THE CENTER FOR VETERINARY MEDICINE
ANNUAL REPORT
Contents
SOME HIGHLIGHTS FROM FISCAL YEAR 2006
Celebrating the Centennial Year
Our Mission and Guiding Principles
FISCAL YEAR 2006 CHALLENGES AND ACCOMPLISHMENTS
Increasing the Availability of Safe and Effective Animal Drugs
Increasing Drug Availability for Aquaculture and Other Minor Uses/Minor Species
Reducing Risk From Antimicrobial Resistance
Controlling Risk From Bovine Spongiform Encephalopathy (BSE)
Avoiding Unsafe Drug Residues in Human Food
Protecting Against Bioterrorism
Ensuring the Safety of Animal Biotechnology
Additional Surveillance and Compliance Actions to Protect Public and Animal Health
Enhancing Productivity Through Achievement of Management Goals
STAFFING, SPACE, AND BUDGET
APPENDICES
C. Awards
D. Publications
SOME HIGHLIGHTS FROM FISCAL YEAR 2006
CELEBRATING THE CENTENNIAL YEAR
FDA’s Centennial Bike Ride
The year 2006 was FDA’s Centennial year, celebrating the anniversary of the Food and Drug Act of 1906. The 1906 law transformed FDA into a scientific regulatory agency, making it the oldest consumer protection agency in the United States. Throughout the year, FDA worked with stakeholder organizations that represent the interests of FDA employees, consumers, professional societies, public health organizations, and industry to celebrate the Centennial. These organizations played important roles in changing mandates and in increasing the Agency’s capacity to carry out its mission over the last century.
GOALS OF FDA’S CENTENNIAL EVENTS
Commemorate the first 100 years of contributions to Americans’ public health and the world community with a focus on the future.
Observe FDA’s role – past, present, and future – in protecting and promoting the health of the public.
Inspire the next generation of science, innovation, and public health through partnerships and alliances with key stakeholders.
Salute the contributions of dedicated FDA employees, alumni, legislators, academicians, industry, advocacy groups, and public health leaders who support the consumer protection mission of the Agency.
As a means of educating the public about FDA’s history and mission, the Center for Veterinary Medicine (CVM) partnered with the Potomac Pedalers Touring Club in its annual Historic Back Roads Bicycle Tour held in September 2006 in Berryville, VA. More than 1,200 riders celebrated FDA’s Centennial by participating in cycling tours of up to 100 miles, providing an opportunity for FDA to lead by example through FDA employee participation in activities that encourage exercise, fitness, and overall personal health. The Potomac Pedalers Touring Club provided well-planned and marked cycling routes, great food, and plenty of friendly volunteers for the event.
A Health Fair provided a venue for FDA, along with numerous community and public health groups, to communicate health information to the public. Groups working with diseases such as Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), hemophilia, and kidney disease, and organizations such as the American Lung Association and VA-MD Regional College of Veterinary Medicine, were represented. The FDA Office of Women’s Health, FDA History Office, and CVM brought exhibit displays. CVM gave riders informational fliers about companion animals, such as: “Taking Care of Pets During a Disaster or Emergency,” “Caution to Pet Owners – Pet Treats and Toys May Cause Problems for Your Pet,” and “Selecting Nutritious Pet Foods.”
The event brought together volunteers from across FDA and the local community to provide health information, encourage fitness, and share FDA’s history of public health protection with the public. Riders and their families enjoyed the day and left with a deeper appreciation of FDA’s rich history and mission.
RECOGNIZING EFFORTS BY TEAMS DRAWN FROM ACROSS THE CENTER AND THROUGHOUT FDA
Feed Safety Team Shows Center’s Ability to Assemble Best Team
CVM is not known for its size, but is recognized for its ability to reach out and find the expertise it needs to tackle scientifically and logistically complex issues. This ability was evident in the way CVM approached the task of developing the Animal Feed Safety System (AFSS).
The Center undertook the AFSS initiative in 2003 to bring together all aspects of its feed safety responsibilities under one unified program. The initiative is “an umbrella regulatory program aimed at protecting human and animal health. The AFSS covers regulation of the labeling, production, and distribution of all feed ingredients and mixed feeds, at all stages of manufacture, distribution, and use,” according to the draft framework the AFSS Team issued in 2005.
To get the job done, CVM drew team members from across the Center and from other parts of the Food and Drug Administration (FDA). Dr. George Graber, Deputy Director of the Office of Surveillance and Compliance, leads the AFSS Team. The Team includes experts from within the Center: a microbiologist, a biologist, chemists, animal scientists, a medicated feed technology specialist, risk assessors, an industry compliance specialist, and several consumer safety officers with expertise in feed manufacturing and regulatory issues.
In addition, the Team has a communications specialist and a regulation writer from the Center Director’s Office, an economist from the Commissioner’s Office, and representatives of FDA’s Office of Regulatory Affairs.
Early in its work, the AFSS Team decided to take a risk-based approach in developing the feed safety system. This approach would allow the greatest attention to be focused on the greatest risks in the manufacturing, distribution, and use of animal feed.
CVM had already assembled a risk assessment team, which resides in CVM’s Office of New Animal Drug Evaluation (ONADE). A previous risk assessment initiative, addressing antimicrobial resistance, had coincided with the development and use of risk assessment methodology to address microbial risks in the food industry. Dr. Barry Hooberman, the member of the CVM risk assessment team who joined the AFSS Team, said, “The CVM risk assessment team has generally viewed one of its goals to be ‘spreading the gospel’ about how the tools of risk assessment can be used to aid decisionmaking in much of what CVM does, whether the issue pertains to new drug approval, surveillance, compliance, or addressing emerging public health issues. Although the risk assessment team is officially housed in ONADE, we have been given a great deal of support in reaching across office boundaries.”
Dr. Hooberman said, “The risk assessment process is a very fluid process, in that it can be adapted to fit a wide range of problems and issues. However, the basic tenets remain constant, and it provides a structure to organize and analyze the relevant data to support decision-making by the risk managers.”
To implement a risk-based system, the AFSS Team needed to develop a risk-ranking tool that incorporates a three-step process. The first step is identifying specific hazards. A hazard can be chemical, physical, or biological contamination (for instance, dioxin or aflatoxins). The second step is determining the likelihood of animal exposure to the contaminant, and the third-step is determining what the consequences of that exposure would be (which could range from reduced productivity in animals to illness or death in animals or humans, for example). Once all three steps have been taken, the feed safety system can be utilized to rank the relative risks of all hazards. The AFSS Team will use the information to develop an approach for determining which feed contaminants present the greatest risk to animal and human health, and for deciding how such risks can be prevented or controlled.
Dr. Hooberman added, “What is particularly challenging about the risk assessment component of the AFSS is that the AFSS Team is developing a risk-ranking scheme that attempts to combine both chemical and biological risks. One other feature that is of particular concern is the need to address data gaps and the resulting uncertainties associated with the risk ranking results.”
After creating the framework document and a concept paper, the AFSS Team sponsored three public meetings to discuss initial concepts for AFSS, the framework, and the first part of the risk assessments. The AFSS Team’s work on the initiative is scheduled to conclude in FY 2007 with recommendations on how to implement the AFSS concepts. This report has highlighted specific FY 2006 accomplishments in the section on “Ensuring Feed Safety.”
Even though its work is not yet completed, the AFSS Team provides an example of the Center’s flexible nature. The Team can draw on expertise from across the Center and even across the Agency to address a complex task such as this one.
Innovative Work of a Multi-Office, Multidisciplinary Inspection Team Receives FDA Recognition
This past year, FDA recognized members of a multi-office, multidisciplinary team that collaborated to conduct a pre-approval Good Laboratory Practices (GLP) inspection of a pharmaceutical company that manufactures several generic animal drugs.1 This was a complex inspection of four different facilities, and it included an audit of data from five bioequivalence studies that impacted four separate generic animal drug applications.
The inspection was “for cause,” conducted because of possible data inconsistencies found in bioequivalence studies that had been submitted to support a generic new animal drug application. Such studies are crucial in generic applications, because the drug must be shown to be bioequivalent to a pioneer drug before CVM can approve the generic drug.
This collaborative effort featured several innovations, including a user-friendly, efficient, technology-driven format the team developed for electronic exchange of data and information submitted by the sponsor, as well as exchange of comments from team members in different locations. In the past, FDA District Offices – which conduct facility inspections for all FDA Centers – had received thousands of pages of documents for use in inspections, with no convenient way to cross-reference studies. In this inspection, FDA’s Denver District Office received two password-protected CDs with all documents in .pdf format. This novel approach allowed detailed explanations of reviewer or inspector concerns to be placed electronically on a page with an embedded link to other examples of similar concerns. This inspection was the first time a District Office had received information from any FDA Center in this format.
In preparation for the inspection, members of the Bioresearch Monitoring and Administrative Actions Teams (from CVM’s Office of Surveillance and Compliance) and the primary reviewer on the Generic Animal Drug Team (from CVM’s Office of New Animal Drug Evaluation) carefully reviewed volumes of study data to categorize possible inconsistencies that the District Office investigators would use to plan the inspection and determine the best utilization of resources.
The actual inspection of the pharmaceutical company involved two inspectors from the Denver District Office and a representative from the Generic Animal Drug Team. Each individual represented unique expertise: a chemist, an experienced field investigator, and a Consumer Safety Officer with a clinical veterinary medicine background. The inspection took place at all four sponsor sites and included employee interviews and review of all clinical data.
The team members collaborated on the Establishment Inspection Report, decisions on final disposition, and further review of data. This inspection was a model of thorough, efficient, cohesive regulatory action. The unique presentation of data will be used as a possible prototype for all FDA Centers involved with pre- and post-regulatory inspections. The professional respect for individual and group expertise and efficient use of resources shown in this joint effort represent an outstanding example of what is being done to fulfill the CVM Mission.
The Generic Animal Drugs GLP Inspection Team received an FDA Group Recognition Award “for exceptional performance and outstanding innovation by CVM and the Office of Regulatory Affairs in coordinating and executing a complex GLP inspection.”
1 The team consisted of members of CVM’s Offices of Surveillance and Compliance and New Animal Drug Evaluation: Jean E. Bowman, D.V.M., John K. Harshman, D.V.M., Zollie A. Perry, Ph.D., George A. Prager, Sharon L. Ricciardo, Vernon D. Toelle, Ph.D. and Fredda Shere-Valenti; and the Denver District Office, FDA’s Office of Regulatory Affairs: Teena H. Aiken, Kent C. Faul, and Eric R. Smith.
RECOGNIZING INDIVIDUAL ACHIEVEMENT
Award Winner Recognized for Creating a High-Performance Division at CVM
Director’s Award to William Marnane: “For providing exceptional leadership in the management of personnel and critical manufacturing initiatives important to the mission and goals of the Center.”
The FY 2006 “Director’s Award,” the highest award the Center presents, went to William Marnane, who, a decade ago, took on the job of developing the Center’s Division of Manufacturing Technologies. Through innovation, enhanced communications with the FDA field staff, and development of a highly productive staff, Mr. Marnane succeeded in developing a Division that offers drug sponsors a more efficient review process.
CVM created the Division in 1996 as part of the Center’s Strategic Plan to centralize all aspects of the chemistry, manufacturing, and control portion of animal drug application review and approval. Mr. Marnane has developed the Division’s organization over the years by creating the Feed/Topical Team, the Biotherapeutics Team, and the Generic Review Team. (The previously existing Chemotherapeutics and Antimicrobial Teams remain in the Division.) The Division is involved with a drug “from birth to death,” Mr. Marnane says. The Division conducts pre-approval reviews of the drug applications to make sure the proposed manufacturing standards are adequate to produce safe and effective drugs. The Division coordinates with FDA field investigators, who inspect the actual manufacturing sites to make sure they can continuously manufacture high-quality drugs, both pioneer and generic. And it reviews supplemental applications and annual reports for changes to approved applications, in addition to carrying out other post-approval responsibilities.
