1. Data Submissions Douglas Warfield, Ph.D. Technical Lead, eData Team
Office of Business Informatics
U.S. Food and Drug Administration
Center for Drug Evaluation and Research
13 May 2019

2. Disclaimer
Presentation represents this U.S. Food and Drug Administration (FDA) presenter’s current thinking on these topics. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
13 May 2019

3. Data Submissions NDA Structure and Content Supplemental Data
Business Informatics & Pre-review Analyses
NDA Structure and Content
Supplemental Data
Related Records
Metadata Content
Traceability (includes CRF data)
* NDA – New Drug Application
* CRF – Case Report Form
13 May 2019

4. Data Submissions Improved validation
Business Informatics & Pre-review Analyses
Robust analyses and reporting of submission data and metadata (including standards)
Automatic validation for review tools
Validation of file/data types in the submission
Improved validation
13 May 2019

5. FDA Reference Guidance
Data Submissions
FDA Reference Guidance
Study Data Specifications
Study Data Standards Resources
CDER Common Data Standards Issues Document
Study Tagging File Specification and Related Files
Electronic Common Technical Document (eCTD)
Electronic Regulatory Submissions and Review Helpful Links
PDUFA REAUTHORIZATION PERFORMANCE GOALS AND PROCEDURES FISCAL YEARS 2013 THROUGH 2017
13 May 2019

6. CDISC Referenced Guidance
Data Submissions
CDISC Referenced Guidance
Case Report Tabulation Data Definition Specification (define.xml)
SEND - Standard for Exchange of Nonclinical Data
SDTM - Study Data Tabulation Model
ADaM - Analysis Data Model
Study Data Tabulation Model Metadata Submission Guidelines (SDTM-MSG)
* Clinical Data Interchange Standards Consortium (CDISC)
13 May 2019

7. Data Submissions Main Topics Structure and Content Dataset Placement
Dataset File Size
Structure of Data
Content of Metadata
Traceability
13 May 2019 7

8. Summary Metrics - Structure and Location
Data Submissions
Summary Metrics - Structure and Location
eCTD NDAs since Jan. 1, 2010 (datasets new/updated)
NDAs >> Correct 310 : Incorrect 715
eCTD Studies since Jan. 1, 2010 (datasets new/updated)
Studies >> Correct : Incorrect 5798
(includes ISS, ISE, BIMO, etc. as Studies)
eCTD CDISC since Jan. 1, 2010 (datasets new/updated)
Studies Tabulations and/or Analysis 5112
47% Tabulations (SEND or SDTM) : 18 % Analysis (ADaM)
100% Tabulations Correct
0% ADaM Correct
13 May 2019

9. Study Data Specifications
Data Submissions
Datasets Placement
Module
datasets
folder
Study analysis
datasets
folder (ADaM)
Study analysis
datasets
folder (legacy)
Study
tabulations
folder
Study Data Specifications
13 May 2019

10. Datasets Placement – Module 4
Data Submissions
Datasets Placement – Module 4
Study
folder
Study analysis
folder
Study
tabulations
folder (send)
Study Data Specifications
13 May 2019

11. Datasets Placement – Module 5
Data Submissions
Datasets Placement – Module 5
Study
folder
Study analysis
folder
Study
tabulations
folder (sdtm)
Study Data Specifications
13 May 2019

12. Study Data Specifications
Data Submissions
Programs Placement
Study analysis
programs
folder (ADaM)
Study analysis
programs
folder (legacy)
Study Data Specifications
13 May 2019

13. Study Data Specifications (2.0) - Datasets Format
Data Submissions
Study Data Specifications (2.0) - Datasets Format
SAS XPORT Transport File format
SAS XPORT transport file format, also called Version 5 SAS transport format, is an open format published by the SAS Institute. The description of this SAS transport file format is in the public domain. Data can be translated to and from this SAS transport format to other commonly used formats without the use of programs from SAS Institute or any specific vendor.
Version
In SAS, SAS XPORT transport files are created by PROC XCOPY in Version 5 of SAS software and by the XPORT SAS PROC in Version 6 and higher of SAS Software. SAS Transport files processed by the CPORT SAS PROC cannot be processed or archived by the FDA.
Sponsors can find the record layout for SAS XPORT transport files through SAS technical support technical document TS-140. This document and additional information about the SAS Transport file layout can be found on the SAS World Wide Web page at
13 May 2019

14. Data Submissions Datasets Submitted
Transport files
Metadata files
Study Data
Reviewers Guide
Clinical (m5) ADaM datasets, metadata, and study data reviewer’s guide with study data.
13 May 2019

15. Study Data Specifications
Data Submissions
Programs Submitted
Should be ASCII (text) files viewable by text editor (notepad, wordpad, etc.).
Study Data Specifications
13 May 2019

16. Subject Profiles & Listings Placement
Data Submissions
Subject Profiles & Listings Placement
Study
folder
Study listings
folder
Study
Subject profiles
folder
Study Data Specifications
13 May 2019

