Specialized Workshop F1Friday October 1, 2021: 8am - 5pm, ET - Lecture List

"Biomarkers Development & Translational Science: Recent Issues from Discovery to Regulatory BAV Guidance"

Part 1: Innovation in Biomarkers Assays Discovery & Development

Part 2: Advancements in Exploratory Biomarkers & Target Engagement (TE) Biomarkers Assays

Part 3: Challenges with Regulatory Biomarker Assay Validation (BAV) as Primary End Points: BMV, CLIA and CDx

Part 4: Ongoing Issues in Biomarker Discovery & Development

Finale: ASK THE REGULATORS!

  • Panel Discussion with Regulators:

    Regulatory Feedbacks on Biomarker Assay Validation (BAV)

    • Dr. Yow-Ming Wang (US FDA CDER)
    • Mr. Abbas Bandukwala (US FDA CDER)
    • Dr. Soma Ghosh (US FDA CDRH)
    • Dr. Kevin Maher (US FDA CDRH)
    • Dr. Shirley Hopper (UK MHRA)
    • Dr. Yoshiro Saito (Japan MHLW)

 

Lecture DETAILS of F1 – Biomarkers Development & Translational Science

Part 1: Innovation in Biomarkers Assays Discovery & Development
  • Lecture 1
    Highly Sensitive Emerging Technologies for Biomarkers: GSK Experience
    - Ms. Mary Birchler, Group Leader Exploratory Biomarkers, GlaxoSmithKline
    • Measurement of Biomarkers various LBA platforms with increased sensitivity compared to standard platforms
      • Comparison of MSD (Industry standard platform) with
        • QuanterixSimoa
        • Protein Simple Ella
      • Importance of using the same reagents for each platform
      • Considerations for providing a more direct comparison among LBA platforms
    • New advanced practical applications of Highly Sensitive technologies
      • Applications for Exploratory Biomarkers vs. Confirmatory Biomarkers for Regulatory submissions
      • Platforms for quantification of protein biomarkers in the sub-picogram range
      • Need of ultrasensitive assays for levels of biomarkers too low to be measured by other sensitive platforms
      • Requirement for just several microliter sera
    • Ultra-sensitive LBA platforms
      • Pros & cons of high sensitive platforms
      • Success & failures through case studies
        • Lesson learned
        • Future developments
        • Implementation in LBA laboratories
    • Case Studies: Addressing reliability and reproductivity challenges with the new emerging high sensitivity platforms for Biomarkers. Comparative sensitivity, precision, and quantitation in human serum samples in LBA
  •  

  • Lecture 2
    Breath Bioanalysis as Non-invasive Matrix for Disease Biomarkers Determination: New Biomarker profiling & Confirmatory technologies
    - Dr. Imelda Schuhmann, Head of Laboratory Biomarker, Novartis
    • Developments in Breath Bionalysis as an encouraging future of non-invasive matrix to analyze biomarkers
      • Exhaled Breath Condensate (EBC) as potential rich source for biomarkers
      • No influence of sample collection on airway function or inflammation
      • EBC Exploratory Biomarkers for respiratory and systemic diseases
      • Current Biomarkers discoveredin EBC
    • Ongoing progresses to standardize breath biomarkers the methods of collection and detection
      • Non-volatile compounds found in EBC
      • Airway Lining Fluid (ALF)
      • Reaction products of volatiles that enter EBC from the gas phase
    • Key aspects to consider for generating reliable biomarker data from Breath Bioanalysis
      • Sample CollectionControl
      • Breath profile
      • Inter- and intra-subject variability
      • Exogenous influence
      • Technical analysis performance
    • How to ensure Reproducibility & Generalizability of the findings
      • Comparing discovery of new biomarkers in EBC
      • Potential comparison between Breath biomarkers and those found in blood and urine
      • How this approach is advancing and how that breath community is exploring breath bioanalysis from different angles
    • Case Studies: Innovative application of breath analysis and consideration on critical aspects, related technical issues including collection, processing and bioanalysis
  •  

