Topic DETAILS of M1

• 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

• 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

• 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

• 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.

• 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