CRIX: Toward a Shared Clinical Infrastructure

1. CRIX:Toward a Shared Clinical Infrastructure Sue Dubman NCI Center for Bioinformatics (NCICB) dubmans@mail.nih.gov

2. Background • In early 2003, NCI and FDA formed the IOTF (Inter-Agency Operational Task Force) to speed new research discoveries to the public • NCI and the FDA are collaborating through the IOTF to implement a common, standards based electronic infrastructure for regulatory data and document submission, review and analysis • This effort is called CRIX (Clinical Research Information Exchange)

3. Why is CRIX Needed? • Changing environment (information explosion, expanding targets, greater financial, consumer, legal and other pressures, etc.) • Slowdown in innovative therapies reaching patients • Expensive, slow, and failure-prone regulatory submission, review and analysis process • Time/money spent on building/maintaining infrastructure, rather than scientific and research endeavors

4. Cheshire Cat Advice • If you don’t know where you are going, any road will take you there…

5. CRIX Vision • Sustainable, secure and standards-based infrastructure for electronic submissions • Standards-based repository for data analysis and review • Global registry for commonly used/referenced data • Common information exchange standards • Mechanism for secure electronic information exchange • Legally enforceable digital signatures compliant with Title 21 Regulations and other guidelines from the outset

6. NCI & FDA Studies CRIX Objectives • More efficient submission based on standards • Reproducible, custom datasets for analysis • Reusable tools for analysis and review • Less data redundancy • Less time on orientation to data by reviewers • Less ambiguity in communications of information • More auditable data • Less manual, paper processing • Use of common standards across the entire community (government, industry, academia) • Interoperability with other caBIGTM data sets, tools, capabilities NO MORE PAPER!

7. Challenges • Eating the elephant one bite at a time • Herding cats with diverse interests – patient care, science, ROI • Lack of consensus on common standards and terms • Fragmented, locally used systems that are rarely interoperable • Systems built to variable standards of quality • Secure and private as a Swiss Bank • Making cash stretch like an elastic band

8. How Do We Address These Challenges? • Start with small strategic pilots/prototypes • Utilize component-based development approach • Base development on existing international standards and data models • Utilize and extend existing NCI caCORE infrastructure • Leverage NCI and caBIGTM developments, principles, guidelines

9. CRIX Development Projects • Firebird • Global investigator registry for commonly used/referenced data • SAFE • Legally enforceable digital signatures compliant with Title 21 Regulations • CRIX CDR (Clinical Data Repository) • Sustainable, secure and standards-based repository for electronic IND submissions of data and documents • Tools for reviews, reporting and analysis • Electronic IND Submissions • Sustainable, secure and standards-based infrastructure for electronic submissions of data and documents

10. Electronic Submissions CRIX Development Plan Electronic Submissions CRIX CDR … Firebird/SAFE ProductionInfrastructure Firebird/SAFE Firebird/SAFE operationalfeasibility technicalfeasibility … CRIX CDR CRIX CDR Infrastructure Development Electronic Submissions

11. CRIX 1.0: Firebird • Automates and centralizes the 1572 registration process • Enables investigators to register online with sponsors • Proves the feasibility and value of CRIX

12. “On the Internet, nobody knows you’re a dog.” • The New Yorker Collection 1993 Peter Steiner from CartoonLink.com. All Rights Reserved. SAFE Overview • Firebird leverages SAFE • For security, identity trust, and eSignatures • To enable legal enforceability on all industry electronic Regulatory, Legal and Financial transactions • Bridges to DHHS credentials

13. Firebird Benefits – Investigators • Allows investigators to centrally manage profile information in a secure repository • Allows investigators to complete 1572 packets for multiple sponsors (annual/protocol specific) within minutes using data stored in the profile • Eliminates paper based manual processes and the need for wet signatures (leveraging SAFE for legally enforceable digital signatures) • Standardizes the 1572 process thereby reducing the trial setup time and reducing overall system costs • Centralizes and simplifies the management of 1572 process at site by registration coordinators • Provides integration with existing sponsor/site databases • Gold standard for all 1572 information for multiple sponsors and FDA

14. Firebird Benefits – Sponsors • Allows sponsors to centrally manage 1572 registration related information and associated workflows in a secure repository across all therapeutic areas • Allows sponsors to setup the 1572 packets (annual/protocol specific) within minutes using wizard based tools and public/private templates • Eliminates paper based manual processes and need for manual data entry and 1572 related local systems (leveraging SAFE standard for legally enforceable digital signatures) • Standardizes the 1572 process thereby reducing the trial setup time and reducing overall system costs • Integration with existing sponsor/site databases • Gold standard for all 1572 information for multiple sponsors and FDA

15. Firebird Project Milestones • Beta • Beta Invitations and Acceptance – Jan/Feb 2005 • Safe credentialing process – March/April 2005 • Technical Phase – May-June 2005 • Operational Phase – Aug/Dec 2005 • Pre-production Q1 2006 • Production Q2 2006