17. Study Data Definitions and Guides
Data Submissions
Study Data Definitions and Guides
define.xml
Study Data
Reviewer’s Guide
SEND (nonclinical) data definitions and reviewer’s guide with study data.
13 May 2019

18. Study Data Definitions and Guides
Data Submissions
Study Data Definitions and Guides
Annotated CRF
define.xml
and define.pdf
Study Data
Reviewer’s Guide
SDTM (clinical) data definitions, annotated CRF, and reviewer’s guide with study data.
13 May 2019

19. Study Data Definitions and Guides
Data Submissions
Study Data Definitions and Guides
define.xml
Study Data
Reviewer’s Guide
Clinical (m5) ADaM data definitions and reviewer’s guide with study data.
13 May 2019

20. Data Submissions Legacy Tabulations Legacy Tabulations
May have
Annotated CRF
define.pdf
Legacy nonclinical (m4) or clinical data (m5) definitions and reviewer’s guide with study data.
13 May 2019

21. Dataset File Size - Split
Data Submissions
Dataset File Size - Split
Study Data Specifications (2.0) - split datasets over 1 gigabyte
Each dataset is provided in a single transport file. The maximum size of an individual dataset is dependent on many factors. In general, datasets greater than 1 GB in size should be split into smaller datasets, each no larger than 1GB in size. Datasets divided to meet the maximum size restrictions should contain the same variable presentation so they can be easily concatenated.
Datasets which are divided should be clearly named to aid the reviewer in reconstructing the original dataset, e.g., xxx1, xxx2, xxx3, etc. The files that have been divided and need to be concatenated should be noted in the data definition document. This documentation should identify the range of subject numbers (or other criteria used for division) in the label for each of the divided datasets.
13 May 2019

22. Direction - New Transport
Data Submissions
Dataset File Resize
Resize by max. column width (70% average reduction)
A helpful approach
CDISC Operational Data Model (ODM) Pilot
Direction - New Transport
Study Container/Package Pilot
Ideas - Compression
13 May 2019

23. Data Submissions Structure of Data
Data models and techniques for representing study research data and collection processes.
Points for Consideration:
Splitting datasets – many techniques used.
Supplemental Qualifiers – too often/many.
Related Records – joining (data types).
Custom Domains – new to reviewers.
Intermediate files are not defined in standard.
13 May 2019

24. Structure of Data: Splitting Datasets
Data Submissions
Structure of Data: Splitting Datasets
A helpful approach – Splitting by category variable (e.g. lab type)
Direction – Collect, Tabulate, Size to minimize dataset size
Ideas – Use more efficient data types and collect only what is needed
13 May 2019

25. Structure of Data: Supplemental Qualifiers
Data Submissions
Structure of Data: Supplemental Qualifiers
A helpful approach – Use sparingly
Direction – Expand main domain to include often used suppquals
Ideas – Use more efficient “data types” and collect only what is needed
13 May 2019

26. Structure of Data: Related Records (RELREC)
Data Submissions
Structure of Data: Related Records (RELREC)
A helpful approach – Data Types match for joining the two related domains
Direction – Enhanced to allow more efficient and effective relationships
Ideas – Related Records by Domain (similar to suppqual)
13 May 2019

27. Structure of Data: Custom Domains
Data Submissions
Structure of Data: Custom Domains
A helpful approach – Model from existing domain (SDTM IG Example)
Direction – Add more standardized domains
Ideas – Specialized therapeutic domains
13 May 2019

28. Metadata Content Issues
Data Submissions
Metadata Content Issues
Study Tagging Files (content)
Study ID and Study Name
Several metadata tags and folder name
Often not the “same”
Standard version used
(312 vs )
define.xml – (expected for standardized)
eCTD Life Cycle Mgt for study datasets
13 May 2019

29. Suggested Approaches to Metadata Content Issues
Data Submissions
Suggested Approaches to Metadata Content Issues
Study Tagging Files
Study ID
Standard version
- 312 vs
Consistent use in standards.
Better specifications.
Expected by FDA.
Better specifications.
define.xml
Use revising datasets.
Update not delete/new.
eCTD Life Cycle Mgt
13 May 2019

30. Standards and Traceability
Data Submissions
Standards and Traceability
Standards Selection
Case Report Tabulation Data Definition Specification (CRT-DDS - define.xml)
Standard for Exchange of Nonclinical Data (SEND)
Study Data Tabulations Model (SDTM)
Analysis Data Model (ADaM)
Traceability in Standards Implementation
13 May 2019

31. Data Submissions Reviewer Perspective Traceability
Study Report >> Analyses >> Data Collected >> eCRF
13 May 2019

32. Current Process – Traceability
Data Submissions
Current Process – Traceability
eCRF
(standardized)
Raw Data*
(not submitted)
Analysis
Creating SDTM and Analysis data from the raw data* is problematic.
SDTM
* Raw Data – research data collected in original tabular electronic form.
13 May 2019

