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 
cber-edata@fda.hhs.gov or CDER at cder-edata@fda.hhs.gov 
 
 
 
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) 
 
 
 
 
 
 
 
December 2023 
 
     
       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DATA 
TECHNICAL CONFORMANCE GUIDE 
 
 
 
 
 
 
 
 
 
 
 
 
December 2023 
     
   
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 
Reviewers Guide (SDRG)  
March 2015  2.1 
SDRG, 2.3 Analysis Data Reviewers (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 Reviewers 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 
i   
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 Reviewers 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 cli nical Study Data Reviewers Guide (csdrg.pdf) and 
Stheec tnioonn -1c.1li n(Bicaacl kSgtruoduyn dD)a ta U Rpedvaiteewd eternss eG uide (nsdrg.pdf) to reflect lower case instead of upper 
cSaesceti.o enC 1T.D4  (rOeqrguairneizsa ltoiowne arn cda Sseu mfilme anraym oef st he Guide)  Clarification on terminology section 
Section 2.3 (Analysis Data Reviewers 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 
ii   
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 Reviewers 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 Reviewers Guides)  Updated footnote text 
Section 2.3 (Analysis Data Reviewers 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 
iii   
Revision History 
Date  Version  Summary of Revisions 
Section 2.3 (Analysis Data Reviewers 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 Reviewers Guide)  Added clarifying text 
Section 2.3 (Analysis Data Reviewers 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 
4.7.2  Section 8.2 .2 (Support on Data Validation Rules)  Provided clarification regarding the submission of 
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. 
iv   
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  
 
