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National Center for Toxicological Research Performance Detail FY 2012 OPA

Table of Contents FY 2012 OPA

Long Term Objective:  Advance Regulatory Science and Innovation

 

Measure

FY

Target

Result

262401: Develop biomarkers to assist in identifying the correlation between an individual’s nutrition, genetic profile, health, and susceptibility to chronic disease in support of personalized nutrition and health. (Output)

2012

1) Develop analytical methods to assess drug-induced heart damage

2) Identify target genes for obesity and the consequent development of metabolic syndrome diseases and heart disease

December 2012

2011

Identify target genes that can predict potential for obesity and type 2 diabetes to provide individually tailored therapeutic treatment and dietary guidelines for use in improving health

December 2011

2010

Identify patterns in serum biomarkers to use in monitoring dietary intervention protocols to reduce obesity

Patterns were identified from analysis of 2009 CBPR data and preliminary analysis of 2010 CBPR data in serum biomarkers that can be used to monitor dietary intervention protocols to reduce obesity.  (Target Met)

2009

N/A

Incorporated the linkage between physical responses to a healthier diet and genetic analyses via the Community Based Participatory Research (CBPR) project resulting in 45 blood samples and approximately 660,000 genotypes (genetic makeup) identified for each participant

(Historical Baseline)

2008

N/A

Examined the effects of better nutrition on serum levels of certain vitamins and metabolites in children via the CBPR project.

(Historical Baseline)

2007

N/A

N/A

 

 

Measure

Data Source

Data Validation

262401

NCTR Project Management System; peer-review through FDA/NCTR Science Advisory Board (SAB) and the NTP Scientific Board of Counselors; presentations at national and international scientific meetings; use of the predictive and knowledge-based systems by the FDA reviewers and other government regulators; and manuscripts prepared for publication in peer-reviewed journals.

NCTR provides peer-reviewed research that supports FDA’s regulatory function. To accomplish this mission, it is incumbent upon NCTR to solicit feedback from its stakeholders and partners, which include FDA product centers, other government agencies, industry, and academia. The NCTR SAB —composed of non-government scientists from industry, academia, and consumer organizations, and subject matter experts representing all of the FDA product centers—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 high quality programs and overall applicability to FDA’s regulatory needs. Scientific and monetary collaborations include Interagency Agreements with other government agencies, Cooperative Research and Development Agreements that facilitate technology transfer with industry, and informal agreements with academic institutions. NCTR also uses an in-house strategy to ensure the high quality of its research and the accuracy of data collected. Research protocols are often developed collaboratively by principal investigators and scientists at FDA product centers and are developed according to a standardized process outlined in the “NCTR Protocol Handbook.” NCTR’s Project Management System tracks all planned and actual expenditures on each research project. The Quality Assurance Staff monitors experiments that fall within the Good Laboratory Practices (GLP) guidelines. NCTR’s annual report of research accomplishments, goals, and publications is published and available on FDA.gov. Research findings are published in peer-reviewed journals and presented at national and international scientific conferences.

 

Measure

FY

Target

Result

263101: Use new omics technologies and pattern-recognition algorithms to analyze imaging data for early-stage disease diagnosis and to study how an FDA-regulated compound or product interacts with the human body. (Output)

2012

1) Establish an imaging consortium of scientific experts from NCTR, CDER, and from other government agencies, industry, and academia to refine the imaging tools

2) Build a knowledge base to annotate existing drug-risk factor associations of immune-related drug reactions

3) Determine pathways of toxicity and preventive strategies for pediatric anesthetics using a high-speed, high-volume method (zebrafish)

December 2012

2011

1) Implement the Voluntary Exploratory Data Submission (VXDS) tool, called VISIONS (VXDS/ Interdisciplinary Pharmacogenomics Review Group (IPRG) Status and Information ON-line System) to accelerate the regulatory review process

2) Present preliminary data on markers that indicate nervous system damage from pediatric anesthetic use at national scientific meetings which may lead to improved guidelines

December 2011

2010

1) Create a demonstrable tool to use in the drug-review process based upon the liver toxicity knowledge base

2) Develop translatable biomarkers for studying pediatric products (e.g. ketamine, methylphenidate, etc.)

