1. Why eCTD & CDISC? GSG-US, Inc. Chaeyong Chang March, 2012

2. FDA approved Prilosec OTC on June 20, 2003.

4. eCTDHybrideNDA

6. SDTMADaM Clinical Reports

7. Datasets Analyses Programs Define.xml adsl.xpt adae.xpt … Tabulations Define.xml dm.xpt ae.xpt … ADaM data include the primary efficacy analyses SDTM data mirror the observed data Module 5 Study Name

8. http://www.fda.gov/ForIndustry/DataStandards/StudyDataStandards/default.htm

9. Mapping SPEC

10. http://www.sas.com/industry/government/fda/faq.html FDA can accept data in the SAS XPORT Transport Format (Open Format) that is processed by the XPORT engine in Version 6 of SAS software and later, and by PROC XCOPY in Version 5.

11. SAS XPT

12. An annotated case report form (CRF) is a blank CRF with annotations that document the location of the data with the corresponding names of the datasets and the names of those variables included in the submitted datasets.

13. Annotated CRF

14. Definition : The data definition file describes the format and content of the submitted datasets. (SDTM & ADaM) Specifications : The specification for the data definitions for datasets provided using the CDISC SDTM IG or SEND IG is included in the Case Report Tabulation Data Definition Specification (define.xml) developed by the CDISC define.xml Team. The latest release of the define.xml is available from the CDISC web site (http://www.cdisc.org/models/def/v1.0/index.html).http://www.cdisc.org/models/def/v1.0/index.html FDA can accept definition file in XML or PDF format.

15. define.xml

16. http://evs.nci.nih.gov/ftp1/CDISC/SDTM/SDTM%20Terminology.html 1. AEACN : Action Taken with Study Treatment (Expected variable) DOSE INCREASED DOSE NOT CHANGED DOSE REDUCED DRUG INTERRUPTED DRUG WITHDRAWN NOT APPLIABLE UNKNOWN 2. AEOUT: Outcome of Event (Permissible variable) FATAL NOT RECOVERED/NOT RESOLVED RECOVERED/RESOLVED RECOVERED/RESOLVED WITH SEQUELAE RECOVERING/RESOLVING UNKNOWN

17. http://evs.nci.nih.gov/ftp1/CDISC/SDTM/SDTM%20Terminology.html 3. LBTESTCD : Laboratory Test Code (Required variable) BILI : Bilirubin; Total Bilirubin AST : Aspartate Aminotransferase;SGOT ALT : Alanine Aminotransferase;SGPT GGT : Gamma Glutamyl Transferase HIV1AB : HIV-1 Antibody HIV12AB : HIV-1/2 Antibody HIV2AB : HIV-2 Antibody T3 : Triiodothyronine;Total T3 T4 : Thyroxine;Total T4 4. EGTESTCD : ECG Test Code (Required variable) QTCB : QTcB - Bazett's Correction Formula QTCF : QTcF- Fridericia's Correction Formula VRMEAN : Summary (Mean) Ventricular Rate QTMAX : Summary (Max) QT Duration

18. http://evs.nci.nih.gov/ftp1/CDISC/SDTM/SDTM%20Terminology.html 5. CMDOSFRQ : Dosing Frequency per Interval(Permissible variable) BID : BD,Twice per day BIS : Twice per week QM : Every Month PRN : As needed Q10H : Every 10 hours QID : 4 times per day QS : Every week QD : Daily

19. LBORRES : Result of Finding in Original Units (Expected Variable) LBORRESU : Original Units (Expected Variable) LBSTRESC : Character Results/Finding in Std. Format (Expected Variable) LBSTREN : Numeric Result/Findings in Std. Format (Expected Variable) LBSTRESU : Standard Units (Expected Variable) Units used for reporting Platelets count in 97 different local laboratories. (LBORRESU) /MM3 10E6/ML /UL 10E9/L 10E3/CL CELLS/MM3 10E3/MCL G/L 10E3/MM3 ( 아산 )GIGA/L 10E3/MMC MM3/10E3 10E3/UL ( 네오딘 )XMMC S.I. Unit : 10^9/L http://www.unc.edu/~rowlett/units/scales/clinical_data.html

20. FDA’s Enterprise Program to improve management of structured scientific data ­Clinical study data ­Nonclinical study data ­Pharmacogenomic (and other –omic) data ­Product quality and manufacturing data ­Post-market surveillance data What is Janus?

