Specialized Workshop M2Monday September 26, 2022: 7am - 5:30pm - Topic List

"Biomarkers & CDx Innovative Strategies for Method Development, Validation, and Sample Collection/Analysis"

From Early-Stage Development to Clinical Translation/Commercialization; Complex & Challenging Applications; Regulatory CDx & BAV Guidelines; Biomarkers for Vaccine Study Endpoints

(You can scroll down to see the details of each topic)

Part 1: Method Development/Validation Strategies for Biomarker & Companion Diagnostic (CDx)

  • Topic 1:

    Ensuring Quality Biomarker & CDx Data: Method Development/Validation Strategies
    Dr. Kristina McGuire, Executive Director Head Precision Medicine & CDx, Regeneron

  • Topic 2:

    Point to Consider in CDx Method Development/Validation: When to start turning a Biomarker Assay into a CDx & Requirements for Validating Biomarker Assay as CDx
    Dr. Robert Neely, Associate Director Pharmacodiagnostics, Bristol Myers Squibb

  • Topic 3:

    Biomarkers & CDx Method Development/Validation for Gene Therapy
    Dr. Katherine Block, Director Biomarker Sciences, Sangamo

  • Topic 4:

    Biomarkers & CDx Method Development/Validation in China: Challenges & Solutions
    Dr. Yixin Wang, Executive Director Diagnostic Sciences & Molecular Assay Development, Bristol Myers Squibb

Part 2: FFP BAV for Mass Spectrometry and comparison with other Biomarker Assays

  • Topic 5:

    Advanced Fit-For-Purpose Biomarker Assay Validation (FFP BAV) Strategies: What Parameters and Acceptance Criteria to choose for different Biomarkers Assays? Similarities and differences for Mass Spec (LCMS), Immuno (LBA), Molecular (qPCR) and Cell-Based (Flow) Biomarkers Assays
    Dr. John Smeraglia, Vice President Head of Translational Biomarkers & Bioanalysis, UCB

  • Topic 6:

    Parallelism Test for Mass Spectrometry FFP BAV: When is it necessary and what does it inform on?
    Dr. Omar Mabrouk, Associate Scientific Director, Biogen

  • Topic 7:

    Spike Recovery, Standard Addition and Dilutional Linearity for FFP BAV: What have we learnt from ICH M10 draft BMV Guideline Section 7.1 for Endogenous Compounds?
    Dr. Qin Ji, Director, AbbVie

Part 3: Biomarkers Development/Validation for Vaccine Study Endpoints

  • Topic 8, 9, 10:

    Fit-For-Purpose Biomarker Assay Validation (FFP BAV) Strategies for Vaccine Immunoassay

    • Topic 8
      Parallelism Difference between Clinical/ Incurred Samples & Convalescent Material
      Dr. Jeroen Stoop, Associate Scientific Director Clinical Immunology, Janssen
    • Topic 9
      What is the Appropriate “matrix” for Demonstrating Linearity for Vaccine Immunoassays?
      Dr. Shannon Harris, Vice President Head of Clinical Assays, HilleVax
    • Topic 10
      Application of Assay Ranges & Interpretation of Dilutional Linearity in Biofunctional Assays
      Dr. Ingrid Scully, Senior Director, Pfizer

Part 4: Extremely Difficult Method Development/Validation and Multiplex Immunoassays for Biomarkers

  • Topic 11:

    Applications of Multiplex Biomarker Assays to Accelerate Drug Discovery & Development
    Dr. Vincent Mikol, Precision Medicine Head, Sanofi

  • Topic 12:

    Strategies to Overcome the Challenges in FFP BAV for Multiplex Cytokine Measurements
    Mr. Michael Wright, Director Soluble Biomarkers & Bioanalysis, GlaxoSmithKline

  • Topic 13:

    ROS (Reactive Oxygen Species) Biomarkers: Challenges & Considerations for Method Development, Sample collection, Sample Handling/Treatment, and Run variability
    Dr. Mitra Azadeh, Director Translational Medicine & Early Stage Clinical Development, Alkermes

