Clinical Research and Healthcare – Where is the Link? 24 February 2004 Orlando, FL

1. Clinical Research and Healthcare – Where is the Link? 24 February 2004 Orlando, FL

2. Medical Records Paper Charts EMR Insurance Claims Basic Clinical Research Investigator-Sponsored Data Acquisition, Analysis Lab Notebooks, Files Healthcare Delivery Patient Information Treatment, Insurance Publications Protocol-driven Clinical Trials Biopharmaceutical Industry-Sponsored Data Acquisition, Analysis Multiple databases EDC, CDMS, CTMS SAE… Regulatory Drug Approval

3. C CRF Operational Data Medical Records Operational Data Submission Submission Data Lab Current State of Clinical Data Transfer

4. Pharma 1 Investigator 1 Pharma 2 . . . Investigator 2 . . Pharma N . Investigator K Regulatory Lab 1 Lab 2 . . . CRO 1 Lab L CRO 2 . . . CRO M Current State: Costly and Time-consuming

5. The Current State of Clinical Information • Healthcare information is found in paper medical records, in disparate databases, in hospital-based information systems--- there are islands of data • Clinical research data may exist in additional databases and/or research notebooks • Clinical trial data is collected on 3-part NCR forms (~90% of trials) or via a multitude of electronic data capture applications

6. Current Technology Issues in Conducting Clinical Trials • Electronic Data Capture (EDC) and/or eClinical Trials and new technologies are being piloted (if not adopted) by the major pharma companies. • Sources for electronic data are many and varied (e.g. EDC, IVRS, hand-held diaries, clinical laboratories, AE databases); ready retrieval of electronic data is very important. • Investigative sites are dealing with multiple and varied systems and interfaces.

7. Many industry stakeholders have realized that proprietary data structures are not necessarily of value….instead, focus should be on the molecule---the therapy. • “Innovation depends upon standardization.” • Dr. Bob O’Neill, Director, Office of Biostatistics, CDER, FDA

8. Sources of electronic data ECG eSubmission for Regulatory Review LAB Operational Database SDS ADaM ODM LAB EDC CRO The Future: Standards to Facilitate Data Flow ….from Source to Reviewers

9. Clinical Data Interchange Standards Consortium CDISC is an open, multidisciplinary, non-profit organization committed to the development of worldwide industry standards to support the electronic acquisition, exchange, submission and archiving of clinical trials data and metadata for medical and biopharmaceutical product development. The CDISC mission is to lead the development of global, vendor-neutral, platform-independent standards to improve data quality and accelerate product development in our industry.

10. CDISC History • Started as ‘grass roots’ volunteer group in Fall 1997 with 25 attendees at first meeting • Invited to form DIA SIAC in 1998 • Independent, non-profit organization in February 2000 • ~130 Corporate Memberships, of which ~50 are Corporate Sponsors (e.g. global pharmaceutical companies, CROs and technology providers) • Originally two working teams (Nomenclature and Modeling); Modeling split modeling into four teams; Nomenclature to Glossary Group • Models developed by consensus-based process

11. Evolution of CDISC Standards Operational Data Interchange & Archive: ODM, LAB Submission Data Interchange & Archive: SDS, ADaM • Data Sources • Site CRFs • Laboratories • Contract • Research • Organizations • Development • Partners • Operational • Database • Study Data • Audit Trail • Metadata • Submission • Data • CRT/Domain Datasets • Analysis Datasets • Metadata ODM = Operational Data Model/Std SDS = Submission Domain Standards LAB = Laboratory Data Model/Std ADaM = Analysis Data Models

12. Progress on the Standards • LAB Standard: Production Version 1.0.1 available; approved HL7 RIM message • V1.0 plus microbiology extension • Four methods of implementation • ODM Standard: Production Version 1.2 available as an XML schema • Define.xml in progress with SDS metadata • SDS Standard: Version 3.0 available • Version 3.1 anticipated to be HL7 Informative Document referenced by FDA Guidance by Q2 2004 • ADaM: Selected analysis dataset models

13. CDISC SDS Standard • Submission Domain Standards Version 3.1 • Incorporates changes based upon results of Version 3.0 FDA pilot • Scheduled to be balloted through HL7 and referenced in FDA Guidance as of April 2004; final documents anticipated by June 2004 • Provides means to submit Case Report Tabulation data to FDA in standard form, thus facilitating • Review of submissions using standard tools • Population of cross-trial database (Janus model) Plan is to reference as specification (HL7-approved CDISC SDS V3.1) in Guidance for FDA Implementation of International Conference on Harmonization (ICH) eCommon Technical Document (eCTD).

