Specialized Session F1Friday April 3, 2020 - Discussion Topic List

"Advanced Immunogenicity Day: Implementation of 2019 FDA Immunogenicity Guidance, NAb Assays, 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

Part 1: Implementation of the Guidance after a year from its Issuance

Part 2: Advanced Immunogenicity Day: What’s new?

Part 3: Current approaches on NAb (Cell-Based and Bridging) Assays



Topic DETAILS of F1 – Advanced Immunogenicity Day

Part 1: Implementation of the Guidance after a year from its Issuance
  • 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?
    • 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
    Dealing with Low and Very Low Cut Point ADA Assays: Lesson Learnt from numerous in-study Cut Point assessment & 2019 US FDA Immunogenicity Guidance
    • 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 3
    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
    • 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


Part 2: Advanced Immunogenicity Day: What's new?
  • Topic 4
    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
    • 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 5
    Challenging the "Persistent Definition" in the Shankar's Paper: Is it clinically relevant? Are the Regulators' enforcing this definition?
    • "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 6
    Latest developments in the Immunogenicity Assays for Nanobodies
    • 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

  • Topic 7
    Latest Developments in the Immunogenicity Assays for Antisense Oligonucleotides (ASO): Building on WRIB recommendations and evolving trends
    • 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 8
    Immunogenicity & Safety Risk Assessment and its Direct Influences on Bioanalytical Strategy
    • 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


Part 3: Current approaches on NAb (Cell-Based and Bridging) Assays
  • Topic 9
    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
    • 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 10
    Novel NAb Assay Design: Lesson Learnt and advanced approaches for the assessment of NAbs to bispecific antibody
    • 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 11
    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
    • 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 12
    Recent Trends and Expectations for NAb Assays: Are "Highly Drug Tolerant" Assays the current industry standard?
    • 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



Agenda at a Glance Agenda at a Glance