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Method Validation and Measurement of Biomarkers
in Nonclinical and Clinical Samples in Drug
DevelopmentClosing RemarksAAPS Workshop Salt
Lake City UTOctober 25, 2003Jean W. Lee,
PhDjean.lee_at_mdsps.com
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Biological processes methods
Biomarkers
Method Data Type
Technology
Genotyping
Descriptive, qualitative
Genomics, Microscopy, PCR
Gene Expression
Qualitative to quasi-quantitative
RT-PCR, cytometry
Macromolecule MS, Ligand Binding Assay
Proteins
Quasi- to definitive quantitative
Biometabolites
Quasi- to definitive quantitative
Small mol. LCMS, LBS
Physiological, Imaging
Clinical Markers Endpoints
Descriptive, quan- qual- itative
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Scope of the biomarker workshop
Goal Validate reliable methods for statistical
meaningful data to meet study objectives

• Quantitational methods
• The more mature technologies with definable
  variability accuracy
• Possibility of setting goals on controlled
  quality for method harmonization and data
  comparability

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How are we doing in meeting the objectives of
workshop?

• Clarify nomenclature of biomarkers and overview
  of biomarker application in various clinical drug
  development
• Identify emerging issues related to the
  validation of new biomarker technologies and
  subsequent data analysis and interpretation
• Discuss approaches in analytical validation
  procedures of biomarkers
• Share experience and case studies and
  perspectives in regulatory issues with fellow
  scientists
• Develop potential consensus of biomarkers method
  validation at different development phases.

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Stage-appropriate validation
Progressive Assay Refinement and Validation
Candidate Selection
IND
NDA
Phase IV
CLIA-like?
GLP-like Validation and Assays
Non-GLP GLP-like Method
Validation
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Do we have consensus?

• Stage development objective driven method
  validation
• Prepare validation plan to define goal
• Define Minimum Requirement
• Define risk and tolerance of risk to gain time,
  or other benefits.

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Key Issues

• Understand the objective Primary, secondary
• Communicate with Team in analytical
  requirements to meet objective and shifts in
  objectives
• Timelines do your best
• Sample collection integrity tissues, biological
  fluids and ex vivo stimulation
• Standardize standards
• Standard calibrators matrix and curve fitting
• Assay dynamic range vs. biological range (data
  base?)
• QC matrix, and preparation

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Key Issues

• Develop a method that is validatable
• Statistical assessments method variability vs.
  biological variability, outliers, utilizing CI
• Contributing factors to method varibaility vs.
  biological variability, possible artifacts
• Sample storage Pool of data base of known
  biomarkers?
• Diagnostics kits development and use during
  drug development phase, during postmarket
  approval phase
• Clinical utility value how will the biomarkers
  use benefit the individual patient? What
  assessments will be use to correlate the benefit
  and the risk of drug intervention?

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Follow-up action plan

• Publish a Conference Report within a year.
• Responsibility LBABFG Biomarker Committee
• Draft manuscript on LBABFG Website
• LBAB Focus Group Biomarker Committee White Paper
  within 18 months.
• Responsibility LBABFG Biomarker Committee
• Continue discussions to address the issues with
  regular teleconferences and meetings
• Input from you and networking with
  experts/resources on specific issues
• 2004 Workshop on biomarker clinical validation
  qualification toward surrogate endpoints.
• Responsibility Another committee will be set up
  with other groups such as AAPS Clinical Sciences.

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Thank you!

• All of you
• Kate Wilson
• LBABFG Biomarker Committee
• Planning Committee
• Daisy McCann, Russ Weiner, Jeff Sailstad, Dean
  Knuth, Peter OBrien
• Facilitators
• Bob Millham, Larry Duan, Masood Khan
• Scribes
• Binodh DeSilva, Marie Green, Dean Knuth, Marion
  Kelley, Keith Joho