Specialized Workshop M2Monday September 27, 2021: 8am - 5pm, ET - Lecture List

"BMV Guidance Day: Recent Issues in Bioanalytical Method Validation Guidance/Guidelines and Regulated Bioanalysis for Small and Large Molecules"

Part 1: Current Regulatory Standards in Bioanalysis

Part 2: Regulations & Science Evolution to Solve Bioanalytical Issue

Part 3: Regulated Bioanalysis of Complex PK Assays

Part 4: Evolving Regulated Bioanalysis Standards

Part 5: Patient-centric Approaches in Regulated Bioanalysis

Part 6: Recent Regulatory Findings

  • Lecture 11A:

    Bioanalytical Regulatory Requirements for Different Biological Matrices
    -Dr. Diaa Shakleya, US FDA

  • Lecture 11B:

    UK MHRA Bioanalytical Observations and Findings
    -Mr. Stephen Vinter, UK MHRA

  • Lecture 11C:

    Recent LBA PK Findings
    -Dr. Mohsen Rajabiabhari, US FDA

  • Lecture 11D:

    Regulatory findings & Observations
    -Drs. Jan Welink, EU EMA


  • Panel Discussion with Regulators:

    Regulators Panel Discussion for Chromatographic and Ligand Bindng Assays

    • Dr. Seongeun Julia Cho (US FDA)
    • Dr. Arindam Dasgupta (US FDA)
    • Dr. Sam Haidar (US FDA - invited)
    • Dr. Mohsen Rajabiabhari (US FDA)
    • Dr. Nilufer Tampal (US FDA)
    • Dr. Diaa Shakleya (US FDA)
    • Dr. Jinhui Zhang (US FDA)
    • Drs. Jan Welink (EU EMA)
    • Mr. Stephen Vinter (UK MHRA)
    • Mr. Michael McGuiness (UK MHRA)
    • Dr. Sandra Prior (UK MHRA)
    • Dr. Anna Edmison (Health Canada)
    • Dr. Catherine Soo (Health Canada)
    • Mr. Gustavo Santos (Brazil ANVISA)
    • Dr. Elham Kossary (WHO)


Lecture DETAILS of M2 – BMV Guidance Day

Part 1: Current Regulatory Standards in Bioanalysis
  • Lecture 1
    Current Industry/Regulatory Standards to Perform Bioanalysis in China
    - Dr. Eric Woolf, Executive Director Regulated PK Bioanalytics Group, Merck
    • Regulatory agencies involved with Bioanalysis in China
      • CFDA - China Food and Drug Administration
      • NMPA -National Medical Products Administration
      • HGRAC - Human Genetic Resources Administration of China
      • CIQ -China Inspection and Quarantine
    • Main guidelines for Regulated Bioanalysis in China:
      • CFDA Guidelines for Clinical Trial Bioanalytical Laboratory
      • China Pharmacopeia 2015, Guidance for Bioanalytical Method Validation
      • CFDA Main Consideration Points for Clinical Data On-Site Verification
    • Direct feedback about issues experienced with bioanalyses to support clinical trials carried out in China
      • Import/Export of samples from China and HGRAC interactions
        • Reagents import challenges
      • Audit experiences
      • Best Industry practices to work with Chinese CRO
    • Strategies to support Global Studies that include China in light of HGRAC and CIQ requirements
      • Implications of secondary versus exploratory end points PK Assays ADA Assay
    • Importance to ensure Consistent Data Generation for Global Studies that utilize multiple Bioanalytical labs
      • How to perform Cross Validation in a global study
    • China as second biggest pharmaceutical market in the world
      • Important CFDA approvals
      • Bristol Myers Squibb OPDIVOR – China’s first cancer immunotherapy
      • Merck KEYTRUDAR for treatment of melanoma
    • Case Studies: Challenges with implementation of bioanalytical LCMS assay and LBA in China; Current issues impacting bioanalytical support for studies conducted inChina

