September/October 1999, Volume IX, No. V, FDA Veterinarian Newsletter
by Karen A. Kandra
The Center for Veterinary Medicine (CVM) is pleased to announce that FDA Commissioner Jane E. Henney, M.D. has approved the appointment of Dr. Andrew J. Beaulieu as Deputy Director, succeeding Dr. Michael J. Blackwell, who left CVM on February 1, 1999.
A native of Washington, D.C., Dr. Beaulieu holds both a B.S. and B.A. degree from the University of Miami, and received his D.V.M. degree cum laude from The Ohio State University. Dr. Beaulieu credits a "back-fence" neighbor, who was an FDA chemist, with planting the FDA seed "way back" when he was in Junior High School, and some very effective cultivation by Dr. Homer Smith, former Regional Veterinary Medical Officer in the Cincinnati District Office with influencing him to apply to the Food and Drug Administration during his senior year at Ohio State. Both gentlemen spoke very convincingly of FDA's underlying "moral purpose", resulting in Dr. Beaulieu's ultimate decision to dedicate his entire career to CVM, beginning as a veterinary reviewer in the Office of New Animal Drug Evaluation (ONADE) in June, 1972. In 1974, Dr. Beaulieu transferred to the Office of Surveillance and Compliance (OSC), where he moved up to Division Director in the Division of Surveillance until 1991, when he became Director of the Division of Therapeutic Drugs for Food Animals in ONADE. In November, 1992, he was appointed a Deputy Director of ONADE. In addition, Dr. Beaulieu also served in the Office of Research for a brief time.
It is Dr. Beaulieu's belief that a regulatory organization's decision-making is greatly influenced by regulatory and judicial precedents, and that institutional knowledge has an impact on virtually everything that is done in such an organization. CVM Director, Dr. Stephen Sundlof says, "There are few if any who command Dr. Beaulieu's historical knowledge of and broad experience within CVM. His recent efforts to re-engineer the new animal drug approval process and his experience with the implementation of the Animal Drug Availability Act (ADAA) will bring valuable perspective to his new job."
During his 27-year CVM tenure, Dr. Beaulieu has provided outstanding leadership in the direction and oversight of many of the Center's activities. He was directly involved in promoting and implementing the "phased-review" process, which provides for mapping out the drug development process between the sponsor and CVM personnel, and permits different parts of the process to proceed simultaneously on different time tracks, shortening the overall drug development and review process. Over the last few years, he has also been responsible for managing to near completion the process of DESI-finalization, an effort that has been ongoing within CVM for more than 20 years. In the past, Dr. Beaulieu served as one of five Project Management System (PMS) managers in CVM, overseeing the planning, allocation, and utilization of resources throughout the Center. More recently, he played a very active role in negotiating the changes represented by the ADAA, and has helped draft interpretive policy and regulations to implement the statutory changes.
In a time of shrinking resources, many challenges are presented for CVM's management team. Dr. Beaulieu hopes to continue working on the New Animal Drug procedural regulations, a long-term project to improve the animal drug approval process, as well as to continue to work toward developing innovative ways to provide for the legal marketing of drugs for minor species. In addition, he has a long-standing commitment to participatory management and team decision-making, which CVM is fostering through its ongoing High Performance Organization (HPO) initiative.
Dr. Beaulieu has been honored with two Awards of Merit, four Commendable Service Awards, a Commissioner's Special Citation, a Deputy Commissioner's Special Recognition Award, and numerous Group Recognition Awards during his distinguished FDA career.
Dr. Beaulieu has effectively represented the Center's interests at the national and international level. His thorough working knowledge of the animal product-related provisions, limitations and practical applications of the Food, Drug, and Cosmetic Act makes Dr. Beaulieu uniquely qualified and a valuable addition to CVM's leadership team.
An avid golfer, Dr. Beaulieu resides in Silver Spring, Maryland with his wife, Julie, and daughters, Elyse and Kathryn, both college students. We wish him the best of luck as he assumes this very deserved role in CVM.
FDA's final rule amending the new animal drug regulations to further define the term "substantial evidence'' published in the July 28, 1999, Federal Register. The purpose of this final rule is to encourage the submission of new animal drug applications (NADAs) and supplemental NADAs for single ingredient and combination new animal drugs. The final rule also encourages dose range labeling. This final rule implements, in part, the Animal Drug Availability Act of 1996 (ADAA), which amended the Federal Food, Drug, and Cosmetic Act. The purpose of the ADAA is to facilitate the approval and marketing of NADAs and medicated feeds.
Before FDA can approve a new animal drug, FDA must find, among other things, that there is substantial evidence that the new animal drug is effective for its intended uses under the conditions of use prescribed, recommended, or suggested in the proposed labeling. The changes made to the definition of "substantial evidence'' by the ADAA and by the further definition of that term in this final rule give FDA greater flexibility to make case-specific scientific determinations regarding the number and types of adequate and well-controlled studies that will provide, in an efficient manner, substantial evidence that a new animal drug is effective.
A copy of this final rule may be obtained from CVM's Federal Register Notices Page or by calling or writing the FDA Veterinarian.
Further information about this final rule may be obtained from the July 28, 1999, Federal Register and from Dr. Herman M. Schoenemann, Center for Veterinary Medicine (HFV-126), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-827-0220.
by Katherine Hollinger, D.V.M., M.P.H.
