STRATEGIC FUTURE
(FY 1999-2004)

The National Center for Toxicological Research (NCTR) is responsible for conducting peer-reviewed research that provides the bases for FDA to make sound science-based regulatory decisions and to promote the health of the American people through enforcement and compliance. NCTR achieves its mission by conducting fundamental and applied research designed to define the biological mechanisms of action underlying the toxicity of products regulated by the FDA. Specific aims of NCTR's research are to understand critical biological events in the expression of toxicity and to develop methods to improve assessment of human exposure, susceptibility, and risk.

Over the next five years, NCTR will face an environment characterized by scientific challenges, continued advances in science and technology, increasingly complex regulatory challenges, and more constrained resources. Toxicologic research, often long-term and animal-intensive, has traditionally sought to understand the toxicity of chemicals through whole animal and cell culture exposure. Toxicologic data resulting from such studies have been used to predict risk to humans. The science of toxicology is moving away from its dependency on whole animal test systems that use large numbers of animals and seek relatively few endpoints. Although extrapolation from animal models to humans has been helpful, animal models have their limitations. Increasing evidence points to a need to identify and protect susceptible subpopulations of people because protecting the average person does not protect the large number of people who may be at higher risk from exposure to drugs, contaminated food, or other regulated products. In addition, the emphasis of toxicologic research has shifted from descriptive studies to studies that are designed to gain a better understanding of the biological mechanisms that cause toxic reactions.

New technologies have enhanced scientific assessment capabilities. The challenge is to apply these new technologies where appropriate to detect risk, ensure safety of FDA-regulated products, and to act in the best interest of the public. The FDA has expedited drug, device and biologic approval procedures to provide needed therapies to consumers more quickly. Continued improvement in this area is expected. Research results that improve the ability of FDA reviewers to evaluate product safety more rapidly and to estimate human risks more accurately are vital to continuing improvements in this area. The development of international trade alliances has increased the need to demonstrate scientifically, mechanisms of action that either provide for safety or improved risk assessment. To accomplish this, the FDA will require global scientific consultation and support.

Financial constraints and increases in the FDA's workload have increased the demand for more efficient, rapid, and economical test methods for assessing human risk in FDA headquarters and field laboratories. To respond to these challenges, the NCTR will continue to support the Agency's overall strategy by maintaining a high-quality, cost-effective research program that is responsive to the Agency's regulatory needs and supports FDA's ability to provide the desired level of consumer protection. NCTR will strive to find better and more economical means of protecting consumers and will focus its research efforts on the Agency's highest priority issues. The Center will continue to leverage research resources through partnerships with other Federal agencies, national and international organizations, universities, and industry to best meet Agency needs.

NCTR, in partnership with other institutions, will develop methods for improving human risk assessment by applying a multi-disciplinary scientific approach to assess toxicity of compounds of regulatory significance to FDA. NCTR will work with scientists in the FDA product centers to develop a computerized systemóa knowledge baseóthat will provide regulators with desktop access for interpretation of scientific data to predict adverse effects on human health. The utility of such a knowledge base is its ability to predict relevant chemical toxicity in humans and animals based on the structure of a drug or a chemical and its capability to reduce analysis time for compounds under review at the FDA.

NCTR is developing new predictive systems that will provide the use of state-of-the-art technology in answering difficult regulatory questions more quickly and with fewer resources. NCTR's new strategies for predicting toxicity include using new test systems that are based on understanding the smallest details of how a chemical produces a toxic effect; refining new and existing tests, as well as conducting studies that help reduce the uncertainty of extrapolating laboratory animal data to humans. Predictive systems will support FDA decisions regarding toxicity and will guide the design of subsequent toxicity research that will come ever closer to predicting human risk, quickly and less expensively.

NCTR will continue to collaborate and consult with scientists from FDA product centers and the Office of Regulatory Affairs in conducting agent-, method-, and concept-driven research to support the expanding regulatory focus of the FDA. Agent-driven research will focus on providing data when there is not an identifiable manufacturer or the scientific literature is weak on specific agents, such as estrogenic compounds, neurotoxins, mold contaminants on food, aquaculture therapeutics, and cosmetic exfoliants. Method-driven research will focus on developing and applying new toxicological and analytical test methods for more rapid, yet sensitive detection of bacterial pathogens and toxins in foods and drugs.

