STATUS OF PROGRAM

FY 1998 Accomplishments:

FDA's Center for Devices and Radiological Health (CDRH) is responsible for ensuring the safety and effectiveness of medical devices and eliminating unnecessary human exposure to man-made radiation from medical, occupational, and consumer products.

Selected Examples of Recent Progress:

1. FDAMA Implementation/Reengineering Activities

FDA has been fully committed to the timely implementation of FDAMA while continuing with its major reengineering effort in the medical device program. FDA's reengineering effort was started out of necessity to address many performance and infrastructure problems, resource constraints, and the inability to afford to continue "business as usual". FDA realized that past priorities were driven by volume and not by impact. To counter this, FDA began to refocus priorities on high-risk areas such as premarket approval applications (PMAs) and "for cause" inspections. FDAMA, which complements and supports the Agency's reengineering efforts, addresses every aspect of FDA's activities. Highlights of some of the FDAMA and reengineering initiatives impacting the medical device program are discussed below.

Early Meetings with Manufacturers --FDA has seen over the past few years how early meetings benefit both the industry and the agency when dealing with the premarket review of new devices. FDA recognized the value of early meetings three years ago when it instituted pre-IDE Agreement and pre-PMA Determination meetings. FDAMA builds on this concept by specifying certain early collaboration meetings for PMAs. The Agency is going beyond the FDAMA requirements by encouraging "exploratory" meetings very early in the premarket review process and continued interactions throughout the review process.

Modular Review - FDA is encouraging modular review in an effort to facilitate the review of new devices. FDA and the sponsor breakdown the PMA submission and review process into a series of stand-alone parts or "bite-size chunks" to be submitted as they are completed. The parts of the application are reviewed separately allowing manufacturers to receive timely feedback during the review process so they know where they stand. This process also allows for more rapid closure when the last parts are submitted because much of the review work has already been done.

Product Development Protocols (PDPs)--Under a PDP, which is an alternative to a PMA, the manufacturer makes a mutual and binding agreement with the FDA in advance. The agreement outlines the criteria that will be used in determining safety and effectiveness, and the pass-fail parameters for each area. The PDP process provides the manufacturer with the advantage of predictability once the agreement has been reached with the FDA. The manufacturer knows what to expect and can control the time and flow of both product development and review by the FDA. Eleven companies have indicated an interest in the PDP process, involving five device review divisions. Four PDP protocols have been approved.

510(k) Paradigm - The FDA is working to change the 510(k)-review system to make it more efficient and less resource intensive, without compromising the public health. The 510(k) paradigm involves the following four approaches:

1) Exempting Class I and selected Class II products: As part of its effort to manage workload and allocate resources most appropriately, the Agency exempted 574 generic types of Class I devices from the requirement of premarket notification. The FDAMA also gave the FDA the authority to directly exempt certain Class II devices rather than first down-classifying them to Class I before they become eligible for exemption. On January 21, 1998, the FDA published a listing of Class II devices that no longer require premarket notification. In the future, additional Class II devices may become exempt from the premarket notification requirement as the FDA considers additional devices for exemption.

2) Streamlining the review of product changes: In the past, about half of the 510(k) workload has consisted of changes to already marketed devices, often involving re-review of data seen in original 510(k)s. For many modifications, manufacturers may notify the Agency that the product has been changed and is in conformance with the agency's design control regulations and that it remains safe, effective and substantially equivalent by using a Special 510(k). These applications are smaller than a traditional 510(k) and undergo a prompt review within the FDA.

3) Abbreviating 510(k) Submissions: Submitters of 510(k)s can reduce the size and content of their submissions by including Summary Reports of their conformance with agency guidance documents and any applicable special controls, as well as "Declarations of Conformity" with the FDA recognized conformance standards in their submissions. The Agency has developed numerous product specific guidance documents and has adopted special controls in accordance with the Safe Medical Devices Act of 1990 for devices going through reclassification to class II. In addition, since the passage of FDAMA, the FDA has recognized over 400 national and international consensus standards. Manufacturers submitting abbreviated 510(k)s that include Summary Reports or Declarations of Conformity can save considerable time and effort in preparing their submissions, and the FDA will spend less time and effort in making its regulatory decisions. The FDA anticipates that abbreviated 510(k)s will expedite the clearance of new devices and will permit the agency to focus its attention on more complicated, higher risk devices.

4) Using third parties to perform selected 510(k) reviews: In a follow up to the pilot program the FDA conducted last year, manufacturers of low-to-moderate risk devices will have the option of having either the CDRH or a qualified third party/Accredited Person perform the primary review of their 510(k)s. The FDA formally began accepting third party submissions under the FDAMA on November 21, 1998. The current list of eligible devices includes 154 types of Class I and II devices. As of November 20, 1998, the FDA recognizes 13 accredited organizations under the FDAMA. Additional parties will be added to the list as they become accredited.

Summary Reports -Last year, the FDA expanded the summary reporting program by offering summary reporting to all manufacturers making 12 device types for which adverse events were well known and clearly defined, and that accounted for a large proportion of all reports. The program benefits both the Agency and industry. The Agency saves resources by not having to review each report separately and manufacturers reduce paperwork and time by submitting reports on a quarterly basis. So far, 16 percent of manufacturers receiving the offer have taken advantage of summary reporting. This reduces the number of individual reports by about 30,000 annually.

Design Controls - The FDA just completed a one-year transition and education period concluding that most firms are using design controls, but some need improvement. The first 313 reports of inspections found that although 73 percent of the firms had design controls procedures in place, many firms were not addressing human factors or electromagnetic compatibility and were not conducting appropriate risk analyses. In 62 percent of the reports, a need for improvement in design control areas was noted. Since June 1998, the FDA has been moving audits of design controls into regular inspection programs.

Changes in the Inspection Process - As a result of decreases in resources over the last 5 years, the number of inspections has dropped nearly 50 percent. Specifically, the medical device inspection program has been significantly reduced in size. Device firms are now being inspected on average once every 7 years, while in FY 1993, firms were inspected once every 3 years. In response to this, the FDA began pilot testing several new approaches to focus and prioritize inspections. These include: a new system for warning letters that will consider a firm's written response to the inspectional observation form and make special provisions for 510(k) and labeling violations; a new model to prioritize inspections based on risk; a new "QSIT" system (Quality Inspection Technique) to evaluate quality systems; and a new Hazard Analysis and Critical Control Point (HACCP) approach to device inspections.

International Harmonization --With the increasing globalization of the medical device market, it is imperative that both the device industry and the FDA have consistent regulatory requirements among major trading nations. The FDA's contribution to internationalizing the regulatory environment includes: (1) recognizing and helping to develop international standards that can be used to satisfy part of the 510(k) requirements; (2) signing a Mutual Recognition Agreement (MRA) with the European Union that helps to facilitate transatlantic trade and reduce costs for compliance with regulatory requirements; and (3) assuming chairmanship of the Global Harmonization Task Force that seeks to harmonize regulatory requirements.

