Specialized Workshop M1Monday September 27, 2021: 7am - 5:30pm - Lecture List

"ADA/NAb Guidance Day: Recent Advancements in the Harmonization of Immunogenicity Testing & Reporting"

Part 1: Harmonization of Immunogenicity Assessment, Reporting and Monitoring

Part 2: Multi Domain Biotherapeutics & Bispecific Biotherapeutics: Harmonization of Immunogenicity Testing & Reporting

Part 3: Integrated Summary of Immunogenicity Harmonization: US FDA, EU EMA, China NMPA Immunogenicity Guidance/Guideline

Part 4: ADA Assay Comparability

Finale: ASK THE REGULATORS!

  • Panel Discussion with Regulators:

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

    • Dr. Susan Kirshner (US FDA)
    • Dr. Daniela Verthelyi (US FDA)
    • Dr. Joao Pedras-Vasconcelos (US FDA)
    • Dr. Haoheng Yan (US FDA)
    • Dr. Mohsen RajabiAbhari, (US FDA)
    • Dr. Kimberly Maxfield, (US FDA - invited)
    • Dr. Günter Waxenecker (Austrian AGES/EU EMA)
    • Dr. Therese Solstad Saunders (Norway NoMA/EU EMA)
    • Dr. Isabelle Cludts (UK MHRA)
    • Dr. Elana Cherry (Health Canada)
    • Dr. Lucia Zhang (Health Canada)
    • Dr. Akiko Ishii (Japan MHLW)

 

Lecture DETAILS of M1 – ADA/NAb Guidance Day

Part 1: Harmonization of Immunogenicity Assessment, Reporting and Monitoring
  • Lecture 1
    On-going Challenges on Harmonization of Immunogenicity Assessment, Reporting and Monitoring Post-Approval
    - Dr. Robert Kubiak, Senior Manager R&D, AstraZeneca
    • Building on recent Industry/Regulators' recommendation on Post-Approval Immunogenicity Monitoring
    • Current industry efforts to harmonize the 2020 Industry/Regulators' recommendations for Immunogenicity based on US FDA Guidance, EU EMA Guideline and Industry Best Practice
      • Assessment, Reporting and Monitoring
    • Cut Points
      • Why do Cut Points tend to be low and very similar across different methods and modalities?
      • Does this indicate that Cut Points do not reflect the biology of the samples but mostly the assay?
      • Is the determination of Cut Points for different indications really useful since current methods of cut point determination tend to give very similar cut points?
    • Sensitivity
      • Is the Industry putting too much emphasis on determination of sensitivity and drug tolerance using surrogate controls?
    • Different ways of reporting Titer:
      • Challenges for Calculating MRD for ACE or SPEAD methods
    • ADA impact on PK and PD
      • Why is the correlation between the titer value and its effect on PK and PD often low?
      • Is titer in ADA assay not reflective of how ADA binds its target?
    • Reporting
      • Limitations of ADA category definitions
      • Evaluable vs. non-evaluable subjects
      • Positive vs negative subjects
      • Persistent vs transient ADA
    • Post-approval Monitoring
      • Is there a good measure of impact of ADA incidence / titer on efficacy?
      • With the exception of anti-TNF biotherapeutics, does detection of ADA provide any new actionable information?
    • Case Studies: Immunogenicity monitoring post approval till reaching ADA negative post treatment in the clinical studies, requirement, value and challenges
  •  

  • Lecture 2
    Immunogenicity Testing Strategies and their Harmonization - Overcoming soluble target presence in drug tolerant ADA Assay
    - Dr. Gregor Jordan, Lab Head, Roche
    • Building on recent Industry/Regulators' recommendations on Harmonizing Expectations for Drug Tolerant ADA Assay in presenceof Soluble Target
    • Theoretical consideration for improving the Drug Tolerance
      • Impact on false positive results of Monomeric target when there is a switch of therapeutic drug
      • What if more therapeutic drugs for the same indication are available and a switch of patients is necessary?
    • Soluble targets generation of false-positive signal ADA assays
      • Is a depletion of soluble target without additional reagent (e.g anti target binder) possible?
      • Overcoming high background signal due to soluble target interference
      • Current strategies to mitigate false-positive signal
      • Recommendations on using competitive blockers to inhibited soluble target interference and increased target tolerance levels
      • Pros/cons of using target immunodepletion using magnetic beads conjugated with an anti-target antibody
      • Advantages of developing the ADA assay under mild acidic conditions
      • Alternative strategies for mitigating target interference when standard anti-target antibodies are ineffective
    • Harmonizing immunogenicity testing for high throughput and easy execution approaches for mitigating soluble target interference
      • High tolerance ADA Assays
      • Reduced false positives
    • Case studies: Novel approaches how to tackle the presence of soluble target and how to translate the challenge of rapid turnaround analysis in a robust and drug tolerant ADA assay
  •  