Section 4.1.4.1 G eCnlearriafli eCdo hnesaiddienrgast i ons: SDTM, SEND, and/or AdaM; clarified the use of the word 
Sreecqtuioirne 6d.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) 
v   
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
vi   
Table of Contents 
1.  INTRODUCTION ............................................................................................................... 1 
1.1  BACKGROUND ...................................................................................................................................... 1 
1.2  PURPOSE ............................................................................................................................................. 1 
1.3  DOCUMENT REVISION AND CONTROL ........................................................................................................ 2 
1.4  ORGANIZATION AND SUMMARY OF THE GUIDE ........................................................................................... 2 
1.5  RELATIONSHIP TO OTHER DOCUMENTS ..................................................................................................... 3 
2.  PLANNING AND PROVIDING STANDARDIZED STUDY DATA .............................................. 4 
2.1  STUDY DATA STANDARDIZATION PLAN ...................................................................................................... 4 
2.2  STUDY DATA REVIEWERS GUIDES ............................................................................................................ 5 
2.2.1  SDRG for Clinical Data ........................................................................................................ 5 
2.2.2  SDRG for Nonclinical Data .................................................................................................. 5 
2.3  ANALYSIS DATA REVIEWERS GUIDE .......................................................................................................... 5 
3.  EXCHANGE FORMAT  ELECTRONIC SUBMISSIONS ........................................................... 6 
3.1  EXTENSIBLE MARK-UP LANGUAGE ............................................................................................................ 6 
3.2  PORTABLE DOCUMENT FORMAT .............................................................................................................. 6 
3.3  FILE TRANSPORT FORMAT ....................................................................................................................... 6 
3.3.1  v5 Transport Format .......................................................................................................... 6 
3.3.2  Dataset Size ........................................................................................................................ 7 
3.3.3  Dataset Column Length ...................................................................................................... 7 
3.3.4  Variable and Dataset Descriptor Length ............................................................................ 7 
3.3.5  Special Characters: Variables and Datasets ....................................................................... 8 
3.3.6  Variable and Dataset Names ............................................................................................. 8 
3.3.7  Variable and Dataset Labels .............................................................................................. 8 
4.  STUDY DATA SUBMISSION FORMAT  CLINICAL AND NONCLINICAL ................................. 8 
4.1  CLINICAL DATA INTERCHANGE STANDARDS CONSORTIUM ............................................................................. 8 
4.1.1  Study Data Tabulation Model ............................................................................................ 9 
  Definition ..................................................................................................................................... 9 
  SDTM General Considerations ..................................................................................................... 9 
  SDTM Domain Specifications ..................................................................................................... 10 
4.1.2  Analysis Data Model ........................................................................................................ 15 
  Definition ................................................................................................................................... 15 
  General Considerations .............................................................................................................. 15 
  Dataset Labels ............................................................................................................................ 16 
  Subject-Level Analysis Data ........................................................................................................ 16 
  Core Variables ............................................................................................................................ 16 
  Key Efficacy and Safety Data ...................................................................................................... 17 
  Timing Variables ......................................................................................................................... 17 
  Numeric Date Variables ............................................................................................................. 17 
  Imputed Data ............................................................................................................................. 17 
  Software Programs..................................................................................................................... 17 
4.1.3  Standard for Exchange of Nonclinical Data ..................................................................... 18 
  Definition ................................................................................................................................... 18 
  General Considerations .............................................................................................................. 18 
  SEND Domain Specification ........................................................................................................ 20 
  Scope of SEND ............................................................................................................................ 23 
4.1.4  General Considerations: SDTM, SEND, and/or ADaM ...................................................... 29 
  Variables in SDTM and SEND: CDISC Required, Expected, and Permissible ............................... 29 
  Dates in SDTM and SEND ........................................................................................................... 30 
  Naming Conventions in SDTM and SEND ................................................................................... 30 
vii   
  SDTM and SEND Versions .......................................................................................................... 30 
  Data Definition Files for SDTM, SEND, and ADaM...................................................................... 30 
  Annotated Case Report Form (aCRF) for SDTM ......................................................................... 31 
  Modification of Requirements During Specific Public Health Emergencies Declared by the 
Secretary of HHS ............................................................................................................................................. 31 
5.  THERAPEUTIC AREA TOPICS ........................................................................................... 32 
5.1  GENERAL ........................................................................................................................................... 32 
5.2  SUPPORTED THERAPEUTIC AREAS ........................................................................................................... 32 
5.2.1  Dyslipidemia Therapeutic Area User Guide v1 ................................................................. 33 
5.2.2  Chronic Hepatitis C Therapeutic Area Data Standard User Guide v1 ............................... 33 
5.2.3  QT Studies Therapeutic Area User Guide v1 .................................................................... 33 
5.2.4  Diabetes Therapeutic Area User Guide v1.0  Supplement for ADaM ............................. 33 
5.2.5  Tuberculosis Therapeutic Area User Guide v2.0 ............................................................... 33 
5.2.6  Diabetic Kidney Disease Therapeutic Area User Guide v1.0 ............................................ 33 
5.2.7  Ebola Therapeutic Area User Guide v1.0 .......................................................................... 33 
5.2.8  Rheumatoid Arthritis Therapeutic Area User Guide v1.0 ................................................. 33 
5.2.9  Malaria Therapeutic Area User Guide v1.0 ...................................................................... 33 
5.2.10  Kidney Transplant Therapeutic Area User Guide v1.0 ...................................................... 33 
5.2.11  TAUG-Influenza v1.1 ........................................................................................................ 34 
5.2.12  Virology Therapeutic Area User Guide v2.1 ..................................................................... 34 
5.2.13  Prostate Cancer Therapeutic Area User Guide v1.0 ......................................................... 34 
5.2.14  Schizophrenia Therapeutic Area User Guide v1.1 ............................................................ 34 
5.2.15  Major Depressive Disorder Therapeutic Area User Guide v1.0 ........................................ 34 
5.2.16  Traumatic Brain Injury Therapeutic Area User Guide v1.0 ............................................... 35 
5.2.17  Duchenne Muscular Dystrophy Therapeutic Area User Guide v1.0 ................................. 35 