16. Cancer Centers/ Cooperative Groups/Community Hospitals City of Hope Johns Hopkins University Mayo Memorial Sloan Kettering Moffitt Cancer Center Stanford University FDA (regulatory perspective) Bio/Pharma BMS Johnson & Johnson Merck Pfizer Centacor Wyeth NCI Cancer Therapy Evaluation Program (CTEP) Division of Cancer Prevention (DCP) Firebird Pilot Participants

17. Firebird/SAFE: Next Steps • Develop and test maturation process for deploying production Firebird (CRIX 1.0) component • Broad community engagement • Sustainable production support • Move Firebird into production • Migrate information for investigators to Firebird • Validation of Firebird production implementation

18. CRIX 2.0: Clinical Data Repository (Janus) • Partnering with industry to: • Implement a prototype a Clinical Data Repository that is standards-based and caBIGTM compliant • Develop a data import facility that accepts data in standard formats • Provide a data access layer that supports collaborative research for multi-site studies on a global basis • Provide tools for review, analysis and reporting

19. What’s in All clinical trial data Protocol Analysis plan Animal tox data What’s out Spontaneous reports Documents Reviews Janus/CRIX Scope* *Pilot includes implementation of existing Janus data model defined under IBM CRADA with FDA only

20. Janus/CRIX Functional Building Blocks • Data – “what happened” • Findings • Events • Domains, attributes • Interventions • Protocol – “what was supposed to happen” • Trial structure (arms, visits) • Planned assessments • Like actual findings, but no result • Planned interventions • Like actual interventions • Analysis plans and results • Analysis datasets (query rule) • Analytic plans • Analytic results

21. Out of Scope for Janus/CRIX Pilot:Potential Extensions • Implement the data services layer for the entire Janus/CRIX model • Implement a fully validated, complete Janus/CRIX Model that is compliant with CFR 21 Part 11 • Conduct performance analysis of Janus/CRIX repository to project expected production scale system requirements and identify any performance constraints • Extend the Janus/CRIX data model so as to support data now gathered in the CDUS and CTMS applications as well as for SAEs, AdAM, and 1571/1572 form information

22. Janus/CRIX - Data Access Vision Tools for Review, Analysis, Reporting … FDA Review Ad Hoc Query Tool SAS I-Review ToxVision WebSDM Spread- sheet Tool Study Specific Data Marts Data Access Layer (BRIDG/CTOM) Janus/CRIX Master Index Janus Extensions Base Janus Model

23. Construct Data Load facility Create DB prototype environment Implement Janus base data model Select & construct data access facility Design test suite Conduct Require’ts gathering Design CSM configuration Implement CSM Security Joint Tasks Construct test environment Review and approve prototype Project Initiation Workshop Conduct prototype testing Develop Use Cases Load test data Phase 1 NCI Tasks Assist in require’ts gathering Develop test data Check Point Check Point Phase 1A Phase 1B Phase 1C Janus/CRIX Project Plan Overview

24. CRIX 3.0: Electronic Submissions • Develop and deploy a secure, electronic infrastructure for facilitating submissions to the FDA including: • Documents: unstructured text or non-standard, special data sets submitted via: • ICH Electronic Common Technical Document (eCTD) • HL7 Regulated Product Submission (RPL) message - under development • Data: Standard, structured data submitted via • ODM and SDTM Define.XML • HL7 v3 Electronic Data Collection Instrument (eDCI) message – under development • Proposal for submission of standardized electronic study data from clinical studies evaluating human drugs and biologics would revise FDA regulations to require clinical study data to be provided in electronic format and require the use of standard data structure, terminology and code sets – Federal Register 69 FR 73119

25. BRIDG BRIDG Putting it All Together (CRIX Target Environment) Documents (Unstructured Text & Non-Standard Data Sets) eCTD or HL7 RPL XML Secure Transport Annual Reports Investigator Brochures etc. Secure Transport Message Exchange Services (ebXML) Message Exchange Services (ebXML) Secure Transport Structured Data (Standard Data Sets) Structured Protocols Findings Events Interventions etc. ODM and SDTM Define.XML or HL7 eDCI XML CRIX/Janus Clinical Data Repository Secure Transport Data Load API Government, Academic or Industry Site Secure Data Access (Authorized to View Basis)

26. Target caBIGTM/CRIX Collaborative Research Environment* Local DBs *Prior to Regulatory Submission NIH/NCI Clinical Center Biopharma Local DBs Virtual Database Local DBs CRO Clinical Center Local DBs Local DBs • caGRID – Grid Services: • Data Services (caBIO/CTOM/BRIDG) • Security Services (CSM) • Semantic Services (caDSR) • Vocabulary Services (EVS) • etc.

27. Production Infrastructure - Principles • Assembles, maintains, and extends pilot components • Open, transparent, inclusive, governance • Government • Academics • Industry • Management through trusted 3rd party • Hosting services • Managing the SAFE credentialing process • Managing Site Registry, Organization Registry, Investigator Registry • Self sustaining

28. “Toto, I have a feeling we’re not in Kansas anymore…”

29. Next CRIX Face-to-Face • Time: 9:00AM - 3:00 PM PST • Location: UCSF, Rock Hall Auditorium, 1550 4th Street, Room 102 • Teleconference Number: 1-866-815-8292 pass code:  706245

30. Acknowledgements and so many more…