, where appropriate, on the
pharmacodynamics of a drug pharmacokinetics
and, where
appropriate, the
pharmacodynamics
of a drug

Suggested eCTD
Module/Folder use:
5.3.3
drug-drug- Use to tag drug-drug interaction (DDI) Clinical study to
interaction-study studies conducted to assess the evaluate the enzyme
influence of drug-drug interactions and transporter-
on pharmacokinetics and, where mediated
appropriate, pharmacodynamics of a pharmacokinetic
drug drug-drug interaction
potential, and where
appropriate,
pharmacodynamics
for a drug

Suggested eCTD
Module/Folder use:
5.3.3
mass-balance-study Use to tag mass balance study to Clinical study with a
obtain quantitative information on radiolabeled drug to
drug absorption, distribution, measure the
metabolism, and excretion properties radioactivity in
various biological
matrices and obtain
quantitative
information on how
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File Tag Name* Intended Use Detailed Description

of Use
the drug is absorbed,
distributed,
metabolized, or
execreted from the
body.

Suggested eCTD
Module/Folder use:
5.3.3
population-pk-report Use to tag report summarizing Suggested eCTD
population pharmacokinetic Module/Folder use:
(population PK) analyses conducted to 5.3.3.5
inform drug development
population-pkpd- Use to tag report summarizing Suggested eCTD
report population Module/Folder use:
pharmacokinetic/pharmacodynamic 5.3.3.5
analyses conducted to inform drug
development
pbpk-report Use to tag report summarizing Suggested eCTD
physiologically-based Module/Folder use:
pharmacokinetic analyses conducted 5.3.3.5
to inform drug development
pbbm-report Use to tag report summarizing Suggested eCTD
physiologically-based Module/Folder use:
biopharmaceutics modelling 5.3.1
conducted to inform recommendations
on biopharmaceutics applications
qsp-report Use to tag report summarizing Suggested eCTD
population quantitative systems Module/Folder use:
pharmacology analyses conducted to 5.3.3.5
inform drug development
cp-general Use to tag checklist document and
clinical pharmacology table
qt-clinical-study Use to tag stand-alone thorough QT Suggested eCTD
studies or QT assessments performed Module/Folder use:
by combining findings from multiple 5.3.4 or 5.3.5
studies
iscp Use to tag integrated analysis of Suggested eCTD
clinical pharmacology - integrated Module/Folder use:
summary of clinical pharmacology 5.3.5.3
report
isi Use to tag integrated analysis of Suggested eCTD
immunogenicity - integrated summary Module/Folder use:
of immunogenicity report 5.3.5.3
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File Tag Name* Intended Use Detailed Description

of Use
study-data-reviewers- Use to tag SDRG for clinical data See Section 2 of
guide Study Data Technical
Conformance Guide:
Planning and
Providing
Standardized Study
Data
analysis-data- Use to tag ADRG for clincial data See Section 2 of
reviewers-guide Study Data Technical
Conformance Guide:
Planning and
Providing
Standardized Study
Data

* If using eCTDv4.0, file-tags are called document type keywords.

8. Study Data Validation and Traceability

Definition of Study Data Validation
Study data validation helps to ensure that the study data are compliant, useful, and will
support meaningful review and analysis. Validation activities occur at different times
during submission and review of study data, including submission receipt and at the
beginning of the regulatory review. Validation of study data that occurs upon receipt of a
submission follows the process for Technical Rejection Criteria for Study Data (See
Appendix F).
Types of Study Data Validation Rules
1. Standards Development Organizations (e.g., CDISC) provide rules that assess
conformance to its published standards (See www.CDISC.org).

2. FDA eCTD Technical Rejection Criteria for Study Data that assess
conformance to the standards listed in the Catalog (See section 7.1, section
8.2.2, and Appendix F).

3. FDA Business and Validator rules to assess that the data support regulatory
review and analysis.

8.1.1 FDA Business and Validator Rules

FDA Business Rules describe the business requirements for regulatory review to help
ensure that study data are compliant and useful and support meaningful review and
analysis. The list of business rules will grow and change with experience and cross-center
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collaborations. All business rules should be followed where applicable. The business
rules are accompanied with validator rules which provide details regarding FDA's
assessment of study data for purposes of review and analysis. The FDA Validator Rules
also represent the latest understanding of what best supports regulatory review. The
Study Data Standards Resources webpage page provides links to the currently available
FDA Business and Validator rules. 80

8.1.2 Support on Data Validation Rules

Sponsors should evaluate their study data before submission against the conformance
rules published by an SDO, the eCTD Technical Rejection Criteria for Study Data (See
Appendix F), and the FDA Business Rules. Sponsors may also wish to use the FDA
Validator Rules to understand what is available to the FDA reviewer. Sponsors should
either correct any discrepancies between study data and the standard or the business rules
or explain meaningful discrepancies in the relevant Reviewer Guide (RG). Additional
information about conformance to the standard, FDA Business Rules, or FDA Validator
Rules that could facilitate review of the submitted data, or establish consistency and
traceability between the study data and the Study Report, should also be provided in the
relevant RG.
eCTD Technical Rejection Criteria for Study Data (See Appendix F
for more details)
FDA implemented an approach to determine compliance with the requirement to
submit electronic standardized study data. The technical rejection criteria are
automated validations by the Center (CDER or CBER) inbound processing system
using the FDA Specifications for eCTD Validation Criteria 81 as described below.

When submitting in eCTD v3.2.2, in order for the FDA automated eCTD validation
process to determine the study start date (SSD) for the submitted study, FDA relies on
the SSD value provided in the Trial Summary dataset (ts.xpt) that is referenced in the
Study Tagging File (STF). 82 This validation confirms the submission of a valid STF
(eCTD validation error 1789) and a Trial Summary (TS) domain (eCTD validation error
1734). For a nonclinical study that contains a study report with file tags ‘pre-clinical-
study-report’, ‘legacy-clinical-study-report’, or ‘study-report-body’, and/or an xpt
formatted dataset, the expectation for content in the TS domain (simplified or full) 83
depends on whether the study is submitted in compliance with a CDISC standard.
Appendix G (Examples of ts.xpt Datasets) provides the appropriate content and an
example of the TS domains for each case. The expectation is that when the SSD is after
the established required deadlines, the study data must comply with the standards in the

80
See http://www.fda.gov/eStudyResources.
81
The FDA Specifications for eCTD Validation Criteria can be accessed through the eCTD Submission
Standards catalog. The catalog is located on the FDA eCTD website available at https://www.fda.gov/ectd.
82
The Study Start Date (SSD) should follow the ISO 8601 standard that provides, at minimum, the year,
month, and day for the study start date.
83
Refer to Appendix G of this document for more information on the simplified TS file and the Study Data
Technical Conformance Guide on the FDA Study Data Standards Resources web page for more
information on the full TS file.
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FDA Data Standards Catalog. The validation will then identify that the required dataset
files (eCTD validation error 1736) are under the correct file tag within the STF (eCTD
validation error 1735). If there are no high validation errors within the eCTD
submission, the submission will continue to be processed.