14. Submission Storage Review Transmitting and Using Data: Current Approach - FDA Electronic Document Room • Data on Physical Media • Tabulation Datasets • Analysis Datasets • Data Listings Datasets • Metadata Files • Subject Profiles • Summary Tables and Graphs Text Datasets SAS Tx File v5 F.E. Wood, CDISC Interchange 2003

15. Submission Storage Review Transmitting and Using Data: Study Data Repository - FDA Electronic Document Room • Electronic Message • Standard Tabulations • Analysis Datasets? Profiles Study Data Repository* Datasets Future-XML Summaries Tools *Planned and Actual F.E. Wood, CDISC Interchange 2003

16. Patient Profile Viewer: example of standard tool for reviews (CRADA)

17. Interchange Standards: Long-term Desired Outcomes • A holistic approach to standards, facilitating data interchange from sites through regulatory submission, utilizing XML • Standards for data acquisition supporting the population of a cross-trial warehouse within FDA • HL7-CDISC models harmonized to yield value for both clinical research and healthcare – sharing of information between EMR and clinical trials • Global adoption of CDISC data standards CDISC Meeting with FDA Commissioner, April 2003

18. Evolution of CDISC Standards Future Uniform Standard Operational Data Interchange & Archive: ODM, LAB Submission Data Interchange & Archive: SDS, ADaM • Data Sources • Site CRFs • Laboratories • Contract • Research • Organizations • Development • Partners • Operational • Database • Study Data • Audit Trail • Metadata • Submission • Data • CRT/Domain Datasets • Analysis Datasets • Metadata ODM = Operational Data Model/Std SDS = Submission Domain Standards LAB = Laboratory Data Model/Std ADaM = Analysis Data Models

19. Operational Data Modeling Submission Data Modeling Regulatory Reviewers Data Sources ODM values can be expressed via SDS metadata • ODM • Operational Data Model • XML format for clinical study • data and metadata • Supports regulatory-compliant • e-Archive format • SDS • Submission Data Standards *Describes content, structure and attributes of data for regulatory submissions *Defines metadata content for standard domains *Facilitates regulatory reviews Define.xml • LAB • Laboratory • Data Model • Defines standard content for • transferring clinical laboratory data from • Labs to sponsors • ASCII, SAS, XML, and • HL7 implementations available Applies submission model for analysis datasets LAB data can be mapped into ODM XML • ADaM • Analysis • Dataset Models • Provides models for commonly used statistical analyses. ODM can be used to represent and archive submission data

20. CDISC and HL7 • Formal Association as of 2001 • Technical Committee (Regulated Clinical Research and Information Management – RCRIM) co-chaired by FDA, CDISC and HL7 • Benefits • Capitalizes on HL7 standards development experience base • Leverages HL7 accreditation and HHS acknowledgement as SDO; FDA support • Expands value and influence of clinical trials standards efforts through harmonization • Provides opportunity for common informatics platform for healthcare and clinical research

21. Shared Goals; Individual Contributions • Shared Purpose (CDISC, FDA/HHS and HL7) • To improve the quality of public health • To have one overarching standard model for data interchange for healthcare information and clinical trial/clinical research data • Domain Expertise • CDISC, FDA and the Pharmaceutical Industry – Regulated clinical research data acquisition, review and archive requirements • HL7 – Healthcare information exchange standards and methodology; accreditation processes

22. Regulated Clinical Research Information Management TC (RCRIM) Initiated as Clinical Trials SIG in Jan. 2001 TC approved in April 2002 • Facilitates development of common standards across variety of organizations to improve information management during clinical research and regulatory evaluation • Defines messages, document structures, and terminology to support collection, storage, distribution, integration and analysis of clinical research data • Assures related or supportive standards produced by other HL7 groups are robust enough to be used in regulated clinical research Joint Leadership: HL7, CDISC, FDA Active Membership: FDA, CDISC, HL7 & others

23. RCRIM: Current Initiatives • Research Process • Standardized representation of clinical trial protocol • Research Data • Periodic reporting of clinical trial laboratory data • Annotation of ECGs • Clinical trial data for regulatory submission (Informative Doc) • Define.xml (Informative Doc) • Non-clinical data for regulatory submissions (SEND) Regulatory Information Structured Product label eStability data Surveillance Individual Patient SafetyReports (eMedWatch) HL7 Ballots Approved • Direct CDISC Involvement