Under Mr. Marnane’s leadership, the Division introduced concepts such as “Quality by Design.” This concept allows a sponsor to demonstrate process knowledge, apply risk assessment and quality system techniques, and significantly improve the quality of the submission. High-quality submissions ease the regulatory burden and can lead to shorter review times, which is consistent with the Division’s efforts to move toward One-Cycle Review. Quality by Design is an example of CVM’s efforts to facilitate drug approval review by improving the Center’s relationship with the animal drug industry. Further improvement will be “the result of more and better communication between a well-organized Division and its customers,” Mr. Marnane said.
Mr. Marnane has also focused attention on coordination with the FDA field staff. “The Division’s organizational structure facilitates frequent interactions between pre-market review staff and FDA field investigators. To further enhance communication with the FDA field, reviewers from the Division participate in on-site pre-approval inspections with field investigators to provide technical support when necessary,” he said.
Undoubtedly, an important part of Mr. Marnane’s success is his development of the Division’s staff. He relied on the management strategy called “High Performance Organization” (HPO), introduced in the Center at about the same time the Center created the Division. “Building the concepts of the HPO into the Division made sense, because the vision and values (contained in HPO) are consistent with the kind of Division that we wanted to build,” Mr. Marnane said. “Quality of life, alignment with Division, Office, and Center goals and objectives, transparency, empowerment, stewardship, metrics, and business plan objectives being sought by the Division were all key components of HPO.”
Mr. Marnane gave the Division staff as much direct involvement and responsibility as possible to achieve the goals. “We have empowered staff through a participative process in which staff members make recommendations on bonus award allocations based on individual performance, participate in the process of interviewing and recommending candidates to be offered a position in the division, and tackle longstanding issues pertinent to consistent review quality across the Division,” he said.
According to Mr. Marnane, “Transparency, coupled with development of a bottom-up philosophy and alignment, were probably the most important building blocks needed for empowerment. The greatest contributors to the success of HPO implementation within the Division of Manufacturing Technologies are the people themselves and their willingness to embrace the concepts of the HPO model.”
INNOVATING FOR MANAGEMENT EFFICIENCY AND SUCCESS
Project Management Employed in Several Areas at CVM
Several years ago, the CVM adopted a strategic plan that called for the Center to “improve, and bring discipline to and through, our business practices.” To give that statement weight, the Center implemented project management, applying it initially to four pilot projects and later to other priority projects. CVM’s project management strategy is designed to help the Center become more effective and efficient in carrying out its core and supporting functions.
In simplest terms, project management is a methodical Picture of CVM's Project Management Team approach to planning and guiding a project from start to finish. At CVM, project management tools, techniques, and processes are flexible, depending on the size, duration, and complexity of the project. We initiate small or simple projects with a brief project definition and timelines monitored using an Excel spreadsheet. On the other end of the spectrum, for large or complex projects, we define fully the goal, objectives, implementation strategies, deliverables, assumptions, and risks, and monitor progress using Microsoft Project software.
CVM’s senior project management official and Director of the CVM Project Management Staff is Madeline Vanhoose, M.S., who recently received certification as a Project Management Professional (PMP) from the Project Management Institute. Madeline works with Susan Dewitt, Project Manager for the CVM Project Management Staff, to implement and support project management throughout the Center. Susan is also the administrator for Enterprise Microsoft Project, CVM’s standard project management software.
We applied project management to the following four high-priority crosscutting projects in 2006:
CVM Communications Clearance Project. Before the communications clearance policy development team completed its work, different offices within the Center had different publication clearance procedures. For example, scientists within the Center who wanted to publish a report or release other information did not have a clear path to follow to obtain appropriate authorization. Collaborating authors in different offices had different and sometimes conflicting publication clearance procedures to follow.
CVM had attempted several times to develop a Center-wide policy, but only with limited success. It decided to apply project management to the goal of drafting a Center-wide policy for staff and management to use in seeking clearance of various publications, such as articles, speeches, and other documents, for release to the general public.
To accomplish this task, the Center formed the Communications Clearance Policy team that included representatives of each office that clears publications, and a project manager. By applying project management principles, the team was to develop a unified policy that, with Center Leadership Team approval, was implemented Center-wide early in FY 2006.
“Lessons Learned” sessions revealed that the team was successful because it used a variety of project management principles, tools, and techniques, including: use of a Project Definition document that defined the goal, objectives, scope, deliverables, risks, assumptions, and project environment impacts; a Team Charter that defined the roles for team members and ground rules for meeting conduct; and a project plan that served as a roadmap and checklist for the efforts of the team and to avoid “scope creep.”
Office of New Animal Drug Evaluation (ONADE) Office-Wide Project Management Pilot Project. The ONADE Project Management Team (PMT), headed by Petra Kotek, M.S., PMP, arose out of the Animal Drug User Fee Act (ADUFA) and the need for the organization to manage animal drug reviews at the application level. The ONADE PMT has two primary focuses.
First, the team brings the tools of project management to bear on submissions to Investigational New Animal Drug files and New Animal Drug Applications, enhancing the abilities of the team leaders and review staff to manage those applications. The team ensures that ONADE is meeting ADUFA timeframes, thus promoting efficiency in the drug approval process in order to get safe and effective drugs to market faster. The team is also developing procedures to facilitate periodic project meetings with drug sponsors, which will allow ONADE to project workload and better manage its human capital.
Second, the team is enhancing the project management of internal ONADE projects, such as development of guidance documents and standard operating procedures. The team works closely with ONADE’s Management Team to ensure that these systems effectively support the new animal drug review process and mission of the Office.
With the incorporation of project management into the drug development process, the ONADE PMT has begun to schedule and manage post-approval meetings for all significant approvals. The goal of the meetings is for CVM and the drug sponsor to document “lessons learned” so future projects run more smoothly and efficiently. Drug sponsors are encouraged to contact the PMT to schedule these meetings.
Document Control Unit Upgrade. CVM has applied project management to the design and development of physical space for housing the Center’s drug application records. The challenge had two parts: to expand the space for documents, and to ensure either that all the documents were properly “backed-up” or that copies were stored in case of damage to the original documents. A special team completed this project near the end of the fiscal year and was conducting closeout evaluation and “lessons learned” sessions at that time.
Animal Feed Safety System Project. Described elsewhere in this annual report, the AFSS is a longer-term project management pilot. The project has successfully achieved its early milestones, including several public meetings.
Other projects initiated this past year to which the Center applied project management include:
The development and proposal of “index” rules under the Minor Use and Minor Species Animal Health Act of 2004, a priority project that had high visibility outside the Center.
The development of import tolerance regulations and guidance that will enable stakeholders to know the process and data requirements needed to apply for a tolerance for drug residues in imported animal food products.
The development of project management templates for some of CVM’s ongoing internal processes with deadline commitments, to help manage these processes more efficiently and achieve their deadlines. Some of these processes include the CVM Annual Report (including this one!), the FDA Veterinarian, and the National Antimicrobial Resistance Monitoring System Retail Meat Annual Study Report.
Project management at CVM continues to evolve and improve, with more resources becoming available to support an increasing number of project managers and projects, and to improve CVM’s business practices. For example, the Center is applying project management to its Information Technology (IT) initiatives. Specifically, it is applying a project management technique called Earned Value Management (EVM), which objectively measures the technical, schedule, and cost performance of an IT project. EVM provides early warnings of performance problems, enabling project managers to take timely corrective action. Kim Sanders, PMP, leads the Office of Information Technology Project Management Office that supports CVM and oversees the planning, execution, and management of all CVM-approved IT projects.
A MESSAGE FROM THE DIRECTOR
Many of the accomplishments we report this year are the result of multidisciplinary and multiorganizational efforts. Teamwork is one of our guiding principles. The initiatives we describe reach across the offices within the Center for Veterinary Medicine (CVM) and outside the Center – throughout the Food and Drug Administration (FDA), to other government agencies (international, Federal, and State), to colleges and universities, and into the private sector. Some of the vignettes contained in the preface describe these sorts of cooperative efforts, and a number of CVM-related FDA awards given this year included recipients who have partnered with us.
We value these alliances, for they bring the best possible combination of skills and experience to bear on problems that are within our mandate, doing so with the minimum expenditure of valuable resources. Virtually all of the accomplishments cited in this annual report involve cooperative efforts, and all of CVM’s offices contributed to the achievement. I would like to highlight some of the successes.
Progress in New Animal Drug Approvals
The major part of the work in this area comes from our Office of New Animal Drug Evaluation, and our Office of Minor Use and Minor Species Animal Drug Development (OMUMS). But other offices contribute much – for example, the Office of Management in the planning and expenditure of funds under the Animal Drug User Fee Act (ADUFA), and the Office of Research in conducting work that supports drug approvals both for major and minor species and uses.
ADUFA. CVM met all of its performance and financial goals under ADUFA during fiscal year 2005, the second year of the program. We worked diligently to accomplish the ADUFA goals for FY 2006. We are using the increased resources from user fees to bolster our ability to review animal drug applications in a timely fashion. We are working against tighter deadlines each year; for example, 230 days to complete reviews of 90 percent of new animal drug applications in FY 2006, compared with 270 days in FY 2005 and 295 days in FY 2004. ADUFA requires recruitment of significant numbers of new staff. We met our FY 2006 goals for hiring new professional staff to review new animal drug applications under ADUFA, and we were pleased with the high caliber of those we were able to employ.
2006 New Animal Drug Approvals. This year, we approved a number of new animal drug applications. EQUIOXX (Firocoxib) oral paste for control of pain and inflammation associated with osteoarthritis in horses is an example of an approval for nonfood animals. For food animals, we approved ZILMAX (zilpaterol hydrochloride), a nonhormonal, nonantimicrobial new chemical entity for improved production efficiency and increased carcass leanness in cattle. And we approved CYDECTIN (moxidectin) oral drench for treating parasites in sheep, a minor species.
Drugs for minor uses and minor species. We made steady progress during the past year in implementing the Minor Use and Minor Species (MUMS) Animal Health Act of 2004, which will significantly expand the availability of drugs for minor species, as well as minor uses in major species of animals. The Agency proposed regulations in August 2006 that will implement a MUMS provision under which FDA may add a minor species drug to an “index” of unapproved new animal drugs that may be legally marketed when the potential market for the drug is too small to support the costs of the drug approval process. We also took major steps toward implementing the “designation” provisions of the Act, which provide incentives to drug sponsors for gaining approval for MUMS drugs.
Achievements in this area resulted from leadership by OMUMS. Other CVM offices contributed, including the Office of Research, which conducted efficacy studies and published an online database for use by researchers. The U.S. Department of Agriculture (USDA), along with scientists in a number of universities, continued to facilitate MUMS approvals through National Research Support Project #7 (NRSP-7).
Attacking Public Health Issues – Ongoing and New
Antimicrobial Resistance. This past year, we took strides in several areas to minimize antibiotic resistance resulting from the use of antimicrobial drugs in animal medicine. Along with our partners – USDA and the Centers for Disease Control and Prevention – we continued to expand monitoring for antimicrobial resistance under the National Antimicrobial Resistance Monitoring System (NARMS). The three agencies strengthened data reporting and began implementing other recommendations made by an outside review panel convened during FY 2005. To provide leadership for all three arms of NARMS (animal, retail meat, and human), Dr. David White of CVM’s Office of Research was named during the year as NARMS director.