  • Lecture 3
    Biomarkers Quantification in Airways Matrix: Innovative method development strategies and fit-for-purpose validation to handle this unusual matrix
    -Dr. Gizette Sperinde, Senior Scientist BioAnalytical Science, Genentech
    • Consideration on quantification of Biomarkers in Airways tissue for inflammatory and respiratory diseases
      • Issues with invasive nature airway tissues sampling
      • Nasal mucosal-lining fluid sample as a surrogate for upper airway activity
      • Importance of detection and quantification of Airways tissues Biomarkers to provide information about asthma and other respiratorydiseases
    • Limitation of existing Commercially Available LBA for Airways tissues Biomarkers
      • Lack of specificity
      • Lack of sensitivity
      • Interferences present in a complex matrix like airways tissue
    • Need for Ultrasensitive & Homebrew LBA to measure specific Airways tissues Biomarkers
      • Detection of low levels of active/specific biomarkers in nasal mucosal-lining fluid samples
      • Method developed
        • Design of Homebrew protocol
        • Custom assay step-by-step development
        • Generation of critical reagents
    • Sample collection & Sample preparation
      • Novel matrices as alternatives: nasosorption and broncosorption as a surrogate for upper airway
      • Evaluations and application of nasosorption devices
      • Standardization of collection protocol to collect Nasal mucosal-lining fluid
      • Absorption and Elution of Nasal mucosal-lining fluid
    • Fit-for-purpose Biomarker Assay Validation (FFP BAV)
      • Evaluation of key assay parameters, standard curve, accuracy, precision, endogenous analyte, reproducibility
      • Consideration to address lack of parallelism in nasal mucosal-lining fluid
      • MRD vs Sensitivity: Risk in compromising assay sensitivity and biomarker detectability
    • Case Studies: Challenges and solutions in the development and FFP BAV of ultrasensitive LBA in complex Airways matrix

 

Part 2: Advancements in Exploratory Biomarkers & Target Engagement (TE) Biomarkers Assays
  • Lecture 4
    Exploratory Biomarker Assays: Back-to-Basic in Bioanalytical Method Development & Validation
    -Dr. Joseph Bower, Senior Vice President, Lab Services,Precision For Medicine
    • Focus onthe high number of Exploratory Biomarkers developed in the Industry vs the fewer biomarkers used for Regulatory Submissions
      • Back-to-Basic in method development strategies for Exploratory Biomarkers
        • Beyond the concept of Context of Use (COU)
    • What do "Context of Use" and "Fit for Purpose" really mean in an actual bioanalytical method development?
      • Since ever…any bioanalytical assay (PK, PD, and ADA) must be designed based on
        • What to measure?
        • Why to measure it?
        • Where to measure?
        • Who need it?
        • How much to measure?
    • Application of the What, Why, Where, Who and How for biomarkers assays development and validation
      • Importance of understanding the biology of the biomarker
      • Importance of acknowledging the limitations of the bioanalytical method
      • Using the most advanced bioanalytical technologies for method development to overcome bioanalytical problems
    • Current lack of industry focus on bioanalytical method development strategies for biomarker assays
      • Lack of guidance on how to approach biomarker assays for internal decision-making
      • Lack of comfort to decide internally what is Fit For Purpose (FFP) or Context Of Use (COU) based on the What, Why, Where, Who and How questions
    • Case Studies: Back-to-Basic in method development of the most common biomarker assays in the industry (Exploratory Biomarkers); Focus on the development of biomarker assays based on their multitude of challenges
  •  