2. FY 1998 Device Review Performance⁽¹⁾

The Medical Device and Radiological Health program devotes a great portion of its resources to the review of device applications--premarket notifications (510(k)s), premarket approval applications (PMAs) and supplements, and investigational device exemptions (IDEs). In FY 1998, significant improvements to the program continued, surpassing previous years' accomplishments. Creative management initiatives, piloted in FY 1997, were implemented throughout the FDA's medical devices premarket review program. The CDRH also continued, for the second year in a row, to maintain a zero backlog of 510(k)s, PMAs, and PMA supplements. A total of 10,016 major product review submissions were received in FY 1998, up from the 9,824 submissions received in FY 1997.

Through its reengineering efforts, enhanced communications with industry, and substantial progress in implementing the device provisions of the FDA Modernization Act, the CDRH continued to make progress in the device premarket review program.

Premarket Approval Applications (PMAs)

PMAs involve new products that represent the highest potential risk and benefit to consumers. As such, the FDA has redirected its limited resources to reviewing these high-impact products where direct intervention from the FDA helps consumers and health care professionals most. Some examples of accomplishment with PMAs are described below:

Approved 46 PMAs, including four approved Humanitarian Device Exemption applications (HDEs).

Improved the total review time for PMA submissions. PMA average total review time from filing to approval was cut by 25 percent, from 16.6 months in FY 1997 to 12.4 months in FY 1998.

¹ All data for PMAs, PMA Supplements, 510(k)s and IDEs are based on CDRH's Office of Device Evaluation's preliminary findings as of 1/5/99. Also, data discussed in this section is based on the decision cohort.

PMA Supplements

After a PMA is approved, the PMA holder may request the FDA approval of changes to be made; for example, changes to the device, its labeling or packaging, or the manufacturing processes used in its production. Unless prior approval is expressly not required by the PMA regulation, changes that affect the safety or effectiveness of the device require FDA premarket approval. The FDA's review of a PMA supplement may be easy or difficult depending on the type of device, the significance of the change, and the complexity of the

technology. Some PMA supplements can be as complex as an original application. Although the statutory time frame is 180 days for PMA supplements, the FDA is committed to reviewing these in shorter time frames and has reduced review time frames through the use of the real-time supplement process, 30-day notices, and expedited reviews.

The FDA Approved 421 PMA supplements. The FDA review time continued to decline for the fourth consecutive year, dropping to 3.6 months. Statutory time frame is 6 months (180 days).

510(k)s

510(k) devices are those found by the FDA to be substantially equivalent to devices already on the market for which premarket approval is not required. About 98 percent of the medical devices marketed in the United States are 510(k) devices.

Improved the average FDA review time for 510(k)s. The average FDA review time was 89 days, an improvement from 97 days in FY 1997 and 110 days in FY 1996.

Investigational Device Exemptions (IDEs)

IDEs are required for clinical investigation of a device if they pose a significant risk to the patient. An approved IDE is also needed to ship an investigational device in interstate commerce for clinical investigation to determine its medical safety and effectiveness. In recent years, the FDA has implemented new strategies, such as pre-IDE meetings, to improve the quality of IDE submissions. Approval statistics for IDEs remain stable with approximately 70 percent approved following initial review.

Reviewed 322 IDE submissions and approved 201. The average FDA review time for these applications was 27 days.

3. Science

Science is an important component of the medical device program's regulatory activities. Science-related activities performed in FY 1998 were in support of premarket science, consensus standards development, and postmarket science. Some of the major activities are detailed below.

Premarket Science Activities:

• Participated in the following device reviews:

  -- 182 IDEs/IDE supplements
  -- 156 Pre-PMAs/PMA/PMA supplements
  -- 146 510(k)s.

• Developed 27 premarket review guidance documents (e.g., blood oxygenator, stentless heart valve, non-invasive blood pressure monitor) and completed a future trends in medical devices survey incorporating input from experts in medicine, industry, academia, government, and third party payers.

Consensus Standards Development Activities:

• The FDA recognized over 400 national and international standards and issued guidance on the Recognition and Use of Consensus Standards (issued 2/19/98) and Frequently Asked Questions on Recognition of Consensus Standards (issued 2/19/98).
• Served as liaison representative to 63 standards organizations.
• Participated in 214 consensus standards activities.
• Conducted test method development for polymer degradation, abrasion testing, hemolysis measurement, and fluoroscopic x-ray equipment.

Postmarket Science Activities:

• Conducted forensic analyses on the degradation of dialyzer membranes, laser pointers, laser range finders, and a compact fluorescent lamp.
• Participated in 21 ad hoc Post-Market Surveillance activities, some of which involved heating pad fires, hazards associated with hospital beds, and medical issues associated with laser pointers.

3. Significant Medical Device Approvals/Clearances

In FY 1998, the FDA approved and cleared many medical device products that were significant advances and first-of-a kind devices that used a new technology or energy source or provided a major diagnostic or therapeutic advancement. For instance, of the 46 PMAs and HDEs approved, many represented important diagnostic or therapeutic advances. Some examples of medical devices representing significant advances are described below:

• Ultrasound devices to evaluate bone density and assist physicians in predicting fracture risk;
• Two devices to evaluate the HER-2 status of breast cancer cells. One test was approved as an aid in selecting patients for HERCEPTIN® (Trastuzumab) treatment. The second test was approved for use as an adjunctive test to help determine prognosis in some breast cancer patients. The results of the test are used to either predict prognosis of the patient or to identify women for particular therapeutic agents;
• The first device to detect free PSA, an antigen associated with prostate cancer. The free PSA test is used in combination with other tests to distinguish prostate cancer from benign conditions;
• The first device to treat patients with disabling angina who experience severe chest pain and who cannot have angioplasty, coronary artery bypass or stents.
• A finger joint replacement for people who have had implant failures or for whom available alternatives would be unsatisfactory because they work with their hands.
• A bladder stimulation device for children with neurogenic bladder disorders as a result of spina bifida.
• A synthetic coronary bypass graft for people who do not have enough vessels suitable for use as grafts.

4. MQSA Activities

During FY 1998, the FDA conducted the following activities:

• Implemented in August 1998, the States as Certifiers Demonstration Project with the States of Iowa and Illinois participating. Proposed regulations for a National program have been drafted.
• Developed amendments to the MQSA final regulations, which will take effect on April 28, 1999, to conform to legislative changes made under the Mammography Quality Standards Reauthorization Act (H.R. 4382) signed by President Clinton on October 9, 1998. This Act extends MQSA authorization through FY 2002 and makes substantive changes, such as:

1. Requires all mammography facilities to send reports written in lay person's terms to all patients receiving mammography services.