5.2.18  Vaccines Therapeutic Area User Guide v1.1..................................................................... 35 
5.2.19  Chronic Obstructive Pulmonary Disease Therapeutic Area User Guide v1 ....................... 35 
5.2.20  Colorectal Cancer Therapeutic Area User Guide v1.0 ...................................................... 35 
5.2.21  Huntingtons Disease Therapeutic Area User Guide v1.0 ................................................. 36 
5.2.22  Post Traumatic Stress Disorder Therapeutic Area User Guide v1.0 ................................. 36 
5.2.23  Clostridium Difficile Associated Diarrhea Therapeutic Area User Guide v1.0 .................. 36 
5.2.24  Acute Kidney Injury v1.0 ................................................................................................... 36 
5.3  LIST OF FDA TECHNICAL SPECIFICATION DOCUMENTS ................................................................................ 36 
5.3.1  Submitting Nonclinical Datasets for Evaluation of Rodent Carcinogenicity Studies of 
Parmaceuticals, Guidance for Industry ............................................................................................... 36 
5.3.2  Submitting Next Generation Sequencing Data to the Division of Antiviral Products ....... 36 
5.3.3  Submitting Clinical Trial Datasets for Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential of Drugs ....................................................................................................... 36 
5.3.4  Bioanalytical Methods Templates .................................................................................... 36 
5.3.5  Submitting Select Clinical Trial Data Sets for Drugs Intended to Treat Human 
Immunodeficiency Virus-1 Infection .................................................................................................... 36 
5.3.6  Submitting Study Datasets for Vaccines to the Office of Vaccines Research and Review 36 
5.3.7  Technical Specifications-Comparative Clinical Endpoint Bioequivalence Study Analysis 
Datasets for Abbreviated New Drug Applications .............................................................................. 36 
5.3.8  Technical Specifications for Submitting Clinical Trial Data Sets for Treatment of 
Noncirrhotic Nonalcoholic Steatohepatitis (NASH) ............................................................................. 36 
5.3.9  Submitting Patient-Reported Outcome Data in Cancer Clinical Trials ............................. 36 
5.3.10  Submitting Clinical Trial Datasets and Documentation for Clinical Outcome Assessment 
Using Item Response Theory ............................................................................................................... 36 
6.  TERMINOLOGY .............................................................................................................. 37 
6.1  GENERAL ........................................................................................................................................... 37 
viii   
6.1.1  Controlled Terminologies ................................................................................................. 37 
6.1.2  Use of Controlled Terminologies ...................................................................................... 37 
  Use of the Specific Controlled Term OTHER ............................................................................. 38 
6.1.3  Maintenance of Controlled Terminologies ....................................................................... 38 
6.2  CDISC CONTROLLED TERMINOLOGY ....................................................................................................... 39 
6.3  ADVERSE EVENTS ................................................................................................................................ 39 
6.3.1  MedDRA ........................................................................................................................... 39 
  General Considerations .............................................................................................................. 39 
6.4  MEDICATIONS .................................................................................................................................... 40 
6.4.1  FDA Unique Ingredient Identifier ..................................................................................... 40 
  General Considerations .............................................................................................................. 40 
6.4.2  WHODrug Global ............................................................................................................. 40 
  General Considerations .............................................................................................................. 40 
6.5  PHARMACOLOGIC CLASS ....................................................................................................................... 41 
6.5.1  Medication Reference Terminology ................................................................................. 41 
  General Considerations .............................................................................................................. 41 
6.6  INDICATION ........................................................................................................................................ 42 
6.6.1  SNOMED CT ...................................................................................................................... 42 
  General Considerations .............................................................................................................. 42 
6.7  LABORATORY TESTS ............................................................................................................................. 42 
6.7.1  LOINC ............................................................................................................................... 42 
  General Considerations .............................................................................................................. 42 
7.  ELECTRONIC SUBMISSION FORMAT ............................................................................... 43 
7.1  ECTD SPECIFICATIONS.......................................................................................................................... 43 
7.2  ELECTRONIC FILE DIRECTORY ................................................................................................................. 44 
7.3  ECTD SAMPLE SUBMISSION .................................................................................................................. 47 
8.  STUDY DATA VALIDATION AND TRACEABILITY ............................................................... 47 
8.1  DEFINITION OF STUDY DATA VALIDATION ................................................................................................ 47 
8.2  TYPES OF STUDY DATA VALIDATION RULES ............................................................................................... 47 
8.2.1  FDA Business and Validator Rules .................................................................................... 47 
8.2.2  Support on Data Validation Rules .................................................................................... 48 
  eCTD Technical Rejection Criteria for Study Data (See Appendix F for more details) ................ 48 
  Technical Rejection Criteria and Use of a Simplified ts.xpt for Clinical Studies .......................... 49 
  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) ............................................................................................................ 49 
8.3  STUDY DATA TRACEABILITY ................................................................................................................... 51 
8.3.1  Overview .......................................................................................................................... 51 
8.3.2  Legacy Study Data Conversion to Standardized Study Data ............................................ 52 
  Traceability Issues with Legacy Data Conversion ....................................................................... 53 
  Legacy Data Conversion Plan and Report .................................................................................. 54 
APPENDIX A: DATA STANDARDS AND INTEROPERABLE DATA EXCHANGE ............................................. 56 
APPENDIX B: TRIAL SUMMARY (TS) PARAMETERS FOR SUBMISSION  CLINICAL .................................. 59 
APPENDIX C: TRIAL SUMMARY (TS) PARAMETERS FOR SUBMISSION  NONCLINICAL ........................... 62 
APPENDIX D: ADDITIONAL DOCUMENTS EVALUATED BY FDA............................................................... 65 
APPENDIX E: EXAMPLE STUDY DATA FOLDER STRUCTURE .................................................................... 66 
APPENDIX F: TECHNICAL REJECTION CRITERIA FOR STUDY DATA VALIDATION IMPORTANT 
INFORMATION .................................................................................................................................... 68 
APPENDIX G: EXAMPLES OF TS.XPT DATASETS ..................................................................................... 71 
ix   
APPENDIX H: HHS DECLARED PUBLIC HEALTH EMERGENCIES AND MODIFICATIONS TO DATA 
STANDARDS REQUIREMENTS. .............................................................................................................. 72 
GLOSSARY  75 
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 cder-edata@fda.hhs.gov or cber-edata@fda.hhs.gov. You can 
submit comments to this document online at https://www.regulations.gov and searching 
Docket No. FDA-2018-D-12160002. 
1.  Introduction 
1.1  Background 
This Study Data Technical Conformance Guide (Guide) provides specifications, 
recommendations, and general considerations on how to submit standardized study data 
using FDA-supported1 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 
  