We continued to develop the utility of NARMS to facilitate the pre-approval review of new animal drugs, through the efforts of people from several offices within CVM. NARMS data on the susceptibility of Salmonella spp. and E. coli to cefquinome were presented in the September 2006 Veterinary Medicine Advisory Committee meeting that addressed the microbial food safety of an antimicrobial drug application currently under review for use in food-producing animals.
A booklet published during the year, “Judicious Use of Antimicrobials for Aquatic Veterinarians,” resulted from a joint effort of the Aquatic Veterinary Medicine Committee of the American Veterinary Medical Association and CVM’s Aquaculture Working Group. The booklet helps aquatic veterinarians treat animals in a way that minimizes the development of resistance in human and animal pathogens.
Bovine Spongiform Encephalopathy (BSE). The Office of Research during the year completed the development of a real-time polymerase chain reaction method for the identification of bovine, sheep/goat, and deer/elk material in animal feeds. This is a major step that will permit identification of material that is prohibited from use in ruminant feed by our BSE feed regulation. After validation, the method will be ready for regulatory use.
The Office of Surveillance and Compliance is working with the FDA Office of Regulatory Affairs (ORA) to develop a risk-based plan for inspection of facilities that process prohibited material; this plan will result in improved product quality and safety through prioritization of facilities inspections based on risk. In FY 2006, investigators exceeded their goals for BSE-related inspections of feed manufacturers and animal product renderers – the result of cooperative efforts involving CVM, ORA, and State agencies.
Animal Drug Residues. Regulatory activity designed to reduce illegal drug residues in domestic meat products continued throughout the year. In addition, we are challenged by the need for safety oversight to catch up with the growth in the volume of imported products, especially seafood, that are under FDA’s jurisdiction, as emphasized in FDA’s strategic plan. Most of the U.S. seafood imports are products of aquaculture; drugs may be used for treatment or production in aquacultured species, both imported and domestically raised. This year, CVM researchers completed the validation of a multi-residue method to detect drug residues in tilapia and trout. This accomplishment means that a multi-residue, multi-class method for drug residue analysis that provides great flexibility for laboratories testing imported and domestic aquacultured products is now available for a total of four of the most commonly aquacultured finfish species.
With the assistance of USDA, CVM researchers developed a provisional method for detecting 17 drugs in honey. This development is significant because the United States imports nearly 100,000 metric tons of honey each year, dwarfing our domestic production, and illegal drug residues have been found in some imported honey.
Avian Flu. In May 2006, we issued a final rule prohibiting the extralabel use in animals of two human drugs approved for prevention of influenza A, adamantane and neuraminidase inhibitor. The rule, which prohibits use of the drugs in chickens, turkeys, and ducks, is based on evidence that such use could lead to the emergence of resistant strains of influenza A virus, causing the anti-influenza drugs to be ineffective in humans.
Side Effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). When we learned that some dog owners were not being informed about the potential for serious adverse reactions of NSAIDs and had not received Client Information Sheets concerning these drugs from their veterinarians, we launched an extensive education program. We had considerable assistance in this effort – which was directed both to veterinarians and pet owners – from the American Animal Health Association and the American Veterinary Medical Association. Our Communications Staff, part of the Office of the Director, took the lead for CVM in designing and conducting the program.
Bioterrorism Vulnerability Assessments. During the year, we participated with other Federal agencies, State agencies, and industry volunteers, in conducting vulnerability assessments for grain elevators and cattle feedlots. These initiatives were carried out under the auspices of the Strategic Partnership Program-Agroterrorism (SPPA), created in FY 2005, to assess the potential risk from terrorist attacks against sectors of the agriculture and food industry.
Innovation – Critical Path to Drug Approvals
FDA has undertaken an initiative that addresses the recent slowdown in innovative medical therapies reaching patients. This high-priority area focuses on the urgent need to improve predictability and efficiency along the critical path from laboratory concept to commercial product. The Agency is addressing its role in advancing development science by working to make sure that its standard-setting process is informed by the best science.
CVM is a participant in this effort. For example, Dr. Raafat Fahmy of our Division of Manufacturing Technologies is conducting critical path research that supports innovation and efficiency in pharmaceutical development, manufacturing, and quality control. His work, done in collaboration with the University of Maryland School of Pharmacy, involves ground-breaking research in chemometric modeling – the application of mathematical and statistical models to predict physical and chemical properties of the active pharmaceutical ingredient and finished drug product – and near infra-red sampling technique.
Implementing Risk Management and Resource Management
We made progress during the year in developing a method for ranking feed contaminants according to the relative risks they pose to animal and public health. In doing so, we have had the assistance of representatives from other FDA offices, State regulatory officials, and feed industry representatives. This effort is a vital part of the Animal Feed Safety System (AFSS).
AFSS is just one of several CVM initiatives to use science-based risk management to obtain maximum public protection with limited resources. Similarly, we are using new management techniques to maximize the use of limited resources. For example, during the year, we utilized the Activity-Based Costing (ABC) System in conjunction with data from the associated Activity Time Reporting (ATR) System to develop management reports that have enabled us to better understand, manage, define, and assign the true costs of doing business.
Organizational Management and Change
The Center Leadership Team collaborates on day-to-day management and policy decisions facing the Center, as well as long-range planning, budgeting, and policy development.2 In making its decisions, the Team considers scientific, economic, international, and environmental issues and their impact on the Center. Through its leadership, the Team continues to develop a work culture in CVM that fosters high performance and reinforces the Center’s vision, values, and behaviors.
Appointments of individuals to serve in key positions are essential to the success of any organization. We made one such selection during the year, the appointment of Dr. Bernadette Dunham as Director, Office of Minor Use and Minor Species Animal Drug Development. Before coming to CVM in 2002 as ONADE Deputy Director, Dr. Dunham was Acting Director of the American Veterinary Medical Association’s Government Relations Division. In that role, she was an effective part of a coalition that helped with the passage of the MUMS legislation.
Providing Leadership Within FDA
CVM continued to provide leadership on an Agency-wide basis during the past year. The Center’s leadership role on the Agency-wide Bioinformatics Board, established in February 2006, is an example. The Board was created to achieve the FDA goal for a modern, well-integrated, efficient, and affordable infrastructure to support FDA administrative and regulatory business operations. CVM also served as the FDA pilot for the development of a marginal cost analysis requested by the President’s Office of Management and Budget. Using ADUFA as an example, the analysis assessed how the impact of a change in funding on performance will help to improve budgetary and policy decisionmaking.
2 CVM’s Center Leadership Team members are as follows:
Dr. Stephen F. Sundlof, Director, Center for Veterinary Medicine
Dr. Andrew J. Beaulieu, Special Assistant to the Director, Center for Veterinary Medicine
Ms. Catherine Beck, Associate Director for Policy and Executive Programs
Dr. Bernadette Dunham, Acting Deputy Director, Center for Veterinary Medicine and Director, Office of Minor Use & Minor Species Animal Drug Development
Dr. David Grau, Senior Management Consultant
Dr. Daniel G. McChesney, Director, Office of Surveillance and Compliance
Mr. David E. Wardrop, Jr., Director, Office of Management
Dr. Marleen Wekell, Acting Director, Office of Research
Dr. Steven D. Vaughn, Director, Office of New Animal Drug Evaluation
Achieving on an Individual and Group Basis
The accomplishments of an organization are often reflected in the public recognition of its people. FDA and CVM management during the year recognized the outstanding work of our Center employees through the presentation of a large number of group and individual awards. In addition to numerous scientific, technical, and administrative awards this year, CVM honored several individuals for excellence in mentoring fellow employees. We recognized Dr. Andrew Beaulieu, Dr. Dennis Bensley, Mr. David Wardrop, and Dr. Haile Yancy for their extraordinary contributions to the lives and careers of numerous CVM staff as dedicated mentors and teachers. Full details for all the awards are in Appendix C.
The large number of articles published by CVM scientists during the year is evidence of their professional productivity. The article topics included antimicrobial resistance, drug metabolism and residues, drug effectiveness, pharmaceutical analysis, methods for detection of unsafe feed ingredients, biotechnology, and more. We have included a complete publications list in Appendix D.
The achievements we report resulted from the hard work of a competent and dedicated staff. As I have noted, this report also documents continued expansion of collaborative activities with many of our stakeholders and partners. These arrangements provide mutual benefit and allow us to fulfill our role in protecting the public health more effectively and efficiently. We are grateful for the support of our stakeholders and partners as we work together for the public good.
Reaching Performance Goals
We present more details on the Center’s many accomplishments in this annual report. The following pages set out the challenges we face and our accomplishments during the past year. As highlighted throughout this report, our performance goals are aligned with the President’s Management Agenda, the Department of Health and Human Service Secretary’s 500-Day Plan and Department-Wide Objectives, and the FDA Strategic Goals. Where we reached our performance goals for FY 2006, we have so indicated. Where we fell short of the goals, we have indicated this also. We believe we best serve the public by reporting our shortcomings along with our accomplishments.
We believe that the reader can best appreciate the Center’s FY 2006 accomplishments by understanding what CVM is all about, including our mission, plans, organization, and sphere of influence. Thus, the first major section of our annual report is “About CVM.”
ABOUT CVM
Our Mission and Guiding Principles
OUR MISSION…
The Center for Veterinary Medicine (CVM) is a consumer protection organization. We foster public and animal health by approving safe and effective products for animals and by enforcing other applicable provisions of the Federal Food, Drug, and Cosmetic Act and other authorities.
OUR GUIDING PRINCIPLES…
We are committed to:
Health Protection. We honor our role in protecting the health of people and animals, and value the principles and spirit of the supporting laws and regulations.
Integrity. We conduct ourselves with honesty and integrity, recognizing that upholding the public trust requires the highest standards of moral and ethical conduct.
Quality. We achieve excellence through the ongoing development of our competencies and continuous quality improvement in all our processes. In particular, we recognize the value and importance of science and law in reaching quality and timely regulatory decisions.
Teamwork. Everyone’s contribution is important. Working together, we place the mission of the Center first and align our contributions, whether individual or in teams, toward that end. We conduct ourselves in accordance with the principles of consultative and participative decisionmaking.
Communication. We communicate information, ideas, decisions, and provide feedback, internally and externally to the organization, in a candid, timely, constructive, and clear manner.
Equity. We treat our customers and each other with fairness, courtesy, respect, and compassion, while fostering an atmosphere of mutual trust.
Diversity. We promote workforce diversity to strengthen and enrich the Center.
Innovation. We apply new concepts, ideas, and creative approaches to improve current operations and to meet the challenges of the future.
Safety and Health. We seek to ensure a safe and healthful workplace.
Quality of Worklife. We create and use programs that enhance our quality of worklife to improve our ability to carryout the mission of the organization.
Our Strategic Plan
CVM’s strategic plan reflects the principles set forth in the President’s Management Agenda, the 500-Day Plan initiative of the Secretary of Health and Human Services, and the Food and Drug Administration’s Strategic Goals.
Our plan, “CVM’s Back to Basics Approach for Carrying Out Our Public and Animal Health Mission,” commits us to focus on our core functions of:
Animal drug review (pre-market activities)
Compliance-related actions
Post-approval monitoring
Animal feed safety
To help us focus on the basics, our plan establishes the following goals. We will:
Set priorities (reviewed annually) and say “no” to lower priority item
Improve, and bring discipline to and through, our business practices
Support and use good science in establishing solid regulatory policy
Improve the capacity of the organization to meet current and future demands on the Center
Develop revenue enhancing strategies for core programs
Our Organization and Responsibilities
We carry out our mission through the efforts of people who are organized into six offices: the Office of the Director, the Office of Minor Use and Minor Species Animal Drug Development, the Office of Management, the Office of New Animal Drug Evaluation, the Office of Surveillance and Compliance; and the Office of Research. All of our offices are located in Rockville, MD, except the Office of Research, which is located in Laurel, MD.
