# Presentation: 173854

## Domain Update: Clinical Trials Management Systems (CTMS) Workspace

***John Speakman***
***Associate Director, Clinical Trials Products and Programs******Center for Bioinformatics and Information Technology***
***National Cancer Institute***

***Presentation to caBIGTM Data Sharing and Intellectual Capital (DSIC) Workspace Face-to-Face Meeting, Ann Arbor, MI***
***May 15, 2007***

## caBIG Workspaces, our Town Halls

**Architecture**

**Vocabularies and Common Data Elements**

**Strategic Planning**

**Training**

**Integrative Cancer Research**

***In Vivo*****   Imaging**

**Tissue  Banks & Pathology Tools**

**Data Sharing & Intellectual Capital**

**Clinical  Trials Mgmt Systems**

**caBIG Program Management and Contracting**

## Translating Molecular Understanding to Patient Outcomes – how are we doing?

**Time**

**Information**

*(from Robert C. Bast, Jr., MD)*

**Translating Molecular Understanding to Patient Outcomes – how are we doing?**

## Explosion of knowledge from biological research, continued growth in research spending
Slowdown in innovative therapies reaching patients
as measured by the number of new submissions to FDA
“The [drug development] process has not kept up with basic scientific innovation”
8% of drugs entering Phase I get to the market
“For drugs entering human clinical trials for the first time between 1989 and 2002 [average] cost per new drug [was] $868 million [...] $500 million to more than $2,000 million [...]
Health Affairs 25, no. 2 (April 2006)

- Slowdown in innovative therapies reaching patients
- as measured by the number of new submissions to FDA
*“**The [drug development] process has not kept up with basic scientific innovation”*
- 8% of drugs entering Phase I get to the market
*“**For drugs entering human clinical trials for the first time between 1989 and 2002 [average] cost per new drug [was] $868 million [...] $500 million to more than $2,000 million [...]*
- Health Affairs 25, no. 2 (April 2006)

**FDA***** (Innovation or Stagnation, aka Critical Path, Woodcock 2004):***

## Common needs helped shape priority areas for the caBIG pilot activities 

- 0

- 5

- 10

- 15

- 20

- 25

- 30

- 35

**Clinical Data Management Tools**

- Staff Resources

**Distributed Data Sharing/Analysis Tools**

**Translational Research Tools**

**Access to Data**

**Tissue & Pathology Tools**

- Center Integration & Management

- Common Data Elements & Architecture

- Meta-Project

- Vocabulary & Ontology Tools & Databases

- Statistical Data Analysis Tools

- Visualization & Front-End Tools

- Remote/Bandwidth

**Proteomics**

**Microarray & Gene Expression Tools**

- Meeting

- LIMS

- Licensing Issues

**Pathways**

- High Performance Computing

- Integration

- Imaging Tools & Databases

- Database & Datasets

**Number of Needs Reported**

**Clinical Trial Management Systems**

**Tissue ****Banks ****& Pathology**

**Integrative Cancer Research**

## Clinical Research IT Infrastructure – building an end-to-end pipeline

**Clinical **
**Systems**

- De-identification
- Services

- Labs,
- EMR,
- Tissue,
- etc.

**Clinical**
**Trials**

**External**
**Reporting**

- HL7/CAM
- SDK

- HL7- v3

- HL7-v3,
- Janus

**Clinical**
**Data Mgmt**

- EDC

- Adverse Events

- Participant Registry

- etc.

**Translation****Service**

- FDA

- SPONSOR

- NCI

- other

**HL7 ****trans-****actional****database**

**Clinical****Research****Information**
**Exchange**
**(IOTF)**

- HL7- v2.x,other

**Research****Data****Warehouse**

- HL7-v3,
- Janus

**Patient****Health****Record**

- Lifecycle Management

## Modular approach

-      Interoperable modules that address specific needs:
- Electronic data capture
- Hospital information Systems interfaces
- Trial lifecycle management
- Adverse event reporting
- Regulatory reporting
- Analysis
- Visualization
-      Anyone can build a
- 	module that plugs in
- 	if they build to
- 	 caBIG standards**	**

