FDAs ArrayTrack and Pharmacogenomics

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FDAs ArrayTrack and Pharmacogenomics

• Daniel A. Casciano, Ph.D.
• NCTR/FDA

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Critical Path for Medical Products

• FDAs report titled Innovation ? Stagnation in
  2004 addressing the need to improve product
  development.
• http/www.fda.gov/oc/initiatives/criticalpath/
• Explicitly states applying technologies such as
  genomics, proteomics, bioinformatics systems, and
  new imaging technologies to the science of
  medical product developmentprovide tools to
  detect safety problems early, and lead to new
  clinical endpoints.
• Major Opportunity Bridging biomarkers to permit
  monitoring of functional pathways, drug efficacy,
  damage, and damage-response in both preclinical
  and clinical models.

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FDAs Critical Path in Drug Discovery
NDA
IND
LEAD
PRELEAD
g Efficacy in vivo
mg Efficacy HTS
kg TOX
P1
P2
P3
Post Market Safety?
Rapid Tox Screening
Prelinical Safety Biomarkers
Clinical Efficacy and Safety Biomarkers
Preclinical Efficacy Biomarkers
PreLead Prioritization
Adopted from Robertson D. G. Toxicol. Sci. 2005
85 809-822
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The FDA Critical Path to New Medical Products

• Microarray is a key technology in PGx and TGx,
  fields identified as crucial in advancing medical
  product development and personalized medicine
• The regulation of microarray-based medical
  diagnostic devices and the review of microarray
  data submitted as part of an IND or NDA will
  become an essential regulatory responsibility of
  the FDA

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FDA Guidance to Industry Pharmacogenomics data
submission

• Invite industry to submit microarray data on a
  voluntary basis (Voluntary genomics data
  submission, VGDS)
• Gain experience with PGx data in drug development
• Access to emerging PGx data for developing
  scientifically sound regulatory polices
• The guidance is intended to facilitate scientific
  progress in the area of pharmacogenomics.
• Two issues How the data
• should be submitted and analyzed (ArrayTrack)
• will be used in regulatory decision making (QC is
  a concern)

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Review Tool for Pharmacogenomics Data Submission
ArrayTrack
Receive the data support future regulatory policy
Verify the biological interpretation
Analyze the data
Microarray DB
Lib
Tool
Data repository
Analysis
Interpretation
ArrayTrack Components
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MicroarrayDB Storing data associated with a
microarray exp

• Microarray database
• Supports both one- and two-channel data,
  including affy data
• Only the CEL file is required for affy data
• Supports toxicogenomics research by storing tox
  parameters, e.g., dose schedule and treatment,
  sacrifice time, etc
• MIAME supportive to capture key data of a
  microarray experiment
• Will be MAGE-ML compliant to ensure inter-
  exchangeability between ArrayTrack and other
  public databases

Microarray DB
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LIB Component Containing functional
information for microarray data interpretation

• Functional data
• Individual gene analysis
• Pathway-based analysis
• Gene Ontology based analysis
• Links expression data to traditional
  toxicological data

Microarray DB
LIB
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TOOL Component- Containing functionality for
microarray data analysis

• Analysis tools
• Four normalization methods
• Mean/median scaling for affy data
• LOWESS for 2-color array
• Gene selection method
• T-test, permutation t-test,
• Filtering using fold changes, intensity, flag inf
  
• Volcano plot, p-value plot
• Data exploring (e.g., HCA, PCA)
• Many visualization tools (e.g., flexible scatter
  plot, Bar chart viewer,

TOOL
Microarray DB
LIB
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ArrayTrack MicroarrayDB-LIB-TOOL- An integrated
environment for microarray data management,
analysis and interpretation
TOOL
Microarray DB
LIB
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Collaborations
TOOL
CRADA with SAS to integrate ArrayTrack with SAS
Microarray
Microarray DB
LIB
NCTR-NIEHS Partnership for making ArrayTrack and
CEBS fully interoperable
Integration with PathArt and Ingenuity Pathways
Analysis (IPA)
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Future Direction - Toxicoinformatics Integrated
System (TIS)
GeneTools
Microarray DB
ProteinLib
PathwayLib
GeneLib
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ArrayTrack Summary

• An integrated solution for microarray data
  management, analysis and interpretation
• Review tool for FDA pharmacogenomics data
  submission
• Training course is provided to the FDA reviewers
  every two months
• At present, 40 reviewers has been trained
• Freely available to public (http//edkb.fda.gov/we
  bstart/arraytrack)
• Users at big Pharma, academic and government
  institutions U.S., Europe Asia