CDER FDA Initiatives

Lilliam Rosario, Ph.D.

Pharmacology/Toxicology Subcommittee on Pharmacogenomics

under the Advisory Committee for Pharmaceutical Sciences

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

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

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 regulatoryreview implications of nonclinical PG/TG data.

• Develop Center expertise and an appropriate infrastructureto support the review of nonclinical PG/TG data.

• Objectives of the committee may continue to evolve with time (for example, proteomics and metabonomics)

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, PulmonaryBarry 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

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.

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.

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

Regulatory Research:Laboratory-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

• 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)?

FDA Office of Science & Health Coordination-Funded Collaborative Project

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 @ CDER

• J. Fuscoe, PI @ NCTR

– Laboratory Component (Outside Collaborators)• Rosetta Inpharmatics

• Agilent

• NIEHS

• Amgen

• Iconix

• Affymetrix (Statistical support)

– Statistical Component• Statisticians from numerous FDA Centers

GOALS

• 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

Goal is to generate and evaluate a complex mixed tissue standard’s utility for assessing platform

features…..

….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/saturation)• 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

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

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

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.

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

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

Proposed Activity Plan for Mock Data Submission

November 20038. Development of Summary Report

November 20037. Final Stakeholder Discussion Forum

October 20036. Completion of Mock Submission

Aug-Oct 20035. Incorporation of Further Refinements and Iterations

August 20034. Intermediate Stakeholder Review and Feedback

July 20033. Pilot Submission

June 20032. Recommendations/Aims/Approach Document Development and Review

May 5, 20031. Concept Definition and Refinement of Scope

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

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

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”.

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.

CDER Guidance: Examples of data sets and data elements

CDER guidance: Examples of data sets and data elements

Nonclinical Data sets; Notice of Pilot Project

“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.

Federal Register / Vol. 68, No. 17 / January 27, 2003 [Docket No. 02N – 0532]

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.

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.

Affymetrix MAS 5.0-Supplied Files

5KBText file containing quality control information.RPT

10MBQuantifies (signal) and qualifies (presence or absence) each transcript and its relative expression level. Text versions creatable.

CHP

10MBCell intensity file; (x,y) coordinates for each cell (i.e. probe) with the intensity of each. Can be used to re-analyze data with different expression algorithm parameters. Readable in a text editor.

CEL

40MBRaw image of the scanned GeneChip array. Only readable in MAS software.

DAT

1KBExperimental information (sample, array, fluidics/scanner). Readable in a text editor.

EXP

40 MB

Chip Image with Defect

Exp. Date: 9/11/02Lot #: 1009208HU133A

Probe Detection Report (from CHP)

Cluster Incl AI851046:UI-M-BH0-ajv-..

0.000219 P1928.7 161692574_at

Cluster Incl AB021743:Mus musculus ...

0.000266 P4422.7 161692573_at

Cluster Incl AI509617:vx14h07.y1 ...

0.021866 P183.0161692572_at

Cluster Incl D85904:Mouse mRNA for ...

0.000266P2116.0161692571_at

Cluster Incl AW122482:UI-M-BH2.2-ao...

0.378184A64.2161692570_at

DescriptionsP-ValueDetec-tion

SignalStat Pairs Used

Stat Pairs

Probe Set ID

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.

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