Office of Management
Budget Formulation and Presentation

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NCTR Performance Goals

The following performance goal table summarizes the performance goals, yearly targets and actual reported data for the National Center for Toxicological Research (NCTR).

Given the uncertainty of final FY 2007 appropriation levels at the time FDA developed the performance targets for the FY 2008 Congressional Justification, FDA has included FY 2007 targets at both the President's Budget and the Continuing Resolution funding levels.

Measure	FY	Target	Result
Long Term Goal: Increase the number of safe and effective new products available to patients, including products for unmet medical and public health needs, emerging infectious diseases and counterterrorism.
1. Use new technologies (toxicoinformatics, proteomics, metabolomics, and genomics) to study the risk associated with how an FDA-regulated compound or product interacts with the human body. (16014) (output)	2008	Explore, via Agency partnerships, the feasibility of using "omics" data in the review process.	9/09
	2007 PB	Determine the feasibility of using systems biology in the drug review process.	1/08
	2007 CR	PB target and development of a test case with collaborative partner for use of systems biology in the drug review process.	1/08
	2006	Present one finding utilizing novel technologies to assess changes in genes and pathology, and the relationship between chemical exposure, toxicity and disease.	NCTR scientists examined the relationship between exposure to type 2 diabetes drugs and gene expression patterns and toxicity.This study suggests that microarray analysis together with toxicological observations can be used to rank drugs for hepatotoxicity and to evaluate the safety of new compounds.
	2005	Develop at least one protocol (proof of concept) to aid in defining drug toxicity studies and studies into mechanistic age-associated degenerative disease.	Three protocols were developed in the Division of Systems Toxicology, including studies of biomarkers of liver toxicity and disease, PPARg agonist effects on rat liver gene expression and age-associated changes in gene expression in F344 rats.
	2004	Use toxicoinformatics, combining information technology with toxicity data, to assess human risk for one regulated product (proof of concept)	Used biologically-based models of cancer-causing mutations to study skin tumor induction by regulated physical and chemical products.
2. Develop computer-based models and infrastructure to predict the health risk of biologically active products. (16003)(output)	2008	Integrate bioinformatics software into commercial or agency data packages for public use. (Due to redeployment and potential loss of income, this implementation may be delayed.)	7/09
	2007 PB	Demonstrate the utility of ArrayTrack in the regulatory environment and training of reviewers.	1/08
	2007 CR	PB target and initial testing of an additional ArrayTrack module
	2006	Interpret at least one toxicology study at the molecular level utilizing the DNA microarray database (ArrayTrack).	Microarray studies were conducted on rats exposed to the nutritional supplements comfrey and aristolochic acid.The resulting gene expression profiles and their relationship with the carcinogenic potential of these compounds were interpreted using the ArrayTrack database.
	2005	Develop a computer-based system to integrate databases, libraries and analytical tools to support risk analysis and assessment.	ArrayTrack has been developed and implemented as a fully integrated system for microarray data management, analysis and interpretation.
	2004	Expand current technologies to include risk assessment for two biologically active products of interest to the FDA.	Modeled in vivo gene mutation and genotoxicity data to gain insight into the mechanism of action and relative risk posed by liver and lung carcinogens.
	2003	Maintain existing computational databases of estrogenic and androgenic compounds for use by reviewers.	The data is available for public access and allows for integration of information across health research fields.
	2002	Maintain existing computational databases of estrogenic and androgenic compounds for use by reviewers.	Developed an integrated Toxicoinformatics System that includes a central data archive, mirrored public databases, and analysis functions.
Data Source: NCTR Project Management System; peer-review through FDA/NCTR Science Advisory Board and the NTP Scientific Board of Counselors; presentations at national and international scientific meetings; and manuscripts prepared for publication in peer-reviewed journals. Use of the predictive and knowledge-based systems by the FDA reviewers and other government regulators; NCTR Project Management System; peer-review through the FDA/NCTR Science Advisory Board; presentations at national and international meetings.
Cross Reference: These performance measures support HHS Strategic Goal 2.
Long Term Goal: Prevent harm from products by increasing the likelihood of detection and interception of substandard manufacturing processes and products through efficient and effective risk targeting, external partnering, effective internal processes and collaboration.
Measure	FY	Target	Result
3. Develop risk assessment methods and build biological dose-response models in support of Food Security.(16007) (output)	2008	Develop rapid screening assay for target contaminants (ricin).	9/09
	2007 PB	Incorporate flow cytometry technology into regulatory procedures to rapidly ID terror agents.	1/08
	2007 CR	PB and continue development of additional Salmonella biochips
	2006	Demonstrate one utility of an oligonucleotide-microarray method as an integrated strategy to respond to antibiotic resistant agents in foodborne pathogens and bioterror agents.	Developed a microarray method to screen 131 antibiotic resistance markers for most of the antibiotics used by the National Antibiotic Resistance Monitoring System.
	2005	Develop molecular method (oligo-microarray) to detect and monitor foodborne pathogenic bacteria.	In collaboration with CFSAN, scientists in the Division of Microbiology developed and validated a Salmonella biochip using microarray technology for rapid and accurate identification of virulence and antimicrobial resistance genes in Salmonella.
	2004	Under the Food Safety Initiative, establish a nutrition program in collaboration with other centers to address the risk associated with obesity in children, nutrition in pregnant women and poor nutrition in sub-populations; and initiate analysis on samples requiring high levels of containment in an accredited biosafety level 3 (BL-3) facility	Collaborative efforts that support this goal / target include participation on a committee involving CFSAN, CVM, and NCTR. This committee has prepared a white paper entitled, "Filling Critical FDA-Related Food and Nutrition Research Gaps." Analyzed surrogate microbes to test methodology as well as the public health risk for foodborne hazards.
