Specialized Workshop M1Monday September 26, 2022: 7am - 5:30pm - Topic List

"Advanced Immunogenicity Testing, Reporting, and Risk Assessment of Biotherapeutics"

Prescription Drug Labeling new FDA Draft Guidance; Harmonization of Regulations; Enhanced Tiered / Cut Points Approaches; Clinical Relevance, Preclinical & Clinical Assessment; Risk-based Approaches, Prediction and Mitigation; NAb Assays, Integrated Approach and ADA Comparison & Monitoring

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

Part 1: Risk-based Approaches, Prediction and Mitigation

  • Topic 1:

    Recent Advancements on Immunogenicity Prediction and Mitigation Tools and its actual Utility
    Dr. Swati Gupta, Executive Director Clinical Immunogenicity, Abbvie

  • Topic 2:

    Biosimilars in vitro & in silico Immunogenicity Prediction Tools: Are they promising tools in Biosimilar Development?
    Dr. Johann Poetzl, Head Program Management Bioanalytics, Sandoz

  • Topic 3:

    Challenges with T Cell Proliferation Assays for Immunogenicity Risk Assessment: What Regulatory Guidance to follow? How to design a Fit-for-purpose Validation for Flow Cytometry?
    Dr. Michele Rasamoelisolo, Senior Director & Head of Specialty Bioanalytics, Teva

Part 2: Preclinical & Clinical Harmonization and Enhanced Tiered & Cut Point Approaches

  • Topic 4:

    Non-GLP Immunogenicity support for GLP studies: What is the relevance of Immunogenicity in GLP studies?
    Dr. George Gunn, Head Immunogenicity/Senior Scientific Director, GlaxoSmithKline

  • Topic 5:

    Current Points of Disagreement in Immunogenicity Harmonization
    Dr. Samuel Pine, Head of Bioanalysis and Immunogenicity, Sanofi

  • Topic 6:

    How to reduce the Immunogenicity Tiered Testing Strategy by using Improved Methodologies and a better understanding of ADA Clinical Relevance
    Dr. Daniel Baltrukonis, Senior Director Biologics, Pfizer

Part 3: NAb Assays and Integrated Approach

  • Topic 7:

    Novel Case Studies in Support of an Integrated Data Approach versus in vitro NAb Assays: Lesson learned and feedbacks received by Regulatory Agencies
    Dr. Anders Holm Millner, Principal Scientist Immunogenicity Assessment, Novo Nordisk

  • Topic 8:

    Current Considerations on Domain Mapping ADA Characterization and its Complementary use in NAb strategy
    Dr. Karen Liao, Principal Scientist Immunogenicity, Merck

Part 4: ADA Assay Comparison & Monitoring

  • Topic 9, 10:

    Recent Developments in ADA Assay Comparisons: New experience acquired following the 2021 Industry/Regulators’ recommendations on this topic

    • Topic 9
      Novel Methodology for Comparing ADA Assay using Incurred Sample from Clinical Trials
      Dr. Nicoletta Bivi, Director Assay Development, Eli Lilly
    • Topic 10
      Criteria to Demonstrate ADA Assay Comparability
      Dr. Yuan Song, Senior Director Cancer Immunotherapy, Genentech
  • Topic 11:

    ADA Assay Monitoring: Current Experience in Establishing a Process to Monitor ADA Assay Trending and Performance over time, Rules for Establishing criteria, Regulatory requirement
    Mr. Matthew Andisik, Director Bioanalytical Operations, Regeneron

Part 5: New FDA Draft Guidance on Prescription Drug Labeling

  • Topic 12:

    Clinical Significance & Immunogenicity Assessments: How does this change with new FDA Drug Label Draft Guidance?
    Dr. Steven Swanson, Senior Principal Scientist Bioanalytical Sciences, Genentech

  • Topic 13:

    Experiences and Observations through Real life Immunogenicity Label Negotiations: Industry perspective on Immunogenicity Section of Labeling Draft guidance
    Dr. Manoj Rajadhyaksha, Executive Director & Global Head of Immunogenicity, Alexion -AstraZeneca Rare Disease

  • Topic 14:

    Immunogenicity Label Negotiations with the Agency: Lesson learned and impact of the new FDA draft Guidance?
    Dr. Michael Partridge, Director Bioanalytical Sciences, Regeneron

  • Topic 15:

    When Immunogenicity has no Clinical Impact: is it my bad assay or is it my unimpactful ADA? Lessons learned from immunogenicity reporting: Focus on the FDA Draft Guidance on Immunogenicity Labeling
    Dr. Robert Kubiak, Associate Director, AstraZeneca

Part 6: White Paper in Bioanalysis

  • 2022 White Paper on Immunogenicity Topics:

    Consensus & Conclusions on Immunogenicity Topics for 2022 White Paper

Finale: ASK THE REGULATORS!

