Implementation Considerations for FDA Submissions

1. New FDA Documents -Discussion of Implementation Considerations Monika Kawohl Principal Statistical Programmer Accovion GmbH, Marburg, Germany

2. FDA Submissions - Experiences • Questions • Who has been involved in preparing SDTM for submission to FDA? • Who has been involved in preparing ADaM for submission to FDA? • Who has been involved in preparing CDISC mock submissions? • Who has experiences with submitting in other/hybrid data formats? • Who has been involved in discussions with the FDA? • Experiences with submission of data pools in CDISC formats to support integrated analyses? • Who has contacted the FDA with general questions orWho provided feedback on current FDA documents? • For standardized data submission questions, contact: EDATA@fda.hhs.gov. • For center specific contacts see:http://www.fda.gov/ForIndustry/DataStandards/StudyDataStandards/default.htm

3. Chance to Get Involved in Discussions with FDA • Support the FDA/PhUSE Collaboration • see http://www.phuse.eu/css • FDA/PhUSE Working Groups • Data Validation and Quality Assessment • Standardizing Data within the Inspection Site Selection Process • Challenges of Integrating and Converting Data across Studies • Standards Implementation Issues with the CDISC Data Models • Development of Standard Scripts for Analysis and Programming • Non-Clinical Road-map and Impacts on Implementation

4. CDER Common Data Standards Issues Document • Version 1.1 (Dec-2011) Updates regarding SDTM • Implementation of Amendment 1 to SDTM 1.2 strongly preferred • Subject Elements (SE) mandatory SDTM domain • EPOCH in every subject-level domain • ELEMENT/ETCD desired but not requested • SUPPAE.AETRTEM • Splitting domains (> 1GB) • provide split domains in separate subdirectory SPLIT??? • File size considerations • use required maximum length of variableinstead of 200 for every character variable

5. CDER Common Data Standards Issues Document • FDA “Expected“ SDTM Variables • Baseline flags (--BLFL) in findings domains • Study day (-DY) for every -DTC • derived based on RFSTDTC • RFSTDTC = start of treatment in most study designs • Death diagnosis or comments in pathology reports • SUBJID = Subject identifier used in Study Report • define.xml + define.pdf (printable version, no need for hyperlinks)

6. CDER Common Data Standards Issues Document • Version 1.1 Updates regarding ADaM • Analysis Datasets should include • appropriate numeric time variables(e.g. with value 8 for “Week 8“) • basic demographic variables (e.g. sex) • all covariates named in the protocol • Analysis datasets should be derivable from SDTM • To support traceability from results to collected data • Not new but important! • General Recommendation: Contact the FDA

7. CDISC/FDA Webinar • CDISC Standards In the Regulatory Submission Process, presented 26 January 2012 • recorded webinar • presentation slides • available at http://www.cdisc.org/webinars • Follow-up on topics of special interest • FAQ Database from CDER Data Standards Questions Team • Accessible by the public? • Importance of Reviewer‘s Guide for adequate documentation • Standard template?

8. FDA Standardized Study Data Draft Guidance • http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292334.pdf (Feb-2012)

9. FDA Study Data Standards Resources • http://www.fda.gov/ForIndustry/DataStandards/StudyDataStandards/default.htm

10. Implementing SDTM Amendment 1, FDA Docs. • Information for new DM variables • Store data in DM only vs. DM + another Domain? • Date/Time of Informed Consent • Date/Time of Death • Date/Time of End of Participation • Derive AE Treatment Emergent Flag in SDTM (SUPPAE)? • When to use SUPPQUAL? • Generally provide SDTM variables “Expected“ by FDA? • Process to ensure appropriate variable length • Process for splitting domains and how to document it

11. Implementing SDTM Amendment 1, FDA Docs. • How to create the define.pdf? • Always create a Reviewer‘s Guide? • Per submission datasets folder(i.e., separate ones per set of SDTM or ADaM data)? • Describing SDTM/ADaM and/or multiple studies together • Contents? • OpenCDISC SDTM (/ADaM) validation • Timing of compliance checks within the process? • Describing/addressing issues • Define.xml schema validation/OpenCDISC define.xml validation • How to describe which SDTM versions and appendices are used?

12. Implementing Controlled Terminology (Updates) • Excerpt from Draft Guidance: Providing Regulatory Submissions in Electronic Format - Standardized Study Data (Feb-2012)“When planning a study (including the design of case report forms, data management systems, and statistical analysis plans), the sponsor should identify which FDA-supported standard terminologies to use for submission.If a sponsor identifies a concept for which no standard term exists, we recommend 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. We consider this good terminology management practice for any organization. The creation of custom terms for a submission is discouraged (i.e., so called extensible code lists)...“ • Use of CDISC New Term Request Webpage? • Experiences/Response Times? • How to deal with CDISC CT Updates within a project? • Documentation of CT version(s) used • How to distinguish between CDISC CT values and sponsor extensions? • Experiences with Updated Trial Summary (TS) domain?

13. Trial Summary (TS) Update • Alignment with ClinicalTrials.gov • New Trial Summary Parameters • Indication of Use per Trial Summary Parameter • Required • Conditionally Required • Expected • Introduction of NULL FLAVOR Variable • Coded Reason if TSVAL=missing • Introduction of underlying CT information variables

14. Trial Summary (TS) Update Sample