Specialized Session F-1 - 8am to 5:30pm, Friday April 13, 2018

"Cut-Points Why, When and How? Current industry standards on Cut-Points and Pre-Existing Antibodies Evaluation"

Work closely with Regulatory Agencies and experts to define how to handle cut-points in complex situations, and pitfalls & challenges in calculation of Screening (SCP) and Confirmatory (CCP) cut-points vs. false positive rates

Outline of Specialized Session F-1

(You can click on each blue topic title below to see details, or simply scroll down to see details)


Session Co-Chair: Dr. Albert Torri, Executive Director Bioanalytical Sciences, Regeneron
Session Co-Chair: Dr. Joe Marini, Scientific Director PK/ADA/PD Bioanalysis, Janssen

Part 1: Issues in Cut Points Determination
Part 2: Issues with Dynamic, NAb, Biosimilars and Outliers Cut Points
Part 3: Pre-Existing Antibodies
Finale: Panel Discusssions with the Regulators


DETAILS of Specialized Session F-1

Session Co-Chair: Dr. Albert Torri, Executive Director Bioanalytical Sciences, Regeneron
Session Co-Chair: Dr. Joe Marini, Scientific Director PK/ADA/PD Bioanalysis, Janssen

Part 1: Issues in Cut Points Determination
  • Lecture 1
    Impact of Positive Control (PC) on Cut Points Determination: Are improved PC representative of patients immune response?
    - Dr. John Smeraglia, Sr Director Bioanalytical Sciences, UCB BioPharma
    • Providing clarity about the importance of PC
      • Impact of PC on determining sensitivity
      • Risk of developing assays with high affinity PC that are not reflective of the patients l immune response
        • Polyclonal
        • Affinity purified polyclonal
        • mAb
      • Risk that greater sensitivity methods are development that not reflective of true immune response
        • Polyclonal immune response
    • Case Studies: Development of improved PC that are representative of patients’ immune response. Actual cases to address this challenge

  • Lecture 2
    Biological Variability and Strategies for Minimum Cut Points Determination: Learning from Actual Case studies
    - Dr. Robert Kubiak, Senior Manager R&D, MedImmune
    • Variability of ADA assays & Biological Variability
      • Lower limit on CP values
    • Applications of minimum CP to differentiate random baseline fluctuations
      • Approaches to achieve the targeted false positive rate
      • Evaluation of several real data of lower CP for risk of more false positives
    • Calculations & considerations based on lesson learnt and actual data
      • Correlation of screening and confirmatory data and CP
    • How to capture the biologic variability when establishing the ADA assay CP?
    • Case Studies: Increase assay sensitivity by using lower CP and risk to identify meaningful ADA positive samples

  • Lecture 3
    Assay-Related Extremely High ADA Titer and Issues with In-Study Cut Points Determination
    - Dr. Rong Zeng, Director, OncoMed
    • Lesson learnt in the interpretation of ADA data
      • Clinical relevance
    • Challenges in Clinical Development of Biotherapeutics
      • Dealing with extremely high ADA titer
    • Sharing observations
      • Follow-up investigations
    • Case Studies: In-study cut point determination in clinical studies, ADA impact on PK and assay-related extreme high ADA titer

  • Lecture 4
    Critical Issues in Cut Points and ADA Assay Validation: Disease populations & patient background responses
    - Dr. Giane Sumner, Director Assay Development, Regeneron
    • Current Industry experiences with CP determination as outlined in the April 2016 FDA draft guidance
      • Complications experienced
      • Working together Industry/Regulators to overcome the difficulties
      • Difficulties with analytical and biological variability
    • CP determination between positive and negative samples for assay validation
      • Interpretation of the validation data and relation to the clinical data
      • Population specific ADA Assay CP
      • Baseline samples evaluation from different clinical studies
      • Appropriateness of the established assay CP in disease population
    • Case Studies: Data from various disease populations and variability in the background response