When submitting in eCTD 4.0, in order for the FDA automated eCTD validation process
to determine the study start date (SSD) for the submitted study, FDA relies on the SSD
value provided in the Trial Summary dataset (ts.xpt) that is associated with a given Study
Id Study Title keyword. 84 This validation confirms the submission of a Trial Summary
(TS) domain (eCTD v4.0 validation error US-eCTD4-516). For a nonclinical study that
contains a study report with document type keyword ‘pre clinical study report’, ‘legacy
clinical study report’, or ‘study report body’, and/or an xpt formatted dataset, the
expectation for content in the TS domain (simplified or full) 85 depends on whether the
study is submitted in compliance with a CDISC standard. Appendix G (Examples of
ts.xpt Datasets) provides the appropriate content and an example of the TS domains for
each case. The expectation is that when the SSD is after the established required
deadlines, the study data must comply with the standards in the FDA Data Standards
Catalog. The validation will then identify that the required dataset files (eCTD v4.0
validation error US-eCTD4-518) are under the correct document type keyword (eCTD
v4.0 validation error US-eCTD4-517). If there are no high validation errors within the
eCTD submission, the submission will continue to be processed.

Technical Rejection Criteria and Use of a Simplified ts.xpt for Clinical

Studies

Technical rejection criteria have been added to the Specifications for eCTD Validation
Criteria to determine compliance with the requirements for submitting standardized study
data 86 when xpt formatted datasets are submitted to FDA in TRC applicable sections
within Module 5.

When a xpt formatted dataset is submitted, the STF (or Context of Uses associated with,
same Study Id Study Title keyword if submitting in eCTD v4.0) for the study is then
checked for the presence of a trial summary (TS) file (full or simplified). A full ts.xpt file
would be expected when the study type and study initiation date meet the criteria for
requiring SDTM and ADaM datasets as described in the current FDA Data Standards
Catalog.

There are cases in which a xpt formatted dataset submitted to TRC applicable sections
within eCTD Module 5 (see sections 7.1, 8.2.2.1, and Appendix F) is not required to

84
The Study Start Date (SSD) should follow the ISO 8601 standard that provides, at minimum, the year,
month, and day for the study start date.
85
Refer to Appendix G of this document for more information on the simplified TS file and the Study Data
Technical Conformance Guide on the FDA Study Data Standards Resources web page for more
information on the full TS file.
86
See pp. 6-9 of the Study Data Guidance.
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include accompanying SDTM and ADaM datasets. In such cases, a simplified ts.xpt file
should be included with the xpt formatted dataset. A simplified ts.xpt file serves to
provide limited machine-readable information such that any submitted xpt formatted
dataset not requiring SDTM and ADaM datasets will be appropriately identified by the
Center’s processing system. 87,88

There may also be cases where SDTM and ADaM are not required even though the study
started after December 17, 2016. The list below comprises possible examples (not an
exhaustive list):
• pilot studies submitted to an ANDA application
• failed studies submitted to an ANDA application

When SDTM and ADaM are not applicable in a study started after December 17, 2016,
see Appendix G, example B for the format of a simplified ts.xpt file that should be used,
where the TSVALNF field is to be populated with the null value “NA” (Not Applicable).
Technical Rejection Criteria and Use of a Simplified ts.xpt for
Nonclinical Studies (eCTD Modules 4.2.3.1, 4.2.3.2, and 4.2.3.4)
When submitting in eCTD v3.2.2, technical rejection criteria have been added to the
Specifications for eCTD Validation Criteria to determine compliance with the
requirements for submitting standardized study data 89 to any nonclinical study report
submitted under eCTD modules 4.2.3.1, 4.2.3.2, or 4.2.3.4 that includes one of the
following three file tags: ‘pre-clinical-study-report’, ‘legacy-clinical-study-report’, or
‘study-report-body’.

When a nonclinical study report is submitted using one of these file tags in the study
tagging file (STF) or the study is submitted with an xpt formatted dataset, the STF for the
study is then checked for the presence of a trial summary (TS) file (full or simplified). A
full ts.xpt file would be expected when the study type and study initiation date meet the
criteria for requiring SEND datasets as described in the current FDA Data Standards
Catalog (e.g., a single dose toxicity study initiated after December 17, 2017 for INDs).

When submitting in eCTD v4.0, technical rejection criteria have been added to the
Specifications for eCTD v4.0 Validation Criteria to determine compliance with the
requirements for submitting standardized study data 90 to any nonclinical study report
submitted under eCTD modules 4.2.3.1, 4.2.3.2, or 4.2.3.4 that includes one of the
following three document type keywords: ‘pre clinical study report’, ‘legacy clinical
study report’, or ‘study report body’.

When a nonclinical study report is submitted using one of these document type keywords
associated with a Study Id Study Title keyword or the study is submitted with an xpt

87
See Appendix F: Technical Rejection Criteria for Study Data Validation Important Information
88
See eCTD Submission Standards located at https://www.fda.gov/eCTD for further information on the
validation tool FDA is currently using and all eCTD validation criteria and rules.
89
See pp. 6-9 of the Study Data Guidance.
90
See pp. 6-9 of the Study Data Guidance.
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formatted dataset, the study is then checked for the presence of a trial summary (TS) file
(full or simplified). A full ts.xpt file would be expected when the study type and study
initiation date meet the criteria for requiring SEND datasets as described in the current
FDA Data Standards Catalog (e.g., a single dose toxicity study initiated after December
17, 2017, for INDs).

There are cases in which a study report submitted to eCTD Modules 4.2.3.1, 4.2.3.2 or
4.2.3.4 using one of the file tags or document type keywords listed above is not required
to include accompanying SEND datasets. In such cases, a simplified ts.xpt file should be
included with the study report. A simplified ts.xpt file serves to provide limited machine-
readable information such that any submitted study report not requiring SEND will be
appropriately identified by the Center’s processing system. 91,92 A simplified ts.xpt file
should not be used when submitting SEND datasets for a study. Doing so will prevent
loading of these datasets resulting in a need for TS correction and resubmission.

A simplified ts.xpt file would be expected when the study type could be modeled in an
applicable SEND Implementation Guide (SENDIG) version (e.g., repeat dose toxicity)
but the study initiation date is prior to the implementation of the requirement (e.g., before
or on Dec. 17, 2016 for NDAs). When this is the case, the following format of a
simplified ts.xpt file may be used:

STUDYID TSPARMCD TSVAL TSVALNF

Use Study ID in STF STSTDTC yyyy-mm-dd (Leave blank)

(eCTD v3.2.2) -or- in
the Study Id Study
Title Keyword
(eCTD v4.0)

There may also be cases where a study initiation date is not relevant. When nonclinical
submissions are primarily text based, do not have tabulated data or line listings, are
specifically sent to or requested by the Agency due to emergent safety concerns (with
prior agreement), or only contain data that are not modeled in an applicable SENDIG, a
simplified ts.xpt file should be used. The list below comprises possible examples of the
types of submissions that meet these criteria (not an exhaustive list):

• Expert pathologist’s report (Working Group Report) or Veterinarian report (e.g.,