	2003	Identify and characterize the role antibiotic resistance plays in emerging and evolving foodborne diseases.	Studies are being conducted to determine whether antimicrobial resistance occurs in bacteria isolated from animal feeds containing antibiotics and to identify the pattern of resistance.
	2002	Report at scientific meetings and/or publish preliminary results on the development of new methodologies to identify genetically modified foods, drug residues in foods and antibiotic-resistant strains of bacteria.	Researchers published approximately 50 publications and made approximately 20 presentations relating to food safety.
4. Develop standard biomarkers to establish risk measures for FDA-regulated products. (16012) (output)	2008	Evaluate the statistical standards for interpreting microarray data to guide reviewers.	9/09
	2007 PB	Develop novel carbon nanomaterial methods for the synthesis and chemical modification multiple materials.	1/08
	2007 CR	PB and continue studies on the pediatric sedative ketamine
	2006	Present one finding utilizing neuropathology and behavioral risk evaluation in the prediction of human outcome to foodborne toxicants.	An ongoing study of the effects of lifetime exposure to the food contaminant, acrylamide, is currently underway and represents the state-of-the-art in terms of the comprehensive, repeated assessment of nervous system function across a variety of domains.The use of behavioral measures that are applicable to humans maximizes relevance for prediction of effects in humans. Concurrent neuropathological analyses compliment, expand and strengthen the risk evaluation.
	2005	Present one finding using neural imaging to identify neurotoxicity in exposed populations.	Preliminary studies were conducted in the Division of Neurotoxicology to develop methods for multiple neuroimaging approaches in adult nonhuman primates. Functional data acquisition was accomplished utilizing positron emission tomography (PET).
	2004	Apply neural imaging to identify and quantify neurotoxicity in exposed populations; and upgrade NCTR's animal quarantine facility to conduct animal research requiring BL3 containment in order to evaluate the effect of bioterrorism agents contaminating the food supply.	A proposal was generated that is designed to determine the reversibility of the development of the effects of the dissociative anesthetic, ketamine, with the use of MicroPET imaging techniques. A portion of the quarantine facility has been "up graded" to conduct animal BSL3) cryptosporidia studies.
	2003	Develop one instrumental rapid sensor detection method. Outfit upgraded laboratory, provide for supplies (agents, chemicals/pathogens) and construct library databases of proteins and test to find toxin related markers; Recruit additional expertise in Computational Science, Chemistry and Microbiology.	The Pyrolysis MAB MS computational system was installed and generating data that shows a very rapid characterization of potential bioterror bacterial strains is possible. Staff was recruited and the BSL-3 laboratory will be ready for use by mid 2004.
	2002	Continue development of solid-phase colorimetric bacterial detection system .Acquire high-resolution mass spectrometer for use with protein from bacteria, food toxins and genomics studies. Upgrade existing laboratory facilities to BSL-3 to support BSE/TSE and microbial bioterrorism work. Recruit additional expertise in Computational Science, Chemistry and Microbiology.	Scientists are working on streamlining this methodology for use on meat as well as seafood. Equipment was purchased and calibrated. An outside firm assessed the NCTR facility for laboratory architecture and requirements; and, a floor plan was developed.One computational scientist, three chemists and two microbiologists were hired.
Data Source: NCTR Project Management System; peer-review through FDA/NCTR Science Advisory Board; presentations at national and international scientific meetings; and manuscripts prepared for publication in peer-reviewed journals. NCTR Project Management System; peer-review through FDA/NCTR Science Advisory Board, the NTP Scientific Board of Counselors, and the Food Safety Initiative Coordinating Committee; presentations at national and international scientific meetings; and manuscripts prepared for publication in peer-reviewed journals.
Data Validation: The National Center for Toxicological Research, under the auspices of the Food and Drug Administration (FDA), provides peer-reviewed research that supports the regulatory function of the Agency.To accomplish this mission, it is incumbent upon the Center to solicit feedback from its stakeholders and partners, which include other FDA centers, other government agencies, industry and academia. The NCTR Science Advisory Board (SAB) is guided by a charter that requires an intensive review of each of the Center's scientific programs at least once every five years to ensure quality programs and overall applicability to FDA's regulatory needs.This board is composed of non-government scientists from industry, academia, and consumer organizations and further supplemented with subject matter experts and scientists representing all of the FDA product centers. Research proposals are monitored through partnerships with other scientific organizations. Scientific and monetary collaborations include inter-agency agreements with other government agencies, Cooperative Research and Development Agreements, technology transfer with industry, and informal agreements with academic institutions. NCTR also uses an in-house strategy to ensure the quality of its research and the accuracy of data collected in specific research studies. Study protocols are developed collaboratively by principal investigators and FDA product centers. Findings are recorded and verified by internal and external peer review. Statistical analyses and the analytic approach on each protocol are checked by members of the scientific staff and the Deputy Director for Research.The Project Management System utilized by the Planning and Resource Management staff at the Center tracks all planned and actual expenditures on each research project.The Quality Assurance Staff monitors the experiments that fall within the Good Laboratory Practices (GLP) guidelines. NCTR's fiscal year research accomplishments, goals and publications are published in the NCTR Research Accomplishments and Plans document and on the web for interested parties. Research findings are presented at national and international scientific meetings and published in peer-reviewed scientific journals.Many of the scientific meetings are sponsored or co-sponsored by NCTR scientists.On a recurring basis the scientists also make presentations and invited speeches in the local university communities; and many serve on international scientific advisory boards.
Cross Reference: These performance measures support HHS Strategic Goal 2.