Part 2: Issues with Dynamic, NAb, Biosimilars and Outliers Cut Points
  • Lecture 5
    Fixed Cut Points vs. Dynamic Cut Points: Is it acceptable to use dynamic cut point for clinical sample analysis?
    - Dr. George Gunn, Head Immunogenicity and Clinical Immunology, GlaxoSmithKline
    • Confirmatory assays are normally evaluated with fixed CP why?
      • Means and Variances same (Fixed CP)
      • Means different, Variances same (Floating CP)
      • Means and Variances different (Dynamic CP)
    • Screening cut-points often set so low that LPC QC cannot be confirmed positive why?
      • Can we use dynamic CP for clinical sample analysis?
      • Can we use dynamic CP if the equal variances test failed using both original and log-transformed normalized data?
    • Pitfalls in CP setting
      • Alternative strategies for setting meaningful CP for assays with very low biological and analytical variability
    • Validation of ADA assays to analyze samples from a clinical study
      • In-study CP determination from pre-dose samples vs validated CP
      • In-study CP statistically compared to the validated CP
      • Data set of validated CP compared to the in-study CP
      • Number of pre-dose samples be used to determine the in-study CP
    • Case Studies: ADA assay in-study CP determination from a clinical study

  • Lecture 6
    NAb Assays Cut Points: Issues & lesson learnt from actual case studies in LBA & Cell-Based Assays (CBA)
    - Dr. Shan Chung, Principal Scientist, Genentech
    • In depth discuss on approaches utilized for NAb assay CP determination
      • Experience with inter-patient variability
      • How to ensure high data integrity during clinical trials
    • NAb assay format
      • Understanding NAb assay design
      • Assay platform selection is based on 2016 & 2017 White Paper Part 3 Recommendations focus on MoA
      • CBA vs LBA for NAb and data comparison
    • Moving from (Cell-based Assays - CBA) to LBA format for NAb
      • Traditional issue with CBA for NAb in providing false data reporting
        • High variability
        • Inadequate CBA controls
        • Issue with performance monitoring
    • Challenges in Developing LBA for NAb
      • Poor drug tolerance
      • Lack of sensitivity
      • Major matrix interference
    • Interpretation of the results and implications for risk assessment
    • Case Studies: Nab assays continue evolution and implementation with focus on CP determination

  • Lecture 7
    Challenges in the determination of Cut Points for Biosimilars: Issues and solution in Comparing Old vs New
    - Dr. Patrick Liu, Vice President Biologics R&D, Teva
    • Choosing the right CP for comparative clinical immunogenicity assessment
      • Critical requirements for biosimilar development
      • Appropriate strategy & approach for CP determination
      • Recent data evaluation and lesson learnt
    • Comparing old biotherapeutic data/CP with new biosimilar data/CP
      • Understanding the ADA assay when testing the Interchangeability
      • Criteria for the development a single ADA assay
      • Regulatory interaction on ADA assay data interpretation based on CP determination
    • Case Studies: Use of a single assay versus multiple assays for ADA assessment for biosimilars and importance of the right CP determination

  • Lecture 8
    Outlier Analysis and Removal for ADA Assay Cut Points
    - Dr. Szilard Kamondi, Bioanalytical Manager, Roche
    • Impact of variability in population
    • Revisit of industry experience in False Positive rate in screening CP and values in confirmation test
    • In depth focus of Screening and Confirmatory ADA Assays evaluation for outlier detection methods for CP determination
      • When should outliers in ADA assay CP be removed?
      • When should CP be re-evaluated?
    • Evaluation of case studies when CP was re-established based on study sample analysis (study-specific CP)
      • Low cut-point estimate
      • When validated CP should be replaced by in-study CP determined from pre-dose samples
      • Statistical test to compare in-study CP with validated CP and Outliers evaluation
    • Case Studies: Discussion on a "new" outlier detection method through case studies that better deals with high sensitivity assays