21. Severity Levels in Janus Validation Criteria Severity Levels in Janus Validation Criteria Severity Description High The error is serious and will prevent the study data from being loaded successfully into the Janus repository. The SDTM study will not be loaded into the Janus repository Medium The error may impact the reviewability of the submission, but will not have an impact on loading the study data into the Janus repository. The SDTM study will be loaded into the Janus repository Low The error may or may not impact the reviewability or the integrity of the submission but will not have an impact on loading the study data into the Janus repository. The SDTM study will be loaded into the Janus repository

22. Janus Validation Criteria Define.xml that fails the structural validation check or check for controlled vocabularies1 Missing mandatory domains—mandatory domains for Janus include DM (demographics), EX (exposures), and DS (disposition) Missing mandatory fields in either the mandatory domains or optional domains provided in the submission Date fields in the submission (all domains) are not compliant with the SDTM specification Domain-specific errors as described in the detailed specifications described below. http://www.fda.gov/ForIndustry/DataStandards/StudyDataStandards/ucm155327.htm

23. Detailed SDTM Validation Criteria

24. Example of Validation Results

25. Rule IDMessageDescription of RuleDomainCategoryTypeWebSDM ID CT0004 Value for AGEU not found in AGEU controlled terminology codelist Variable values should be populated with terms found in 'Age Unit' (C66781) CDISC controlled terminology codelistDMTerminologyErrorR5062 SD0083Duplicate USUBJID The value of Unique Subject Identifier (USUBJID) variable must be unique for each subject across all trials in the submission.DMConsistencyError SD0084Negative AGE value The value of Age (AGE) cannot be less than 0.DMLimitErrorR5006 SD1002 Start date must be before end date Subject Reference Start Date/Time (RFSTDTC) must be less than or equal to Subject Reference End Date/Time (RFENDTC).DMLimitError SD1020Missing DM dataset Demographics (DM) dataset should be included in every submission.DMPresenceError

26. Example of Validation Results Rule IDMessageDescription of RuleDomainCategoryTypeWebSDM ID SD0006 No baseline result in [Domain] for subject All subjects should have at least one baseline observation (--BLFL = 'Y') in EG, LB, QS, and VS domains, except for subjects who failed screening (ARMCD = 'SCRNFAIL') or were not fully assigned to an Arm (ARMCD = 'NOTASSGN'). EG, LB, QS, VSPresenceWarningIR5005 SD0007 Inconsistent value for Standard Unit Identifies Short Name of Measurement, Test or Examination values where standard units value (Standard Units) is not consistent across all records EG, LB, QS, VSConsistencyErrorIR5006 SD0080 AE start date must be less than or equal to latest disposition date Start Date/Time of Adverse Event (AESTDTC) must be less than or equal to the Start Date/Time of the latest Disposition Event (DSSTDTC)AEConsistencyWarningIR5517 SD0081 Observation date must be less than or equal to latest disposition date Date/Time of Collection (--DTC) must be less than or equal to the Start Date/Time of the latest Disposition Event (DSSTDTC)EG, LB, VSConsistencyWarningIR5517 SD0002 Null value in variable marked as Required Required variables (where Core attribute is 'Req') cannot be null for any record.AllPresenceErrorIR5001

27. FDA request eCTD (CDISC) as a Submission -We don’t have another option!!! It is desired that taking a charge of SDTM conversion process by DM team is better than SAS Programming team according to our experience. - Prevent chance of manipulating raw data - Require to prevent SAS programmer’s own idea It is desired that applying CDISC at early stage of project - Lower Cost / Time - Increase SDTM Data Quality Janus is under developing

28. Global STATISTICS Group, Inc. 미주 최초의 한국인 CRO Website: www.gsg-us.com Contact: chaeyong.chang@gsg-us.com Phone: : 070-8623-7410 ( 한국 ) 609-921-1550 (USA) 감사합니다