CDER FDA Initiatives

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CDER FDA Initiatives
Lilliam Rosario, Ph.D.
Pharmacology/Toxicology Subcommittee on
Pharmacogenomics under the Advisory Committee
for Pharmaceutical Sciences
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CDER FDA Initiatives
A. Formation of Non-Clinical Pharmacogenomics
Subcommittee B. Regulatory Research-Lab Based
Initiatives C. Collaboration with Iconix
Pharmaceuticals D. Collaboration with Expression
Analysis/Schering Plough
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CDER FDA Initiatives
A. Formation of Non-Clinical Pharmacogenomics
Subcommittee B. Regulatory Research-Lab Based
Initiatives C. Collaboration with Iconix
Pharmaceuticals D. Collaboration with Expression
Analysis/Schering Plough
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Nonclinical Pharmacogenomics Subcommittee Goals

• Recommend standards for the submission and
  review of
• nonclinical PG/TG data sets.
• Develop internal consensus regarding the added
  value, best
• interpretations, and drug development and
  regulatory
• review implications of nonclinical PG/TG data.
• Develop Center expertise and an appropriate
  infrastructure
• to support the review of nonclinical PG/TG data.
  
• Objectives of the committee may continue to
  evolve with time
• (for example, proteomics and metabonomics)

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CDER Nonclinical Pharmacogenomics Subcommittee
ODE I ODE V Patricia Harlow, Cardio-Renal
Paul Brown, Dermal/Dental John Leighton, ?
Oncology Maria Rivera, Anti-Inflammatory Lilliam
Rosario, Oncology Josie Yang, Anti-Inflammatory
ODE II OTR Wafa Harrouk,Metabolic/Endocrine
Frank Sistare, ? Applied Pharm. Research Timothy
Robison, Pulmonary Barry Rosenzweig, Applied
Pharm Research Scott Pine, Applied Pharm
Research ODE III Karol Thompson, Applied
Pharm Research Lynnda Reid, Reproductive/Urologic
Siham Biade, Imaging/Radiopharm CBER
David Essayan, Clin. Pharm. Tox ODE IV Hao
Zhang, Anti-Virals ? Co-Chairs
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Nonclinical Pharmacogenomics Subcommittee
Functions

• Interface with other CDER review disciplines
  (e.g., clinicians, statisticians) and other
  Centers within the Agency in recommending review
  standards.
• Develop specific initiatives to keep committee
  members abreast of the latest developments in
  PG/TG.
• Assist other subcommittees and Center groups in
  developing educational opportunities in PG/TG.
• Provide forums for communication to regulated
  industry on PG/TG.
• Obtain external expertise to evaluate scientific
  developments in PG/TG.
• Provide internal expertise in evaluating
  nonclinical PG/TG data submissions.

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Nonclinical Pharmacogenomics Subcommittee
Activities

• Contributed input to CDER management concerning
  research information package/no regulatory
  impact.
• Contributed to the nonclinical section of CDER
  draft guidance on pharmacogenetics and
  pharmacogenomics.
• Initiated process toward development of draft
  guidance on the content and format of nonclinical
  pharmacogenomic data submissions.
• Participated in the formation and preparations
  for a Pharmacology Toxicology Subcommittee on
  Pharmacogenomics under the Advisory Committee
  for Pharmaceutical Sciences (first meeting on
  June 10, 2003)
• Participates in collaboration with Iconix
  Pharmaceuticals.
• Participates in collaboration with Expression
  Analysis/Schering Plough.

