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Advances in Approaches to Food and Drug Safety

Assessment

William Slikker, Jr., PhD, ATS

National Center for Toxicological Research

U.S. Food and Drug Administration

Jefferson, Arkansas

The views expressed in this presentation do not necessarily reflect those of the FDA.

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NCTR is Unique

Established in January 1971 by Executive Order as a non-regulatory national resource owned and managed within DHHS by FDA to conduct integrated toxicological research and foster interagency, academic, and industrial collaboration in support of risk assessment needs related to public health.

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NCTR Vision

NCTR is an internationally recognized FDA research center that provides innovative, vital scientific technology, training, and technical expertise to improve public health.

NCTR—in partnership with researchers from government, academia, and industry—develops, refines, and applies current and emerging technologies to improve safety evaluations of FDA-regulated Products.

NCTR fosters international and intragovernmental cooperation to improve and protect public health and enhance the quality of life for the American people.

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Department of Health and Human ServicesFood and Drug Administration

National Center for Toxicological Research

… NIH FDA CDC …

HHS

CVMCTP NCTRCFSANCDRHCDERCBER ORA

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FDA Strategic Goals

Strengthen FDA for today and tomorrow– Science foundation– Partnerships and communication

Improve Patient and Consumer Safety– Strengthen science foundation– Provide patients access to risk benefit information

Increase Access to New Medical and Food Products– Critical Path to Personalized Nutrition and Medicine

Improve the Quality and Safety of Manufactured Products and the Supply Chain– Modernize science-based standards and tools to provide high quality

manufacturing processing and duplication

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NCTR Strategic Goals

Innovative toxicology for regulatory decisions

Promote personalized medicine and nutrition

Bioinformatics

Food safety

Mentorship/training

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NCTR/FDA Research Strategy

Focus research resources on:

– Regulatory issues to enhance decision making

– Technical innovations to speed FDA-regulated product review and safety assessment

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PrimateLaboratories

ARL Bld.

FDA Nano Core Facility

NTP/FDA Photx. Laboratories

FDA Disaster Recovery

General AnimalHousing

Visitor Housing 23 PathologyLaboratories

9 BSL-3Suites

Bio-ImagingCenter

82 Accredited animal and 123 experimental laboratories / 1M sq ft. in 30 buildings

Dietary Preparation

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Fred Beland, Ph.D.Dir., Division of

Biochemical Toxicology

Department of Health and Human ServicesFood and Drug Administration

National Center for Toxicological Research

Vicky Ross-Barsh, Assoc. Dir. for

Executive Programs & Services

Paul Howard, Ph.D.Assoc. Dir. for

Scientific Coordination

Thomas F. Flammang, Ph.D.Senior Advisor

for Science

Jennings PartridgeAssoc. Dir. for Regulatory

Compliance & Risk Management

Martha Moore, Ph.D.Dir., Division of Genetic & Reproductive Toxicology

Carl Cerniglia, Ph.D.Dir., Division of Microbiology

Merle Paule, Ph.D.Dir., Division of Neurotoxicology

Jeanne F. AnsonNCTR Executive Officer &

Assoc. Dir. for Office of Planning & Resource Management

Office of Research Coordinating Council

Office of the DirectorWilliam Slikker, Jr. Ph.D.

Jim Kaput, Ph.D.Dir., Division of Personalized

Nutrition & Medicine

Donna Mendrick, Ph.D.Dir., Division of

Systems Toxicology

Jeff Carraway, DVMDir., Division of

Veterinary Services

Margaret Miller, Ph.D. Assoc. Dir. for

Regulatory Activities

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Advancing FDA Science

Nanotechnology

Food Safety

Critical Path

Bio-imaging

Nutrition and Obesity

Regulatory Science

Bioinformatics

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ArrayTrack™: An Integrated Solution for Omics Research

Microarray data

Proteomics data

Metabolomics data

OH

HO H

Chemical data

Clinical and nonclinical data

Public data

ArrayTrack™

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Results from the MicroArray Quality Control (MAQC) Study

MAQC Main Paper

Validation of Microarray Results

RNA Sample Titrations

One-color vs. Two-color Microarrays

External RNA Controls

Rat Toxicogenomics Validation Nat. Biotechnol. 24(9) and 24(10s), 2006

137 Participants from 51 Organizations

Six research papers published in Nature Biotechnology on Sept and Oct 2006

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An Array of FDA EndeavorsIntegrated Nature of VGDS, ArrayTrack™, MAQC, and Best Practice Document

ArrayTrack™

MAQCVGDSE-Submission

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Bio-Imaging at FDA

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Bio-Imaging at NCTR/FDA

Biospec MRI7 Telsa, 30 cm bore

MicroPET23 cm bore

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Pediatric Anesthetics

Ketamine, a non-competitive NMDA receptor antagonist, has been used as a general pediatric anesthetic for surgical procedures in infants.

Ketamine is one of the most commonly used agents for mild sedation in pediatric emergency departments, endoscopy suites, catheterization laboratories, radiology suites, and intensive care units.