  • Lecture 2
    How Bioanalytical laboratories deal with GLP, GCP and GCLP recommendations/framework nowadays: Sanofi's perspective
    - Dr. Kathrin Heermeier, Head of Biomarkers & Clinical Bioanalyses Germany, Sanofi
    • Differences between GLP and GCLP in the lab
      • Level of detail in the guidance documents
      • GLP governs international laboratory quality systems for pre-clinical testing
      • GCP alone does not define laboratory bioanalysis requirements
      • EU EMA reflectionpaper provides recommendations for quality systems that encompasses GCP but with elements applicable to laboratory analysis
        • Handling unexpected results; Patient ICF status; Communication members of clinical trial team; Subject confidentiality; Blinded/unblinded sample analysis
    • GCLP are similar GLP but with additional discussions related to ethical principles and patient safety
      • GCLP proposed in2003 and adopted by the WHO
      • GCLP are applicable internationally
      • GCLP are not part of testing regulations in the US or Europe
    • Case Studies: Increased outsourcing of GLP work to CROs and possible consequences for internal bioanalytical labs in pharma companies


Part 2: Regulations & Science Evolution to Solve Bioanalytical Issue
  • Lecture 3
    Challenges when Changing Assay Platform (LBA to LCMS): a case story
    - Mr. Sune Hove Sporring, Manager LCMS Group Development Bioanalysis, Novo Nordisk
    • Strategies to change the platform in Regulated Bioanalysis
      • LBA used in Bioanalysis in GLP tox studies
      • LBA used in Bioanalysis in Clinical single dose and multiple dose
      • Need to develop a LCMS method for combination project
        • Co-dosed with a compound that cross-reacts with original LBA
      • LCMS method used for all combination project pre-clinical & clinical
    • Comparison and Cross-validation LBA and LCMS
      • Lesson learned form 2014 & 2015 White Paper Recommendations
      • Confirm that both technologies measure the same analyte
      • Both QC samples and incurred samples should be used
      • Acceptance criteria: two-thirds of sample results within 30%
      • If a Hybrid Assay is used, it is recommended to use the same capture reagent of LBA
    • Step-by-step Bioanalytical Investigation
      • What to do if spike QC are comparable but not Incurred Samples?
      • Time dependent difference in the results
      • Why are LCMS results lower than LBA?
      • Considerations of LCMS higher specificity vs LBA
    • Case Studies: Cross-validation experience in the development of a ~5kD peptide by both LBA and LCMS

  • Lecture 4
    Current Challenges for Support of Oncology Drug Development: Bioanalytical Complexity of Polypharmacy and Combination Therapies in Oncology
    - Dr. Chris James, Director Bioanalytical, Amgen
    • Increasing Challenges for Bioanalysis in Oncology Drug Development
      • Oncology Represents approximately 35% of all R&D efforts
      • Increasing development of biologics and other novel drug entities
      • Combinations of immuno-modulatory, targeted therapies and cytotoxics
      • Extensive use of supportive and prophylactic treatments in oncology patients leading to complex polypharmacy
      • Novel clinical study designs and testing of multiple combinations therapies
    • Challenges for Bioanalytical method development for novel drug entities and to access methods for competitor’s molecules
      • Need to test Co-med selectivity and potentially Co-med stability
        • First discussed at WRIB in 2010 since Regulatory Agencies began questioning the stability of samples containing co-administered compounds
        • No examples found so far (2010-2019 WRIB) where analyte stability was affected by co-administered compounds
        • Scientific rationale for such stability assessment requirements was again questioned at 2019 WRIB during ICH M10 discussion
      • Current Regulatory Guidance/Guidelines still include the conduct of stability experiments for
        • FDC (fixed dose combination)
        • Co-med regularly administered to patients
    • Case Studies: Performing co-med stability as part of many bioanalytical challenges for Polypharmacy and Combination Therapies in Oncology