OFFICE OF THE DIRECTOR (OD)
OD directs overall Center activities, coordinates and establishes Centerwide policy, and provides guidance for the implementation of the Center’s “Back to Basics” strategic plan. The Center Director serves as CVM’s representative and spokesperson concerning our activities, interacting with the general public, industry, the media, other government agencies, and national and international organizations.
The Director approves new animal drug applications and exercises other statutory authority that has been delegated to him. Other functions are performed through a Deputy Director and Associate Director for Policy and Executive Programs. The Office conducts communication and education programs, coordinates policy development and implementation, provides project management support for the Center, offers the services of the CVM Ombudsman, manages the Veterinary Medicine Advisory Committee, and coordinates the Center’s international activities. The Office of Animal Care and Use coordinates accreditation and compliance with regulatory requirements of the Agency’s animal care and use programs, and provides consultation on these issues.
OFFICE OF MANAGEMENT (OM)
OM provides executive leadership and direction for management and administrative programs, policies, and issues at Center and Agency levels. OM management serves in strategic leadership positions on CVM and FDA councils and committees. The Office provides the Center’s liaison services to the Agency’s Office of Shared Services, the Rockville Human Resources Center, and the Office of the Chief Information Officer to ensure efficient administrative services, as well as the effective delivery of information resources management services to CVM employees.
OM leads and directs the planning, development, and execution of the CVM budget, including the oversight of the Animal Drug User Fee Act (ADUFA) of 2003. It also serves as the Center liaison with the Agency concerning Government Accountability Office and Inspector General studies/inquiries. OM provides leadership for the Center’s Activity-Based Costing/Activity Time Reporting System and integrates it into the business culture of the Center’s operation.
OM directs the interaction with the CVM program offices and other FDA offices to assist with the efficient delivery of such services as property management, space and workplace planning, facilities management/operations, and workplace safety. In addition, OM represents management on issues regarding the FDA and National Treasury Employees’ Union Collective Bargaining Agreement.
The CVM Staff College directs the development and implementation of the competency-based management, leadership, team-building curriculum, and an extensive scientific/technical curriculum. The College sets the Center’s expectations with regard to required competencies through the Staff College Knowledge Center.
OM supports the vital information resources management function to enhance employees’ abilities to efficiently work with the integrated Information Technology (IT) systems to reach CVM goals.
OFFICE OF MUMS ANIMAL DRUG DEVELOPMENT (OMUMS)
The Minor Use and Minor Species Animal Health Act of 2004 provided for the establishment of OMUMS. The Office reports directly to the CVM Director and is responsible for overseeing the development and legal marketing of new animal drugs for minor uses in major species (disease conditions that are rare) and minor species (including, for example, pet animals – except dogs, cats, and horses; many animals of agricultural importance, such as sheep, goats, catfish, honey bees; and zoo animals).
OMUMS is responsible for writing the implementing regulations for those provisions of the MUMS Act relating to Designation and Indexing and is assisting in the drafting of the implementing regulations for Conditional Approval. The Office is currently responsible for designating new animal drugs. This responsibility may involve a determination of whether the intended use of a new animal drug qualifies as a minor use in a major species. Once implementing regulations are finalized, OMUMS will also be responsible for all aspects of animal drug indexing.
OFFICE OF NEW ANIMAL DRUG EVALUATION (ONADE)
ONADE’s mission is to protect the public health by ensuring the availability of an adequate number of safe and effective animal drugs to meet the therapeutic and production needs of animals. ONADE administers the core function of drug review, which involves directing the approval process for animal drugs. FDA must review an animal drug for safety, effectiveness, and quality before the drug can be legally marketed in interstate commerce. CVM approves drugs intended to benefit the health and productivity of food animals and the health of companion animals.
Drug sponsors must submit clinical tests to establish drug safety and effectiveness. Sponsors of drugs intended for food animals must also prove that food products derived from treated animals do not contain unsafe drug residues and that the food products are safe with respect to microbial safety. The sponsors must develop analytical methods to detect and measure drug residues in edible animal products. The Federal Food, Drug, and Cosmetic Act provides for approval of both pioneer and generic animal drugs and for FDA-granted authority to use investigational animal drugs. CVM classifies the animal drugs it approves, for distribution and use purposes, as over-the-counter, prescription, or veterinary feed directive.
ONADE administers the ADUFA, which authorizes FDA to collect fees in support of the review of new animal drugs. Under ADUFA, CVM agreed to pursue a comprehensive set of review performance goals to improve the timeliness and predictability of the review of new animal drug applications and investigational new animal drug submissions.
OFFICE OF SURVEILLANCE AND COMPLIANCE (OS&C)
OS&C has primary responsibility for three of CVM’s four core functions: compliance-related actions, post-approval monitoring, and animal feed safety. OS&C monitors the safety and effectiveness of approved drugs after they enter the market. Working with the U.S. Department of Agriculture and State agencies, OS&C monitors the occurrence of unsafe drug residues in meat and poultry products, and guides efforts to protect consumers through educational and enforcement activities related to drug residues. The Office coordinates enforcement actions against unapproved drugs that are on the market and that threaten public and animal health. Working with epidemiologists in CVM’s Office of Research, OS&C utilizes epidemiological skills to protect public and animal health.
OS&C conducts surveillance and compliance programs to protect animal feed from contamination by toxic materials such as mycotoxins, pesticides, heavy metals, and industrial chemicals, and to prevent the establishment and amplification of bovine spongiform encephalopathy through feed. The Office administers the feed mill licensing program and coordinates biennial inspections of medicated feed manufacturers. It approves food additives for use in animal feed and reviews genetically modified plant varieties for safety. OS&C coordinates the Center’s counterterrorism efforts. The Office’s Bioresearch Monitoring Team oversees inspections of both nonclinical (laboratory) and clinical studies to provide assurance of the integrity of data submitted in support of animal drug applications. OS&C also coordinates the Center’s administrative actions involving approved drugs, such as actions to withdraw drug approvals.
OFFICE OF RESEARCH (OR)
OR conducts applied research in support of regulatory decision-making related to each of CVM’s core functions. The Office is located in a state-of-the-art research complex containing offices, laboratories, animal buildings, and pastures.
In support of the drug review function, OR conducts studies in animal drug safety and efficacy, antimicrobial resistance mechanisms, metabolism, standardization of test methods, and pharmacokinetics/pharmacodynamics. The goal of these efforts is to provide a science base for guideline development. OR supports the compliance program of the Center through the development of analytical methods and evaluation of screening tests for detection of drug residues in imported and domestic food products. The position of Director of the National Antimicrobial Resistance Monitoring System (NARMS) resides within OR, and OR is responsible for the monitoring of retail meats for antimicrobial resistant foodborne bacterial pathogens under NARMS. These pathogens are also subjected to molecular typing as part of the national PulseNet program. OR conducts research to understand the microbiology of animal feeds and the dissemination of resistant bacteria via livestock feeds. The Office is also developing methods to detect material prohibited by the BSE feed regulation that could compromise animal feed safety.
OR prepares a detailed annual report. For a copy, write to: Center for Veterinary Medicine, Office of Research, 8401 Muirkirk Road, Laurel, MD 20708, attention Ms. Katie Orr.
Our Sphere of Influence
CVM’s efforts to help ensure that domestic and imported animal food products are safe affect millions of consumers. On the average, American consumers eat 110 pounds of meat, 70 pounds of poultry, 15 pounds of fish, 590 pounds of dairy products, and 30 pounds of eggs each year. Besides protecting the health of consumers in a population that has now passed 300 million, CVM works to safeguard the health of food-producing animals in the United States: 8.8 billion chickens, 264 million turkeys, 96 million cattle, 60 million pigs, and 6.1 million sheep are produced each year. The United States produces more than $100 billion worth of livestock and livestock products each year.
CVM approvals are now in effect for several hundred animal drug applications, including generics, for use in food-producing animals. We have approved many of these drugs for administration through animal feed. Under a law passed by Congress in 1996, CVM began licensing firms that manufacture certain medicated feeds; presently, there are 1,070 licensed feed mills. In addition, we have published regulations that authorize use of more than 50 food (feed) additives. Several hundred more approved drug applications, including generics, are available to maintain the health of our Nation’s increasing pet population, which now includes 65 million dogs and 75 million cats, in addition to 11 million birds and 6 million horses.
FDA is responsible for ensuring the safety of all animal feed and feed ingredients mixed by commercial and noncommercial feed manufacturers. We estimate the number of firms, including livestock and poultry producers and firms in a variety of specialized industry groups, to be at least 90,000. We also regulate nearly 400 animal drug manufacturers and other sponsors of animal drug applications and Type A medicated articles (new animal drugs intended for use in the manufacture of medicated animal feed).
The drugs we approve help the Nation’s 69,000 veterinarians accomplish their task of maintaining the health of the Nation’s animals.
Our Stakeholders and Partners
OUR STAKEHOLDERS
Many organizations and millions of individuals have a stake in the outcome of CVM’s work, including consumers, animal owners, veterinarians, and firms in the regulated industries – companies that market the drugs, feeds, and other products that we regulate. Our stakeholders also include trade associations; consumer organizations; State, Federal and foreign regulatory agencies; and international standard-setting organizations.
We use a variety of methods to keep stakeholders informed and to seek their advice and opinions about our policies and programs. These methods include public meetings; requests for comment on proposed regulations and guidance documents; the CVM Web site; and a variety of informal means, such as letters, phone calls, and e-mails.
OUR PARTNERS
Our success in promoting and protecting the public health depends not only on the active involvement of our stakeholders, but also on the formation of partnerships with those whose goals align with ours. Government downsizing, a changing economy, technical advances, and other factors have prompted FDA and CVM increasingly to seek out partnering opportunities to maximize the use of our resources.
The concept of collaboration and partnership is generally known as leveraging, and we are working to make it one of the foundations of our day-to-day operations. Our partners include:
Other Federal agencies with whom we share related regulatory responsibilities, such as the U.S. Department of Agriculture’s (USDA) Food Safety and Inspection Service (e.g., surveillance for animal drug residue and antimicrobial resistance) and Animal and Plant Health Inspection Service (e.g., BSE) and the U.S. Environmental Protection Agency (EPA) (e.g., pesticides). For example, the Interagency Residue Control Group, with members from FDA, USDA, and EPA, coordinates information on residues of animal drugs, pesticides, and environmental contaminants in animal food products.
Centers for Disease Control and Prevention, National Center for Infectious Diseases (e.g., surveillance for antimicrobial resistance).
USDA’s Agricultural Research Service and Cooperative State Research, Education, and Extension Service.
State agencies, especially through the Association of American Feed Control Officials, which partner with us to conduct inspections for compliance with the BSE feed regulation and other feed inspections and to carry out other regulatory and surveillance functions.
Veterinarians, who share with us numerous public and animal health goals, such as testing and surveillance of animal drugs for safety and effectiveness, avoiding drug residues in food products, minimizing the development of antimicrobial resistance through prudent drug use practices, and educating producers and related industries as to their public health responsibilities.
Foreign regulatory agencies that have responsibility and authority for controlling animal drugs and feeds in their countries; we leverage such international work through our participation and leadership in the International Cooperation on Harmonisation of Technical Requirements for the Registration of Veterinary Medicinal Products, the CODEX Committee on Residues of Veterinary Drugs in Foods, and other multilateral organizations.
