1. NCI Clinical Case Report Form (CRF) Standardization Activities George A. Komatsoulis, Ph.D. Deputy Director Center for Biomedical Informatics and Information Technology (CBIIT) National Cancer Institute

2. A wonderful fact to reflect upon, that every human creature is constituted to be that profound secret and mystery to every other. Charles Dickens:A Tale of Two Cities 1859 3. Childhood Cancer: Dramatic Improvement in Survival *5-year relative survival rates, based on follow up of patients through 2003. Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division of Cancer Control and Population Sciences, National Cancer Institute, 2006. 5 - Year Relative Survival Rates * Age Year of Diagnosis 0 - 4 Years 5- 9 Years 10- 14 Years 1975 - 1977 1996 - 2002 1975 - 1977 1996 - 2002 1975 - 1977 1996 - 2002 79.7 77.9 80.1 58.8 58.2 57.3 4. High Participation in Clinical Research Winchester et al.,CA Cancer J Clin2001;51;119-130 5. Childhood ALL: Molecular Sub-types Impact Risk Tsao et al.Modern Pathology(2004)17: 832839Rubnitz and Pui,Oncologist ( 1997)2 :374-380 6. Childhood Cancer Treatment Demonstrates the New Molecular Medicine Model

Treatment is delivered in an environment that blends care and research

Researchers and practitioners are able to correlate experimental laboratory data with clinical data (treatment, history, pathology,outcome, etc.)

Clinical data are utilized to continuously evaluate outcomes

Researchers develop and refine evidence-based strategies at an individualized level

Care providers improve quality by adherence to care standards

Information flow is critical this model cannot be achieved without the ability to reuse and aggregate data in novel ways! 7. Improving the Return on the Nations Investment in Cancer Research

Human Clinical Trials are of immense importance to providing new and improved treatments for patients, yet by their nature they have several undesirable traits including potential harm to patients and immense expense.

For these and other reasons, it is absolutely essential to maximize the return on investment (ROI) in human clinical research either by (1) decreasing the costs associated with trials or (2) increasing the amount of information extracted from any single clinical trial

Two primary mechanisms by which data sharing and data standards can aid in ROI:

• Reduce the time and costs associated with setting up a clinical trial

• Enhance the ability of other groups to reuse the data collected in one clinical trial (for example, in longitudinal studies)

In order to reuse data, it is necessary to have a thorough understanding of its meaning

8. And the Lord said, Behold, the people is one, and they have all one language; and this they begin to do; and now nothing will be restrained from them, which they have imagined to do. Go to, let us go down, and there confound their language, that they may not understand one another's speech. Genesis , Chapter 11, 500-450 BCE What we have here is failure to communicate Strother Martin inCool Hand Luke1967 9. Attribute Value Agent NSCNumber 007 Name Taxol 10. Attribute Value NCI Meaning Agent A chemical compound administered to a human being to treat an existing disease or condition, or prevent the onset of a disease or condition nSCNumber 007 Identifier given to a chemical compound by the US Food and Drug Administration (FDA) Nomenclature Standards Committee (NSC) Name Taxol Name of a chemical compound given by the NCI Cancer Therapeutics Evaluation Program (CTEP) 11. Attribute Value NCI Meaning CIA Meaning Agent A chemical compound administered to a human being to treat an existing disease or condition, or prevent the onset of a disease or condition A sworn intelligence agent; a spy nSCNumber 007 Identifier given to a chemical compound by the US Food and Drug Administration (FDA) Nomenclature Standards Committee (NSC) Identifier given to an intelligence agent by the National Security Council Name Taxol Name of a chemical compound given by the NCI Cancer Therapeutics Evaluation Program (CTEP) Code name given to intelligence agents by the Central Intelligence Agency (CIA) 12. Attribute Value NCI Metadata CIA Metadata Agent A chemical compound administered to a human being to treat an existing disease or condition, or prevent the onset of a disease or condition A sworn intelligence agent; a spy nSCNumber 007 Identifier given to a chemical compound by the US Food and Drug Administration (FDA) Nomenclature Standards Committee (NSC) Identifier given to an intelligence agent by the National Security Council Name Taxol Name of a chemical compound given by the NCI Cancer Therapeutics Evaluation Program (CTEP) Code name given to intelligence agents by the Central Intelligence Agency (CIA) 13. Empowering Data Reuse: Semantic Metadata

Reuse therefore requires semantic metadata; information that conveys what is being recorded and what constitutes a valid response for that particular element.

An international standard (ISO/IEC 11179) exists for such semantic metadata, this standard has been leveraged to create the cancer Data Standards Repository (caDSR).

The basic unit of metadata in the caDSR is a Common Data Element or CDE.