  • Lecture 5
    Tissue-based Target Engagement (TE) & PD Biomarker Assays: Advancements in Longitudinal Biomarker Studies in Primary Tissues
    -Dr. Richard Wnek, Director, Translational Molecular Biomarkers, Merck
    • Focus on Feasibility, Safety, and Adequacy of biopsies/tissue sampling in oncology and/or AID clinical trials to enable TE (PD) measures at drug site of action
      • Current and Emerging Technologies necessary to accommodate biopsies/tissue sampling
    • How sciences evolved from 2017 recommendations on assessment Tissue-based Target Engagement
      • Advanced approaches to measuring Drug-Target Engagement in tissue biopsies
      • Importance of Measuring and quantifying the binding of a drug to a protein target directly inside tissues
      • Considerations to avoid major artificial perturbations of cellular homeostasis and integrity to confirm cellular mechanism-of-action (MoA)
    • Newly developed strategy to measureat the site of action
      • Drug exposure
      • Target engagement
        • Total drug
        • Target concentration
        • Target bound to drug
    • TE/PD Biomarkers assays in Tissues method development challenges and solutions
      • Improving Recovery
      • Ensuring in vivo drug-target association/disassociation
      • QC preparation in tissue homogenate to verify bound target
      • Ensuring Sensitivity & Selectivity
    • Case Studies: Study rationale, clinical case studies and drug development decisions impacted.Assay format design, method development strategies and current industry best practice for Biomarker Studies in Primary Tissues
  •  

  • Lecture 6
    Recent Developments in Target Engagement (TE) Assays at GSK
    - Dr. Michael Naughton, Investigator, Senior Analyst Exploratory Biomarkers, GlaxoSmithKline
    • Strategies for the Development & Validation of TE assays to support PK/PD study progression
      • Ongoing increased request of TE assays by clinical teams
      • Concentration time profile of the total target concentration
      • Importance of interaction of the drug with the endogenous target for decision-making
      • Challenges with TE assayfor soluble target
      • Assay to detect the free portion of the soluble target
        • Free assays
        • Bound assays
        • Direct assessment of total assay
      • Evaluation of competitivity
    • Data analysis and interpretation
      • KD value of the interaction partners
      • Complex stability
      • Impact of sample manipulation
      • Effect of dilutions in the increase in free target concentration
      • Risk for erroneous Targe Engagement underestimation
    • Validation approaches
      • Consideration for each component measured
      • Pass/fail criteria for the PK/PD assessment
    • Case Studies: Updated TE assay strategies to verify the correct selection of the assay-platform, reagents and conditions

 

Part 3: Challenges with Regulatory Biomarker Assay Validation (BAV) as Primary End Points: BMV, CLIA and CDx
  • Lecture 7
    Biomarker Development using Mass Spectrometry: Current Challenges with Regulatory Biomarker Assay Validation (BAV) as PD Endpoints to Support Clinical Development - Bioanalytical Lab/BMV or Certified Clinical Lab/CLIA?
    -Dr. Omar Mabrouk, Principal Scientist Biomarkers, Biogen
    • Real cases to better understand when Clinical Biomarker Assay should be performed in a certified clinical lab or bioanalytical labs
      • PD Endpoints to Support Clinical Development
        • Protein Biomarkers by IP-LCMS as very important surrogate endpoints for disease diagnosis, progression, and prognosis
      • Biomarker assay for patient selection/stratification in Drug Development Clinical
    • Updated considerations on newly developed biomarker assays performed in a bioanalytical lab in support of clinical trials
      • Experience from small molecules biomarkers development and validation
      • Present challenges when deciding whichregulations to apply to a biomarker assays study
      • Clinical Biomarker assays not intended for individual patient treatment/medical decisions
    • Case Studies: Lesson Learned will be discussed based on novel data on BAV with main focus on Parkinson's disease biomarkers assays by IP-LCMS to assess pharmacodynamic endpoints to support clinical development
  •  