Dr. Linda Tollefson and Dr. Katherine Hollinger of the FDA's Center for Veterinary Medicine (CVM), and Dr. Paula Fedorka-Cray of USDA's Agricultural Research Service (ARS), represented the National Antimicrobial Resistance Monitoring System-Enteric Bacteria (NARMS-EB) at a meeting of ResistVet collaborators in Morelia, Mexico to develop a plan to monitor for antimicrobial drug resistance in foodborne pathogens. This meeting was held in conjunction with the joint annual meetings of the Mexican Society of Infectious Diseases and the National Congress of Antimicrobials and Chemotherapy, held from June 30 to July 3, 1999, and oral presentations and poster sessions were conducted on nosocomial infections, antimicrobial resistance and many other topics.
The NARMS representatives met with ResistVet organizer Dr. Mussaret Zaidi of the Research Department in the O’Horan General Hospital, Yucatan and collaborator Dr. Alejandro Macia of the Department of Microbiology at the School of Medicine and Leon General Hospital to discuss plans to initiate the antimicrobial resistance monitoring program in 5 states in Mexico (Durango, Michoacan, Guanajuanto, Mexico City and Yucatan) and Guatamala. These five states and the site in Guatamala are located in areas with significant animal agriculture in close proximity to the monitoring centers. Much of the food consumed in these areas is locally produced, unlike food distribution in the United States that is distributed nationally and internationally. The monitoring program will target the foodborne pathogens, salmonella and campylobacter. Planning of the surveillance program focused on the numbers and potential sources of isolates, technical and laboratory methodology and resources available to implement the system. Isolates will be obtained from clinical human sources from hospital and daycare settings, from retail food, and from live, healthy animals in collaboration with producers and veterinarians. Testing will be conducted at the hospital laboratories and results will be pooled into a database.
In the joint meeting of the WHO-Resistnet and ResistVet participants the NARMS-EB representatives presented information describing the NARMS-EB program and gave a review of some of the data collected from the program in 1998. Dr. Tollefson gave an overview of NARMS-EB, the objectives, achievements and limitations of the monitoring program. The program collects isolates of foodborne pathogens: E. coli, salmonella and campylobacter isolates, from clinically affected humans, food animals at slaughter and diagnostic laboratory isolates. The resistance patterns of the salmonella isolates are determined by microbroth dilution to seventeen antimicrobial drugs and by E-test to eight antimicrobials for campylobacter isolates. The laboratory methods used to test the isolates are identical for the human and animal portions of the program. The human isolates are submitted from fifteen sites nationally and tested at the Centers for Disease Control and Prevention in Atlanta. The animal isolates are collected from slaughter plants, processing plants and the National Veterinary Services Laboratory and tested at USDA's Agricultural Research Service in Athens, Georgia. The objectives of the program are to provide timely information to veterinarians and physicians, prolong the lifespan of approved drugs, provide descriptive data on the trends in antimicrobial susceptibility of salmonella from human and animal populations and identify areas for more detailed investigation.
Dr. Hollinger presented a talk on "Multi-drug resistance in Salmonella isolates from poultry at slaughter" and Dr. Fedorka-Cray presented "An overview of antimicrobial resistance in Campylobacter and related research." Other presentations described antimicrobial drug resistance patterns in salmonella and campylobacter, water contamination and antimicrobial resistance patterns on poultry and swine farms in Yucatan.
Data was presented from the 15 hospital-based centers distributed throughout Mexico, Costa Rica and Guatamala, in the Resistnet surveillance program begun in 1996. The surveillance program has tested susceptibility of over 5,000 clinical human isolates of E. coli, Staph. aureus, Pseudomonas aeruginosa, Salmonella and Shigella to commonly used antimicrobials. E. coli was the most commonly isolated organism tested in the program and represented 22 percent of all isolates. A 1996 Mexico City study of 70 children with symptoms of enteric disease indicated 46 percent requiring antibiotic treatment. A second study conducted in 1997 of 19 children observed for 20 weeks indicated that up to 70 percent of ill children received antibiotics for treatment of severe diarrheas. Molecular microbiological techniques were described for epidemiologic surveys of the isolates to identify clusters and potential outbreaks. Bayer representative, Dr. Raul Vazquez, described the company’s strategy for the responsible use of antibacterials in Latin America and provided background information on food animal drug use in Mexico.
The meeting concluded with discussion of the protocol for the proposed monitoring program. The program will be implemented in August with the testing of 50 to 100 samples per site for isolation of Salmonella for four consecutive weeks. The first samples will be collected from daycare centers and collection of approximately 50 salmonella isolates is expected. The Epidemiology Department at the School of Veterinary Medicine in Yucatan will be participating in the program, providing animal isolates for the program. Other areas planned for inclusion in the program are testing of seafood for Salmonella, Vibrio cholera and Shigella.
Proposed next steps include plans to exchange advanced training in isolation and susceptibility testing of foodborne pathogens, training in laboratory methodology and technology transfer. Surveillance will be implemented in a stepwise manner to begin with sampling for Salmonella from children in daycare settings and will expand to include retail poultry isolates. Incorporation of other sources of human and animal samples and addition of Campylobacter are planned for next year.
This collaboration between NARMS and the Mexican ResistVet group is the initiation of the first international monitoring system for foodborne pathogen surveillance and antimicrobial drug susceptibility monitoring in the Americas. Long-term goals include development of an international database to make information available to prevent outbreaks of foodborne disease and identify emerging pathogens.
