1. CDISC based eSubmission Key Points of the CDISC SDTM/ADaM Pilot
Monika Kawohl
Senior Statistical Programmer
Accovion GmbH, Marburg, Germany

2. Outline Coverage & Aim Process CDISC Model Specifics
SDTM
ADaM
Define.xml
FDA Reviewers‘ Feedback
Summary and Conclusions
CDISC German UG Meeting 02-Sep-2008

3. Coverage Legacy data conversion of 1 study to SDTM
SDTM domains (SAS V5 XPT format)
Annotated CRF
ADaM datasets created from SDTM
Analysis Results based on ADaM datasets
All tied together via Metadata in define.xml
eCTD structure but PDF TOC files
CDISC German UG Meeting 02-Sep-2008

4. Coverage - Pilot Submission Structure
eCTD/eNDA hybrid: PDF TOCs, eCTD folders
Source: Project Report – CDISC SDTM/ADaM Pilot
CDISC German UG Meeting 02-Sep-2008

5. Aim Verify interoperability of CDISC standards
Obtain FDA reviewers‘ feedback
Provide implementation example
Gap analysis of single CDISC Standards
But ...
Not intended as guidance regarding
Contents
Process applied
CDISC German UG Meeting 02-Sep-2008

6. Process CDISC German UG Meeting 02-Sep-2008
Source: Webcast – Results and Lessons from the CDISC SDTM/ADaM Pilot Project
CDISC German UG Meeting 02-Sep-2008

7. Process – Legacy Data Conversion
Source-centric mapping specification
QC of specifications before programming started
Mapping via ETL Tool
CDISC German UG Meeting 02-Sep-2008

8. Process – SDTM/ADaM/define.xml
SDTM “without“ derived => ADaM => SDTM some derived
Facilitates usage of derived data in SDTM review tools
Lineage issue
Explorative use - final decision pending
Definition of metadata at specification level
Prescriptive use of metadata reduces consistency issues
(Suite of SAS macros used available to CDISC members)
Concise computational algorithm descriptions
No programs were submitted
CDISC German UG Meeting 02-Sep-2008

9. Process – Prescriptive Use of Metadata
CDISC German UG Meeting 02-Sep-2008

10. Process – Quality Control (QC)
QC of specifications
QC of programming/mapping against specifications
Option: independent re-programming
QC of Analysis Results against SAP
QC of define.xml
Verifying links and contents
Verifying of technical requirements via tools
Consistency via automated process based on metadata
CDISC German UG Meeting 02-Sep-2008

11. CDISC Model Specifics CDISC SDTM IG V3.1.1 CDISC SDTM V1.1 CDISC ADaM
CDISC ADaM IG was not yet available (in preparation)
CDISC CRT-DDS (define.xml) V1.0
CDISC ODM V1.3 for define.xml
define.xml V1.0 standard based on ODM V1.2
Custom stylesheet
Schema extension for ADaM part
CDISC German UG Meeting 02-Sep-2008

12. CDISC SDTM Specifics
SDTM “without derived“
Includes SDTM required derived variables, e.g., USUBJID, --BLFL, (--DY)
SDTM “with some derived“
Purpose: viewing derived data in standard domain structures
Includes data derived in the ADaM creation step
Population Flags (SUPPDM)
AE Treatment Emergent Flag and MedDRA variables (SUPPAE)
Endpoint Flag and Result Divided by UL of Normal Range (SUPPLB)
Total Score as sum of single scores (New record in QS)
ADaM => SDTM ensures consistency of derivation results
CDISC German UG Meeting 02-Sep-2008

13. CDISC ADaM Specifics Important since SDTM datasets not analysis-ready
ADSL concept of ADaM V2.0
ADSL very helpful for all reviewers
Baseline Characteristics
Treatment Variables
Population Flags
Patient Completion Status
Start and End of Study Drug, Date Patient was Last Observed
All analysis datasets instead of datasets for key analyses
At least Analysis Metadata could be limited to key results
CDISC German UG Meeting 02-Sep-2008

14. CDISC ADaM Specifics (Continued)
Tracebility and transparency of analysis datasets
Clear lineage from CRF to analysis
Clear, unambigous metadata (computation methods)
Include all CRF data + derived data
Appropriate data selection via flags
Facilitate reproduction of analysis results
Allow for sensitivity analysis, test of robustness
Sponsor-specific standards, e.g. variable names, PARAMs
NOW available: Draft ADaM IG
CDISC German UG Meeting 02-Sep-2008

