Training Session F1 - Friday April 5, 2019, 7am to 5:30pm

"Cut Points – The Evolution: Issues in Statistical Evaluation & current Regulatory Perspectives of Cut Points and impact on Immunogenicity Assay development"

Building on Industry/Regulators’ recommendations & Working together for harmonization

New! Interpretation & Implementation of the 2019 FDA Final Immunogenicity Testing Guidance - Focus on Key Components of "Immunogenicity Testing of Therapeutic Protein Products - Developing and Validating Assays for Anti-Drug Antibody Detection Guidance"

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


Part 1: Setting the Stage in Preparation of Final Recommendations

Part 2: Industry Practical Experience in Cut Points Statistical Evaluation vs Interpretation & Implementation of the 2019 FDA Final Immunogenicity Testing Guidance

Part 3: What’s New and What Make Sense in Cut Point Determination: Are we in agreement with the Interpretation & Implementation of the 2019 FDA Immunogenicity Guidance?

Part 4: 2019 White Paper on Cut Points
  • Consensus and Conclusions on Cut Points

  • Interpretation & Implementation of the 2019 FDA Final Immunogenicity Testing Guidance on Pre-Existing Antibodies, Cut-Point of Screening Assay Cut-Point of Confirmatory Assay, Cut-Point of Neutralization Assay, Cut-Point in the Target Population

Finale: Regulatory Experience and Perspectives


DETAILS of Training Course F-1

Part 1: Setting the Stage in Preparation of Final Recommendations
  • Lesson 1
    Evolution of WRIB Recommendations on Cut Point from 2015 WP to 2018 WP: Where are we now and what next?
    • How the 2015-2018 White Paper in Bioanalysis Recommendations on CP have impacted the current industry practice and regulations
    • Understanding where we started in 2015 and where we are now
      • Progresses based on Industry/Regulators’ experience at WRIB
      • Current Guidance/Guidelines on CP: US FDA & EU EMA
    • Crucial importance of CP to ensure correct interpretation of Immunogenicity Data
      • Lessons learned and clinical considerations – Why we do it?

  • Lesson 2
    Clarification on False Positive/Negative Rate for Screening/Confirmatory Assay Cut Point: Building on 2018 White Paper in Bioanalysis Recommendations
    • Current understanding False Positive and False Negative rates from a tiered assay based on 2018 Recommendations
      • Expected % of false positive in screening assay vs % of false positive in confirmatory assay
      • Industry/Regulators’ expectations in the ability of a confirmatory assay in removing false positives
      • Application of FDA/EMA guidance/guideline for false positive rate in confirmatory assays
    • Use of tighter criteria for False Positive rates and potential risk of increasing False Negative rates
      • Statistical evaluation based on actual case studies
      • % of False Positive rate and its correlations with confirmed positive samples and ADA positive subjects
      • How False Positive rates can impact Clinically Relevance

  • Lesson 3
    Impact of Presence of Pre-Existing Antibodies on Cut Points Determination and Immunogenicity Assessment Strategy
    • Recent approaches in the correct evaluation of pre-existing Ab in drug-naïve matrix
      • Impact on the bioanalytical approach used and data analysis
    • Clinical cases studies on biotherapeutic candidates in development for which pre-existing Ab were detected
      • Identification of pre-existing Ab and impact on normal biological variability
    • Impact of pre-existing Ab on ADA assay CP calculations
      • Strategies for mitigating the Impact of pre-existing Ab
      • Exclusion of data from pre-existing Ab positive samples to avoid generation of inappropriately high CP

  • Lesson 4
    Practical Approaches to Cut Points Setting in Presence of Pre-Existing Antibodies>: What Approach the Regulators Prefer?
    • CP setting in presence of pre-existing Ab
      • Since no Regulatory Guidance/Guidelines exist, what’s the best approach for an ADA assay CP determination when a high prevalence of pre-existing Abs is observed
        • Best approach recommended and preferred by Regulators
      • Importance of pre-study to reduce the risk of False Negative rates in-study
    • Novel clinical case studies on complications with pre-existing Ab
      • Detection of pre-existing Ab and interpretation of post-treatment data
      • How to distinguish between pre-existing Ab and post-treatment immune responses
      • Determination a meaningful drug-induced response
      • Clinical Relevance of pre-existing Ab and impact on PK/PD safety and efficacy
    • How pre-existing Ab can significantly interfere with screening assay CP calculations
      • Increased risk of False Negative rates
      • Consideration on the nature and prevalence of interfering pre-existing Ab


