Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Blueprints to blue sky – analyzing the challenges and solutions for IHC companion diagnostics

4,237 views

Published on

Manual assessment of biomarker expression is associated with significant inter- and intra reader variability. In some cases there are also limitations when it comes to sensitivity and specificity of manual biomarker assessment.
In one example to the left, the “pure” contribution of inter-reader variability associated with Ki67 assessment was quantified across 20 tumors and 126 participating labs. In that study, it was demonstrated how image analysis can be used to significantly reduce inter-reader variability.
In a another study, the National Danish Validation study of Her2, it was demonstrated how improved sensitivity/specificity of quantitative HER2 protein expression wrt gene amplification lead to significant cost savings in reflex testing.
By automating aspects of stain quality control, it will become scalable to he point where EQA organizations may be able and willing to offer more frequent – perhaps even on-demand – proficiency testing and calibration services.
It is possible that objective and quantitative standards will contribute to improve compliance with protocol recommendations.
In clinical multi-center trials it will be easier to standardize and monitor data from each center.
And it is our hope tha larger diagnostic pathology labs will be able to benefit from such a method by closely monitoring drift in staining quality for biomarkers.

Published in: Healthcare
  • DOWNLOAD FULL BOOKS, INTO AVAILABLE FORMAT ......................................................................................................................... ......................................................................................................................... 1.DOWNLOAD FULL. PDF EBOOK here { https://tinyurl.com/y8nn3gmc } ......................................................................................................................... 1.DOWNLOAD FULL. EPUB Ebook here { https://tinyurl.com/y8nn3gmc } ......................................................................................................................... 1.DOWNLOAD FULL. doc Ebook here { https://tinyurl.com/y8nn3gmc } ......................................................................................................................... 1.DOWNLOAD FULL. PDF EBOOK here { https://tinyurl.com/y8nn3gmc } ......................................................................................................................... 1.DOWNLOAD FULL. EPUB Ebook here { https://tinyurl.com/y8nn3gmc } ......................................................................................................................... 1.DOWNLOAD FULL. doc Ebook here { https://tinyurl.com/y8nn3gmc } ......................................................................................................................... ......................................................................................................................... ......................................................................................................................... .............. Browse by Genre Available eBooks ......................................................................................................................... Art, Biography, Business, Chick Lit, Children's, Christian, Classics, Comics, Contemporary, Cookbooks, Crime, Ebooks, Fantasy, Fiction, Graphic Novels, Historical Fiction, History, Horror, Humor And Comedy, Manga, Memoir, Music, Mystery, Non Fiction, Paranormal, Philosophy, Poetry, Psychology, Religion, Romance, Science, Science Fiction, Self Help, Suspense, Spirituality, Sports, Thriller, Travel, Young Adult,
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here

Blueprints to blue sky – analyzing the challenges and solutions for IHC companion diagnostics

