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Daniel C. Sullivan, MD
Application of High Resolution CT Imaging Data toLung Cancer Drug Development: Measuring Progress
Progress Toward Quantitative Imaging
May 13-14, 2010Bethesda, MD
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RSNA Interests
RSNA is interested in fosteringmore emphasis on quantitativeimaging in clinical care
Facilitating imaging as abiomarker in clinical trials helpsRSNA move this agenda forward.
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Science involvesMeasurements
Lee Hartwell, PhDNobel Prize in Physiology orNobel Prize in Physiology or
Medicine, 2001Medicine, 2001President and Director, FredPresident and Director, Fred
Hutchinson Cancer ResearchHutchinson Cancer ResearchCenter, SeattleCenter, Seattle
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2009 Take-home Messages
Images are inherently quantitative: They aren-dimensional datasets
We must improve our image acquisition
parameters so that pixel/voxel values reflectthe biological parameter(s) of interest.
We must optimize image processingalgorithms to extract the pixels or voxels thatare relevant to our clinical question(s).
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2009 Challenges
In what clinical settings are quantitativeimaging results important?
How do we educate/communicatethose to radiologists?
How do we influence market demandand ROI for these capabilities?
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Progress?
Status of QIBA and related activities
Collecting evidence; making the case
Educating/communicating
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QIBA Background
Began May, 2008
Mission: Improve value and practicalityof quantitative imaging biomarkers byreducing variability across devices,patients, and time.
Build measuring devices rather thanimaging devices.
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Factors Affecting QIBA Scope
NIST definition of a measurement result: Ameasurement result is complete only whenaccompanied by a quantitative statement of
its uncertainty. The uncertainty is required inorder to decide if the result is adequate forits intended purpose and to ascertain if it isconsistent with other similar results.
FDA: A biomarker must be qualified for itsintended purpose
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QIBA Committee Leadership
CT Quantitative CommitteeAndrew Buckler, MS, Chair (Buckler Biomedical LLC)P. David Mozley, MD, Co-Chair (Merck)Lawrence Schwartz, MD, Co-Chair (Memorial Sloan-KetteringCancer Center)
Nicholas Petrick, PhD, Group 1A Subcommittee Chair (FDA)Michael McNitt-Gray, PhD, Group 1B Subcommittee Chair
(UCLA)Charles Fenimore, PhD, Group 1C Subcommittee Chair(National Institute of Standards and Technology (NIST)
Anthony Reeves, PhD, Volcano (Cornell University)
MRI Quantitative CommitteeGudrun Zahlmann, PhD, Chair (Roche)Sandeep Gupta PhD, Co-Chair (GEHC)
Ed Jackson, PhD, Co-Chair (MD Anderson Cancer Center)Mark Rosen, MD, PhD, Clinical Test-Retest Subcommittee(UPenn)
Daniel Barboriak, MD, Data Simulation (Synthetic Data)Subcommittee (Duke University Medical Center)
CT Quantitative CommitteeAndrew Buckler, MS, Chair (Buckler Biomedical LLC)P. David Mozley, MD, Co-Chair (Merck)Lawrence Schwartz, MD, Co-Chair (Memorial Sloan-KetteringCancer Center)
Nicholas Petrick, PhD, Group 1A Subcommittee Chair (FDA)Michael McNitt-Gray, PhD, Group 1B Subcommittee Chair
(UCLA)Charles Fenimore, PhD, Group 1C Subcommittee Chair(National Institute of Standards and Technology (NIST)
Anthony Reeves, PhD, Volcano (Cornell University)
MRI Quantitative CommitteeGudrun Zahlmann, PhD, Chair (Roche)Sandeep Gupta PhD, Co-Chair (GEHC)
Ed Jackson, PhD, Co-Chair (MD Anderson Cancer Center)
Mark Rosen, MD, PhD, Clinical Test-Retest Subcommittee(UPenn)
Daniel Barboriak, MD, Data Simulation (Synthetic Data)Subcommittee (Duke University Medical Center)
PET/CT Quantitative Committee
