PAREXEL Consulting experts detail operational aspects of independent reviews in the context of immunotherapy clinical trials.

1. © 2018 PAREXEL INTERNATIONAL CORP.
OPERATIONAL ASPECTS
OF INDEPENDENT
REVIEWS FOR
IMMUNE-ONCOLOGY
CLINICAL ENDPOINTS
Dr. Oliver Bohnsack
Senior Director Scientific and Medical

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STAND ALONE WITH OR WITHOUT COMBINATION TREATMENTS
• Radiation Therapy
• Chemotherapy
• Immunotherapy
• Targeted Therapy
• Hormone Therapy
• Stem Cell Transplant
• Precision Medicine

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TYPES OF COMPOUNDS
WITH OR WITHOUT COMBINATION TREATMENTS
• Radiation Therapy
• Chemotherapy
• Immunotherapy
• Targeted Therapy
• Hormone Therapy
• Stem Cell Transplant
• Precision Medicine
• Adoptive cell transfer therapy
• Monoclonal antibody therapy
• Immune checkpoint inhibitor therapy
• Immunosuppression therapy
• Vaccine therapy
• Cytokine therapy
• Oncolytic viral therapy
• Combination therapy
 Estimated ~3000 Oncology trials currently ongoing globally

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Collect and hold repository
Collect and hold
Collect and hold – read ready
Full service
TECHNOLOGY DRIVEN WORKFLOW
Site Upload/
Shipment
Collection/
Import
Check (IAG
compliance)
Acquisition Preparation Review Results

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IMAGING IN BASKET TRIALS
*Image courtesy of Memorial Sloan Kettering Cancer Center

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EXPEDITED REVIEW
• Eligibility Review
• Safety Review
• Confirmation of Progression/Response
12%  44%
”Speed” Aspect

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BERLIN, GERMANY
CENTRAL REVIEW AND SITE
VERSUS CENTRAL DISCORDANCE

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SITE READ PROCESS
• Imaging capabilities of sites are rarely taken into consideration for trials with imaging based
endpoints
Increased risk of bad quality images
• No standardized protocol training for site radiologists
Discrepancy and inconsistency in assessment
• Sites Drs’ clinical interpretation is for patient management
Discrepancy with trial requirements and criteria
• Images are clinically interpreted by multiple site radiologists using non-standardized
approach
Subject level differences

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CENTRAL READ PROCESS
• Blinded Reads
Controlled pool of trained readers
Blinded to treatment, site assessments and clinical data
• Reader Selection
Selected based on expertise, experience and training
• Reader Training
Trial and criteria specific training
Trained and tested on study criteria and analysis software
• Reader Performance Monitoring
Variability + Adjudication agreement metrics

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PROJECT TRAINING AND TESTING
Prepares reader and ensures they are ready to begin
Training tailored to each
trial’s specific criteria and
clinical protocol
Individual testing to
ensure readers
understand criteria
independently
Consensus testing to
ensure group is reading
consistently

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SITE VS CENTRAL DISCORDANCE
Factors Site Central
Workflow Not optimized for a clinical trial
review
• Standardized workflow for clinical
trial review
• Consistency in Image
interpretation
Focus Clinical Focus Imaging Focus
Datasets Access to all the data including
non radiographic data and clinical
status of the subject
Limited/non-availability of non
radiographic data
Reads Not Blinded • Blinded
• Elimination of Bias
Image Quality Site preference Standardization per protocol

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SITE VS. CENTRAL DISCORDANCE
Factors Site Central
Training • No standardized training for site
radiologists
• Most clinical radiologists are not
familiar with or are not using
RECIST
•Training on protocol, Charter,
study criteria and image analysis
application
•Training, testing and monitoring
of the readers and reads
Efficacy
Assessment
• Variability as per sites’ expertise and
experience
• Single subject scans are assessed
by multiple radiologists
Done strictly in line with protocol
by experts
Understanding and
utilization of study
criteria
Risk of inaccurate assessment Small risk of inaccurate
assessment

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SOLID TUMORS AND HEMATOLOGIC MALIGNANCIES
DIFFERENCES IN IMAGE ANALYSIS + DIFFERENT ASSESSMENT
CRITERIA
Solid Tumors
• RECIST 1.1
• irRECIST
• irRC
• mRECIST
• iRECIST
Hematologic Malignancies
• Cheson
• Lugano
• LYRIC
• Hallek
• NCI-WG
• Clinical review by an Oncologist
Complex criteria used in clinical trials and in central read, rarely in
the hospital for routine patient care and treatment decision making.

