Building Partnerships with NCTR

The mission of the National Center for Toxicological Research (NCTR) is to conduct peer-reviewed scientific research that provides the basis for the FDA to make sound science-based regulatory decisions, and to promote the health of the American people through its core activities of premarket review and postmarket surveillance. This involves fundamental and applied research specifically designed to define biological mechanisms of action underlying the toxicity of products regulated by the FDA. This research is aimed at understanding critical biological events in the expression of toxicity and at developing methods to improve assessment of human exposure, susceptibility, and risk, and apply these scientific findings to the FDA's pre-market application review and product safety assurance effort. The Center actively seeks research collaborations through Interagency and Cooperative Research and Development Agreements (IAGs, and CRADAs). Guiding principles for conducting leveraging activities with the FDA can be found on the FDA website at http://www.fda.gov/oc/leveraging/principles.htm.

Examples of current leveraging efforts

Title: Collaborative research between NCTR and AstraZeneca to develop a nonhuman primate model for studying the consequences of long-term anticonvulsant medication on complex brain functions in developing animals.

PI/Spokesperson: Merle Paule, PhD., Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, Arkansas.

Objectives:

• To establish acquisition (learning) curves for several operant behaviors in infant/juvenile rhesus monkeys during chronic oral exposure to vehicle and the N-methyl-d-aspartic acid (NMDA) receptor antagonists dizocilpine, and remacemide hydrochloride
• To determine whether such exposure results in any significant changes in the acquisition and performance of these behaviors
• To determine whether such exposure results in any significant changes in clinical chemistry or ophthalmic parameters
• To determine plasma distribution profiles and concentrations for each of these agents at various stages of chronic exposure
  

Public Health Impact:  Hundreds of thousands of people suffer from epilepsy; therefore, if this drug is determined to be safe and effective it may have a wide-reaching public health impact.

How long to Accomplish? The term of the agreement is five years.

Title: Rapid population-based screening methodology for genetic polymorphisms in adverse drug metabolizing and/or cancer-related risk alleles. (Risk-Tox DNA Microarray)

PI/Spokesperson: Fred Kadlubar, Ph.D., Division of Molecular Epidemiology, National Center for Toxicological Research, Jefferson, Arkansas.

Objective:

• NCTR partners with Genometrixr through a CRADA, to develop a "Risk-Tox" DNA microarray platform for rapid, high throughput genotyping. The goal is to be able to genotype patients for all the major enzyme variants that would enable us to predict carcinogen susceptibility, adverse drug reactions, chemotherapeutic drug efficacy and individualized dosing. Such efforts could have a major impact on the ability to understand the likelihood of adverse health effects in susceptible sub-populations.

Public Health Impact: Large impact. May eventually be used to define the genotype of every person who is taking prescription drugs, and to predict individual risk.

How long to Accomplish? The agreement is for 2.5 years.

Title: Development of a jointly (FDA/NIEHS) funded and operated Phototoxicology Research and Testing Laboratory.

PI/Spokesperson: Paul Howard, Ph.D., Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas.

Objective:

• A phototoxicology facility capable of conducting photocarcinogenesis studies has been developed at NCTR in response to the CFSAN nomination of the alpha- and beta- hydroxy acids to the National Toxicology Program for carcinogenesis testing. Mice are exposed to simulated solar light, or many other light sources, to determine the acute and chronic effect of the interaction of light with drugs or cosmetics. Utilization of this state-of-the-art facility to address basic science phototoxicological problems will enhance our understanding of the nature of skin cancer development, and the interaction of drugs and cosmetics in this process. There is considerable interest in development of CRADAs and collaborative research projects using this unique facility.

Public Health Impact: A large portion of the population uses skin care products in relation to sunlight exposure.

How long to Accomplish?  Ongoing. Many possibilities exist for future CRADAs and collaborative work with other government agencies.

Mechanisms for leveraging

There are several mechanisms to leverage with the Center, including: 

• Cooperative Research and Development Agreements (CRADA's), with industry
• Interagency Agreements (IAG's) with other government agencies
• Technology Transfer with industry
• State/Local governments

Additional information on leveraging is contained on the following website: http://www.fda.gov/oc/ofacs/partnership/techtran/1stpg.htm

New opportunities for leveraging:

• Bioinformatics.  The application of computer technology to biology; a combination of techniques and models in statistical, computational, and life sciences to understand the significance of biological data.
• Chemoinformatics.  The application of computer technology to chemistry; a combination of techniques and models in statistical, computational and analytical sciences to understand the significance of chemical data.
• Computational Biology.  The mutual application of computers and biology to questions of biological and medical importance.
• Computational Chemistry.  The application of computers in the physical sciences; an interdisciplinary approach involving theoretical chemistry, computer sciences, mathematics, and numerical analysis to define research needs and address challenging problems.
• Metabonomics.  Metabolite identification dealing with theory and key experimental features of hyphenating NMR with chromatographic techniques for bioanalysis.
• Proteomics.  Attempts to catalog and characterize proteins derived from the genetic code, compare variations in their expression levels under different conditions, study their interactions and identify their functional role.

Contact information:

Jeanne Anson., 870-543-7359, janson@nctr.fda.gov  
Other places to look in FDA:   http://www.fda.gov/oc/leveraging/default.htm