1.2   Purpose 
This Guide provides technical recommendations to sponsors4 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, pro cessing, 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 standards 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 
(cder-edata@fda.hhs.gov or cber-edata@fda.hhs.gov). 
 
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). 
 
1.3   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.  
 
1.4  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 ac cessed 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 reviewers guide and an analysis data reviewers 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. 
 
1.5  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 Specifications8 
  Guidance to Industry Providing Regulatory Submissions in Electronic Format: 
Submissions Under Section 745A(a) of the Federal Food, Drug, and Cosmetic 
Act9 
  Guidance to Industry Providing Regulatory Submissions in Electronic Format: 
Certain Human Pharmaceutical Product Applications and Related Submissions 
Using the Electronic Common Technical Document Specifications10 
2.   Planning and Providing Standardized Study Data 
2.1   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://advance.phuse.global/display/WEL/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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2.2  Study Data Reviewers 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 The SDRG 
should be file-tagged as data-tabulation-data-definition, with a clear leaf title. 
2.2.1  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). 
2.2.2  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). 
 
2.3  Analysis Data Reviewers Guide 
The preparation of an Analysis Data Reviewers 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 
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 
12For 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 Reviewers Guide for nonclinical studies is not specified. However, 
an example can be found at https://advance.phuse.global/display/WEL/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 Reviewers Guide for clinical studies is not specified. However, an 
example can be found at https://advance.phuse.global/display/WEL/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 Reviewers Guides are separate documents from an overall reviewers guide which is 
placed in Module 1 of the eCTD. 
16 A specific template for an Analysis Data Reviewers Guide is not specified. However, an example can be 
found at https://advance.phuse.global/display/WEL/Deliverables. 
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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. The ADRG should be file-tagged as analysis-data-definition, 
with a clear leaf 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 
3.1   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 CDISCs 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. 
3.2   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 FDAs 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.  
3.3  File Transport Format 
3.3.1   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).  
 
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 
22 See http://www.sas.com 
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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. 
 
3.3.2  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. 
3.3.3  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 USUBJIDs 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 
thr3o.u3.g4h  dVataarsieatb mlee arngde sD.  ataset 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.  
 
Table 1: Maximum Length of Variables and Dataset Elements 
Element  Maximum Length in Characters 
Variable Name  8 
Variable Descriptive Label  40 
Dataset Label  40 
23 http://support.sas.com/techsup/technote/ts140.pdf 
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3.3.5  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.  
 
3.3.6  Variable and Dataset Names 
Please implement the SDO technical specifications when preparing your datasets for 
submission. Datasets submitted in legacy formats should follow the convensions 
described in other documents.24  
  
Use V7 as the valid variable name option (VALIDVARNAME) and extend for the valid 
member name option (VALIDMEMNAME). 
 
3.3.7  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 [ 
4.  Study Data Submission Format  Clinical and Nonclinical  
4.1  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 
24 
https://documentation.sas.com/doc/e n/lrcon/9.4/p18cdcs4v5wd2dn1q0x296d3qek6.htm#n0nfuxt1u6y9jin12
0gszztjh00o 
https://documentation.sas.com/doc/en/lesysoptsref/9.4/p124dqdk8zoqu3n1r4nsfqu5vx52.htm 
25 See http://www.cdisc.org. 
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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 
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 using the replace lifecycle 
operator to update the original file.  
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 
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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 subjects 
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 subjects 
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 subjects 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 
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 
26 CDISC, https://www.cdisc.org/standards/foundational 
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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 
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 
27 Although this convention is inconsistent with the SDTMIG, FDA recommends its use so that Screen 
Failure, Not assigned, and Not tr eated are not specified as a treatment arm.  
28 Technical Specification Document(s) can be found on the FDA Study Data Standards Resources 
webpage, https://www.fda.gov/industry/fda-resources-data-standards/study-data-standards-resources. 
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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) 
  
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 
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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). 
 
For clinical studies, please 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. 
 
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. ISTEST and ISTESTCD names should be specific to the test 
being performed and should not use the same generic name across different tests (i.e., 
referring to multiple Screening, Confirming, or Titer neutralizing antibody test 
results as ISTEST=Antibody). 
 
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. 
 
When submitting a full ts.xpt, please 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. 
29 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/providing-
regulatory-submissions-electronic-fo rmat-standardized-study-data. 
30 https://www.fda.gov/forindustry/datastandards/studydatastandards/default.htm 
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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 subjects 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, 
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 instruments instructions. 
Responses for logically skipped items should be (1) recorded and/or scored according to 
the instructions provided in the instruments 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 logically skipped items are 
available from the instrument developer, then records for logically skipped items should 
be included in the submission dataset with the following:  
  QSSTAT = NOT DONE; 
  QSREASND = LOGICALLY SKIPPED ITEM; and 
  QSORRES, QSSTRESC, and QSSTRESN would be assigned according to the 
instruments instructions. 
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If instructions on how to record and/or score responses to logically skipped items are not 
available from the instrument developer, then records for logically skipped items should 
be included in the submission dataset with the following:  
  QSSTAT = NOT DONE; 
  QSREASND = LOGICALLY SKIPPED ITEM; and 
  QSORRES, QSSTRESC, and QSSTRESN all set to null. 
 