We partner through cooperative agreements, cost-sharing contracts, cooperative research and development agreements, interagency agreements, cosponsorship agreements, and informal agreements. We hold joint workshops, cosponsor training sessions, work with scientists on mission-related research, and cooperate with others in many ways.
We include a number of examples of current partnership arrangements in this annual report.
FISCAL YEAR 2006 CHALLENGES AND ACCOMPLISHMENTS
Introduction
Although the Center for Veterinary Medicine (CVM) is organized into six separate offices, our Guiding Principles call for the staff to work together, placing the mission of the Center first. In fact, most of our significant accomplishments involve the efforts of people from two or more offices, through teams, committees, and day-to-day coordination.
Thus, the presentation of FY 2006 accomplishments is not organized according to office structure, but according to crosscutting topics. These topics reflect issues of significant public interest. The report introduces each of these areas of concern with a statement of the challenges that CVM faced as it attempts to meet its “Back to Basics” goals.
To help us achieve our strategic goals in FY 2006, CVM established targets for the year – a number of specific performance goals (the performance goals may be either program goals or management goals). Individual offices have primary responsibility for achieving some of the performance goals, but two or more offices share many of the performance goals because they relate to activities that require collaborative efforts.
The report highlights our performance goals in the appropriate sections below and indicates (with a a or X) whether we accomplished the goals.
We have worked during the past year to focus on the priorities in the President’s Management Agenda and the HHS-wide program and management objectives. We also focused on achieving FDA’s Strategic Goals:
Enhance protection for patients and consumers and empower them with better information about regulated products
Increase access to innovative products and technologies to improve health
Improve product quality, safety, and availability through better manufacturing and product oversight
Transform administrative systems and infrastructure to support FDA operations
Throughout this report, we give examples of how our FY 2006 accomplishments responded to the targets set by the President, the Department, and the Agency, including the long-term goals established by the Agency to support achievement of its strategic goals.
Increasing the Availability of Safe and Effective Animal Drugs
The Challenge
Statutory standards and the needs of CVM’s stakeholders – and especially the needs of the billions of animals whose health CVM seeks to protect – require that the center make the right pre-approval decisions and do so efficiently and expeditiously. CVM’s challenge is to protect public and animal health by ensuring that there is an adequate supply of animal drugs to meet therapeutic and production needs of animals. The Animal Drug User Fee Act (ADUFA) of 2003 challenges CVM to expedite and improve the review of new animal drug applications so as to increase the availability and diversity of safe and effective drugs.
FY 2006 Accomplishments
The Center responded to the pre-approval challenges in a number of ways, as described below. In general, CVM directed these actions toward achieving the FDA’s long-term goal of increasing access to safe and effective veterinary products.
This report lists significant FY 2006 new animal drug approvals in Appendix B. During the year, CVM issued five original new animal drug application approvals, 16 significant supplemental application approvals, and 17 significant generic animal drug application approvals.
ADUFA
Implementing ADUFA was a major CVM emphasis during FY 2006. ADUFA authorizes the collection of fees totaling $43 million over 5 years to enable FDA to hire and train additional scientific reviewers and implement enhanced processes to accelerate and improve the new animal drug review process.
This legislation is helping make safe and effective new animal drug products available more quickly. Specifically, the law establishes performance goals, including 5-year goals to be implemented by the end of FY 2008. CVM has made steady progress in implementing ADUFA; the Center can report the following:
CVM met or exceeded all FY 2004 and FY 2005 ADUFA performance goals. All applications and submissions received in FY 2004 have been completed, and CVM met or exceeded each of the FY 2004 ADUFA review performance goals. As of September 30, 2005, CVM was meeting or exceeding all the ADUFA review timeframe goals for applications and submissions for FY 2005.
CVM continued to make substantial progress in recruiting additional personnel for its review staff. CVM met its goal of having 50 percent of additional CVM review staff recruited and on-board by the first quarter of FY 2006.
CVM published policy and procedure documents to improve the new animal drug review process. The Center is committed to improving the efficiency, quality, and predictability of the new animal drug review process. In keeping with this commitment, CVM published four policy and procedure documents that were adopted in FY 2005. These are available on the CVM homepage on the FDA Web site at http://www.fda.gov/cvm.
The FY 2005 ADUFA Financial Report shows that CVM met the legal conditions that must be satisfied before the Agency can collect and spend user fees. During FY 2006, CVM worked to achieve goals set for the year. Performance and financial reports for FY 2006 will be published separately.
FY 2006 Performance Goals
aContinue implementation of the Animal Drug User Fee Act of 2003 (ADUFA).
Meeting this goal accomplishes the Department-wide objective of increasing access to high quality, effective health care that is predictably safe.
aBuild enhancements into the review process by defining and completing critical Standard Operating Procedures (SOPs) and Guidances for Industry (GFIs), interim performance measures, and outcome measures to standardize processes to be efficient, consistent, and clear.
aImplement a Performance Management System using the Submission Tracking and Reporting System (STARS), Activity Time Reporting, Activity-Based Costing and Project Management systems, limiting resource expenditures on work outside of our core business.
aDevelop improved SOPs for review processes and develop scientific policies for review staff.
aDirect and target training and educational opportunities for staff and management to improve the knowledge base of the review organization.
ENHANCING THE REVIEW PROCESS BY DEFINING AND COMPLETING CRITICAL REGULATIONS AND GUIDANCE DOCUMENTS
Regulations and guidance documents are important mechanisms for implementing improvements in the animal drug approval process. During FY 2006, CVM completed work on important revisions to CVM regulations on supplemental applications and other changes to approved applications to implement the manufacturing changes provisions of the Food and Drug Administration Modernization Act of 1997. The final rule will require manufacturers to assess the effect of a manufacturing change on the identity, strength, quality, purity, and potency of a drug as those factors relate to safety and effectiveness, along with other changes. This initiative responds to the Agency’s strategic goal of improving product quality, safety, and availability through better manufacturing and product oversight.
CVM issued a number of draft and final guidance documents during the year. These included:
Draft guidance for industry #183, “Animal Drug User Fees: Fees Exceed Costs Waivers and Reductions,” which explains the procedures FDA expects to use to evaluate waiver requests under the “fees exceed costs” waiver provision of ADUFA.
Documents prepared under the auspices of the International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products (VICH). VICH is a trilateral (European Union-Japan-United States) program aimed at harmonizing technical requirements for veterinary product registration. An example is a guideline, “Environmental Impact Assessments for Veterinary Medicinal Products, Phase II-Final” (GL-38). The document provides guidance for the use of a single set of environmental fate and toxicity data to be used by applicants/sponsors to obtain marketing approval in all VICH regions for those veterinary medicinal products identified as recommending data during the Phase I process.
Guidance # 171: “Waivers of In Vivo Demonstration of Bioequivalence of Animal Drugs in Soluble Powder Oral Dosage Form Products and Type A Medicated Articles.”
Additional guidance documents published during FY 2006 are listed in Appendix A (Significant Regulations, Guidances and Other Documents).
ACTIONS TO INCREASE THE EFFICIENCY OF THE REVIEW PROCESS
The Center took a number of actions during FY 2006 to improve the efficiency, quality, and predictability of the animal drug review process. For example, Office of New Animal Drug Evaluation (ONADE) divisions continued to work with animal drug industry representatives to reduce the number of drug application review cycles. Presented here are other actions the Center has taken.
Development of Standard Operating Procedures. The Center continued to develop standard operating procedures (SOPs) for review processes, scientific policies for review staff, and procedures for expedient resolution of scientific issues. For example, ONADE completed work on SOPs for refusal to file, refusal to review applications, and for scheduling and holding meetings with outside parties.
Implementation of a Performance Management System. CVM continued during FY 2006 to implement a quality business system using an activity-based model to demonstrate better performance-to-budget efficiency. ONADE is working with a consultant to merge Activity-Based Costing (ABC) and Activity Time Reporting (ATR) data with project management and application review. Using the ATR system that has been in place since October 2003, the Office Management Team (OMT) members planned their resource availability for various performance goals so that resources can be balanced between animal drug review work and other essential non-review work. This balance facilitates the maximum utilization of available assets. The OMT has begun implementing after-action reviews on a quarterly basis, responding to the President’s Management Reform Agenda initiative for Budget and Performance Integration.
As an example of ONADE’s performance management initiatives, the Division of Manufacturing Technologies has effectively utilized available information from CVM’s Corporate Database Portal to evaluate core business activities, specifically to assess past performances/work-flow, predict incoming submissions, determine resource allocations, and propose process improvements. This initiative is the first attempt to use both the Submission Tracking and Reporting System (STARS) and ATR data to make business decisions regarding workload and resource allocations at a Division level.
In 2006, the Center used this analysis to place new hires in teams with the highest potential workload and to reallocate review responsibilities within the Division for increased efficiency. For instance, the responsibility for the review of drug substance information has been reassigned within the Division to only two teams: the Chemotherapeutics Team for synthetic drug substances and the Biotherapeutics Team for fermentation drug substances. A trend analysis also revealed that the Center needs to focus more on review activities and building efficiencies into the review process if it is to meet the ONADE goal of doing better than ADUFA timeframes for FY 2007. The Center will continue to use this type of analysis to make effective business decisions at the Division level.
Providing Training and Educational Opportunities. CVM continued to direct and target training and educational opportunities for staff and management to improve reviewers’ knowledge base. This training includes core curricula for new reviewers, policy and procedure competency, and expansion of the scientific knowledge base. CVM also offered training to review scientists to help them maintain and develop the cutting-edge knowledge required for reviewing applications that contain information on emerging technologies.
As an example of training opportunities during FY 2006, some of CVM’s reviewers visited a large, integrated swine operation to familiarize themselves with current production practices. The staff toured the feed mill, farrow-to-finish facilities, and packing plant. The experience will enable reviewers to discuss more accurately protocol development, label language, data sets, and drug usage issues with drug sponsors.
RESEARCH TO SUPPORT ANIMAL DRUG REVIEW
Drug sponsors are responsible for submitting studies to prove that their drugs are safe and effective. Complementary work – accomplished by CVM, its contractors, and collaborators – may alter the type and number of studies required for approvals, thus improving the efficiency of the drug approval process. An example of this is a pharmacokinetics/pharmacodynamics (PK/PD) program to assess the effects of drugs in diseased animals, an important contribution because most data submitted to CVM are generated in healthy animals.
In a follow-up to a previous PK/PD study of enrofloxacin in beef steers, preliminary analysis of data from a recent study has demonstrated that the instillation of sterile saline or culture medium (the “carrier” used to introduce the bacteria into the lung in the infection model) had no effect on plasma or bronchial fluid pharmacokinetics of the drug in beef steers. CVM scientists could conclude, therefore, that the PK effects observed were due to the bacterial infection and not the carrier.
Data from this study will be combined with some of the data from the earlier enrofloxacin study, which utilized the infection model, to document the bronchial fluid levels of the drug and the impact of infection on PK parameters. At the end of the year, these results are being prepared for publication.
CVM scientists also completed the animal phase of an investigation into determining the levels of endotoxin/pyrogens that can be present in veterinary pharmaceuticals without causing a safety concern to the animals. Results from this pilot study, which were undergoing analysis at the close of the fiscal year, will determine the parameters to be used and the physiological biomarkers to measure during a larger study. Data from the larger study will help reviewers determine safe limits for these compounds.
Increasing Drug Availability for Aquaculture and Other Minor Uses/Minor Species
The Challenge
The Minor Use and Minor Species Animal Health Act of 2004 (MUMS) challenges CVM to implement measures that will significantly expand the availability of drugs for minor uses and minor species. Because the potential sales volume is low, animal drug manufacturers lack economic incentive to seek animal drug approvals for minor uses (diseases that are rare) or minor species (animal species other than cattle, horses, pigs, chickens, turkeys, dogs, or cats). The need in aquaculture is a good example. The U.S. aquaculture industry is expanding, and the need for therapeutic and production drugs is growing as well.