  • Topic 14:

    Biomarkers in Disease Tissues and Complex Matrices: Challenges & Considerations for Operational, Preanalytical and Bioanalytical aspects
    Dr. Alessandra Vitaliti, Executive Director Biomarker Development, Novartis
    Dr. Arvind Kinhikar, Laboratory Head, Novartis

Part 5: White Paper in Bioanalysis

  • 2022 White Paper on Biomarker Topics:

    Consensus & Conclusions on Biomarker Topics for 2022 White Paper

Finale: ASK THE REGULATORS!

  • Panel Discussion with Regulators:

    Regulatory Feedbacks on Submitted studies and Inspections/audits Outcomes on Biomarkers & CDx

    • Mr. Abbas Bandukwala (US FDA CDER)
    • Dr. Yang Lu (US FDA CDER)
    • Dr. Kevin Maher (US FDA CDRH)
    • Dr. Leslie Wagner (US FDA CBER)
    • Dr. Shirley Hopper (UK MHRA)
    • Dr. Therese Solstad (Norway NoMA)
    • Dr. Chad Irwin (Health Canada)
    • Dr. Julie Joseph (Health Canada)
    • Dr. Yoshiro Saito (Japan MHLW)

 

Topic DETAILS of M2

Part 1 Method Development/Validation Strategies for Biomarker & Companion Diagnostic (CDx)
  • Topic 1

    Ensuring Quality Biomarker & CDx Data: Method Development/Validation Strategies
    Dr. Kristina McGuire, Executive Director Head Precision Medicine & CDx, Regeneron

    • Method Development Strategies for Biomarkers & CDx
      • Importance of Biomarkers & CDx as the promise of Personalized Medicine continues to grow
      • How to ensure that Biomarkers & CDx Assays provided quality data
    • Review of current diagnostic development & approval
      • Considerations at the various development stages
      • CDx approval process
      • Regulatory landscape
    • Requirements for CDx data
      • Considerations at the various development stages
      • Generation of data is of sufficient quality to support diagnostic needs
      • Oncology based Companion Diagnostic (CDx)
    • Challenges facing Biomarkers & CDx development
      • Assay/technology
      • Study design considerations
      • Regulatory challenges
    • Case Studies: Method Development/Validation Strategies for Biomarkers & CDx
  •  

  • Topic 2

    Point to Consider in CDx Method Development/Validation: When to start turning a Biomarker Assay into a CDx & Requirements for Validating Biomarker Assay as CDx
    Dr. Robert Neely, Associate Director Pharmacodiagnostics, Bristol Myers Squibb

    • Method Development/Validation of Biomarkers in Clinical Trials
      • Key concepts for CDx development/integration
    • Risk mitigated approaches for potential CDx Assays
      • Considerations on the various frameworks for Biomarker & CDx assay development
      • What quality systems to use for biomarkers path forward for each stage of development of a CDx
      • Evaluation of the most suitable technologies for CDx assays
    • Investing early on CDx partner collaboration
      • Strategies to develop biomarkers able to be converted into novel CDx
      • CDx strategies for next generation implementation
      • Using a 3rd party lab for early trial analysis with transition plans to CDx
    • Post marketing commitment to deliver a CDx
      • Development of Biomarkers as CDx as part of the regulatory strategies
    • Biomarker selection and translation into CDx candidates
      • Development of multiplex platforms for CDx
    • Case Studies: Biomarkers assays as CDx development and conversion for Precision Medicine and Clinical Development
  •  

  • Topic 3:

    Biomarkers & CDx Method Development/Validation for Gene Therapy
    Dr. Katherine Block, Director Biomarker Sciences, Sangamo