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 
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. 
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, 
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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 
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 
31 Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985). APACHE II: a severity of disease 
classification system. Critical Care  Medicine, 13 (10): 818829.29. 
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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).  
  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 
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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.  
 
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 
sponsors 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; refer 
to Section 7.1 for additional information about the STF. 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
 
For submissions to CBER and CDER, SEND datasets are.x rmeqlu. ired when submitting a 
draft 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, resubmit the updated datasets using the replace operator. Information about 
using the replace operator to update 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 
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. 
34 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/data-standards-catalog 
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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 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. 
 
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  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 
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 3as 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 
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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. 
 
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. 
  BLQ35 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. 
35 According to the FDAs Bioanalytical Method Validation Guidance for Industry (May 2018), study 
samples with concentrations listed b elow 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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  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. 
 
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 
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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 
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 Agencys 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 
36 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/providing-
regulatory-submissions-electronic-fo rmat-standardized-study-data.
37 See CDISC SENDIGv3.1 (Section 1.1) available at www.cdisc.org.  
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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 Agencys 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 These 
data form the basis of the rationale on how the sponsor concluded that it is reasonably 
38
safe to conduct the proposed clinical trial. If the nonclinical pharmacology or .tox icology 
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 isoutlined below
 
A.  SEND is  required39 for s. ingle-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 
38 21 CFR 312.23(a)(8). 
39 See the Data Standards Catalog fo r 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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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-
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. 
 
 
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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 INDs40 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 
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 FDAs 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 
(CDERAnimalModelQualification@fda.hhs.gov). 
 
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 CDERs 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 
40 On March 11, 2020, FDA published a Federal Register notice (85 FR 14205) announcing the dates that 
FDAs support began and requireme nts become effective for specific Animal Rule data standards. That 
document omitted the 36-month implementation period for certain INDs as required by FDAs 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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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, please 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 Agencys 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. 
 
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 required42 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. 
41 21 CFR 312.23(a)(8). 
42 See the Data Standards Catalog fo r 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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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 
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). 
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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, CDERs preference 
is that SENDIG-DARTv1.1 should be used in conjunction with the most recently 
updated and required SENDIG for nonclinical studies, as listed in the FDA Data 
Standards Catalog. 
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. 
For the purposes of SDTM and SEND submissions, all required, expected, and 
permissible variables that were collected, plus any variables that are used to compute 
derivations, should be submitted.43  
 
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. Please follow CDISC guidance for terminology.44 
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 
43 See CDISC SDTM Implementation Guides and the SEND Implementation Guides at www.cdisc.org for 
additional information on variables r eferenced throughout this Guide. 
44 See http://www.cancer.gov/cancertopics/terminologyresources/page6. 
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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, 
PCD TC 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.45 
  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.  
  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 
45 See http://www.cdisc.org. 
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define.xml.46 In addition to the define.xml, a printable define.pdf should be provided if 
the define.xml cannot be printed.47 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-
edata@fda.hhs.gov 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 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. 
  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.48  
 
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).49 Information about the specific modifications to the SEND 
requirement for COVID-19 related commercial IND applications that were permitted by 
46 See https://www.cdisc.org/standards/data-exchange/define-xml. 
47 Detailed FDA PDF specifications  are located on FDAs Electronic Common Technical Document Web 
site, http://www.fda.gov/ectd. 
48 Previously acrf.pdf was called blankcrf.pdf. 
49 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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CDER during the COVID-19 PHE and the 180-day wind-down period can be found in 
Appendix H. 
 
5.  Therapeutic Area Topics 
5.1  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 
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. 
 
5.2  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:  
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5.2.1  Dyslipidemia Therapeutic Area User Guide v1 
5.2.2  Chronic Hepatitis C Therapeutic Area Data Standard User Guide v1 
5.2.3  QT Studies Therapeutic Area User Guide v1 
5.2.4  Diabetes Therapeutic Area User Guide v1.0  Supplement for ADaM 
5.2.5  Tuberculosis Therapeutic Area User Guide v2.0 
5.2.6  Diabetic Kidney Disease Therapeutic Area User Guide v1.0 
5.2.7  Ebola Therapeutic Area User Guide v1.0 
The Ebola Virus Disease (EVD) TAUG identified the ISARIC50 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. 
5.2.8  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. 
5.2.9  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.  
5.2.10 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 
50 International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) 
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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.  
5.2.11 TAUG-Influenza v1.1 
5.2.12 Virology Therapeutic Area User Guide v2.1 
5.2.13 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. 
 