IMPLEMENTATION OF MUMS LEGISLATION
Overview of MUMS Law Implementation
DESIGNATION: Provides incentives for approvals. FY 2006 action: Designations granted under interim processes and progress made in preparing final regulations.
CONDITIONAL APPROVAL: Provides for marketing of safe drugs while effectiveness studies are underway. FY 2006 action: Development of policies and procedures for interim conditional approval and preparation of proposed regulations.
INDEXING: Permits marketing of unapproved drugs under certain circumstances. FY 2006 action: Proposed regulations published.
The Law’s Major Provisions
This MUMS legislation provides innovative, flexible ways to provide drugs to treat minor animal species as well as uncommon diseases in the major animal species. The new law modifies provisions of the Federal Food, Drug, and Cosmetic Act in three key ways, providing for:
Indexing–In August 2006, FDA issued proposed regulations that, when finalized, would provide administrative procedures and criteria for Index listing a new animal drug for use in a minor species. The new law provides that FDA may add a minor species drug to an Index of unapproved new animal drugs that may be legally marketed when the potential market for the drug is too small to support the costs of the drug approval process, even under a conditional approval. The Index is limited to nonfood-producing minor species with a limited exception for some early life stages of food animals, such as certain fish eggs. The proposed regulations describe a process under which the Agency would make determinations regarding the eligibility of a new animal drug for Indexing, the selection of a qualified expert panel, and the findings of the qualified expert panel.
Work is ongoing to develop the administrative document control and electronic tracking processes needed to support the Indexing system described in the proposed Indexing regulations.
Designation–This aspect of the legislation provides incentives for minor use/minor species approvals. For example, at the time that a designated drug gains approval or conditional approval, it is awarded 7 years of exclusive marketing rights. FDA published proposed implementing regulations in September 2005. The proposed regulations describe the criteria CVM would use for granting or denying the requests, define content and format requirements for Designations, and specify other implementing procedures. CVM completed its review of comments on the proposed regulations and drafted final regulations during FY 2006.
During the fiscal year, CVM processed 63 submissions relating to Designation, and the Office of Minor Use and Minor Species Animal Drug Development (OMUMS) granted 31 requests for Designation. Designations have been listed on the MUMS Web page, (http://www.fda.gov/cvm/MUMSDrugDesg.htm), each within a few weeks of being granted.
Conditional Approval–The sponsor of a minor use/minor species veterinary drug can ask CVM for Conditional Approval, which allows the sponsor to market the drug for up to 5 years after proving the drug is safe and establishing a reasonable expectation of effectiveness, but before collecting all of the effectiveness data needed to support a full approval. During FY 2006, CVM developed procedures and policies to implement Conditional Approval prior to finalization of regulations, and worked on drafting the proposed regulations for Conditional Approval.
Communication with Stakeholders
OMUMS has reached out to stakeholders to update them on the status of MUMS Act implementation. During the year, OMUMS met with numerous potential new animal drug sponsors interested in utilizing the Designation and/or Conditional Approval provisions of the MUMS Act. OMUMS staff members have given general presentations about MUMS to a number of groups, and have also answered numerous telephone and e-mail inquiries about various aspects of the MUMS legislation and its implementation.
FY 2006 Performance Goals
aReview comments received on the proposed Designation regulations to implement the Minor Use and Minor Species (MUMS) Animal Health Act
of 2004.
aDraft proposed regulations to implement section 572 (Indexing) of the MUMS Animal Health Act of 2004.
aPublish MUMS drug designations on the MUMS Web page.
aDevelop procedures and policies in cooperation with the Office of New Animal Drug Evaluation to implement conditional approval prior to finalization of regulations.
Meeting these goals accomplishes FDA’s long-term goal of increasing access to safe and effective veterinary products.
RESEARCH TO SUPPORT DRUG APPROVALS (MUMS)
Food Safety Database. CVM has published an on-line database of literature (designated the PhishPharm Database) detailing drug metabolism, residues, and pharmacokinetics in multiple fish species. This database includes information from more than 450 articles, including not only the pharmacokinetic data, but also specific information regarding the holding conditions, i.e., the water temperature, salinity, size of the animals, drug dosage, and methods of administration. The database is a valuable tool for researchers and regulators and can be accessed by going to http://www.aapsj.org/view.asp?art=aapsj070230 and scrolling down to the zip links.
Efficacy studies. CVM researchers have developed a reproducible model for infecting channel catfish with a fungus (Saprolegnia parasitica) for testing the efficacy of potential therapeutic agents. This model will be used in future studies supporting a publicly held Investigational New Animal Drug (INAD) application.
Antimicrobial Susceptibility Testing Standards. During FY 2006, CVM researchers provided data to support the development of two international antimicrobial susceptibility testing (AST) standards for aquatic bacteria. These tests have been accepted as Official Methods by the Clinical and Laboratory Standards Institute (CLSI, formerly the National Committee for Clinical Laboratory Standards). The standards (M-42-A and M-49-A), published in July 2006, provide the first internationally recognized standards for AST of aquatic bacteria.
National Research Support Project #7 (NRSP-7). NRSP-7 is a national agricultural research program sponsored by the U.S. Department of Agriculture, in collaboration with CVM and others, to obtain clearances for drugs for minor species and minor uses. The program had a very active year in FY 2006. Its Public Master File (PMF) for the use of oxytetracycline immersion for otolith marking of finfish was used by a fourth sponsor to support an approved new animal drug application. A new PMF for the use of tylosin for the control of American foulbrood in honeybees was used to support the first new approval in decades for a drug for use in honeybees. Significant studies were submitted and accepted to support projects for the use of a progesterone intravaginal device for sheep, erythromycin for salmonids, and crude carp pituitary for finfish. New projects are in development for drugs for fish, deer, goats, and pheasants.
At fiscal year end, NRSP-7 had 20 active projects for rabbits, various fish species, sheep, goats, game birds, deer, and honeybees. To date, NRSP-7 files have supported 26 unique minor species drug approvals, and PMFs are available to support additional approvals.
Reducing Risk From Antimicrobial Resistance
The Challenge
Scientific evidence demonstrates that the use of antimicrobial drugs in food-producing animals can result in the selection for resistant bacteria. Resistant foodborne bacteria can then be transferred to humans, resulting in illness. If the patient needs antimicrobial drug treatment, that therapy may be compromised because the drugs of choice may be ineffective. CVM is challenged to develop policies and programs that reduce this risk to human health.
FY 2006 Accomplishments
In cooperation with other agencies, CVM has undertaken proactive surveillance, research, education, risk assessment, and risk management programs to reduce the risk to human health that can result from the use of antimicrobials in food-producing animals. The Center achieved significant progress in these efforts during the past year, responding to the FDA strategic goal of enhancing patient and consumer protection.
MONITORING FOR THE DEVELOPMENT OF RESISTANCE
CVM plays an active leadership role in the National Antimicrobial Resistance Monitoring System (NARMS), established a decade ago as a collaborative effort between CVM, the U.S. Department of Agriculture (USDA), and the Centers for Disease Control and Prevention (CDC). The NARMS program monitors changes in antimicrobial drug susceptibilities of selected enteric bacterial organisms in humans, animals, and retail meats to a panel of antimicrobial drugs important in human and animal medicine. The ultimate goal of these activities is to prolong the lifespan of approved drugs by promoting prudent and judicious use in animals of antimicrobial drugs and to identify areas for more detailed investigation. FY 2006 achievements include the following.
Implementing Recommendations of Expert Panel. During the fiscal year, CVM started implementation of several recommendations of a panel of outside experts, convened during FY 2005 for a review of all three arms of the NARMS program. These changes included enhanced sampling strategies in the retail meat program and human component, application of NARMS data in CVM’s drug pre-approval process, and other modifications, all of which are described in the following subsections.
Appointment of NARMS Director. To lead the NARMS program, CVM named Dr. David White of CVM’s Office of Research (OR) as NARMS director, with oversight responsibilities for all three arms of the NARMS program.
Expansion of Web site and Data Reporting. NARMS’ expansion continued in FY 2006, including progress in the development of a uniform Web site and reporting scheme for all three components of NARMS: the human isolates (conducted by CDC), animal isolates (directed by USDA), and retail meat (administered by CVM). The Web site, which incorporates annual reports, is on line at http://www.cdc.gov/drugresistance/actionplan/aractionplan.pdf. The three agencies strengthened data reporting during FY 2006 by developing complementary databases, improving timeliness of reporting, and harmonizing data presentation between the three agencies.
Growth of DNA Fingerprinting. CDC coordinates PulseNet, a national network of laboratories (including CVM’s) that perform molecular subtyping (or “fingerprinting”) of foodborne disease-causing bacteria by pulsed-field gel electrophoresis (PFGE). PFGE can be used to distinguish strains of organisms at the DNA level. Participants submit data electronically to CDC; the databases are available on-demand, allowing for rapid comparisons and early identification of common source outbreaks.
OR does PFGE analysis on all retail meat isolates, and submits them to the PulseNet3 database. OR also performs analysis on isolates from food-producing animals and humans. During FY 2006, OR performed PFGE analysis on more than 1,000 isolates of Salmonella, E. coli, and Campylobacter recovered from food animals, retail meats, and humans. Multi-drug resistant (MDR) Salmonella serotypes and clones have been included in CVM’s submissions. This database will assist CDC and CVM in monitoring the emergence of multi-drug resistant foodborne bacterial pathogens in the United States in an effort to better understand how antimicrobial resistance develops, spreads, and persists in animal production environments and retail meats.
Ensuring Data Accuracy. During the year, NARMS microbiologists teamed with FoodNet epidemiologists on two visits to participating State public health laboratories, with a goal of ensuring continued accuracy of generated data. These visits were part of the NARMS program’s continued partnering with other active and passive surveillance systems to help public health officials better understand the dynamics of foodborne illness in the United States.
Publication of Retail Meat Annual Report. Sites in 10 States that are part of the FoodNet system collect and culture samples of ground beef, pork chops, chicken breast, and ground turkey for the presence of Salmonella, Campylobacter, E. coli, and Enterococcus organisms. The isolates are sent to OR for identity confirmation, serotyping of the Salmonella isolates, antimicrobial susceptibility testing, and molecular characterization. CVM published the 2004 retail meat annual report during the past year. The report provides data on the prevalence of antimicrobial resistance in nearly 4,700 samples of foodborne bacteria in retail meats. The report is accessible at http://www.fda.gov/cvm/NARMSReport2004.htm.
Human Arm Expansion. The human arm of NARMS has expanded to include all 50 States plus three local health departments. CDC has developed a new Campylobacter sampling scheme, which took effect on January 1, 2005, with continued revision in 2006. The new strategy is being implemented in three stages to ensure a more robust, nationwide system.
Improvement in Testing Methods. The agencies involved in NARMS continued during FY 2006 to improve their testing methods. These improvements included development and implementation of a Campylobacter broth microdilution method approved by the Clinical and Laboratory Standards Institute. This method is being incorporated into public health systems in Canada, Europe, Central and South America, and is being used in World Health Organization (WHO) training laboratories worldwide. The method enhances the quality of data and ensures intra- and inter-laboratory reproducibility among the three arms of NARMS and other surveillance systems worldwide. NARMS also continued to participate in the External Quality Assurance System (EQAS) of the WHO Global Salmonella Surveillance and Laboratory Support Project (Global Salm-Surv). The EQAS supports the assessment of the quality of serotyping and antimicrobial susceptibility testing of Salmonella in all participating laboratories.
