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

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

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

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

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

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

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

Summary Metrics - Structure and Location Data Submissions Summary Metrics - Structure and Location eCTD NDAs since Jan. 1, 2010 (datasets new/updated) NDAs 1025 >> Correct 310 : Incorrect 715 eCTD Studies since Jan. 1, 2010 (datasets new/updated) Studies 8371 >> Correct 2573 : 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

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

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

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

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

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 http://www.sas.com/fda-esub. 13 May 2019

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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. 3.1.2.) define.xml – (expected for standardized) eCTD Life Cycle Mgt for study datasets 13 May 2019

Suggested Approaches to Metadata Content Issues Data Submissions Suggested Approaches to Metadata Content Issues Study Tagging Files Study ID Standard version - 312 vs. 3.1.2. 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

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

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

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

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

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

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 edata@fda.hhs.gov

CDER eData Mailbox For Sponsors, CROs to ask any question related to submission data edata@fda.hhs.gov or cder-edata@fda.hhs.gov

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.

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.

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).

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.

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.

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.

Frequently Asked Questions Q. Is the Study Data Reviewer Guide (SDRG), published by PhUSE Working Group at http://www.phusewiki.org/wiki/index.php?title=Study_Data_Reviewer%27s_Guide 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.

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.

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). 

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.

Any Questions ? Email: edata@fda.hhs.gov