1. CONFIDENTIAL Integration of SDTM File Creation into Study Analysis: A Practical Approach Anna Kunina, Edzel Cabanero, Efim Dynin, Lindley Frahm 04Apr2008

2. CONFIDENTIAL Introduction About CV Therapeutics –Company focused on applying molecular cardiology to the discovery and development of molecular drug for the treatment of cardiovascular diseases. –One product on the market, 3 submissions are currently under review (1 in Europe, 2 in US) About authors –Statistical programmer-analysts who developed and implemented presented approach at CVT Biostatistics department.

3. CONFIDENTIAL CRTs/SDTM submissions based on CDISC 2 submissions based on CDISC version 2 – 2002, 2005. Prepared by Clinical Data Management in SAS. 2 submissions based on CDISC version 3.1.1 – 2007. Prepared by Statistical Programming in SAS. In addition 5 individual studies SDTM files submitted along with final study reports. Overall SDTM files according to CDISC version 3.1.1 were submitted for 19 studies, 2 studies SDTM files are currently under internal review. Currently CVT does not submit ADaM files.

4. CONFIDENTIAL Submissions based on CDISC version 2 Method #1– parallel aproach Raw Data Analysis Files CRTs/ SDTM Files TLFs SAS Programs SAS Programs

5. CONFIDENTIAL Advantages Easy to achieve consistency across studies (standard programs) SDTM files are created only if and when they are needed. Disadvantages ●Main problem – discrepancies between SDTM files and analysis - duplicate efforts to create analysis type variables in SDTM, that have already been derived in analysis - still no guarantee that analysis and SDTM files match - need to cross check

6. CONFIDENTIAL Method #2 – ‘Mesh Approach’ Raw Data SAS Programs * Analysis Files TLFs SDTM Files * A single SAS Program creates both an Analysis File and an SDTM file.

7. CONFIDENTIAL Advantages No problem of consistency between analysis and SDTM files, no need for cross-checking. SDTM files prepared well in advance before submission. Data checking fits well in the process. Disadvantages Analysis files and SDTM files are too dependent on each other, no room for flexibility. Even a small change in one part leads to rerun of the whole process. SDTM files may not be required for the project.

8. CONFIDENTIAL Method #3 recommended by CDISC – ‘SDTM Files first’ Raw Data SDTM Files Analysis Files TLFs

9. CONFIDENTIAL Advantages Consistency between SDTM files and analysis is built in the process. SDTM files prepared well in advance before submission.

10. CONFIDENTIAL Disadvantages Changes in SDTM files (change of CDISC version, changes to have cross-studies consistency in submission, etc.) do require rerun of analysis. Even if there is no impact in content, the audit trail is destroyed. SDTM files may not be required for the project. Extra manipulations to create supplemental qualifier SDTM files and then integrate them back into analysis files. Need to link supplemental qualifiers with main domains makes it difficult to implement data checking at SDTM files level. Need extra time to allow for early creation of final SDTM files early on.

11. CONFIDENTIAL Method #4 currently used at CVT – Pre-SDTM files Raw Data Pre-SDTM Files Analysis Files TLFs SDTM Files

12. CONFIDENTIAL Pre-SDTM file (e.g. PS_DM, PS_AE, etc.) is a superset of all SDTM variables to be included in a given CDISC domain (e.g. DM, AE, etc.) and analysis files; raw data variables to be included in supplemental qualifier SDTM files; raw data and derived variables to be used to create analysis files or for data checking in SDTM required data structure.

13. CONFIDENTIAL Advantages Balance between dependency and flexibility. - Consistency between SDTM and analysis files. - No duplication in creating analysis type SDTM variables and analysis files variables. - Main domains files and supplemental qualifier files created in the same process. - Changes to SDTM files compared to Pre-SDTM files are possible with saved audit trail. SDTM files created if and when needed. Pre-SDTM files convenient for data checking.

14. CONFIDENTIAL Disadvantages Requires extra time for planning, programming and validation of Pre-SDTM files. Actual SDTM file creation is on critical path for submission.

15. CONFIDENTIAL Process of creating SDTM files Pre-SDTM Files Raw Data SAS Programs Variable Definition Templates PS_ files Variable Definition Tables Main Domains Programs SUPPQUAL Programs SDTM files Variable Definition Tables SDTM Files

16. CONFIDENTIAL Lessons learned Planning and preparation is a key. Changes in SDTM files compared to Pre-SDTM files do happen – minimize as much as possible. Create ‘double-duty’ variables – use grouping variables (--CAT, --SCAT, --SPID, --GRPID) to reflect analysis. Creating drafts of trial design domain files at the stage of Pre-SDTM files is beneficial for analysis. SE, SV are convenient tools for data checking. Pre-SDTM files can serve as analysis files.

17. CONFIDENTIAL Database, data extracts and SDTM files Make raw data variables from database the same as SDTM file variables only if they are exactly the same. Examples: -ORRES variables, AETERM. If there any differences between CDISC requirements and meta data collected in the study, raw data variables should not match SDTM file variables.