blueprints to blue sky – analyzing the challenges and solutions for ihc companion diagnostics

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.

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.

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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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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


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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


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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



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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



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Introduction to Blueprint and Blue Sky

5% Targeted Therapy


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


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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…


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


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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


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Potential Uses of the Method

Proficiency Testing and Calibration (EQA)

Clinical Trials

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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?


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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 Positive Reference Standard

10X

40X


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Case Study – PD-L1


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Case Study – PD-L1 External Evaluation

1 2 3 4 5

A

B

Cell Signaling antibody - Clone E1L3N


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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


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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



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Collaboration is Key

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Collaboration is Key

Contact us at [email protected]

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]

blueprints to blue sky – analyzing the challenges and solutions for ihc companion diagnostics

Healthcare

clinical samples

research use

new safety

new tests

quality professional

assay multiple drugs

future of quality

regulatory management