2.6 NATIONAL CENTER FOR TOXICOLOGICAL RESEARCH

2.6.1 Program Description, Context, and Summary of Performance

The National Center for Toxicological Research (NCTR) conducts FDA mission-critical, peer-reviewed research that is targeted to develop a more scientifically sound basis for regulatory decisions and reduce risks associated with FDA-regulated products to protect, promote, and enhance America's public health. Specific aims of NCTR's research are:

• To develop new strategies, methods, and systems to predict toxicity and anticipate new product technology in order to support FDA's commitment to bring this technology to the market rapidly.
• To understand mechanisms of toxicity and design better risk assessment/detection techniques and methods for use in pre-market review and product health surveillance.

The NCTR provides the Agency with a high-quality, cost-effective, health science research program, which provides new scientific knowledge through the application and leveraging of research findings from the National Institutes of Health (NIH) and academia to enhance the FDA's regulatory practices. NCTR also leverages Agency scientific research resources through partnerships with other federal agencies, national and international organizations, and industry to best meet Agency needs.

As a critical resource for enhancing the science base of the FDA, the center director and scientists foster scientific forums with NCTR's stakeholders, namely the product centers and the Office of Regulatory Affairs (ORA). These recurring discussions allow NCTR the opportunity to present and validate its planned/ongoing research, as it relates to the Agency's priorities, as well as to solicit the anticipated research needs of the product centers and the ORA. NCTR's strategic research goals support the FDA's mission to bring safe and efficacious products to the market rapidly and to reduce the risks of products on the market. NCTR's strategic goals are as follows:

1. Develop new strategies and methods to test/predict toxicity and assess/detect risk for FDA regulated products (new and those already on the market).
2. Develop computer-based systems (knowledge bases) that predict human toxicity to enhance the efficiency and effectiveness of pre-market product reviews.
3. Conduct research to understand mechanisms of toxicity, assess new product technology, and provide methods for use in FDA standards development and product risk surveillance.

FY 99 Program Accomplishments

Some NCTR accomplishments that highlight the Center's multidisciplinary capabilities and high quality research are: 1) Geneticists and toxicologists developed better and new biological assays to predict human risk. 2) Preliminary studies in genetics show that women possessing a specific gene mutation in the folate metabolism pathway are more likely to have children with Down's syndrome. 3) Molecular epidemiologists worked with academia and industry to develop and validate a microchip product designed to identify individuals at risk to cancer and/or adverse drug interactions. 4) Toxicologists in partnership with industry, other government agencies and FDA Centers, have developed a computer technology to model the interaction of naturally occurring estrogen with its receptor; this technology can quickly identify chemicals or drugs with estrogenic activity that may cause unwanted effects including reactions with other drugs and therapies. 5) Through an interagency agreement with the NIH, National Institute of Environ-mental Health Sciences (NIEHS), studies to establish safe levels of the corn contaminant, fumonisin B1, in the diet were completed, and a phototoxicity center to evaluate toxic interactions between drugs or cosmetics and exposure to sunlight was constructed. 6) Within the Presidential Food Safety Initiative (FSI), NCTR scientists developed techniques to simultaneously detect multiple species of food borne pathogens, and developed a consumer product, licensed to industry under the trademark, Fresh Tag TM, to detect seafood decomposition, ensuring a safer food supply. 7) Finally, to support the Presidential Initiative on Antiterrorism, NCTR researchers have reported a novel method to rapidly identify pathogenic characteristics associated with naturally-occurring and bioengineered microorganisms that could be used in a terrorist attack; the technique works equally well with mixtures of organisms.

2.6.2 Strategic Goals

Approach

One of the Agency's and the NCTR's highest priorities is to increase the ability of FDA reviewers to evaluate and predict rapidly and accurately the adverse effects of FDA regulated human products. This capability is critical to the Agency's ability to carry out its mission to analyze the safety and efficacy of FDA-regulated products during the premarket application review process. 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 uses a multidisciplinary approach to predict human toxicity and to evaluate human risk using appropriate animal and non-animal models.