  • Lecture 3
    Biosimilar ADA Assay Validation & Harmonization - How to demonstrate appropriateness of one assay approach
    - Dr. Johann Poetzl, Head Program Management Bioanalytics, Sandoz
    • Building on recent Industry/Regulators' recommendations on Biosimilar ADA Assay Harmonization
    • Immunodepletion curves
      • Use of biosimilar candidate vs reference product applied to demonstrate appropriateness of one assay approach
      • What acceptance criteria should be applied?
      • Discussion on proposals for acceptance criteria
    • Looking for a sensitive range to demonstrate suitability of one assay
      • Starting concentration for ADA Positive Control high or low?
      • Effects close to detection limit may increase complexity of immunodepletion curve result interpretation
    • Positive Control
      • Polyclonal, monoclonal, anti-Fab or anti-"full-protein"
    • Capture Reagent
      • Critical role in demonstrating appropriateness of one assay approach
    • Current best practice to demonstrate that ADA assay can adequately detect antibodies against both biosimilar and originator
      • Practical recommendations to harmonize ADA Assays for optimal comparative immunogenicity assessment of biosimilars
      • Two-assay (based on the biosimilar and originator respectively)
      • One-assay approach (based on the biosimilar)
      • On-going challenges in immunogenicity assessment to evaluate differences between biosimilarproduct and the originator product
      • Evaluation of incidence and severity of human immune responses
    • The use of one assay approach
      • Elimination of "between-assay" variability
      • Cut points: one screening and one confirmatory CP
      • Sample analysis: both the biosimilar and the reference product analyzed using the same assay
      • Additional parameters to evaluateto gain confidence that one assay can detect antibodies against both the biosimilar and the originator
      • Understanding how to perform a harmonized antigenic equivalence comparison
      • Positive Control (PC): how to assess the ability of the biosimilar and the originator to bind in a similar manner to the PC
      • Evaluation of drug tolerance in confirmatory assays
    • Case Studies: Lessons learned from recent Biosimilar ADA assay applications, bioanalytical comparability testing, challenges and regulatory feedbacks

 

Part 2: Multi Domain Biotherapeutics & Bispecific Biotherapeutics: Harmonization of Immunogenicity Testing & Reporting
  • Lecture 4
    New Developments in Bispecific monoclonal Antibody (BsmAb) Immunogenicity: Challenges and strategies for harmonizing next-generation of bispecific antibody immunogenicity testing & reporting
    - Dr. Kate Peng, Director Department BioAnalytical Sciences, Genentech
    • Building on recent Industry/Regulators’ recommendation on Bispecific monoclonal Antibody (BsAb) Immunogenicity
    • Value of applying integrated approaches for bsAb immunogenicity assessment
      • Observation of unexpected immunogenicity outcomes during bsAb development
      • BsAb greater risk for immunogenicity
        • More engineering modifications
        • Complexed manufacturing processes
      • Well-established immunogenicity assessment strategy for the conventional monospecific Ab may not be adequate for BsAbs
      • Limitations of available tools for bsAb immunogenicity assessment
    • Considerations on using a combination of tools for BsAb immunogenicity assessment
      • In silico, in vitro and in vivo studies
      • Innovative assay development strategies when comparing BsmAbs to the conventional monospecific antibody therapeutics
    • Current experience in development, submission, review, and approval ofBsAbs
      • Lesson learnt from Regulatory expectations for bispecific
      • Importance of MoA to design the right immunogenicity strategy
    • Case Studies: New immunogenicity findings of a BsAb and how to harmonize the approaches to achieve specific and sensitive ADA assays
  •  

  • Lecture 5
    Development of an Appropriately Designed PK assay to NAb impact on Exposure of Bispecific Drugs - An integrated PK/NAb approach
    - Dr. Gregor Lotz, Group Leader Bioanalytics, Roche
    • Building on recent Industry/Regulators' recommendation on T-Cell Engaging Bispecific Antibodies
    • Use of selected specific ADA PCfor accurate evaluation of ADA
      • Impact on exposure
      • Interference on target-antigen binding
      • Lesson learnt on mosunetuzumab, glofitamab and cevostamab
    • Bioanalytical strategy for bispecific drugs customized depending on
      • MOA
      • Target biology
      • Availability of the critical reagents
      • Positive Control (PC)
    • Novel development of PK assay of a T-Cell Bispecific Drug based on its MoA
      • Advanced structural binding analysis of ADAs to specificbispecific drug sites
      • Assessment of impact on targeting
      • Identification of relevant patient ADA binding features
      • Strategies to select an appropriate anti-idiotypic ADA-positive controls (PC) with similar binding features
      • Innovative approaches for developing assay bispecific drugs binding to two different targets on two different cells simultaneously
    • Case Studies: new data on investigational T-cell engaging bispecific antibodies, development of a novelPK assay to evaluate neutralizing anti-drug-antibody impact on exposure of T-cell bispecific drugs
  •  