Part 3: Pre-Existing Antibodies
  • Lecture 9
    Cut point & Pre-Existing Antibodies for Vaccine: Challenges and current industry standards of immunogenicity assays for vaccines
    - Dr. Vibha Jawa, Director Biologics and Vaccine Development, Merck
    • Challenges of immunogenicity assays for vaccines: The wanted immunogenicity”
      • Need for a specific set of specialized assays to demonstrate the immunogenicity of vaccine
      • Developing immunogenicity assays to measure to immune responses that correlate with protection against disease
        • Lack of information on the correlate of protection
        • Difficulty of obtaining reagents and references
        • Lack of validation guidance/guidelines
    • Overcoming the issues of pre-existing Ab to existing vaccines for new vaccines
    • CP for protection
      • CP for vaccines assays: level of immune response at which an individual is likely to be protected
      • Low titer of high-affinity antibodies
      • High titer of low-affinity antibodies
    • Case Studies: Different requirements for clinical vaccine immunogenicity assays. Challenges in validating immunogenicity assays for vaccine and CP determination

  • Lecture 10
    Strategies for Mitigating the Impact of Pre-Existing Antibodies on Cut Points Determination: How to handle pre-existing Ab in a similar class of drug?
    - Dr. Daniel Baltrukonis, Group Leader Large Molecule, Pfizer
    • Impact of pre-existing Ab on ADA assay CP calculations
      • Increased risk of false negative
      • Nature & prevalence
      • Exclusion of data from pre-Ab positive samples to avoid generation of inappropriately high CP
    • No Guidance/Guidelines or recommendation exist on the best approach for an ADA assay CP determination when a high prevalence of pre-existing Abs is observed
    • Challenges with pre-existing Ab
      • When pre-existing Ab are detected how to ensure that post-treatment data can be interpret correctly?
        • What approach is recommended?
      • Considerations on pre-existing Ab in a similar class of drugs
    • CP setting in presence of pre-existing Ab
      • Best approach recommended and preferred by Regulators
    • Case Studies: Approaches used in pre-study to reduce the risk of false-negative responses in-study

  • Lecture 11
    Challenges with Pre-Existing Antibodies in Multi-Domain Biotherapeutics (MDB): Lesson learnt from actual case studies
    - Dr. Seema Kumar, Associate Director, EMD Serono
    • Extra complications with pre-existing Ab in MDB development
      • How to distinguish between pre-existing Ab and different immune responses in MDB
    • Challenges in monitoring multiple pre-existing reactivity against MDB
      • Different approaches for detecting pre-existing reactivity
      • Approaches for ADA assay development for MDB
      • CP calculation and data reporting
        • Complicated process of setting the CP in presence of pre-existing reactivity
        • Handling cases where a large percentage of normal individuals exhibited pre-existing reactivity
    • Case Studies: Recent examples of pre-existing Ab seen in the clinic and their relevance in MDB development


Finale: Panel Discussions with the Regulators
  • Finale:
    Ask the Regulators
    - Dr. Daniela Verthelyi, Chief Immunology Lab, US FDA
    - Dr. Susan Kirshner, Associate Chief Immunology Lab, US FDA
    - Dr. João Pedras-Vasconcelos, Biotech Product Quality & Immunogenicity Reviewer, US FDA
    - Dr. Meenu Wadhwa, Section Leader, UK MHRA-NIBSC
    - Dr. Isabelle Cludts, Biotherapeutics, UK MHRA-NIBSC
    - Dr. Pekka Kurki, Research professor, Finland Fimea
    - Dr. Elana Cherry, Division Chief, Biologics and Genetic Therapies Directorate, Health Canada
    - Dr. Akiko Ishii, Director, Div. Biological Chemistry and Biologicals, Japan MHLW-NIHS
    • Address your questions on Cut-Points and Pre-Existing Antibodies Evaluation and interact directly with US FDA, EU EMA, Health Canada and Japan MHLW
      • Current Regulatory Recommendations on the Setting of the Cut Point









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