Specialized Workshop F1 - Discussion Topic List

"Advanced Immunogenicity: Implementation of 2019 FDA Immunogenicity Guidance, Nab Assays Harmonization, ADA Validation Reporting, Immunogenicity Risk Assessment, Regulatory Feedbacks & Controversial Issues"

Implementation of the Guidance after a year from its issuance; Current approaches on Nab (Cell-Based and Bridging) Assays; ADA Validation Reporting; Immunogenicity Risk Assessment and impact on bioanalytical strategy; Regulatory Feedbacks on submitted studies; Inspections/audits outcomes based on the new Guidance; and Case Studies on successfully implementation in compliance with the new Guidance and avoid observations and 483s

Chairs:
  • Dr. Haoheng Yan, Product Quality and Immunogenicity Assay Reviewer, US FDA
  • Dr. Manoj Rajadhyaksha,Director Bioanalytical Science, Regeneron

Immunogenicity Guidance/Guidelines and their Application to Biosimilar and Nanobodies

Reflection a Year Later on the 2019 FDA Immunogenicity Guidance

Advanced Immunogenicity Day: What’s new?

Current approaches on NAb (Cell-Based and Bridging) Assays

ASK THE REGULATORS!

  • Panel Discussion with All the Regulators:

    Regulatory Feedbacks on submitted studies and Inspections/audits outcomes based on the new Guidance

    • Dr. Joao Pedras-Vasconcelos (US FDA)
    • Dr. Haoheng Yan (US FDA)
    • Dr. Mohsen RajabiAbhari, (US FDA)
    • Dr. Isabelle Cludts (UK MHRA)
    • Dr. Elana Cherry (Health Canada)
    • Dr. Lucia Zhang (Health Canada)
    • Dr. Akiko Ishii (Japan MHLW)

White Paper on Immunogenicity

  • White Paper

    Consensus, Recommendations, and Panel Discussions on Immunogenicity
    - Dr. Manoj Rajadhyaksha, Director Bioanalytical Science, Regeneron
    - and Immunogenicity White Paper Working Experts Group

 

Topic DETAILS of F1 – Advanced Immunogenicity Day

Chairs:
  • Dr. Haoheng Yan, Product Quality and Immunogenicity Assay Reviewer, US FDA
  • Dr. Manoj Rajadhyaksha, Director Bioanalytical Science, Regeneron
Immunogenicity Guidance/Guidelines and their Application to Biosimilar and Nanobodies
  • Topic 1
    Reflection a Year Later on the 2019 US FDA Immunogenicity Guidance: How has the FDA Guidance been applied together with the EMA Immunogenicity Guideline and Best-Industry Practices?
    - Dr. Isabelle Cludts, Scientist Biotherapeutics Department National Institute for Biological Standards and Control, UK MHRA
    - Dr. Robert Kubiak, Sr. Manager R&D, AstraZeneca
    • Building on the 2019 White Paper in Bioanalysis recommendations on the interpretation & implementation of 2019 US FDA Immunogenicity Guidance
    • EU EMA vs US FDA vs Industry Best Practice / 2015-2019 White Paper in Bioanalysis
      • Comparative Analysis of Regulatory Guidance on Immunogenicity Testing for Therapeutic Protein Products
      • Drug Tolerance in ADA/NAb assays continues to be a major concern for the Regulatory Agencies
      • Recent Industry/Regulators' Recommendations on Positive Controls
      • LPC levels for screening and confirmatory assays
      • PK, PD, ADA Data Correlation
    • Current Regulatory Guidelines vs MRD
      • FDA guidance on immunogenicity assay development/validation stresses the importance of selecting appropriate minimum required dilution (MRD) for the assay.
      • No papers discuss how to determine correct MRD.
      • Z' factor was proposed for MRD selection but its utility is really doubtful
        • Common agreement on how important MRD is
        • No clarifications on what a good MRD should look like
    • Working together in drafting a recommendation on best practice for MRD & Case studies
  •  