  • Panel Discussion with Regulators:

    Regulatory Feedbacks on Submitted studies and Inspections/audits Outcomes on Immunogenicity

    • Dr. Susan Kirshner (US FDA CDER)
    • Dr. Daniela Verthelyi (US FDA CDER)
    • Dr. João Pedras-Vasconcelos (US FDA CDER)
    • Dr. Seth Thacker (US FDA CDER)
    • Dr. Mohanraj Manangeeswaran (US FDA CDER)
    • Dr. Eric Brodsky (US FDA CDER)
    • Dr. Kimberly Maxfield (US FDA CDER)
    • Dr. Lin Zhou (US FDA CDER)
    • Dr. Mohsen Rajabi Abhari, (US FDA CDER)
    • Dr. Nirjal Bhattarai (US FDA CBER)
    • Dr. Zuben Sauna (US FDA CBER)
    • Dr. Vijaya Simhadri (US FDA CBER)
    • Dr. Meenu Wadhwa (UK MHRA)
    • Dr. Isabelle Cludts (UK MHRA)
    • Dr. Lucia Zhang (Health Canada)

 

Topic DETAILS of M1

Part 1: Risk-based Approaches, Prediction and Mitigation
  • Topic 1

    Recent Advancements on Immunogenicity Prediction and Mitigation Tools and its actual Utility
    Dr. Swati Gupta, Executive Director Clinical Immunogenicity, Abbvie

    • Current understanding on Immunogenicity and how often is this a “Risk
      • Weight of evidence approach for assessing immunogenicity risk
      • Regulatory Guidance & Evolving Industry standard
    • Roadmap for Immunogenicity
      • Risk Assessment
      • De-risking
    • Tier-based strategy
      • in silico & in vitro
      • Utility of current prediction tools
    • Technical know-hows and benchmarking data
      • Application of in vitro toolbox in assessing immune risk for devices & ocular therapeutics
    • Case Studies: Immunogenicity Prediction and Mitigation for Different textures and Monoclonal antibody
  •  

  • Topic 2

    Biosimilars in vitro & in silico Immunogenicity Prediction Tools: Are they promising tools in Biosimilar Development?
    Dr. Johann Poetzl, Head Program Management Bioanalytics, Sandoz

    • In silico & in vitro methods to assess and refine immunogenicity risk for biosimilar
      • Minor modifications of the biosimilar
      • Impurities compared to reference product
    • Available methods
      • pros & cons of the methods in regard to biosimilar development
    • In silico
      • Computational tool
      • HLA-binding algorithms
      • NetMHCIIpan-2.0
    • In vitro
      • Peptide/HLA binding assay
      • T cell activation assay
      • Epitope mapping
    • Ex vivo
      • MAPPS assay
      • DC internalization assay
      • DC activation assay
    • Latest considerations on currently used predictive tools in biosimilar development
      • Which tools were applied so far and why
      • Future opportunities for such kind of tools in “targeted” biosimilar development
    • Case Studies: Present in vitro & in silico methods for Biosimilar Immunogenicity prediction
  •  

  • Topic 3:

    Challenges with T Cell Proliferation Assays for Immunogenicity Risk Assessment: What Regulatory Guidance to follow? How to design a Fit-for-purpose Validation for Flow Cytometry?
    Dr. Michele Rasamoelisolo, Senior Director & Head of Specialty Bioanalytics, Teva

    • Importance of Measuring stimulation-induced proliferation
      • Getting insight into the frequency of T cells that are responsive to a specific antigen of interest
      • Assessment of modulation by immunomodulatory compounds
    • Regulatory Guidance for Risk Assessment
      • 2021 US FDA Guidance “ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin”
      • Advantages of proliferation assay for Immunogenicity Risk Assessment
      • Challenges of proliferation assay in testing the immunogenicity
    • Assay Design of the T cell proliferation by Flow Cytometry
      • Monitoring of the number of cell divisions over a pre-determined period of time
      • Different Cell proliferation protocols
    • Fit-for-purpose validation
      • Parameters & criteria
      • Validation results
    • Assays for immunogenicity risk assessments for the purpose of ANDA for peptides
      • Innate and adaptive immune response assays
    • Case Studies: Method development/validation of T Cell Proliferation Assays for Immunogenicity Risk Assessment