FDA PROPOSES TO RECLASSIFY SHEEP AS A MINOR SPECIES
In the July 26, 1999, Federal Register, FDA's Center for Veterinary Medicine (CVM) published a proposed rule to reclassify sheep as a minor species for all data collection purposes. This proposal allows sponsors of supplemental new animal drug applications to extrapolate human food safety data from a major species such as cattle to sheep. In particular, this will allow the extrapolation of the tolerances for residues of new animal drugs in cattle to sheep.
A copy of this proposed rule may be obtained from CVM's Federal Register Notices Page or by calling or writing the FDA Veterinarian.
Since 1983, FDA has permitted some flexibility in the means to meet data requirements to support the approval of new animal drugs intended for "minor species.'' Specifically, these classifications permit data extrapolation from a major species to support the safety and effectiveness of a new animal drug for a minor species.
"Minor species" are defined by exclusion as any species other than horses, cattle, swine, dogs, cats, chickens, and turkeys. Sheep have been classified as a minor species for the purposes of target animal safety and effectiveness studies. However, they have been considered a major species for the purpose of determining the human food safety of edible products.
In a January 1983 final rule on minor species drugs, FDA said that sheep were classified as a major species for human food safety purposes because some consumers in the United States eat a large proportion of lamb and mutton in their diets. However, the Agency stated that it would be willing to reevaluate this conclusion if new data became available.
New data have become available since publication of the 1983 final rule. These data allow FDA to conclude that sheep should be a minor species with respect to all data requirements. The new data concern the similarity of drug metabolism between sheep and cattle rather than consumption levels. FDA now believes that the body of evidence concerning drug metabolism is more significant in determining the major/minor status of species than consumption data because it demonstrates the reliability of data extrapolated from a major species.
Interested persons should submit written comments on the proposed rule by October 25, 1999, to the Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD 20852. Comments should be identified with Docket number 99N-2151.
Further information about this proposed rule may be obtained from Dr. Meg Oeller, Center For Veterinary Medicine (HFV-130), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-827-7581, e-mail: firstname.lastname@example.org.
The primary goal of scientific research in FDA's Center for Veterinary Medicine (CVM) is to provide knowledge and procedures that ensure the safety of animal derived food and animal health products. To achieve this goal, CVM conducts both intramural and extramural research programs relevant to regulatory and public health needs.
CVM’s extramural research program brings to CVM the ideas and views of academic scientists and as such, is critical to maintaining access to cross-cutting and state-of-the-art science. Occasionally, projects funded through the extramural program may result in new, exceptionally innovative and practical ideas and procedures that represent an immediate advance in technology useful to food safety and drug regulation.
One of the developments that resulted from CVM funding for research into new methods for the analysis of drugs and pollutants in food animal tissues in the late 1980's and early 1990's was a process called matrix solid phase dispersion, or MSPD. The process involves blending tissues with a solid-phase bonded silica, such as the material used in solid phase extraction (SPE) columns, to simultaneously perform sample homogenization, sample matrix disruption and the formation of a column material from which individual drugs, drug classes or multiple drug classes can be eluted from a single sample. This process, first reported in 1989 by Steven A. Barker and Austin R. Long at Louisiana State University, was subsequently patented (U.S. patent # 5,272,094, issued Dec. 21, 1993) and has since been developed for commercial applications by at least two international companies. The primary interest has been in the use of MSPD for the isolation of pesticides in tissues from food animals and of herbicides and pesticides from fruits and vegetables.
The methods developed have been shown to be equivalent to or better than existing "official" methods. MSPD not only can increase the cost effectiveness of analytical methods but also contributes to the minimization of environmental and scientist solvent exposure hazards. Since the first publication of the process in 1989, approximately 50 new methods for drugs, pollutants and natural products using MSPD have been published, ranging from the isolation of tocopherols in human blood samples to the determination of herbicides in corn. These MSPD applications and the materials to perform them have primarily been promoted by Varian's Sample Preparation Products division in the U.S (which licensed the patent in 1995) and by International Sorbent Technology in the United Kingdom.
by Paul M. Raynes
Deputy Director, Division of Federal-State Relations
FDA Office of Regional Operations
The Fairmont Hotel in Dallas, Texas was the setting for a recent Food and Drug Administration (FDA) sponsored workshop for State veterinarians and feed control officials from all fifty States, Puerto Rico, the U.S. Virgin Islands and Canada, to provide a briefing on the latest developments with the Bovine Spongiform Encephalopathy (BSE) feed regulation. More than 170 State and Federal regulators took part in the two-day workshop that featured speakers from FDA’s Center for Veterinary Medicine (CVM) and Office of Regulatory Affairs (ORA), USDA’s Animal and Plant Health Inspection Service (APHIS) and Canada’s Food Inspection Agency.
The BSE regulation, now in effect for two years, restricts the use of mammalian protein in feeds for cattle and other ruminants. The regulation requires protein renderers, protein blenders, feed manufacturers and distributors to label feeds that contain prohibited material with the following warning statement: "Do not feed to cattle or other ruminants". It was developed to prevent the establishment and amplification through feed of BSE.
This workshop was a follow-up to a 1997 meeting in Kansas City where the regulation was first discussed with an audience of more than 100 Federal and State regulators. As he had done in Kansas City, Dr. John Honstead, a veterinary medical officer with CVM’s Division of Animal Feeds, briefed the Dallas audience on the science related to BSE. He explained that BSE is one type of spongiform encephalopathy while others can be found in sheep, minks, cats and humans. Dr. Honstead reported that, although the BSE epidemic in the United Kingdom continues to abate, there are growing concerns that the incidence of a similar disease in humans called "new variant" Creutzfeldt-Jakob disease (CJD) is increasing. And, unlike its counterpart, sporadic CJD, the "new variant" does not discriminate regarding age. The latest cases have involved victims under the age of 30.