15. CDISC ADaM Concept Sample
Selected variables from adqsadas.xpt
Communication of analysis performed
SDTM reference
ADSL variables
CDISC German UG Meeting 02-Sep-2008

16. CDISC define.xml Specifics
SDTM and ADaM metadata included in 1 define.xml file
Facilitate links between SDTM and ADaM and vice versa
Define.xml included in tabulations and analysis eCTD folder
Navigation improved (define.pdf comparable)
Framed version solves back button issue (IE specific)
CDISC German UG Meeting 02-Sep-2008

17. CDISC define.xml Specifics (Continued)
Valuable sample for Analysis Metadata
List of Analysis Results
Standardized results description incl. links to
Analysis output, underlying dataset, specifications (e.g. SAP)
Layout not 100% consistent with new Draft ADaM documents
CDISC German UG Meeting 02-Sep-2008

18. Define.xml – Analysis Metadata Sample
Link to Analysis Metadata (s.b.)
Link to CSR Table
Link to Variable Metadata of ADSL
Link to SAP
CDISC German UG Meeting 02-Sep-2008

19. CDISC define.xml Specifics (continued)
Deviations from Draft Metadata Submission Guidelines
All derivations described via computation methods
Separate column
Comment column reserved for ADaM links to source datasets
No Variable Value Level Metadata
Limited to Controlled Terminology for test codes and names
Controlled Terminology representation subdivided in
Code Lists (Code and Decode)
Discrete Value Listings
Printing Issue
CDISC German UG Meeting 02-Sep-2008

20. CDISC define.xml Specifics Demo
CDISC Pilot (Variable Metadata)
CDISC Draft Metadata Submission Guidelines (Variable Metadata)
CDISC German UG Meeting 02-Sep-2008

21. CDISC define.xml Specifics Demo
CDISC Pilot (Controlled Terminology)
CDISC Draft Metadata Submission Guidelines (Value Level Metadata)
CDISC German UG Meeting 02-Sep-2008

22. FDA Reviewers‘ Feedback
Standard disclaimer (NOT the general FDA view)
Overall, data were suitable for reviewers‘ needs
Value of SDTM depends on reviewers‘ training status
Use define.xml comments to explain “CDISC jargon“
Integration of Reviewer‘s Guide recommended
ADaM essential since SDTM not Analysis-Ready
ADSL variables, e.g. treatment in each dataset
Derived variables in SDTM helpful
Use of SDTM based review tools
CAVEAT: Results may not be reproducible based on sole SDTM (additional analysis flags to be considered)
CDISC German UG Meeting 02-Sep-2008

23. FDA Reviewers‘ Feedback (continued)
Use of SDTM Review Tool WebSDM
SDTM compliance check
SDTM/define.xml consistency check
Graphical Patient Profiles
Merge of core variables (e.g. sex, treatment) to domains
Merge of SUPPQUAL to parent domains
Export of combined data to other tools
Reviewers at time of Pilot more familiar with other tools
CDISC German UG Meeting 02-Sep-2008

24. FDA Reviewers‘ Feedback (continued)
Data documentation via define.xml
Concept, Content, Navigation, Reviewer‘s Guide 
Printing 
Sample for multiple-studies submission is missing
FDA committed to standards
Success of SDTM/ADaM depends on
Training (implementers and reviewers)
Experience (implementers and reviewers)
Availability of suitable review tools
CDISC German UG Meeting 02-Sep-2008

25. Summary and Conclusions
Overall, data were suitable for reviewers‘ needs
Very helpful implementation example
No guidance => evolution of CDISC standards
Importance of ADaM when submitting SDTM
Familiarity with CDISC models is a key factor
Implementer
Reviewer
Watch out for next pilot: multiple-studies safety data
CDISC German UG Meeting 02-Sep-2008

26. References
CDISC SDTM/ADaM Pilot Project – Project Report (SDTMADaMPilotProjectReport.pdf)
Slides from the CDISC Pilot Webcast (bmc_cdisc_sdtm-adam_pilot_v-2.pdf)
Cathy Barrow‘s presentation at CDISC EU IC (CDISC presentations website)
Revised Pilot Submission Package as provided by CDISC (CDISC Members Only website)
CDISC German UG Meeting 02-Sep-2008

27. Thank you! Questions?