Comprehensive Toxicological Assessments of FDA Selected Nominations to the National Toxicology Program; Selected NTP/NIEHS Nominations of FDA Importance

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FDA-NIEHSInteragency Agreement

• Comprehensive Toxicological Assessments of FDA
  Selected Nominations to the National Toxicology
  Program Selected NTP/NIEHS Nominations of FDA
  Importance

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Assistant Secretary for Health DHHS
NTP Executive Committee Heads, DHHS Agencies,
EPA, OSHA, NCI Asnt. Sec. Labor
National Toxicology Program (Dr. Ken Olden)
NTP Board of Scientific Counselors
NCTR/FDA NIEHS/NIH NIOSH/CDC
Steering Committee
Technical Reports Subcommittee
Reports on Carcinogens Subcommittee
Chemical Evaluation Committee
Working Group Report on Carcinogens
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FDAs Mission

• To Protect and Promote Public Health
• FADAMA directs FDA to draw on the resources from
  organizations outside FDA with shared interest to
  help accomplish FDAs Mission LEVERAGING
• Using intellect, time, money and resources in a
  manner that Maximizes their value in enhancing
  FDAs role of protecting and promoting public
  health

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NCTRs LEVERAGING EFFORTS

• An example of an ongoing successful partnership
  is the one FDA enjoys with the NIEHS/NTP, which
  funds research and bioassays on FDA-regulated
  products, at NCTR.
• Jane Henney - 10/04/00 FDA Leveraging Handbook

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FDA-NIEHS InterAgency Agreement Signed December
6, 1992
Dr. J.E. Henney, FDA Deputy Commissioner for
Operations
Dr. K.L. Olden, Director, NIEHS
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IAG Concept/Genesis

• Innovative Applied Toxicology Studies
• FDA Scientists Involved in Protocol Design
• Mechanistic/Mode of Action Studies Support
  Chronic Study Interpretation/Risk Assessments
• Reports in Timely Manner
• Utilize NCTRs Expert Scientific Staff / Unique
  Facilities

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IAG Supports FDA Research

• High Quality/Science-Based Safety Assessments
  Support Risk Management Decisions
• Reduce Uncertainty in Risk Assessments and
  Risk-Benefit Analysis
• Measurable - Real Time Regulatory Impact

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IAG History (Fiscal Years)

• 1993 - IAG Signed
• 1995 - IAG Open-Ended
• 1996 - Expanded to Include Putative Endocrine
  Disruptor Chemicals
• 1998 - Resources to Develop a FDA-NIEHS
  Phototoxicity Research and Testing
  Center
• 1999 - Resources Set Aside to Renovate 5A Animal
  Rooms (pending)
• 2000 - Additional FDA High Priority Compounds
  Including Dietary Supplements
• 2001 - AIDS Therapeutic Mixtures

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Compounds/Agents Nominated - IAG

• Chloral Hydrate (CDER)
• Fumonisin B1 (CFSAN)
• Malachite Green (CVM)
• Urethane/Ethanol (CFSAN)
• Riddelliine (CFSAN/NIEHS)
• Glycolic Salicylic Acids (CFSAN)
• Endocrine Disrupting Chemicals (FDA / NIEHS)
• Phototoxicology Nominations (CFSAN/NTP)
• Dietary Supplements (CFSAN/NTP)
• AIDS Therapeutic Mixtures (NTP/CDER)
• Thimerosal (CBER)

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FDA-NIEHS IAG
FDA Nominations
FDA/NIEHS Nominations

• Chloral Hydrate
• Fumonisin B1
• Malachite Green
• Urethane/Ethanol
• ? ? Hydroxy Acids
• Glycolic Acid
• Salicylic Acid
• Retinyl Palmitate
• Thimerosal

• Riddelliine
• Endocrine Disruptors
• Methoxychlor
• Genistein
• Nonylphenol
• Vinclozolin
• Ethinyl Estradiol
• Aloe Vera
• AIDS Therapeutics

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FY 1999 NTP Nominations

• Radio Frequency Radiation Emissions (CDRH)
• DNA-Based Safety Assessment of Selected
  Vaccines/Therapeutics (CBER)
• Cefuroxime and Clarithromycin (CDER)
• p53 Study with Senna (CDER)
• p53 TGAC Studies with Pilocarpine (OOPD)

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FY 2000 FDA Nominations

• trans-Retinyl Palmitate (PT) CFSAN
• D C Red No. 27 (PT) CFSAN
• D C Red No. 28 (PT) CFSAN
• Lemon Oil (PT) CFSAN
• Lime Oil (PT) CFSAN
• Thimerosal (Ethyl Mercury) CBER

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IAG Chemical/Agent Starts FY 2001

• Aloe vera (Dr. Boudreau)
• Phototoxicology Studies
• Orally Administered Studies
• trans-Retinyl Palmitate (Dr. Culp)
• Phototoxicology Studies
• AIDS Mixtures (Dr. Beland)

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FDA-NIEHS IAG
Scientific Oversight - Peer Review

• Toxicology Study Selection and Review Committee
  (TSSRC)
• FDA Product Center(s) Protocol Review
• NCTR Protocol Review
• NCTR Support Group Review
• NTP/NIEHS Protocol Review
• IAG Executive Team Funding Approval
• NIEHS/NTP BSC Technical Report Subcommittee