Gloria Dunnavan, Director of CVM’s Division of Compliance, wore several hats during the workshop. She reviewed the Inspection Reporting Checklist, giving the audience the rationale as to why certain questions were being asked. She also led the audience in a question and answer session to gain feedback useful in making needed changes to the checklist. She also shared the program with Ricky Rodriguez from FDA’s Dallas District Office, discussing enforcement issues and reviewing guidance documents.
The States also played an important role in the presentation of this workshop. Two States, Virginia and California, provided detailed accounts of their perspectives and experience with inspections for compliance with the regulation. Similar presentations were then given by FDA personnel from the Denver and Detroit District Offices providing a Federal perspective. The session concluded with a fascinating look at similar efforts "north of the border" from our regulatory counterpart, Mr. Sergio Tolussa, with the Canadian Food Inspection Agency.
Other topics included import activities, future initiatives and the use of a problem solving breakout session to deal with several scenarios involving the use of prohibited materials. Finally, Dr. Linda Detwiler from USDA/APHIS, discussed a memorandum of understanding with USDA and provided some insight as to her agency’s role in the prevention of BSE in this country.
This workshop generated a great deal of interaction among the participants including many questions, solutions to problems, ideas for inspectional techniques, educational initiatives and enforcement approaches. Thanks to the development of this regulation, we can continue to say that there has not been a single case of BSE reported in the United States. Educational efforts such as this with our regulatory partners will help assure that we can continue to make that claim.
Aquaculture is becoming an increasingly important source of fish available for human consumption. As the number of aquaculture facilities grows, so does the need to develop safe and effective drugs for treating fish diseases. It is also important to understand the effect these treatments have on non-target organisms and on the aquatic environment. As a result, the FDA's Center for Veterinary Medicine (CVM) Office of Research (OR) has greatly expanded its commitment to aquaculture research. In January 1999, Renate Reimschuessel V.M.D., Ph.D., accepted a position at CVM to begin to develop a research program in aquaculture.
Dr. Reimschuessel, former Director of the Aquatic Pathobiology Center at the University of Maryland School of Medicine, has over fifteen years experience conducting research on aquatic animals. She has a multidisciplinary background and has published work in the areas of fish husbandry, aquatic toxicology, microbiology, pharmacokinetics, developmental biology and pathology.
One of Dr. Reimschuessel’s first tasks is to enhance the capacity of the current aquaculture facility. Additional water delivery lines are being installed to increase water flow to the fish systems and improve water quality. Work is also in progress to construct closed, recirculating water systems to simulate more intensive aquacultural techniques.
"This is an incredible facility that will allow us to conduct state-of-the-art aquaculture research" stated Dr. Reimschuessel as she toured the building. There are four main research rooms of approximately 4600 sq. ft., one radioisotope fish lab of 600 sq. ft., a storage room, two mechanical/filtration rooms and two support rooms which house computers, desks and a small library. Incoming water from either the well or municipal supply goes into the primary filtration system comprised of separate calcite and carbon contactors. Temperature is controlled by separate heat exchangers and chillers, which provide hot and cold running water to mixing valves at the fish tanks. A centralized computer system monitors the flow-through water system temperature and pH.
Outside the building is a 25,000-gallon water storage tank with venturi systems to remove carbon dioxide from the well water. Wastewater is sent to either two 20,000-gallon "clean" water holding tanks or two 10,000-gallon radioactive wastewater holding tanks. Dr. Reimschuessel is in the process of obtaining three 1500-gallon tanks to hold saltwater.
Research at the facility will focus on both regulatory priorities and the needs of the aquaculture community. Species that will be studied during the first year include tilapia (Oreochromis sp.), rainbow trout (Oncorhynchus mykiss), Atlantic salmon (Salmo salar), channel catfish (Ictalurus punctatus) large mouth bass (Micropterus salmoides), toadfish (Opsanus tau), and goldfish (Carassius auratus). All of these species, except goldfish, are currently raised or maintained for food purposes. Goldfish will serve as a model for ornamental fish and as a disease model. Goldfish are an established model of infection by atypical Mycobacteria spp.(fish pathogens as well as increasingly important pathogens for immune-compromised humans).
Dr. Reimschuessel has designed her research objectives, in general, to provide data to assist the Food and Drug Administration in assuring that fish derived from the aquaculture production environment are safe for human consumption. Her priorities include studying the biodistribution, residue persistence, metabolism, efficacy, and environmental effects of drugs and other chemicals used in aquaculture. There will be a large effort to develop a rationale for crop grouping (grouping species for drug approvals based on similarities in anatomy, physiology and drug metabolism). Other studies are designed to investigate the impact of drugs on the environment, non-target species and the pathogens associated with aquatic species. Of increasing importance are studies designed to understand the development and transmission of antimicrobial resistance in both pathogens and environmental microbes. Understanding those mechanisms will help in the development of treatment strategies that minimize the development of resistant pathogens.