1) Developed drug selection criteria for the Liver Toxicity Knowledge Base, collected data, performed high-content assays, and developed a systematic approach to characterize the potential risk of liver injury of these drugs. Tool is being piloted.

(Target Met)

2) Established zebrafish facility for toxicity assessments and have eliminated some potential candidates, narrowing search and evaluating data to identify translatable biomarkers.

(Target Met)

2009

Analyze imaging data by application of pattern-recognition algorithms to other tissues and diseases

1) Reviewed novel methods to normalize the spectra generated from various magnetic resonance imaging (MRI) scanners, an approach that will translate across tissues

(Target Met)

2) Improved pattern recognition algorithms to interpret complex Magnetic Resonance Spectroscopy (MRS) scans to an accuracy rate of over 96% for nine types of tissues

(Target Met)

2008

1) Identify omics data in the review process

2) Determine limitations of the algorithms (e.g. staging disease)

1) Reviewed seven VXDS submissions using omics tools
(Target Met)

2) Developed algorithm to classify four disease categories
(Target Met)

2007

1) Test systems biology in drug review process to assess value in drug review and approval

2) Develop proof-of-principle that pattern recognition can supplement MRS brain scan interpretation

1) Developed urinary biomarkers for kidney failure

(Target Met)

2) Identified azidothymidine (AZT) effects on mitochondria

(Target Met)

3) Successfully developed prototype algorithm from 30 MRS brain scans
(Target Met)

263102: Develop computer-based models and infrastructure to predict the health risk of biologically active products. (Output)

2012

Develop 3D/4D Quantitative Spectrometric Data-activity Relationship (QSDAR) models for predicting endocrine disruptor activity

December 2012

2011

Deliver the alpha version of the FDA SNPTrack to support the FDA review of pharmacogenetics (how genetic variations affect individual responses to drugs) data and provide more personalized treatment options

December 2011

2010

 Develop molecular signature and biomarker modules in  

 ArrayTrack to support VXDS

Molecular signature and biomarker functions developed in ArrayTrack to support VXDS (Target Met)

2009

Expand ArrayTrack™ to include two new libraries and classification methods for model building and predictions on clinical, nonclinical, and toxicological microarray data

Developed ArrayTrack™ Version 3.5.0

(Target Met)

2008

Create bioinformatics data package

Developed SNPTrack Version 1
(Target Met)

2007

Increase the utility of ArrayTrack™ and training for reviewers

1) Completed JMP® and ArrayTrack™ integration

(Target Met)

2) Offer regulatory training on ArrayTrack™ to reviewers
(Target Met)

 

Measure

Data Source

Data Validation

263101
263102

NCTR Project Management System; peer-review through FDA/NCTR SAB and the NTP Scientific Board of Counselors; presentations at national and international scientific meetings; use of the predictive and knowledge-based systems by the FDA reviewers and other government regulators; and manuscripts prepared for publication in peer-reviewed journals.

NCTR provides peer-reviewed research that supports FDA’s regulatory function. To accomplish this mission, it is incumbent upon NCTR to solicit feedback from its stakeholders and partners, which include FDA product centers, other government agencies, industry, and academia. The NCTR SAB —composed of non-government scientists from industry, academia, and consumer organizations, and subject matter experts representing all of the FDA product centers—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 high quality programs and overall applicability to FDA’s regulatory needs. Scientific and monetary collaborations include Interagency Agreements with other government agencies, Cooperative Research and Development Agreements that facilitate technology transfer with industry, and informal agreements with academic institutions. NCTR also uses an in-house strategy to ensure the high quality of its research and the accuracy of data collected. Research protocols are often developed collaboratively by principal investigators and scientists at FDA product centers and are developed according to a standardized process outlined in the “NCTR Protocol Handbook.” NCTR’s Project Management System tracks all planned and actual expenditures on each research project. The Quality Assurance Staff monitors experiments that fall within the GLP guidelines. NCTR’s annual report of research accomplishments, goals, and publications is published and available on FDA.gov. Research findings are published in peer-reviewed journals and presented at national and international scientific conferences.