  • Topic 2
    The new (Nov. 2019) US FDA Draft Guidance on "Clinical Immunogenicity Considerations for Biosimilar and Interchangeable Insulin Products"
    • US FDA Perspective on Immunogenicity Assays for Biosimilar Programs: Case studies and lessons learned
    • Current Industry Standards in Bioanalysis of Biosimilars
    - Dr. Haoheng Yan, Product Quality and Immunogenicity Assay Reviewer, US FDA
    - Dr. Johann Poetzl, Group Head Bioanalytics, Sandoz
    • What's new in the 2019 FDA Draft Guidance on "Clinical Immunogenicity Considerations for Biosimilar and Interchangeable Insulin Products"?
    • Is it time to update the 2015-2016 White Paper in Bioanalysis recommendations on Biosimilar immunogenicity?
    • Regulators' feedback on immunogenicity strategy
      • Methods to evaluate immunogenicity of Biosimilars
      • Evolution of immunogenicity strategies for biosimilars
      • Concrete industry standards on expectations regarding immunogenicity assessment
      • Current discussions on case by case aspects of immunogenicity evaluation in Biosimilar
        • What's the impact of "No requirement to reproduce historic data"
        • Significant impact on results of assay reagents & assay format
    • Discussion on issues for establishing Biosimilarity for compounds with elevated biotransformation
      • How is immunogenicity impacted?
    • Case studies on learnings and emerging trends in bioanalytical assay development for Biosimilars
  •  

  • Topic 3
    Latest developments in the Immunogenicity Assays for Nanobodies
    - Dr. Samuel Pine, Head Bioanalysis and Immunogenicity, Ablynx/Sanofi
    • Limited immunogenicity data for Nanobodies
      • Novel class of therapeutic proteins
    • An update on the current immunogenicity strategies for Nanobodies
      • NAb Assays
        • Specific approaches for Nanobodies
        • Bridging ADA assay
      • Pre-Existing ADA
        • Potential immunogenicity risk factor
        • Endogenous antibodies and overlap with Nanobodies epitopes
        • Possible impact of pre-existing ADA on Nanobodies safety & efficacy
        • Assay to evaluate pre-existing ADA responses
    • Case studies on assessment of multiple treatment-naïve samples to determine the immunogenicity of Nanobodies
  •  

    Reflection a Year Later on the 2019 FDA Immunogenicity Guidance
    • Topic 4
      Reflection a Year Later on the 2019 US FDA Immunogenicity Guidance: How has the FDA Guidance been applied together with the EMA Immunogenicity Guideline and Best-Industry Practices?
      - Dr. Robert Kubiak, Sr. Manager R&D, AstraZeneca
      - Dr. Isabelle Cludts, Scientist Biotherapeutics Department National Institute for Biological Standards and Control, UK MHRA
      • Building on the 2019 White Paper in Bioanalysis recommendations on the interpretation & implementation of 2019 US FDA Immunogenicity Guidance
      • EU EMA vs US FDA vs Industry Best Practice / 2015-2019 White Paper in Bioanalysis
        • Comparative Analysis of Regulatory Guidance on Immunogenicity Testing for Therapeutic Protein Products
        • Drug Tolerance in ADA/NAb assays continues to be a major concern for the Regulatory Agencies
        • Recent Industry/Regulators' Recommendations on Positive Controls
        • LPC levels for screening and confirmatory assays
        • PK, PD, ADA Data Correlation
      • Current Regulatory Guidelines vs MRD
        • FDA guidance on immunogenicity assay development/validation stresses the importance of selecting appropriate minimum required dilution (MRD) for the assay.
        • No papers discuss how to determine correct MRD.
        • Z' factor was proposed for MRD selection but its utility is really doubtful
          • Common agreement on how important MRD is
          • No clarifications on what a good MRD should look like
      • Working together in drafting a recommendation on best practice for MRD & Case studies
    •  

    • Topic 5
      Dealing with Low and Very Low Cut Point ADA Assays: Lesson Learnt from numerous in-study Cut Point assessment & 2019 US FDA Immunogenicity Guidance
      - Dr. Sam Song, Immunogenicity Lead, Takeda
      • New case studies in support of the recent recommendation on Cut Point from 2019 White Paper in Bioanalysis
      • How ADA Assay Conditions impact Low and Very Low Cut Point values
        • Assays used to detect ADA rely on a Cut Point to define positive / negative status of samples
      • Positive Control (PC) performance for Low and Very Low Cut Point
        • Optimization of analytical conditions based on PC
        • Low & Very Low Cut Points and failure to distinguish assay background from true biological response
        • How to improve ADA assay ability to differentiate assay noise vs. true biological response
      • Case studies on lesson learnt from numerous in-study Cut Point assessment and approaches to deal with Low & Very Low Cut Points
    •  

    • Topic 6
      Immunogenicity Monitoring Expectations for Low Risk vs High Risk Molecules: When it is needed, how much is needed, how it should be reported & 2019 US FDA Immunogenicity Guidance
      - Dr. Michael Partridge, Assoc. Director Bioanalytical Sciences, Regeneron
      • More clarity & consensus around immunogenicity monitoring for low risk vs high risk molecules
        • Regulatory expectations vs current industry standards
          • When it is needed
          • How much is needed
          • How it should be reported
      • ADA/NAb Assay Strategies for Low Risk Molecules
        • Background/context
        • Understanding current industry practices for molecules of low immunogenicity risk
        • Is there a real need for additional NAb measures?
          • Complement NAb analysis of exposure and efficacy
          • Meaningful and impactful NAb data
          • Experience with a specific low risk molecule
      • How to facilitate immunogenicity program decision making for Low Risk vs High Risk Molecules
        • Assay development and validation, data interpretation and reporting
      • Case studies on Low Risk Molecules immunogenicity monitoring
        • Working together for a White Paper recommendation