Veterinary Cardiologist)
• Nonclinical safety report
• Carcinogenicity protocol amendments or Carcinogenicity risk assessments
• Exploratory or tolerability toxicology study summaries (e.g., text based, limited
animals used with few endpoints tested). Does not include those studies that would be

91
See Appendix F: Technical Rejection Criteria for Study Data Validation Important Information
92
See eCTD Submission Standards located at https://www.fda.gov/eCTD for further information on the
validation tool FDA is currently using and all eCTD validation criteria and rules.
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submitted to the Agency to support the adequacy of dose selection for subsequent
nonclinical studies (e.g., dose range finding studies to support dosing for rodent
carcinogenicity studies).
• Literature study reports specifically used as nonclinical support for safety
• Nonclinical study protocols
• Study types not currently modeled in an applicable SENDIG
• Specialized toxicity studies conducted where there are no study parameters modeled
in an applicable SENDIG (e.g., a single-dose toxicity study conducted to only assess
otic endpoints)
• The Agency, at its discretion, could allow for use of a simplified ts.xpt file with
submission of a study report (e.g., for reasons of safety or significant clinical concern)

When a study initiation date is not applicable, the following format of a simplified ts.xpt
file should be used, where the TSVALNF field is to be populated with the null value
“NA” (Not Applicable):

STUDYID TSPARMCD TSVAL TSVALNF

Use Study ID in STF STSTDTC (Leave blank) NA
(eCTD v3.2.2) -or- ]
in the Study Id Study
Title Keyword (eCTD
v4.0)

It is recommended that the Study Data Standardization Plan (SDSP) should be used
during development (See section 2.1) to communicate the intent to submit SEND
datasets. The SDSP can be updated so that all historical, current, and planned use of study
data standards is included. When appropriate, the SDSP may also be used to further
explain the intended use of simplified ts.xpt files. SDSP instructions are available
(https://phuse.global/Deliverables) and allow flexibility to accommodate any type of
submission. Use of the SDSP will allow for identification of potential data
standardization issues and timely discussion with the review division, if needed.

For additional information on the Technical Rejection Criteria, see Appendix F. The FDA
Data Standards Catalog may be found at: https://www.fda.gov/industry/study-data-
standards-resources/study-data-submission-cder-and-cber

The CDER resource ‘Creating Simplified ts.xpt Files’, using free and open-source
software may be found at https://www.fda.gov/industry/study-data-standards-
resources/study-data-submission-cder-and-cber

If there are any questions as to the appropriate use of the simplified ts.xpt file, contact the
CDER eDATA Team at [email protected] or CBER eData Team at cber-
[email protected].

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Study Data Traceability

8.1.3 Overview
An important component of a regulatory review is an understanding of the provenance of
the data (e.g., traceability of the sponsor’s results back to the CRF data). Traceability
permits an understanding of the relationships between the analysis results (tables, listings
and figures in the study report), analysis datasets, tabulation datasets, and source data.
Traceability enables the reviewer to accomplish the following:
• Understand the construction of analysis datasets
• Determine the observations and algorithm(s) used to derive variables
• Understand how the confidence interval or the p-value was calculated in a
particular analysis
• Relate counts from tables, listings, and figures in a study report to the underlying
data

Based upon reviewer experience, establishing traceability is one of the most problematic
issues associated with any data conversion. If the reviewer is unable to trace study data
from the data collection of subjects participating in a study to the analysis of the overall
study data, then the regulatory review of a submission may be compromised. Traceability
can be enhanced when studies are prospectively designed to collect data using a
standardized CRF, e.g., CDASH. Traceability can be further enhanced when a flow
diagram is submitted showing how data move from collection through preparation and
submission to the Agency.

Reviewers evaluating nonclinical studies have similar needs to the above list, though in
the case of nonclinical studies traceability allows the reviewer to understand and trace
relationships between analysis results, single animal listings in the Study Report, and the
tabulation data sets. Traceability between the Study Report and tabulation data can be
enhanced when data in collection systems has a well-defined relationship to the SEND
standard.

8.1.4 Legacy Study Data Conversion to Standardized Study Data

Legacy study data are study data in a non-standardized format, not supported by FDA,
and not ever listed in the Catalog. Sponsors should use processes for legacy data
conversion that account for traceability. Generally, a conversion to a standard format will
map every data element as originally collected to a corresponding data element described
in a standard. Some study data conversions will be straightforward and will result in all
data converted to a standardized format. In some instances, it may not be possible to
represent a collected data element as a standardized data element. In these cases, there
should be an explanation in the RG as to why certain data elements could not be fully
standardized or were otherwise not included in the standardized data submission. The
legacy data (i.e., aCRF, legacy tabulation data, and legacy analysis data) may be needed
in addition to the submission of converted data.

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In cases where the data were collected on a Case Report Form (CRF) or electronic CRF
but were not included in the converted datasets, the omitted data should be apparent on
the annotated CRF and described in the RG. The tabular list of studies in the
Standardization Plan should indicate which studies contained previously collected non-
standard data that were subsequently converted to a standard format.

For nonclinical studies where data are converted to SEND from a previously
established collection system, instances may arise where it is not possible to represent
a collected data element as a standardized data element. In these cases, there should
be an explanation in the nSDRG as to why certain data elements could not be fully
standardized or were otherwise not included in the standardized data submission. As
the Study Report should contain a complete representation of the study data in the
individual animal listings, no non-standardized electronic study data should be
submitted.
Traceability Issues with Legacy Data Conversion
FDA does not recommend a particular approach to legacy clinical study data conversion,
but rather explains the issues that should be addressed so that the converted data are
traceable and adequate to support review.

Table 3 presents some of the issues that can be observed during a review when legacy
study data are converted to SDTM and submitted with legacy analysis datasets.

Table 3: Traceability Issues: Legacy Data Conversion to SDTM Only

1. Limited ability to determine location of collected CRF variables in the converted SDTM
data unless the legacy aCRF is re-annotated.
2. Limited traceable path from SDTM to the legacy analysis data.
3. Limited ability to replicate/confirm legacy analysis datasets (i.e., analysis variable
imputation or derived variables) using SDTM datasets.
4. Limited ability to confirm derivation of intermediate analysis datasets or custom
domains.
5. Difficulty in understanding the source or derivation methods for imputed or derived
variables in integrated/pooled data, supplemental qualifiers, and related records.

Table 4 presents the issues when legacy study data and legacy analysis data are
independently converted to SDTM and ADaM formats, respectively, rather than ADaM
datasets being created directly from the SDTM datasets (converted from legacy study
data).

Table 4: Traceability Issues: Independent Legacy Data Conversion to

SDTM and ADaM
Issues
1. Limited ability to determine location of collected CRF variables in the converted
SDTM data unless the legacy aCRF is re-annotated.
2. Limited traceable path from SDTM to the legacy analysis data.
3. Limited ability to replicate/confirm legacy analysis datasets (i.e., analysis
variable imputation or derived variables) using SDTM datasets.
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Issues
4. Limited ability to confirm derivation of intermediate analysis datasets or custom
domains.
5. Limited traceable path from SDTM to the ADaM datasets.
6. Limited ability to replicate ADaM datasets (i.e., analysis variable imputation or
derived variables) using SDTM datasets.
7. Limited traceable path from ADaM to the Tables, Figures and the Clinical Study
Report (CSR).
8. Difficulty in understanding the source or derivation methods for imputed or
derived variables in integrated/pooled data, supplemental qualifiers, and related
records.