Richard Frank, MD, PhD, Chair (GE Healthcare)Richard Wahl, MD PhD, Co-Chair (Johns Hopkins)Paul Kinahan, PhD, Co-Chair (University ofWashington)
David Clunie, MBBS, Subcommittee Co-Chair(RadPharm)
Jeffrey Yap, PhD, Quality Control Metrics andCovariates Rationale Technical Subcommittee Chair
(Dana Farber Cancer Institute)
Timothy Turkington, PhD, ROI Definitions TechnicalSubcommittee Chair (Duke University Medical Center)
Ling X. Shao, PhD, Software Tracking TechnicalSubcommittee Chair (Philips Healthcare)
PET/CT Quantitative Committee
Richard Frank, MD, PhD, Chair (GE Healthcare)
Richard Wahl, MD PhD, Co-Chair (Johns Hopkins)Paul Kinahan, PhD, Co-Chair (University ofWashington)
David Clunie, MBBS, Subcommittee Co-Chair(RadPharm)
Jeffrey Yap, PhD, Quality Control Metrics andCovariates Rationale Technical Subcommittee Chair
(Dana Farber Cancer Institute)
Timothy Turkington, PhD, ROI Definitions TechnicalSubcommittee Chair (Duke University Medical Center)Ling X. Shao, PhD, Software Tracking TechnicalSubcommittee Chair (Philips Healthcare)
COPD/Asthma CommitteePhil Judy, PhD, Chair (Brigham & Womens)David Lynch, MD, Co-Chair (National Jewish)
COPD/Asthma CommitteePhil Judy, PhD, Chair (Brigham & Womens)David Lynch, MD, Co-Chair (National Jewish)
Steering CommitteeDan Sullivan, MD, Co-Chair (Duke; RSNA)Andy Buckler, MS, Co-Chair (Buckler Biomedical LLC)Kevin ODonnell, PhD, Co-Chair (Toshiba)
Steering CommitteeDan Sullivan, MD, Co-Chair (Duke; RSNA)Andy Buckler, MS, Co-Chair (Buckler Biomedical LLC)Kevin ODonnell, PhD, Co-Chair (Toshiba)
fMRI CommitteeCathy Elsinger, PhD, Co-Chair (Nordic Neurolab, Inc)Jeffrey Petrella, MD, Co-Chair (Duke)
Joy Hirsch, PhD, Co-Chair (Columbia)
fMRI CommitteeCathy Elsinger, PhD, Co-Chair (Nordic Neurolab, Inc)Jeffrey Petrella, MD, Co-Chair (Duke)
Joy Hirsch, PhD, Co-Chair (Columbia)
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QIBA Process
Identify sources of variability
Collect groundwork data
Devise mitigation strategies Write and promulgate Profiles.
Important progress step: NISTinvolvement to assist with developing acompliance process.
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CTSA Imaging Working Group
3 Subcommittees:
Cores (Structure; Administration;Financing)
Imaging Informatics (Integrate existingtools)
Clinical Trials (UPICT UniformProtocols for Imaging in Clinical Trials)
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Image Sharing Network Pilot Project
RSNA plus 5 medical centers
2-year, $4.7 million contract from NIBIB
American Recovery and Reinvestment Actfunds from 2009
Patient control of medical history andimaging examinations through individual
accounts in personal health recordsystems
Web-based system
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UPICT TemplateExecutive Summary
Context of the Imaging Protocol within the Clinical TrialSite Selection, Qualification and TrainingSubject SchedulingSubject PreparationImaging-related Substance Preparation and AdministrationIndividual Subject Imaging-related Quality ControlImaging ProcedureImage Post-processingImage AnalysisImage InterpretationArchival and Distribution of Data
Quality ControlImaging-associated Risks and Risk ManagementAPPENDICES
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Imaging Biomarkers
Roundtable
FNIH
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Generic Roadmap
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Imaging Biomarker RoundtableAd Hoc Committees
1. Open Image Archives
Richard Avila
Gudrun Zahlmann
1. Publication Guidelines
Paul Kinahan
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FDA Approval Vs. Qualification
Approval(or Clearance) is acknowledgementthat, for the stated claim, the drug or devicehas been shown to have acceptable safety
and effectiveness.Qualification is acknowledgement that, within a
stated context of use, the measurement canbe relied upon to have a specific
interpretation in drug development andregulatory decision-making.