24. CDISC and RCRIM Standards(Collaborative Groups ~ FDA, CDISC, HL7, SEND, CDC, NIH, LOINC, etc.) HL7 Reference Information Model RIM Regulated Clinical Research Information Management Technical Committee HL7 RCRIMTC V3 RIM V3 RIM V3 RIM V3 RIM CDA CDA Inf.Doc Inf.Doc Inf.Doc Inf.Doc Define.xml Protocol Elements ADaM SDS ODM LAB ECG Patient Safety Report Product Label eStability Data SEND Non-Clin SDS CDISC FDA Collaborative Groups

25. Benefits of CDISC-HL7 Alliance Capitalizes on HL7 standards development experience base Leverages HL7 accreditation and HHS acknowledgement as SDO; FDA support Expands value and influence of clinical trials standards efforts through harmonization Provides opportunity for common informatics platform for healthcare and clinical research

26. Proof-of Concept Project • Designed to demonstrate compatibility between HL7 RIM-derived Clinical Document Architecture (CDA) and CDISC Operational Data Model (ODM) • Single source entry for medical records and clinical trials • eSource documentation contributes to patient chart, not the reverse (i.e. extraction from EMR); reduces regulatory issues • Minimizes redundancy in data entry, thus improving data integrity/quality • Can potentially be driven from electronic protocol • First stage POC initiated through Duke Hospital and DCRI • Have commitments from two major technology partners, an academic institution and an academic research organization; establishing more pharma support for this breakthrough project (five interested in ‘ringside seat’)

27. Single Source Proof-of-Concept eSource Single Source ePatient Record CDA ODM Clinical Database • Leverages healthcare (HL7) and research (CDISC) data interchange standards; tool interoperability • Facilitates investigator workflow; eliminates transcription steps • Compliance with 21CFR11 and HIPAA feasible • Enables online monitoring

28. eProtocol/SAP eSource Single Source ePatient Record CDA ODM CRT/Analysis Datasets Define.xml • Leverages healthcare (HL7) and research (CDISC) data interchange standards; tool interoperability • Facilitates investigator workflow; eliminates transcription steps • Compliance with 21CFR11 and HIPAA feasible • Enables the protocol (PLAN) to drive the entire process

29. Agreement w/ statement“Standards should be extended to facilitate data collection at investigative sites…” % Agree * Source: CDISC-CenterWatch Research Project

30. 2002-2003 Regional Comparisons “Sponsor should collaborate in the standardization of EDC practices and systems for sites” International N. America CDISC-CenterWatch 2003 InternationalProject

31. Medical Records Insurance Claims Basic Clinical Research Investigator-Sponsored Data Acquisition, Analysis Healthcare Delivery Patient Information Publications Protocol-driven Clinical Trials Biopharmaceutical Industry-Sponsored Data Acquisition, Analysis Regulatory Drug Approval

32. Insurance Claims Basic Clinical Research Investigator-Sponsored Data Acquisition, Analysis Shared Information Publications Healthcare Delivery Patient Information Protocol-driven Clinical Trials Biopharmaceutical Industry-Sponsored Data Acquisition, Analysis Regulatory Drug Approval

33. Information and Contacts • For standards and information, see www.cdisc.org • Quarterly updates available via e-mail; contact Shirley Williams swilliams@cdisc.org • Technical questions: Julie Evans jevans@cdisc.org or Public Discussion Forum • Education and Membership: Frank Newby fnewby@cdisc.org • Rebecca Kush: rkush@cdisc.org

34. Knowing is not enough; we must apply. Willing is not enough; we must do. - Goethe- CDISC could not be what it is without all of our kind supporters who ‘apply’ and ‘do’…. THANK YOU!

39. The CDISC Vision “The exchange of all clinical trial data between any two parties will be achieved by the application of the appropriate CDISC data models and standards.”