## NCI Clinical Trials Working Group

- National Cancer Advisory Board Group
- Report “Re-engineering the Cancer Clinical Research Enterprise” *(June 2005)*
- Remit: advise on *“whether, and*
*	**in what ways, the NCI-supported*
*	**national clinical trials enterprise*
*	**should be restructured to realize*
*	**the promise of molecular*
*	**medicine for advancing*
*	**oncologic clinical practice in the*
*	**21**st** Century”*

## CTWG Theme #1: Coordination

**	***“**The CTWG envisions an enhanced cancer clinical trials enterprise in which increased participation by the extramural community in the prioritization process more effectively focuses resources on those trials judged most likely to facilitate advances in treatment. The success of this strengthened prioritization process depends on a**** ******shared foundation of comprehensive, up-to-date information about the status of cancer clinical trials****.”*
*-**	**CTWG Report*

## Recommendation:NCI Clinical Trials Database 

- Comprehensive cross-enterprise picture of clinical trials completed and underway – will reduce duplication of effort
- Outcomes, toxicity and adverse event information can be collected and disseminated rapidly to the community
- Single source of truth on trial status
- Enhanced cross-trial data
- 	mining / analysis; community-
- 	accessible
- Potential to include data from
- 	other sponsors (public and
- 	private)
- Leveraging of community and
- 	NCI experience and expertise in
- 	construction of clinical trial
- 	databases

**Notes:**
Benefits
  Establishing a NCI Clinical Trials Repository:
  Provides opportunity for Research Community involvement and input  
  Provides one source for all clinical trials information for researchers, physicians and patients
  Will facilitate routine review of safety, efficacy, and administrative data reported from on-going cancer trials
  Allows for better informed allocation and investment of resources based in improved data quality and veracity 

## CTWG Theme #2: Standardization

**	***“**Transformation of the cancer clinical trials system [...] hinges on establishing ****enterprise-wide standardization****”*
*	**“**Creating an ****interoperable information technology platform**** would facilitate the reporting, analysis, and sharing of data across sites and promote team science. [...] ****Standard case report forms**** would reduce [...] the need for investigative sites to manage a wide array of different forms and data entry processes. Instituting a widely recognized ****credentialing system for research personnel and sites**** would eliminate the need to reestablish credentials each time a trial is initiated”*
*-**	**CTWG Report*

- Between systems supporting NCI-sponsored trials
- Alignment of NCI intramural/extramural databases to facilitate the sharing and exchange of clinical research data
- Secure, transparent, appropriate community access to clinical trials data
- Study Initiation Tool: Web
- 	portal to support clinical
- 	research activities, including
- 	tools and services to support
- 	protocol initiation
- Elimination of manual
- 	reconciliation

**Recommendation: Establish Interoperability and Harmonization**

**Notes:**
Talk to Benefits
  Supports a collaborative environment – will facilitate the reporting, analysis, and sharing of data across sites and promote team science
  Supports a common infrastructure that allows community members to submit data once and for the NCI staff to have access to the shared data

This initiative consists of 3 primary activities:
  Harmonizing internal NCI Clinical Trials systems 
  Harmonizing NCI external systems by
  Adopting applications developed through the caBIGTM program, or
  Making current IT systems compatible with caBIG guidelines
  Define and develop a web-based trial initiation portal to facilitate protocol activation at sites
  The content on the portal will be similar to the trial initiation materials provided to sites by industry sponsors

## Recommendation: Library ofStandard Case Report Forms

- Reduction of time, cost and effort
- Standardized data capture, cross-trial analysis
- Maximize the capture of critically important data
- Simpler regulatory review
- Leveraging of past and current NCI standardization work
- Leveraging also on experience of what does and does not secure adoption

**Notes:**
  Efforts to establish the Cancer Research Community needs will be built upon the CRF Standardization efforts already completed or on-going (i.e, leverage CRFs developed by CTEP, DCP and those contained within C3D, etc.)