Toxicologic research, often long-term and animal intensive, studies chemical toxicity in animal and cell cultures to predict risk to humans. The science of toxicology is moving away from its dependence on whole animal test systems that use large numbers of animals and seek relatively few endpoints because costly, time intensive animal systems do not mimic human systems exactly. This forces scientists to develop and use alternate systems and tests to better understand chemical toxicity and strengthen the extrapolation from animal models to humans. Increasing evidence of adverse drug/chemical reactions in humans points to a need to identify and protect susceptible subpopulations of people at higher risk from exposure to drugs, contaminated foods, or other regulated products because the American public has greater access to these products. In addition, the emphasis of toxicologic research has shifted from descriptive studies, that explain what happens, to studies that are designed to gain a better understanding of the biological mechanisms that cause the underlying effects of a toxic agent. NCTR uses transgenic rodents (such as those carrying easily assayed reporter genes) and human cell lines to predict human toxicity (Performance Goal 1). NCTR researchers continue to develop laboratory methods that closely mimic human genetic response and predict human genetic damage due to drug interactions. Other NCTR programs through partnerships and collaborative projects with other federal agencies, use human data they have collected to understand the mechanisms of carcinogenesis, particularly as they are related to individual susceptibility (Performance Goal 2).

Human studies are conducted by our scientists in collaboration with peers at the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER); other agencies (for example, the Environmental Protection Agency (EPA), the National Institute for Environmental Health Sciences (NIEHS), the National Toxicology Program (NTP); and universities, and medical centers around the world. 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 the FDA's ability to determine and ultimately manage risk both in the United States and in collaboration with regulators and scientists throughout the world.

Performance Goals	Targets	Actual Performance	Reference1
1. Introduce the knowledge of new genetic systems into the application review process. (16001)	FY 01: Provide peer reviewed articles on new genetic and transgenic systems and knowledge to product reviewers. FY 00: New biological assay to measure genetic change and validate two existing models that predict human genetic damage. FY 99: Develop better biological assays to measure genetic changes and predict human genetic damage.	FY 01:   FY 00:   FY 99: The Big Blue Rat and NCTR Tk+/- in vivo bioassays were developed and two cell lines were used to predict human genetic damage. FY 98: Utilized model animal and cell culture transgenic systems to evaluate risk to the human genome. FY 97: Conducted genetic screening and evaluated additional toxic results (e.g., cell death and mutagenesis) in relationship to DNA biomarkers of damage.	Increase
2. Develop with other organizations gene chip and gene array technology. (16002)	FY 01: Develop, "risk chip" technology to screen large numbers of people for biomarkers simultaneously. FY 00: Conduct molecular epidemiology studies to identify biomarkers of the most frequently occurring cancers in highly susceptible subpopulations. FY 99: Complete biochemical and epidemiology studies to define the basis of susceptibility of humans to the toxicity of regulated products.	FY 01:   FY 00:     FY 99: Biochemical studies on pancreatic and colorectal cancer were completed and epidemiology studies on cancer are in the enrollment phase. FY 98: Conducted case control molecular epidemiology studies to assess breast and prostate cancer in African-American women/men. FY 97: Initiated studies to evaluate the use of molecular biomarkers in clinical studies and to identify subpopulations at increased risk.	Increase
TOTAL FUNDING: ($000)	FY 01: 17,798 FY 00: 16,068
1 Increase: Indicates achievement of the goal is dependent upon increased resources in FY 01. NPR: Goal supports an FDA National Partnership for Reinventing Government Goal

C. Goal by Goal Presentation of Performance

1. Introduce the knowledge of new genetic systems, specifically transgenic systems and data, into the application review process. (16001)

• Context of Goal: Currently, industry has been submitting drug applications with data from transgenic systems. It is critical that NCTR scientists in collaboration with Agency reviewers understand and accurately interpret data derived from these systems in safety assessment. NCTR is developing, evaluating and comparing in vivo and in vitro transgenic tools for this purpose. Reviewer request for data or information on transgenic systems will be the measure of applicability to the review process.
• Data Sources: NCTR Project Management System; peer-review through FDA/NCTR Science Advisory Board, presentations at national and international scientific meetings, manuscripts prepared for publication in peer-reviewed journals.
• Performance: A panel of transgenic cell lines has been developed and characterized; assayed phenolpthalein and diphenylhydrazine for CDER to assess mutation induction in the human genome.