2. Clarifies the responsibility of the mammography facility to retain mammogram records so women have the ability to obtain the original record of their mammogram.

3. Mandates direct written notification to all patients of their exam results in lay person's terms.

4. Permits the FDA to conduct a limited demonstration project to determine the feasibility of inspecting mammography centers of excellence on a less than annual basis.

Trained and certified an additional 16 MQSA inspectors raising the current total of MQSA inspectors to 235. Also published four issues of the quarterly newsletter, Mammography Matters, to assist facilities in complying with MQSA regulations.

Issued 4,700 MQSA three-year facility certificates and conducted 9,413 facility inspections.

Performed 212 audit inspections under the Inspector Quality Assurance program.

Developed and implemented the Certification Accreditation Support System (CASS). This information system is designed to manage the mammography facility accreditation and certification process for over 10,000 mammography facilities. CASS manages the transmission of information from the accreditation bodies, processes certification information and provides standard reports to multiple sources external to the FDA.

Calibrated 480 sensitometers and 480 densitometers on a routine basis for use in the MQSA Inspection Program (in order to test the quality of film processors).

5. Radiation Control for Health and Safety Act (RCHSA)

The following activities were conducted in FY 1998:

• Cooperated with the U.S. Customs Service to refuse entry of imported laser pointers that fail to meet the FDA mandatory performance standard.
• Administered and managed field testing of diagnostic medical x-ray equipment. Nationwide, 1773 tests were conducted in FY 1998 with an average noncompliance rate of 16 percent. Also, administered and enforced radiation standards for diagnostic and cabinet x-ray equipment, laser products, microwave ovens, television receivers and monitors, sunlamp products, mercury vapor lamps, and ultrasonic therapy equipment. Hazard evaluations and compliance with performance standards were determined through review of manufacturer reports, laboratory or field-testing and limited inspections.
• Organized an Inter-Agency Forum on Photosciences and performed measurements and calibrations to support related studies. The forum resulted from a petition to the FDA requesting changes in various regulations concerning suntanning lamps, tanning cosmetics, and drug interactions with ultraviolet light.
• Issued a Safety Notice to physicians regarding interference with implanted medical devices from security equipment such as metal detectors and anti-theft article surveillance equipment.
• Published Federal Register notices of proposed amendments to the x-ray performance standard dealing with mammography and dental x-ray equipment and proposed amendments to the laser standard. The laser amendments will harmonize FDA requirements with most of the requirements in international standards.
• Provided training to FDA and State investigators in basic x-ray physics and field test procedures for diagnostic x-ray equipment and in field testing procedures for sunlamps.

6. Postmarket Assurance

The FDA receives and evaluates more than 60,000 reports of device problems each year, including mandated reports received from device manufacturers, importers and user facilities; and voluntary reports received through the consolidated MedWatch program. The FDA also receives postmarket surveillance data from laboratory and statistical studies, field inspections and investigations, 510(k)s, PMAs, PMA supplements, and postmarket surveillance studies. The FDA performed the following activities in FY 1998:

• Issued ten postmarket safety notifications, including one Safety Alert and two Public Health Advisories targeting health care professionals, professional organizations, manufacturers, and other Federal agencies. Some examples of topics addressed were: failure of the nuclear medicine gamma camera; interference between digital TV transmissions and medical telemetry systems; medical devices and Year 2000 compliance; illegal promotion of contact lenses; and the interaction of anti-theft and metal detector systems with pacemakers, ICDs, and spinal cord stimulators.
• Completed a pilot study evaluating the methodologies for designing and implementing a sample based Sentinel medical device user facility reporting network (Medical Device Surveillance Network). This network, which may eventually replace the current universal user reporting system, was mandated as part of the FDA Modernization Act of 1997. Currently, 24 user facilities have been recruited into the Sentinel pilot to form the basis for the evaluation.
• Continued to support electronic adverse event reporting. The FDA plans to initiate rulemaking to have all adverse event reports submitted electronically from manufacturers. The Electronic Data Interchange (EDI) Phase II will also be implemented (EDI Phase I invited firms to transfer certain adverse event reports to CDRH electronically). The EDI Phase II will: (1) make it possible for all types of MDR Reporters to send all MDR Report Forms to the CDRH faster, cheaper, and with fewer errors than other technology using contemporary computer-communication technology; and (2) allow the CDRH to process, correct and enter such reports into MAUDE with a minimum amount of intervention. In addition, the FDA is evaluating the use of an Internet template for receiving MDR reports.

7. Enforcement

The FDA acted on the following enforcement and legal proceedings in FY 1998:

• Six Seizures
• 326 Domestic Warning Letters
• 25 Foreign Warning Letters, 10 with Automatic Detention
• Two Injunctions
• 960 Recalls

Examples of Significant Enforcement Activities:

GAMBRO Healthcare, Inc: On August 25, 1998, a corporate-wide Warning Letter was issued to GAMBRO Healthcare, Inc. dealing with serious GMP problems found during inspections at its facilities in Colorado, Virginia, Florida, and Mexico. GAMBRO is a major manufacturer of dialysis equipment and supplies critical to the management of patients with kidney failure in the U.S. and abroad. The inspections followed reports of several patient deaths. To date, most of the firm's manufacturing problems have been corrected. The FDA continues to work with the company to resolve remaining issues and to ensure that problems remain fixed.

Ophthalmic Excimer Lasers: Unapproved excimer laser systems intended to correct myopia, hyperopia and astigmatism were built or obtained illegally by individuals (mostly physicians) in an attempt to circumvent the FDA premarket approval procedures. Over a four year period, the Agency investigated reports concerning these unapproved lasers. Some of these units were seized. The latest seizure activities occurred during the months of June, July, August and September 1998.

Abtox Plazlyte Sterilization System: Reports of at least ten serious eye injuries associated with the use of the AbTox Plazlyte Sterilization System during January 1998 suggested that the units led to cornea injuries with damage to vision in patients who had undergone cataract surgery. At least two patients were known to require corneal transplants. A three month investigation at hospital facilities and the manufacturer resulted in the seizure and destruction of twenty-six AbTox sterilizers valued at over 2.8 million dollars.

Mentor Corporation: In May 1998, the Mentor Corporation (parent corporation), Mentor Texas, Inc. (manufacturing facility of both silicone saline-fill (inflatable) breast prosthesis and silicone gel-filled breast prosthesis) and two individuals entered into a Consent Decree of Permanent Injunction with the government because the firm was operating with deviations from the Quality System Regulation. If the firm fails to correct the deviations within the established time frames, the firm will pay an administrative civil penalty in the amount of $10,000 each day.