    • When/Why a CDx is needed for Gene Therapy
      • Anti-AAV pre-existing Ab as a Predictive Biomarker
    • Biomarkers formats of pre-existing Abs assays
      • Cell-based NAb/TI Assays (Neutralizing Antibodies/Transduction Inhibition Assays)
      • TAb Assays Bridging LBA based (Total Antibody)
      • Timeline/development considerations for each assay
    • Disease Diagnosis vs predictive biomarker for patient selection
      • FDA Guidance for Gene Therapy
    • CDx Assay development
      • Overview of the process and key aspects
    • CDx Validation
      • CLIA vs CLSI guidelines
      • Impact of Regulatory environment
      • Regulatory requirements for such testing and the need for developing CDx devices prior to marketing approval of the therapeutic product
      • CLIA vs Clinically Regulated assay
      • Pros/cons of using CLIA vs Regulated Assay for enrollment
    • Case Studies: Method Development/Validation for Gene Therapy Biomarkers Assay and transition to CDx

  • Topic 4:

    Biomarkers & CDx Method Development/Validation in China: Challenges & Solutions
    Dr. Yixin Wang, Executive Director Diagnostic Sciences & Molecular Assay Development, Bristol Myers Squibb

    • Overcoming challenges of Biomarker and CDx Assay development in China
      • Problems conducting clinical trials in China
      • New challenges in regulation, quality and operations
    • Special requirements for Biomarker & CDx
      • Levels of development experience
      • Quality standards from vendorsn
      • Implementation of technology platforms
    • Biomarker Development Strategies in China
      • Biomarker selection and prioritization
      • Addressing the necessity of a biomarker study
      • Assay platform selection and assay setup
      • Evaluation of the feasibility of a biomarker assay
      • Evaluation of resources to develop and validate the assay
    • Regulatory Requirement in China
      • HGRAC application and approval
      • Unique aspect for conducting biomarker studies in China
      • Newly implemented HGR regulations
      • China biosecurity law
    • Case Studies: Learnings obtained in development of biomarker and diagnostic assays for China clinical studies.

Part 2: FFP BAV for Mass Spectrometry and comparison with other Biomarker Assays
  • Topic 5:

    Advanced Fit-For-Purpose Biomarker Assay Validation (FFP BAV) Strategies: What Parameters and Acceptance Criteria to choose for different Biomarkers Assays? Similarities and differences for Mass Spec (LCMS), Immuno (LBA), Molecular (qPCR) and Cell-Based (Flow) Biomarkers Assays.
    Dr. John Smeraglia, Vice President Head of Translational Biomarkers & Bioanalysis, UCB

    • Current approaches to Fit-for-Purpose Biomarker Assay Validation (FFP BAV)
      • Practical applications of the What, Why, Where, Who and How for FFP BAV for better evaluating key aspect of Context of Use
      • Assessing pathobiology
      • Importance of understanding the biology of the biomarker
      • Internal decision making
      • Submission critical
    • Determining appropriate Technology Platform Biomarker Assays
      • Similarities and differences for Biomarker Assays
      • Mass Spec Assays (LC-MS/MS, HRMS, IA-MS)
      • Immunoassays (LBA),
      • Molecular assays (qPCR)
      • Cell-Based assays (Flow Cytometry)
      • Acknowledging the limitations of the bioanalytical method
    • Defining key assay development and validation parameters for FFP BAV
      • How biomarker context of use impacts assay decisions in order to fulfil the need in a clinical trial
      • Lack of guidance on how to approach biomarker assays for internal decision-making
    • Case Studies: FFP BAV across the use of mass spec, ligand binding assay, flow cytometry and qPCR assays

  • Topic 6:

    Parallelism Test for Mass Spectrometry FFP BAV: When is it necessary and what does it inform on?
    Dr. Omar Mabrouk, Associate Scientific Director, Biogen