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. 
5.2.14 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.
5.2.15 Major Depressive Disorder Therapeutic Area Use r Guide v1.0 
When reviewing the Major Depressive Disorder TAUG, please also reference the 
FDAs Guidance for Industry document for MDD. Additionally, please consult the 
Division of Psychiatry Products when planning the submission.
 
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5.2.16 Traumatic Brain Injury Therapeutic Area User Guide v1.0 
5.2.17 Duchenne Muscular Dystrophy Therapeutic Area User Guide v1.0  
5.2.18 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 subjects 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 
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, please 
consult with your review team on how the data should be reported. 
5.2.19 Chronic Obstructive Pulmonary Disease Therapeutic Area User Guide v1  
5.2.20 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. 
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5.2.21 Huntingtons Disease Therapeutic Area User Guide v1.0 
5.2.22 Post Traumatic Stress Disorder Therapeutic Area User Guide v1.0 
5.2.23 Clostridium Difficile Associated Diarrhea Therapeutic Area User Guide 
v1.0 
5.2.24 Acute Kidney Injury v1.0 
5.3  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.51 
5.3.1  Submittin g Nonclinical Datasets for Evaluation of Rodent Carcinogenicity 
Studies of Parmaceuticals, Guidance for Industry 
5.3.2  Submitting Next Generation Sequencing Data to the Division of Antiviral 
Products 
5.3.3  Submitting Clinical Trial Datasets for Evaluation of QT/QTc Interval 
Prolongation and Proarrhythmic Potential of Drugs 
5.3.4  Bioanalytical Methods Templates 
5.3.5  Submitting Select Clinical Trial Data Sets for Drugs Intended to Treat 
Human Immunodeficiency Virus-1 Infection 
5.3.6  Submitting Study Datasets for Vaccines to the Office of Vaccines Research 
and Review 
5.3.7  Technical Specifications-Comparative Clinical Endpoint Bioequivalence 
Study Analysis Datasets for Abbreviated New Drug Applications 
5.3.8  Technical Specifications for Submitting Clinical Trial Data Sets for 
Treatment of Noncirrhotic Nonalcoholic Steatohepatitis (NASH) 
5.3.9  Submitting Patient-Reported Outcome Data in Cancer Clinical Trials 
5.3.10 Submitting Clinical Trial Datasets and Documentation for Clinical 
Outcome Assessment Using Item Response Theory 
 
51 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/providing-
regulatory-submissions-electronic-f ormat-standardized-study-data. 
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6.  Terminology 
6.1  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 recommends that 
sponsors use, where appropriate, the terminologies supported and listed in the Catalog. 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. 
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,52 as well as important information on exposure-response relationships53 
and population pharmacokinetics.54 
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 
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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.  
 
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. 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 
It is understood that the expansion of controlled terminology may lag behind scientific 
advancement, and that sometimes there may not be a relevant term within a controlled 
terminologys value set to describe a clinical trial event, finding, or observation. 
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 
52 See the guidance for industry Providing Clinical Evidence of Effectiveness for Human Drugs and 
Biological Products, available at htt ps://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.  
53 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.  
54 See the guidance for industry Population Pharmacokinetics, available at 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs. 
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within the submission, reference them in the relevant RGs, and use them consistently 
throughout the application.  
 
If a sponsor identifies an entire information domain55 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-
FDA supported terms across all nonclinical studies within an application is 
recommended, it is understood that that this may not always be possible. 
6.2  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.56 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.  
6.3  Adverse Events 
6.3.1  MedDRA 
  General Considerations 
MedDRA is used for coding adverse events.57 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 
MedDRA at the time that data across studies are pooled. 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.58 In addition, sponsors should use 
55 By information domain, we mean a logical grouping of clinical or scientific concepts that are amenable 
to standardization (e.g., adverse even t data, laboratory data, and histopathology data, imaging data).  
56 See http://www.cancer.gov/cancertopics/terminologyresources/page6. 
57 See https://www.meddra.org/. 
58 See http://www.meddra.org/standardised-meddra-queries. 
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the MedDRA-specified hierarchy of terms. The SDTM variables for the different 
hierarchy levels should represent MedDRA-specified primary SOC-coded terms.  
6.4  Medications 
6.4.1  FDA Unique Ingredient Identifier  
  General Considerations 
The Unique Ingredient Identifier (UNII)59 should be used to identify active ingredients 
(specifically, active moieties) that are administered to investigational subjects in a study 
(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 FDAs 
Substance Registration System, hosted by the National Library of Medicine.60 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. 
6.4.2  WHODrug Global 
  General Considerations 
World Health Organization (WHO) Drug Global61 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 
59 See http://www.fda.gov/ForIndustry/DataStandards/SubstanceRegistrationSystem-
UniqueIngredientIdentifierUNII/.   
60 The Substance Registration System can be accessed at https://precision.fda.gov/uniisearch. 
61 See http://www.who-umc.org/. 
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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.  
 