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E

B Ketamine (24-hr)

Control (24-hr)A

Control (24-hr)C

D Ketamine (24-hr)

Control (24- hr)

Ketamine (24-hr)F

E Control (24-hr)

Slikker et al., 2007

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Effects of ketamine-induced anesthesia on the frontal cortex of the developing monkey

Slikker et al.,2007

Fluoro

-Jade

C-Posi

tive Ne

uronal

Cells

0

5

10

15

20

25

Caspa

se 3-P

ositive

Neuro

nal Ce

lls0

5

10

15

20

25

ControlKetamine-infused

Silver

-stainin

g (Grain

Densi

ty)

0

50

100

150

200

250

300

GD 122(24-hr)

PND 5(24-hr)

PND 35(24-hr)

PND 5(3-hr)

* *

*

*

* *

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(B)

(C)

Zou et al., 2009

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A

B

C

Slikker et al., 2007

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Dorsal

Ventral

Left Right

Drs. Xuan Zhang (NCTR), Marc Berridge (UAMS), Tucker Patterson, Glenn Newport, Cheng Wang, and Merle Paule (NCTR)

22N=7 SUV=total radioactivity in ROI x body weight / injection dose

Time (s)0 10 20 30 40 50 60 70 80 90 100 110 120

0

1

2

3

4

Dynamic Uptake of [18F]-AnnexinV

ControlKetamine

SUV

Rat

io

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Nanotechnology at NCTR, ARL/ORA

Nanotechnology “Will eventually impact all Centers of the FDA”– Component of regulated products– Contaminant in regulated products– Challenge to our safety assessment paradigm

Nanotechnology Working Group– Coordinate NCTR’s and ARL/ORA’s participation in FDA’s nanotechnology

effort

Nanotechnology Core Facility – Support NCTR research efforts and serve as FDA core

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Nanotechnology at NCTR, ARL/ORAOverall Strategy

Research projects requested by FDA Centers (protocol-based studies)– FDA resources– through NTP IAG– through CRADA, MOU, etc

Engage/Dialogue– FDA – NNI– NTP/NIEHS – OECD – EPA – DOD– SOT

Support/Resources– NCTR/ORA Nanotechnology

Core Facility– UALR– UAMS– UA

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Nanotechnology Core Facility

Resources (on site, purchased, or funds available)– Transmission electron microscope (TEM)– HPLC with light scatter detection– Confocal microscopy (fluorescence detection)– Confocal microscopy (Raman and FTIR detection)– High resolution darkfield microscopy (hyperspectral detection)– Atomic force microscope– Particle size analyzers (1 nm -1 mm)– Inductively coupled plasma mass spectrometer (ICP-MS)– BET material surface analyzer– Wavelength dispersive X-ray fluorescence spectrometer– Sample preparation for electron microscopy

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Collaborations with Agencies/Universities/ Research Facilities

CRADAs– Argus Research Laboratories– Primedica Corp– AstraZeneca– Litmus– LLCPI– Pfizer, Inc.– RxGen, Inc. – SAS Institutes, Inc.– Sigma Tau Research, Inc.– University of Illinois– University of Arkansas at Little

Rock– University of Arkansas for

Medical Sciences

IAGs– Environmental Protection Agency (EPA)– Federal Aviation Administration (FAA)– National Institute of Environmental Health

Science (NIEHS) – National Cancer Institute (NCI)– National Institutes of Health (NIH)/National

Institute of Environmental Health Science (NIEHS)

– Environmental Protection Agency (EPA)/National Health and Environmental Effects Research Laboratory (NHEERL)

– National Institutes of Health (NIH)/National Institute of Child Health and Human Development (NICHD)

– National Institutes of Health (NIH)/National Toxicology Program (NTP)

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FDA/NIEHS IAG..…to conduct comprehensive toxicological assessments on selected FDA and NIEHS high priority chemicals nominated to the National Toxicology Program…

Chloral Hydrate (CFSAN) Fumonisin B1 (CFSAN)Malachite Green (CVM)Urethane/Ethanol (CFSAN)Riddelliine (CFSAN)α & β Hydroxy Acids (CFSAN)*

– Glycolic Acid– Salicylic Acid

Ephedra (NCI/ODS - CFSAN)Retinyl Palmitate (CFSAN)Ketamine (CDER)Bisphenol A (CFSAN)Acrylamide (CFSAN)Bitter Orange (CFSAN)Usnic Acid (CFSAN)Di-(2-ethylhexyl) Phthalate (CBER/CDRH)Permanent Makeup Pigments (CFSAN)

Endocrine Active Chemicals– Methoxychlor– Genistein (CFSAN)– Nonylphenol (CDER)– Vinclozolin– Ethinyl Estradiol (CDER)

Riddelliine (CFSAN/Adducts)Aloe vera (NCI-Oral & Dermal)AIDS Therapeutics

– Zidovudine (AZT)– Nevirapine (NVP)– Lamivudine (3TC)– Nelfinavir (NFV)– Efavirenz

Glucosomine/Chrondroitin (CFSAN)AZT P53 ko Mouse Study (CDER)

FDA Nominations NTP/NIEHS Nominations

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FDA and kFDA Collaboration

The letter of agreement was signed

NCTR/FDA and NITR/KFDA Joint Workshop on Toxicogenomics - July 15-16, 2009– kFDA Participants: Drs. Sue Nie Park, Hong-Ki Min, Ki-Suk

Park, Ho-Sang Jeong, and Wan-Seob ChoCollaborative projects– Liver Toxicity Knowledge Base (Dr. Weida Tong at NCTR

and Dr. Ho-Sang Jeong at kFDA)

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FDA Science

NCTR

CBER

ORA CDRH

CDER

CFSAN

CVM