    • Parallelism for LBA vs Mass Spectrometry
      • A “must” for Biomarker LBA
      • What does parallelism inform on outside an LBA context?
      • Is parallelism really needed for Mass Spec assays?
    • When is parallelism critical for confidence building in a Mass Spec context?
      • Data using heavy peptide spikes in authentic matrix as a surrogate
      • Should the CPTAC guidance be considered (Assay Characterization Guidance Documents)?
    • Reagent free MS vs. Hybrid Assays (IA-MS)
      • Differences between immunocapture vs. non-immunocapture LC-MS assays and the need for parallelism
      • Is parallelism for Hybrid Assays more similar to LBA due to the IA component of this assay even if they use it only for enrichment?
      • Demonstration of different parallelism experiments in a multiplexed LC-MS assay
    • Case Studies: Parallelism experiment for fit for purpose biomarker assay validation of Mass Spectrometry assay

  • Topic 7:

    Spike Recovery, Standard Addition and Dilutional Linearity for FFP BAV: What have we learnt from ICH M10 draft BMV Guideline Section 7.1 for Endogenous Compounds?
    Dr. Qin Ji, Director, AbbVie

    • Current Lack of Regulatory Guidance for Biomarker Assay Validation (BAV)
      • ICH M10 BMV Section 7.1. does NOT cover Quantitation of Biomarkers as the scope of ICH M10 is dosed drug quantification
      • Similarities between Dosed Drug Endogenous Counterpart vs Biomarkers:
      • Compare & contrast Bioanalytical Method Validation vs Biomarker Assay Validation (BMV vs BAV) for Endogenous Compounds
    • Parallelism Assessment for BMV for PK/TK Studies
      • Regulatory agencies excellent progress on providing guidance for the parallelism
      • 2018 US FDA Guidance & 2019 ICH M10 DRAFT Guideline
      • Industry key opinion literature LBA assay & Mass Spec assay
      • Recommendations for multiple aspects related to BAV parallelism assessment
    • Parallelism Experiment Approaches for Biomarkers
      • Difference between LC-MS and LBA platforms
      • Spike recovery
      • Standard addition
      • Dilutional linearity
      • Hybrid approach: parallelism QCs.
      • Acceptance Parameter Calculations
      • Comparing spike recovery and standard addition in LC-MS biomarker quantification
    • Case Studies: Parallelism Assessment for Fit-for-Purpose LCMS Biomarker Bioanalysis

 

Part 3: Biomarkers Development/Validation for Vaccine Study Endpoints
  • Topic 8, 9, 10:

    Fit-For-Purpose Biomarker Assay Validation (FFP BAV) Strategies for Vaccine Immunoassay

    • Topic 8:

      Parallelism Difference between Clinical/ Incurred Samples & Convalescent Material
      Dr. Jeroen Stoop, Associate Scientific Director Clinical Immunology, Janssen

      • Vaccine Immunogenicity Assays as Biomarker Assays
        • Evaluation of the immune response elicited by vaccine administration
        • Biomarkers as defined in the BEST FDA Guidance
      • Vaccine Assay COU
        • Intended of use of the assay is to quantify vaccine induced immune responses
        • Importance to validate the assay performance using trial-specific samples
      • The impact of Clinical/Incurred Sample selection on fit for purpose Validation Parameters for Vaccine Immunoassays
        • Use of Convalescent samples vs Vaccine Subject Samples
        • Impact different Coating Antigens on different LBA using the same format
        • Changes in Assay Range caused by sample selection
        • Differences in LOD/LOB (Limit of Blank) depending on the Sample selection
        • Considerations on samples selection differences predominantly driven by the accuracy of the assay rather than by the linearity and intermediate precision
      • Evaluation of Parallelism data using Clinical Samples
        • Risk of only using commercial samples in assay validation
        • Differences between clinical/ incurred samples and convalescent material
      • Approaches for setting an LLOQ close to the starting dilution
        • Calculating the LLOQ for Virus Neutralization Assays (VNAs)
        • Can the data be evaluated below the starting dilution?
      • Case Studies: Fit for Purpose Validation for Vaccine Immunoassays used for biomarkers study endpoints