Part 3: Regulated Bioanalysis of Complex PK Assays
  • Lecture 5
    Challenges Developing & Validation Free/Total PK Assays in Regulated Bioanalysis: Pfizer experience
    - Dr. John Kamerud, Director Bioanalytical, Pfizer
    • Free or Total Regulatory Expectations vs. what is most relevant?
      • Evolving science for Free & Total PK Assays
      • Free biotherapeutic,Free Target ligand
      • Bound: Mono- and/or bivalent complexes biotherapeutic/ligand
    • Assay Formats for Free or Total PK Assays
      • Importance of developing the right LBA critical reagents
      • Bestassay format designto measure free/total
    • Modeling to predict proportion of free vs total drug
    • Impact of assay artifacts on free/total
      • Complexity of the dynamic binding equilibrium in vivo
      • Controlling multiple sources of perturbation
      • Strategies for reliable ex vivo quantification
    • Case Studies: Learning from advanced & well-established experience on Free & Total PK Assays Method Development and Validation

  • Lecture 6
    Recent Bioanalytical Challenges Associated with MDB PK Assays & BMV Guidance
    - Dr. Seema Kumar, Director & Head of Clinical Bioanalytical Sciences, EMD Serono
    • Focus on bioanalytical challenges associated with MDB PK assays
      • Drug development stage appropriate PK assays for MDB development
      • Importance of MoA to design the right bioanalytical strategy
      • Importance of high-quality critical reagents against complex domains for achieving the specificity & sensitivity needed
        • Unconventional critical reagent generation strategies for complex MDBs.
    • MDB Bioanalytical Method Validation
      • Shed/circulating Target Tolerance
      • Monomer vs multimer Target Interference
      • Reagent stability
      • Assay trending
      • Assay ID update on major vs minor changes to the validated assay
    • Impact of in vivo biotransformation on PK
      • Structural instability of MDB
    • Ultra-sensitive Bioanalytical platform to achieve desired
      • Sensitivity
      • Target tolerance for PK assay of complex MDBs
    • Case Studies: PK Assays development and validation for of MDB in non-clinical and clinical development


Part 4: Evolving Regulated Bioanalysis Standards
  • Lecture 7
    Importance of Incurred Sample Stability (ISS) in Regulated Bioanalysis: Strategies & Investigations and Lesson Learned
    - Dr. Katty Wan, Director, Small Molecule Group Lead Clinical Assay Group, Pfizer
    • Incurred Sample Stability (ISS) although closely linked to ISR, is currently not a Regulatory Requirement
      • How incurred sample instabilities are found?
        • Mostly through ISR failures
        • Some through inconsistent results from repeats
    • Why Investigate ISS?
      • Can become a Regulatory Requirement in some cases?
        • "ISS evaluations should be performed when ISS investigations are required"
        • "unique cases where problems with ISS persist additional ISS/stability evaluations may be justified"
      • Scientific Reasons: Stability of the analyte in the matrix may not be completely predicted with the QC samples
      • Operational Reasons: Sample collection or processing did not follow the prescribed conditions
    • ISS Strategy
      • During Method Development
        • ISS may be predictable based on metabolism, biology or chemistry
        • Stabilization strategy should be evaluated during MD
        • Effectiveness monitoring should be conducted during sample analysis by evaluating ISR and ISS
      • During Sample Analysis
        • Unacceptable ISR or inconsistent results from repeats may trigger ISS investigations
        • Document the plan for investigation
        • Based on investigational outcome, perform impact assessment or justify the actions taken
    • Case Studies: Investigation procedures using non-pooled subject samples to avoid “dilution effect” of the “problematic samples”; incurred sample LTS evaluation; use of ISS to set boundary for sample analysis