Table 5 presents the issues when legacy data are converted to SDTM and ADaM formats
in sequence (i.e., converting legacy study data to SDTM and then creating ADaM from
the SDTM). The key concern is the traceability from ADaM to the Tables, Figures and
CSR.

Table 5: Traceability Issues: Legacy Data Conversion to

SDTM and ADaM in Sequence
1. Limited ability to determine location of collected CRF variables in the converted
SDTM data unless the legacy aCRF is re-annotated.
2. Limited traceable path from SDTM to the legacy analysis data.
3. Limited ability to replicate/confirm legacy analysis datasets (i.e., analysis
variable imputation or derived variables) using SDTM datasets.
4. Limited ability to confirm derivation of intermediate analysis datasets or custom
domains.
5. Limited traceable path from ADaM to the Tables, Figures and the CSR.
6. Difficulty in understanding the source or derivation methods for imputed or
derived variables in integrated/pooled data, supplemental qualifiers, and related
records.

Legacy Data Conversion Plan and Report

Sponsors should evaluate the decision involved in converting previously collected non-
standardized data (i.e., legacy study data) to standardized data (i.e., SDTM, and ADaM).
Sponsors should provide the explanation and rationale for the study data conversion in
the RG. To mitigate traceability issues when converting legacy data, FDA recommends
the following procedures:

1. Prepare and submit a legacy data conversion plan and report.

• The plan should describe the legacy data and the process intended for the
conversion.
• The report should present the results of the conversions, issues encountered
and resolved, and outstanding issues.
• The plan and report should be provided in the SDRG.
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2. Provide an aCRF, for clinical data, that maps the legacy data elements.
• Sponsors should provide two separate CRF annotations, one based on the
original legacy data, and the other based on the converted data (i.e., SDTM)
when legacy datasets are submitted. The legacy CRF tabulation data should
include all versions and all forms used in the study.

• Record significant data issues, clarifications, explanations of traceability, and

adjudications in the RG. For example, data were not collected or were
collected using different/incompatible terminologies, or were collected but
will not fit into, for example, SDTM format.
• Legacy data (i.e., legacy aCRF, legacy tabulation data, and legacy analysis
data) may be needed in addition to the converted data.

Submission of a Legacy Data Conversion Plan and Report is not expected for nonclinical
studies where data were collected in a previously established data collection system.

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Appendix A: Data Standards and Interoperable Data Exchange

This appendix provides some of the guiding principles for the Agency’s long-term study
data standards management strategies. An important goal of standardizing study data
submissions is to achieve an acceptable degree of semantic interoperability (discussed
below). This appendix describes different types of interoperability and how data
standards can support interoperable data exchange now and in the future.

At the most fundamental level, study data can be considered a collection of data elements
and their relationships. A data element is the smallest (or atomic) piece of information
that is useful for analysis (e.g., a systolic blood pressure measurement, a lab test result, a
response to a question on a questionnaire).

A data value is by itself meaningless without additional information about the data (so
called metadata). Metadata is often described as data about data. Metadata is structured
information that describes, explains, or otherwise makes it easier to retrieve, use, or
manage data. 93 For example, the number 44 itself is meaningless without an association
with Hematocrit and the unit of measurement (e.g. "%"). Hematocrit in this example is
metadata that further describes the data.

Just as it is important to standardize the representation of data (e.g., M and F for male and
female, respectively), it is equally important to standardize the metadata. The expressions
Hematocrit = 44; Hct = 44, or Hct Lab Test = 44 all convey the same information to a
human, but an information system or analysis program will fail to recognize that they are
equivalent because the metadata is not standardized. It is also important to standardize the
definition of the metadata, so that the meaning of a hematocrit value is constant across
studies and submissions.

In addition to standardizing the data and metadata, it is important to capture and represent
relationships (also called associations) between data elements in a standard way.
Relationships between data elements are critical to understand or interpret the data.
Consider the following information collected on the same day for one subject in a study:

Systolic Blood Pressure = 90 mmHg

Position = standing
Systolic Blood Pressure = 110 mmHg
Time = 10:23 a.m.
Time = 10:20 a.m.
Position = lying

93
Metadata is said to “give meaning to data” or to put data “in context.” Although the term is now
frequently used to refer to XML (extensible markup language) tags, there is nothing new about the concept
of metadata. Data about a library book such as author, type of book, and the Library of Congress number,
are metadata and were once maintained on index cards. SAS labels and formats are a rudimentary form of
metadata, although they have not historically been referred to as metadata.
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When presented as a series of unrelated data elements, they cannot reliably be

interpreted. Once the relationships are captured, as shown below using arrows, the
interpretation of a drop in systolic blood pressure of 20 mmHg while standing, and
therefore the presence of clinical orthostatic hypotension, is possible. Standardizing study
data therefore involves standardizing the data, metadata, and the representation of
relationships.

Time = 10:20 a.m. ßà Position = lying ßà Systolic Blood Pressure = 110 mmHg
Time = 10:23 a.m. ßà Position = standing ßà Systolic Blood Pressure = 90 mmHg

With these fundamental concepts of data standardization in mind, data standards can be
considered in the context of interoperable data exchange.

Interoperability
Much has been written about interoperability, with many available definitions and
interpretations within the health care informatics community. In August 2006, the
President signed an Executive Order mandating that the Federal Government use
interoperable data standards for health information exchange. 94 Although this order was
directed at Federal agencies that administer health care programs (and therefore not the
FDA), it is relevant to this guidance because it defined interoperability for use by Federal
agencies:

“Interoperability” means the ability to communicate and exchange data accurately,

effectively, securely, and consistently with different information technology systems,
software applications, and networks in various settings, and exchange data such that
clinical or operational purpose and meaning of the data are preserved and unaltered.

Achieving interoperable study data exchange between sponsors, applicants and FDA is
not an all-or-nothing proposition. Interoperability represents a continuum, with higher
degrees of data standardization resulting in greater interoperability, which in turn makes
the data more useful and increasingly capable of supporting efficient processes and
analyses by the data recipient. It is therefore useful to understand the degree of
interoperability that is desirable for standardized study data submissions.

In 2007, the Electronic Health Record Interoperability Work Group within Health Level
Seven issued a white paper that characterized the different types of interoperability based
on an analysis of how the term was being defined and used in actual practice. 95 Three
types of interoperability were identified: technical, semantic, and process interoperability.
A review of these three types provides insight into the desired level of interoperability for
standardized study data submissions.

Technical interoperability describes the lowest level of interoperability whereby two

different systems or organizations exchange data so that the data are useful. The focus of

94
See Executive Order 13410 available at http://www.cga.ct.gov/2006/rpt/2006-R-0603.htm.
95
See Coming to Terms: Scoping Interoperability for Health Care available at
http://www.hln.com/assets/pdf/Coming-to-Terms-February-2007.pdf.
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technical interoperability is on the conveyance of data, not on its meaning. Technical

interoperability supports the exchange of information that can be used by a person but not
necessarily processed further. When applied to study data, a simple exchange of non-
standardized data using an agreed-upon file format for data exchange (e.g., SAS transport
file) is an example of technical interoperability.