     

    Advanced Immunogenicity Day: What's new?
    • Topic 7
      Challenging the "Persistent Definition" in the Shankar's Paper: Is it clinically relevant? Are the Regulators' enforcing this definition?
      - Dr. Manoj Rajadhyaksha, Director Bioanalytical Science, Regeneron
      • "Questioning again the Persistent Definition" in the Shankar's Paper
      • Extensively discussed in 2016 White Paper in Bioanalysis
        • 2016 Link: https://www.future-science.com/doi/pdf/10.4155/bio-2016-4989
        • "To illustrate and describe ADA duration, a graphical option can be considered when sample size is statistically significant."
        • "To properly classify the ADA duration data, at least 1 year of immunogenicity data were recommended."
          • "A 16- or 12-week duration were both deemed acceptable to characterize the patient as having an ADA as persistent response and an adequate sampling schedule should be selected."
        • "The duration of follow-up testing for ADA-positive patients should be data driven and should not default to continuous monitoring until subjects become baseline negative"
      • Current understanding of the persistent definition in the Shankar paper
        • Is it clinically relevant?
      • Regulatory expectations
        • Shankar's paper vs home brewed definitions
          • Possibility to employ home brewed persistent definitions for ADA responses
          • Cases where the Shankar's paper definition is enforced by Regulators
      • Working together to bring consistency in the Persistent Definition
    •  

    • Topic 8
      Latest Developments in the Immunogenicity Assays for Antisense Oligonucleotides (ASO): Building on WRIB recommendations and evolving trends
      - Dr. Marco Petrillo, Senior Scientist Biomarker Group, Biogen
      • Building on the 2018 White Paper in Bioanalysis recommendations on Immunogenicity Assays for ASO with new case studies and updated data
      • Final developments & conclusions on ASO Immunogenicity determination
        • Immunogenicity assays development in support of several ASO studies
          • Delivery vector
          • mRNA
          • Expressed protein
      • Unique challenges in developing a suite of bioanalytical assays for ASO
        • Specific bioanalytical strategies taking into consideration
          • Multiple differences in how ASO are dosed
          • Mechanism by which ASO exert their therapeutic effects
        • Infeasible ADA assays
          • Limitations of typical bridging LBA
          • Assay details and solutions/mitigations of these challenges
      • Case studies on recent data on Bioanalytical support for ASO therapeutics for multiple studies
    •  

    • Topic 9
      Immunogenicity & Safety Risk Assessment and its Direct Influences on Bioanalytical Strategy
      - Dr. Vibha Jawa, Director Risk Assessment and Clinical Immunogenicity, Merck
      • 2019 FDA Immunogenicity Guidance
        • Regulatory Expectations for risk assessment
          • More comprehensive risk assessment being performed and provided prior to IND submission
      • This risk assessment
        • Immunogenicity & safety
        • Impact on the bioanalytical and preclinical/clinical strategy
        • Preclinical data (NHP)
          • how to monitor ADA in case the NHP react to human
      • Risk mitigation approaches for reducing immunogenicity in Clinic
        • Bioanalytical approaches for in vitro immune cell binding assay to predict immunogenicity
        • Use of human immune cell derived ex vivo assays
          • Are they robust, sensitive, specific?
      • Regulatory perspective
        • Recent interactions with Regulators
        • Clinical relevance of in vitro NAb assays
        • Mechanism of Action-based Approach
      • Case studies on how, when and what is needed for risk assessments in the context of next generation biotherapeutics

     