Dr. Reimschuessel is currently preparing research protocols designed to address a number of these priorities. She is actively collaborating with scientists conducting aquaculture-related research at the University of Maryland, Johns Hopkins University, Fort Detrick, and the Maryland Department of Natural Resources. She also teaches veterinary students and veterinarians in the AquaVetâ program each May at the Marine Biological Laboratory, Woods Hole, Massachusetts. She will be developing a research internship program at CVM for fourth-year veterinary students interested in aquaculture. She says "I hope to continue getting veterinarians involved in fish medicine and research. It is a specialty in its infancy. Programs that educate veterinarians about aquatic species will help increase correct diagnosis and treatment of diseases, thereby reducing arbitrary or inappropriate use of therapeutic agents in farm-raised fish. With CVM’s increasing research efforts and support for the minor species drug program, we should be able to provide veterinarians with a greater choice of safe and effective treatments."
by Ron Scherzberg
A new category of drugs, veterinary feed directive (VFD) drugs, has been created to allow drugs to be administered in animal feed, but only under the order of a licensed veterinarian. Proposed regulations covering the ordering of use and the distribution of VFD feeds (medicated feeds containing VFD drugs) were published in the Federal Register of July 2, 1999. The Animal Drug Availability Act of 1996 (ADAA) amended the FD&C Act to establish the VFD drug category. Thus far, one VFD drug, tilmicosin, has been approved for use in treating swine respiratory disease.
In the past, drugs used in animal feeds were approved as OTC drugs. While the FD&C Act did not prohibit approval of prescription drugs for use in animal feeds, such approvals were impractical because some states' pharmacy laws required a licensed pharmacist on the premises to dispense the drugs, while other states prohibited feed manufacturers from possessing and dispensing prescription drugs. The VFD solves this problem by eliminating the pharmacist involvement and allowing the veterinarian to order the use of VFD drugs in feed. This participation by the veterinarian satisfies FDA’s concerns that the drugs be used only in appropriate circumstances and under greater control than OTC drugs.
The VFD process is straightforward in practice. A veterinarian, operating within the confines of a veterinarian-client-patient relationship, examines and diagnoses animal conditions and determines whether a condition warrants use of a VFD drug. If it does, the veterinarian will issue a signed VFD containing information specified by the drug’s approval regulation. The veterinarian keeps a copy of the form and provides the completed and signed original and a copy to the client. The client keeps the copy and gives the original to the feed manufacturer which authorizes the VFD feed to be shipped to his animal feeding operation. While not specifically required, we believe the drug manufacturer will provide preprinted "fill in the blank" triplicate VFD forms to the veterinary profession for the sake of efficiency and accuracy. This has been done with tilmicosin, the one approved VFD drug.
The ADAA has a statutory requirement that anyone intending to distribute VFD feeds notify CVM prior to beginning. A distributor means the VFD feed manufacturer or anyone in the distribution chain who ultimately supplies VFD feed to the animal producer. This could include the veterinarian if he is the source of VFD feed. A VFD feed may not be distributed to a client without a signed VFD. However, VFD feed may be sent down the distribution chain if the consignee provides the distributor with a signed "acknowledgment letter affirming that it will only ship the VFD feed to a VFD holder or to another distributor who supplies a similar acknowledgment letter. Feed manufacturers or any distributor may stockpile VFD feeds in anticipation of orders.
We recognize that there are instances when direct contact among the veterinarian, client and feed distributor is not practical. To counter this problem and facilitate rapid movement of VFD feeds, we are proposing to allow facsimile transmission of the VFD. While not proposed, we are also noting that telephone and
e-mail are other avenues to consider for transmission of the VFD. We have concerns about the clarity, completeness and security of these latter two forms of VFD distribution. For this reason, we are inviting comments on the use of e-mail and phone transmission to our final rule, and on how to ensure such orders will be clear, complete and secure.
Another area of concern is the length of time a VFD may be valid (expiration date) and the number of refills or reorders that may be allowed. For example, if a hog operation historically has a disease outbreak in the post-weaning stage, does the veterinarian need to write a VFD each time a group of pigs is weaned? We think not, however, CVM would not allow an open-ended VFD. Limits must be placed on length of time a VFD is valid and/or amount of animals that can be treated. Again, the proposed rule invites comments on this issue by September 30, 1999, to assist CVM in developing the final rule.
Extra-label use of VFD drugs or VFD feeds is prohibited, that is, the VFD drug may be used only as specified in the drug’s published regulation.
FDA's Center for Veterinary Medicine (CVM) will sponsor a workshop entitled "Microbiological Safety of Drug Residues in Food" to be held on September 20-21, 1999. The Workshop will be held at the Doubletree Hotel, 1750 Rockville Pike, Rockville, Maryland 20852, from 8:00 a.m. to 6:00 p.m. on Monday, September 20, and from 8:00 a.m. to 2:00 p.m. on Tuesday, September 21. It will discuss the use of model systems to establish Acceptable Daily Intakes (ADIs) for antimicrobial drug residues in food.
The Workshop will focus on human consumption of new animal drug residues in food and direct effects on human intestinal microflora. The document entitled "A Proposed Framework for Evaluating and Assuring the Human Safety of the Microbial Effects of Antimicrobial New Animal Drugs Intended for Use in Food-Producing Animals" (CVM's Framework document) will not be discussed at the September 20-21 Workshop. Information about workshops on the Framework document will be announced in a future CVM UPDATE(s) and from CVM's Antimicrobial Resistance Page.