    • Topic 9:

      What is the Appropriate “matrix” for Demonstrating Linearity for Vaccine Immunoassays?
      Dr. Shannon Harris, Vice President Head of Clinical Assays, HilleVax

      • Vaccine Immunoassay Validation
        • Current lack of Regulatory Guidance for Vaccine Assays
        • Compare & contrast the considerations when selecting an appropriate matrix or diluent for validating immunoassays
        • BMV for Administered Drugs (PK Assays) vs Validation of Assays to measure the immune response elicited by a Vaccine
        • Vaccine Immunoassays need to measure across a broad range of Ab levels in pre- and post-vaccination samples
      • Limitations of Guidelines for PK Assays
        • Designed to measure low levels of Abs or targets in undiluted matrices
        • BMV Guidance/Guideline not directly applicable to Vaccine immunoassays
      • Unique characteristic of Vaccine Immunoassays
        • Presumptive negative human sera may have non-specific or weakly active Abs that when spiked with positive immune sera react in unanticipated ways that may not be reproducible across different lots of negative human sera
      • Outcomes for Vaccine Assay characteristics
        • LOD, LLOQ, Dilutability, linearity and specificity may be different if assay buffer, presumptive negative sera or antibody-depleted sera are used as the diluent in assay validation
        • Use of a non appropriate matrix or diluent can lead to assay artifacts that may or may not be representative of how the assay is routinely performed
      • Designing assay Validation Strategy
        • Consideration on the diluent choice to ensure the outcome is meaningful with regards to how the assay will be performed routinely
      • Case Studies: Determination of the appropriate matrix for demonstrating Linearity for Vaccine Immunoassays

    • Topic 10:

      Application of Assay Ranges & Interpretation of Dilutional Linearity in Bio-Functional Assays
      Dr. Ingrid Scully, Senior Director, Pfizer

      • Importance of Bio-functional assays
        • Support Vaccine Clinical Development
      • Differences in
        • Linearity
        • Dilutional Linearity
        • Dilutability
      • Interpretation of the Linearity of dilution
        • Linearity of an assay
        • Ability to elicit results that are directly proportional to the analyte specific IgG concentration in a test sample
        • Regression analysis results for dilutional linearity
      • Dilutional linearity
        • Determined using constructed positive sera
        • Ability of the assay to quantify anti-X antigens specific IgG with adequate precision
      • Validation of assay in support for clinical and non-clinical research programs
        • Development, qualification and validation of clinical assays
        • Evaluation of Vaccine immunogenicity
      • Case Studies: Determination of Vaccine immunoassays Assay Ranges & Dilutional Linearity

 

Part 4: Extremely Difficult Method Development/Validation and Multiplex Immunoassays for Biomarkers
  • Topic 11:

    Applications of Multiplex Biomarker Assays to Accelerate Drug Discovery & Development
    Dr. Vincent Mikol, Precision Medicine Head, Sanofi

    • Multiplex Biomarker Assays for NAFLD
      • Strategies for the development of a Multi-omics Analysis
      • Proteomics
      • Metabolomics (lipids, free fatty acids and oxysterols)
      • miRNA sequencing from liver biopsies
      • RNA sequencing (RNA-seq) on a subset of patient samples from extreme phenotypes with unequivocal diagnosis
    • Nonalcoholic Fatty Liver Disease (NAFLD)
      • One of the most common cause of chronic liver disease
    • Biomarkers for the Stratification of the ABOS cohort
      • ABOS cohort is a unique cohort of patients followed up for 10 years
      • Biomarkers from liver biopsies and serum/plasma samples collected at baseline, at 1, 5, and 10 years after bariatric surgery.
      • Stratification of patients in 3 distinct groups according to their liver status (NASH, NAFL, Healthy).
    • Biomarker Signature
      • Predictive score of disease progression from NAFLD to NASH
      • Validation of Biomarker signature in an independent cohort
    • Case Studies: Applications of Multiplex Biomarker Assays strategies for stratification of the ABOS cohort