Part 2: Industry Practical Experience in Cut Points Statistical Evaluation
  • Lesson 5
    Issues & Solutions in Cut Points Statistical Evaluation: BMS Experience
    • Evaluation of case studies of in-study CP and combined population CP
      • Neutralizing Ab Assays CP
      • BMS practices in determination of confirmatory CP
    • Statistical strategies for different possible situations and common challenges
      • Data analysis and useful statistical tools
      • Common approaches for the evaluation of various types of CP
        • Important parameters to consider
    • Screening CP vs Confirmatory CP and when samples need to be repeated to confirm them as positive
      • Indication of unsuitable screening assay CP
      • Examples of case by case decisions from BMS

  • Lesson 6
    Issues & Solutions in Cut Points Statistical Evaluation: Genentech Experience
    • Determination of validation and in-study CP from Genentech’s experience
      • Screening, Confirmatory, and Titer CP
      • Impact of different disease population of CP
      • Practical statistical approach for efficient determination for CP
    • When you need to re-examine and re-evaluate CP calculations
      • Issues and bias with screening CP
      • Evaluation of signal above true negative samples
      • Importance to base the final decision on confirmatory CP

  • Lesson 7
    Issues & Solutions in Cut Points Statistical Evaluation: Regeneron Experience
    • Bioanalysts & Biostatisticians’ collaborations on CP determination
      • Lesson learned in working closely with our biostat colleagues
      • Importance of a combination of a strong bioanalytical background and practical statistical experience
    • Fundamental concepts for statistical design for CP determination for a bioanalyst
      • Statistical analyses for a bioanalytical lab in CP determination
      • Practical use Excel for CP determination
    • Case studies
      • What a bioanalyst can do
      • When a biostatistician is needed and when not

  • Lesson 8
    Issues & Solutions in Cut Points Statistical Evaluation: Roche Experience
    • Issue and practical solution in CP determination of immunogenicity screening and confirmatory ADA assays
      • Case study on decision-making process for in-study CP determination
    • Lessons learned by Roche over many years of experience in resolving CP issues
      • Better understanding of statistical support for a reliable CP calculation
      • Statistical resolution of conflicting data
      • Evaluation of % inhibition of the Negative Control in the confirmatory CP determination
    • Thorough evaluation of ADA assay background in CP determination
      • High background and its impact on signal suppression


Part 3: What’s New and What Make Sense in Cut Point Determination
  • Lesson 9
    Developing ADA Assays that Adequately Capture Biological Noise, so that Cut Points Make Clinical Sense
    • Strategies to develop ADA Assays with CP able to address the main challenges in sample analysis, pre-existing antibodies, in-study validation
      • Focus on Clinical Relevance
      • Sensitivity needed to capture biological noise
    • Case studies on determination of CP that make sense
      • What is the best approach to develop them?
      • What are the requirements?
      • Strategies and procedures
    • Ensuring clinical relevance while meeting Regulatory expectations for screening and confirmatory CP
      • Case studies on use of ultrasensitive assay to determine CP and inclusion of subjects with extremely low titers
      • Risk of developing ADA assays with CP that may detect clinically irrelevant signals which may mask more relevant ADA responses
      • Are the more stringent assay requirements resulting in more “unevaluable” results being reported?
      • Does this make Clinical sense?

  • Lesson 10
    Proposal for a New Approach for Cut Point Determination Able to Provide a More Meaningful Clinical & Biological Relevance
    • Sharing Pfizer’s recent evaluations of a novel, simple approach in CP determination
      • Current industry issues with too low CP, increase of ADA positive subjects and Clinical Relevance
      • Statistic impact of outliers removal on
        • Lower CP determination
        • Biological variability
    • Attempting a CP determination by combining Screening and Confirmatory data to identify and remove positive samples due to pre-existing Ab
    • Case studies using the predicted failure rate of the Negative Control and the Low Positive Control, based on method analytical variability, to check the suitability of the determined CP
      • Comparison of this novel CP determination approach with the traditional one and impact on Clinical Relevance


Finale: Regulatory Experience and Perspectives
  • Lesson 11
    FDA Experiences & Perspectives on Issues & Solutions in Cut Points Statistical Evaluation
    • Discussion on common CP issues observed in submitted studies
    • Application on the recent FDA Guidance for CP determination
    • Industry improvements in determining CP for immunogenicity evaluation:
      • Are current methods able to meet regulatory expectations on ADA assay CP?
      • Establishing correct CP able to distinguish ADA positive samples from ADA negative samples
      • Common statistical approaches used by the Industry for CP determination & Regulators’ preference
    • Overall Regulatory perspective on current industry standards in CP determination







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