Semantic interoperability describes the ability of information shared by systems to be

understood, so that nonnumeric data can be processed by the receiving system. Semantic
interoperability is a multi-level concept with the degree of semantic interoperability
dependent on the level of agreement on data content terminology and other factors. With
greater degrees of semantic interoperability, less human manual processing is required,
thereby decreasing errors and inefficiencies in data analysis. The use of controlled
terminologies and consistently defined metadata support semantic interoperability.

Process interoperability is an emerging concept that has been identified as a

requirement for successful system implementation into actual work settings. Simply put,
it involves the ability of systems to exchange data with sufficient meaning that the
receiving system can automatically provide the right data at the right point in a business
process.

An example of process interoperability in a regulatory setting is the ability to quickly and

automatically identify and provide all the necessary information to produce an expedited
adverse event report in a clinical trial upon the occurrence of a serious and unexpected
adverse event. The timely submission of this information is required by regulation to
support FDA’s mandate to safeguard patient safety during a clinical trial. Process
interoperability becomes important when particular data are necessary to support time-
dependent processes.

Because the vast majority of study data are submitted after the study is complete,
achieving process interoperability for study data submissions in a regulatory setting is
relatively unimportant, at least for the foreseeable future. It is reasonable to conclude that
it is most desirable to achieve semantic interoperability in standardized study data
submissions.

In summary, the goal of standardizing study data is to make the data more useful and to
support semantically interoperable data exchange between sponsors, applicants, and the
FDA such that it is commonly understood by all parties.

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Appendix B: Trial Summary (TS) Parameters for Submission – Clinical

Sponsors may use additional TS Parameters not listed in the table below if they are
needed to describe the trial.

FDA Desired
TSPARMCD TSPARM FDA Notes
- Clinical
Actual Number of
Y ACTSUB
Subjects
Y ADAPT Adaptive Design
Added on to Existing
Y ADDON
Treatments
Planned Maximum
Y AGEMAX
Age of Subjects
Planned Minimum
Y AGEMIN
Age of Subjects
Comparative
Y COMPTRT
Treatment Name
Confirmed Response
Conditional CRMDUR If applicable.
Minimum Duration
If applicable. the value should be the
CDISC Therapeutic exact listing as in section 5.2 of the
Conditional CTAUG
Area User Guide Technical Conformance Guide.
Use as many rows as needed.
Current Therapy or Where ADDON = ‘Y’. Use as many
Conditional CURTRT
Treatment rows as needed.
Data Cutoff GRPID relates DCUTDTC to
Y DCUTDESC
Description DCUTDESC.
GRPID relates DCUTDTC to
Y DCUTDTC Data Cutoff Date
DCUTDESC.
ECG Reading For QTc evaluation per ICH E14 or ICH
Conditional EGBLIND
Blinded E14/S7B Q&As
ECG Continuous For QTc evaluation per ICH E14 or ICH
Conditional EGCTMON
Monitoring E14/S7B Q&As
ECG Planned For QTc evaluation per ICH E14 or ICH
Conditional EGLEADPR
Primary Lead E14/S7B Q&As
ECG Used Same For QTc evaluation per ICH E14 or ICH
Conditional EGLEADSM
Lead E14/S7B Q&As
For QTc evaluation per ICH E14 or ICH
Conditional EGRDMETH ECG Read Method
E14/S7B Q&As
ECG Replicates at For QTc evaluation per ICH E14 or ICH
Conditional EGREPLBL
Baseline E14/S7B Q&As
ECG Replicates On- For QTc evaluation per ICH E14 or ICH
Conditional EGREPLTR
Treatment E14/S7B Q&As
ECG Twave For QTc evaluation per ICH E14 or ICH
Conditional EGTWVALG
Algorithm E14/S7B Q&As
Extension Trial
Y EXTTIND
Indicator
Planned Country of
Y FCNTRY Use as many rows as needed.
Investigational Sites
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FDA Desired
TSPARMCD TSPARM FDA Notes
- Clinical
If applicable. the value should be the
FDA Technical exact listing as in the appendix of the
Conditional FDATCHSP
Specification Technical Conformance Guide.
Use as many rows as needed.
Healthy Subject
Y HLTSUBJI
Indicator
Trial
For a healthy volunteer study,
Conditional INDIC Disease/Condition
TSVALNF = 'NA'.
Indication
Where STYPE =
Conditional INTMODEL Intervention Model
‘INTERVENTIONAL’.
Where STYPE =
Conditional INTTYPE Intervention Type
‘INTERVENTIONAL’.
Y LENGTH Trial Length
Planned Number of
Y NARMS
Arms
Number of
Y NCOHORT
Groups/Cohorts
Trial Primary
Y OBJPRIM Use as many rows as needed.
Objective
Trial Secondary
Y OBJSEC Use as many rows as needed.
Objective
Ongoing Study
Y ONGOSIND
Indicator
Exploratory If applicable. Use as many rows as
Conditional OUTMSEXP
Outcome Measure needed.
Primary Outcome
Y OUTMSPRI Use as many rows as needed.
Measure
Secondary Outcome
Conditional OUTMSSEC Use as many rows as needed.
Measure
If STYPE = ‘INTERVENTIONAL’ and
Conditional PCLAS Pharmacologic Class
where applicable for INTTYPE.
Pediatric Postmarket
Y PDPSTIND
Study Indicator
Pediatric Study
Y PDSTIND
Indicator
Pediatric
Y PIPIND Investigation Plan
Indicator

Planned Number of
Y PLANSUB
Subjects

Where ‘1’ denotes all subjects

Randomization
Conditional RANDQT randomized to the investigational
Quotient
treatment.

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FDA Desired
TSPARMCD TSPARM FDA Notes
- Clinical
Rare Disease
Y RDIND
Indicator
Y REGID Registry Identifier Use as many rows as needed.
Conditional RLPSCRIT Relapse Criteria If applicable.
Stable Disease
Conditional SDMDUR If applicable.
Minimum Duration
Y SENDTC Study End Date
Y SEXPOP Sex of Participants

Clinical Study
Y SPONSOR
Sponsor
The value should be the exact term listed
in the FDA Data Standards Catalog in
Y SDTMVER SDTM Version Column E. If multiple SDTM Versions
are used for a study the every version
should be listed on each row.
The value should be the exact term listed
in the FDA Data Standards Catalog in
Y SDTIGVER SDTM IG Version Column F. If multiple SDTM IG
Versions are used for a study the every
version should be listed on each row.
Sponsor's Study
Conditional SPREFID If applicable.
Reference ID

If no stopping rule, STOPRULE =

Y STOPRULE Study Stop Rules
‘NONE’.
If applicable. Use as many rows as
Conditional STRATFCT Stratification Factor
needed.