  A key benefit for the research community will be a reduction in the time, cost and effort of initiating & executing clinical research trials by (this text is an expansion of the first sub-bullet):
  Substantially reducing the need to re-train staff on CRF use 
  Minimizing duplication of work
  Eliminating the need to regenerate data collection instruments (note: may still have to generate DCIs, but effort required will be substantially reduced

## Each investigator has to re-credential for each
	trial (For NCI CTEP, once a year)
Credentialing process is entirely paper-based
Investigator fills out FDA 1572 form on paper
Sends in with CV and (sealed) financial
	disclosure form
Sites usually have no control of what goes to
	the sponsor
Credentials are mutually incompatible
It’s not just the investigator; Sites are endlessly recredentialed
Simplification of cumbersome trial initiation process
Enablement of rapid communication of changes in investigator/site status to sponsors
An infrastructure that allows rapid communication to all sites
Can keep investigators abreast of changes in clinical trials (e.g., legal, safety, regulatory)

- 	trial (For NCI CTEP, once a year)
- Credentialing process is entirely paper-based
- Investigator fills out FDA 1572 form on paper
- Sends in with CV and (sealed) financial
- 	disclosure form
- Sites usually have no control of what goes to
- 	the sponsor
- Credentials are mutually incompatible
- It’s not just the investigator; Sites are endlessly recredentialed
- Simplification of cumbersome trial initiation process
- Enablement of rapid communication of changes in investigator/site status to sponsors
- An infrastructure that allows rapid communication to all sites
- Can keep investigators abreast of changes in clinical trials (*e.g.*, legal, safety, regulatory)

**Recommendation: Investigator and Site Credential Repository**

## The CTMS Operating Model (post-CTWG)

**Project Execution Teams**

**Project Execution Teams**

**Project Execution Teams**

**Project Execution Teams**

**Developers**

**Adopters**

**Task Force(s)**
- (Tactical view, focused primarily on  CTWG Informatics Initiatives)

**Special Interest Group**

- Informational

- Relationship Legend

- Tasking

## December 2006: 10 SIGs

**(****Green=Original****, ****Blue = caBIG Additions****, ****Orange = CTWG Additions****)**

## A Gray Area

**RegDEx Janus****	**
**RegDEx FIREBIRD**** **
**NCICB Clinical Data System (CDS)****	**
**NCICB DCP/DESK****	**
**NCICB Serious Adverse Event Reporting System**
**NCICB Clinical Trials Object Model (CTOM)****	**
**NCICB caMatch****	**
**NCICB Cancer Central Clinical Database (C3D)**
**caBIG C3PR**
**caBIG Protocol Lifecycle Tracking (PLT)****	**
**caBIG caAERS****	**
**caBIG BRIDG**
**caBIG Study Calendar****	**
**caBIG caXchange****	**
**caBIG CTMS Integration Project****	**
**caBIG Compatibility and Grid Enablement - CTMS Vendors**
**CTWG CTDB****	**
**CTWG Study Initiation Tool****	**
**CTWG Investigator & Site Credentialing Repository****	**
**CTWG Case Report Form Standardization****	**
**CTWG Systems Interoperability and Harmonization**

***“******NCICB”***

***“******caBIG”***

## What is the Clinical Trials Management Systems Workspace Trying to Achieve?

**Facilitate the **_**planning**_** and instantiation of clinical trials, (and their **_**monitoring**_** of trials once they are instantiated)**
**Facilitate the **_**conduct **_**of clinical trials**
**Facilitate the **_**reporting and sharing**_** of clinical trial data to existing/new destinations, **
**Achieve **_**interoperability**_
- Increase the ability of systems to *access *and* use* the data and functionality of other systems
- Facilitate the integration of new sources and destinations of data

## Special Interest Groups and Projects

**Interoperability**** **
**System Interoperability and Harmonization**
**Structured Protocol Representation (BRIDG)**
**Clinical Trials Interoperability Project**

**Planning/**
**Monitoring**** **
**Investigator and Site Credential Repository**
**Study Initiation Tool**
**Protocol Lifecycle Tracking **
**FIREBIRD**
**DCP/DESK**

**Conduct**
**Standardized Case Report Forms**
**Cancer Central Clinical Database (C3D)**
**Participant Registry **
**Laboratory Interface**
**Financial/Billing**
**Study Calendar**
**Subject Prescreening**
**Vendor Systems**

**Reporting/**
**Sharing**** **
**Clinical Trials Database**
**Routine Data Exchange**
**Clinical Trials Object Model**
**Janus (FDA Repository)**
**Adverse Event Reporting and Collection**