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LONDON, U.K.
MONITORING
READER METRICS
HOW TO GET THE BEST OUT
OF EXPERT READERS

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MONITORING READER METRICS
BICR assessment data used to monitor reader performance
• Intra-reader variability
• Inter-reader variability
• Adjudication rate
• Adjudication agreement rates

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INTRA AND INTER-READER VARIABILITY
Intra-reader variability
• Set of cases are AGAIN reviewed by reader in a blinded way
• Shows the consistency of reader over a period of time
• Some readers ‘get better’ with experience on a study
– Common for indication like HCC, RCC, Ovarian or GBM
– Common for “new” readers with less prior trial reading experience
Inter-reader variability
• Same set of cases read by all readers on a clinical trial
• A measure of consistency across readers for a protocol
• Defining ‘significance’ variability is always a challenge
• For trials with limited number of readers (up to 4), often replaced by adjudication related metrics

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CENTRAL READS
Primary Reads – Single read vs Double read
Double read with Adjudication
Eligibility Reads – Central confirmation of eligibility
• Eligibility Questionnaire
• Not full efficacy reads
Central confirmation of PD

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ADJUDICATION
Interpretation of radiographic images
• Target Lesion Selection:
• Location, number, reproducibility
• Non‐Target Lesion Progression
• Must be unequivocal
• Perception of New Lesions
• Understand treatment effect › New or more conspicuous? › Hindsight changes
• Lesion Measurement Differences:
• Enhancing lesions › Spiculated lesions › Bone lesions › Image sequence
• Image quality or missing image data
• Clinical data
Adjudication largely depends on the experience, expertise and training of a reader

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FACTORS AFFECTING ADJUDICATION RATE
Number of adjudication variables
Adjudication variables are based on imaging related endpoints
CR vs PR vs SD vs PD vs NE (Endpoint :ORR, BOR, PFS, Others)
PD vs NON-PD (Endpoint: PFS)
Indication Adjudication variables
Number of
Subjects
Adjudication %
CLL PD vs NON-PD 390 36
Prostrate PD vs NON-PD 1717 18
Breast PD vs NON-PD 417 52
Breast any 363 52
Lung any 350 60

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ADDITIONAL FACTORS AFFECTING ADJUDICATION RATE
Tumor type
Indication Number of Subjects Adjudication %
Ovarian Cancer 353 54
Prostrate Cancer 1682 19
Breast Cancer 511 45
Lung Cancer 584 49
Higher adjudication rate may be in Ovarian and Lung cancer.
Each indication has its own challenge in terms of:
• Selection of potential measurable lesions
• Evaluation of lymph nodes
• Differentiating benign from malignant lesions

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ACCEPTABLE ADJUDICATION RATES IN ONCOLOGY
No specification by FDA
Use of the 2 primary readers with adjudicator, blinded read paradigm, adjudication rates of 25-
60% have been observed in oncology trials
 lower is better
Other factors that influence:
– Duration of treatment
– Number of assessment points
– Complexity of the assessment
– Subjectivity of the assessment

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ADJUDICATION AGREEMENT RATES
Adjudication Agreement Rate
• Percent where the adjudicator agrees with a reader of cases that go for adjudication
• More reliable source than just Adjudication Rate
• More independent parameter
 Not affected by factors that affect adjudication rate
Acceptable Range
• Ideal scenario = All readers with agreement rate of ~50%
• Kappa zone / Confidence intervals are used to identify unacceptable ranges
• 33% is sometimes considered a good cut-off for monitoring

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ADJUDICATION & ADJUDICATION AGREEMENT RATE

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ADJUDICATION AGREEMENT RATE

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AGREEMENT AND DISCREPANCY RATE

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THANK YOU
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