NCTR's research is guided by a comprehensive peer-review process. A Science Advisory Board composed of outside experts and FDA center science liaisons routinely evaluates and advises senior management on NCTR's quality and direction of each research area.

STRATEGIC GOAL AREA: PREMARKET REVIEW

FY 1999 Performance Goal Highlights Demonstrate a model toxicity knowledge base to support and expedite product review.

Cluster Rationale: NCTR's highest priority is to assist FDA product centers make timely and cost-effective premarket review decisions by developing knowledge bases to aid in assessing human toxicity. FDA reviewers face an ever-increasing quantity and complexity of data in new drug and product applications. Clearly, tools that can provide reviewers quick access to relevant scientific information and a capability for predicting toxicity would expedite review decisions. NCTR, in consultation with other FDA centers, government agencies and industries, is developing a knowledge base that will predict the toxicological activity of a compound by using biological indicators of damage, chemical structures via molecular modeling, and advanced mathematical and computer tools.

This cluster contains a single performance goal: to demonstrate a model toxicity knowledge base to support and expedite product review. Data developed at NCTR on the toxicity of estrogen and antiestrogen compounds is being coupled with data obtained through scientific collaborations (government, industry and academic) and published in literature and is being incorporated into a learning set for predictive computations. NCTR is adapting statistical techniques and applied computational techniques to construct this model knowledge base.

Knowledge base systems developed by FDA scientists can be used by reviewers and scientists outside of the FDA and the concept can be applied to other products being developed to improve human health. The proposed utility of knowledge bases is in their ability to enhance prediction of chemical toxicity in humans based on structure and known mechanistic interactions. Scientific data generated and published throughout the world can be incorporated into specific knowledge bases to answer complex questions within FDA, other government regulatory organizations, and industry, since the system will be made available publicly.

Resources, Approaches, Processes, Skills, and Technologies: The Agency will need to maintain a strong scientific computing capability to devise ever-better tools to facilitate product approval. NCTR will use Center and on-site contractor resources (FTEs and dollars) from analytical chemistry, computational science, and genetic and reproductive toxicology to achieve this performance goal. The Center has an on-site information technology capability that provides expertise in the molecular modeling, structure activity relationships, 3-dimensional chemical structure and the selection and acquisition of hardware and software for future developments and improvements. The novelty of this approach is the union of several disciplines focused on a common goal.

STRATEGIC GOAL AREA: PREMARKET REVIEW

FY 1999 Performance Goal Highlights Develop better biological assays to measure genetic changes and predict human genetic damage. Conduct biochemical and epidemiological studies to define the basis for susceptibility of humans to the toxicity of regulated products.

Cluster Rationale: The human response to a toxic agent is a complex process. To adequately predict the adverse effects of human exposure to a toxic agent, a group of tests must be developed, validated, and applied. NCTR is using a multi-disciplinary approach to predict human toxicity and evaluate human risk using appropriate model systems.

Human studies are conducted by our scientists in collaboration with peers at the Center for Biologics Evaluation and Research and the Center for Drug Evaluation and Research, other agencies, universities, and medical centers around the world.

NCTR will use transgenic rodents (i.e., those carrying human genes) and human cell lines to predict human toxicity. NCTR researchers are continuing to develop laboratory methods that closely mimic human genetic response and predict human genetic damage. Use of the neonatal mouse assay will provide information about the toxicity of agents in a developing animal, information not provided by the more traditional studies in adult rodents. Moreover, traditional studies in adult rodents take longer than those conducted in the neonatal mouse assay. Other NCTR programs are using human data to understand the mechanisms of carcinogenesis particularly as they are related to individual susceptibility. International collaborative studies exploring human biomarkers will help to identify and potentially screen subpopulations at higher risk for developing certain types of cancer. This will improve FDA's ability to determine and ultimately manage risk both in the United States and in collaboration with regulators and scientists throughout the world.