  • Lecture 6
    ADA Characterization for Biotherapeutics in Oncology and Ophthalmology: New methods for ADA-specificity and ADA Isotype analysis
    - Dr. Kay-Gunnar Stubenrauch, Head Large Molecule Bioanalytical Sciences 1, Roche
    • Building on recent Industry/Regulators' recommendations on Expectations for ADACharacterization, Specificity and Isotyping
    • Adaption of the Fit-for-Purpose (FFP) and Context of Use (COU) philosophy from Biomarkers to Immunogenicity Testing and new methods for
      • ADA specificity
      • ADA Isotype analysis
    • Complex ADA response induced by Multi Domain Biotherapeutics (MDB)
      • "Unsuitability of classical ADA assays" and new challenges for some MDB to
        • Specify ADAs
        • Identify the immunogenic domains of aMDB
    • Novel methods for ADA characterization to specify immunogenic responses against a MDB
      • Including specific consideration of assay reagents
      • Development of Domain Detection assays (DDA)
      • Domain Competition Assays (DCA)
      • Strategies for assessment of multi-specific ADA responses
    • Characterization ofADA isotypes to elucidate the mechanism of immune responses
      • Isotyping performed using a FFP approach when necessary to answer specific questions
      • When are isotyping or domain-specific assays needed?
    • Case studies: Purpose-driven approaches of extended ADA characterization for Biotherapeutics in Oncology and Ophthalmology with evaluation of domain-specific ADA responses

 

Part 3: Integrated Summary of Immunogenicity Harmonization: US FDA, EU EMA, China NMPA Immunogenicity Guidance/Guideline
  • Lecture 7
    Challenges and Approaches in developing a "living" Integrated Summary of Immunogenicity (ISI) for US FDA & EU EMA submissions: Sanofi's global experience and perspectives
    - Dr. Sue Richards, Presidential Scientific Fellow Translational Medicine and Early Development Sanofi
    • Building on recent Industry/Regulators’ recommendation to develop an Integrated Summary of Immunogenicity (ISI)
    • Best practices for immunogenicity submissions for Integrated Summaries of Immunogenicity
      • ISI as "living" integrated summary document
      • Populating ISI early in product development
      • ISI update as the clinical program progresses through IND stages into BLA and post-approval stages
      • Practical aspects in generating a “living” integrated immunogenicity summary document or folder
      • Using a "folder" approach where relevant information, reports are stored
      • Developed a report template used for all programs
      • ISI Statistical Analysis Plan (SAP) to address what data/analysis populations
    • Industry experience and lessons learnt in submitting ISI to EMA and FDA and reporting
      • ADA Incidence, titer, onset, persistence/transience
      • Neutralizing capacity of detected ADA
      • Impact on drug PK and PD and association with clinical outcome
    • Is an ISI harmonization really needed?
      • Currently no ISI harmonized methodology
      • Use of flexible ISI approach
      • Alignment to product development stage
      • Alignment to product risk profile
      • Considerations around risks to safety, PK, PD and efficacy
    • Case Studies: Lessons learned in developing a "living" Integrated Summary of Immunogenicity (ISI) for US FDA & EU EMA submissions
  •  

  • Lecture 8
    Recent Developments in a PK, PD, ADA Integrated Approach vs. NAb Assay
    - Dr. Anders Holm Millner, Principal Scientist Immunogenicity Assessment, Novo Nordisk
    • Building on recent Industry/Regulators' recommendations on PK, PD, ADA Integrated Approach
    • Importance of using an integrated data approach instead of using in vitro NAb assays for low risk immunogenicity molecules
      • What an appropriate PK assay should be
      • What is required for PD marker or biomarker
      • How these data can be correlated to binding ADA for revealing neutralization
      • When the integrated data approach would be more valuable than in vitro NAb assay
      • Which PK assay format are appropriate to use for both PK and NAb
      • When it is possible to make the same conclusions from this correlation without NAb data
    • Current strategies to identify the neutralizing effect without NAb assays
      • Clinical value of NAb assays for low risk molecules
      • Understanding when in vivo neutralizing activity of ADAs is required
    • Case Studies: Evaluation of PK, PD, ADA data correlation where NAb assays are not needed; PK assay used to monitor the presence of in vivo neutralizing activity and relationship with clinical outcomes
  •  

