1. Updates on CDISC Standards Validation NJ CDISC User Group September 19, 2013

2. Topics CDISC standards validation initiative FDA update on SEND checks OpenCDISC v1.4.1 release OpenCDISC plans

3. CDISC validation projects • Past • ADaM validation checks • Define.xmltool (schema only) • CAB project • Current plan (CDISC Intrachange 2013) • Each CDISC development team will create a comprehensive list of business rules as a supplement to their standards • Rationale • Standards developers are the best experts in defining standards compliance requirements

4. CDISC ADaM Validation Checks • First v1.0 was introduced in 2010-10 • Current v1.2 was released on 2012-07 • v1.2 includes 244 checks based on ADaM IG text • ADSL and BDS data only • Today the team is planning 2 iterations • update existing checks and create new checks for ADAE, ADTTE data • update checks after a new release of ADaMIG

5. Define.xml XML Schema Validation for Define.xml v1.0, 2009-11 Validator for Define.xmlschema, 2009-12 Define.xml v2.0 includes many business rules embedded in standard specifications Today the team is working on detailed list of validation rules Executable specification will be published as Schematron

6. SDTM and SEND • CAB/VP project, 2010 • Evaluated compliance rules for SDTM/define.xml • Reviewed checks across different vendors • Current plan: • Create comprehensive list of business rules as a supplement to new standards. E.g., SDTM v3.1.5, TA standards, etc. • Challenges: • Extra resources are needed • Synchronization across teams • Exact project scopeand formatare still under discussion

7. FDA’s validation rules for SEND data http://www.fda.gov/downloads/ForIndustry/DataStandards/StudyDataStandards/UCM367129.xlsx

8. Off-Topic: FDA’s Position Statement Study Data Standards for Regulatory Submissions FDA recognizes the investment made by sponsors over the past decade to develop the expertise and infrastructure to utilize Clinical Data Interchange Standards Consortium (CDISC)[1] standards for study data. The submission of standardized study data enhances a reviewer’s ability to more fully understand and characterize the efficacy and safety of a medical product. The Prescription Drug User Fee Act (PDUFA V)[2] Performance Goals state that FDA will develop guidance for industry on the use of CDISC data standards for the electronic submission of study data in applications. In the near future, FDA will publish guidance that will require study data in conformance to CDISC standards.[3] FDA envisions a semantically interoperable and sustainable submission environment that serves both regulated clinical research and health care. To this end, FDA will continue to research and evaluate, with its stakeholders, potential new approaches to current and emerging data standards. FDA does not foresee the replacement of CDISC standards for study data and will not implement new approaches without public input on the cost and utility of those approaches. September 13, 2013 http://www.fda.gov/ForIndustry/DataStandards/StudyDataStandards/ucm368613.htm

9. OpenCDISC v1.4.1 release, 2013-09-12 Bug fixes, enhancements, but no global changes Support for QS Terminology CDISC CT checks for extensible codelists are Informational and independent from user’s codelists in Define.xml SDTM 3.1.1 with all applicable checks Simplified, consistent and concise error messages and rule descriptions Excel report includes versions of Validator, CT, and MedDRA Enhancement to check definition syntax

10. SDTM Terminology • New CDISC Control Terminology checks based on CT rather than on outdated SDTM IG assignments • PKUNIT instead of UNIT in PC and PP domains • PKPARM, SCTEST, etc. • QS Terminology (CT0100-CT0255 checks) • CT 1:1 consistency checks for paired variables • TSPARM/TSPARMCD, EGTEST/EGTESTCD, etc. • Terminology checks on non-extensible codelists were changed to Errors • CT0001 (ACN), CT0002 (AESEV), CT0030 (RELTYPE), CT0059 (NY), etc.

11. Examples of SDTM checks “tuning” Rule SD0006 (“No baseline results”) was modified to exclude NOTASSGN subjects Rules SD0026 and SD0029 (“units are required”) were modified to exclude PH, SPGRAV and all Antibody lab tests Rule SD0037 (data vs. user’s codelist) was modified to exclude EGORRES variable Rule SD0069 (“No Disposition record for subject”) was modified to exclude SCRNFAIL and NOTASSGH subjects Rule SD1037 (“Missing value for --TOX, when --TOXGR is populated”) was modified to ignore records with TOXGR=0

12. SEND specific • Fixed incorrect variable labels and order of variables in domains • Several Check ID replacement for consistency with SDTM checks • CT1003-> CT0088, CT1004->CT0089, etc.

13. ADaM Checks compliant with ADaM Validation Checks 1.2 Change all consistency rules to only run when primary variables are populated Remove AD1002 - Expected variable is not present within dataset.  This is not a real rule.  It was copied from SDTM logic Changes to improve label validation (AD0018) Addition of other rules interpreted from IG, which were not released by CDISC team

14. OpenCDISC v2.0 • Date of release is planned for 2013Q4 • Support for Define.xml v2.0 • Metadata driven • Specifications based on Define.xml v2.0 format • Validation organized by functional area. E.g., • SDTM Compliance • Control Terminology • Metadata • Regulatory Specific • Data Quality

15. Example of metadata driven checks • SD1117 “Duplicate records” in Findings domain • The “generic” check uses 10 Key Variables

16. Key variables as defined in SDTM IG SDTM IG: “Note that the key variables shown in this table are examples only. A sponsor‘s actual key structure may be different.”

17. Combined Key variables * added by OpenCDISC as common cases in actual study data

18. The check implementation options • Generic check with 20 key variables? • Separate check for each domain? • v.2.0 approach • Take domain key variables from Standard metadata • If define.xml is available, then utilize key variables provided in Study metadata • Compare Standard and Study key variables

19. OpenCDISC Network • More direct involvement in OpenCDISC project development process • Beta testing • Requirements input • Additional resources for new projects • Better support • Face-to-face meetings with users • Webinars • Training and sharing users experience • First meeting is before CDISC Interchange 2013

20. References • CDISC ADaM resources http://www.cdisc.org/adam • CDISC define.xml resources http://www.cdisc.org/define-xml • FDA Study Data Standards Resources http://www.fda.gov/ForIndustry/DataStandards/StudyDataStandards/default.htm • OpenCDISC http://www.opencdisc.org

21. Questions/Feedback Sergiy Sirichenko sergiy@opencdisc.org Max Kanevsky max@opencdisc.org Mike DiGiantomassomike@opencdisc.org http://www.opencdisc.org/