    Current approaches on NAb (Cell-Based and Bridging) Assays
    • Topic 10
      Cell-based NAb Assays Development & Validation: Assay sensitivity and drug tolerance – and the relevance for clinical outcome. Building on WRIB Industry/Regulators’ Recommendations with new data & case studies
      - Dr. Madeleine Dahlbäck, Department Manager Immunogenicity Assay Development, Novo Nordisk
      • Recommendations on Cell-Based NAb Assays started with the 2013-2015 White Paper in Bioanalysis
      • Clinical relevance Cell-Based NAb assays
        • Impact or no impact on efficacy and safety
        • Assays sensitivities vs drug tolerance
          • Strategies and attempts to improve both sensitivity and drug tolerance of the assays
          • Loss of sensitivity when drug tolerance is improved with different pre-treatment methods
      • Recent interaction with Regulators
        • Limitations of cell-based assays.
        • Is it acceptable to use the less sensitive but more drug tolerant assay for all samples (during treatment + follow up samples)?
        • Do Regulators expect two different types of NAb assays to be developed?
          • One assay for follow up samples with max sensitivity
          • Another less sensitive and more drug tolerant assay for samples during treatment
      • Working together on an Industry/Regulators' recommendation on what to do when the clinical relevance of in vitro NAb assays is doubtful in projects with a low immunogenicity risk
        • Do Cell-Based NAb assays add value when antibody titers are very low and transient and there is no effect on clinical outcome?
      • Case studies on Cell-Based NAb assays to evaluate the in vitro neutralizing effect of ADA at follow up after drug washout
    •  

    • Topic 11
      Novel NAb Assay Design: Lesson Learnt and advanced approaches for the assessment of NAbs to bispecific antibody
      - Dr. Bonnie Wu, Assoc. Scientific Director Biologics Development Sciences, Janssen
      • Building on the 2015 White Paper in Bioanalysis recommendations on Bispecific Immunogenicity with novel case studies and evolved industry experience
        • 2015 Link: https://www.future-science.com/doi/pdf/10.4155/bio.15.226
        • "Bispecific therapeutic proteins may require additional mechanistic characterizations associated with immune responses in addition to ADA testing such as monitoring cytokine release and other immune system modulation events"
        • "Testing for specificity against the functional domain may be justified as the incidence and clinical impact merits"
      • Recent Trends and Expectations for Nab Assay for Bispecific Antibody
        • Focus on bispecific mechanisms of actions (MoA)
        • Complexity in the development of NAb assay to support characterization of Bispecific ADA
        • Innovative approaches for detecting NAb for Bispecific Antibody based on the Bridging ADA Assay Format and unique Critical Reagents
      • Development of a Neutralizing Antibody Assay with Improved Drug Tolerance
        • Challenges due to the high levels of drug expected in serum samples from clinical studies
        • Impact of sample pre-treatment upon positive control/analyte (ADA) activity/stability
      • Bioanalytical advances in NAb assay design
        • Focusing on strategies for novel modalities such as bispecific antibodies.
        • Current practices on conducting NAb analysis of ADA positive samples from treatment unaffected patients
      • Case studies on Novel NAb Assay Design Bispecific
        • What to measure in the clinic?
          • What's optimal timing for implementation in the clinic?
          • Regulatory perspective
    •  

    • Topic 12
      Consideration for Functional Cell-based Neutralizing Antibody Assay: Experience and decision-making process, when to use them and when they were deemed unsupportable or not-ideal
      - Dr. George Gunn, Head Immunogenicity and Sr. Scientific Director, GlaxoSmithKline
      • Advantage of Cell-based Assay for Neutralization Antibody
        • Cases where a competitive LBA for neutralizing antibody testing
          • May not fully reflect natural counterpart
          • May introduce artificial effects
      • Strategies to determine Assay Format for the Assessment of NAb Responses to Biotherapeutics
        • Factors for selection of cell-based NAb vs non-cell-based NAb
        • LBA comparison with Cell-based Nabs
        • Development of cell-based binding assays to provide more physiological binding than competitive LBA
      • 2013-2020 Industry experience
      • Case studies where Functional Cell-based Neutralizing Antibody Assay were used when they were deemed unsupportable
    •  

    • Topic 13
      Recent Trends and Expectations for NAb Assays: Are "Highly Drug Tolerant" Assays the current industry standard?
      - Dr. Yuling Wu, Assoc. Director Clinical Immunology and Bioanalysis Group, AstraZeneca
      • Challenges to develop NAb assays that simultaneously possess high levels of drug tolerance and sensitivity
      • Risk in using extensive pre-treatment steps
        • Reduction of the NAb assay sensitivity
        • Risk of introducing a sensitivity difference between the ADA assay and the NAb assay
      • New approaches for highly drug tolerant Neutralizing Antibody (NAb) Assays
        • Efficient drug removal in competitive LBA
          • Improving NAb assays drug tolerance
          • Avoiding potential underestimation of NAb incidence
          • Avoiding interference due to carryover of the drug-capture reagent
      • Novel applications
        • Bead-based drug depletion methods
        • Alternative NAb assay format based on the conventional bridging ADA
      • Importance of using highly drug tolerant NAb assays
        • For pre-existing antibodies
        • For correlating clinical impact
      • Case studies on bioanalysis of ADA positive clinical samples with elevated drug levels using Highly Drug Tolerant NAb Assays