NCTR Overview

Daniel A. Casciano, Ph.D.National Center for

Toxicological Research

Organization of Presentation

• Some information on FDA• Organization of the NCTR• Function of SAB

Department of Health and Human ServicesFood and Drug Administration

Office of the CommissionerCommissioner of Food and Drugs

Center forBiologics

Evaluation and Research

Center forFood Safety and Applied

Nutrition

Center forDrug

Evaluationand Research

Center forVeterinary Medicine

Center forDevices and Radiological

Health

NationalCenter for

Toxicological Research

Office ofthe Chief Counsel

Office ofEqual Opportunity

Office of theAdministrative Law

Judge

Office of the Senior Associate

Commissioner

Office ofInternational and

Constituent Relations

Office of Policy, Planning, and

Legislation

Office ofManagement and

Systems

Office of Regulatory Affairs

Center for Drug Evaluation and Research

MISSION: The Center assures that safe and effective drugs are available to the American people.

ISSUES: Prescription Drug User Fee Act (PDUFA), Adverse Events Reporting, Gene Therapy, Monitoring Drug Information and Advertising, Drug Quality, Drug Safety

Center for Food Safety and Applied Nutrition

MISSION: The Center is responsible for promoting and protecting the public’s health and economic interest by ensuring that the nation’s food supply is safe, sanitary, wholesome, and honestly labeled. The program also ensures that cosmetic products are safe and properly labeled.

ISSUES: Food Safety, Joint Institute for Food Safety and Applied Nutrition, Dietary Supplements, Food Labeling, Seafood Decomposition, Phototoxicity(Hydroxy acids)

Center for Veterinary Medicine MISSION: CVM is responsible for ensuring that

animal drugs and medicated feeds are safe and effective for their intended uses and that food from treated animals is safe for human consumption.

ISSUES: Food Safety, Antibiotic Resistance, Aquaculture.

Center for Devices and Radiological Health

MISSION: The mission of CDRH is to protect the public health by providing reasonable assurance of the safety and effectiveness of medical devices and by eliminating unnecessary human exposure to radiation emitted from electronic products (medical, industrial, and consumer).

ISSUES: Reuse of Single-Use Medical Devices, Medical Device Surveillance, Medical Errors, Regulations, FDAMA, Reengineering, Device GMP Inspections, Tissue-Based Products (BSE/TSE), Genetic Assay Kits, People Scanners (X-Rays), Ultrasound, Electro-magnetic Radiation

Center for Biologics Evaluation and Research

MISSION: The mission of CBER is to protect and enhance the public health through regulation of biological and related products including blood, vaccines, therapeutics and related drugs and devices according to statutory authorities.

ISSUES: Biologic Review Actions, Major Drug Approvals, Vaccine Approvals, Bioterrorism, Research in Proteomics, Compliance Activities, Action Plans (Blood, Tissue, Devices), Xenotransplantation

Office of Regulatory Affairs

MISSION: The Office of Regulatory Affairs (ORA) is the lead office for all Field activities of the Food and Drug Administration.

ISSUES: International Harmonization, Imports, Leveraging (EPA, States), Seafood and Dairy Exports, Laboratory Information Bulletins, Research, Bioresearch Monitoring Program (BIMO), Adverse Action Reports (All Centers), Recalls, Seafood Decomposition, Bacterial Contamination

DEPARTMENT OF HEALTH AND HUMAN SERVICESFOOD AND DRUG ADMINISTRATION

NATIONAL CENTER FOR TOXICOLOGICAL RESEARCH

Division of BiochemicalToxicology

Division of Geneticand Reproductive

Toxicology

Division of Biometryand Risk Assessment

Division of Microbiology

Division of Chemistry Division ofNeurotoxicology

Division of VeterinaryServices

Division of MolecularEpidemiology

Office of Research

Division of Facilities,Engineering and

Maintenance

Division ofAdministrative

Services

Office of ManagementServices

Division of Planning

Division of FinancialManagement

Division ofInformationTechnology

Office of Planning,Finance, and

Information Technology

Office of Management

Office of the Director

Division of Microbiology

National Center for Toxicological Research

Food and Drug Administration

Jefferson, Arkansas

Carl E. Cerniglia, Ph.D.

Director

DIVISION OF MOLECULAR EPIDEMIOLOGY

OVERVIEW

Fred F. Kadlubar, Ph.D. Director

Division ofBiochemical Toxicology

Frederick A. Beland, Ph.D.Director

Division of Genetic and Reproductive Toxicology

Martha M. Moore, Ph.D.Director

Division of Neurotoxicology

William Slikker, Jr., Ph.D.Director

Division of Biometry and Risk Assessment

Ralph L. Kodell, Ph.D.Director

Division of Chemistry

Robert J. Turesky, Ph.D.Director

Division of Veterinary Services

William M. Witt, D.V.M., Ph.D.Director

FDA/NCTR/NIEHS Interagency Agreement

William T. Allaben, Ph.D.