Y SSTDTC Study Start Date

Y STYPE Study Type
Trial Blinding
Y TBLIND
Schema
Y TCNTRL Control Type
Conditional TDIGRP Diagnosis Group Where HLTSUBJI = ‘N’.
Y THERAREA Therapeutic Area
Y TITLE Trial Title Use as many rows as needed.
Trial Phase
Y TPHASE
Classification
Investigational
Conditional TRT Therapy or If STYPE = ‘INTERVENTIONAL’.
Treatment

Y TTYPE Trial Type Use as many rows as needed.

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Appendix C: Trial Summary (TS) Parameters for Submission – Nonclinical

The term ‘Conditional’ means a parameter might not be relevant to a trial or study design.
If the TS Parameter is relevant to the study design and is listed as ‘Conditional’ in the
table below, it should be included in the SEND dataset submitted to the FDA.

Sponsors may use additional TS Parameters not listed in the table below if they are
needed to describe the trial.

FDA
Desired - TSPARMCD TSPARM FDA Notes
Nonclinical
Age of subjects planned for the study population as an
integer. Either AGE or AGETXT should be populated
See Notes AGE Age
(not both). If the planned age is a range, then use
AGETXT
Age of subjects planned for the study population
expressed as a range. Either AGE or AGETXT should
See Notes AGETXT Age Text
be populated (not both). If an age integer value is
available, populate the AGE variable instead
Y AGEU Age Unit
Conditional ASOCSTDY Associated Study If applicable.
Y DOSDUR Dosing Duration See Section 4.1.3.2
End Date/Time of
Y DOSENDTC
Dose Interval
Start Date/Time
Y DOSSTDTC
of Dose Interval
Experimental End
Y EXPENDTC
Date
Experimental
Y EXPSTDTC
Start Date

Y GLPFL GLP Flag

Good Laboratory
Y GLPTYP
Practice Type
Time to Interim
Conditional INTSAC Include when the study has an interim sacrifice
Sacrifice
We recognize that pharmacologic class can change
Pharmacologic
Y PCLASS throughout the drug development timeline. Refer to the
Class
MED-RT for terminology.
The planned number of doses administered per a
specific interval, as defined in the SENDIG Animal
Planned Dose
Conditional PDOSFRQ Rule v1.0. Use of PDOSFRQ is recommended for all
Frequency
study types modelled in FDA-supported SENDIG
versions when relevant.
Planned
Pharmacologic
Y PPTCNAM
Target Common
Name

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FDA
Desired - TSPARMCD TSPARM FDA Notes
Nonclinical
Planned
Pharmacologic
Y PPTEGID
Target Entrez
Gene Identifier
Planned
Pharmacologic
Y PPTEGSYM
Target Entrez
Gene Symbol
Planned
Pharmacologic
Y PPTMDA
Target Mode of
Action
Conditional RECSAC Recovery Period Include when the study has a recovery sacrifice

Route of
Y ROUTE
Administration
Strain/Substrain
Conditional SBSTRAIN If applicable.
Details
Y SDESIGN Study Design
Sex of
Y SEXPOP
Participants
SEND Controlled
Y SNDCTVER Terminology
Version

SEND
Y SNDIGVER Implementation
Guide Version

Y SPECIES Species
Planned Number
Y SPLANSUB
of Subjects

Test Subject
Y SPLRNAM
Supplier

Sponsor's Study
Y SPREFID
Reference ID
Sponsoring
Y SSPONSOR
Organization
Y SSTYP Study Type
Y STCAT Study Category
Y STDIR Study Director

Conditional STENDTC Study End Date If applicable.

Y STITLE Study Title

Y STRAIN Strain/Substrain

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FDA
Desired - TSPARMCD TSPARM FDA Notes
Nonclinical
The status of the study report associated with the
Study Report dataset, as defined in the SENDIG Animal Rule v1.0.
Y STRPSTAT
Status Use of STRPSTAT is recommended for all study types
modelled in FDA-supported SENDIG versions.

Y STSTDTC Study Start Date

Test Facility
Y TFCNTRY
Country
Time to Terminal
Y TRMSAC
Sacrifice
Investigational
Y TRT Therapy or
Treatment
Primary We recognize that the CAS number may not be
Y TRTCAS Treatment CAS immediately available, especially at the opening IND
Registry Number submission.
Primary We recognize that the UNII code may not be
Y TRTUNII Treatment Unique immediately available, especially at the opening IND
Ingredient ID submission.
Y TRTV Treatment Vehicle
Test Facility
Y TSTFLOC
Location
Test Facility
Y TSTFNAM
Name

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Appendix D: Additional Documents Evaluated By FDA

The Agency recognizes that there may be additional documents beyond Therapeutic Area
User Guides (TAUGs), Implementation Guides (IGs), and Models that provide technical
information about how to implement a CDISC standard and that these documents fall
outside the scope of the FDA Data Standards Catalog.

Immediately below is a list of SDO properties that have been evaluated by CBER and
CDER and are considered to align with their current business needs.

• CDISC OCCDSv1.0
• CDISC SEND Tumor Combinations-v1.0
• CDISC ADaM popPK Implementation Guide-v1.0
• CDISC SDTMIG for Medical Devices v1.1 (SDTMIG-MDv1.1)
• CDISC ADaMIG for Medical Devices v1.0 (ADaMIG-MDv1.0)
• CDISC Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

Immediately below is a list of SDO properties that have been evaluated by CBER and
CDER and are not considered to align with their current business needs. Consider
referring to FDA comments that were submitted to the SDO for more details. This list
may not be comprehensive of all properties and absence form this list does not indicate
encouragement to use. Consult with your division for more specific instructions:

• CDISC OCCDSv1.1
• CDISC ADaM Examples of Traceability-v1.0
• CDISC ADaM Metadata Submission Guidlines-v1.0
• CDISC Document: Interim User Guide for COVID-19
• CDISC Document: Guidance for Ongoing Studies Disrupted by COVID-19
• CDISC SENDIG-DARTv1.2

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Appendix E: Example Study Data Folder Structure 96

Study_001S
Study_001L
(Standardized Data Tabulation
(Legacy Data):
Datasets):
M4 (Non-Clinical)

96
If submitting in eCTD v4.0, the application type should be lowercase (nda123456) and the sequence
folder must not have leading zeros (‘1’, not ‘0001’).
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Study_002S Study_002L
(Standardized Data): (Legacy Data):
M5 (Clinical)

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Appendix F: Technical Rejection Criteria for Study Data Validation Important

Information

IMPORTANT

When submitting in eCTD v3.2.2, if a file is referenced within a study section in Module
4 or 5, a STF and ts.xpt must be present to identify the study ID and SSD to which the
file belongs. The ts.xpt needs to contain either a study ID (STUDYID) or Sponsor
Reference ID (SPREFID) value that matches with the STF study ID.

When submitting in eCTD v4.0, if a file is referenced within a study section in Module 4
or 5, a Study Id Study Title keyword, document type keyword, and ts.xpt must be present
to identify the study ID and SSD to which the file belongs. The ts.xpt needs to contain
either a study ID (STUDYID) or Sponsor Reference ID (SPREFID) value that matches
with the keyword study Id.

If a clinical study submitted to CDER or CBER started after December 17, 2016, the files
for NDAs, BLAs, and ANDAs 97 must comply with CDISC standards as specified in the
guidance Providing Regulatory Submissions in Electronic Format—Standardized Study
Data.