 

Measure

FY

Target

Result

263201: Develop science base for supporting FDA regulatory review of new and emerging technologies. (Output)

2012

Develop new characterization methods for nano-based zinc oxide within FDA-regulated products

December 2012

2011

Validate FDA standard operating procedures (SOPs) for detection of nanoscale materials in FDA-regulated products in collaboration with ORA/Arkansas Regional Laboratory (ORA/ARL)

December 2011

2010

 Establish and implement SOPs  

 in research protocols for

 detection of nanoscale materials  in FDA-regulated products in collaboration with ORA/ARL

Established and implemented three SOPs for research protocols to detect nanoscale materials in FDA-regulated products in collaboration with ORA/ARL.

(Target Met)

2009

Establish an operational joint NCTR/ORA Nanotechnology Core Facility to provide analytical support, materials characterizations, and electron microscopy support for nanomaterial studies

Established and operationalized the NCTR/ORA Nanotechnology Core Facility

(Target Met)

2008

N/A

N/A

2007

N/A

N/A

 

Measure

Data Source

Data Validation

263201

NCTR Project Management System; peer-review through FDA/NCTR SAB and the NTP Scientific Board of Counselors; presentations at national and international scientific meetings; use of the predictive and knowledge-based systems by the FDA reviewers and other government regulators; and manuscripts prepared for publication in peer-reviewed journals.

NCTR provides peer-reviewed research that supports FDA’s regulatory function. To accomplish this mission, it is incumbent upon NCTR to solicit feedback from its stakeholders and partners, which include FDA product centers, other government agencies, industry, and academia. The NCTR SAB —composed of non-government scientists from industry, academia, and consumer organizations, and subject matter experts representing all of the FDA product centers—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 high quality programs and overall applicability to FDA’s regulatory needs. Scientific and monetary collaborations include Interagency Agreements with other government agencies, Cooperative Research and Development Agreements that facilitate technology transfer with industry, and informal agreements with academic institutions. NCTR also uses an in-house strategy to ensure the high quality of its research and the accuracy of data collected. Research protocols are often developed collaboratively by principal investigators and scientists at FDA product centers and are developed according to a standardized process outlined in the “NCTR Protocol Handbook.” NCTR’s Project Management System tracks all planned and actual expenditures on each research project. The Quality Assurance Staff monitors experiments that fall within the GLP guidelines. NCTR’s annual report of research accomplishments, goals, and publications is published and available on FDA.gov. Research findings are published in peer-reviewed journals and presented at national and international scientific conferences.

 

Measure

FY

Target

Result

264101: Develop risk assessment methods and build biological dose-response models in support of food protection. (Output)

2012

Expand Rapid B system to include new pathogen-specific (PS) assays (tests)

December 2012

2011

1) Develop base guidelines to assess extent of kidney toxicity caused by the combination of melamine and cyanuric acid and ultimately improve diagnosis and treatment

2) Develop and initiate protocols (research/study design, approach, and methods) for RAPID-B tests for viruses and toxins to aid FDA in protecting public health from viruses and toxin contamination

December 2011

2010

1) Rapidly detect toolkits for  

foodborne pathogens applicable  to fresh produce; evaluate in  field situations

2) Develop and initiate approved protocols for Bisphenol A (BPA), a component in baby bottles and formula containers

1) Developed and validating field-rugged technologies for rapid screening of samples to rule in, or rule out, contamination with select foodborne pathogens applicable to fresh produce

(Target Met)

2) Research completed on Bisphenol A (BPA) resulting in the publication of data to improve the prediction of internal exposures of target tissues in human infants and fetuses.

(Target Met)

2009

1) Detect rapid pathogen

2) Identify antibiotic resistance markers

1) Validated RAPID-B  detection of E. coli in nine food types

(Target Met)

2) Identified 775 antimicrobial resistance genes in Salmonella

(Target Met)

2008

Develop ricin screening assay

Developed cell-based assay and polymerase chain reaction (PCR)-based biochemical assay
(Target Met)

2007

Develop flow cytometry technology

1) Developed test kits and methods for pathogens

(Target Met)

2) Developed additional Salmonella biochip
(Target Met)

 

Measure

Data Source

Data Validation

264101

NCTR Project Management System; peer-review through FDA/NCTR SAB and the NTP Scientific Board of Counselors; presentations at national and international scientific meetings; use of the predictive and knowledge-based systems by the FDA reviewers and other government regulators; and manuscripts prepared for publication in peer-reviewed journals.