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FDA-NIEHS IAG
Toxicology Study Selection and Review Committee
(TSSRC)

• Reviews research concepts and plans
• Reviews PI designed protocols
• Recommends protocol modifications (e.g. dose
  level selection, design changes, additional
  studies) and protocol implementation
• Monitors the progress of each study

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IAG Principle Investigators

• Chloral Hydrate - Dr. Frederick Beland
• Fumonisin B1 - Dr. Paul Howard
• Malachite Green - Dr. Sandra Culp
• Urethane/Urethane-Ethanol - Dr. Fred Beland
• Glycolic Acid/Salicylic Acid - Dr. Paul Howard
• Endocrine Disruptors - Dr. Barry Delclos, Dr.
  Andy Scallet, Dr. Sherry Ferguson, Dr. Dan
  Doerge, Dr. Suzanne Morris
• Riddelliine - Dr.'s Peter Fu Ming Chou
• Aloe Vera - Dr. Mary Boudreau
• Retinyl Palmitate - Dr. Sandra Culp
• AIDS Therapeutics - Dr. Frederick Beland
• Thimerosal - Dr. William Slikker

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IAG Benefits

• Enhance Regulatory Decision Process
• Support Quantitative Risk Assessments
• New/Innovative Research Approaches
• Speed Research/Testing Process
• Utilize NCTR Scientific/Contract Staff
• FTE/Post-Doc Support
• Facilities Renovation (Phototoxicology)
• Equipment Purchase
• Travel for Scientific Meetings

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Funding Source Comparison
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FDA-NIEHS Phototoxicology Research and Testing
LaboratoryNTP Center for Phototoxicology
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IAG (FDA/NIEHS) Overhead to NCTR through FY 2000
Overhead generated from the IAG (FDA/NIEHS)
covers the cost of doing business for NIEHS.
Resources from "overhead" support facilities
maintenance, equipment maintenance,
contracts/procurement administration, security,
utilities, laundry services, library services,
janitorial services, supply management. These
indirect costs are determined by usage and vary
in rate according to the usage in each area.
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IAG (FDA/NIEHS) Post Doc Positions
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Animal Room Occupation

• 53 A and B used for IAG (Endocrine Disruptors,
  Priority Chemicals
• A 7 ten-rack rooms (70)
• 2 seven-rack rooms (14)
• 4 five-rack rooms (20)
• B 11 five-rack rooms (55)
• 53 C and D New born mouse and other Center
  studies
• C 10 five-rack rooms (50)
• 17 two-rack rooms (34)
• D 4 five-rack rooms (20)
• 60 of Bldg 53 is used for IAG

• 100 of Bldg. 5 is used for IAG
• Building 5 Phototoxicology
• 1 Control Room
• 1 Dose Room (2 Lights)
• 6 Animal Rooms
• Building 14 Neurotoxicology others (No IAG
  studies)

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IAG (FDA/NIEHS) CostsPriority Chemicals
Costs are through the life of the project.
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IAG (FDA/NIEHS) CostsEndocrine Disrupting
Chemicals
Costs are through the life of the project.
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IAG (FDA/NIEHS) Pathology Resources
Project Hours

• Pathology hours through August 2000

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IAG (FDA/NIEHS) ADP Resources
Project Hours

• ADP hours through August 2000

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IAG (FDA/NIEHS) Animal Care/Diet Prep Resources
Cage Weeks
.Cage weeks reported through August 2000
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IAG (FDA/NIEHS) Animal Care/Diet Prep Resources
by Chemical
Cage Weeks
.Cage weeks reported through August 2000
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FDA/NIEHS IAG Billed Estimated Costs through FY
2005
Some out year projects not yet submitted to
Planning for costing are estimated based on
similar animal studies.
Billed to NIEHS
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FDA-NIEHS IAG
IAG Concept Genesis

• Innovative applied toxicology studies
• Involve FDA scientists in protocol design
• Conduct specific mechanistic/mode of action
  studies in support of sound science-based
  safety/risk assessments
• Reports in a timely manner
• Utilize NCTRs unique facilities and expert
  scientific staff

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FDA-NIEHS IAG
Chemical/Agent Selection, Nomination Approval

• FDA Chemical Selection Working Group
• NTP Interagency Chemical Coordination and
  Evaluation Committee
• NTP Executive Committee
• FDA Study director assigned to chemical
• Study director develops research plan
• Study director/PI develops protocol(s)

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FDA-NIEHS IAG
TSSRC

• Core Members
• NCTR Deputy Director for Research (chair)
• FDAs NTP Liaison (vice-chair/Executive Sec)
• NIEHS Project Officer

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FDA-NIEHS IAG
TSSRC

• Ad Hoc Members
• NCTR Study Director/PIs
• FDA NIEHS scientists
• Other federal agencies (USDA, NCI, NIOSH)
• Academia
• International (Agriculture Canada, U.K.)
• Industry

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FDA-NIEHS IAG
Public Health Benefit

• The FDA-NIEHS IAG has leveraged resources -
  public funds and scientific expertise - in a most
  effective and efficient manner which enables both
  FDA and NTP to better identify chemical/agent
  hazards, assess safety and human health risk, to
  the benefit of the American public.

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IAG Cost Include

• Labor
• Government
• ORISE
• PAI
• ROW
• Bionetics
• Travel
• Supplies
• Equipment
• Overhead