Part 2: Preclinical & Clinical Harmonization and Enhanced Tiered & Cut Point Approaches
  • Topic 4:

    Non-GLP Immunogenicity support for GLP studies: What is the relevance of Immunogenicity in GLP studies?
    Dr. George Gunn, Head Immunogenicity/Senior Scientific Director, GlaxoSmithKline

    • Understanding the relevance of Immunogenicity in GLP studies
      • Current experience & discussion in non-clinical immunogenicity
      • Research efforts geared toward the assessment of potential immunogenicity in a preclinical setting
    • Approaches to nonclinical immunogenicity assessment
      • What to include for Non-GLP Immunogenicity support for GLP studies
      • Predicting immunogenicity prior to clinical trials
    • Regulatory guidance in non-clinical immunogenicity
      • Points to consider
      • Significant attention from regulatory bodies
    • Addressing status, strategies and challenges related to immunogenicity to support of GLP studies
    • Case Studies: Evolution of immunogenicity to support of GLP studies

  • Topic 5:

    Current Points of Disagreement in Immunogenicity Harmonization
    Dr. Samuel Pine, Head of Bioanalysis and Immunogenicity, Sanofi

    • Existing consensus obtained on Immunogenicity Harmonization from recent discussions and White Papers
    • Need for further discussions around which of the Validation Parameters remain points of disagreement
      • Importance of harmonizing Cross Validation approaches/procedures for ADA Assays
      • Cut Point assessment in populations with high prevalence of pre-existing ADA
      • Sensitivity Assessment
      • Acceptance Criteria
      • Immunogenicity Reporting with a focus on Clinical Pharmacology Impact and Clinical Relevance
    • Case Studies: Controversial ADA Assays Validation Parameters

  • Topic 6

    How to reduce the Immunogenicity Tiered Testing Strategy by using Improved Methodologies and a better understanding of ADA Clinical Relevance
    Dr. Daniel Baltrukonis, Senior Director Biologics, Pfizer

    • Considerations on the Standard Immunogenicity Tiered Testing Strategy
      • Is the currently used a tiered testing strategy the best “strategy”?
      • ADA assay tiers of screen, confirm and titer are variations of the same methodology
      • Screening Assay, Confirmatory Assays, Titer assays Neutralizing Assay, Characterization, Domain Mapping
    • Is a simplification of this testing strategy possible?
      • Lesson learned on the assessment of ADA to biotherapeutics
      • Use of state-of-the-art improved methodologies
      • Better understanding of what ADA tiered data provides
      • Better understanding of ADA Clinical Relevance
      • For most programs, the tiered testing strategy is not providing additional value and a case can be made that only the screening assay is needed
    • Focus on Screening Assays
      • Clinical data in support of the importance of Screening Assays
      • Understanding that screen and confirmatory data are highly correlated
      • When and why confirmatory and/or titer assays may not be necessary
      • Proposals on how to make data driven decisions on reducing the tiered strategy
    • Case Studies: Use of new methodologies and ADA clinical relevance data to reduce the Immunogenicity Tiered Testing Strategy, Clinical examples from both the assay validation and clinical sample analysis highlighting these relationships

 

Part 3: NAb Assays and Integrated Approach
  • Topic 7:

    Novel Case Studies in Support of an Integrated Data Approach versus in vitro NAb Assays: Lesson learned, and feedbacks received by Regulatory Agencies
    Dr. Anders Holm Millner, Principal Scientist Immunogenicity Assessment, Novo Nordisk

    • New data & further experience in using an integrated data approach instead of using NAb assays
      • Current understanding of when to use an in vitro NAb assays and when to use an integrated data approach for assessment of neutralising antibodies
    • Documenting the superiority of using an integrated data approach rather than relying on in vitro neutralising antibodies
      • Assessment of PK/PD of a PEGylated product
    • Discussion on Regulatory Submissions without a dedicated in vitro neutralising assay
      • Bi-specific antibody drug accepted by Regulatory Agencies
      • Learning from the new interactions with Regulatory Agencies regarding integrated data approach vs NAb assays
    • What data need to be submitted to support only an integrated data approach and to satisfy Regulatory Agencies’ requirements for NAb assays
    • Case Studies: New evaluations of PK, PD, ADA data correlation where NAb assays are not needed

