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Operational Aspects of Independent Reviews for Immune-Oncology Clinical Endpoints

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

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Operational Aspects of Independent Reviews for Immune-Oncology Clinical Endpoints

  1. 1. © 2018 PAREXEL INTERNATIONAL CORP. OPERATIONAL ASPECTS OF INDEPENDENT REVIEWS FOR IMMUNE-ONCOLOGY CLINICAL ENDPOINTS Dr. Oliver Bohnsack Senior Director Scientific and Medical
  2. 2. © 2018 PAREXEL INTERNATIONAL CORP. / 2 STAND ALONE WITH OR WITHOUT COMBINATION TREATMENTS • Radiation Therapy • Chemotherapy • Immunotherapy • Targeted Therapy • Hormone Therapy • Stem Cell Transplant • Precision Medicine
  3. 3. © 2018 PAREXEL INTERNATIONAL CORP. / 3 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
  4. 4. © 2018 PAREXEL INTERNATIONAL CORP. / 4 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
  5. 5. © 2018 PAREXEL INTERNATIONAL CORP. / 5 IMAGING IN BASKET TRIALS *Image courtesy of Memorial Sloan Kettering Cancer Center
  6. 6. © 2018 PAREXEL INTERNATIONAL CORP. / 6 EXPEDITED REVIEW • Eligibility Review • Safety Review • Confirmation of Progression/Response 12%  44% ”Speed” Aspect
  7. 7. © 2018 PAREXEL INTERNATIONAL CORP. / 7 BERLIN, GERMANY CENTRAL REVIEW AND SITE VERSUS CENTRAL DISCORDANCE
  8. 8. © 2018 PAREXEL INTERNATIONAL CORP. / 8 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
  9. 9. © 2018 PAREXEL INTERNATIONAL CORP. / 9 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
  10. 10. © 2018 PAREXEL INTERNATIONAL CORP. / 10 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
  11. 11. © 2018 PAREXEL INTERNATIONAL CORP. / 11 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
  12. 12. © 2018 PAREXEL INTERNATIONAL CORP. / 12 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
  13. 13. © 2018 PAREXEL INTERNATIONAL CORP. / 13 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.
  14. 14. © 2018 PAREXEL INTERNATIONAL CORP. / 14 LONDON, U.K. MONITORING READER METRICS HOW TO GET THE BEST OUT OF EXPERT READERS
  15. 15. © 2018 PAREXEL INTERNATIONAL CORP. / 15 MONITORING READER METRICS BICR assessment data used to monitor reader performance • Intra-reader variability • Inter-reader variability • Adjudication rate • Adjudication agreement rates
  16. 16. © 2018 PAREXEL INTERNATIONAL CORP. / 16 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
  17. 17. © 2018 PAREXEL INTERNATIONAL CORP. / 17 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
  18. 18. © 2018 PAREXEL INTERNATIONAL CORP. / 18 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
  19. 19. © 2018 PAREXEL INTERNATIONAL CORP. / 19 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
  20. 20. © 2018 PAREXEL INTERNATIONAL CORP. / 20 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
  21. 21. © 2018 PAREXEL INTERNATIONAL CORP. / 21 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
  22. 22. © 2018 PAREXEL INTERNATIONAL CORP. / 22 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
  23. 23. © 2018 PAREXEL INTERNATIONAL CORP. / 23 ADJUDICATION & ADJUDICATION AGREEMENT RATE
  24. 24. © 2018 PAREXEL INTERNATIONAL CORP. / 24 ADJUDICATION AGREEMENT RATE
  25. 25. © 2018 PAREXEL INTERNATIONAL CORP. / 25 AGREEMENT AND DISCREPANCY RATE
  26. 26. © 2018 PAREXEL INTERNATIONAL CORP. / 26 THANK YOU © 2018 PAREXEL INTERNATIONAL CORP. / 26

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