NCTR provides peer-reviewed research that supports FDA’s regulatory function. To accomplish this mission, it is incumbent upon NCTR to solicit feedback from its stakeholders and partners, which include FDA product centers, other government agencies, industry, and academia. The NCTR SAB —composed of non-government scientists from industry, academia, and consumer organizations, and subject matter experts representing all of the FDA product centers—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 high quality programs and overall applicability to FDA’s regulatory needs. Scientific and monetary collaborations include Interagency Agreements with other government agencies, Cooperative Research and Development Agreements that facilitate technology transfer with industry, and informal agreements with academic institutions. NCTR also uses an in-house strategy to ensure the high quality of its research and the accuracy of data collected. Research protocols are often developed collaboratively by principal investigators and scientists at FDA product centers and are developed according to a standardized process outlined in the “NCTR Protocol Handbook.” NCTR’s Project Management System tracks all planned and actual expenditures on each research project. The Quality Assurance Staff monitors experiments that fall within the GLP guidelines. NCTR’s annual report of research accomplishments, goals, and publications is published and available on FDA.gov. Research findings are published in peer-reviewed journals and presented at national and international scientific conferences.

1.      Develop biomarkers to assist in identifying the correlation between an individual’s nutrition, genetic profile, health, and susceptibility to chronic disease in support of personalized nutrition and health. (262401)  

 

Context:  NCTR’s goal is to define the correlations between an individual’s nutrition, genetic profile, health, and susceptibility to chronic disease in support of personalized nutrition and health. This research will provide baseline data that supports the FDA goal of providing consumers clear and timely information to help promote personalized nutrition and health. Identifying biomarkers of health, susceptibility to chronic disease, and gene-micronutrient interactions is essential to gaining a more complete scientific understanding of health. NCTR is implementing a novel research program for personalized nutrition and health that relies on the “challenge homeostasis” concept for identifying markers of health and susceptibility. This approach implements a safe, but acute, challenge to the body’s ability to regulate and maintain balance. NCTR will use its current omics capabilities, in conjunction with its expanded genomic analyses capabilities, to conduct this research. The intervention design proposed by NCTR establishes a model that may be used by the emerging International Micronutrient Genomics Project that will compare gene-micronutrient interactions across populations and cultures.

 

Performance:  NCTR’s Division of Personalized Nutrition and Medicine (DPNM) expanded its research into identifying correlations between an individual’s nutrition, genetic profiles, and health. Since 2008, FDA/NCTR and USDA/ARS have had an ongoing partnership with a community development center in the Mississippi Delta region of Arkansas to conduct community-based participatory research (CBPR) that studies the effects of dietary intake and its influence on the development of obesity-associated diseases. This ongoing collaboration analyzes dietary intake patterns, micronutrient levels in the blood samples of children and adults, and calories expended.  In 2010, scientists from NCTR analyzed data from the 2009 CBPR study using standard statistical approaches and novel methods to assess individual responses. The result of the analyses identified patterns in serum biomarkers that could be used to monitor dietary intervention protocols to reduce obesity. In FY 2011, NCTR plans to analyze the DNA sequence of 400 candidate genes from the CBPR participants to identify target genes that can predict potential for obesity and type 2 diabetes.  For FY 2012, NCTR will continue to identify target genes for obesity and the consequent development of metabolic syndrome diseases and heart disease. In addition, NCTR will develop analytical methods to assess drug-induced heart damage to provide data on the mechanisms underlying heart damage caused by therapeutic drug treatment. New methods that lead to earlier detection may reduce the rate of severe heart failure and improve therapeutic patient treatment.