40. “Working group” e.g. CDISC, FDA, RCRIM Proposed standard HL7 Membership Accredited Standard RCRIM Draft FDA Guidance Final FDA Guidance FDA Public HL7 RCRIM Standards Process Flow

41. CDISC Standards Development Process (COP-001) Stage I: Standard Definition/Team Initiation Need for Specific Standard(s) Identified (any stakeholder) Proposal to Board of Directors (via OIS) Review per strategy, budget priorities Team Leader ID And Team Formation (multidisciplinary) (OIS) Working Plan (timelines, deliverables communication mech., resources req’d) (Team ) Approved Not Approved Stage II: Standards Development/Review/V 1.0 Release Testing Consensus (Initial) Version Harmon- ized Version Review Version Released (Production) Version 1.0 Comments addressed Public Review TCC Review External Focused Review Comments to address by team Stage III: Education & Support Respond To Comments And Questions Educational Programs (EDU, OIS) TCC Review Stage IV: Standards Update & Maintenance NewReleased (Production) Version Annual Review of Released Version (comments, chg reqsts, tests, plans)(Team) Working Plan(timelines, deliverables,communication mech.,resources req’d)(Team) Consensus(Revised)Version Harmon-ized Version Public Reviewasneeded Optional Ex Focused Review Note: Occasional bug fix releases may be issued as needed with team review only.

42. “Standard data models are very important so that there can be efficient interchange of clinical data between my company and…other parties” % Agree * 2003 Results; Respondents (n=750), Pharma (n = 211) CRO (n= 146) Tech Provider (n=38)

43. “Sponsors Should Collaborate in the Standardization of EDC Practices and Systems for Investigative Sites” Percent of Investigative Sites

44. “Do you advocate the usage of eSource now or in the future?” BioPharma CRO

45. CDISC Timeline Initial CDISC Model (SMM) V3.x SDS FDA Guidance (Projected) ADaM Models Nomenclature & Modeling Groups V1.0 SDS V2.0 SDS V1.0LAB V0.8 ODM V1.0 ODM V1.1 ODM V3.0SDS 1997 2004 2002 2003 1998 1999 2000 2001 HL7 RCRIM TC* LAB & SDS models passed HL7 ballot Formal Agreement with HL7; CT-SIG Volunteer CDISC Group Initiated CDISC Europe Intiated CDISC Incorporated: Independent Non-Profit Organization CDISC Japan Initiated Formed DIA SIAC Formed DIA eClin/Stds SIAC SDS = Submission Domain Standards ODM = Operational Data Model LAB = Laboratory Data Model ADaM = Analysis Dataset Models *RCRIM TC: Regulated Clinical Research and Information Management Technical Committee; Co-chaired by HL7, CDISC and FDA

46. CDISC in the “World of Standards” 2000 ICH Japan MHW US FDA EU EMEA Pharmaceutical Industry EU USA Japan EFPIA PhRMA JPMA REGULATORY AUTHORITIES Health Care Providers & Pharmacies SDS ODM ADaM LAB Clinical Trials Models: NCI, OMG, RIM Standards: HL7, XML Dictionaries: MedDRA, LOINC

47. CDISC in the “World of Standards” 2003 International Conference on Harmonization (ICH) U.S. Dept. of Health and Human Services (HHS) EFPIA JPMA PhRMA EMEA MHLW KIKO U.S. FDA CDC NIH/NCI NLM TC: RCRIM DICOM Protocol Std ISO CDISC Health Level 7 (HL7) ADaM SDS ODM LAB Reference Information Model RIM LOINC MedDRA SNOMED Clinical Document Architecture eCTD = Dictionary, Codelist = Document Standard, or Architecture = Organization = Standard = Model

48. Speaking of health benefits/opportunities to be realized from making more effective use of IT…. • I think that CDISC will be a big part of moving FDA onto an electronic information architecture where we can realize all of these opportunities. I think this will have a profound and positive impact on our drug review process, allowing us to design trials that can be less expensive and still tell us more about the risks and benefits of a new medical product. And I think that the most significant and perhaps enduring legacy to your efforts could be the very immediate and significant impact it has on improving the lives of patients. • Mark B. McClellan, MD, PhD, FDA Commissioner

49. Single Source: Potential Flow for Clinical Trial Data HL7 Messaging CDISC ODM Interchange Maps to CDA, includes ODM support of Regulated Clinical Research data interchange and archive; uses SDS metadata CDISC SDS HL7 CDA EMR Database FDA Submission Database Clinical Trial eSource Document (w/ required CRF fields identified) eCRF Data (Document) Operational Database @Sponsor eVerification/Audit Data Entry [or Dictation] by Investigator or CRC Hospital Lab data Central LAB Data Transfers

50. Submission Domain Standards (SDS) Version 3 Interventions Events Findings Other Exposure AE Labs Incl Excl* Demog ConMeds Disposition Vitals Subj Char* RELATES* Extra Data* Subst Use* MedHist PhysExam ECG Comments* Study Design* QS*, MB* CP*, DV* * New in Version 3 Study Sum*