Continued Outreach. During FY 2006, CVM published NARMS information on CVM’s Internet site, in peer-reviewed publications, in the FDA Veterinarian, in scientific meeting proceedings and abstract books, and on posters presented at scientific meetings. The Center also presented NARMS results at a number of major scientific meetings.
3 The Foodborne Diseases Active Surveillance Network (FoodNet) is the principal foodborne disease component of CDC’s Emerging Infections Program (EIP). FoodNet is a collaborative project of CDC, EIP sites in 10 States, USDA, and FDA.
FY 2006 Performance Goals
aDevelop the detection capability of multi-drug resistant foodborne bacterial pathogens through participation in national surveillance programs including FoodNet and PulseNet.
aFood Safety-Antimicrobial Resistance: Continue research to identify food animal species causing human drug resistance.
aNational Antimicrobial Resistance Monitoring System (NARMS): Continue efforts to maximize cooperation and communication between
FDA, USDA, and CDC to increase efficient use of limited resources in addressing problems of mutual interest.
aImplement recommendations from external review of all three arms of the NARMS program.
Meeting these goals accomplishes the Department-wide objective of achieving continuous improvement in the safety of food and drugs.
UTILIZATION OF NARMS DATA AND RISK ASSESSMENT IN THE PRE-APPROVAL PROCESS
NARMS has traditionally been more involved in the post-approval aspects of CVM’s mission, but during FY 2006, the Center continued to develop pre-approval aspects of NARMS and NARMS data. For example, the NARMS retail component tested Salmonella and E. coli isolates from the past several years against cefquinome (not yet approved in the United States) and showed a highly susceptible population. However, Salmonella isolates displaying resistance to ceftiofur did possess increased minimum inhibitory concentrations (MICs) to cefquinome, suggesting that resistance may develop in several steps, beginning with ceftiofur resistance.
These and other NARMS data were presented in the September 2006 Veterinary Medicine Advisory Committee (VMAC) meeting that addressed the microbial food safety of an antimicrobial drug application currently under review for use in food-producing animals in accordance with CVM’s Guidance for Industry #152, “Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to Their Microbial Effects on Bacteria of Human Health Concern.” Among other documents, VMAC reviewed “Cefquinome Formulations for Parenteral Injection for the Treatment of Bovine Respiratory Disease,” prepared by the drug sponsor and available on the CVM Web site.
RESEARCH TO SUPPORT ANTIMICROBIAL RESISTANCE SURVEILLANCE AND REGULATION
The overarching goal of antimicrobial resistance research at CVM is to identify and implement methods to reduce microbial hazards associated with antimicrobial drug use in food-producing animals. This effort includes basic and applied research focusing on the prevalence, propagation, and persistence of antimicrobial resistant bacteria in the animal production environment and on foods of animal origin. A comprehensive research effort will help ensure that any regulatory actions taken to control antimicrobial resistance will be based on sound science. CVM’s FY 2006 research included accomplishments within several broad objectives, including the following:
Use Existing Microbiological Collections to Examine Historical Susceptibility of Foodborne Bacterial Pathogens to Antimicrobial Agents. To better interpret the public health threat represented by current antimicrobial resistance levels, CVM contracted with the American Type Culture Collection (ATCC) to measure resistance among banked historical collections of Salmonella, Campylobacter, and E. coli. The Center has completed antimicrobial susceptibility testing of these isolates and has begun studies to examine the genetic bases of resistance, including the distribution of plasmid types in different isolates. Data from this study will help the Center better assess the impact over the past 6 decades of antimicrobial use in veterinary and human medicine.
In 2006, CVM evaluated the isolates collected from 1950 to 1999 for their evolutionary development and changes in their antimicrobial resistance profiles. Preliminary data, presented in two scientific meetings during FY 2006, indicate that increasing resistance to antimicrobials is related to more recently evolved complexes.
Identify the Food-Producing Animal Species That Contribute to Antimicrobial Resistance in Foodborne Pathogens. CVM’s ongoing Bacterial Source Tracking project investigates the animal origin of Salmonella and Campylobacter isolates associated with foodborne-related bacterial infections in humans. OR scientists are using a variety of phenotyping and genotyping techniques to determine if a human Salmonella infection can be traced to a specific food-producing animal species. Results obtained during FY 2006 reveal that serotyping, antibiograms, multilocus sequence typing, and PFGE can show some host-specific clustering for specific Salmonella serotypes. Other Salmonella serotypes may require a combination of phenotypic and genotypic methods to identify the animal source of a human infection. However, definitive answers may not be possible even with these tools.
In addition, preliminary data obtained using a subset of Salmonella isolates suggests that a combination of serotyping, antibiograms, PFGE, and multi-locus sequence typing may be required to fully characterize the strains. These data also show that multi-drug resistant strains from all animal origins are evolving to less susceptible phenotypes. Other genetic techniques are being explored for their capacity to compare distinct bacterial isolates.
Controlling Risk From Bovine Spongiform Encephalopathy (BSE)
The Challenge
The discovery of a third BSE-infected cow in the United States during FY 2006 added to CVM’s challenge to strengthen controls that will prevent the spread of BSE through feed. (The first infected cow was discovered in December 2003, the second in June 2005, and the third in March 2006. The first cow had been imported from Canada, and the other two were more than 10 years old.) BSE is a chronic, degenerative, always fatal neurological disease affecting the central nervous system of cattle. BSE belongs to a family of diseases known as transmissible spongiform encephalopathies (TSEs) that includes several ruminant and nonruminant animal diseases. Laboratory and epidemiological evidence strongly suggests that people can contract a human TSE, variant Creuzfeldt-Jakob Disease (vCJD), by consuming food from BSE-infected cattle. In the absence of adequate controls, BSE could spread among the cattle population through feed ingredients derived from infected cattle.
FY 2006 Accomplishments
CVM continued to provide the expert scientific knowledge and review on BSE for the Agency. Much of the Center’s effort during the year focused on enforcing and strengthening FDA’s BSE feed regulation. CVM made significant progress in developing analytical methods that will enhance efficient, effective compliance with the regulation. Following are highlights of some of the Center’s achievements during the fiscal year, as the
Center focused on:
The FDA strategic goal of consumer protection, and
The Department-wide objective of achieving the safety of food for animals and humans.
STRENGTHENING THE BSE REGULATION AND CVM’s INSPECTIONAL EFFORTS
Strengthening the BSE Feed Regulation. CVM analyzed and addressed all comments submitted to FDA’s FY 2005 proposal to amend the BSE feed regulation to prohibit from use in the food or feed of all animals certain cattle materials that have the highest risk of carrying the BSE-infectious agent and drafted the final rule. The BSE feed regulation currently prohibits the use of certain mammalian-origin proteins – known as “prohibited material” – in ruminant feed (e.g., for cattle and sheep). Its purpose is to prevent the establishment and amplification of BSE in the United States through feed.
BSE-Infected Cow. Following the March 2006 confirmation by the USDA of a 10-plus-year-old cow found positive for BSE, FDA worked with Federal and State authorities to investigate the origin of the feed consumed by the cow. USDA confirmed that the cow did not enter the animal feed or human food supply. FDA investigators visited feed mills in the vicinity and reviewed their inspection history to evaluate compliance with the FDA feed regulation.
Risk-Based Inspectional Planning. CVM’s Office of Surveillance and Compliance is working closely with FDA’s Office of Regulatory Affairs (ORA) to develop new and/or revised performance goals for CVM programs. As part of this effort, the Center is reviewing the BSE compliance program and has proposed a risk-based approach to the frequency of inspections. CVM completed a risk-based work-planning module for the BSE compliance program that will help prioritize future investigational efforts. CVM is developing inspection/compliance performance goals, based on a risk-based evaluation of the Feeds Manufacturing Program, to be implemented in FY 2008.
The ultimate outcome of the risk-based approach to inspections, which is being implemented throughout FDA, is improved product quality and safety through better oversight of the manufacturing facilities, such as rendering plants and feed mills. CVM will prioritize BSE-related inspections based on risk, helping to target firms or facilities that engage in riskier practices. This prioritization will result in more efficient use of the limited resources that are available for inspectional purposes, while maintaining a high level of compliance.
The process involves setting compliance priorities by conducting a series of annual assessments that identify the internal and external hazards a regulated firm faces; addressing risk estimate and characterization of the hazard; and determining the consequences to the public health as a result of Agency action versus inaction. The risk-based approach will also include a procedure for conducting statistically based audits of areas not identified as high risk.
Inspections and Recalls. Through the FY 2006 work-planning process, CVM allocated adequate field resources to allow for selected inspections of animal feed industry firms subject to the animal protein prohibition in the BSE feed rule. These firms include renderers, feed mills, feed distributors, feed retailers, transporters, on-farm mixers, and ruminant feeders. For the fiscal year, CVM collaborated with ORA to conduct a total of 472 directed BSE inspections, including all renderers, protein blenders, and feed mills known to process products containing prohibited material. These inspections included the 310 targeted BSE inspections listed as one of the performance goals.
Following discovery during FY 2006 of possible contamination of animal feeds in violation of the BSE feed regulation, 40 recalls of product were made; 38 of those involved a single feed manufacturer.
Training and Outreach. CVM continued to provide BSE inspection training to FDA investigators and State inspectors during the fiscal year. Included in this training were inspectors from more than 10 States and investigators from as many FDA District Offices. CVM also explained its BSE inspectional checklist revision to State officials at the Feed Administrator’s Seminar held by the Association of American Feed Control Officials.
FY 2006 Performance Goals
aEnsure the safety of marketed animal feeds by conducting 310 targeted BSE inspections of all known renderers, protein blenders, and feed mills processing products containing prohibited material (in conjunction with the Office of Regulatory Affairs [ORA]).
aIn conjunction with ORA, provide educational training seminars, courses, and feed safety meetings to State feed control officials and FDA investigators on policies and inspectional procedures concerning the animal protein prohibition.
aTest proposed risk management proposals in terms of the effects on the spread and the rate of elimination of BSE if introduced into the United States, with the help of the Harvard BSE Risk Assessment simulation.
aDevelop a new or revised inspection/compliance performance goal that is more risk-based and outcome-oriented.
aIn the FY 2006 work plan, allocate resources to be able to conduct annual, targeted BSE inspections of all known renderers and feed mills processing products containing prohibited material.
In the FY 2006 work plan, allocate resources to be able to conduct selected inspections of animal feed industry firms subject to the animal protein prohibition, including renderers, feed mills, feed distributors, feed retailers, transporters, on-farm mixers, and ruminant feeders.
X Finalize a proposed rule that revises the existing feed ban rule. Carefully analyze comments received on the October 2005 proposed rule.
Work on the rule was ongoing at the end of the fiscal year.
aAdapt the real time PCR methodology to identify prohibited animal proteins in rendered materials from the European Union as well as materials rendered in the United States.
aContinue to evaluate commercially available rapid tests for prohibited proteins in animal feeds.
X Issue draft Guidance for Industry explaining what commercial test kit manufacturers should do to verify that their kits meet label claims for detecting prohibited proteins (in conjunction with the Office of Chief Counsel).
Work on the guidance document was ongoing at the end of the fiscal year.
DEVELOPING ANALYTICAL METHODS FOR DETECTING PROHIBITED PROTEINS
The availability of practical, validated methods to detect protein from different animal species could improve effectiveness and efficiency in the enforcement of the BSE feed regulation. Methods to detect mammalian protein have been available for some time, but because not all mammalian proteins are prohibited from ruminant feed, methods are needed to identify protein from prohibited species, such as cattle.