 

2.      Use new omics technologies and pattern-recognition algorithms to analyze imaging data for early-stage disease diagnosis and to study how an FDA-regulated compound or product interacts with the human body. (263101)

 

Context:  With the advent of new technologies such as toxicoinformatics, proteomics, metabolomics, and genomics, and the expanding capabilities of noninvasive imaging technologies, FDA has the necessary tools to detect disease at an earlier stage and to better understand how an FDA-regulated compound or product interacts with the human body. The accelerated rate at which technological advances are being made in the marketplace dictates that FDA accelerate its rate of innovation in the regulatory-research arena. Combining genomic knowledge with microPET imaging (Positron Emission Tomography imaging for small animals) is expected to facilitate the search for genetic predictors of drug response. Devices such as microPET that reveal clinical and pharmacogenomic information will serve to individualize medicine both for the diagnosis and treatment of disease, and allow for monitoring the efficacy of treatment regimens. The enormous amount of data generated by these technologies also requires the development of new tools to allow researchers and reviewers to use the data to evaluate potential risks related to use of an FDA-regulated compound or product.

   

Performance: In the spring of FY 2010, NCTR established a zebrafish facility that has already yielded data on translatable biomarkers to assess pediatric products such as ketamine and methylphenidate. These research findings will help the medical community understand the relationship between the amount, type, duration, and frequency of pediatric anesthetic use and its adverse effects on children in order to provide rapid screening tests and understand pathways of toxicity and prevention of pediatric anesthetics. In addition, in FY2010 NCTR developed a set of criteria to select drugs for the Liver Toxicity Knowledge Base (LTKB) project, collected risk factors and mechanistic data for them from literature, and developed a systematic approach to characterize the potential risk of liver injury of these drugs. The development of a knowledge base for liver toxicity will be useful as a hypothesis-generating tool for designing liver toxicity-related experiments and as a reference tool in the FDA drug approval process.

In FY 2011, NCTR will implement a VXDS data submission tool, called VISIONS that will accelerate the regulatory-review process. In addition, researchers will present preliminary data on markers that indicate nervous system damage from pediatric anesthetic use at national scientific meetings which may lead to improved product-use guidelines. For FY 2012, NCTR will continue its research in pediatric anesthetics by discovering pathways of toxicity and preventive strategies using a high-through, high-volume method. In addition, NCTR will utilize scientific expertise from across government and academia to refine the imaging tools and plans to build a database that will contain information on known drug-risk factor associations of immune-related drug reactions.

 

3.      Develop computer-based models and infrastructure to predict the health risk of biologically active products. (263102)

 

Context:  To effectively support large datasets generated using new technologies such as toxicoinformatics, proteomics, metabolomics, and genomics, NCTR scientists develop and enhance scientific analytical software in collaboration with colleagues from government, academia, and industry to advance the incorporation of this data analysis into the regulatory process. NCTR’s key objective is to develop computer-based models and infrastructure to predict the health risk of biologically active products. NCTR scientists invented ArrayTrack™, a software that allows for the management, analysis, and interpretation of vast amounts of omics data and is an important tool for the American public to benefit from the vast amount of bioinformatic data being generated from the new technologies. The expanded use of ArrayTrack™ and other bioinformatic tools allows FDA to support the rapid translation of scientific research into reliable and safer treatments and better risk evaluations by improving the analysis and management of available data.

 

Performance: In FY 2010, NCTR enhanced the ArrayTrack™ tool by adding a protein and metabolite panel and a Gene Ontology for Functional Analysis (GOFFA) library, as well as a Support Vector Machine for outcome prediction and data mining. ArrayTrack allows for the addition of new capabilities to handle priorities and evolving technologies and now includes a Microbial Library and new data processing and visualization tools. NCTR’s goal in FY 2011 is to deliver the alpha version of the FDA SNPTrack to support the FDA review of pharmacogenetics data and provide more personalized treatment options. In FY 2012, NCTR’s goal is to develop a 3-D/4-D Quantitative Spectral Data Activity Relationships (QSDAR) model that will predict endocrine disruptor activities.

 

4.      Develop science base for supporting FDA regulatory review of new and emerging technologies. (263201)

 

Context:  NCTR’s goal to develop a science base to support the FDA regulatory review of new and emerging technologies by establishing a joint NCTR/ORA Nanotechnology Core Facility will strengthen the FDA’s ability to prevent potential health-endangering products from entering the marketplace. It is anticipated that NCTR’s nanotechnology research program will expand as the number of nanoscale products that the regulated community seeks to market increases. The FDA has already reviewed and approved some nanotechnology-based products, and expects a significant increase in the use of nanoscale materials in drugs, devices, biologics, cosmetics, and food. Improved understanding of nanomaterials, their transport, and their toxicity will provide a framework for regulatory guidelines for safe and effective use of nanomaterials in FDA-regulated foods, cosmetics, and medical products and provide early recognition of potential safety issues before they become adverse events in the patient population.

