1. PhUSE SDE, 28-May-20081 1 A SAS based Solution for define.xml Monika Kawohl Statistical Programming Accovion

2. PhUSE SDE, 28-May-20082 2 Presentation Topic – define.xml Excerpt from the CDISC Draft Metadata Submission Guidelines define.xml Sample

3. PhUSE SDE, 28-May-20083 3 Presentation Outline Electronic Submission Context & Purpose XML Basics define.xml Sections/Elements define.xml Generation Process Expected define.xml Enhancements Summary & Conclusions

4. PhUSE SDE, 28-May-20084 4 Electronic Submission Context & Purpose Define Document Mandatory when Submitting Data to FDA Purpose Describe Structure and Contents of Data Facilitate Review via Standardized Metadata Format Aim: More Efficient Overall Review Process define.xml Preferred Data Definition Format for SDTM define.xml Human- and Machine-Readable Benefit of define.xml not Restricted to Submissions

5. PhUSE SDE, 28-May-20085 5 define.xml Documentation/Samples CDISC Case Report Tabulation Data Definition Specification (define.xml), Version 1.0, February 9, 2005  Sample define.xml Included CDISC Metadata Submission Guidelines, Appendix to the SDTM IG V3.1.1, Draft Version 0.9, July 25, 2007  Sample define.xml Included as Part of Sample Submission CDISC SDTM/ADaM Pilot (Pilot 1), January 31, 2008  Mock Submission Package Available for CDISC Members

6. PhUSE SDE, 28-May-20086 6 XML Basics Schema (Extension:.XSD) Declaration of Elements and their Attributes Prerequisite for Machine-Readability XML File (Extension:.XML) Data and Metadata in Machine-Readable Format Usage of Elements and Attributes as Defined in Schema Style Sheet (Extension:.XSL) Definition of Layout in Browser Tool for Human-Readability Usage of Elements and Attributes as Defined in Schema

7. PhUSE SDE, 28-May-20087 7 <ODM... <ItemGroupDef OID="DM" Name="DM" Repeating="No" IsReferenceData="No" Purpose="Tabulation" def:Label="Demographics" def:Structure="One record per subject" def:DomainKeys="STUDYID, USUBJID" def:Class="Special Purpose" def:ArchiveLocationID="Location.DM">... Style Sheet Reference Interaction of XML, XSL, XSD

8. PhUSE SDE, 28-May-20088 8 define.xml Sections/Elements Data Metadata (TOC) Variable Metadata Variable Value Level Metadata Computational Algorithms Controlled Terminology/Code Lists Annotated CRF Optional: Supplemental Data Definition Document Navigation via Bookmarks and Hyperlinks

9. PhUSE SDE, 28-May-20089 9 Data Metadata

10. PhUSE SDE, 28-May-200810 Data Metadata – XML Code <ItemGroupDef OID="LB" Name="LB" Repeating="Yes" IsReferenceData="No" Purpose="Tabulation" def:Label="Laboratory Tests" def:Structure="One record per lab test per time point per visit per subject" def:DomainKeys="STUDYID,USUBJID,LBTESTCD,VISITNUM,LBTPTNUM" def:Class="Findings" def:ArchiveLocationID="Location.LB">... lb.xpt

11. PhUSE SDE, 28-May-200811 Variable Metadata

12. PhUSE SDE, 28-May-200812 Variable Metadata – XML Code <ItemGroupDef OID="LB"... <ItemRef ItemOID="LB.LBTESTCD" OrderNumber="5" Mandatory="Yes" Role="Topic"/>... <ItemRef ItemOID="LB.LBBLFL" OrderNumber="22" Mandatory="No" Role="Record Qualifier"/>... <ItemDef OID="LB.LBTESTCD" Name="LBTESTCD" DataType="text" Length="8" Origin="CRF" Comment="CRF Pages 5, 10, 15, 20" def:Label="LAB Test or Examination Short Name">... <ItemDef OID="LB.LBBLFL" Name="LBBLFL" DataType="text" Length="1" Origin="Derived" def:Label="Baseline Flag" def:ComputationMethodOID="COMPMETHOD.LBBLFL">

13. PhUSE SDE, 28-May-200813 Variable Value Level Metadata

14. PhUSE SDE, 28-May-200814 Variable Value Level Metadata – XML Code <ItemRef ItemOID="LB.LBTESTCD.ALB" OrderNumber="1" Mandatory="No"/>...... <ItemDef OID="LB.LBTESTCD.ALB" Name="ALB" DataType="float" Length="8" SignificantDigits="1" Origin="CRF" Comment="CRF Pages 5, 15" def:Label="Albumin" def:DisplayFormat="5.1"/>