  • Topic 8:

    Current Considerations on Domain Mapping ADA Characterization and its Complementary use in NAb strategy
    Dr. Karen Liao, Principal Scientist Immunogenicity, Merck

    • Current industry experience in Domain Mapping ADA characterization
      • ADA domain specificity implementation in for Multi-Domain Biotherapeutics (MDBs)
      • Regulatory requirements for Domain Mapping
      • Considerations on selection of domain material for domain specificity testing
    • Value provided by domain specificity testing
      • Modality-dependent
      • Mechanism of Action (MOA)-dependent
      • Overall Immunogenicity Risk Assessment
    • Is Domain Specificity correlating with Neutralizing Antibody generation?
      • When Domain specificity may not correlate with neutralizing antibody
      • How much value does domain specificity testing provide when sensitive NAb assay is available?
      • When Domain Specificity can be used as complementary in NAb strategy
    • Case Studies: Domain Mapping ADA Characterization and its potential use in NAb strategy

 

Part 4: ADA Assay Comparison & Monitoring
  • Topic 9, 10:

    Recent Developments in ADA Assay Comparisons: New experience acquired following the 2021 Industry/Regulators’ recommendations on this topic

    • Topic 9
      Novel Methodology for Comparing ADA Assay using Incurred Sample from Clinical Trials
      Dr. Nicoletta Bivi, Director Assay Development, Eli Lilly
      • Comparability of the Technical Performance of assay formats
        • Data from the same biotherapeutic across different laboratories
        • Lessons learned and points to consider for developing a reliable comparability strategy
      • Use of Clinical Samples
        • Rationale for using of clinical samples
        • Application of pooling strategy
      • Comparison of assay performance
        • Between laboratories
        • Against the original development data
      • Similarities and differences between ACE and ACE-Bridge
        • Potential impact of low-affinity ADA on validation parameters
        • Potential impact on clinical samples assessment
      • Current Industry strategies on ADA Assay Comparability
        • On same Biotherapeutic
        • On different biotherapeutics
        • Pros/cons and challenges
      • Case studies: Application of a methodology for comparing immunogenicity assay using incurred sample from clinical trials
    • Topic 10
      Criteria to Demonstrate ADA Assay Comparability
      Dr. Yuan Song, Senior Director Cancer Immunotherapy, Genentech
      • What criteria to use for ADA Assay Comparability based upon current Regulatory Guidance and Industry Best Practice
        • Considerations on a lack of formal guidance on criteria to demonstrate ADA Assay Comparability
      • ADA assays comparability strategy based on
        • An integrated approach driven by science
        • Immunogenicity risk assessment
        • Clinical impact
      • Applications of ADA assay Compatibility
        • Same assay in different labs
        • Different assays in the same lab for the same program
      • Case studies: Demonstration of ADA assays comparability in several different situations
  • Topic 11:

    ADA Assay Monitoring: Current Experience in Establishing a Process to Monitor ADA Assay Trending and Performance over time, Rules for Establishing criteria, Regulatory requirement
    Mr. Matthew Andisik, Director Bioanalytical Operations, Regeneron

    • Defining an ADA Monitoring Process for Clinical Assays
      • Current of industry recommendations/publications
      • Regulatory insights with respect to monitoring assay performance in non-quantitative assays
    • Implementation Strategies
      • Assessment of how much data and what type of data (e.g., validation data vs. production data) are needed to set appropriate threshold limits
      • Ensuring data used to establish threshold limits are representative of assay performance (e.g., day-to-day, analyst-to-analyst, and platform variability)
      • Statistical analysis to determine threshold limits
      • Establishing a priori criteria and incorporating into assay acceptance criteria
    • Looking forward
      • Challenges around reassessing threshold limits throughout the life cycle of an assay
      • Application to other non-quantitative assays (i.e., NAb Assays)
      • Assessing what additional value assay monitoring provides beyond current assay controls (i.e., qualification of critical reagent lots, floating cut points, etc.)
    • Case Studies: Implementation of an ADA monitoring strategy for various assays, including challenges based on how threshold limits are set.