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CDER FDA Initiatives
A. Formation of Non-Clinical Pharmacogenomics
Subcommittee B. Regulatory Research
Lab-Based Initiatives C. Collaboration with
Iconix Pharmaceuticals D. Collaboration with
Expression Analysis/Schering Plough
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Regulatory ResearchLaboratory-Based Initiatives

• Early active laboratory participants in ILSI
  collaborations (nephrotoxicty and genotoxicty)
• Affymetrix GeneChip system collaboration -
  cardiotoxicity focus
• Rosetta research collaboration - cardiotoxicity
  focus
• NCTR collaborations ongoing (several biological,
  database, statistical, reference standards)
• Schering-Plough collaboration - PBL gene
  expression and vasculitis

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FDA Office of Science Health Coordination-Funded
Collaborative Project

• Genome scale expression data submitted to the FDA
  could be generated from a variety of microarray
  platforms
• Oligonucleotide or cDNA-based arrays
• Numerous commercial platforms
• In-house custom arrays
• Can a standard be developed that would help
  assure the FDA of the biological truth of the
  submitted microarray data (independent of
  platform and site of processing)?

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FDA Office of Science Health Coordination-Funded
Collaborative Project
Evaluation of Performance Standards and
Statistical Software for Regulatory Toxicogenomic
Studies

• Laboratory Component (FDA)
• K. Thompson, PI _at_ CDER
• J. Fuscoe, PI _at_ NCTR
• Laboratory Component (Outside Collaborators)
• Rosetta Inpharmatics
• Agilent
• NIEHS
• Amgen
• Iconix
• Affymetrix (Statistical support)
• Statistical Component
• Statisticians from numerous FDA Centers

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GOALS
Goal is to generate and evaluate a complex mixed
tissue standards utility for assessing platform
features..

• No manufacturing defects
• Insignificant platform lot-to-lot variability
• Assess integrity of feature location
• Unambiguous consensus sequence annotation
• Lack of cross-contamination in tiled probe
  features

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.and for assessing experimental performance

• Quality (integrity /purity) of starting sample
• Quality of processed (labeled/amplified) sample
• Hybridization performance (probe sensitivity,
  specificity)
• Image scanning limitations (background/slope/satur
  ation)
• Transformation process into rough measured data
  (background/slope/saturation)
• Normalization/scaling to an analytical value
  worthy of comparison
• Data selection and analysis procedures to focus
  biological thinking (false positive/false
  negative minimization)
• Biological conclusions that are independent of
  platform and represent biological truth

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Proposed Steps for Testing Feasibility of Mixed
Tissue Standard using Benchmark Genes

• Identify tissue-selective, low variance
  Housekeeping (i.e., always expressed) rat
  genes from control animal data in large
  databases. These genes should optimally exhibit
  a consistent rank order of expression level in
  defined samples (by age, sex, strain).
• Select tissues with most consistent expression
  among control animals and most coverage of probes

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CDER FDA Initiatives
A. Formation of Non-Clinical Pharmacogenomics
Subcommittee B. Regulatory Research-Lab Based
Initiatives C. Collaboration with Iconix
Pharmaceuticals D. Collaboration with Expression
Analysis/Schering Plough
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Collaboration with Iconix Pharmaceuticals

• Provides research access to DrugMatrix system
  for evaluation purposes.
• Provides hands-on experience using chemogenomic
  data and tools, including the application of
  molecular toxicology markers to predict drug
  actions.
• Provides first-hand experience with a very large
  dataset linked to traditional toxicology
  outcomes.
• Iconix continues to provides training and support
  in the areas of QA/QC methods associated with
  gene expression microarray data generation,
  analysis of data across multiple gene microarray
  product platforms, and the derivation and
  validation of markers of toxicity and mechanism
  from integrated chemogenomic datasets.