  • Lecture 9
    Differences between China NMPA Immunogenicity Guideline and US FDA & EU EMA Guidance/Guideline
    - Dr. Tong-Yuan Yang, Senior Scientific Director Biotherapeutics, Janssen
    • The 2021 China NMPA "Technical Guideline for Drug Immunogenicity Study"
      • Structure and Content
      • ADA Assay Method Development and Validation
    • Assessment of validation parameters for non-clinical assays
    • Expectations for in vitro cytokine release tests for non-clinical data package
    • Definition of titer
    • Characterization of ADA responses
      • Isotyping
      • Domain specificity
      • Neutralization activity
    • Neutralization Assay and when Cell-Based Assay are sufficient
    • PK, PD, ADA Integrated Approach vs. NAb Assay
      • PK and PD assays as indicative for the presence of NAbs
    • ADA Assay Precision, Selectivity and Drug Tolerance
    • What about the Integrated Summary of Immunogenicity (ISI)?
    • Case Studies: Possible harmonization of Immunogenicity Guedelines

 

Part 4: ADA Assay Comparability
  • Lecture 10
    Immunogenicity Assay Comparability for Biologics: Current perspectives from CDER Office of Biotechnology Products
    - Dr. JoaoPedras-Vasconcelos, Sr. Staff Fellow Office of Biotechnology Products, US FDA
    • Currently, ADA Assay Comparability is not possible due to differences among the bioanalytical methods used
    • At the 2019 WRIB an approach to attempt the comparability of bioanalytical methods for immunogenicity assessment was proposed for the first time within the global bioanalytical community including
      • How to implement this approach in ADA assay development within same clinical program
      • How to use Bioanalytical method comparability as the first potential step toward the evaluation of clinical immunogenicity comparability within the same program
    • The discussion on ADA Comparability across drug programs continued in 2020-2021 within the Industry. However:
      • No official position or recommendations from Regulators
        • Currently, this is the realm of meta-analysis and needs to interpreted with care
        • Regulators do not recommend it
      • No assay comparability data using platform agnostic methods or covering more than one drug have been submitted to Regulatory Agencies yet
  •  

  • Lecture 11
    ADA Assays Comparability: Importance of & Lot-lot bridging, Sanofi's Experience
    - Dr. Rachel Palmer, Head Biomarkers and Clinical Bioanalysis, Sanofi
    • Considerations on a lack of formal guidance on criteria to demonstrate ADA Assay Comparability
    • Method Transfer
      • What to do when anADA Assay transfers are required during the lifecycle of a program
      • Method transfers to support analysis in difference countries
      • Transition from internal to external labs when all data is needed for the filing
    • Parameters to consider in ADA Assay Comparability
      • Antibody status vs titer match
      • Patient samples with and without antibodies
      • Matrix spiked with PC antibodies
    • Criteria for ADA Assay Comparability
      • Percentage match positive/ negative
      • Percentage of titers must match between +/- 1 titer dilution
    • Current Regulatory Expectations
      • Currently, ADA Assays Comparability can only be done in the same clinical program using bridging studies with blinded positive and negative samples tested in prior assay, and retested in second assay
      • Comparability between different assays within the same program requires bridging studies with retesting positive and negative samples from original study
      • At least 90-95% concurrence in sample testing should be achieved to be able to pool total immunogenicity data across various studies in the clinical program
      • Regulators only accept ADA Assays Comparability within the same clinical program, not across clinical programs with different drugs
    • Case Studies: Illustrate potential approaches for ADA Assay Comparability and Discussion of options if results do not meet Assay Comparability Criteria
  •  

  • Lecture 12
    ADA Assay Comparability: Sharing the Latest Data on the Evolution of the CP-ARC Concept, Roche's Experience
    - Dr. Roland Staack, Head Large Molecule Bioanalytical Sciences 2, Roche
    • Unpublished & Unpresented brand-new data in support of the CP-ARC concept
      • Anti-drug Antibody–Reagent Complexes at Cut-Point
      • Next Step in the controversial discussion on ADA Assay Comparability
      • Moving the CP-ARC concept forward from the initiation phase
      • Working on further aspects to support CP-ARC concept
    • Improving the current situation to enable a better comparability of ADA assays
      • Status of Industry/Regulators scientific discussions sound comparability of the bioanalyticalmethods
      • What if the Assay comparability fails?
    • Regulatory Expectations for Immunogenicity Assay Comparability
      • What is the next stepto achieve the ultimate goal of comparability of the clinical immunogenicity of differentcompounds
    • How to reach a global bioanalytical community consensus at WRIB
      • How the assay performance parameters should be reported for ADA Assay Comparability
        • Sensitivity
        • Drug tolerance
      • Evaluation of avidity binding
    • Case Studies: Novel data and concepts which may change the current way of doing ADA analysis




Agenda at a Glance Agenda at a Glance