Imaging trials introduce novel and unique sources of data. Blinded Independent Central Review is primary source of data. - Utilization of standard assessment criteria - Multiple datasets for given patient/visit - Key aspects of CDM for RECIST trials: >>RECIST version >>Site vs. Central review data >>Central review performance

1. Data Challenges in Imaging Trials –
Image Review Data
03April 2013
Kevin Shea
Senior Director Clinical Solutions
C3i, Inc.
kshea@c3i-inc.com
610-772-5726

2. Key Points
»Imaging trials introduce novel and unique sources of data
»Blinded Independent Central Review is primary source of
data
 Utilization of standard assessment criteria
 Multiple datasets for given patient/visit
»Key aspects of CDM for RECIST trials:
 RECIST version
 Site vs. Central review data
 Central review performance
2 4/3/2013© 2011 C3i, Inc. Confidential and Proprietary to C3i, Inc.

3. Agenda
»Background
»Central Image Review
»RECIST
»Data Management Considerations
»Conclusions
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4. Background
»Solid tumor oncology trials
»Imaging assessment as surrogate endpoint
»Variations in modality, techniques, reader assessment,
training
»Standardization – consistency, repeatability
»RECIST – well-adopted standard
»CDM processes to monitor assessment data – track quality
and safety
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5. Data Specific to Imaging Trials
Sources of Data
» Imaging – X-Ray, CT, MRI, PET, etc.
» Imaging Technician Report
» Radiologist Report
» QA Report
» Imaging Core Lab
 Dual Read Review
 Adjudicator Review
5 4/3/2013© 2011 C3i, Inc. Confidential and Proprietary to C3i, Inc.

6. Central Review of Images
Imaging Core Lab
»Focus on objectivity and precision
»No role in clinical care of patient
»Limited reader pool
»Training and review of cases – focus on consistency
»BICR – ideal process: dual reader w/ adjudication
»Various quality processes incorporated to enhance
consistency and ensure cross-site view of data
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7. Blinded Independent Central Review
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Agree
Disagree

8. Comparison - Site and Central Review
Imaging Site
» Clinical focus
» Do not generally utilize
RECIST
» Variety of readers
» Not blinded
» Access to all clinical data
» Limited protocol training
Central Review
» Focus on imaging
» RECIST w/ limited pool of
readers
» Blinded
» Limited access to clinical data
» Image Review Charter
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9. RECIST Overview
»Response Evaluation Criteria In Solid Tumors
»Based on WHO criteria (1981)
»Established 2000 (v.1.0), Updated 2009 (v.1.1)
»PII focus, PIII applicability
»Endpoints – ORR, PFS, TTP
»Well-adopted in Imaging Core Labs
»Challenges at AROs and local imaging sites
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10. RECIST Parameters
»Serial review – baseline to completion
»Quantify representative tumor burden
»Qualitative assessment of remaining lesions
»Lesion classification
»Consistent assessment categories
»Associate changes in tumor burden with efficacy
 Response (may require confirmation)
− Time point response
− Best overall response
 Progression – Date of progression
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11. RECIST Lesion Classifications
»Target Lesions
 representative of disease
 able to reproducibly measure and track over time
»Non-target
 all other lesions or sites of disease
 tracked qualitatively
»New – post-baseline presence of new disease
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12. RECIST Target Lesion Selection Criteria
»Uni-dimensional measurement
»Number
 Maximum of Five Target Lesions
 No more than two per organ
»Length
 ≥ 10 mm LD or 2x slice (extra nodal)
 ≥15 mm Short Axis Diameter (nodal)
»Lymph Nodes
 Must be >10 mm to be considered pathological
 Must be ≥ 15 mm to be measureable
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13. Evaluation Process
»Baseline – establish initial tumor burden, comparator of
subsequent time points
 Target Lesions – Sum of Longest Diameters (SLD)
 Non-Target Lesions – document all other disease
»Post-Baseline
 Target
− Sum Diameters
− Compare to BSL/Prev TPs, Establish nadir
 Non-Target – evaluate for substantial change
 New – Review for presence
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14. RECIST Response Criteria
»CR – Complete Response
 Disappearance all extra nodal lesions, nodal ≤ 10 mm
»PR – Partial Response
 30% reduction in Tumor Burden
»SD – Stable Disease
 Neither response (CR/PR) or progression (PD)
»PD – Progressive Disease
 Target-PD – SoD ≥ 20% and ≥ 5 mm from nadir
 Non-Target-PD – unequivocal progression
 Presence of new lesion
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15. RECIST Data
» Generally utilized in PII/PIII Solid Tumor Trials
» Adheres to clearly defined assessment criteria
» Accepts images from different modalities
» Focused on a set of key endpoints
» Both quantitative and qualitative data
» Data must be evaluated and derived at a given timepoint and across all
timepoints collected to date
» Study-specific requirements may alter parts of the core algorithm
15 4/3/2013© 2011 C3i, Inc. Confidential and Proprietary to C3i, Inc.

16. Data Management Considerations
»RECIST version challenges
»Site vs. Central Review data
»Central Review
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17. RECIST Version Challenges
»Migrating to v. 1.1
»Maintaining v.1.0 and v. 1.1 studies
»Target lesions
 Total number
 Number per organ
»Lymph nodes
»Sum of Diameters
»Non-target progression
»New Lesions
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18. RECIST Version Impact
»CRF Design
»Derivation procedures
»Edit checks
»Data quality reviews
»Emphasis on training and quality control
»Focus on non-target progression and new lesions
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19. Site vs. Central Review
»Comparison of endpoint results
»Concordance noted in previous studies
»Correlation not dependent on techniques
»Intra-study comparisons should be established early
»Track throughout study w/ focus on key events
 Soft-locks/data safety monitoring
 Prior to locking a site
 Prior to final DB lock
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20. Site vs. Central Review
»Develop processes to analyze:
 Previous study data
 Consistency of sites with central
− Distinguish trends
− Establish “normal discordance” rate
 Identify outlier sites
»Outlier sites can be reviewed further
 Re-training
 Imaging technique
 CMO reviews
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21. Evaluation of Central Review Data
»Monitor BICR discordance and adjudication
 Win-Loss Adjudication Rates
 Intra-Reader Variability
 Inter-Reader Variability
»Analyze variability
 Tumor type
 Intervention
»Evaluate metrics between RECIST 1.0 and 1.1 studies
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22. Management of Central Review Data
»Establish normal levels of variability and discordance for v. 1.0
and v. 1.1
»Analyze for variables
»Assess for suitability in future studies
»Establish parameters for site and central review data based on
RECIST version
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23. Conclusions
»Imaging trials introduce new sources of data
»Central review of imaging data generates congruent data sets
for a given patient/visit but must be analyzed against local
imaging site review
»Management and analysis of data in RECIST trials should
consider:
 Version of RECIST utilized
 Site vs. Central review data
 Central review performance
Happy to discuss:
Kevin Shea, C3i, Inc.
kshea@c3i-inc.com or +1 610-772-5726
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