14. The ISO 11179 Model in the caDSR 15. The cancer Data Standards Repository (caDSR) 16. Enterprise Vocabulary Service (EVS) 17. Square Pegs and Round Holes 18. Clinical Trials Working Group

National Cancer Advisory Board Group

Report Re-structuring the National Cancer Clinical Trials Enterprise (June 2005)

Remit: advise onwhether, andin 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 the21stCentury

Twenty-two Initiatives

19. Clinical Trials Working Group (CTWG) CTWG Goal CTWG Initiative Enhanced Coordination Establish a comprehensive database containing regularly-updated information on all NCI-funded clinical trials Enterprise Wide Standardization Achieve industry and FDA concurrence on standard Case Report Forms incorporating Common Data Elements Promote establishment of national clinical trial information technology infrastructures that are fully interoperable with NCIs cancer Biomedical Informatics Grid (caBIG) Develop a credentialing system for investigators and sites that is recognized and accepted by NCI, industry sponsors, clinical investigators, and clinical trial sites 20. Characteristics of a library of standardized CRF modules

A library of modules, containing questions to be used in CRFs in all oncology trials

These modules would not be a set of required forms,per se , instead they contain the set of data elements that must be collected during a trial

These modules do not restrict investigators from collecting additional information

21. Genius is one percent inspiration and ninety-nine percent perspiration Thomas Alva Edison,Harpers Monthly , September 1932 22. Case Report Forms Based on Common Data Elements (CDEs) 23. CRF Standardization Global Process

Inventory

• Existing case report forms (whether harmonized or not)

• Initial inventory from forms whose metadata are captured in the cancer Data Standards Repository (caDSR)

Prioritize

• Based on the inventory and Steering Committee feedback, select the areas for harmonization.

Analyze and Harmonize (Working Groups)

• Come to agreement on the core questions associated with a specific CRF

• Reach out to the community for additional CRFs in this area

• Come to agreement on the core data to be collected on this specific CRF

Community Input

• Important to ensure acceptance of the harmonized CRFs

• CRF SIG and caBIG program will provide the mechanism to receive input

Standardization

• Approval by stakeholders

24. CRF Analysis Methodology

Part I:Question intent

Part II:Partition

• Mandatory

• Conditional

• Optional

• Non-harmonized

Part III:Detailed Analysis

Important caveat: We should not be creating new questions that have not been asked on an existing CRF

25. CRF Questions:Partition Issues

Regulatory Requirements

• FDA Representatives, Compliance Officers, Regulatory Affairs Officers

Sponsor Requirements

• NCI Division Representatives, Principal Investigators

Data Reuse Requirements

• Principal Investigators, Data Managers, Biostatisticians, Oncology Nurses and the rest of our community

External Standards Requirements

• Standards Organizations (CDISC, HL7, FHA, etc.)

26. CRF Questions:Detailed Analysis

Question by question (or CDE by CDE) analysis

Must harmonize:

• Question meaning

• Question text

• Valid responses

General Strategy (Proposed order of precedence)

• • Reuse an existing CDE

• • Create a hybrid CDE

• • Create a new CDE

The same constraints apply to CDE level analysis

27. Demography: A Definition

Pronunciation:di-'m-gr&-fE

Function:noun

Etymology:Frenchdmographie,from GreekdEmospeople + French-graphiegraphy

Definition:The statistical study of human populations especially with reference to size and density, distribution, and vital statistics

28. Sources of CRFs: Demography Analysis

CTEP Phase 2 Enrollment

CTEP Phase 3 Enrollment

DCP Enrollment Form

C3D (CCR) Enrollment

ACOSOG Registration

CALGB Registration

GeminX Demographics

NSABP Registration

NSABP Entry

OHSU Enrollment

OHSU 1754 Enrollment

OHSU Registration

RTOG Registration

SWOG Registration

SWOG S0522 Registration

UNMC Enrollment

CDASH Demography

29. Working Group Members

Sharon Elcombe, Mayo (Informatician)

Rhonda Facile, CDISC (Data Standards)

Howard Fingert, Pfizer (Clinician)

Lara Fournier, Oregon Health Science University (Informatician)

Marsha Ketcham,Univ. of Nebraska Cancer Center (Clinical Research Coordinator)

Darlene Kiniry, NSABP (Informatician)

George Komatsoulis, NCI Informatician

Brenda Maeske, SAIC/CBIIT (Data Element Specialist)

Beverly Meadows, DCP (Oncology Nurse)

Jon Neville, Cpath (Drug Policy)

Susan Pannoni, City of Hope ()

Stephine Wasielewsky, Univ. of Wisconsin Cancer Center

Dianne Reeves, CBIIT (Oncology Nurse)