A single approach for risk assessment of both cancer and noncancer health outcomes is an important goal for FDA's risk assessment staff. Existing cancer and noncancer databases are being examined by FDA centers and are useful in helping to predict a broad spectrum of human risk. A new emerging project in the risk assessment area involves determining human risk from foodborne pathogens. This work is being proposed under the FDA Food Safety Initiative.

Resources, Approaches, Processes, Skills, and Technologies: Information technology will help evaluate human models and monitor neonatal mouse studies. To accomplish these goals, a strong collaborative effort must continue to be fostered within the Agency and external partnerships must be encouraged, established, and maintained. Communication between scientists and reviewers, as exemplified in the most recent FDA Science Forum, will ensure that complex scientific issues are addressed quickly and that critical data are available to regulators.

STRATEGIC GOAL AREA: POSTMARKET ASSURANCE

FY 1999 Performance Goal Highlights Support product review by developing faster, more accurate tests based on mechanisms of toxic action. Develop rapid and sensitive foodborne bacteria methods for identifying pathogens, and microbial contaminants.

Cluster Rationale: Most regulatory research begins as a precise exploration of a specific agent, a concept, or the use of a particular method. Once techniques are developed, these novel approaches can be applied to answer compelling questions of human health and safety. This cluster includes two performance goals that address the Agency strategy of developing science-based product and process standards.

Agent-driven research supported through an interagency agreement with the National Institute for Environmental Health Sciences (NIEHS)/ National Toxicology Program (NTP) has permitted NCTR to enhance the rodent bioassay to include the use of studies based on mechanisms of toxic action to improve bioassay interpretation and potentially speed up product review. Currently, NCTR is conducting special studies on four compounds of special concern to FDA: chloral hydrate, fumonisin B1, malachite green, and urethane in the presence of alcohol. Work is underway to develop testing protocols for the widely used skin exfoliants, alpha hydroxy acids. NCTR has started long-range multi-generation studies of compounds that disrupt normal endocrine function. These studies are designed to provide data on how estrogens and anti-estrogens may affect the developing fetus.

The Agency's need for state-of-the-art quantitative identification of toxic agents to strengthen the Agency's postmarket assurance is the basis of NCTR's method-driven research effort. In collaboration with FDA's Center for Food Safety and Nutrition (CFSAN), and as part of the Food Safety Initiative, NCTR is developing methods to identify microorganisms in food and to assess whether these microorganisms are undergoing change, thus becoming more virulent.

Research within this cluster capitalizes on partnerships with other FDA centers and with other agencies such as NIEHS and the United States Department of Agriculture (USDA). Regular meetings of scientific experts are held to develop a consensus on the best approach to take in improving the science-based process for the Agency.

Resources, Approaches, Processes, Skills, and Technologies: To accomplish these goals, NCTR needs continued review and input by other FDA centers, the Office of Regulatory Affairs, and outside experts to encourage and promote FDA-relevant research. National Toxicology Program studies require NCTR to maintain an accredited animal facility that includes a quality assurance staff, pathology capabilities, computerized record keeping, and high-quality animal husbandry and diet preparation support.

FDA's Science Board emphatically affirmed the need for a vigorous, high quality intramural program of scientific research which will provide the essential foundation of sound regulatory policy and performance. It was their position that such a program would ensure that the FDA is, and will continue to be, best positioned to carry out its statutory responsibilities.

Research conducted within this cluster requires a broad range of scientific expertise (i.e., analytical chemistry, microbiology, biochemistry, molecular biology, and biometry). Scientists within NCTR work collaboratively with Agency peers and in partnership with other agencies via interagency agreements and with industry via cooperative research and development agreements to achieve the outcomes desired.

Strategic Goal Area:	PREMARKET REVIEW
Cluster:	Build Knowledge Bases
1. Demonstrate a model toxicity knowledge base to support and expedite product review.
Agency Strategies:	Develop science-based standards; Streamline reviews.
Data Sources:	Evaluation of the prototype Estrogen Knowledge Base by FDA reviewers.
Baseline Data:	FY 1995:	A knowledge base strategy was developed.
	FY 1996:	Computer hardware and software were procured and installed and systems integration was completed.
	FY 1997:	Prototype presented at FDA Science Forum.

