# Presentation: 284882

## Sue Dubman
NCI Center for Bioinformatics (NCICB)
dubmans@mail.nih.gov 

**NCI Center for Bioinformatics (NCICB)**
- _[dubmans@mail.nih.gov](mailto:dubmans@mail.nih.gov)_** **

**CRIX:***Toward a Shared Clinical Infrastructure*

## 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)

## 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

## Cheshire Cat Advice

- If you don’t know where you are going, any road will take you there...

## 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

## 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!**

## 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

## 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

## 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

## CRIX Development Plan

**Firebird/SAFE**

**CRIX CDR**

**Electronic**
** ****Submissions**

**technical****feasibility**

**operational****feasibility**

**...**

**...**

**Production****Infrastructure**

**Infrastructure ****Development**

**Firebird/SAFE**

**Firebird/SAFE**

**CRIX CDR**

**CRIX CDR**

**Electronic **
**Submissions**

## 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

## 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

## 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

## 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

## 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

## 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)

## 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

## 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

## Janus/CRIX Scope*

- What’s in
- All clinical trial data
- Protocol
- Analysis plan
- Animal tox data

- What’s out
- Spontaneous reports
- Documents
- Reviews

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

## 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

## 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

## Janus/CRIX - Data Access Vision

**Tools for Review, Analysis, Reporting**

**Ad Hoc**
**Query**
**Tool**

**Spread-**
**sheet**
**Tool**

**Master Index**

**Janus**
**Extensions**

**Base Janus Model**

**Janus/CRIX**

**FDA**
**Review**

**SAS**

**WebSDM**

**ToxVision**

**I-Review**

**Study Specific Data Marts**

**...**

**Data Access Layer (BRIDG/CTOM)**

## Janus/CRIX Project Plan Overview

## 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

## Putting it All Together (CRIX Target Environment)

**Annual Reports**
**Investigator Brochures**
**etc.**

**Government, Academic or Industry Site**

**Documents ****(Unstructured Text &**
**Non-Standard Data Sets)**

**Structured Data**
**(Standard Data Sets)**

**CRIX/Janus**
**Clinical Data**
**Repository**

- Secure
- Transport

- Secure
- Transport

**Structured Protocols**
**Findings**
**Events**
**Interventions**
**etc.**

- ODM and
- SDTM Define.XML or HL7 eDCI XML

**Data**
**Load**
**API**

- eCTD or
- HL7 RPL XML

**Message**
**Exchange**
**Services**
**(ebXML)**

- Secure
- Transport

**Message**
**Exchange**
**Services**
**(ebXML)**

**Secure**
**Transport**

- Secure Data Access
- (Authorized to View Basis)

## Target caBIGTM/CRIX Collaborative Research Environment*

**NIH/NCI**

**caGRID – Grid Services:**
**Data Services (caBIO/CTOM/BRIDG)**
**Security Services (CSM)**
**Semantic Services (caDSR)**
**Vocabulary Services (EVS)**
**etc.**

**Virtual**
**Database**

**Biopharma**

**CRO**

**Local**
**DBs**

**Local**
**DBs**

**Local**
**DBs**

**Clinical Center**

**Local**
**DBs**

**Clinical Center**

**Local**
**DBs**

***Prior to Regulatory Submission**

## 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

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

## 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

## Acknowledgements

***and so many more...***