Community Medical Imaging, Inc.: In August 1998, Community Medical Imaging, Inc. (CMI), Chicago, IL (a mammography facility), its president, and its supervisory radiologist entered into a Consent Decree of Permanent Injunction with the government because the firm was operating without a certificate and performing examinations in violation of the Mammography Quality Standards Act (MQSA). The parties agreed to pay the government a total of $30,000 and both CMI and its president were prohibited from performing examinations for 5 years. This is the first civil money penalty action the government has taken under MQSA.

The "Stimulator": The Agency is presently litigating an appeal filed by two corporations and two individuals that were enjoined from distributing a device known as the "Stimulator." The Stimulator is a gas-grill igniter, which was re-packaged and marketed nationally by the defendants-appellants as a pain-relieving device. The Agency initiated action in 1995 to obtain injunctive and other equitable relief under the Federal Food, Drug, and Cosmetic Act (FDCA). On December 30, 1997, the district court entered an order granting summary judgment for the United States, permanently enjoining the defendants from distributing the Stimulator in violation of the FDCA, and ordering them to offer refunds to all customers who had purchased their devices on or after May 4, 1995. The defendants appealed the district court's summary judgment order on March 23, 1998.

The FDA performed the following activities:

Design Controls: Because the quality of medical devices is largely established during the design phase, the Quality System Regulation (QSR), which went into effect June 1, 1997, includes new requirements for design control. The FDA just completed a transition and education period, which showed that most firms are using design controls, but some need improvement. The first inspection report from the transition period showed 73 percent of the firms had design control procedures in place. However, many firms were not addressing human factors or electromagnetic compatibility and were not conducting appropriate risk analysis. In 62 percent of the reports, a need for improvement in design control areas was noted.

Changes in the Inspection Process: The Agency continued collaboration with the FDA-Industry Grassroots Task Force resulted in three new inspection initiatives.

• A pilot system for issuing Warning Letters for GMP, 510(k), or labeling violations. For GMP problems, FDA will evaluate the firm's written response before deciding whether to issue a Warning Letter. If the firm's response is satisfactory, the FDA will issue a special Post-Inspection Notification Letter instead of a warning letter. For 510(k) and labeling violations, the FDA will issue an untitled letter instead of a Warning Letter. If the firm's response is satisfactory, no Warning Letter will be issued.
• Guidance criteria for determining whether a manufacturing change to a PMA device needs a pre-approval inspection. The FDA's goal is to reduce regulatory burdens and delays while maintaining public health safeguards.
• A risk-based inspection model which focuses on devices with a high likelihood of causing serious injuries or death, and addresses for-cause and bioresearch monitoring inspections.

Quality System Inspection Technique (QSIT) and Hazard Analysis Critical Control Points (HACCP): The FDA is considering two additional approaches that will increase inspection efficiency. The QSIT will enable the FDA to perform a more focused, "top-down" evaluation of a firm's quality systems. The HACCP process identifies those processes most critical for ensuring product safety and makes them the focus of the inspection.

Bioresearch Monitoring: The FDA relies on Institutional Review Boards (IRBs) to monitor a great deal of clinical research. Recent feedback from the IRBs has shown that many need a better understanding of the differences between drug and medical device clinical trials. To respond to this need, the FDA has increased outreach to IRBs by encouraging them to access the FDA's web page, and increasing our participation in IRB seminars and workshops.

National Center for Toxicological Research

STATUS OF PROGRAM

FY 1998 Accomplishments:

The National Center for Toxicological Research (NCTR) operates under a strategic plan that is reviewed by stakeholders which include: the NCTR and the Food and Drug Administration (FDA) senior staff, Office of Regulatory Affairs (ORA), regulatory centers (directors, senior scientists, and planners), the FDA Office of Science, the FDA Office of Planning and Evaluation; and, an FDA/NCTR Science Advisory Board (consisting of experts from academia, industry, and other Agency scientific organizations).

The plan provides guidance on research direction for the Center as it strives to meet the needs of the Agency consistent with the requirements of the Government Performance and Results Act (GPRA). Research at the NCTR is divided into three strategic goals that are fully integrated into the FDA's strategic framework. The goals include: (a) developing new strategies for the prediction of toxicity. The new strategies are less resource intensive, faster and more heavily based on known mechanisms of toxic action than the currently used animal tests; (b) developing computer-based systems that predict human toxicity. The application of unique computer-based predictive systems will improve our ability to predict the toxicity of chemicals in animals and humans. These computer-based tools will permit reviewers of data in new product submissions to be more efficient and more effective in their regulatory decisions; and c) conducting method-, agent-, and concept-driven research to assist in solving current, critical regulatory problems for the Agency.

Selected Examples of Current Progress

1. Development of new strategies for the prediction of toxicity

Molecular biology has allowed scientists to insert portions of the human genome into the DNA of cells in culture, rodents or bacteria. By using this transgenic technology, scientists are learning more and more about how specific chemicals cause toxicity in humans. The NCTR, in partnership with other research centers and the FDA product centers, has developed a battery of transgenic models that can be used to screen for toxicities and better understand the mechanisms of toxicity. The models include human lymphoblastoid cell lines and cell lines in which human genes have been inserted (MCL5); the Big Blue Transgenic Rat, the X174 transgenic mouse, the p53 knockout mouse, and a newly derived Tk⁺/- mouse. The strength of the transgenic program is the multidisciplinary environment in which it exists. Neurotoxicologists, reproduction specialists, and scientists working on mechanisms all have access to tools that will allow them to unravel complex mechanistic puzzles. Accomplishments to date using in vitro tools include evaluation of tamoxifen, phenolphthalein and chloral hydrate in transgenic and nontransgenic human lymphoblastoid cells. Accomplishments using in vivo tools include continued characterization of transgenes as reliable and sensitive reporter genes for cancer.

The neonatal mouse carcinogenicity test has been validated at the NCTR and has proved to be highly sensitive to genotoxic (direct acting) carcinogens (>24 carcinogens of regulatory significance). This test shows promise as an alternative tumorigenicity bioassay and has been proposed by the International Conference on Harmonization for this purpose. The NCTR is working with reviewers from the Center for Drug Evaluation and Research (CDER) to identify the circumstances for which this test would be suitable for a two-year bioassay alternative.

The uncertainty caused by extrapolating from high to low dose, from animals to humans and from route and duration of exposure involved in estimating risk and setting exposure levels has been addressed by the NCTR. The scientists have developed and presented (at both scientific conferences and in manuscripts) a unified approach to safety assessment for both carcinogenic and noncarcinogenic effects. The approach is to restrict the use of mathematical models to the range of observed data and use a consistent method of extrapolating to acceptable levels of exposure, thus de-emphasizing numerical estimates of risk.