33. Best Practice – Traceability
Data Submissions
Best Practice – Traceability
eCRF
(standardized)
Standardized Raw Data* should create SDTM, and SDTM should then create Analysis (ADaM preferred)
Raw Data*
(not submitted)
Standardized eCRF create SDTM, and SDTM should then create Analysis (ADaM preferred)
SDTM
Analysis
* Raw Data – research data collected in original tabular electronic form.
13 May 2019

34. eData Team’s Perspective on submitting data!!
Data Submissions
Approaches, Direction, Ideas
Structure and Content
Dataset File Size
Structure of Data
Content of Metadata
Traceability
eData Team’s Perspective on submitting data!!
13 May 2019

35. Frequently Asked Questions from eData Mailbox
Lisa Lin
Program Management Officer
eData Team
Office of Business Informatics
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
As Doug mentioned early, eData team has a lot of responsibilities. One of our eData team tasks is answering questions from sponsors via

36. CDER eData Mailbox
For Sponsors, CROs to ask any question related to submission data or

37. Frequently Asked Questions
Q. What are the standards version acceptable by FDA now?
A. Please refer to Data Standards Catalog at Study Data Standards Resources website for the current standards versions preferred by the Agency.

38. Frequently Asked Questions
Q. We plan to submit the datasets without the folder mapping as outlined in the Study Data Specifications (we do not have subfolders for legacy, sdtm, adam, legacy). Is this acceptable?
A. No. You should submit datasets with the folder structure outlined in the Study Data Specifications, because we have automated processes that will utilize this folder structure to identify your data for use in standard review tools.

39. Frequently Asked Questions
Q. Currently we have some documents in .sas file format for module 5, could you please advise if it is acceptable to submit .sas file format and what is the agency recommendation?
A. Any submitted programs (scripts) generated by an analysis tool should be provided as ASCII text files or PDF files. If the programs created by the analysis tool use a file extension other than .txt, the file name should be changed including the native file extension for the ASCII text program files, e.g. adsl_r.txt or adsl_sas.txt, etc. For file format types accepted by eCTD, please refer to Electronic Common Technical Document (eCTD).

40. Frequently Asked Questions
Q. The define.xml files have numerous supporting files that are needed to be able to open and read the file properly, like .xsd, .htm, .css, .html, .gif, .xsl. Would you please confirm that it is acceptable to submit these files and where to place them?
A. The Agency prefers that sponsors include these files with the define.xml, per the Study Data Specifications, which also references the Case Report Tabulation Data Definition Specification (define.xml). Please place them at the same location as the define.xml.

41. Frequently Asked Questions
Q. For define files, if submitting a define.xml, does a define.pdf also need to be submitted?
A. Please refer to CDER Common Data Standards Issues Document (pg. 4), CDER prefers that sponsors submit both the define.pdf and define.xml formats. The define.pdf is primarily for printing purposes and need not include hyperlinks.

42. Frequently Asked Questions
Q. Is the sponsor required to submit data in both SI and US Conventional units in SDTM, or just US Conventional units?
A. FDA is exploring the possibility of publishing a core list of lab test where conversion to US conventional units for submission is preferred. In the meantime, we suggest you to check with the review division as early as possible to minimize the potential of conversion needs during review. Please see the CDER/CBER Position on Use of SI Units for Lab Tests  for more information.

43. Frequently Asked Questions
Q. Is the Study Data Reviewer Guide (SDRG), published by PhUSE Working Group at considered as the preferred SDRG by CDER?
A. Yes, the SDRG was developed jointly by CDER, industry and CDISC. It is preferred as an optional mean for providing a description of standardized (SDTM) data sets. It is intended to supplement the Define file, and provide standard documentation that will serve as an aid for reviewers as they manage/use the submission data.

44. Frequently Asked Questions
Q. Can an electronic submission based on CDISC standards include studies whose datasets were developed using different versions of SDTM (e.g. Study A = V3.1.1, Study B = V3.1.2, etc.)?
A. Yes, different studies within an application may reflect different supported versions (e.g. a submission may have some phase II studies in SDTM v3.1.2 and all phase III studies in v3.1.3). When pooling data across multiple studies (e.g. ISS, ISE), the integration datasets should be submitted in one standardized version.

45. Frequently Asked Questions
Q. Shall we use the LATEST version of openCDISC published by opencdisc.org for our submissions?
A. Yes, Agency prefers sponsors using the latest version of OpenCDISC to validate their data before submission.  OpenCDISC is a tool helping Agency and sponsors to check the conformance of standardized data.  Our ultimate goal is to have sponsors submitting quality standardized data and help reviewers to do better review in timely manner.  OpenCDISC current version includes more checks (covering CDISC conformance rules, issues listed in Study Data Specifications and CDER Common Data Standards Issues Document). 

46. Frequently Asked Questions
Q. When will CDISC Standardized Data be required?
A. At this time, SDTM is not mandated as a submission standard. However, as part of its efforts to continue the advancement of review efficiency, FDA prefers sponsors to submit study data in conformance with the standards listed in the Data Standards Catalog at Study Data Standards Resources website.

47. Any Questions ?