  • Lecture 8
    Characterizing the Expression Levels of Specific Proteomic Biomarkers Mechanism Based by Mass Spec: From Proteomic Screen to CLIA Assay Development and Validation
    - Dr. Mike Baratta, Scientific Director/Chief of Staff, Clinical Biomarker Development Innovation and Development, Takeda
    • Effort to develop a Bioanalytical strategy for Proteomic Biomarkers by Mass Spec
      • Complete proteomic screening
      • Target Discovery
      • Clinical endpoints predictive screening value definition
      • Development challenges and clinical sample assessment
      • Biomarker Assay Validation (BAV) under CLIA
    • Personalized medicine approach for oncology compounds with a strong focus on
      • Characterization of expression levels of specific Proteomic Biomarkers
      • Effort to correlate exposure levels with predefined clinical endpoints
      • Support to clinical trials, and potentially a CDx
    • Quantitation of the most Mass Spec responsive peptide sequences for each protein
      • Maximize adequate signal to noise in patient predose serum samples
      • Analysis of the signature peptide in serum
      • Identification of the specific peptide of interest and the systematic approach
    • Case Studies: Development and validation under CLIA of a Mass Spec assay to quantitate expression levels of four target-based proteins
  •  

  • Lecture 9
    Alnylam Experience with Biomarker Assay Validation (BAV) by Mass Spec as Primary Efficacy End Points: How to bring a biomarker assay to the rigor to meet its specific use
    - Dr. Valerie Clausen, Associate Director Bioanalytical Sciences, Alnylam
    • Biomarkers Assay Evolution
      • Understanding the whole translational medicine process and different regulatory requirements
      • Discovery/Exploratory Biomarkers vs Biomarkers used for Regulatory Submission
        • What are the important features that distinguish the method validation/qualification?
        • BAV for CLIA assay, if used for a primary endpoint biomarker?
    • Challenges in using two assays for the same biomarker within one study
      • Primary endpoint analysis vs. CLIA/patient treatment decisions
      • How to run a cross-comparison?
    • How to proceed in the conversion of a biomarker assay developed for Drug Development to meet the requirement for Clinical Trials Primary Efficacy End Points
      • What are the regulatory requirements?
      • What is the additional work needed for this conversion?
      • How to progress a discovery/exploratory biomarker into a prognostic/diagnostic biomarker
      • How to handle the transfer/refinement/validation of methods from discovery into clinicalPrimary Efficacy End Points
    • Case Studies: Understanding the challenges in the development, validation and use of biomarker assays by Mass Spec from exploratory space to the regulatory space
  •  

  • Lecture 10
    Clinical Flow Cytometry Biomarkers Development, Validation and Data Interpretation: Current Scientific & Regulatory Challenges
    - Dr. Erin Stevens, Associate Research Fellow / Lab Head - Early Clinical Development, Pfizer
    • Current regulatory environment for Clinical Flow Cytometry Biomarkers
      • Considerations for assay development,validation and clinical sample analysis
      • Importance of closely monitoring flow cytometry data and performance
      • How to ensure quality of data by ensuring assay robustness and reproducibility
      • Data interpretation for flow cytometry data from patient samples
    • BAV parameters for Clinical Flow Cytometry
      • Typical validation procedure
      • Immunophenotyping Assays
      • Receptor Occupancy (RO) Assays
      • Pharmacodynamic (PD) Assays
    • Application of Flow Cytometry from Exploratory Biomarkers to Biomarkers for Regulatory Submissions
      • Flow Cytometry current standards in the Bioanalytical Lab
      • Flow Cytometry Biomarkers Assays to demonstrated clinical primary endpoints
      • Application of a robust FFP Validation protocol for Flow Cytometry assay to support clinical efficacy
    • Case Studies: Flow Cytometry Biomarkers Assay development, validation and clinical sample analysis in support of clinical studies
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  • Lecture 11
    When to start turning a Biomarker Assay into a Companion Diagnostics (CDx)
    - Dr. Flora Berisha, Scientific Director Strategic Oncology Diagnostics, Janssen
    • Considerations on the various frameworks for Biomarker and CDx assay development
      • What quality systems to use for biomarkers path forward for each stage of development of a CDx
      • Strategies to develop biomarkers able to be converted into novel CDx
      • Evaluation of the most suitable technologies for CDx assays
      • Development of Biomarkers asCDx as part of the regulatory strategies
      • Importance of Biomarkers/CDx used for patient selection/stratification
    • Biomarker selection and translation into CDx candidates
      • CDx strategies for next generation implementation
      • Development of multiplex platforms for CDx
    • Case Studies: Biomarkers assays asCDx development and conversionfor Precision Medicine and Clinical Development
  •  