15. PhUSE SDE, 28-May-200815 Computational Algorithms Complex Derivations Derivations Used More than Once

16. PhUSE SDE, 28-May-200816 Computational Algorithms – XML Code Derive mean of pre-treatment measurements. Create new record with result and flag LBBLFL=&apos;Y&apos;... <ItemDef OID="LB.LBBLFL" Name="LBBLFL" DataType="text" Length="1" Origin="Derived" def:Label="Baseline Flag" def:ComputationMethodOID="COMPMETHOD.LBBLFL"> Masking of Special Characters Ampersand, Apostrophe, Quote, Less Than, Greater Than &apos;  ‘

17. PhUSE SDE, 28-May-200817 Controlled Terminology/Code Lists External Dictionary References incl. Versions e.g., MEDDRA, WHODRUG

18. PhUSE SDE, 28-May-200818 Controlled Terminology/Code Lists– XML Code <ItemDef OID="LB.LBBLFL" Name="LBBLFL" DataType="text" Length="1“ Origin="Derived" def:Label="Baseline Flag" def:ComputationMethodOID="COMPMETHOD.LBBLFL">... <CodeList OID="YF" Name="YF" DataType="text"> YES

19. PhUSE SDE, 28-May-200819 Annotated CRF (blankcrf.pdf)

20. PhUSE SDE, 28-May-200820 Supplemental Data Definitions Optional PDF Document Additional Information Useful for Data Review General Assumptions Flowcharts Derivation Dependancies Reviewers' Guide

21. PhUSE SDE, 28-May-200821 define.xml - SAS Based Generation Process Use All Metadata Already Available in SAS Provide Additional Information Required Set-up at Design and Specification Level Format: Excel Spreadsheets Contents: CDISC Terminology, Study Specific Metadata (CRF Pages) Combine Metadata and Additional Information in SAS Create XML File in SAS Use Stylesheet Provided with CDISC Sample

22. PhUSE SDE, 28-May-200822 Available Metadata vs. Additional Information Required Metadata Section AvailableRequired DatasetSAS Dictionary Tables: Name, Label CDISC Metadata Terminology Class, Structure, Keys Attributes for Machine-readability VariableSAS Dictionary Tables: Name, Label, Type, Format Length, Significant Digits CDISC Metadata Terminology Role, (Origin) Study Specific Metadata (Origin), Comment CRF Page References Derivation Descriptions

23. PhUSE SDE, 28-May-200823 Available Metadata vs. Additional Information Req. - Continued Metadata Section AvailableRequired Variable Value Level Parent Dataset Contents: Values of --TESTCD, --TEST Values of QNAM, QLABEL (Attributes of Parent Variables:) e.g., Type, Length e.g., CRF Page References Adaptation on Value Level: Type, Length, Format Significant Digits, Display Format Origin, Comment Computational Algorithms - Reference Name Derivation Description Code ListsSAS Format Library: Name, Code, Decode, Type -

24. PhUSE SDE, 28-May-200824 Excel File Format for Variable Metadata

25. PhUSE SDE, 28-May-200825 Process Flow SAS Formats Dataset Metadata Variable Metadata Computa- tional Algorithms EXCEL SAS Datasets EXCEL Draft Variable Value Level Metadata EXCEL Edited Variable Value Level Metadata DEFINE.XMLDEFINE.XML Annotated CRF Supple- mental Data Definitions XPT Files

26. PhUSE SDE, 28-May-200826 Automated Consistency Checks SDTM Adherence Checks Availability of Datasets and Variables Order of Variables in Dataset Labels and Data Type Variables with Controlled Terminology (SAS Format Attached) Consistency Checks for Well-formed XML Code Intra Document Links, e.g. Computational Methods Additional Manual Checks Required

27. PhUSE SDE, 28-May-200827 Expected Enhancements – ADaM Integration Aspects of CDISC Pilot 1 => CDISC define.xml Standard Link to Analysis Metadata (s.b.) Link to CSR Table Link to Variable Metadata of ADSL Link to SAP

28. PhUSE SDE, 28-May-200828 Expected Enhancements - Continued Correction of Software Issues with 2007 define.xml Sample Adaptation to Latest CDISC ODM Standard V2.0 => V3.0 Improved Printability Stylesheet Enhancements Alternative Options (define_xml_printable.pdf) Extension for CDISC ADaM Specific Metadata Executable Computational Algorithm?

29. PhUSE SDE, 28-May-200829 Summary & Conclusions Presented Solution Just One of Many Options Driven by Available Skills XML Code Easy to Implement according to CDISC Standards Biggest Challenge: Process Set-up Advantages Early Integration (Design and Specification Level)  Increased Consistency, Lower Risk of Redundancy SDTM Adherence Check Built-in Consistency with SAS Datasets CDISC define.xml Standard is Work in Progress

30. PhUSE SDE, 28-May-200830 Thank you! Questions?