Main Workshop DAY 3 - Thursday April 4, 2019, 7am to 6:45pm

"LBA, Cell-based Assays/Flow Cytometry & Emerging Technologies DAY"

(You can click on each blue topic title below to see details, or simply scroll down to see details)

Day 3A: LBA, Cell-based Assays/Flow Cytometry & Emerging Technologies

Novel Bioanalytical Developments in Cancer Immunotherapy & Gene Therapy

Immunogenicity - Interpretation & Implementation of the 2019 FDA Final Immunogenicity Testing Guidance: Focus on Key Components of "Immunogenicity Testing of Therapeutic Protein Products - Developing and Validating Assays for Anti-Drug Antibody Detection Guidance"

Vaccine Assays & Biomarker Assays

2019 White Paper on LBA, Cell-based Assays/Flow Cytometry & Emerging Technologies

  • Consensus and Conclusions on LBA, Cell-based Assays/Flow Cytometry & Emerging Technologies

  • Interpretation & Implementation of the 2019 FDA Final Immunogenicity Testing Guidance

 

Day 3B: ICH M10 BMV Draft Guideline - Ligand Binding Assays

Harmonized Topics among US FDA, EU EMA, Health Canada, Japan MHLW regulations

  • Topics will be announced once ICH Draft Guideline is Published

Unresolved Issues and On-going Industry/Regulators’ Discussions

  • Topics will be announced once ICH Draft Guideline is Published

Panel Discussion on ICH M10 BMV Draft Guideline - Ligand Binding Assays

  • Industry Recommendations to ICH M10 Major Participating Regulatory Agencies

    • Dr. Brian Booth (US FDA / EWG Regulatory Chair)
    • Dr. Jan Welink (EU EMA / EWG Member)
    • Dr. Akiko Ishii (Japan MHLW / EWG Rapporteur)
    • Dr. Yoshiro Saito (Japan MHLW / EWG Member)
    • Dr. Anna Edmison (Health Canada / EWG Member)
    • Ms Thais Correa Rocha (Brazil ANVISA / EWG Member)

 

 

Day 3A Details:
LBA, Cell-based Assays/Flow Cytometry & Emerging Technologies

Novel Bioanalytical Developments in Cancer Immunotherapy & Gene Therapy

  • Topic 1
    Using Flow Cytometry for Predicting Response to Immunotherapy: Case Studies of Strengths and Gaps in Clinical Validation
    • Recent applications of Flow Cytometry in Cancer Immunotherapy
      • Baseline and/or on-treatment frequencies of immune cell types measured by Flow Cytometry
      • Evaluation of significant correlation with response to cancer immunotherapy
    • Case studies & keys findings
      • Assessment of strengths and gaps in the Flow Cytometry assays developed and validated for this purpose
      • Challenges, strategies and considerations in Clinical Validation
  •  

  • Topic 2
    On-going developments in CAR-T Bioanalytical Strategies & Challenges by Flow Cytometry
    • On-going research and achievements in Chimeric Antigen Receptor T-cells (CAR-T)
      • Flow Cytometry as a key technology in developing CAR-T personalized therapy
      • Patient’s T cells engineered to express artificial T-cell receptors
      • Possibility of surface expression of several antigens with the generation of CAR T-cells with dual specificity
      • Automated analyses of Flow Cytometry data for prediction of clinical response to CAR-T Cell Therapies
    • Scientific and regulatory challenges in development of CAR-T Therapy
    • Lesson learnt from the characterization of CAR-T Therapy
      • Evaluation of Flow Cytometry based approaches
      • Monitoring of cell products for use in Clinical Studies
    • CAR-T Therapy What’s Next?
      • How Bioanalysis can help CAR-T development?
      • Bioanalytical strategy, assay development and validation
      • Advanced use of Flow Cytometry bioanalytical methods in cell-based pharmacokinetics or cellular kinetics in adoptive cell therapy

 

Immunogenicity

  • Topic 3
    What’s New for Improving ADA Assay Drug Tolerance & Sensitivity? Do Acid Dissociation, SPEAD, ACE, PandA, BEAD & Co do what we think they do? Is there any other alternative/innovative/less complex and time-consuming approach?
    • Improving Drug Tolerance in ADA/NAb assays continues to be a major concern for the Regulatory Agencies
      • What’s new from the 2018 White Paper Recommendations Part 3
      • What are the most recent progresses?
    • Pros and Cons of current approaches for improving Drug Tolerance
      • Acid dissociation: Does it do what we think it does?
        • What are the alternatives to the current Acid-Dissociation techniques?
      • Is there room for improvement to avoid sample pre-treatments issues?
        • Impact on sensitivity, precision, binding affinity, dimerization, denaturation, analyte loss
      • Are we losing ADA in the sample pre-treatments so that samples are determined as negative or low positive when actually ADA are lost in the process?
        • Can recovery test help avoid potential bias?
      • Is the magnetic beads technology able to overcome the issues of the other approaches?
        • Evaluation of the high specificity to remove therapeutic drug from study samples
    • Considerations on how Drug tolerance test is currently performed
      • Risk in over or under-estimating drug tolerance due to the use of surrogate Positive Control
  •  