6.5  Pharmacologic Class 
6.5.1  Medication Reference Terminology  
  General Considerations 
The Veterans Administrations Medication Reference Terminology (MED-RT)62 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).63 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.64 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. 
62 See MED-RT Documentation (nih.gov). 
63 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. 
64 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.  
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6.6  Indication 
6.6.1  SNOMED CT 
  General Considerations 
The International Health Terminology Standards Organizations (IHTSDO) Systematized 
Nomenclature of Medicine  Clinical Terms (SNOMED CT)65 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).66 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 
tests needed for patient selection), the indication section in a label may not be fully 
represented by available SNOMED CT codes.
 
 
6.7  Laboratory Tests 
6.7.1  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. 
65 Available at http://www.ihtsdo.org/snomed-ct/. 
66 See https://www.fda.gov/ForIndus try/DataStandards/StructuredProductLabeling/default.htm. 
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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 
For information on how to incorporate datasets into the eCTD, please reference 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.67 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. 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.68 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, please 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 using the replace operator. 
 
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, 
it is recommended that these toxicity risk assessments are 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  
 
67 See eCTD Technical Conformance Guide for further details. Available at 
https://www.fda.gov/drugs/electroni c-regulatory-submission-and-review/ectd-resources. 
68 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. 
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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 8.2.2 (Support on Data Validation Rules) of this 
Technical Conformance Guide. 
 
7.2  Electronic File Directory 
Study datasets and their supportive files should be organized into a specific file directory 
structure when submitted in the eCTD69 format (See Figure 1 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. 
 
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 1. 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, please see Appendix E: Example Study Data Folder 
Structure. 
 
69 See http://www.ich.org/products/ctd.html. 
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Figure 1: 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 
3  type performed (e.g., study123, iss, ise). Do not place 
     [study] 
files at 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 
7  Place any split ADaM datasets in this subfolder. 
            split 
Place software programs for ADaM datasets, tables and 
6 
          programs  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. 
7  Place split legacy analysis datasets in this subfolder. 
            split 
Place software programs for legacy analysis datasets, 
6 
           programs  tables and figures in this subfolder. 
Place miscellaneous datasets that dont qualify as 
4  analysis, profile, or tabulation datasets in this subfolder. 
       misc 
This subfolder was formerly named listings. 
4  Place patient profiles in this subfolder. 
       profiles 
Contains subfolders for tabulation datasets. Do not place 
4 
      tabulations  files at this level. 
Place legacy (non-standardized) tabulation datasets in 
5 
       legacy  this folder. 
Place any split legacy tabulations datasets in this 
6 
          split  subfolder. 
Place SDTM tabulation datasets in this subfolder. Should 
       sdtm   5 
only be used in m5 for clinical data. 
6  Place any split SDTM files in this subfolder. 
          split 
Place SEND tabulation datasets in this subfolder. Should 
5 
         send  only be used in m4 for animal data. 
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7.3  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 Electronic Submissions page provides more information 
regarding the test submission process.70 
8.  Study Data Validation and Traceability 
8.1  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).  
8.2  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. 
8.2.1  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 
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.71  
 
70 See https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/submit-ectd-or-
standardized-data-sample-fda.   
71 See http://www.fda.gov/eStudyResources. 
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8.2.2  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 Criteria72 as described below.  
 
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).73 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)74 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 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.  
 
72 The FDA Specifications for eCTD Validation Criteria can be accessed through the eCTD Submission 
Standards catalog. The catalog is loc ated on the FDA eCTD website available at https://www.fda.gov/ectd. 
73 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. 
74 Please refer to Appendix 2 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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  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 
data75 when xpt formatted datasets are submitted to FDA in TRC applicable sections 
within Module 5.  
 
When a xpt formatted dataset is submitted, 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 
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 using one of the STFs (see sections 7.1, 8.2.2.1, and Appendix F) 
is not required to 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 Centers processing system.76,77 
 
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)  
 
Technical rejection criteria have been added to the Specifications for eCTD Validation 
Criteria to determine compliance with the requirements for submitting standardized 
study data78 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. 
 
75 See pp. 6-9 of the Study Data Guidance. 
76 See Appendix F: Technical Reject ion Criteria for Study Data Validation Important Information 
77 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. 
78 See pp. 6-9 of the Study Data Guidance. 
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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).  
 
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 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 Centers processing system.79,80  
 
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) 
 
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 pathologists 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 
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 
79 See Appendix F: Technical Rejection Criteria for Study Data Validation Important Information 
80 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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  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 
 
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://advance.phuse.global/display/WEL/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, please 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 cder-edata@fda.hhs.gov or CBER eData Team at cber-
edata@fda.hhs.gov.  
8.3  Study Data Traceability  
8.3.1  Overview 
An important component of a regulatory review is an understanding of the provenance of 
the data (e.g., traceability of the sponsors 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  
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  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. 
 