2. Development of computer-based systems that predict human toxicity

Development of Toxicological Knowledge Bases (TKB) with predictive capability to support regulatory decision-making and identify research gaps is among the NCTR's key strategic goals. The Endocrine Disruptor Knowledge Base (EDKB) is a prototype TKB that will assist in risk and regulatory decisions for exogenous compounds that may alter estrogen responses and disrupt vertebrate endocrine systems. The basic system infrastructure has been completed; therefore, providing for an Internet-based bibliography, bioactivity and chemical structure database, computer-based predictive models (Quantitative Structure Activity Relationships [QSAR] and Holographic QSAR [HQSAR]), and classification models. During this past year, in-house in vitro competitive binding assays have been completed for 100 active and 100++ inactive compounds. This data provides the training and validation sets for predictive model development. Several computational chemistry methodologies were evaluated and found to yield statistically robust correlations for predicting estrogenicity. In addition, pattern recognition work using nuclear mass resonance and mass spectrometry analysis is being conducted in support of the EDKB. The FDA Office of Women's Health provided partial support for this work. The EDKB required investment in scientific hardware and software systems that are being supported through a Cooperative Research and Development Agreement (CRADA) with the Chemical Manufacturers Association. This CRADA also funded in vitro experiments at the NCTR. Collaborations have been explored with FDA scientists at the FDA Center for Devices and Radiological Health (CDRH) (estrogenic activity of phthalates in nonylphenol), the FDA Center for Food Safety and Applied Nutrition (CFSAN) (activity of naturally occurring chemicals in foods), and the CDER (analysis of approximately 12,000 chemicals in CDER databases). In addition, the NCTR has established a computational toxicology working group within the FDA to encourage the use of predictive models across the Agency. The NCTR has developed a partnership with the Environmental Protection Agency (EPA) for their use of the EDKB by the Endocrine Disruptor Screening and Testing Committee (EDSTAC). This system will be used to support both the validation and testing phases of the EPA's efforts to meet the requirements of the 1996 congressionally mandated Safe Drinking Water Act and Food Safety Act amendments.

3. Method-, Agent-, and Concept-Driven Research

Relating animal toxicity data to humans continues to be a perplexing problem for scientists and regulators alike. A diverse group of scientists at the NCTR in conjunction with collaborators in other FDA centers and academia are exploring new, innovative approaches to better predict human risks from existing rodent bioassay data. This research is supported in part by an interagency agreement with the National Inistitue for Environmental Health Sciences - National Toxicology Program. Over the past year, studies on fumonisin B₁ (the universal corn product contaminant) have been completed and data has been provided to the FDA CFSAN for use in setting a tolerance level for this mycotoxin in food products. Bioassays and mechanistic studies were initiated at the request of the FDA Center for Veterinary Medicine (CVM) on malachite green (a therapeutic agent used in acquaculture) and studies are in process to assess the effects of ethanol on the carcinogenicity of urethane for the CFSAN. The NCTR has started long-range multigeneration studies of compounds that disrupt normal endocrine function. This research is focused on reproductive and carcinogenic endpoints of estrogens and antiestrogens. Testing protocols have been developed and work is underway to develop facilities to evaluate the harmful effects of skin exfoliates such as alpha hydroxy acids.

In support of the Food Safety initiative, the NCTR: 1) has developed a rapid method for identifying 14 pathological microorganisms; 2) is working closely with the CVM to develop new methods for surveillance of resistance; and, 3) is developing techniques to verify that competitive exclusion products (used in poultry) do not contain antibiotic resistance to pathogenic bacteria.

New technology to characterize bacteria using mass spectrometry has led to identification of two biomarkers for E.coli and Shigella flexneir. This novel methodology is being developed for use in assessing toxicity associated with biological warfare agents in support of Secretary Shalala'a Bioterroism initiative.

FY 1998 Accomplishments:

The Tobacco Rule

In FY 1998, FDA remained committed to completing the creation of a new program to implement its final tobacco rule. The most important responsibility related to implementation of the final rule, during this first full year of operation, was the establishment of an effective regulatory program to ensure that retailers were aware of and in compliance with the new rules prohibiting sales to minors. In addition, FDA remained actively involved in defending the Agency's assertion of jurisdiction and choice of regulatory measures in court and in providing technical assistance to the Congress during consideration of comprehensive tobacco legislation.

The age and photo identification requirements of the final rule went into effect on February 28, 1997. FDA engaged in two major activities in support of its rule -- enforcement and outreach. In FY 1998, most of the program's funds were expended for contracts and in support of investigations to ensure that tobacco products were not sold to minors and to ensure that those industries directly affected by the rule knew what their new responsibilities were.

Enforcement. A key influence on a retailer's decision to comply with the rule is the extent to which the retailer perceives that he or she is likely to be found in violation and the certainty of punishment for that violation. The Agency's compliance strategy is designed to ensure that every retailer will be visited and revisited if he/she is found to be in violation of the rule.

FDA expanded its enforcement efforts and solicited bids from all 57 states and territories to contract with FDA to do compliance checks. By the close of FY 1998, FDA had signed contracts with 43 states and territories to conduct approximately 186,500 compliance checks by September 30, 1999. FDA staff train the designated state and local officials, answer questions from tobacco retailers and provide technical assistance to states.

All 10 states who participated in the FY 1997 program renegotiated contracts to continue doing compliance checks. In at least two states, the programs had been so successful that they chose to expand the limited coverage provided by the first contract. The subsequent contracts substantially increased the areas of the state that would be included in the investigations.

The existing contracts resulted in 39,439 attempted and completed compliance checks during FY 1998, including reinspection of retailers found to have violated the rule. The Agency's legal staff and Office of Policy established the framework for the imposition of civil money penalties, sent out complaints, and negotiated or litigated contested cases. In FY 1998, FDA began seeking civil money penalties from those found to have violated the rule's restrictions on sales to minors for a second time. A penalty schedule for violations of other portions of the regulation will be developed when these provisions go into effect.

FDA introduced an intermediate mediation step in order to provide an alternative, less formal mode of resolving the matter prior to litigation. Many of those found to have violated the rule more than once have been small businesses, such as individual proprietorships, small convenience stores, or gasoline stations. The mediation step has allowed many of these retailers the opportunity to present their case in an informal setting by phone and also to present non-legal mitigating factors. This step has proven successful, with almost all cases settling at this stage to the satisfaction of the retailer.

It is estimated that between 500,000 and a million retailers may sell tobacco. Although several states have license records for retailers, many states have either inadequate or nonexistent lists. This necessitated creating and maintaining a national list of retailers that sell tobacco products. In support of its program, the Agency designed, and continues to modify, a computer system equipped to print compliance check forms for each state with the names of the retailers to be visited; receive and track results of the investigations; print compliance and violation letters; and establish and maintain the legal record for later civil money penalty proceedings.

FDA contracted to study the tobacco program's business processes, outline the program's work flow and conduct a requirements analysis. From this, a system design to automate the program's processes was proposed, as well as a plan to obtain and maintain a list of retailers selling tobacco in each state that would be more complete, accurate and user friendly than lists constructed during the first full year of operation.