  1. 1. HORIZON DISCOVERY Blueprints to Blue Sky – Analyzing the Challenges and Solutions for IHC Companion Diagnostics Hannah Murfet, MCQI CQP, BSc, DipQ Martin Kristensson ,M.Sc.
  2. 2. 2 Presenter Hannah Murfet (MCQI CQP, BSc, DipQ) Product Quality Manager, Horizon Discovery Hannah is a medical biochemist turned quality professional with a strong interest in the future of quality and regulatory management with focus on advances in medical technology. Hannah is involved with the Chartered Quality Institute predominantly as Vice Chair of the Next Generation Network and first appointed young representative to the Advisory Council, through which she advocates the role quality management in business.
  3. 3. 3 Presenter Martin Kristensson, M.Sc. Director of Sales & Project Manager (Digital Pathology), Visiopharm Martin has been with Visiopharm since 2011 where he has worked in various aspects of the business including technical support, professional services, as an application scientist, and most recently as the Director of Sales for Digital Pathology. His expertise in Project Management, was a key component in initiating Visiopharm's clinical validation projects, and is continuously supports pathology laboratories in the transition to digital pathology, including on-site validation projects covering image analysis for diagnostics.
  4. 4. 4 The Impact of Biomarkers Biomarkers are changing drug development 1990’s 2013 1 Drug : 1 Assay Multiple Drugs : Multiple Assays FOR RESEARCH USE ONLY
  5. 5. 5 The Impact of Biomarkers New biomarkers are increasing complexity Different tumor indications and combination of influencing markers Different IHC Antibody Clones Different staining protocols and platforms Different clinical decision points Different assessment methods Challenged by limitations in IHC precision Challenged by limited biopsy tissue Source: FDA-AACR-ASCO Public workshop on March 24 2015. http://www.fda.gov/downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM439878.pdf FOR RESEARCH USE ONLY
  6. 6. 6 Challenges Facing the Clinical Pipeline • Clinical Trial time lines and use of multiple partners/geographies can lead to drift in assay performance • Outsourcing to CROs can make managing variation more difficult • Unnecessary and sustained variability can affect study performance • Manual evaluation methods leading to the potential of variation • New drugs rely on successful and effective adoption of diagnostics to ensure reimbursement • Proficiency Testing – ensure standardization and accuracy of diagnostic testing are met. • Clinical Samples are not readily available Research & Development • Assay Development • Sample Screening • Patient Stratification Clinical Studies • Phase II & III • CLIA Studies • Patient Stratification On Market • Companion Diagnostics • Proficiency Testing/Ring Trials FOR RESEARCH USE ONLY
  7. 7. 7 The Regulatory Challenge New biomarker complexities impact the regulatory challenge Safety and efficacy determined in clinical trial with emphasis on marker positive Multiple tests have the potential to change the selected group for each test For new tests, bridging studies become necessary to support new safety and efficacy Potential for mismatched approved drug/device combinations *Source: FDA-AACR-ASCO Public workshop on March 24 2015. http://www.fda.gov/downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM439878.pdf FOR RESEARCH USE ONLY
  8. 8. 8 The Impact of Biomarkers What is PD-L1? Biomarker with a major role in suppressing anti- tumor immunity Variation in tumor expression and response Pre-analytical and analytical variables Differences in application of assays therefore clear stratification will be necessary Open questions remain on utility of PD-L1 as a predictive marker *Source: FDA-AACR-ASCO Public workshop on March 24 2015. http://www.fda.gov/downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM439878.pdf FOR RESEARCH USE ONLY
  9. 9. 9 The Impact of Biomarkers The PD-L1 Challenge 4-8 drugs in development Parallel development programs Variation in trial design Multiple companion diagnostics – different test for each drug Source: FDA-AACR-ASCO Public workshop on March 24 2015. http://www.fda.gov/downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM439878.pdf FOR RESEARCH USE ONLY
  10. 10. 10 Introduction to Blueprint and Blue Sky *Source: FDA-AACR-ASCO Public workshop on March 24 2015. http://www.fda.gov/downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM439878.pdf Blueprint Proposal – Industry group* Blue Sky – Development of novel IHC tools FOR RESEARCH USE ONLY
  11. 11. 11 Bluesky Development Unlimited supply mechanism (cell line derived) Reproducible production pathway Independent from tissue archives The same material source can be used for multiple tests On-slide controls Assessment using QDP Reference Material FOR RESEARCH USE ONLY
  12. 12. 12 FACTORS INFLUENCING DATA QUALITY Tissue preparation (e.g. fixation) Staining- protocols & sufficiency Reading and interpretation Bluesky Development – the devil is in the data… FOR RESEARCH USE ONLY Knowledge generation processTissue processing and sampling Tissue staining Imaging ConclusionReading and interpretation Data analysis Dependencies Sensitivity, Specificity, Reproducibility
  13. 13. 13 Reading and Interpreting Biomarker Expression FOR RESEARCH USE ONLY
  14. 14. 14 Reading and Interpreting Biomarker Expression Improving reproducibility Example Ki67 Data: NordiQC NEG 2+ 3+ TOTAL NEG 217 217 2+ 46 5 2 53 3+ 0 1 41 42 263 6 43 312 Site III, Denmark HER2-CONNECT Manual Reading TOTAL N 156 %Agreement 84.29% 95% C.I. 80%-88% 2 cores per patient Improving diagnostic accuracy Example HER2, reduces 2+ with 70% compared to humans. Reduce cost of reflex testing w. 4.000 EUR per 100 patients. Data European Validation Study FOR RESEARCH USE ONLY
  15. 15. 15 Potential Uses of the Method Proficiency Testing and Calibration (EQA)
  16. 16. 16 IHC Bluesky Application: Key Questions Does your assay accurately and reproducibly measure what you say? Does the assay actually identify a biological difference of clinical significance? Does your validation show evidence to support improvements in the clinical workflow? How do you monitor for your IHC analytical performance? FOR RESEARCH USE ONLY
  17. 17. 17 IHC Bluesky Application: Utility of HDx Reference Standards Reference Material Performance can be assessed when optimizing a protocol or platform Guide the evaluation of antibodies Protocols can be assessed for use of the same antibody clone Concordance or discordance can be assessed to determine reproducibility FOR RESEARCH USE ONLY
  18. 18. 18 Case Study – PD-L1 HDx Reference Standard Development 1 2 3 4 5 A B Cell Signalling antibody - Clone E1L3N FOR RESEARCH USE ONLY
  19. 19. 19 Case Study – Assessing the Negative and Positive Reference Standards by QDP Percentage positive H-Score FOR RESEARCH USE ONLY
  20. 20. 20 Case Study – PD-L1 Positive Reference Standard 10X 40X FOR RESEARCH USE ONLY
  21. 21. 21 Case Study – PD-L1 FOR RESEARCH USE ONLY
  22. 22. 22 Case Study – PD-L1 External Evaluation 1 2 3 4 5 A B Cell Signaling antibody - Clone E1L3N FOR RESEARCH USE ONLY
  23. 23. 23 Case Study – Highlighting variability in the workflow The same cell signalling antibody and same concentration +ve core Supposed to be the -ve core FOR RESEARCH USE ONLY
  24. 24. 24 IHC Blueprint Proposal Goal • A package of information upon which analytical comparison of various diagnostic assays may be conducted. • This includes understanding the analytical performance of different PD-L1 biomarker assays. • Study to be designed through collaboration with industry stakeholders and independent third party. Samples • Mix of sample types that are representative of target patient populations. • Focus on NSCLC and PD-L1 IHC Testing. Staining • Diagnostics stakeholders to stain IUO assays Evaluation • Company pathologists and independent third party • Published results Source: FDA-AACR-ASCO Public workshop on March 24 2015. http://www.fda.gov/downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM439440.pdf FOR RESEARCH USE ONLY
  25. 25. 25 Collaboration is Key
  26. 26. 26 Collaboration is Key Contact us at technical@horizondiscovery.com
  27. 27. Your Horizon Contact: t + 44 (0)1223 655580 f + 44 (0)1223 655581 e info@horizondiscovery.com w www.horizondiscovery.com Horizon Discovery, 7100 Cambridge Research Park, Waterbeach, Cambridge, CB25 9TL, United Kingdom Your Visiopharm Contact: Hannah Murfet, MCQI CQP, BSc, DipQ Product Quality Manager h.murfet@horizondiscovery.com Martin Kristensson, M.Sc. Director of Sales/Project Manager mkr@visiopharm.com

×