In January 1996, CVM published the availability of a guidance document entitled "Microbiological Testing of Antimicrobial Drug Residues in Food." This guidance document defines when antimicrobial drugs would be exempt from additional microbiological testing and when additional testing would be required. The document also establishes 1.5 mg/person/day as the ADI of microbiologically active residues that would be allowed in food without additional microbiological testing. The Center also expressed the intention of validating model systems that could be used to evaluate the effect of low levels of antimicrobial drugs on the human intestinal microflora. The guidance document is available on the Home Page or by calling or writing the FDA Veterinarian.
In 1995 and 1996, CVM funded research to validate an in vitro and an in vivo model system that could be used to set ADIs for antimicrobial drug residues in food based on perturbations of the human intestinal microflora. The results of this research will be presented at the September workshop. In addition, other methods for determining ADIs for antimicrobial residues used internationally and in Europe will also be presented and discussed. Based on the information presented and discussed at the workshop, CVM intends to reevaluate its guidance document for testing microbiological effects of antimicrobial residues on the human intestinal microflora.
Registration for the workshop is free. However, registration is required. For additional information and registration form, please contact Ms. Lynda Cowatch, CVM, FDA, HFV-150, 7500 Standish Place, Rockville, MD, 20855, telephone: (301) 827-5281 or FAX (301) 594-2298. A copy of the registration form is also available on the Home Page.
A limited number of rooms at a special rate have been set aside at the Doubletree Hotel for workshop participants. Due to this limited number, workshop participants are urged to contact the hotel as soon as possible to make their reservations. Please mention that you are planning to attend the "FDA Microbiological Safety Workshop," code B583, at the hotel. The telephone number for the Doubletree Hotel is 1-800-222-8733 or 301-468-1100, and the Fax number is 301-468-0163.
The Animal Health Institute (AHI)) is sponsoring a workshop entitled "Validation, Format and Transfer of Medicated Feed Methods Workshop." It will be held on October 12, 1999, from 7:30 a.m. to 5:00 p.m. at the Holiday Inn Old Town Select, 480 King Street, Alexandria, Virginia.
The purpose of this workshop is to present three Animal Health Institute Guidance Documents entitled "Guidance on the Validation of Analytical Procedures for Medicated Feeds," ADS M23-001.01, "Guidance on Analytical Methods Documents for Medicated Feeds," ADS M23-002.01, and "Guidance on Protocols for Conduct of Method Transfer Trials for Medicated Feed Assays," ADS M23-003.01. These guidance documents were developed with Center for Veterinary Medicine (CVM) participation. CVM will present the current CVM procedures/requirements for conducting a Sponsor-Monitored Method Trial for Medicated Feeds. Information concerning the guidance documents will be presented which will clarify and streamline the development and evaluation of analytical procedures for medicated feeds. The goal is to improve the process and shorten the regulatory review time for food animal products.
A few of the topics that will be presented include Overview of the Current Process, Importance of Medicated Feed Method Trials from the Surveillance and Compliance Perspective, Presentation of Animal Health Institute Guidance Documents, Validation of Analytical Procedures for Medicated Feeds, Contract Research Organization Perspective, and State Laboratory Perspective.
The registration fee for the workshop is $165, and covers the cost of the registration, continental breakfast, luncheon, and refreshment breaks. The deadline for registration is September 24, 1999. For further information, please contact Carol Bowley at AHI at 202-637-2440, or Mary Leadbetter at CVM at 301-827-6964.
The Food and Drug Administration (FDA) has announced the availability of the following draft guidances for industry: "Guidance for Industry: Stability Testing for Medicated Premixes (#91)" "Guidance for Industry: Impurities In New Veterinary Drug Substances (#92)," "Guidance for Industry: Impurities In New Veterinary Medicinal Products (#93), "Guidance for Industry: Efficacy of Anthelmintics: General Recommendations (#90),'' "Guidance for Industry: Efficacy of Anthelmintics: Specific Recommendations for Bovines (#95)," "Guidance for Industry: Efficacy of Anthelmintics: Specific Recommendations for Ovines (#96)," and "Guidance for Industry: Efficacy of Anthelmintics: Specific Recommendations for Caprines (#97)." These draft guidance documents have been developed by the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (VICH).
Copies of all these draft guidance documents may be obtained from CVM's Guidelines and Guidances Page or by calling or writing the FDA Veterinarian.
Further information on VICH is available from Dr. Sharon R. Thompson (HFV-3), Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-594-1798, e-mail: email@example.com and from Dr. Robert C. Livingston, Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Place (HFV-1), Rockville, MD 20855, 301-594-5903, e-mail: firstname.lastname@example.org.
Further information about draft guidance documents #91, #92, and #93 is contained in a July 22, 1999, Federal Register notice. Information on draft guidance document #91 is also available from William G. Marnane (HFV-140), Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-827-6966, e-mail email@example.com. Information on draft guidance documents #92 and #93 is available from Dr. Kevin J. Greenlees, Center for Veterinary Medicine (HFV-150), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-827-6977, e-mail firstname.lastname@example.org.
Further information about draft guidance documents #90, #95, #96, and #97 is contained in a July 16, 1999, Federal Register notice. Information on these draft guidance documents is also available from Dr. Thomas Letonja (HFV-130), Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-827-7576, e-mail: email@example.com.
The Food and Drug Administration has issued final guidance concerning consumer-directed (direct-to-consumer or DTC) broadcast advertisements for prescription animal and human drugs and human biologicals. The final guidance describes an approach that could fulfill the requirements under regulations to provide consumers general risk information through media such as television, radio, or telephone.
