blueprints to blue sky – analyzing the challenges and solutions for ihc companion diagnostics
TRANSCRIPT
HORIZON DISCOVERY
Blueprints to Blue Sky – Analyzing the Challenges and Solutions for IHC Companion Diagnostics
Hannah Murfet, MCQI CQP, BSc, DipQMartin Kristensson ,M.Sc.
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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.
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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.
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The Impact of Biomarkers
Biomarkers are changing drug development
1990’s 2013
45% Targeted Therapy
5% Targeted Therapy
1 Drug : 1 Assay Multiple Drugs :
Multiple Assays
FOR RESEARCH USE ONLY
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The Impact of Biomarkers
New biomarkers are increasing complexity
5% Targeted Therapy
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
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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
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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
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The Impact of Biomarkers
What is PD-L1?
5% Targeted Therapy
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
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The Impact of Biomarkers
The PD-L1 Challenge
5% Targeted Therapy
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
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Introduction to Blueprint and Blue Sky
5% Targeted Therapy
*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
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Bluesky Development
5% Targeted Therapy
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
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FACTORS INFLUENCING DATA QUALITY
Tissue preparation (e.g. fixation)Staining- protocols & sufficiencyReading and interpretation
Bluesky Development – the devil is in the data…
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Knowledge generation processTissue processing and sampling
Tissue staining Imaging ConclusionReading and interpretation
Data analysis
Dependencies
Sensitivity, Specificity, Reproducibility
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Reading and Interpreting Biomarker Expression
Improving reproducibilityExample Ki67 Data: NordiQC
NEG 2+ 3+ TOTALNEG 217 2172+ 46 5 2 533+ 0 1 41 42
263 6 43 312
Site III, Denmark HER2-CONNECT
Manual Reading
TOTALN 156
%Agreement 84.29%95% C.I. 80%-88%
2 cores per patient
Improving diagnostic accuracyExample 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
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IHC Bluesky Application: Key Questions
5% Targeted Therapy
5% Targeted Therapy
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
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IHC Bluesky Application: Utility of HDx Reference Standards
5% Targeted Therapy
Reference Material
5% Targeted Therapy
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
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Case Study – PD-L1 HDx Reference Standard Development
5% Targeted Therapy
1 2 3 4 5
A
B
Cell Signalling antibody - Clone E1L3N
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Case Study – Assessing the Negative and Positive Reference Standards by QDP
Percentage positive H-Score
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Case Study – PD-L1 External Evaluation
1 2 3 4 5
A
B
Cell Signaling antibody - Clone E1L3N
FOR RESEARCH USE ONLY
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Case Study – Highlighting variability in the workflowThe same cell signalling antibody and same concentration
+ve core
Supposed to be the -ve core
FOR RESEARCH USE ONLY
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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
Your Horizon Contact:
t + 44 (0)1223 655580f + 44 (0)1223 655581e [email protected] www.horizondiscovery.comHorizon Discovery, 7100 Cambridge Research Park, Waterbeach, Cambridge, CB25 9TL, United Kingdom
Your Visiopharm Contact:Hannah Murfet, MCQI CQP, BSc, DipQProduct Quality [email protected]
Martin Kristensson, M.Sc.Director of Sales/Project [email protected]