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Quantitative
Imaging Test Drugor DeviceApproval[National
regulatoryagencies, e.g., FDA
CDRH or CDER]
Evidentiary Studies forCoverage Decisions
[Payer organizations,e.g., CMS]
QuantitativeImaging Test Result
Qualification[National
regulatoryagencies, e.g., FDA
CDER]
Clinic
al
TrialData
Quantitative Imaging TestDiscovery/Development/Technical
Performance[Private & Academic Sectors]
Use in RoutineClinical Care
Use in ClinicalResearch
d i i k Q lifi i
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2) Biomarker Sponsor submits to BQC a written
request for qualification of an exploratory biomarker.
3) BQC evaluates qualification request.
5) Biomarker Qualification Review Team (BQRT)
requests briefing document from biomarker sponsor.
6) BQ Project Manger schedules face-to-face meeting
between the sponsor and the BQRT.
7) BQRT evaluates the briefing document and preparesfor the Biomarker Qualification face-to-face meeting.
8) BQRT and Sponsor BQDS Meeting.
9) BQRT identifies and requests additional data from
sponsor.
Proposed Imaging Biomarker Qualification Process
1) Informal discussion of a potential biomarker sponsor
with the Biomarker Qualification Coordinator (BQC).
4) Biomarker Qualification Management Team
(BQMT) accepts or declines the sponsors request to
proceed with qualification process.
CON
SULTATI O
NANDADVICEPR
OCESS
10) BQRT receives full data package and review period
begins
11) BQRT writes draft biomarker qualification review.
12) BQC routes the draft biomarker qualificationreviews to all Offices
13) BQ Project Manager schedules the BQ review for
presentation at a CDER Regulatory Briefing.
REVIEW
PRO
CESS
14) CDER Regulatory Briefing presentation and
discussion is held.
15) CDER Office Directors make decisions to accept or
reject the BQRT recommendations.
16) BQC drafts letter for sign-off by the Director of
CDER communicating to the sponsor the results of thebiomarker qualification.
Request
Letter
Briefing
Documen
t
Full Data
Package
Signoff
Letter
A) Declaratory information about the class of tests
drawn from test validation sources.
B) Phantom and other controlled condition support
material for stand-alone assessment and required
initial and ongoing quality control specifics.
E) Clinical Performance Groundwork to characterize
sensitivity and specificity for readers using the
imaging test when interpreted as a biomarker under
limited conditions.
D) Process map detailing steps contemplated to
support qualification of the biomarker
C) Implement and refine protocols for the intended
use
H) Promote use of the imaging biomarker through
education.
Sponsoring Collaborative National Regulatory Agencies
F) Clinical Efficacy Groundwork to qualify biomarker
as a surrogate endpoint in "real world" imaging
conditionsG) Draft advice guidance on incorporation of imaging
biomarker into clinical trials.
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Progress?
Status of QIBA and related activities
Collecting evidence; making the case
Educating/communicating
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NIBIB/RSNA Workshop on
Comparative Effectiveness Research (CER)
for Diagnostic Imaging
April, 2010
Challenges:
CER traditionally is focused on Outcome
The benefit of one test over another isusually small: ergo, large trials.
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CER Recommendations Enhance the collection of clinical data on
diagnostic tests to facilitate retrospectivestudies. Important items to include in electronicdatabases: reasons for ordering the test, technical characteristics of test,
test interpretation findings and reports instandardized format
post test decisions about course of care patient outcomes
The study of the impact of tests onsubsequent care and on patient outcomesneeds to become a major part of the researchagenda of diagnostic imaging.
April 2010 Constantine Gatsonis, PhD
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Educating/Communicating
Quantitative imaging content inscientific and educational componentsof RSNA Annual Meeting
Quantitative Imaging Reading Roomdisplays of available tools (imageprocessing algorithms, and structured
reporting products).
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Integrating the Imaging BiomarkerEnterprise
Public Data
Infrastructu
re
QIBADefine Profiles and
ConductGroundwork
BiopharmaPrescribe in
ClinicalTrials
Developers /VendorsValidate
Performance
UPICTManageProtocol
s
Consensu
s
Protocols
510(k)
s
Qualificatio
n Data
Profiles
NDAs
Predicate
Users and PurchasersSpecify in Tenders and
Utilize
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