The final guidance will continue a multifaceted approach to disseminating product labeling in connection with broadcast advertisements -- ordinarily containing these four sources: (1) a toll-free telephone number; (2) referral to a print advertisement in a concurrently running print publication, or provision of enough product brochures in various convenient outlets; (3) referral to a healthcare provider (physician, pharmacist, veterinarian or other healthcare provider); (4) an Internet web page address.
As required in the prescription drug advertising regulations, advertisements broadcast over radio, TV or through telephone communications systems must include a thorough "major statement" prominently disclosing all of the major risks associated with the drug. In addition, sponsors of broadcast advertisement are also required to present a brief summary or alternately may make "adequate provisions."
This guidance encourages sponsors to consider the benefits of providing consumers with nonpromotional, consumer friendly product information in addition to the required product labeling. FDA is currently evaluating its regulations as they relate to DTC print promotion and will address this issue in greater detail at a later date.
Minor revisions in the final guidance include:
deleting the option to offer to fax product labeling to consumers under the toll-free telephone component of adequate provision.
emphasizing the importance of broad dissemination of the print advertisement component of the adequate provision approach.
acknowledging that the print brochures alternative component of the adequate provision approach was likely to be feasible only when broadcasting was fairly limited in scope.
acknowledging explicitly that healthcare providers other than physicians and pharmacists can be sources of additional human drug product information. In the case of animal drugs, only veterinarians can provide information.
clarifying the differences in approach for telephone, television, and radio advertisements.
Those interested in commenting on the final guidance may contact FDA at the following address:
Dockets Management Branch (HFA-305)
Food and Drug Administration
5630 Fishers Lane
Rockville, MD 20852
For additional information on direct-to-consumer guidance documents and a complete list of frequently asked questions visit the FDA website.
by Ian F. De Veau, Ph.D.
Increasing attention has been directed to the influences of gender and physiological states, such as pregnancy and lactation, on the pharmacokinetics of human drugs. Prior to 1993, FDA guidelines for the clinical evaluation of human drugs recommended that women of childbearing age be excluded from phase 1 and early phase 2 clinical studies until reproductive toxicity studies were conducted and some evidence of effectiveness had become available. Though the guideline did not exclude using women as test subjects in later clinical studies, its effect was to do just that. This policy raised ethical, legal, and scientific questions about its suitability. One of the concerns was that the physiological, metabolic, and hormonal differences between women and men were such that it would be difficult to conclude how well the pharmacokinetic behavior of a drug in women could be predicted by its pharmacokinetic behavior in men. Not knowing about a drug's pharmacokinetic profile in women means not knowing its efficacy, since the effectiveness of most drug treatments is correlated to blood levels. It has been shown that significant differences between women and men in drug elimination are common (Wilson, 1984 and Loebstein et al., 1997). In 1993, FDA reversed its position concerning the use of women in early clinical trials to address potential gender differences in drug elimination. This change is part of an overall trend in FDA policy to broaden the human population base used routinely in clinical trials. FDA's goal is to address the potential impact of gender, age, and ethnic background on the pharmacokinetics and the pharmacodynamics of human drugs.
Gender and physiological state also influence the pharmacokinetic parameters of veterinary drugs. Witkamp et al. (1992) reported that the half-life of sulfamethazine was about 75 percent and 40 percent lower in female goats and cattle, respectively, than in males of the same species. The half-life of thiamphenicol is shorter in 4-6 month old beef and dairy calves compared to mature lactating dairy cows (Abdennebi et al., 1994). Furthermore, Bengtsson et al. (1997) found statistical differences between pregnant and lactating sheep in the clearance, volume of distribution, and elimination half-life of penicillin-G.
This potential influence of gender and physiology on drug elimination could impact the regulation of drug use in cattle. As a hypothetical example, a drug sponsor submits a new parasiticide to CVM for approval. The application states that the drug is intended only for use in beef cattle. The sponsor needs to provide pharmacokinetic data for only beef animals. This would include either steers (castrated males) or non-lactating beef cows. The sponsor need not perform any pharmacokinetic studies on lactating dairy cows. Let's further say that, upon review of the submitted data, CVM determines that the drug is safe and effective for treatment of parasites in beef cattle and does not represent a human food or environmental safety risk. The drug is approved. What if, at a later date, the drug sponsor seeks approval for use of this drug to treat the same condition in lactating dairy cows? Do the pharmacokinetic data obtained from beef cattle adequately predict drug elimination in lactating dairy animals, or should CVM require the drug sponsor to generate additional drug elimination data to demonstrate safety and efficacy for this new production class? CVM's Office of Research is investigating the existence of pharmacokinetic differences between beef and dairy cattle.
Phenylbutazone was the first drug studied by the Office of Research to investigate pharmacokinetic differences between bovine production classes. Phenylbutazone is a non-steroidal anti-inflammatory and anti-pyretic drug approved for use in horses. However, phenylbutazone can have severe side effects in humans, and it is not approved for use in any food-producing animal because of food safety issues. In spite of this, there is evidence of its extra-label use in cattle. Phenylbutazone is used to treat mastitis in lactating dairy cows (Dascanio et al., 1995 and Shpigel et al., 1998); bacterial infections in neonatal calves (Semrad et al., 1993); and musculoskeletal disorders in steers and bulls (Williams et al., 1990). It is a lipophilic drug that is highly plasma protein bound (> 98 percent, Boudinot et al., 1990) and undergoes minimal biotransformation in cattle (Lees et al., 1988). There is evidence that phenylbutazone elimination half-life is different among different age groups of cattle. For example, the elimination half-lives for neonatal calves, dry dairy cows, and mature bulls are 207 (Semrad et al., 1993), 40 (Lee et al., 1988), and 62 hours (Williams et al., 1990), respectively. To the best of our knowledge, no one has compared two different production classes with respect to phenylbutazone pharmacokinetics.