Use new technologies (toxicoinformatics, proteomics, metabolomics and genomics to study the risk associated with how an FDA-regulated compound or product interacts with the human body. (16014)

Context of Goal: Staying abreast of new technologies in science is important for the Agency to protect public health.This goal is designed to establish core competencies within the FDA that can form a foundation for future high technology science thus harnessing technology to apply to the drug approval process. Techniques developed under this goal will utilize the emerging knowledge of the human genome and rapid biological analyses to improve human health, and to insure the safety of marketed products.
Performance: NCTR developed a unique and sophisticated analytical infrastructure to assess the safety of FDA-regulated products using genomics, proteomics, and metabolomics in conjunction with traditional biomarkers of safety.The development of this research approach is directed toward creation of a more relevant and quantitative risk assessment paradigm. A systems biology approach to toxicity testing will provide data that will be more easily extrapolated to the human, making data interpretation more facile and relevant. The result will be new disease markers and drug targets that aid in design of products to prevent, diagnose and treat disease. Syst ems toxicology provides a step on the critical path toward applying novel technologies used in the evaluation of safety assessment in emerging issues of potential risks. Scientists are actively pursuing collaborations in the systems biology realm of research with industry, academia, and within FDA.They are been at the forefront in discussions with scientists and other federal agencies on standards development in the rapidly evolving technology. This technology is rapidly becoming a practical approach to drug safety studies and is fully expected to become a standard component in the development of new drugs.Due to redeployment in FY07, the total number of studies will decrease. This slows the incorporation of these data into the review process in determining safety of new drug submissions.

Develop computer-based models and infrastructure to predict the health risk of biologically active products. (16003)

Context of Goal: Using a scientifically based endocrine disruptor knowledge base (EDKB), FDA-regulated drugs, food additives, and food packaging have been shown to contain estrogenic activity.This raised the level of concern regarding adverse effects on human development/reproduction and contributions of these compounds to high incidences of cancer and/or risk of other diseases. Following the success achieved with the EDKB, NCTR scientists will develop modules for omics data and populate knowledge bases, to put on the desks of FDA reviewers.
Performance: The development of the knowledge base for assessing risk associated with other regulated products continues. NCTR developed an integrated Toxicoinformatic System that includes a central data archive, mirrored public databases, and analysis functions.The central data archives contain a set of relations databases that store experimental information. These databases are continually being updated, enhanced with new linkages and additional experimental data and are being used to assess compounds for NCTR, CFSAN, CDER, EPA and the European Committee for Validating Alternative Methods. Scientists used biologically based models of skin tumor development that use oncogene and tumor suppressor gene mutation frequency to describe skin tumor development. Comparisons will be made between spontaneous tumor induction, after treatment with simulated solar light (as would be encountered in a tanning salon), and after simulated solar light in combination with various cosmetic products.FDA reviewers are being trained on the software, ArrayTrack, a fully integrated system for microarray data management, analysis, and interpretation; and, are using it as a pilot for assessing voluntary pharmacogenomic data submissions from industry to the Agency. ArrayTrack is under continuous development and modules are being developed for proteomics (protein) and metabolomics (metabolism) data.With decreased program dollars due to redeployment in FY07, completion of this module for anesthetic and cardiovascular risk will be put on hold.