  • Lecture 12
    Considerations for Quality Oversight of CLIA Laboratory Testing for Companion Diagnostic (CDx) Tests for Routine Patient Care
    - Dr. Kistina McGuire, Senior Director, Precision Medicine Companion Diagnostics and Biomarker Operations, Regeneron
    • Companion Diagnostic Testing
      • Requirement for significant quality systems to ensure clinical success,
      • Premarket Approval (PMA) by Regulatory Authorities for concurrent drug and diagnostic approval
    • Post marketing surveillance
      • Following drug/diagnostic approval routine testing for patient care is often not utilizing the same test or test system
      • Patient testing may not adhere to the same quality standards
      • Leaving question as to the validity of their test result and therapy designation
    • CAP/CLIA does not require an approved CDx to be used for patient testing
      • Clinical laboratories face cost pressures that may drive them to implement LDT assays over an approved CDx
    • A thorough review of the CDx approval process and/or clinical laboratory testing should be conducted to ensure patient testing has adequate quality oversight to protect patient therapy decisions
      • Understanding the validation requirements for CDx assays
      • Critical considerations for CDx development
      • Different requirements for CDx sample analysis
    • Case Studies: Commercial testing in CLIA labs and the lack of regulatory oversight to ensure the approved CDx is used to prescribe

 

Part 4: Ongoing Issues in Biomarker Discovery & Development
  • Lecture 13
    Assessing Parallelism for Biomarkers Assays "When Lack of Parallelism is Expected"
    - Dr. Yan Zhang, Scientific Senior Director, Translational Sciences, Bristol-Myers Squibb
    • Consideration on specific problematic parallelism evaluations for biomarker assays
      • Parallelism test failure
      • Expected lack of parallelism
      • Impossibility to assess parallelism
      • Is it possible to justify Lack of Parallelism for Biomarker assays use for Regulatory submission?
    • Approaches to ensure reliable data in absence of parallelism
      • Method development strategies to improve assay performance & confidence
      • Parallelism impact on MRD and sensitivity
      • Balance among Parallelism, MRD and need for high/ultrasensitive biomarker assays
      • Issues around sensitivity when developing and validating biomarker assays
      • Understand the expectations and limitation in defining the biomarker assay MRD
    • Case Studies: What to do if parallelism fails or cannot be assessed? How to create confidence in you assay without parallelism?
  •  

  • Lecture 14
    Challenges in Sample collection for PD Biomarkers involving Functional Assays in Multicenter Clinical Trials
    - Mr. José Duarte, Scientist Clinical Protein Biomarker Development, Roche
    • Challenges and solutions to reliably collect sample forPD biomarkers assay used in multicenter clinical trials
      • Pre-determined acceptance criteria for healthy and disease population
      • Minimum sample receipt time
      • Maximum sample stability time point
      • Impact on Reproducibility, Required specificity, sensitivity and assay robustness
    • Importance of how the samples are handled to ensure that the quality of samples is maintained
      • Challenges associated with sample collection in multicenter, longitudinal clinical trials
      • Issues with limited sample stability
    • Is it possible to avoid the requirement for sample analysis at a local facility?
      • Current industry best practice for the use of special procedures at clinical sites to freeze the blood
      • Strategies for specific cellular controls, preserved controls for qualified cells and other major cell types
    • Case Studies: Lesson learned on impact of sample collection on biomarker assays from multicenter clinical trials




Agenda at a Glance Agenda at a Glance