  • Topic 4
    Surrogate Positive Controls (PC) Challenges, Concerns, Appropriateness for ADA Assays: How to deal with recovery, purity, stability, multiple epitope recognition, HPC & LPC criteria and FDA draft Guidance
    • Recent Industry/Regulators’ Recommendations on Positive Controls
      • Practical application of the 2017-2018 White Paper in Bioanalysis Part 3
    • Strategies for the generation of feasible Positive Control for ADA Assays
    • Current challenges in the development of drug-related surrogate Positive Control
      • Novel antibody engineering approaches
    • Impact on ADA Assays performance
      • Multiple epitope recognition
      • Purity and stability
      • Positive Control influence on Cut Point Determination
      • Are improved Positive Controls representative of patients’ immune response?
      • Impact of PC on determining sensitivity
      • Strategies to overcome the risk of developing ADA assays with high affinity PC that are not reflective of the patients’ immune response
      • Experiment needed when the Positive Control is changed
    • Value/relevance of performing
      • “Recovery” of surrogate Positive Control in individual samples for ADA assay robustness
      • Stabilities in surrogate Positive Control for actual ADA sample stability
        • Best practices in the stability testing of ADA vs Positive Control
    • Implication of Recommended LPC failure rate in the new FDA Guidance
      • LPC levels for screening and confirmatory assays
    • Critical evaluation of actual Clinical ADA data in case of LPC failure rate higher than recommended from the new FDA Guidance
  •  

  • Topic 5a
    Clinical Relevance of ADA and Impact on Bioanalysis - Better Understanding of Clinical Relevance of ADA: Are Highly Sensitive & Drug Tolerant ADA Assays Helping with Clinical Correlation or just Increasing the Noise? Building on 2018 White Paper Recommendations
    • Recent case studies on Clinically Meaningful Immunogenicity
      • Is the cost in ADA assay improvements in sensitivity providing clinical insights?
      • Decision-making immunogenicity data and analyses
      • Recent considerations in redefining Clinical Immunogenicity Assessment
      • What have we learned from using drug tolerant ADA assays in clinical setting?
      • What’s the clinical relevance of low affinity ADA?
    • Clinically Meaningful Immunogenicity Profile Impact on Safety & Efficacy
      • Essential ADA/Nab assays developed to characterize the immunogenicity profile
      • Interpretation of ADA data and determination of clinical impact
    • Updated data and lesson learnt with highly sensitive and drug tolerant immunogenicity assays in understanding the clinical impact of ADA
      • Focus on clinical relevance of ADA and not just incidence rates
      • Clinically relevant ADA data generated by
        • Modifying the outlier removal process used to generate ADA assay CP
        • Reporting only persistent ADA
  •  

  • Topic 6
    PK, PD, ADA Data Correlation, Clinical Relevance and Current Industry Experience with New Modality Biotherapeutics for Ophthalmology
    • Original data from an ophthalmology clinical program
      • Expected specific challenges
        • Small volumes
        • Complex sample collection
        • Rare ocular matrices
    • New complications
      • New Modality Biotherapeutics (NMB) validation for PK, ADA and soluble targets/biomarkers assays
      • Novel bioanalytical issues and possible solution
      • Unique challenges of immunogenicity testing of ophthalmology biotherapeutics
        • Highly concentrated drug into the eye
        • Direct drug administration into the eye
        • Long duration of biologics
        • Major drug interference
    • PK, PD, ADA Data Correlation
      • ADA monitoring in serum/plasma and in ocular matrices
        • Interpretation of drug exposure
        • Correlation with histopathology and Tox findings
      • PD Assays
        • Protein biomarkers quantification in ophthalmology at very low concentration and in small volume of aqueous humor
        • Use of Ultra-sensitive platforms
      • PK Assays
        • Challenges with ocular drug administration far from the site of action within the eye
        • Bioanalysis in the various ocular tissues & fluids for PK, formulation or device suitability

 

PK & Biomarker Assays

  • Topic 7
    Soluble Target and ADA Impact on PK Assays: Analyzing, Interpreting and Reporting Factors that Impact PK data
    • What is your PK assay telling?
      • Interpretation Factors that impact PK measurements of biotherapeutics
      • How presence of high concentrations of circulating target, assay reagents, format and conditions can significantly impact the PK parameters/profiles
    • Case studies on impact based on what drug species is being detected
      • Impact of soluble target on PK profiles
    • Understanding the PK assay as well as the strengths and limitations of the resulting data
      • Crucial data interpretation to draw accurate conclusions
      • Interpreting potential association of PK assays with clinical outcomes
    • Case studies where an outcome was impacted by misleading interpretation of PK Assays due to soluble target and ADA impact
      • How are ADA interference in PK assays being analyzed and reported?
      • Recommendations on How PK assays can advise on ADA
      • Type of outcome and general analysis description
      • Findings and interpretation
  •  

