The Impact of the VGDS voluntary genomic data submission process at the FDA' A tool for enabling cha

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The Impact of the VGDS (voluntary genomic data
submission) process at the FDA. A tool for
enabling change in non-clinical and clinical drug
development processes.

• Panel A- The Promise of the Post-Genomic Era
  The Development of Personalized Medicine
• May 4, 2006
• Michael Orr, Ph.D., DABT
• Office of Clinical Pharmacology, Genomics
• Center for Drug Evaluation and ResearchU.S. Food
  and Drug Administration

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Disclaimer

• The views expressed in this presentation are the
  ones of the author and may not necessarily
  reflect the position of the U.S. Food and Drug
  Administration.

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Outline

• VGDS (voluntary genomic data submission) program
  at the FDA
• PTSC (Predictive Safety Testing Consortium), a
  novel process for improving safety testing at
  C-Path
• NSAID (Non-steroidal anti-inflammatory drugs)
  chemoprevention, and personalized medicine

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Reasons for VGDS Submissions

• Science
• Discuss use of genomics in drug development
  program without regulatory decision making
• Data and tools to generate and analyze data are
  discussed
• Ask what if questions
• Can be unrelated to drug, e.g. development of
  registries
• Regulation
• Helps sponsor to be prepared
• Know answers to what if questions
• Learn about possible regulatory impact of use of
  genomic data set
• IPRG does NOT provide regulatory guidance

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VGDS Value and Benefits

• Sponsor
• Opportunity to have informal, scientific meeting
  with FDA PG experts
• Eliminate uncertainty about PG data submissions
  and review at FDA
• Strategic use of VGDS
• Receive and benefit from informal peer-review
  feedback on PG issues and/or questions
• Gain insight into current FDA thinking about PG
• May avoid future delays in review
• FDA
• Familiarize with PG experiments, data analysis
  and interpretation approaches
• Education
• Ensure data driven development of new policies
  and guidances
• Build consensus around PG standards
• Both
• New strategies for using PG in drug development
• Learn about benefits and limitations
• Discuss analysis approaches

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Update VGDS Program So Far

• VGDS statistics
• 25 submissions received
• 15 sponsor meetings held (2 bilateral with EMEA)
• 5 submissions informed to be submitted
• Impact
• Overall feedback 4.5 out of 5 (formal survey)
• Multiple submissions from single sponsor
• Follow-on submissions
• Great interest in bilateral meetings

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Development of Biomarkers for Clinical Use
(Drug-Test Co-Development)
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VGDS Submission Types

• Therapeutic Areas
• Cancer (multiple types)
• Alzheimer's Disease
• Hypertension
• Diabetes
• Depression
• Obesity
• Rheumatoid Arthritis

• Scientific and PGx Areas
• Biomarkers
• Genotyping Devices
• Microarrays
• 2D Gels
• NMR
• Analysis Software
• Databases
• Biostatistics
• Enrichment design
• Registry design
• Toxicology

Data based on 25 submissions
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VGDS Lessons Learned

• Meeting Preparation
• Early communication
• Evaluation of sponsor questions
• Data Submission
• Need for standards (e.g. HL7, CDISC, others)
• Dedicated server, access rights for IPRG
  (intranet)
• Regulatory and Policy Impact
• Innovative trial designs (e.g. enrichment
  strategies)
• Involvement of Clinical Review Divisions
• Drug-Test Co-development

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VGDS Lessons Learned, contd

• Data Review
• Most data/information is VERY exploratory
• Whole genome scans (SNPs and gene expression)
• Statistical considerations
• Biological interpretation, e.g. pathway analysis
• More thorough data analysis is valued by
  sponsors sponsor and FDA present results
• Education
• Creation of FDA/CDER course on pharmacogenomics
• Rotations in Genomics Group to expose reviewers
  to genomic data sets (new candidates always
  welcome!)
• Other
• Sponsors appreciate opportunity for open,
  informal data exchange and discussion
• Biomarker validation critical