NCTR RESOURCESFDA Allocation

0

5

10

15

20

25

30

35

40

$(00

0)

93 94 95 96 97 98 99 00 01

Fiscal Year

FTE ALLOCATION

215220225230235240245250255260

FTEs

93 94 95 96 97 98 99 00 01Fiscal Year

NCTR RESOURCES

0

10

20

30

40

50

60

93 94 95 96 97 98 99 00 01

Fiscal Year

$(00

0)

IAG/CRADAFDA

Out-year Budget RequestsFY2002Requested Appropriated

Premarket Review: DietarySupplements; Microarray,Knowledge Bases

$11,700,000; 14 FTE

Improve Product Review $617,000; 1 FTE Reduce Entry of Sub-

standard Foreign Products$834,000; 2 FTE

Product Safety $1,100,000; 3 FTE Sustain Public Confidence $1,893,000; 1 FTE Science and Risk

Assessment$1,400,000; 5 FTE

Managing Food Safety $3,700,000; 9 FTE $400,000; 2 FTE Bioterrorism $1,500,000; 8 FTE

Cost of Living Increases $1,094,000

Out-year Budget RequestsFY2003

• Premarket Review: Proteomics, Genomics, Gene Chip, Microarray and Bioinformatics to Support and Guide Premarket Review ($2,646,000)

• Antimicrobial Resistance ($500,000)

• Dietary Supplements ($500,000)

• Food Safety ($12,000,000)

• Cost of Living ($2,953,000)

What Do We Do For FDA?

• NTP Bioassay• Food Safety Initiative• Fresh Tag™• Bioterrorism• Intellectual Resource

Fundamental Research

• DNA adduct• Artificial GI tract• Estrogen and computational toxicology• Nutrition (PCR)• Transgenic animals• Risk Assessment procedures• Operant behavior• Toxicogenomics, Proteomics

Function of SAB

• Advise NCTR Director on science, budget and other issues (NCSS subcommittee)

• Members serve on full SAB for review of site-visit reports

• Members serve as chair and/or committee member of program/division site-visit teams

Toxicology in the Next Millenium

04/22/23

Toxicology Data Continuum

Genomic Proteomic Biochemical

MechanismCellular Tissue/Organ Organism

Geneexpression

Protein synthesis

ProteinModification

functional Activity

Adaptation, repair

or damageDysfxn

TOXICITY!

CGTCCAACTGACG

TCTACAGGCTTAT

TTAGCGCTATAAG

AGTCATACCTGTA

TATATATAGGCGA

ATTCGCCACGTAG

TACCCGGGTAT…..

DNA sequencing cDNA arrays 2D- PAGE

Genome Transcriptome Proteome

DNA RNA Proteins

CGTCCAACTGACG

TCTACAGGCTTAT

TTAGCGCTATAAG

AGTCATACCTGTA

TATATATAGGCGA

ATTCGCCACGTAG

TACCCGGGTAT…..

DNA sequencing cDNA arrays 2D- PAGE

Genome Transcriptome Proteome

DNA RNA Proteins

Better Predictive Tests

• DNA- and protein-based technologies• Transgenics• Biomarkers (rodent/human

homologues)• Alternative to animals• Computational Science

Current Genomics Project at the NCTR

• Human genotyping• Gene expression profiles

• Expose rat cells in primary culture to a variety of toxicants; evaluate gene expression.

• Expose intact animal to same toxicants; evaluate gene expression in interested organ.

• Expose human cells in primary culture to same toxicants; evaluate gene expression.

• Predict in vivo human response.

NCTR Gene Expression Microarray Project

Effects of Chemical Toxicants on Gene Expression Profiles

34

Development of SNP-ChipsHigh throughput genotyping using DNA microarray technology will be used to allow facile genetic screening of human populations for:

• Adverse Drug Reactions• Cancer Susceptibility, Early Diagnosis & Recurrence • Drug Efficacy in Subsets of the Population• Individualized Drug Dosing

Rapid screening for variant genes involved in metabolism, DNA repair, and cellular homeostasis should allow the selection of genetically heterogeneous groups for inclusion in clinical trials and thereby increase our ability to protect public health in a diverse population.

Developing Proteomics

Problems

• Commercial vs. In-house development of chips

• Toxicogenomics staffing

Some Solutions

• Creative recruitment (Cellular and Molecular Toxicology Group)

• Leveraging• Collaboration• IPA

04/22/23

Toxicology Data Continuum

Genomic Proteomic Biochemical

MechanismCellular Tissue/Organ Organism

Geneexpression

Protein synthesis

ProteinModification

functional Activity

Adaptation, repair

or damageDysfxn

TOXICITY!