Aaron Seib, OmnicommSystems (Informatician)

Ann Setser, CTEP (Oncology Nurse)

Adel Taweel, Univ. of Birmingham, UK (Informatician)

Susan Varghese, BAH

Gary Walker, Quintiles/CDASH

30. Actions to date

Harmonized Demography Module created by Working Group

Module reviewed within caBIG Clinical Trial Management Systems (CTMS) workspace

Module approved for wider review by NCI Clinical/Translational Operating Committee (CTROC)

Module circulated for wide review:

• caBIG listservs

• CTMS Steering Committee

• Cancer Policy Today and other ASCO vehicles

Comments received and analyzed

Presented to CTROC, governing board for CTMS Working Group activities at NCI

• CTROC Approved Demography Module as an NCI Standard

Some implementation Details Still to be determined

31. CDASH and caBIG: Complementary Activities

The CDASH initiative that is managed by the CDISC consortium and the NCI/caBIG Case Report Form (CRF) Harmonization activity are both concerned with harmonizing and standardizing the collection of data in clinical trials, but their focus and granularity differ somewhat

• CDASHs efforts are focused on elements that are common toallclinical trials

• caBIG is focused on trials in the oncology space

NCI/caBIG CRF modules will (at a minimum) include all CDASH mandatory questions plus additional content that is essential in the oncology space.

NCI mandatory CDASH mandatory 32. caBIG/CDASH Collaboration Mechanisms

Mutual Staffing Support

• NCI/caBIG is providing staff to many CDASH streams

• CDASH project director (Rhonda Facile) sits on the NCI Task Force that manages the CRF project

Project Inputs

• Where CDASH streams complete before NCI CRF modules are defined, the CDASH module is one of the inputs to the NCI working groups and vice versa

Terminology and Metadata Support

• NCI Enterprise Vocabulary Services (EVS) provides terminology support for CDISC/CDASH

• NCI cancer Data Standards Repository (caDSR) provides a repository to maintain CDISC/CDASH data elements

33. , , , , : Tell me, O Muse, of the man of many devices, who wandered full many ways after he had sacked the sacred citadel of Troy Homer:The Odyssey (8 thCentury BCE) 34. Status: Round 1

Round 1:Demography Module

• Reviewed and Approved

• Form template with instructions are in the caDSR

• Ready for implementation

Entered Early Adopter Phase November 1, 2008

35. Status: Round 2

Round 2 Modules:

• Adverse Events

• Medical History

• Physical Exam

• Participant Identification

• Registration

• Enrollment

• Protocol Deviations

Completed Community review September 5, 2008

Comments reconciled by Workgroup October 3, 2008

Presented to CTROC for review

36. Status: Round 3

Round 3 Modules:

• Agents

• Laboratory Tests/Results

• Staging/Extent of Disease

• Outcome Measures

Kick-off Teleconference September 4, 2008

Groups will run approximately three to four months

37. Implementation of Subsequent Modules

Begin successive modules every 3 to 4 months

Observe the same schedule

• Community Review

• Reconciliation of comments

• Submission to CTROC for approval

• Early adoption to gather more pragmatic information

• Close early adoption and make module changes

• Release module(s)

• Mandate widespread use three months later

38. CRF Planning Matrix 39. Change Management and Review

Every calendar year the total library of CRFs will be reviewed for changes

Older versions will be appropriately archived yet accessible as required

caBIG will providesupport for updates and release with version control

Modifications will be requested and changes will be vetted by community and the NCI.

All CRF Versions will be provided andMaintained on the NCI website

The Demography CRF module will become a candidate for review in April 2010.

40. Thank You

Study Conduct Task Force

• Don Connelly (MN)

• Sharon Elcombe (Mayo)

• Lara Fournier (OHSU)

• Andrea Hwang (Irvine)

• Bob Lanese (Case)

• Joyce Niland (City of Hope)

SAIC CDE Curation Team

• Janice Chilli

• Mary Cooper

• Tommie Curtis

• Kathleen Gundry

• Brenda Maeske

CBIIT

• Ken Buetow

• Dianne Reeves

• Ed Helton

• John Speakman

• Denise Warzel

• Krishnakant (Avinash) Shanbhag

BAH CTMS Support

• Ryan Budd

• Riki Ohira

• Susan Varghese

• Derek Walker

CDASH

• Rhonda Facile

• Gary Walker

CCCT

• Beverly Meadows

• Lee Ann Jensen

• Sheila Prindiville

caBIG CTMS Steering Committee

American Society for Clinical Oncology (ASCO)

Workgroup Participants

the bravest are surely those who have the clearest vision of what is before them, glory and danger alike, and yet notwithstanding, go out to meet it. Thucydides,c.400 BCE