1. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 1 On the Trail of the Holy Grail of SDTM Implementation Three Unique Case Studies © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. Ken Stoltzfus Clinical Data Strategies Octagon Research Solutions PhUSE 2011

2. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 2 About Octagon Octagon Research Solutions – A development partnering organization that offers regulatory, clinical, process and IT solutions to the life sciences industry. Octagon experience on topic : – 600 studies converted to SDTM & ADaM (10,000+ domains) in support of over 54 regulatory submissions to the FDA – CDISC SDTM Co-authors – CDISC SDS Team Lead – Current CDISC team membership: SDS, ADaM, CDASH, SEND, SHARE, and Controlled Terminology – CDISC-authorized SDTM trainers

3. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 3 Agenda Standards Governance Case Studies Protocol-Restricted Medications Cardiovascular Medical History Signs and Symptoms Company Alpha: Company Gamma: Company Beta:

4. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 4 © 2010 Octagon Research Solutions, Inc. All Rights Reserved. Standards Governance What exactly is standards governance? – Oversight – Decision-making – Development – Maintenance – Compliance

5. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 5 Standards Governance Standards People Processes Technical Solutions Leadership Content decision-makers Developers Data stewards Internal standards CDISC standards Interpretation Development Business Guidelines Maintenance SOPs Request system CDR MDR

6. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 6 Case Studies Ladies and gentlemen: The case studies you are about to see are true. Only the names have been changed to protect the innocent. Any resemblance to real CRFs, whether ongoing or legacy, is purely coincidental.

7. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 7 Case Study 1 – Company Alpha

8. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 8 Snapshot of the Starting Point Background Responding to questions from FDA reviewer Data mining difficult across unstandardized databases Standards Governance None, although mandate issued to implement CDASH and SDTM No accompanying authorization for standards governance Standards development performed by focused group of SAS programmers, Biostatisticians, and EDC builders

9. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 9 The eCRF Study: CA-027 Centre: Subject: Visit Signs and Symptoms 0010 0006 Application Site Time of ApplicationDate of Application None Mild Moderate Severe Unknown SeverityDiameter Post-application 8 hr mm Post-application 24 hr mm Post-application 16 hr mm Rash Date of Assessment CELOC CESTDTC CECAT = CEOCCUR = Y CETERM = CESEV CEPRESP = Y CEOCCUR = U CESEV is null CEOCCUR = N CESEV is null VISITNUM STUDYID USUBJID CETPT SUPPCE SSAPPDATSSAPPTM RASHDMU RASHDM QNAM =

10. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 10 The eCRF Study: CA-027 Centre: Subject: Visit Signs and Symptoms 0010 0006 Application Site Time of ApplicationDate of Application None Mild Moderate Severe Unknown SeverityDiameter Post-application 8 hr mm Post-application 24 hr mm Post-application 16 hr mm Rash Date of Assessment X1LOC X1DTC X1CAT = X1ORRES = Y X1TEST = X1ORRES = U X1ORRES = N VISITNUM STUDYID USUBJID X1TPT SUPPX1 SSAPPDATSSAPPTM QNAM = X1ORRESU Occurrence of Rash X1TEST = Severity X1ORRES = X1TEST = Diameter X1ORRES =

11. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 11 The eCRF Study: CA-027 Centre: Subject: Visit Signs and Symptoms 0010 0006 Application Site Time of ApplicationDate of Application None Mild Moderate Severe Unknown SeverityDiameter Post-application 8 hr mm Post-application 24 hr mm Post-application 16 hr mm Rash Date of Assessment FALOC FADTC FACAT = FAORRES = Y FATEST = FAORRES = U FAORRES = N VISITNUM STUDYID USUBJID FATPT SUPPFA SSAPPDATSSAPPTM QNAM = FAORRESU Occurrence FATEST = Severity FAORRES = FATEST = Diameter FAORRES = FAOBJ =

12. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 12 © 2010 Octagon Research Solutions, Inc. All Rights Reserved. The Discussion & The Decision Proposal 1: CE USUBJIDVISITCETPTCETERMCESTDTCCESEVCMOCCURCMPRESP 0010:00061Post-application 8 hrRASH2010-03-22MILDYY 0010:00061Post-application 16 hrRASH2010-03-22NONENY 0010:00061Post-application 24 hrRASH2010-03-22NONENY 0010:00062Post-application 8 hrRASH2010-03-29MILDYY 0010:00062Post-application 16 hrRASH2010-03-29MODERATEYY 0010:00062Post-application 24 hrRASH2010-03-29MODERATEYY Proposal 2: X1 USUBJIDVISITX1TPTX1TESTX1DTCX1ORRESX1ORRESU 0010:00061Post-application 8 hrOccurrence of Rash2010-03-22Y 0010:00061Post-application 8 hrSeverity2010-03-22MILD 0010:00061Post-application 8hrDiameter2010-03-221mm 0010:00061Post-application 16 hrOccurrence of Rash2010-03-22NONE 0010:00061Post-application 16 hrSeverity2010-03-22 0010:00061Post-application 16 hrDiameter2010-03-22mm Proposal 3: FA USUBJIDVISITFATPTFATESTFAOBJFADTCFAORRESFAORRESU 0010:00061Post-application 8 hrOccurrenceRASH2010-03-22Y 0010:00061Post-application 8 hrSeverityRASH2010-03-22MILD 0010:00061Post-application 8hrDiameterRASH2010-03-221mm 0010:00061Post-application 16 hrOccurrenceRASH2010-03-22NONE 0010:00061Post-application 16 hrSeverityRASH2010-03-22 0010:00061Post-application 16 hrDiameterRASH2010-03-22mm

13. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 13 Case Study 2 – Company Beta

14. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 14 Snapshot of the Starting Point Standards Governance Small DM group managing company’s collection standards Several internal resources with SDTM expertise from DM and SAS programming performed original SDTM mappings Eventual highly-visible, strong mandate from senior VP Background Budget crisis Smarter use of resources Quicker study start-up CDISC standards

15. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 15 The eCRF Study: CB-019 Centre: Subject: Visit Cardiovascular Medical History 0005 0002 Date Medical History Taken Evaluation of subject’s medical history for: Left ventricular hypertrophy No YesUnknown Coronary artery disease No YesUnknown Myocardial infarction No YesUnknown Ventricular arrhythmia No YesUnknown Hypertension No YesUnknown Date of most recent MI Number of MI Date of most recent LVEF Most recent LVEF % VISITNUM STUDYID USUBJID MHDTC MHCAT = MHTERM MHOCCUR SUPPMH QNAM = MIDAT MINO LVEFDAT LVEFPCT

16. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 16 The eCRF Study: CB-019 Centre: Subject: Visit Cardiovascular Medical History 0005 0002 Date Medical History Taken Evaluation of subject’s medical history for: Left ventricular hypertrophy No YesUnknown Coronary artery disease No YesUnknown Myocardial infarction No YesUnknown Ventricular arrhythmia No YesUnknown Hypertension No YesUnknown Date of most recent MI Number of MI Date of most recent LVEF Most recent LVEF % VISITNUM STUDYID USUBJID MHDTC MHCAT = MHTERM MHOCCUR SUPPMH Findings FADTC FATEST = Date of most recent MI FAORRES = FATEST = Number of MI FAORRES = FATEST = Date of most recent LVEF FAORRES = FATEST = Most recent LVEF FAORRES = FAORRESU FAOBJ = MHPRESP = Y

17. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 17 © 2010 Octagon Research Solutions, Inc. All Rights Reserved. The Discussion & The Decision Proposal 1: MH USUBJIDVISITMHTERMMHDTCCMOCCUR 0005:00021Hypertension2009-05-12N 0005:00021Ventricular arrhythmia2009-05-12N 0005:00021Myocardial infarction2009-05-12Y 0005:00021Coronary artery disease2009-05-12Y 0005:00021Left ventricular hypertrophy2009-05-12Y Proposal 2: FA (+ MH dataset above) USUBJIDVISITFATESTFAOBJFADTCFAORRESFAORRESU 0005:00021Date of most recent MIMyocardial infarction2009-05-122008-10-14 0005:00021Number of MIMyocardial infarction2009-05-121 0005:00021Date of most recent LVEFLeft ventricular hypertrophy2009-05-122008-11-07 0005:00021Most recent LVEFRASH2009-05-1237%

18. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 18 Case Study 3 – Company Gamma

19. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 19 Snapshot of the Starting Point Background Implementation of a CDR Need for standard metadata for safety domains Foundation for TA domains Standards Governance Lightly-supported group of clinicians and statisticians for purposes of centralized decision-making for SDTM mapping Standards governance group nearly paralyzed by workload Limited representation led to limited buy-in to standards

20. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 20 The eCRF Study: CG-203 Centre: Subject: Visit Protocol-Restricted Medications 0055 0014 Date of Assessment Did the subject take the following medications during the 24 hours prior to spirometry? Short acting Beta 2-agonists No YesUnknown Date Time Long acting Beta 2-agonists No YesUnknown Date Time Anticholinergics No YesUnknown Date Time Inhaled corticosteroids No YesUnknown Date Time Last Taken VISITNUM STUDYID USUBJID CMCAT = CMSTDTCCMTRT SUPPCM QNAM = PRMDAT CMOCCUR CMPRESP = Y

21. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 21 The eCRF Study: CG-203 Centre: Subject: Visit Protocol-Restricted Medications 0055 0014 Date of Assessment Did the subject take the following medications during the 24 hours prior to spirometry? Short acting Beta 2-agonists No YesUnknown Date Time Long acting Beta 2-agonists No YesUnknown Date Time Anticholinergics No YesUnknown Date Time Inhaled corticosteroids No YesUnknown Date Time Last Taken VISITNUM STUDYID USUBJID DVCAT = DVSTDTC SUPPDV QNAM = PRMDAT PRM_NYU DVTERM = PRE-SPIROMETRY SHORT ACTING BETA 2-AGONIST USAGE DIVERGENT FROM PROTOCOL DVTERM = PRE-SPIROMETRY LONG ACTING BETA 2-AGONIST USAGE DIVERGENT FROM PROTOCOL DVTERM = PRE-SPIROMETRY ANTICHOLINERGIC USAGE DIVERGENT FROM PROTOCOL DVTERM = PRE-SPIROMETRY INHALED CORTICOSTEROID USAGE DIVERGENT FROM PROTOCOL If PRM_NYU = Y

22. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 22 The eCRF Study: CG-203 Centre: Subject: Visit Protocol-Restricted Medications 0055 0014 Date of Assessment Did the subject take the following medications during the 24 hours prior to spirometry? Short acting Beta 2-agonists No YesUnknown Date Time Long acting Beta 2-agonists No YesUnknown Date Time Anticholinergics No YesUnknown Date Time Inhaled corticosteroids No YesUnknown Date Time Last Taken VISITNUM STUDYID USUBJID XCCAT = XCDTC SUPPXC QNAM = PRMDAT XCTEST = PRE-SPIROMETRY SHORT ACTING BETA 2-AGONIST USAGE DIVERGENT FROM PROTOCOL XCTEST = PRE-SPIROMETRY LONG ACTING BETA 2-AGONIST USAGE DIVERGENT FROM PROTOCOL XCTEST = PRE-SPIROMETRY ANTICHOLINERGIC USAGE DIVERGENT FROM PROTOCOL XCTEST = PRE-SPIROMETRY INHALED CORTICOSTEROID USAGE DIVERGENT FROM PROTOCOL XCORRES

23. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 23 © 2010 Octagon Research Solutions, Inc. All Rights Reserved. The Discussion & The Decision Proposal 1: CM USUBJIDVISITCMTRTCESTDTCCMOCCURCMPRESP 0055:00141Short acting Beta 2-agonists2010-08-09T11:22YY 0055:00141Long acting Beta 2-agonistsNY 0055:00141AnticholinergicsNY 0055:00141Inhaled corticosteroids2010-08-09T21:01YY 0055:00142Short acting Beta 2-agonists2010-08-23T10:15YY 0055:00142Long acting Beta 2-agonistsNY Proposal 2: DV USUBJIDVISITDVCATDVTERMDVSTDTC 0055:00141Protocol-Restricted Medications PRE-SPIROMETRY SHORT ACTING BETA 2-AGONIST USAGE DIVERGENT FROM PROTOCOL 2010-08-09T11:22 0055:00141Protocol-Restricted MedicationsPRE-SPIROMETRY INHALED CORTICOSTEROID USAGE DIVERGENT FROM PROTOCOL2010-08-09T21:01 0055:00142Protocol-Restricted Medications PRE-SPIROMETRY SHORT ACTING BETA 2-AGONIST USAGE DIVERGENT FROM PROTOCOL 2010-08-23T10:15 Proposal 3: XC USUBJIDVISITXCTESTXCDTCXCORRES 0055:00141PRE-SPIROMETRY SHORT ACTING BETA 2-AGONIST USAGE DIVERGENT FROM PROTOCOL2010-08-09T11:22Y 0055:00141PRE-SPIROMETRY LONG ACTING BETA 2-AGONIST USAGE DIVERGENT FROM PROTOCOLN 0055:00141PRE-SPIROMETRY ANTICHOLINERGIC USAGE DIVERGENT FROM PROTOCOLN 0055:00141PRE-SPIROMETRY INHALED CORTICOSTEROID USAGE DIVERGENT FROM PROTOCOL2010-08-09T21:01Y 0055:00142PRE-SPIROMETRY SHORT ACTING BETA 2-AGONIST USAGE DIVERGENT FROM PROTOCOL2010-08-23T10:15Y 0055:00142PRE-SPIROMETRY LONG ACTING BETA 2-AGONIST USAGE DIVERGENT FROM PROTOCOLN

24. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 24 Summary

25. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 25 Conclusion SDTM implementation is complex, but ultimately achievable given the following: – Access to necessary expertise across functional areas – Thorough consideration of downstream analysis needs – Empowered standards governance No single perfect method

26. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 26 Acknowledgements Barry Cohen Dave Evans Lex Jansen Tore Haglund Stephen Harrison Harpreet Sahni

27. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 27 Contact Information Ken Stoltzfus Clinical Data Strategies Octagon Research Solutions 585 East Swedesford Road, Suite 200 Wayne, PA 19087 USA Tel: 1-610-535-6500 (Ext. 5891) kstoltzfus@octagonresearch.com

28. © 2011 Octagon Research Solutions, Inc. All Rights Reserved. The contents of this document are confidential and proprietary to Octagon Research Solutions, Inc. 28 Questions