If a nonclinical study submitted to CDER started after December 17, 2016, the files for
NDAs, BLAs, and ANDAs (or December 17, 2017, for commercial INDs) 98 must comply
with CDISC standards as specified in the guidance Providing Regulatory Submissions in
Electronic Format—Standardized Study Data.

If a nonclinical study submitted to CBER started after March 15, 2023, the files for NDAs,
BLAs, ANDAs, and commercial INDs 99 must comply with CDISC standards as specified
in the guidance Providing Regulatory Submissions in Electronic Format—Standardized
Study Data.

If a clinical study submitted to CDER or CBER started on or prior to December 17, 2016
and the study contains an xpt dataset (other than the ts.xpt), for NDAs, BLAs, and
ANDAs, 100 a simplified ts.xpt (see Appendix G) file should be submitted. 101

97
This requirement is discussed in the guidance for industry Providing Regulatory Submissions in
Electronic Format—Standardized Study Data (June 2021), available on the FDA guidance web page at
https://www.fda.gov/RegulatoryInformation/Guidances/default.htm, and on the FDA Study Data Standards
Resources web page at https://www.fda.gov/forindustry/datastandards/studydatastandards/default.htm. We
update guidances periodically. For the most recent version of a guidance, check the FDA guidance web
page.
98
Ibid.
99
Ibid.
100
Ibid.
101
The study ID and the SSD are used to determine the start date for the study. For more information, see
the sections 7.1 and 8.2.2.1.
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If a nonclinical study submitted to CDER started on or prior to December 17, 2016, for
NDAs, BLAs, and ANDAs (or December 17, 2017, for commercial INDs), 102 a
simplified ts.xpt (see Appendix G) file should be submitted whether or not the study
contains an xpt dataset (other than the ts.xpt).

If a nonclinical study submitted to CBER started on or prior to March 15 2023, for

NDAs, BLAs, ANDAs, and commercial INDs, 103 a simplified ts.xpt (see Appendix G)
file should be submitted whether or not the study contains an xpt dataset (other than the
ts.xpt). This process will be implemented by CBER March 16, 2023

eCTD validation for study data (Technical Rejection Criteria) WILL APPLY to the
following eCTD sections:
• 4.2 Study Reports
• 5.3 Clinical Study Reports and Related Information

eCTD validation for study data (Technical Rejection Criteria) WILL NOT APPLY to
the following eCTD sections:
• 4.2.1 Pharmacology
• 4.2.2 Pharmacokinetics
• 4.2.3.3 Genotoxicity
• 4.2.3.5 Reproductive and Developmental Toxicity
• 4.2.3.6 Local Tolerance
• 4.2.3.7 Other Toxicity Studies
• 5.3.1.3 In Vitro – In Vivo Correlation Study Reports and Related Information
• 5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies
• 5.3.2 Reports of Studies Pertinent to Pharmacokinetics Using Human Biomaterials
• 5.3.3.5 Population PK Study Reports and Related Information 104
• 5.3.5.3 Reports of Analyses of Data from More than One Study
• 5.3.5.4 Other Study Reports and Related Information
• 5.3.6 Reports of Postmarketing Experience

102
See footnote 80.
103
See footnote 80.
104
PK/PD modeling and simulation study reports can be placed under this section, under Module 5.3.3.5.
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Table 6: eCTD Technical Rejection Criteria for Study Data Expectations 105

Modules & Application

Data Type Center Study Start Date Requirement
Submodules Type

On/Prior to Submit simplified

December 17, 2016 ts.xpt*
NDA, BLA,
ANDA
After Comply with CDISC
December 17, 2016 standards
CDER
On/Prior to Submit simplified
December 17, 2017 ts.xpt*
4.2.3.1, 4.2.3.2, Commercial
Non-clinical
4.2.3.4 IND
After Comply with CDISC
December 17, 2017 standards

On/Prior to Submit simplified

NDA, BLA, March 15, 2023 ts.xpt*
ANDA,
CBER
Commercial
IND After Comply with CDISC
March 15, 2023 standards

Submit simplified ts.xpt

On/Prior to if study contains an xpt
December 17, 2016 dataset
NDA, BLA, (other than ts.xpt)
5.3.1.1, 5.3.1.2, ANDA
5.3.3.1, 5.3.3.2,
CDER & After Comply with CDISC
Clinical 5.3.3.3, 5.3.3.4,
CBER December 17, 2016 standards
5.3.4, 5.3.5.1,
5.3.5.2
Commercial
Rejection criteria not applied
IND

*Rejection criteria will be applied if a study report with a ‘pre clinical study report’, ‘legacy clinical
study report’, or ‘study report body’ designation is included, and/or an xpt file (other than the ts.xpt) is
submitted.

105
For eCTD v3.2.2, this table only applies to eCTD validation 1734, 1735, and 1736. An STF must be
provided for all applications and data types for both CDER and CBER (eCTD validation 1789).
For eCTD v4.0, this table only applies to eCTD validation US-eCTD4-516, US-eCTD4-517, and US-
eCTD4-518. A Study Id Study Title keyword and document type keyword must be provided for all
applications and data types for both CDER and CBER (eCTD4-070). For more information, see the
Specifications for eCTD Validation Criteria available at https://www.fda.gov/drugs/electronic-regulatory-
submission-and-review/electronic-common-technical-document-ectd.

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Appendix G: Examples of ts.xpt Datasets

Examples of simplified ts.xpt datasets for a clinical study:

Sponsors should submit a dataset named ‘ts.xpt’ with four variables (STUDYID,
TSPARMCD, TSVAL, and TSVALNF). Example datasets are shown below.
For a study with a valid SSD (example A):
STUDYID TSPARMCD TSVAL TSVALNF
study ID in STF (eCTD SSTDTC yyyy-mm-dd
v3.2.2)-or- in the Study Id
Study Title keyword (eCTD
v4.0)

For a study without a valid SSD (example B):

STUDYID TSPARMCD TSVAL TSVALNF
study ID in STF (eCTD SSTDTC Use the value ‘NA’
v3.2.2) -or- in the Study Id
Study Title keyword (eCTD
v4.0)

Examples of simplified ts.xpt datasets for a nonclinical study:

Sponsors should submit a dataset named ‘ts.xpt’ with four variables (STUDYID,
TSPARMCD, TSVAL, and TSVALNF) and one row of information. Example datasets
are shown below. 106
For a study with a valid SSD (example C):
STUDYID TSPARMCD TSVAL TSVALNF
study ID in STF (eCTD STSTDTC yyyy-mm-dd
v3.2.2)-or- in the Study Id
Study Title keyword (eCTD
v4.0)

For a study without a valid SSD (example D):

STUDYID TSPARMCD TSVAL TSVALNF
study ID in STF (eCTD STSTDTC Use the value ‘NA’
v3.2.2)-or- in the Study Id
Study Title keyword (eCTD
v4.0)

106
See section 8.2.2 for more information on submitting a simplified TS for non-standardized data.
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Appendix H: HHS Declared Public Health Emergencies and Modifications to Data

Standards Requirements

Table 7. Archive of Information About the Specific Modifications to Data Standards

Requirements that Were Permitted During Specific HHS Declared Public Health
Emergencies (PHEs)

Section Details
4.1.4.7.1 HHS Declared PHE: SARS-CoV-2 (COVID-19) pandemic (Jan. 31, 2020 -
May 11, 2023)
Impacted Electronic Data Standards: The Standard for Exchange of
Nonclinical Data (SEND) for commercial INDs submitted to CDER.
Modification to Requirement: FDA will not require datasets in SEND
format until the time of submission of a marketing application for products
with COVID-19 specific indications.
Means of Public Notification: Implementation announced in Version 4.7.1
of the Study Data TCG (June 2021) and expiration announced in Version 5.2
of the Study Data TCG (May 2023).
Rationale for Modification: To help prevent delays in the initiation of
clinical trials for products with a proposed indication to diagnose, cure,
mitigate, treat, or prevent COVID-19 (COVID-19 specific indications).