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VGDS Impact

• Developing VGDS Best Practices document based
  on VGDS submissions to the Agency
• MAQC (Microarray Quality Control Project)
• provide quality control tools to the microarray
  community to avoid procedural failures
• develop guidelines for microarray data analysis
• reference datasets and reference RNA samples
• Critical need for biomarker validation
• PTSC (Predictive Safety Testing Consortium)
  moving forward with safety biomarker validation
  (Critical Path Institute)
• Developed proposed process map for validation of
  genomic biomarkers of preclinical drug safety
• Developing IT infrastructure to handle -omic
  data
• Statistics Task Force being created

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Outline

• VGDS (voluntary genomic data submission) program
  at the FDA
• PTSC (Predictive Safety Testing Consortium), a
  novel process for improving safety testing at
  C-Path
• NSAIDs, chemoprevention, and personalized
  medicine

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New Press Release from the FDA

• Press Release March 16, 2006
• Critical Path Opportunities Report
• Critical Path Opportunities List 76
  Opportunities
• Ex. Topic 1 Better Evaluation
• 1. Biomarker qualification and standards
• Standards for microarray and proteomics-Based
  identification of biomarkers
• Role of beta-adrenergic receptors polymorphisms
  in asthma treatments
• Website http//www.fda.gov/oc/initiatives/critic
  alpath/

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New Press Release from the FDA
FDA News March 16, 2006 Media Inquiries FDA
and the Critical Path Institute Announce
Predictive Safety Testing Consortium Consortium
Will Share Tests to Understand Safety of
Potential New Drugs Earlier The Food and Drug
Administration (FDA) and The Critical Path
Institute (C-Path) today announced the formation
of the Predictive Safety Testing Consortium
between C-Path and five of Americas largest
pharmaceutical companies to share internally
developed laboratory methods to predict the
safety of new treatments before they are tested
in humans. The FDA, while not a member of the
Partnership, will assist it in an advisory
capacity. This unprecedented sharing of potential
early indicators of clinical safety may
streamline the cost and time of preclinical drug
safety evaluation and better inform the use of
personalized medicine. The Consortium was
announced today at a press conference detailing
the release of the Critical Path Opportunities
List -- 76 initial research priorities that, if
accomplished, will modernize the drug development
process by 2010 and help get new medical
discoveries to Americans faster and at a lower
cost.
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System Biology Approaches -omic Technologies
(Preclinical or Clinical Utilization)
Technologies
Technologies
Nielsen, J., and Oliver, S. (2005). The next wave
in metabolome analysis. Trends Biotechnol.
23(11), 544-546.
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Proposed Process Map for Validation Genomic
Biomarkers of Preclinical Drug Safety Evaluation
Study Protocol Proposal
FDA Protocol Review
FDA Report Review
Dose- Ranging Study
Validation Study Report
Cross- Validation Consortium
Known Valid Biomarker
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Potential Future Outcomes

• Novel safety biomarkers for industry and
  regulators
• A step forward in defining a mechanism for
  translating scientific findings into actionable
  information

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Outline

• VGDS (voluntary genomic data submission) program
  at the FDA
• PTSC (Predictive Safety Testing Consortium), a
  novel process for improving safety testing at
  C-Path
• NSAIDs, chemoprevention, and personalized
  medicine

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NSAIDs and Personalized Medicine

• NSAIDs show promise as chemopreventive agents for
  cancer such as colorectal neoplasia
• MOA for NSAIDs are believed to be via the
  anti-inflammatory action
• Specifically, the inhibition COX enzymes (COX1
  and COX2)
• Large inter-individual pharmacokinetic
  differences have been observed

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NSAIDs and Personalized Medicine

• NSAIDs metabolized via Cyp2C and UGT enzymes,
  both of which are highly polymorphic
• Opportunity to apply pharmacogenomic/pharmacogenet
  ic approaches to understand the large
  inter-individual pharmacokinetic variability
• Still, genetic differences are only part of the
  picture
• Combine PK data, pharmacogenetic, safety
  biomarker information to personalize therapy for
  the individual patient
• Goal Maximize efficacy and minimize adverse
  events

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Potential Opportunity

• Personalize therapy for NSAIDs such as
  COX2-selective agents when used for cancer
  prevention
• Identify right drug, for the right patient, and
  right dose

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Acknowledgements
Dr. Larry Lesko Dr. Felix Frueh Dr. Shashi
Amur Dr. Federico Goodsaid Dr. Allen Rudman