 

Performance:  To strengthen FDA’s nanotechnology product evaluation capability, in FY 2010 the NCTR/ORA Nanotechnology Core Facility was opened, equipped, and staffed with a Senior Electron Microscopy Technician and a Staff Fellow with expertise in nanotechnology.  The Nano Facility is providing support to FDA through materials characterization î º external techniques to probe into the internal structure and properties of a material î º analytical support, and electron microscopy support for a broad range of nanomaterial studies. In FY2010, Standard Operating Procedures were established for 1) Transmission Electron Microscope (TEM), 2) tissue preparation for TEM, and 3) particle-size determination with more SOP development in progress. The Nano Facility is supporting various collaborative studies with FDA/ORA, NIEHS/NTP, NCI/NCL, and USAF on quantification and migration of nanosilver, particle-size determination of nanosilver, and the toxicity of nanomaterials on cultured brain cells and on cells used in genotoxicity assays.  Research on nanomaterials in food-packaging, cosmetics, and sunscreen has started producing some findings. For example, the results of a study on nano- and submicron-particles of titanium dioxide in sunscreens which suggests that their use does not result in internal exposure to the nano- and submicron-particles of titanium dioxide was published in Toxicological Sciences, 2010.  For FY 2011, NCTR’s goal is to validate the SOPs at the agency-level. With the SOPs validated, NCTR can pursue its FY 2012 goal to develop new characterization methods for nano-based zinc oxide within FDA-regulated products.

 

5.      Develop risk assessment methods and build biological dose-response models in support of food protection. (264101)  

 

Context:  To address research needs and build the FDA’s capability to assess and reduce food-related health threats, NCTR researchers evaluate key regulatory issues of food safety, conduct multidisciplinary studies to develop risk-assessment methods, and develop biological dose-response models vital to food security. Identifying the prevalence of antibiotic-resistant genes and the genetic fingerprinting of these genes will help identify similar strains isolated from different samples. Another food-related health threat, especially for infants and children, is the presence of BPA, an endocrine disruptor that can mimic hormones and a compound used in a wide variety of household items including baby bottles, drinking bottles, and liners for canned food. NCTR will be initiating studies in collaboration with the National Institute of Environmental Health Sciences (NIEHS) National Toxicology Program to address the health concerns associated with exposures to low doses of BPA during critical periods of perinatal development. Effects reported include alterations in the central nervous system (CNS) anatomy, lesions in prostate and mammary glands, urinary tract abnormalities, and the early onset of puberty.

 

Performance:  NCTR scientists discovered in FY 2010, a new and potentially patentable technique called Direct Impact Corona Ionization (DICI) mass spectrometry. This technique enables plasma vaporization of whole-cell bacteria to produce information-rich spectral fingerprints that can accurately identify bacteria and could prove invaluable to rapid detection methods.  Also in FY 2010, NCTR conducted research in partnership with the National Institutes of Health to determine if BPA administered to a pregnant nonhuman primate crosses the placenta and exposes the fetus to measurable levels of BPA in utero. As a result of this research, FDA will gain an improved understanding of the pharmacokinetic profile of BPA and the associated risk of exposure to BPA in various stages of development.  NCTR has aggressive goals for FY 2011 in the area of risk assessment with plans to: 1) develop base guidelines to assess extent of kidney toxicity caused by the combination of melamine and cyanuric acid and ultimately improve diagnosis and treatment;  2) conduct a successful FERN Level 4 validation for the RAPID-B  E. coli O157 test method so it can be approved for use in regulatory reviews or food emergency situations; and 3) develop and initiate protocols for RAPID-B tests for viruses and toxins to aid FDA in protecting public health from viruses and toxin contamination. In FY 2012, NCTR will expand the RAPID-B system to include new pathogen specific assays (tests).


Next page: Office of Regulatory Affairs FY 2012 OPA