2. Develop, in partnership with industry, academia, and government, gene chip and gene array technology to provide high volume screening of biomarkers for susceptible subpopulations identified in molecular epidemiology. (16002)

• Context of Goal: The importance of risk chip technology is that it allows researchers to screen large numbers of people simultaneously for different types of biomarkers. This will allow the identification of individuals at risk for adverse drug reactions and will facilitate FDA review of individual susceptibility using profiles of agents with known toxicities and allow selection of a diverse group for clinical trials. For instance, the technology will allow scientists to identify people at high risk for various cancers. Development of these techniques is being done in collaboration with private industry.
• Data Sources: NCTR Project Management System; peer-review through FDA/NCTR Science Advisory Board, presentations at national and international scientific meetings, manuscripts prepared for publication in peer-reviewed journals.
• Performance: Collaborative Research and Development Agreement established to automate the assessment of polymorphism's using gene chip technology.

Strategic Goal 2:

Approach

An Agency-wide need, as identified by the NCTR Stakeholders, is the application of unique computer-based predictive systems to aid in assessing human toxicity to optimize non-clinical and clinical predictability. The FDA reviewers face an ever-increasing quantity and complexity of data in new drug and product applications. Clearly, tools that provide reviewers quick access to relevant scientific information and a capability for predicting toxicity can expedite review decisions. The NCTR, in partnership with other FDA centers, government agencies and industries, is developing a computer-based predictive system that can predict the toxicological activity of a compound by using biological indicators of damage, chemical structures via molecular modeling, and advanced mathematical and computational tools.

Performance Goal 3 within this strategic goal is designed to build on the prototype knowledge base system established to assess estrogenic compounds. Data developed at the NCTR on the toxicity of estrogen and anti-estrogen compounds, coupled with data obtained through scientific collaborations (government, industry, and academia) and published in the literature is incorporated into a learning set for predictive computations. The NCTR adapted statistical techniques and applied computational techniques to construct this model system. This knowledge will now be applied to other receptor binding systems such as androgens, anti-thyroid compounds, and chemicals effecting the neuroendocrine system. This technology will save FDA and other agencies both time and money in evaluating over 85,000 chemicals which require testing under legislative mandate. Natural and synthetic estrogens are found in a broad range of FDA regulated compounds such as food packaging, drugs, devices, etc. Predictive modeling can assist FDA and other regulatory agencies to assess the need for regulation based on predicted toxicity and risk.

The Agency needs to maintain a strong scientific computing capability to devise better tools to facilitate product approval. NCTR uses Center and on-site contractor resources (FTEs and dollars) from analytical chemistry, computational science, neurotoxicology, genetic and reproductive toxicology, and molecular epidemiology to achieve this performance goal. The novelty of this approach is the combination of several disciplines focused on a common goal. NCTR has also partnered with the Chemical Manufacturers Association (CMA) to develop the capabilities needed.