  • Topic 12:

    Strategies to Overcome the Challenges in FFP BAV for Multiplex Cytokine Measurements
    Mr. Michael Wright, Director Soluble Biomarkers & Bioanalysis, GlaxoSmithKline

    • Strategic role of Multiplexed Biomarker Assays
      • Attractive means to support Precision Medicine
      • Push towards biomarker rich study programs
      • Greater characterisation of disease biology
      • Potentially identify Companion Diagnostics (CDx)
    • Multiplex Cytokine Assays
      • Use of data as part of pattern recognition, i.e. as part of a cohort of assays used to generate an index score(s),
      • Use of data as a panel, where the measurement of each marker can answer a different question.
    • Demonstrating Assay Control
      • Validation parameters
      • Techniques
    • Issues in moving from Multiplexed Assays to better performing Single Plex Assays
      • As the biology becomes more understood and the program progresses
      • Requirement to generate baseline cytokine data
      • Downsides of changing from Multi to Single Plex
      • Requirement to validate a second assay
      • Requirement to perform extensive cross validation experiments to assess concordance
    • Using state-of-the-art of High-sensitivity Multiplex assays
      • Use these assays throughout the drug development pathway
      • Avoid the need for concordance assessments
      • Avoid the challenge of deciding what to do when assays do not correlate
    • Case Studies: Experiences to date with assessing high sensitivity multiplex cytokine assays

  • Topic 13:

    ROS (Reactive Oxygen Species) Biomarkers: Challenges & Considerations for Method Development, Sample collection, Sample Handling/Treatment, and Run variability
    Dr. Mitra Azadeh, Director Translational Medicine & Early Stage Clinical Development, Alkermes

    • Biomarkers of Reactive Oxygen Species (ROS)
      • ROS are important cell signaling molecules for normal physiology
      • ROS also play a major role in the induction of Oxidative Damage in multiple organelles leading to tissue toxicity
      • Activity detected in human biosamples to support clinical safety strategies
      • Exploring relationships between ROS biomarkers and safety/tox signals
    • Preservation of ROS activity in biosamples
      • Sample collection
      • Sample handling
      • Storage procedures
    • Immunoassay Variability
      • Method optimization
      • ROS as are transient species
      • Assessment of the impact of sample freeze-thaw
      • Impact of antioxidant supplementation on ROS levels
      • Checking assay variability
      • QC trending
    • Case Studies: Use of ROS biomarker immunoassays and evaluation of trends in the general population amongst various age, race, and gender groups. Data from the evaluation of multiple sample panels

  • Topic 14:

    Biomarkers in Disease Tissues and Complex Matrices: Challenges & Considerations for Operational, Preanalytical and Bioanalytical aspects
    Dr. Alessandra Vitaliti, Executive Director Biomarker Development, Novartis
    Dr. Arvind Kinhikar, Laboratory Head, Novartis

    • Strategies for Fit for purpose Biomarkers Assay Validation (FFP BAV) in
      • Disease Tissues
      • Surrogate Tissues
      • Complex matrices
    • Importance to analyze Disease Tissues
      • The most direct way to study biomarkers for human diagnostic, disease progression, efficacy, and safety monitoring
      • Many tissues are not easily accessible or not accessible at all
      • Need to use surrogate tissues
    • Importance to look for correlation between the level of selected biomarker in the tissue and in a more accessible matrix, e.g. serum or plasma.
    • Challenges in Method Development and BAV in different tissues
      • Operational (access to tissue for method development and validation, costs)
      • Pre-analytical (specimen collection standardization, sample processing, sample heterogeneity)
      • Bioanalytical (sample volume, normalization, analytical platform selection) aspects.
    • Case Studies: Approaches taken for a fit for purpose assay development and validation for different tissues, biomarker types and bioanalytical methods




Agenda at a Glance Agenda at a Glance