FDA launched a multi-year effort to provide reliable retailer lists and an infrastructure designed to maintain the list and make it user friendly. FDA has also contracted to design and implement an information technology system that will automate all the program's various functions. This new system will increase program efficiency and communications. The various system design components will be implemented incrementally as they are developed beginning in early 1999. The entire system should be operational by 2001.

Outreach. The combination of compliance checks and an active outreach program maximizes retailer compliance with access restrictions. A strong compliance outreach program ensures that those directly affected by the age and photo identification provisions understand what their responsibilities are, why such measures are needed, and the consequences of failing to comply. In FY 1998, the Agency designed a comprehensive outreach program designed to inform retailers and ensure compliance. This multi-faceted program consisted of advertising, direct mail, press events/materials, exhibits and speeches, and dissemination of materials requested via a hotline or mail order.

In FY 1998, the Agency designed a multi-media advertising campaign, including radio, print, and billboard advertising. A free retailer kit was created to make it easier for retailers to comply with the new regulation. A series of focus group discussions were held with retailers, sales clerks, young people between 18 and 27, children ages 12 to 18, and the general public to test the advertising campaign and retailer kits.

The campaign was announced by Vice President Gore and launched in one media market in February 1998. In FY 1998, FDA funded advertising campaigns, targeting retailers and sales clerks, in 75 media markets -- typically the top two media markets in each state with which FDA has a contract to conduct compliance checks. The top 10 media markets, including New York City, Los Angeles, and Chicago were included. In addition to reminding retailers and sales clerks not to sell to minors and to check young people's photo identification, the campaign also urges customers to cooperate with retailers attempting to meet their responsibilities to help keep young people tobacco-free. Approximately 500,000 retailers kits were produced and distributed to stores across the country.

FDA conducted a tracking study in 10 media markets to evaluate the effectiveness of the campaign. Findings indicate that awareness of the photo identification age provision rose dramatically from approximately one-third of retailers to more than one-half of all retailers. There was a three-fold increase in recall of the fine for repeat violations in the test markets. Further, twice as many clerks used 27 as the cut-off age after the campaign compared to before the campaign. Importantly, retailers reported that minors were somewhat less likely to try to buy tobacco and retailers said that customers were less likely to be irritated when asked to show photo identification as a result of the advertising campaign.

Three in four retailers who recalled receiving the free retailer kit displayed at least one of the materials. Finally, more than 90 percent of those retailers displaying FDA materials wanted to receive additional materials and said that the materials they had received helped them educate customers and clerks.

Lastly, the Agency displayed exhibits about the tobacco program at more than 25 national consumer and health professional conferences and participated in dozens of speeches at events and conferences across the country.

Defense of the Agency's Action, Technical Assistance to Congress, and Other Activities

On August 13, 1998, the Fourth Circuit issued its decision finding the FDA's assertion of jurisdiction and issuance of regulations on nicotine-containing cigarettes and smokeless tobacco invalid. Pending the Supreme Court's review of the government's certtiorari petition, or decision not to hear the case, the Court of Appeal's mandate is stayed.

The Agency is also defending its rule in actions by numerous vending machine operators.

In FY 1998 Congress actively considered comprehensive tobacco legislation. FDA provided technical assistance to members and committees requesting assistance during these deliberations.

The Federal Food, Drug and Cosmetic Act provides that state or local restrictions that are more stringent than FDA regulations of devices are preempted but provides for a waiver procedure. During FY 1998, FDA received and granted preemption waivers for state and localities. The final rule granting exemptions for age and identification requirements was published in early FY 1998. Work is ongoing on requests dealing with other state access requirements.

FDA has coordinated its enforcement program with the tobacco control activities of SAMHSA to provide for the efficient and effective administration of the two agencies responsibilities. Most importantly, FDA has assisted states asking to use FDA investigations to comply with its Synar survey requirements, to preclude any conflict with the state responsibilities or place any added burden on the states. Instead FDA's activities have provided some states with assistance in meeting an unfunded requirement.

BIOTERRORISM

FY 2000 Funding Request

Dollars in Millions

FDA is requesting a total of $ 13.4 million for this Presidential initiative in FY 2000. In FY 1999, there is a proposal to provide FDA $ 3.3 million in funding to engage in relevant anti-bioterrorism activities, through a supplemental request. Funding for this initiative is included as part of the Public Health and Social Services Emergency Funds (PHSSEF) budget request. FDA is requesting funds to ensure the expeditious development and licensure of new vaccines.

FDA is currently involved in a number of activities with regard to bioterrorism. The Agency participates in an interagency group formed by the Department's Office of Emergency Preparedness with the Department of Defense, Veterans Administration, the Centers for Disease Control and Prevention, and the National Institutes of Health to plan for responses in a civilian emergency. FDA also has drafted a proposed regulation to amend its new drug and biological product regulations to identify the kind of evidence needed to demonstrate the efficacy of drug and biological products used to ameliorate or prevent the toxicity of chemical, biological, radiological, or nuclear substances. These would be used when definitive studies in humans ethically cannot be conducted because they would involve administering lethal or permanently disabling toxic substances to healthy human volunteers without a proven treatment. The rule would allow animal data to be used to establish the efficacy of drugs and vaccine products that can be used to ameliorate or treat the effects of a terrorist attack involving a chemical or biological agent, and may lead to the approval of additional drugs and vaccines that can be stockpiled by the Office of Emergency Preparedness and the government in the case of an emergency involving a terrorist attack.

In conjunction with the National Security Council's efforts regarding bioterrorism preparedness, the Assistant Secretary for Health and the Assistant Secretary for Planning and Evaluation have asked FDA, in conjunction with the Department of Defense, to develop a research agenda for the rapid development of diagnostic tools and treatment for disease outbreaks that might be caused by bioengineered biological weapons agents. The plan will include more focused development strategy, more efficient testing, and a more streamlined federal approval process for new vaccines and pharmaceuticals.

FDA has also been involved in the Administration's efforts to develop a negotiating position on mandatory declarations for compliance protocols to the Biological Weapons Convention (BWC). Under the BWC, the U.S. and 140 other countries have prohibited the development, production, and stockpiling of biological and toxin weapons. As part of the President's Biological Weapons initiative, FDA is contributing to development of a series of mandatory declarations about facilities and activities that are especially suited for possible biological weapons purposes.

Despite the Department of Defense's unique contributions to bioterrorism, the primary responsibility for responding to potential domestic bioterrorist attacks fall on the civilian organizations, including local and state emergency response groups, and federal agencies with disaster prevention/response missions. The primary focus of the national responses to bioterrorist threats must be on civilian groups and agencies such as FDA and CDC.

Goal: Foster the national capabilities needed to respond to potential chemical and biological threats from bioterrorism, including development of new vaccines and drugs, safeguards for the food supply, and research for diagnostic tools and treatment of disease outbreaks.