 

Part 5: New FDA Draft Guidance on Prescription Drug Labeling
  • Topic 12:

    Clinical Significance & Immunogenicity Assessments: How does this change with new US FDA Drug Label Draft Guidance?
    Dr. Steven Swanson, Senior Principal Scientist Bioanalytical Sciences, Genentech

    • The new US FDA draft Drug Label Draft Guidance
      • How is this new guidance expected to change immunogenicity in product labeling
    • Thorough review of the dedicated Subsection, 12.6
      • Immunogenicity information, what’s new/old?
    • Request to evaluate if ADA are clinically significant or not
      • Evaluation of safety data
      • Evaluation of pharmacokinetic data as they relate to an immune response
    • What if ADA do not have clinical significance?
      • When the Adverse Reaction Section (6) should not contain immunogenicity data
    • Expected impact of this new Guidance for Immunogenicity assessment
      • Opportunity to better describe the impact of ADA
      • Challenge to be able to accurately define if ADA are significant or not
    • Case Studies: Clinical significance of immunogenicity and regulatory requirements from the US FDA Drug Label Draft Guidance

  • Topic 13:

    Experiences and Observations through Real life Immunogenicity Label Negotiations: Industry perspective on Immunogenicity Section of Labeling Draft guidance
    Dr. Manoj Rajadhyaksha, Executive Director & Global Head of Immunogenicity, Alexion -AstraZeneca Rare Disease

    • Understanding the context of the Immunogenicity Section of the Label for Biologic Molecules
    • Agreement on the Variability in Label Content for Biologics
      • Different label information for similar modality and similar mechanism of action (MoA)
      • Bioanalytical aspects
      • Impact on results reporting
    • Utility of this section to the Clinicians
      • Label issues associated with patient outreach
    • US FDA draft Drug Label Draft Guidance
      • Steps in the right direction
      • Room for improvement
    • Discussion on some salient features of the language that needs to be incorporated in the Section 6.2.
      • The inconsistencies
      • The need for harmonization
      • The expectations
    • Case Studies: Experiences and observations through real life label negotiations

  • Topic 14:

    Immunogenicity Label Negotiations with the Agency: Lesson Learned and impact of the new FDA draft Guidance?
    Dr. Michael Partridge, Director Bioanalytical Sciences, Regeneron

    • Previous/Current Inconsistent and highly variable reporting of Immunogenicity information/data on product labels
      • Pre-existing ab
      • Treatment-emergent ab
      • NAbs
      • Placebo/comparator groups
      • Impact on PK, efficacy and/or safety
    • Different information for Protein therapeutics within the same class or even against the same target
    • Expected impact of the recent FDA draft guidance in Drug Labeling
      • How will this Guidance change the labeling practice?
      • Will this Guidance promote uniformity across product classes and across jurisdictions?
    • Product labels highlight the challenges for ADA labeling
      • Already marketed products
        • List every study individually or pooled
        • Definition of treatment period in multiple studies
      • Potential gaps in the Guidance
        • Pre-existing reactivity
        • Placebo/comparator groups
        • Information about ADA impact on PK, safety and efficacy located in different sections
    • Case Studies: Immunogenicity labeling from a range of products and experience in immunogenicity label negotiations with FDA

  • Topic 15:

    When Immunogenicity has no Clinical Impact: is it my bad assay or is it my unimpactful ADA?
    Lessons for immunogenicity reporting: Focus on the FDA Draft Guidance on Immunogenicity Labeling

    Dr. Robert Kubiak, Associate Director, AstraZeneca

    • In February 2022 FDA issued a draft guidance on immunogenicity information in labeling therapeutic proteins
      • The Guidance makes a distinction for reporting immunogenicity using “inadequate” and “adequate” methodology
      • The Guidance does not specify what makes a methodology inadequate vs adequate
      • Hallmarks typically used to judge adequacy of bioanalytical methods
    • Ability to detect ≤100 ng/mL of ADA at drug concentrations expected to be present at ADA sample collection time points
      • The significance of 100 ng/mL ADA as a threshold for clinical impact on safety, PK, PD and efficacy is not very clear
    • The “impactful” ADA concentrations may depend on the following
      • The ratio molecular weights of ADA and the drug
      • PK concentrations
    • Ability to detect ADA impact on PK/PD requires
      • Sufficient proportion of subjects with ADA to make statistically meaningful inferences
      • Sufficient proportion of ADA with titers high enough to impact PK/PD
      • ADA prevalence in the placebo group should not be higher than in the active group of the study
    • Case Studies: “Inadequate” vs. “Adequate” bioanalytical methods as related to labeling




Agenda at a Glance Agenda at a Glance