## Planning and Monitoring

**Planning and Monitoring**

- (CTWG) Investigator and Site Credentials Repository
- FIREBIRD
- Federal Investigator Registry of Biomedical Research Data: Electronic Investigator Credential Management System (electronic version of FDA Form 1572)
- (CTWG) Study Initiation Tool
- Protocol Lifecycle Tracking
- Manage and document a protocol through the entire life cycle of the trial, starting at Concept Development and continuing through to Submissions & Publications
- DESK (DCP Enterprise System Knowledgebase):
- Set of web-enabled systems to support the scientific and administrative work of the NCI Division of Cancer Prevention

## Time-intensive, paper-intensive, labor-intensive regulatory review is not just an FDA/pharma problem
It is slowing the delivery of innovative new therapies
NCI is a clinical trial sponsor
Paper processes are time-intensive to us too

Approach: NCI-FDA Inter-Agency Oncology Task Force (IOTF) will build an electronic regulatory infrastructure
Facilitate adoption of electronic data standards, standardized terminologies, and electronic submissions
Reduce the cost of information gathering,
	submissions and analysis / review
Allow secure transmission of data
Allow it to be mined

- Time-intensive, paper-intensive, labor-intensive regulatory review is not just an FDA/pharma problem
- It is slowing the delivery of innovative new therapies
- NCI is a clinical trial sponsor
- Paper processes are time-intensive to us too
- Approach: NCI-FDA Inter-Agency Oncology Task Force (IOTF) will build an electronic regulatory infrastructure
- Facilitate adoption of electronic data standards, standardized terminologies, and electronic submissions
- Reduce the cost of information gathering,
- 	submissions and analysis / review
- Allow secure transmission of data
- Allow it to be mined

## Automates/centralizes investigator registration and accreditation process (currently uses FDA Form 1572 – cumbersome,
	repetitive)
Enables
	investigators to
	register online
Digital signature
	technology
Operational
	pilot with
	NCI, FDA
	and pharma
	just completed

- 	repetitive)
- Enables
- 	investigators to
- 	register online
- Digital signature
- 	technology
- Operational
- 	pilot with
- 	NCI, FDA
- 	and pharma
- 	just completed

**First IOTF component: FIREBIRD**

**Notes:**
Firebird will automate the registration process for FDA form 1572, which is used by sponsors of clinical trials—including NIH and pharmaceutical companies—as well as FDA.

## Development Strategy

**Development Strategy**

- Component 1

- Component 1

- Component 2

- Component 2

- Component x

- Component x

**RDE 1.0**

**RDE 2.0**

**RDE x.0**

- technicalfeasibility

- operationalfeasibility

**...**

**...**

**Production****Infrastructure**

**Infrastructure ****Development**

## Government Action in support of IOTF

- December 18, 2006: FDA 21 CFR Part 15 Public Hearing
- Electronic Submission of Regulatory Information, and Creating an Electronic Platform for Enhanced Information Management
- March 27, 2007: NIH/NCI/FDA Request for Information on potential Public/Private partnership arrangements
- Deadline for responses: May 31, 2007

## Conduct

**Conduct**

- (CTWG) Standardized Case Report Forms
- Cancer Central Clinical Database (C3D)
- Cancer Central Clinical Participant Registry (C3PR)
- Clinical Data Hub (caXchange): extracting lab data from clinical lab systems for use in trials, extensible to any clinical data source
- Study Calendar (PSC): Patient scheduling system
- Subject Prescreening (caMatch): investigate automated screening of potential study participants against eligibility criteria
- Support for vendors of commercial clinical trials systems working to achieve caBIGTM compatibility

## Cancer Central Clinical Database (C3D)

**Clinical trial data management system**
**Based on template forms (CRFs) composed of Common Data Elements**
**Automatic lab data loading and Common Toxicity Criteria (CTC) grading **
**Automated reporting to NCI sponsor systems**
**Host-it-yourself or ASP (hosted at NCI)**
**Used by NCI Clinical Center and multiple NCI Cancer Centers today to run trials**
**Contains more than 2.0 million lab results, over 350,000 completed Case Report Forms, more than 3,000 patients and more than 125 active studies**

## Participant Registry (C3PR)

**Relationship management for participants and trials including patients, physicians, nurses, PIs, etc.**
**Single point of data entry for storing sensitive information; can potentially evolve into a National Registry of trial patients**

## Clinical Data Hub (caXchange)

- HL7v3  CT Lab Messages with actual clinical trial data

**Other Cancer Centers**

- Lab data
- File in
- .csv format

**Cancer Center**

- caAdapter
- (.csv to v3)

