Sue Dubman

1
CRIXToward a Shared Clinical Infrastructure

• Sue Dubman
• NCI Center for Bioinformatics (NCICB)
• dubmans_at_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 dont 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
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!
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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

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CRIX Development Plan
Electronic Submissions
CRIX CDR

Firebird/SAFE
ProductionInfrastructure
Firebird/SAFE
Firebird/SAFE
operationalfeasibility
technicalfeasibility

CRIX CDR
CRIX CDR
Infrastructure Development
Electronic Submissions
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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

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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

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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

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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

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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

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Firebird Pilot Participants

• 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)

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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

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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

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Janus/CRIX Scope

• Whats in
• All clinical trial data
• Protocol
• Analysis plan
• Animal tox data

• Whats out
• Spontaneous reports
• Documents
• Reviews

Pilot includes implementation of existing Janus
data model defined under IBM CRADA with FDA only
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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

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Out of Scope for Janus/CRIX PilotPotential
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

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Janus/CRIX - Data Access Vision
Tools for Review, Analysis, Reporting

Ad Hoc Query Tool
FDA Review
SAS
I-Review
Spread- sheet Tool
WebSDM
ToxVision
Study Specific Data Marts
Data Access Layer (BRIDG/CTOM)
Janus/CRIX
Master Index
Janus Extensions
Base Janus Model
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Janus/CRIX Project Plan Overview
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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

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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)
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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.

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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

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Toto, I have a feeling were not in Kansas
anymore
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Next CRIX Face-to-Face

• Time 900AM - 300 PM PST
• Location UCSF, Rock Hall Auditorium, 1550 4th
  Street, Room 102
• Teleconference Number
• 1-866-815-8292
• pass code  706245

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Acknowledgements
and so many more