Information Published in the Study Data TCG During the PHE:

HHS Declared Public Health Emergency Reference:
There is currently an outbreak of respiratory disease caused by a novel
coronavirus. The virus has been named “SARS-CoV-2” and the disease it
causes has been named “Coronavirus Disease 2019” (COVID-19). On
January 31, 2020, the Department of Health and Human Services (HHS)
issued a declaration of a public health emergency related to COVID-19 and
mobilized the Operating Divisions of HHS.FN1

Impacted Electronic Data Standard(s) and submission type(s):

The Standard for Exchange of Nonclinical Data (SEND) for commercial
INDs submitted to CDER.

Rationale and Data Standards Requirement

Datasets for nonclinical studies that can be modeled in an FDA-supported
Standard for Exchange of Nonclinical Data (SEND) Implementation Guide
(SENDIG) version and were initiated after an applicable SEND
implementation date outlined in the FDA Data Standards Catalog are required
to be submitted in SEND format. However, for the duration of the COVID-19
public health emergency, to help prevent delays in the initiation of clinical
trials for products with a proposed indication to diagnose, cure, mitigate,
treat, or prevent COVID-19 (COVID-19 specific indications), FDA will not
require these datasets in SEND format until the time of submission of a
marketing application for products with COVID-19 specific indications. For
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Section Details
further information and resources including the guidance for industry,
Providing Regulatory Submissions In Electronic Format – Standardized
Study Data, refer to the following website:
https://www.fda.gov/industry/study-data-standards-resources/study-data-
submission-cder-and-cber.

To help simplify submissions for products with COVID-19 specific

indications under commercial IND development that currently do not have
SEND datasets available for a nonclinical study, FDA recommends that a
simplified ts.xpt file be submitted with each nonclinical study requiring
SEND, as outlined in the FDA Data Standards Catalog
(https://www.fda.gov/industry/fda-resources-data-standards/study-data-
standards-resources). The simplified ts.xpt file will help facilitate acceptance
of the IND submission at the electronic gateway. The ts.xpt file should
include the use of the null value (i.e., “NA”) to populate the TSVALNF field.
Further instructions for creation of the simplified ts.xpt can be found in this
Study Data Technical Conformance Guide under Section 8.2.2 and in the
FDA “Simplified ts.xpt creation Guide” (https://www.fda.gov/industry/study-
data-standards-resources/study-data-submission-cder-and-cber). Additional
questions may be directed to [email protected].
FN1
Secretary of Health and Human Services, Determination that a Public
Health Emergency Exists (originally issued Jan. 31, 2020, and subsequently
renewed), available at
https://www.phe.gov/emergency/news/healthactions/phe/Pages/default.aspx.

Information Published in the Study Data TCG During the 180-Day

Wind-Down Period Prior to the Reinstatement of the SEND
Requirement for Commercial INDs (May 12, 2023 – November 7, 2023)

[Notification of PHE Expiration] CDER’s allowance for specific

modifications to the SEND requirements during the COVID-19 Public Health
Emergency (PHE) expired at the end of the day on May 11, 2023, with the
expiration of the COVID-19 PHE declared by the HHS Secretary in
accordance with section 319(a) of the Public Health Service Act (42 U.S.C.
247d(a)). Information about the specific modifications to the SEND
requirements that were permitted during the COVID-19 PHE can be found in
Appendix H.

Certain circumstances that were specific to the COVID-19 PHE warrant the
allowance of additional time to transition from the policies adopted during the
COVID-19 PHE to the reinstatement of the SEND requirement for
commercial INDs. To allow for a wind-down period, SEND will not be
required to be submitted for commercial INDs with COVID-19 indications
for an additional 180 days after the expiration of the COVID-19 PHE (i.e.,
through November 7, 2023). A simplified ts.xpt file may continue to be used
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Section Details
as needed for the additional 180 days, until November 8, 2023. As a
reminder, SEND is required at the time of submission of a marketing
application for products with COVID-19 specific indications, even if SEND
was not submitted under the commercial IND.

As was the case during the COVID-19 PHE, cross-referencing nonclinical

studies submitted to a commercial IND for a COVID-19 indication does not
obviate the requirement of SEND for a commercial IND for a non-COVID-19
indication.

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Glossary
The following is a list of acronyms and terms used in this Guide:

aCRF: Annotated Case Report Form

ANDA: Abbreviated New Drug Application
ADaM: Analysis Data Model
ADRG: Analysis Data Reviewer’s Guide
ADSL: Subject-Level Analysis Data
ASCII: American Standard Code for Information Interchange
CBER: Center for Biologics Evaluation and Research
CDASH: Clinical Data Acquisition Standards Harmonization
CDER: Center for Drug Evaluation and Research
CDISC: Clinical Data Interchange Standards Consortium
CS: Chemical Structure
CSR: Clinical Study Report
eCTD: Electronic Common Technical Document
GLP: Good Laboratory Practice
ICH: International Council for Harmonisation
IND: Investigational New Drug
ISE: Integrated Summary of Efficacy
ISO: International Organization for Standardization
ISO 8601: ISO character representation of dates, date/times, intervals, and durations
of time
ISS: Integrated Summary of Safety
ITT: Intent-to-Treat
LOINC: Logical Observation Identifiers and Codes
MedDRA: Medical Dictionary for Regulatory Activities
MED-RT: Medication Reference Terminology
MOA: Mechanism of Action
NDA: New Drug Application
NDF-RT: National Drug File – Reference Terminology
PDF: Portable Document Format
PHE: Public Health Emergency
PE: Physiologic Effect
RG: Reviewer Guides (e.g., cSDRG, nSDRG, ADRG located in eCTD m4 and
m5)
SDO: Standards Development Organization
SDRG: Study Data Reviewer Guide (original term, replaced by cSDRG and
nSDRG)
cSDRG: SDRG used for clinical data
nSDRG: SDRG used for nonclinical data
SDTM: Study Data Tabulation Model
SEND: Standard for Exchange of Nonclinical Data
SNOMED: Systematized Nomenclature of Medicine
UNII: Unique Ingredient Identifier

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XML: eXtensible Markup Language

XPORT: SAS Transport Version 5

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