Monika Kawohl Senior Statistical Programmer Accovion GmbH, Marburg, Germany

1. CDISC based eSubmissionKey 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

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

4. Coverage - Pilot Submission Structure • eCTD/eNDA hybrid: PDF TOCs, eCTD folders Source: Project Report – CDISC SDTM/ADaM Pilot

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

6. Process Source: Webcast – Results and Lessons from the CDISC SDTM/ADaM Pilot Project

7. Process – Legacy Data Conversion • Source-centric mapping specification • QC of specifications before programming started • Mapping via ETL Tool

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

9. Process – Prescriptive Use of Metadata

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

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

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

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

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

15. Communication of analysis performed ADSL variables SDTM reference CDISC ADaM Concept Sample • Selected variables from adqsadas.xpt

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)

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

18. Link to Analysis Metadata (s.b.) Link to CSR Table Link to Variable Metadata of ADSL Link to SAP Define.xml – Analysis Metadata Sample

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

20. CDISC define.xml Specifics Demo • CDISC Pilot (Variable Metadata) • CDISC Draft Metadata Submission Guidelines(Variable Metadata)

21. CDISC define.xml Specifics Demo • CDISC Pilot (Controlled Terminology) • CDISC Draft Metadata Submission Guidelines(Value Level Metadata)

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)

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

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

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

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 2008(CDISC presentations website) • Revised Pilot Submission Package as provided by CDISC(CDISC Members Only website)

27. Thank you!Questions?