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

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

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Agenda

»Background

»Central Image Review

»RECIST

»Data Management Considerations

»Conclusions

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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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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

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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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Blinded Independent Central Review

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Agree

Disagree

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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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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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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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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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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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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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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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

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Data Management Considerations

»RECIST version challenges

»Site vs. Central Review data

»Central Review

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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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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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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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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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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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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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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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