"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Prescription Drug Labeling new FDA Draft Guidance; Harmonization of Regulations; Enhanced Tiered / Cut Points Approaches; Clinical Relevance, Preclinical & Clinical Assessment; Risk-based Approaches,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 9
-
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
-
Current understanding on Immunogenicity and how often is this a “Risk”
-
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
-
In silico & in vitro methods to assess and refine immunogenicity risk for biosimilar
-
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
-
Importance of Measuring stimulation-induced proliferation
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
-
Understanding the relevance of Immunogenicity in 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
-
Considerations on the Standard Immunogenicity Tiered Testing Strategy
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
-
New data & further experience in using an integrated data approach instead of using NAb assays
-
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
-
Current industry experience in Domain Mapping ADA characterization
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 9
- 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
-
The new US FDA draft 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
- Already marketed products
- Case Studies: Immunogenicity labeling from a range of products and experience in immunogenicity label negotiations with FDA
-
Previous/Current Inconsistent and highly variable reporting of Immunogenicity information/data on product labels
-
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
-
In February 2022 FDA issued a draft guidance on immunogenicity information in labeling therapeutic proteins