- HL7 v3
- XML

- HL7v3 CT Lab Messages with dummy clinical trial data

- C3PR Lookup

- C3PR Database

- HL7 v3
- XML

- Router

- Lab Domain APIs

- CTOM Database

**caXchange HUB**

- C3PR Query Interface

**NCI**

- HL7 v3

**Clinical Data Hub (caXchange)**

**Notes:**
HL7 v2

## Patient Study Calendar (PSC)

- Allows the schedule of patient interactions prescribed by a study protocol to be described
- Development of a template schedule that can be easily adapted for a variety of protocols
- Prospective application to allow the capability to alert clinicians to schedule patient appointments
- Ability to record date, time and nature of actual events, including deviations from the proscribed protocol schedule
- Ability to report to user upcoming events, create alerts for missed events and deviations and provide reports for study coordinators, investigators and administrators on patient accrual

## Eligibility Prescreening (caMATCH / bct.org)

**Eligibility Prescreening (caMATCH / bct.org)**

## Reporting and Sharing

**Reporting and Sharing**

- (CTWG) Clinical Trials Database
- Routine Data Exchange Group
- Group investigating the automated reporting of routine data to NCI (e.g., NCI-sponsored trial data, annual summary reporting from Cancer Centers)
- Clinical Trials Object Model
- Next Generation Clinical Trials Data Warehouse
- Janus
- FDA Clinical Trial Data Repository
- Adverse Event Reporting and Collection
- Automated local collection and querying of adverse event data, and automated submission to multiple destinations including NCI Expedited Adverse Events

## Cancer Adverse Event Reporting System (caAERS)

## Interoperability

**Interoperability**

- (CTWG) System Interoperability and Harmonization
- Structured Protocol Representation (BRIDG)
- An overarching model of the clinical trials domain, built in collaboration with CDISC, industry and FDA
- Clinical Trials Interoperability Project
- Integration of new and forthcoming application modules so that they reuse each other’s data and functionality

## BRIDG

**A strategic initiative involving caBIGTM and:**
- the Clinical Data Interchange Standards Consortium (CDISC)
- Health Level Seven (HL7)
**	****to develop a single domain representation for clinical research**
- i.e., a formal domain analysis model of the shared semantics of clinical research
- will ensure computable semantic interoperability
**BRIDG will incorporate existing CDISC standards**
**In caBIGTM, BRIDG forms the basis of interoperable clinical trial tool development**

## Data Sharing in CTMS

**Safety / regulatory (FDA / Janus, NCI / Clinical Trials Database)**
**Future trial cohort planning**
**Outcomes research (modeled on databases like SEER)**

## Five (are there five?) levels of data sharing in clinical trials

**Sharing patient clinical trial data:**
**within an institution during the conduct of a clinical trial (*****e.g.*****, to notify the study calendar that an adverse event has occurred and that the patient’s schedule may be affected)**
**among multiple institutions participating in the same study**
**with a sponsor or a regulatory body as required by contract agreement or by law**
**between colleagues as part of a negotiated, agreed-upon collaboration**
**publicly for anyone to review**

## Potential DSIC Issues in Clinical Trials - General

**Study SEER as a model for clinical data release**
**Investigate restrictive data use contracts signed with pharmaceutical sponsors (*****e.g.*****, data can be reused as long as there’s no possibility of others making a material profit)**
- Maybe we need a map of the contract landscape out there – how widespread, how varied, how much sponsor trial data is retained by centers
- Is there anything we can do (a) proactively, e.g., suggested boilerplate for the NCI community when negotiating standard contracts (b) retroactively to free up any of this information
**Investigate IRB / DSMB / DSMC restrictions to data sharing**
- Again, maybe we need a map of the landscape, perhaps by finding centers to deliver “trial balloons”
- Build up a canon of “successful language” of submissions
**Map the investigator mindscape – get a consensus**
- Identify whether there’s a need for a post-publication embargo period
- Assemble pro-sharing talking points

## Application-by-Application CTMS Map

## Thank you! Q & A

**john.speakman@nih.gov**
*Join us in Portland, Oregon, May 30-31 for the first caBIGTM Clinical Trials Management Systems Workspace face-to-face meeting of 2007*