C. Goal by Goal Presentation of Performance

3. Develop a computer based model to predict the impact of increased exposure to estrogens and anti-estrogen compounds on public health.(16003)

• Context of Goal: Recent recognition that drugs, food additives, food packaging (all regulated by FDA) and environmental chemicals (regulated by EPA) may have estrogenic activity has affected mechanisms that regulate human systems. This has raised the level of concern regarding adverse effects on human development and reproduction and contributions to high incidences of cancer and/or toxicity. NCTR scientists will identify and predict, using the Endocrine Disrupter Knowledge Base (EDKB), whether the elevation of exposure to the American public to naturally occurring and synthetic estrogens and anti-estrogens can adversely impact public health.
• Data Sources: Use of the EDKB computer-based predictive system 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.
• Performance: Predictions have been made on the estrogenic properties of specified compounds for CDER and Center for Food Safety and Applied Nutrition (CFSAN). Collaborating with EPA, NCTR is evaluating 52,000 compounds for estrogenic properties, 8,000 of these are regulated by FDA. The baseline was established in FY 99 and computer-based predictive systems used to evaluate toxins became available in FY 99.

Strategic Goal 3:

Approach

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 goal includes three performance goals that address the Agency strategy for developing science-based product and process standards.

Research supported through an interagency agreement with the NIEHS/NTP permits the NCTR to enhance rodent bioassay studies to include those based on mechanisms of toxic action to improve bioassay interpretation and potentially speed up product review and ultimately reduce the costs of pre-clinical trials (Performance Goal 4). Currently, the NCTR is conducting special studies on three compounds of special concern to the FDA: chloral hydrate, malachite green, and urethane in the presence of alcohol. Recently, phototoxicology facilities have been completed to evaluate the harmful effect of skin exfoliants, such as alpha hydroxy acid. Additionally, NCTR is conducting long-term multi-generation studies of compounds that disrupt normal endocrine function. These studies provide data on how estrogens and anti-estrogens may affect the developing fetus.

The Agency needs state-of-the-art quantitative identification of toxic agents to strengthen its risk assessment of products on the market. In collaboration with the FDA's CFSAN, Center for Veterinary Medicine (CVM) and as part of the Food Safety Initiative (Performance Goal 5), the NCTR is developing methods to identify markers of foodborne pathogens and to assess whether these microorganisms are undergoing change, thus becoming more virulent. To address the question of human risk from foodborne pathogens, NCTR scientists are working to build biologically based dose-response models of microbial infection to assess survival, growth, and infectious components of microbial risk. Research within this goal capitalizes on partnerships with other FDA centers and with other agencies such as the United States Department of Agriculture (USDA). Working with CFSAN and CVM, NCTR has committed resources to investigate the safety of genetically modified foods.

The Presidential Initiative to combat terrorist activities is a combined activity of the Department of Justice, Federal Emergency Management Agency, Department of Health and Human Services, Department of Defense (DOD), Veterans Administration, and state and local health departments. A focus of this activity is to enhance research and development to provide new capabilities to identify and to respond to potential chemical and biological threats of terrorism. NCTR is developing novel techniques to identify newly arising bacteriological and chemical contaminants in the food supply (Performance Goal 6). These techniques can crossover to provide methods of assessment for potential biochemical terrorist capabilities. To accomplish these goals, the NCTR needs continued review and input from other FDA centers, and outside experts to encourage and promote FDA-relevant research. NTP studies require the 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. The scientific expertise to support these goals range from analytical chemists to microbiology, biochemistry, molecular biology, neurotoxicology and biometry.

C. Goal by Goal Presentation of Performance

4. Conduct studies on FDA-regulated compounds to relate the mechanism(s) by which a chemical causes toxicity to the biological outcome. These studies enhance the relevance of the data for prediction of human toxicity; expand the number of FDA compounds studied by two per year. (16004)