FDA is requesting a total of $13.4 million for this Presidential initiative in FY 2000. Among the pathogens that have been adopted as biological warfare agents are the organisms that cause smallpox, anthrax, plague, tularemia, brucellosis, and Q-fever. Initiation of anthrax and botulinum toxin research/review programs are of primary importance. FDA is requesting funds to ensure the expeditious development and licensure of new vaccines for anthrax and botulinum. These resources are needed to support staff that would perform reviews of applications and research, which would lay the groundwork for the design of new types of vaccines for anthrax, botulinum and other toxins.

An important aspect of the proposed program is that it would ensure the availability of experts in this area who would expedite the licensing process of these vaccines. Guiding products through the regulatory process, including pre-clinical testing, clinical trials, and the licensing application review, proceeds much faster if the product reviewers have hands-on experience with the products. Expeditious development and licensing of these products is a primary goal of this initiative.

Additional funds would be used to conduct application reviews of new drug products and new uses of existing drug products. These resources will contribute to the Agency's role with respect to planning and coordinating the health and medical response of the federal government in the aftermath of terrorist acts involving chemical or biological agents.

FDA would also provide an appropriate second response to a potential biohazard event with adequately trained and equipped investigators. FDA laboratories will develop a 4-hour detection and decontamination methodology. The Agency has begun the process of developing protocols for C. Botulinum decontamination and rapid method identification of botulinum, an organism that could be used in incidents of bio-terrorism. The Agency would begin the development of protocols for the identification and decontamination of other bioterrorism organisms including E. Coli, Yersinia, Bacillus anthracis, Vibrio cholerae, C. Perfringens, S. Aureus, B. Cereus, Shigella, mycotoxins, and other potential human pathogens.

Under Emergency Support Function (ESF) #8, FDA is the lead DHHS agency for assuring the safety of regulated foods, drugs, medical devices, and biological products. FDA will need to arrange for the seizure, removal, and/or destruction of any contaminated and unsafe products. FDA needs to train individuals and provide protective clothing and safety equipment and supplies for these activities.

Disease-causing microbial agents and their toxins are attractive terrorism agents because they are relatively simple and cheap to produce. Food supplies are among the most vulnerable routes for the delivery of lethal or incapacitating quantities of chemical or biological agents. With the increasing international nature of the food marketplace and trade agreement requirements for mutual recognition, bioterrorism considerations in food safety must have an international perspective. Mass spectrometric techniques for the rapid general detection of biological agents will be developed. Food products have natural levels of microorganisms, pathogenic and benign, which can interfere with detection methods for specific biological agents. While rapid methods of detection are available/under development for many pathogens, there are many for which rapid detection methods are not available. Many methods cannot distinguish virulent from non-virulent strains of the same organism, and tests for the organism may not detect preformed toxins. Techniques are also needed to confirm the results of less specific detection methods, including the development of information for criminal and other legal actions.

Techniques will be developed to detect the genetic modification of microorganisms. Rapid approaches are needed for the determination of the genetic information describing virulence or pathogenicity factors, including those that can be transferred to other organisms in order to circumvent detection, prevention, and treatment mechanisms. Once the agent is identified, rapid methods for its detection can be developed for use in monitoring programs.

FOODS-- ($ .5 million, 3 FTE)

Requested funding will provide FDA the capability to develop responses to potential terrorist attacks related to the food supply. Disease-causing microbial agents and their toxins are attractive terrorism agents because they are relatively simple and cheap to produce. Food supplies are among the most vulnerable routes for the delivery of lethal or incapacitating quantities of chemical or biological agents. Biological agents were used by a cult in a food-related terrorist incident in Oregon in 1984. Terrorist threats can have significant economic impact and result in political destabilization. The Israeli citrus, Chilean grape, and Sri Lankan tea episodes are samples of the continuing nature of this aspect of the problem. With the increasing international nature of the food marketplace and trade agreement requirements for mutual recognition, bioterrorism considerations in food safety must have an international perspective. Research will be coordinated with activities under the Food Safety Initiative and under the Technical Support Working Group, and will cover the following activities:

Extension of rapid methods development under FSI to cover terrorist threat agents to extend the development of rapid, multianalyte methods to include agents, such as botulinum toxins and anthrax, that are more likely to be bioterrorism agents in addition to natural microbial contaminants. These technologies would be transferred to FDA Field Laboratories and other Federal and state monitoring laboratories.

Development of mass spectrometric techniques for the rapid general detection of biological agents. Food products have natural levels of microorganisms -- pathogenic and benign -- which can interfere with detection methods for specific biological agents. While rapid methods of detection are either available or under development for many pathogens, there are many for which rapid detection methods are not available. Many methods cannot distinguish virulent from non-virulent strains of the same organism, and tests for the organism may not detect preformed toxins. The use of surrogate material as terrorist threat agents has also been successfully employed. It is often easier to determine what an agent is not than what it is. Techniques are also needed to confirm the results of less specific detection methods, including the development of information for criminal and other legal actions. Location of this capability in the Washington, DC, area is extremely important because of the large number of potential targets.

Development of techniques to detect the genetic modification of microorganisms to make them more toxic, antibiotic or vaccine resistant, or to detect cellular stress responses to exposure to such agents as an approach to the identification of the agent.

Rapid approaches for the determination of the genetic information describing virulence or pathogenicity factors, including those that can be transferred to other organisms in order to circumvent detection, prevention, and treatment mechanisms. Determine cellular stress responses to bioterrorism agents is a potential rapid approach to the recognition/identification of threat agents. Once the agent is identified, rapid methods for its detection can be developed for use in monitoring programs.

Human Drugs -- ($1.0 million, 3 FTE)

The Presidential initiative designed to expand activities to allow the U.S. to appropriately respond to potential terrorist attacks involving chemical or biological agents is as important as when first introduced. We need to ensure that the necessary capabilities and procedures are in place to respond to such an act, specifically by enhancing preventive health and medical services systems capable of responding quickly and effectively to such incidents.

FDA is currently involved in a number of activities with regard to bioterrorism. FDA participates in an interagency group formed by the Department's Office of Emergency Preparedness with the Department of Defense, Veterans Administration, the Centers for Disease Control and Prevention, and the National Institutes of Health to plan for responses in such a civilian emergency. The Agency has also drafted a proposed regulation to amend its new drug and biological product regulations to identify the kind of evidence needed to demonstrate the efficacy of drug and biological products used to ameliorate or prevent the toxicity of chemical, biological, radiological, or nuclear substances. These would be used when definitive studies in humans ethically cannot be conducted because they would involve administering lethal or permanently disabling toxic substances to health human volunteers without a proven treatment. The rule would allow animal data to be used to establish the efficacy of drugs and vaccine products that can be used to ameliorate or treat the effects of a terrorist attack involving a chemical or biological agent, and may lead to the approval of additional drugs and vaccines that can be stockpiled by the Office of Emergency Preparedness and the government in the case of an emergency involving a terrorist attack.