  • Topic 8a
    Vaccine Clinical Assays - Challenges in Bioanalytical Method Development & Validation, Concomitant Vaccines Testing, and Life-Cycle Management of Assays: Merck experience
    • The assay development and validation process for vaccine at Merck
    • Bioanalytical challenges with vaccines
      • Concomitant vaccines testing
      • Bioanalytical methods
      • Life-cycle management of assays
      • Validation & troubleshooting of vaccine test
    • Case studies on Cell-mediated immunity assays
      • Flow Cytometry Assays
      • ELISPOT Assays
    • Applied vaccine clinical assay practices
      • Clinical efficacy endpoint in vaccine clinical trials
    • Regulatory expectations for vaccines bioanalysis
      • US FDA Center for Biologics Evaluation and Research (CBER) for Vaccine and Gene Therapy
      • EU EMA scientific guidelines on vaccines and Clinical evaluation of new vaccines
        • 2018 revised guideline on the clinical evaluation of vaccines
  •  

  • Topic 8b
    Vaccine Clinical Assays - From Clinical assay to Immunogenicity: GSK experience
    • The assay development and validation process for vaccine at GSK
    • Case studies on humoral immunity assays
      • LBA clinical Immunogenicity assay
      • Main challenges in the vaccine field
      • How to establish assay reference standards
      • Determination control samples and their use and utility in determining assay acceptance
      • Antibody functional assays
        • Viral neutralization assays
    • Updates from the 2018 White Paper in Bioanalysis discussion on Cut Points for Vaccines
    • Statistical methods are used to
      • Determine the limit of blank (true negative samples)
      • Assay LOD and LLOQ
      • Most important features for Vaccine ADA assays
  •  

  • Topic 9a
    Exploratory Biomarkers – What are they? Guidance on how to approach Exploratory Biomarker Assays for Internal Decision-making: What is meant by COU and FFP
    • Consideration on the high number of Biomarkers developed for projects in discovery stage – "the exploratory one"
      • How are "exploratory" biomarkers defined?
      • What are the criteria behind that definition?
    • Lack of industry focus on Exploratory Biomarkers vs Confirmatory/Regulated Biomarkers
      • Lack of guidance on how to approach biomarker assays for internal decision-making
      • Lack of comfort to decide internally what is Fit for Purpose (FFP) or exactly the Context Of Use (COU)
        • What is meant by COU and FFP for exploratory biomarkers?
      • Debunking the notion that FFP means not validated
        • "FFP is not the F-word of the biomarker world"
    • Working together to draft recommendation able to provide clarity within the Industry for exploratory biomarkers
      • Case studies on based on a specific biomarker of great interest across industry
      • Neurofilament light
        • A case study in COU iterative assay development for biomarkers
  •  

  • Topic 9b
    Exploratory Biomarkers – What are they? Current Industry Standards to Handle Assay Development, Validation, Transfer and Refinement of Exploratory Biomarkers from Discovery into Development
    • Exploratory biomarkers discovery/determination and how to progress them into a prognostic/diagnostic biomarker
      • Current industry practice on how companies handle the transfer/refinement/qualification of methods from Discovery into Development for exploratory biomarkers
      • Is it possible to use biomarkers assays developed for Discovery in FIH clinical studies for an “exploratory biomarker”? If not, why?
      • How to transfer biomarker platforms from discovery to clinical studies?
        • Transferring a biomarker exploratory Hybrid LBA/LCMS assay to a "regulators’ preferred" traditional LBA for a confirmatory clinical biomarker
      • When does an "exploratory biomarker" become a "clinical biomarker"?
      • When does a "clinical biomarker" become a "diagnostic"?
    • Exploratory Endpoints in clinical studies
      • On-going debate on how to approach this issue
      • How to deal with possible but unconfirmed biomarkers
      • What are the regulatory expectations for exploratory biomarker assay used in clinical trials?
        • Characterization, data reporting or non-reporting
  •  

  • Topic 10
    Accuracy in Biomarkers Assays? Establishing a Meaningful Approach to Determine Absolute Accuracy in LBA & Flow Cytometry Assays
    • Regulatory Statement:
      • "Accuracy is one of the utmost fundamental requirements for validation of any assay including fit-for-purpose biomarker assays"
      • How the industry can work together to overcome the lack of absolute accuracy for biomarkers assays not having an appropriate or exact reference standard
        • Currently, LBA & Flow Cytometry assays are able to measure only relative accuracy instead of absolute accuracy
      • From 2018 White Paper in Bioanalysis Part 3: "As flow cytometry assays lack the availability of reference standards and the data generally fall into the category of quasi-quantitative, it is thus not possible to validate accuracy in the traditional manner"
    • Establishing analytic acceptance criteria for quasi-quantitative assays for Biomarkers
      • Addressing biomarker LBA & Flow Cytometry Accuracy issues
        • Exploration within the different technologies
      • How to improve the current reference standards used in LBA and Flow Cytometry Biomarkers assays?
        • Need to find more appropriate reference material
      • Importance to carefully and reliable assess the differences between the endogenous protein and the reference material
        • Is it possible to quantify the impact on absolute accuracy of current reference standards vs endogenous biomarkers?
    • Current discussions on Absolute Accuracy within the Flow Cytometry Community
      • Struggles to establish a meaningful approach for validating method accuracy
  •  

 

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