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CDER FDA Initiatives
A. Formation of Non-Clinical Pharmacogenomics
Subcommittee B. Regulatory Research-Lab Based
Initiatives C. Collaboration with Iconix
Pharmaceuticals D. Collaboration with Expression
Analysis/Schering Plough
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Collaboration with Expression Analysis/Schering
Plough

• Conduct a mock submission of microarray data
• Provide a suitable framework in which to augment,
  reduce, or further define a potential list of
  recommendations
• Contribute to the development of consensus around
  the specific elements of applicable
  recommendations, within the context of a mock
  submission
• Contribute to building and refining a process in
  which microarray data may be submitted to FDA

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Proposed Activity Plan for Mock Data Submission
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Areas to Address

• Laboratory infrastructure
• Data management
• Study-specific array performance
• Study-specific experimental design
• Study-specific pre-processing and statistical
  analysis methods
• Interpretation of results

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Data Management

• Data management, bioinformatics, and statistical
  analysis systems and software
• Data files and file structures
• Variables and definitions
• Linkage mechanisms between microarray and other
  datasets
• Histopathology
• Clinical chemistry
• Phenotype

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CDER Guidance (January 1999) Providing
Regulatory Submissions in Electronic Format

• Animal line listings as datasets
• Animal line listings that you would provide on
  paper or in PDF format may be provided as
  datasets. Just as you provide data for each
  domain (e.g., body weights, clinical signs) as a
  table in a paper or PDF submission, with
  electronic datasets, each domain should be
  provided as a single dataset.

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CDER Guidance Recommendations

• Provide each dataset as a SAS transport file.
• Size is less than 25 MB per file (not
  compressed).
• Data variable names should be no more than 8
  characters.
• A more descriptive data variable label, up to 32
  characters in length, should be provided.
• Data elements should be defined in data
  definition tables (1 set of data definition
  tables/study).
• Each animal should be identified with a single,
  unique number for all the datasets in the entire
  application.
• The variable names and codes should be consistent
  across studies.
• Provide the duration of treatment based on the
  start of study treatment.

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CDER Guidance Examples of data sets and data
elements
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CDER guidance Examples of data sets and data
elements
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Nonclinical Data sets Notice of Pilot Project
Federal Register / Vol. 68, No. 17 / January 27,
2003 Docket No. 02N 0532
This pilot project is part of an effort to
improve the process for submitting nonclinical
data. Eventually, FDA expects to recommend
detailed data standards for the submission of
nonclinical data. FDA received recommendations
for a standard presentation of certain clinical
data from the Clinical Data Interchange Standards
Consortium, Inc. ( CDISC). CDISC is currently
facilitating the work on similar standards for
nonclinical data sets.
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Comparison of CDER guidance to MIAME/Tox Proposal

• CDER guidance paradigm appears more comprehensive
  with less restrictive vocabulary e.g. CDER
  proposal treats LABTEST as a variable, while
  MIAME/Tox proposes a field for each possible
  Clinical Chemistry test.
• MIAME/Tox collects information on in vitro
  experiments whereas the Agency generally does not
  receive line listing for Pharmacology data.
• MIAME/Tox did not collect information on drug
  plasma levels whereas toxicity studies submitted
  to the Agency may include PK assessments.

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Considerations for the submission of array data

• Sponsors provide annotations to non-clinical data
  containing array information by following a
  Guidance-compliant format.
• The Guidance may have to be extended to include
  how the array data may be submitted.
• Include the following files raw data files post
  image analysis (e.g., .cel and .chp in the
  case of Affymetrix array data) linked by animal
  identifier.
• Include summary report to describe any
  normalizations, data processing, and/or
  statistical analysis i.e., how conclusions were
  derived.

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Affymetrix MAS 5.0-Supplied Files
40 MB
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Chip Image with Defect
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Probe Detection Report (from CHP)
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Suggestions for the Submission of Array Data

• By evaluating several submissions, we can gain
  understanding of the fields/issues that need to
  be reconciled for database purposes.
• This proposal,
• Works with current guidance.
• Does not create any additional burden for the
  Sponsor.
• Leaves possibility of in-house database creation.

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CDER FDA Initiatives
A. Formation of Non-Clinical Pharmacogenomics
Subcommittee B. Regulatory Research-Lab based
initiatives C. Collaboration with
Iconix D. Collaboration with Expression
Analysis/Schering Plough