Real-Time PCR Methods
CVM completed the development of a real-time polymerase chain reaction (rtPCR) method for the identification of bovine, sheep/goat, and deer/elk in animal feeds. (“Real-time” means that the technicians detect the presence of prohibited material as the reaction is taking place, so they do not have to further process the sample.) The method is capable of detecting such materials at levels at least as low as 0.1 percent in feed. It can detect bovine or ovine (sheep/goat) materials produced according to the requirements of the European Union as well as those processing conditions used in the United States.
CVM completed a thorough in-house evaluation of the method, using the same acceptance criteria used for our evaluation of commercial diagnostic test kits. CVM also demonstrated this method to representatives of 10 laboratories that will be participating in the validation trial.
Once validated, this method will be available to ORA and any State laboratories that want to use it. Feed microscopy remains the official regulatory method. However, the new rapid test could be used to screen more samples prior to using feed microscopy, saving time and effort in the laboratories. It could also be used to confirm positives found by feed microscopy.
Commercial Diagnostic Kits
Commercially available diagnostic test kits marketed for the detection of ruminant proteins in animal feed could be important tools for surveillance and quality assurance. FDA does not have preclearance authority over such kits, but does have authority over labeling claims; CVM undertook evaluation of these kits to assess their usefulness and accuracy of claims made. The Center has now completed the evaluation of four commercially available test kits using criteria developed by CVM. Three of the four tests were unable to detect bovine meat and bone meal in animal feed at a level of 0.1 percent, the level that is detectable using feed microscopy (the current regulatory method), and therefore are not useful tools from a regulatory standpoint. However, two of the test kits have been shown to have the capability of detecting bovine meat and bone meal at the 1 percent level.
Avoiding Unsafe Drug Residues in Human Food
The Challenge
Improper use of approved drugs or use of unapproved drugs in domestic animals can result in unsafe residues in meat, poultry, seafood, and milk. Firms or individuals who repeatedly present animals for slaughter that are adulterated with illegal drug residues may represent a significant public health risk. In fact, investigation of repeat violators is a top priority. In addition, investigating first-time violations of residues from drugs prohibited from extralabel use in food-producing animals, residues of drugs not approved for food animal use, and very high-level drug residues are high priorities for investigation.
Also, CVM is challenged by the need for safety oversight to catch up with the rapid growth in the volume of imported products, especially seafood, that are under FDA’s jurisdiction. Meeting this challenge requires CVM to implement compliance and research initiatives directed toward regulating drug residues in aquacultured species, which account for a high proportion of all U.S. seafood imports.
FY 2006 Accomplishments
The following summarizes CVM’s FY 2006 efforts to avoid unsafe residues in meat, milk, and seafood.
ENFORCEMENT TO CONTROL DRUG RESIDUES IN MEAT
Under CVM’s direction, FDA’s Office of Regulatory Affairs (ORA) and State agencies working on the Agency’s behalf under contracts or cooperative agreements investigated 493 firms under the Tissue Residue Program. FDA issued 45 tissue residue-related Warning Letters. CVM’s Division of Compliance also reviewed and approved three tissue residue-related injunction actions in FY 2006. Two injunctions were filed in court during the year.
Enforcement actions resulted in consent decrees of injunction entered against several firms whose actions resulted in illegal drug residues in edible tissues. Two examples follow.
In February 2006, a U.S. District Court entered a Consent Decree of Permanent Injunction against a Kentucky cattle company that buys and sells cattle and delivers cattle for slaughter as human food. The firm does not medicate animals, but due to inadequate recordkeeping practices, the firm has been responsible for delivering for slaughter numerous cattle containing illegal drug residues. The residues, found over a 10-year period, included gentamicin, penicillin, tilmicosin, and sulfadimethazine. Under the terms of the Consent Decree, the defendants must develop and implement a residue avoidance plan for the cattle that they handle.
In June 2006, a Consent Decree of Permanent Injunction was filed in another U.S. District Court against individuals responsible for the operations of an Indiana family-owned livestock grower/dealer and dairy farm. The injunction action was based on 23 illegal residues in the edible tissue of 10 bovine animals sampled by the U.S. Department of Agriculture between 1999 and 2005. The drug residues included antibiotics such as streptomycin, neomycin, gentamicin, oxytetracyline, flunixin, and sulfadimethoxine. Under the terms of the Consent Decree, the defendants must implement systems for identifying animals, recordkeeping, drug control, drug accountability, and drug residue withdrawal control.
FY 2006 Performance Goal
Continue developing more efficient rapid analytical methods for screening imports at the border.
IMPORT TOLERANCES
CVM currently is drafting a proposed rule and draft guidance for industry on procedures for establishing and revoking import tolerances. FDA plans to publish a proposed rule relating to the implementation of the import tolerances provision of the Animal Drug Availability Act of 1996 (ADAA). The ADAA authorizes FDA to establish tolerances (import tolerances) for drug residues in imported food products of animal origin for drugs that are used in other countries but are unapproved new animal drugs in the United States. The Center is currently reviewing and considering requests for import tolerances. Without a tolerance, any amount of residue from a drug not approved in the United States causes the food to be adulterated under the Federal Food, Drug and Cosmetic Act. The United States imports nearly $15 billion worth of animal products, including nearly $3 billion in aquaculture products, underscoring the importance of regulation in this area.
CONTROLLING DRUG RESIDUES IN AQUACULTURE PRODUCTS
Imported seafood products account for an increasingly higher percentage of U.S. seafood consumption, and a major proportion of the imported seafood is a product of aquaculture. For example, most of the imported Atlantic salmon and tilapia (importation of the latter has more than doubled in the past 5 years), and approximately half of the 500-million- pounds or more of imported shrimp comes from aquacultural operations. In addition, the U.S. domestic aquaculture industry produces nearly $1 billion worth of product each year.
CVM works closely with FDA’s Center for Food Safety and Applied Nutrition (CFSAN) and ORA to assist in prioritizing analytical method development for drug residues in imported and domestic aquaculture seafood. CVM also works closely with CFSAN on the prioritization of sampling for CFSAN’s Compliance Program, Chemotherapeutics in Aquaculture Seafood, and provides technical support for drug residue compliance actions as well as other drug use issues. As new analytical methods become available and validated, they are incorporated into CFSAN’s sampling program as resources allow.
In FY 2001, CVM awarded a 5-year contract for data collection on aquaculture drug use in countries that exported seafood to the United States. The contract has been completed, and CVM now has a user-friendly database with foreign drug use information. The Center also has a risk assessment tool that the Center can use to create different scenarios in determining risk to U.S. consumers from foreign drug use in aquaculture. This information will be used in the Center’s collaborative efforts with CFSAN and ORA.
RESEARCH TO SUPPORT SAFETY OF IMPORTED AND DOMESTIC FOOD PRODUCTS
CVM scientists, in collaboration with scientists in FDA district laboratories, have continued to develop improved methods to detect veterinary drug residues in food products, many of which are imported. Much of the effort in FY 2006 was focused on the development of methods for drug residues in honey and in fish.
Drug Residues in Imported Honey. Illegal drug residues continue to be found in imported honey. Honey is different than most food products that may contain animal drug residues. Seafood, meat, and milk contain large amounts of protein and fats, while honey contains primarily sugars. Because of these significant differences, the traditional approaches used to isolate drug residues do not work for honey.
CVM researchers during FY 2006 developed a provisional multi-residue method for 17 drugs in honey. The method uses liquid chromatography-tandem mass spectrometry (LC-MS/MS), both to confirm the identity of the drug and determine the amount of drug residue present. The USDA Beltsville Bee Laboratory, in an ongoing collaboration with CVM, is generating needed biologically incurred residue samples for the drugs in the multi-residue method.
A method for detecting nitrofurans in honey, which was developed during FY 2005, is being transferred to ORA for use in regulatory testing. Additionally, CVM scientists are providing guidance and recommendations to the Florida Department of Agriculture and Consumer Services (FDACS) in developing a method for detecting fluoroquinolones in honey. Because of the assistance provided by CVM, the data generated by the FDACS method meet FDA requirements for confirming the identity of a drug residue. This has allowed FDA to take regulatory actions based on positive results from testing conducted by the State of Florida.
Drug Residues in Fish. This year, CVM researchers completed the validation of a multi-residue method for drug residues in tilapia and trout. The method has now been validated for use in four of the most commonly aquacultured finfish species, since the method has previously been validated in salmon and catfish. The availability of a multi-residue, multi-class, multi-species method for drug residue analysis provides great flexibility for laboratories testing imported aquaculture products.
CVM researchers during FY 2006 tentatively identified 3-O-desmethyl-ivermectin as the major ivermectin metabolite present in rainbow trout. The identification of this metabolite is a key step in development of methods for the detection of ivermectin residues. Previous published methods for ivermectin in fish have used parent ivermectin, the major residue found in terrestrial animals, as the marker residue for unapproved use. The identification of the metabolite will facilitate the development of better methods to detect the unapproved use of ivermectin in imported aquaculture products.
Ensuring Feed Safety
The Challenge
Threats to the safety of the Nation’s animal feed supply could come from several sources, including bioterrorism. Contaminants and unsafe additives in animal feed can harm the animals, as well as humans who consume animal products, and can adversely affect the Nation’s food and feed supplies. Improper manufacture of animal feeds can also result in health problems for animals and humans.
FY 2006 Accomplishments
Following are highlights of CVM’s FY 2006 accomplishments with regard to feed safety. In addition to the actions described below, CVM completed a variety of ongoing assignments, including processing several medicated feed mill licensing applications during the year. Firms that manufacture certain medicated feeds are required to be licensed.
RISK-BASED SYSTEM – ANIMAL FEED SAFETY SYSTEM (AFSS)
CVM is developing a nationwide, comprehensive risk-based system that would be preventive. The Center is designing the AFSS to detect hazards before feed products are distributed, and thus minimize detrimental animal and human health effects. The AFSS incorporates FDA’s historic feed safety role. It is focused on making the Agency’s feed safety program more comprehensive, preventive, and effective in addressing feed hazards that present the greatest risks to animal and human health, with risk considerations made open to public review and comment. Additional background on AFSS is available on the AFSS page that was added to CVM’s Web site during FY 2006, http://www.fda.gov/CVM/AFSS.htm. The report describes some of the AFSS accomplishments during the year in the following paragraphs.
The AFSS Team continued exploring systems approach options for ensuring that all feed manufacturers use adequate control steps throughout the animal feed production process to ensure the safety of the products they produce, distribute, and use.
The Team also drafted a standard operating procedure describing the process for development of analytical methods when the Agency decides to establish a regulatory limit for a feed contaminant, such as a mycotoxin or heavy metal.
CVM held a public meeting in September 2006 to present work in progress on a method for ranking feed contaminants according to the relative risks they pose to animal and public health. Contaminants are potentially toxic or deleterious biological, chemical, or physical hazards that are inadvertently present in animal feeds and feed ingredients. The relative risk posed by a feed contaminant to animal and human health consists of two components – health consequence scoring and exposure scoring. At this meeting, the Center described the methods it plans to use to develop animal and human health consequence scoring for chemical, physical, and biological feed contaminants. At one or more subsequent public meetings, FDA will present information about the exposure of animals and humans to contaminants in feed.
COMPLIANCE CHALLENGES IN ANIMAL FEED SAFETY
Review of Data from Dioxin Surveys
Dioxin in Animal Fat. In a survey of more than 500 animal fat samples, USDA found elevated dioxin levels of 2.0 parts per trillion (ppt) toxic equivalents (TEQ) or greater in 16 samples from slaughtered steers, heifers, and barrows. As a follow-up to the discovery of these elevated l