One of FDA's goals in this area is to foster the national capabilities needed to respond to potential chemical and biological threats from bioterrorism, including developing new vaccines and drugs, safeguards for the food supply, and research for diagnostic tools and treatment of disease outbreaks.

Biologics - ($ 10.4 million, 37 FTE)

FDA is requesting $10.4 million to conduct groundwork research for the design of new types of vaccines for anthrax, botulinum and other potential toxins.

Biological agents are organisms, or toxins from living organisms, that can be used against people, animals, or crops. The agents used for biological warfare are drawn from pathogens or toxins that exist in nature. Among the pathogens that have been adopted as biological warfare agents are the organisms that cause smallpox, anthrax, plague, tularemia, brucellosis, and Q-fever. However, a terrorist could use virtually any pathogen or toxin. The recent incident in Japan where a radical group used a poisonous nerve agent in a subway station has heightened the awareness of the vulnerability of free societies to bioterrorist attacks.

FDA is participating in the development of strategies to properly distribute, triage and use important products in the event of biological terrorist attacks. FDA is responsible for the regulation of vaccines and antisera which are still the primary means of therapy for exotic viruses, bacteria and bacterial toxins. The development of such emergency planning is personnel intensive and the contribution of the FDA is critical.

To ensure the expeditious development and licensure of new vaccines for anthrax and botulinum, resources are needed to support a critical research/reviewer staff. This staff would conduct research that would lay the groundwork for the design of new types of vaccines for anthrax, botulinum and other potential toxins. Very few laboratories in the country are doing research that is necessary for vaccine development in this area.

An important aspect of the proposed research/reviewer program is that it would ensure the availability of experts in this area who would expedite the licensing process of these vaccines. Guiding products through the regulatory process, including pre-clinical testing, clinical trials, and the licensing application review, proceeds much faster if the product reviewers have hands-on experience with the products. Expeditious development and licensing of these products needs to be one of the primary goals of any bioterrorism initiative.

While initiation of anthrax and botulinum toxin research/review programs are of primary importance, other bacterial agents also have the potential for use as bioterrorism agents. These include plague, tularemia, cholera, Q fever, small pox and staphylococcal enterotoxin B. Of these agents, perhaps plague and tularemia should be given highest priority because of the fatality rate associated with the untreated disease. FDA has an ongoing research program dealing with the immunological aspects of tularemia. This program needs to be expanded to counter the bioterrorism threat.

FDA has limited resources devoted to poxvirus biology. To meet the demands of a national effort to implement the bioterrorism initiative, the poxvirus unit needs more support. There is a need to assess the issues related to the attenuation of avian/other poxviruses as alternative vaccine candidates. The other research/reviewer FTE would be responsible for assessing the issues related to poxvirus late gene function and DNA replication as factors in vaccine and poxvirus antiviral development. With the additional staff, the senior investigator would be adequately supported to be able to contribute to the development of technologies necessary to ensure the expeditious review of new poxvirus products and the development of new information related to poxvirus biology that could be utilized in both the regulation and in the development of new poxvirus products.

FDA regulates and performs research on immune globulins. A study has been proposed to determine whether hyperimmune globulins, given systemically, can reach mucosal secretions in sufficient amounts to provide protection from bacterial or viral infections in the gastrointestinal system. It has been shown that antibodies against botulinum toxin are beneficial in treating infants with food-borne botulism. Research suggests that immunoglobulin infusions could provide mucosal protection against pathogens, but this has not been shown in model of food-borne disease. Results would enhance development of treatment strategies which use passive immunization for protection against food-borne bacterial pathogens and toxins.

Many radiological, chemical, and biological toxic agents target preferentially the hematopoietic compartment leading to defects in hematopoiesis manifested by a compromised immune defense system, oxygen and nutrient distribution to various tissues, and other defects. Various approaches have been attempted to protect the hematopoietic stem cells from insults, and to repopulate stem cells through transplantation. Recently, reports in the literature have suggested that a number of chemokines can protect hematopoietic cells from damage derived from radiation and toxic chemicals. In addition, other data suggest that agents that regulate angiogenesis are critical to growth and survival of stem cells in the bone marrow. There is increasing interest in the development of chemokines and angiogenic agents for a variety of applications. FDA has taken the lead in the regulation of devices for selection of hematopoietic cells, chemokines that regulate stem cells, hematopoietic growth factors, and also expects to be involved with anti-angiogenic agents.

Despite the Department of Defense's unique contributions to bioterrorism, the primary responsibility for responding to potential domestic bioterrorist attacks fall on the civilian organizations, including local and state emergency response groups, and federal agencies with disaster prevention/response missions. The primary focus of our national responses to bioterrorist threats must be on civilian groups and agencies such as the FDA and the CDC.

One of FDA's goals in this area is to increase the national ability to prevent or react to potential terrorist biological attacks by developing products to prevent or treat diseases caused by biological agents, and to increase the protection of adults against vaccine-preventable diseases and minimize attendant health-care costs.

Devices and Radiological Health -- ($ .5 million, 4 FTE)

This funding will enable FDA to conduct premarket review research activities on diagnostic products used to identify biological agents used in potential terrorist activities. The program will use antimicrobial therapy along with vaccine prevention to prevent further spread. At least five potential agents have been identified for high priority study. FDA will develop on-site expertise in the basic analytical techniques to be applied to the pathogens of interest. FDA will use these studies to develop guidance and standards for use by sponsors and to ensure a standardized and rapid review process. Using the requested resources, FDA will extend its review and research activities by expanding the limited scientific expertise and laboratory capabilities existing within the organization. Without this increased in-house capability, the review process is delayed substantially when FDA finds it necessary to consult with experts outside the Agency on particular scientific and safety issues.

National Center for Toxicological Research -- ($ 1.0 million, 2 FTE)

This funding will enable FDA to expand a novel approach pioneered at the NCTR to identify the biomarkers of toxicity associated with biological warfare agents, the type of agents that would be used by bioterrorists and types that would be difficult to detect using existing technology. Microbiologists at the NCTR will utilize their extensive knowledge of the polymerase chain reaction technology to improve the identification of micro-organisms that may contain virulent genetic changes. The NCTR is well suited and well situated to contribute to FDA's bioterrorism research. The Center is geographically located centrally in the U.S. in a sparsely populated area, adjacent to the U.S. Army Pine Bluff Arsenal, a facility with personnel trained in handling and storing chemical agents. The Center is well equipped with analytical chemistry, microbiology, animal facilities and a broad toxicology expertise. Over the past two decades researchers at the Center have conducted toxicity studies on nerve agents and have maintained an active microbiology research group. The Center has the ability to respond in the event of an attack with animal studies and microbiological surveillance to identify the agent.