8.3.2  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. 
 
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 
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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. 
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). 
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Issues 
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. 
 
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. 
 
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  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 Agencys 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.81 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  
 
81 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 (ext ensible 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.  Position = lying  Systolic Blood Pressure = 110 mmHg 
Time = 10:23 a.m.  Position = standing  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.82 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.83 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 
82 See Executive Order 13410 available at http://www.cga.ct.gov/2006/rpt/2006-R-0603.htm. 
83 See Coming to Terms: Scoping In teroperability 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 FDAs 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 
Conditional  EGBLIND  For QT submissions. 
Blinded 
ECG Continuous 
Conditional  EGCTMON  For QT submissions. 
Monitoring 
ECG Planned 
Conditional  EGLEADPR  For QT submissions. 
Primary Lead 
ECG Used Same 
Conditional  EGLEADSM  For QT submissions. 
Lead 
Conditional  EGRDMETH  ECG Read Method  For QT submissions. 
ECG Replicates at 
Conditional  EGREPLBL  For QT submissions. 
Baseline 
ECG Replicates On-
Conditional  EGREPLTR  For QT submissions. 
Treatment 
ECG Twave 
Conditional  EGTWVALG  For QT submissions. 
Algorithm 
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 
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. 
Rare Disease 
Y  RDIND    
Indicator 
Y  REGID  Registry Identifier  Use as many rows as needed. 
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FDA Desired 
TSPARMCD  TSPARM  FDA Notes 
- Clinical 
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    
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  s ubmission. 
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 are 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. 
 
  Occurrence Dataset Structure (OCCDS) v1.0 
 
 
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 
refering 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: 
 
  OCCDS v1.1 
  ADaM Examples of Traceability v1.0 
  ADaM Metadata Submission Guidlinesv1.0 
  CDISC Document: Interim User Guide for COVID-19 
  CDISC Document: Guidance for Ongoing Studies Disrupted by COVID-19 
 
   
 
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Appendix E: Example Study Data Folder Structure  
 
Study_001S  
Study_001L 
(Standardized Data 
(Legacy Data): 
Tabulation Datasets): 
 
)
l
a
c
i
n
i
l
C
-
n
o
N
(
 
4
M
 
 
 
   
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Study_002S   Study_002L  
(Standardized Data): (Legacy Data):
   
 
 
)
l
a
c
i
n
i
l
C
(
 
5
M
 
     
 
 
   
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Appendix F: Technical Rejection Criteria for Study Data Validation Important 
Information 
I M P O R T A N T 
 
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. 
 
If a clinical study submitted to CDER or CBER started after December 17, 2016, the files 
for NDAs, BLAs, and ANDAs84 must comply with CDISC standards as specified in the 
guidance Providing Regulatory Submissions in Electronic FormatStandardized 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)85 must comply 
with CDISC standards as specified in the guidance Providing Regulatory Submissions in 
Electronic FormatStandardized Study Data.  
 
If a nonclinical study submitted to CBER started after March 15, 2023, the files for NDAs, 
BLAs, ANDAs, and commercial INDs86 must comply with CDISC standards as specified 
in the guidance Providing Regulatory Submissions in Electronic FormatStandardized 
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,87 a simplified ts.xpt (see Appendix G) file should be submitted.88  
 
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), 89 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).  
 
84 This requirement is discussed in the guidance for industry Providing Regulatory Submissions in 
Electronic FormatStandardized St udy 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. 
85 Ibid. 
86 Ibid. 
87 Ibid. 
88 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. 
89 See footnote 80. 
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If a nonclinical study submitted to CBER started on or prior to March 15 2023, for 
NDAs, BLAs, ANDAs, and commercial INDs, 90 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 Information91 
  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 
 
   
90 See footnote 80. 
91 PK/PD modeling and simulation s tudy 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 Expectations92 
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 
After  Comply with CDISC 
IND 
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 one of the three file tags, pre-clinical-study-
report, legacy-clinical-study-report, or study-report-body is included, and/or an xpt file (other than 
the ts.xpt) is submitted. 
 
   
92 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 more information, see 
the Specifications for eCTD Validation Criteria found here: 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  SSTDTC  yyyy-mm-dd   
 
For a study without a valid SSD (example B): 
STUDYID  TSPARMCD  T  SVAL  TSVALNF 
study ID in STF  SSTDTC  Use the value NA 
 
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.93  
For a study with a valid SSD (example C): 
STUDYID  TSPARMCD  TSVAL  TSVALNF 
study ID in STF  STSTDTC  yyyy-mm-dd   
 
For a study without a valid SSD (example D): 
STUDYID  TSPARMCD  T  SVAL  TSVALNF 
study ID in STF  STSTDTC  Use the value NA 
 
   
93 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 edata@fda.hhs.gov. 
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] CDERs 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 Reviewers 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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