  • Lecture 8
    Application of the ICH M10 Section 7.1: Endogenous Compounds Quantification by Mass Spec when Authentic Biological Matrix contains High Endogenous Level
    - Dr. Allena Ji, Director Clinical Mass Spectrometry Laboratory Biomarkers and Clinical Bioanalyses, Sanofi
    • Similarities & Differences between
      • Endogenous Compounds PK Assay and
      • Biomarker Assays
    • Authentic Matrix Selection and ICH M10 Draft Guidelines
      • ICH M10 Section 7.1 Analytes that are also Endogenous Compounds
        • 7.1.1 Quality Control Samples; 7.1.2 Calibration Standards; 7.1.3 Selectivity, Recovery and Matrix Effects; 7.1.4 Parallelism; 7.1.5 Accuracy and Precision; 7.1.6 Stability
    • How to select Authentic matrix for Endogenous Compounds Assays
      • What common criteria are usedto succeed in determining the assay LLOQ
      • What are common troubles and how to solve them
      • How to obtain mean endogenous level of the authentic matrix used for STDS/QCs preparation
      • Issues with high endogenous level in the authentic matrix used for preparation of calibrators
      • Need screen numerous (15+) blank matrix lots to estimate the range of endogenous analyte level using the Standard Addition approach in a surrogate matrix
    • Strategies for selection of authentic matrix lots
      • Importance to select low endogenous levels with the ratio of endogenous level to desired LLOQ is ≤ 4
        • The smaller of the ratio, the better to achieve desired LLOQ
      • What to do if the above criterium is not met?
        • Should the LLOQ be adjusted to a higher level which still Fit-For-Purpose (FFP) of intended study use?
        • What if the adjusted LLOQ in authentic matrix is not suitable for use?
        • If authentic matrix and surrogate matrix do not meet the criteria for FFP Validation, can the diluted authentic matrix with a surrogate matrix serve as a desired matrix for STD curve?
    • How to use Watson LIMS to calculate endogenous compounds concentration
      • What are the procedures?
      • How are the results correlate to the those from excel calculation?
      • How to arrange Blank 0 and Blank 00 samples in a batch in order to determine the Endogenous Level in the STDs and QCs
    • Case Studies: Using ICH M10 Section 7.1 draft Guideline for Endogenous Compoundsquantification


Part 5: Patient-centric Approaches in Regulated Bioanalysis
  • Lecture 9
    The role of Regulated Bioanalysis in Patient-centric Approaches
    - Dr. Daniela Fraier, Head of Small Molecules Regulatory Bioanalysis, Roche
    • Role of Bioanalysis in patient-centric approaches
      • What is the impact on traditional bioanalysis when sample collection is not done in a "controlled" clinical environment
      • Bioanalytical Support of patient-centric dosing
    • Additional validations needed
      • Ensuring drug stability
      • Challenges with the handling of unstable analytes
    • Case Studies: Bioanalytical support of Patient Centric Sampling in a Regulated Environment

  • Lecture 10
    Challenges in BMV of a PK assay on a Point of Care (POC) Devices/Technologies for drug monitoring and dose adjustments: Next generation Bioanalytics and impact on drug discovery/development (POC/microsampling)
    - Dr. Sally Fischer, Senior Director BioAnalytical Sciences, Genentech
    • POC and Microsampling Technologies as tools for drug development
      • Ability to provide fast turnaround times
      • Ability to generate data comparable to Lab-based bioanalytical assays
      • Not a Diagnostic (Dx) tools but drug development tools
    • Application of POC Technologies for
      • Enrollment and stratification for acute diseases
        • Acute Respiratory Distress Syndrome(ARDS)
        • Sepsis
      • Mitigation and management of Adverse Events (AE) such as Cytokine Release Syndrome (CRS)
      • Therapeutic drug monitoring and dose adjustment
    • Current POC and Microsampling available technologies
      • Sampling & testing for neonates and pediatrics
      • Improve patient convenience and clinical participation through at home sampling
      • Advance diversity and inclusion of underrepresented populations
    • Case Studies: POC technologies vs traditional lab-based bioanalysis; different collection methods and results comparison; Challenges of implementation and consideration for use.

Agenda at a Glance Agenda at a Glance