• Context of Goal: This goal examines endocrine disrupting compounds such as nonylphenol, a component of plastic food wrap, so that the Agency can determine what adverse effects result from extensive use of plastics in packaging food materials. Resource limitations (e.g. staff, laboratory space and equipment) along with other NCTR Agency Center projects and priorities permit NCTR to initiate studies on only high priority, FDA nominated compounds. These compounds are chosen by an FDA committee for study under NIEHS/NTP Interagency Agreement. The compounds are submitted by the centers for discussion and evaluation and the representatives vote for the ones that need to be assessed via the NTP mechanism. These are taken to the NTP and if selected for funding, NCTR develops the protocols in conjunction with the nominating center and submits to NTP for review and approval. Protocols involve a comprehensive look at the chemical in question (both bioassay and mechanistic studies tailored to the regulatory questions of risk/benefit assessment.)
• Data Sources: Evidence that mechanistic data are used in the regulatory process, NCTR Project Management System; peer-review through FDA/NCTR Science Advisory Board.
• Performance: Bioassay for malachite green has been initiated to assess the toxicity of the use of this as an aquaculture antibiotic for use in aiding FDA in setting risk guidance for this chemical. The target level for FY 99 was goal 16005 in the FY 99 Performance Plan.

5. Develop methods and build biological dose-response models to replicate bacterial survival in the stomach to quickly and accurately predict risks associated with antimicrobial resistance and foodborne pathogens/contaminants. (16007)

• Context of Goal: Certain pathogens are rapidly becoming resistant to drugs due to their common use. This effort addresses this problem as part of the Presidential Food Safety Initiative to assure the American public is eating safe food.
• Data Sources: 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.
• Performance: A rapid screening method to detect the presence of 12 foodborne pathogens including Salmonella spp., Listeria monocytogenes and Campylobacter jejuni has been developed. The target level for FY 99 was goal 16006 in the FY 99 Performance Plan.

6. Identify biomarkers of toxicity associated with biological warfare agents using innovative new technologies. (16012)

• Context of Goal: A major administration initiative is the concern that biological agents may be released on the American public by a hostile force. NCTR is focusing its efforts to develop ways to quickly respond to minimize the impact. Techniques being developed in support of food safety have crossover potential to support this national effort. Identification of biomarkers is important because it will allow rapid identification of and response to potential biological threats of terrorism. These proteins identify specific genes that are potential targets for introduction of pathogenicity. The methodology as well as the biomarkers will be useful for rapid identification of hazards.
• Data Sources: 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.
• Performance: Novel mass spectrometer technique has been developed to detect and identify pathogenic microbes.

2.6.3 Verification and Validation

As a research component of the FDA, the National Center for Toxicological Research provides peer-reviewed research that supports the regulatory function of the Agency. To accomplish this mission, it is incumbent on the Center to solicit feedback from its stakeholders and partners, which include other FDA centers, other government agencies, industry and academia. Scientific program services are provided by the Science Advisory Board (SAB) composed of non-government scientists from industry, academia, and consumer organizations. The SAB is guided by a charter that defines the scope of the review to include quality of the science and the overall applicability to FDA regulatory need. This board is further supplemented with subject matter experts and scientists representing all of the FDA product centers. Programs described under each Performance Goal are evaluated at least once every five years by the SAB.

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 and technology transfer with industry, and grants or informal agreements with academic institutions.

NCTR uses several strategies 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 by and verified by internal and external peer review. Statistical analyses are performed by the principal investigator and reviewed by members of the Biometry staff. The analytic approach is checked by different members of the scientific staff and the Deputy Director for Research to verify the scientific integrity of the data.

To ensure that the performance data are accurate and timely, the NCTR Planning and/or the Quality Assurance staff uses a project management system to monitor research progress at the project level on a quarterly basis. Specific good laboratory practices are monitored by the Quality Assurance staff for the experiments that fall within these guidelines. NCTR's computer based project management system is capable of tracking planned and actual research expenditures for research projects in all three strategic goals and in the performance goals. Accomplishments and goals are published annually in the NCTR Research Accomplishments and Plans document. Publications reporting research findings are tracked by project, and final reports are archived and distributed to interested parties. Over the past four or five years, NCTR has published yearly 175-250 research documents, manuscripts, book chapters, and abstracts in recognized scientific journals.

NCTR's research findings are also 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. The scientists make over 400 presentations and invited speeches a year at local science seminars and at national and international meetings. Many NCTR scientists also serve on international scientific advisory boards.

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