Strategic Goal Area:	PREMARKET REVIEW
Cluster:	Develop New Strategies for the Prediction of Toxicity
1. Develop better biological assays to measure genetic changes and predict human genetic damage.
Agency Strategies:	Develop science-based standards; Streamline reviews.
Data Sources:	FDA product center liaisons confirm data from these studies beneficial to evaluate human health concerns.
Baseline Data:	FY 1994:	Completed genetic toxicity evaluation of the pediatric sedative, chloral hydrate, in human transgene system.
	FY 1995:	Evaluated programmed cell death (apoptosis) induced by chloral hydrate and tamoxifen.
	FY 1996:	Expanded number of endogenous and exogenous reporter gene systems.
	FY 1997:	Conducted genetic screening and evaluated additional toxicity induced outcomes (e.g., cell death and mutagenesis) and their relationship to DNA adducts.
2. Complete biochemical and epidemiology studies to define the basis of susceptibility of humans to the toxicity of regulated products.
Agency Strategies:	Develop science-based standards; Streamline reviews.
Data Sources:	Human biomarker monitoring using chemical and epidemiologic studies which characterize biomarkers of cancer for use in risk assessment.
Baseline Data:	FY 1995:	Developed scientific staff to address extrapolation of toxicity data.
	FY 1996:	Developed world-wide collaboration effort to measure biomarkers of cancer.
	FY 1997:	Studies underway to use molecular biomarkers in clinical studies and identify subpopulations at increased risk.
3. Develop modeling tools to predict better risk for cancer, reproductive, developmental, neurological, genetic, and acute toxicological outcomes.
Agency Strategies:	Develop science-based standards; Streamline reviews.
Data Sources:	Confirm the value of a model risk assessment procedure for cancer, reproductive, developmental, neurological, genetic and acute toxicological endpoints via publication and peer review evaluation.
Baseline Data:	FY 1994:	Worked with CDER on statistical guidance for design analysis and interpretation of animal tumorigenicity studies.
	FY 1995:	Participated in national and international conferences and committees on risk assessment procedures.
	FY 1996:	Developed and analyzed an approach to safely assess carcinogenic, reproductive, developmental, neurological, genetic and acute toxicology endpoints.
	FY 1997:	Concept was reviewed by an outside group of experts and prepared for publication.

Strategic Goal Area:	POSTMARKET ASSURANCE
Cluster:	Conduct Agent-, Concept-, and Method-Driven Research
1. Support product review by developing faster, more accurate tests based on mechanisms of toxic actions.
Agency Strategies:	Develop science-based product and process standards.
Data Sources:	Results of the bioassays and mechanistic studies on high priority FDA compounds are available to FDA reviewers to assist in risk assessment.
Baseline Data:	FY 1994:	Rangefinding study on chloral hydrate completed. Acute toxicity study on fumonisin B1 initiated.
	FY 1995:	Chronic bioassay (2-year studies) started on chloral hydrate and fumonisin B1.
	FY 1996:	Two new compounds of interest to FDA were nominated, malachite green and urethane in the presence of alcohol.
	FY 1997:	Complete dosing regimen for two year chronic bioassay on chloral hydrate and Fumonisin B1. Rangefinding studies on genistein, methoxychlor and nonylphenol were initiated plus a multi-generation study of endocrine disruptors was initiated. Phototoxicity assessment of alpha hydroxy acids was nominated for study.
2. Develop rapid and sensitive methods for identifying pathogens, foodborne bacteria, and microbial contaminants.
Agency Strategies:	Develop science-based product and process standards.
Data Sources:	Complete validation of PCR methods and initiate transfer to other FDA centers. Propose methods for Bacteriological Analytical Manual.
Baseline Data:	FY 1994:	Developed species-specific DNA probes for rapid detection of anaerobic bacteria.
	FY 1995:	Developed PCR and Mass Spectrometry procedures to detect and identify major foodborne bacteria fungi of FDA concern.
	FY 1996:	Applied 13 sets of DNA primers to the identification of 11 foodborne pathogens.
	FY 1997:	Developed new protein based mass spectral techniques to identify mutant bacteria.