Develop risk assessment methods and build biological dose-response models in support of Food Security. (16007)

Context of Goal: The Agency is mandated by law to assure that the American public is eating safe food. Therefore, the Agency must strengthen its scientific basis for food security policies and regulatory decisions through the development of novel, vigorous risk assessments (models and techniques) and through the use of artificial intelligence and computational science for risk assessments. Concurrently, the Agency must accelerate the identification and characterization of mechanisms and methods development/ implementation to support surveillance and risk assessment for imported foods and/or microbial contamination.
Performance: Researchers at the NCTR, the Center for Food Safety and Applied Nutrition (CFSAN), and the Center for Veterinary Medicine (CVM) are continuing to perform studies on bacterial identification techniques both in the food supply and in microbial contamination.This research includes the elucidation of the mechanisms of resistance to antimicrobial agents among bacteria from poultry and vegetables. Microbiological experiments have been conducted that suggest a technique to reduce or eliminate contamination of the environment in agricultural uses of clinically important antibiotic drugs.The pattern of resistance development in bacteria found in animals fed antibiotic and differences in survival rates of drug-resistant pathogens compared to non-resistant pathogens will continue to be studied .Efforts included the evaluation of various molecular methods to detect and identify the foodborne pathogens Campylobacter and Salmonella species and Vibrio parahaemolyticus from various foods and environmental matrices .Development of the Salmonella biochip for rapid and accurate identification of virulence and antimicrobial resistance genes in Salmonella assists in meeting the future challenges of food biosecurity.The joint effort between NCTR and CFSAN microbiologists will be useful in transferring microarray technology to the FDA field laboratories and law enforcement mobile labs.

Develop standard biomarkers to establish risk for FDA-regulated products. (16012)

Context of Goal: Identification of biomarkers is important because it will allow rapid identification of and response to potential contamination and to signal a potential risk to the public. These proteins identify specific genes that are potential targets for introduction of foodborne pathogenicity.The methodology as well as the biomarkers will be useful for rapid identification of hazards. Scientists will be able to expand a novel approach pioneered at the NCTR to rapidly identify biomarkers of toxicity associated with biological warfare agents. These types of agents used by bioterrorists would be difficult to detect using existing technology.This research is conducted in collaboration with the Centers for Disease Control (CDC), the Department of Defense (DOD), Naval Research Labs, the Joint Institute for Food Safety and Applied Nutrition (JIFSAN) and the Center for Food Safety and Applied Nutrition (CFSAN).NCTR a Biosafety Level-3 animal quarantine facility and the laboratory can be used to evaluate the effect of possible contamination agents.Due to funding restrictions, projects that would utilize this facility have been delayed. NCTR has developed a multidisciplinary approach integrating neurochemical/neurobiological (including genomics and proteomics), neuropathological, neurophysiological, and behavioral assessments to determine adverse effects and explore modes of neurotoxic action. Unique features of NCTR's neurotoxicology research efforts are the capabilities to determine target-tissue chemical concentrations and cellular level interactions of neurotoxicants and to reduce the uncertainty associated with extrapolating findings across species by effectively using rodent and nonhuman primate animal models as well as humans, wherever possible. The nature of the ketamine- (a commonly-used pediatric sedative) induced neuronal cell death observed in the developing nonhuman primate will be studied. Control and ketamine-treated animals will be assessed using histochemical, functional, genomic, and proteomic approaches whenever possible. Studies are in process in in vivo nonhuman primates to determine exposure times and durations essential to establish safe anesthetic exposure scenarios and to develop a translational biomarker for clinical application.
Performance: Studies are being conducted to compare and contrast several new mass spectrometry techniques to more rapidly evaluate microbial risk. Scientists have shared expertise and laboratory infrastructure to prevent or minimize threats from bioterrorism through the development of a Memorandum of Agreement with the Arkansas Department of Health. Preliminary neuroimaging studies conducted in the Division of Neurotoxicology at the NCTR include developing methods for multiple imaging approaches in adult nonhuman primates. These studies include risk assessment in primates exposed to cocaine during development while others served as non-dosed controls. Functional data acquisition was accomplished with 18F-fallypride for dopamine D2 receptors and FECNT for dopamine transporters using positron emission tomography (PET).Further studies using fMRI are planned.

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Office of Management Budget Formulation and Presentation

NCTR Performance Goals

Office of Management
Budget Formulation and Presentation