Phenylbutazone was administered to a group of lactating dairy cows at a dosage of 6 mg/kg body weight. Plasma and milk samples were taken periodically and analyzed for phenylbutazone. The clearance, volume of distribution at steady state, and elimination half-life were 3 mL/hr/kg body weight, 147 mL/kg body weight, and 40 ± 6 hr, respectively (De Veau et al., 1998). These values were similar to that determined for dry dairy cows (Lee et al., 1988). Phenylbutazone was excreted into the milk at levels several times greater than could be predicted by simple diffusion. One possible explanation for the higher than predicted levels of phenylbutazone in milk would be significant phenylbutazone binding to milk proteins. Phenylbutazone elimination half-life was determined from milk data and was calculated to be 47 ± 4 hr. Mammary clearance of phenylbutazone was 0.009 mL/hr/kg body weight, or about 0.34 percent of total body clearance.
A pharmacokinetic study on a group of beef steers, using the same dosage of phenylbutazone, was also completed. Plasma samples were taken periodically and analyzed for phenylbutazone. Pharmacokinetic parameters were calculated. The results are being reviewed by Office of Research management and should be available for publication shortly.
Additional pharmacokinetic studies are currently being conducted at Office of Research using several model drugs of differing lipophilicity, plasma protein binding, and mode and degree of biotransformation. This should give CVM a more complete understanding on predicting when a drug is likely to be eliminated differently by the two production classes of cattle.
Abdennebi, E.H., Sawchuk, R.J., & Stowe, C.M. (1994) Thiamphenicol pharmacokinetics in beef and dairy cattle. Journal of Veterinary Pharmacology and Therapeutics, 17: 365-368.
Bengtsson, B., Jacobsson, S.-O., Luthman, J. & Franklin, A. (1997) Pharmacokinetics of penicillin-G in ewes and cows in late pregnancy and in early lactation. Journal of Veterinary Pharmacology and Therapeutics, 20: 258-261.
Boudinot, F.D., Williams, R.J., & Smith, J.A. (1990) Effect of non-linear plasma protein binding on unbound and total plasma phenylbutazone concentrations in cows. Journal of Veterinary Pharmacology and Therapeutics, 13: 132-136
Dascanio, J.J., Mechor, G.D., Grohn, Y.T., Kenny, D.G., Booker, C.A., Thompson, P., Chiffelle, C.L., Musser, J.M.M. & Warnick, L.D. (1995) Effect of phenylbutazone and flunixin meglumine on acute toxic mastitis in dairy cows. American Journal of Veterinary Research, 56: 1213-1218.
De Veau, E.J.I., W. Pedersoli, R. Cullison, and J. Baker. 1998. Pharmacokinetics of Phenylbutazone in Plasma and Milk of Lactating Dairy Cows. Journal of Veterinary Pharmacology and Therapeutics 21: 437-443.
Lees, P., Ayliffe, T. & Maitho, T.E. (1988) Pharmacokinetics, metabolism and excretion of phenylbutazone in cattle following intravenous, intramuscular and oral administration. Research in Veterinary Science, 44: 57-67.
Loebstein, R., Lalkin, A., & Koren, G. (1997). Pharmacokinetic changes during pregnancy and their clinical relevance. Clinical Pharmacokinetics, 33: 328-343.
Semrad, S.D., McClure, J.T., Sams, R.A. & Kaminski, L.M. (1993) Pharmacokinetics and effects of repeated administration of phenylbutazone in neonatal calves. American Journal of Veterinary Research, 54: 1906-1911.
Shpigel, N.Y., Winkler, M., Ziv, G. & Saran, A. (1998) Relationship between in vitro sensitivity of coliform pathogens in the udder and the outcome of treatment for clinical mastitis. Veterinary Record, 142: 135-137.
Witkamp, R.F., Yun, H.-I., van’t Klooster, G.A.E., van Mosel, J.F., van Mosel, M., Ensink, J.M., Noordhoek, J. & van Miert, A.S.J.P.A.M. (1992) Comparative aspects and sex differentiation of plasma sulfamethazine elimination and metabolite formation in rats, rabbits, dwarf goats, and cattle. American Journal of Veterinary Research, 53: 1830-1835.
Williams, R.J., Boudinot, F.D., Smith, J.A., & Knight, A.P. (1990) Pharmacokinetics of phenylbutazone given intravenously or orally to mature Holstein bulls. American Journal of Veterinary Research, 51: 367-370.
Wilson, K. (1984). Sex-related differences in drug disposition in man. Clinical Pharmacokinetics, 9: 189-202.
FDA's Center for Veterinary Medicine has published two final guidance documents for industry entitled "Validation of Analytical Procedures: Definition and Terminology" (Guidance Document #63) and "Validation of Analytical Procedures: Methodology'' (Guidance Document #64.) These guidances have been adapted for veterinary use by the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (VICH). They will be implemented in October 1999.
Copies of these final guidance documents may be obtained from CVM's Guidelines and Guidances Page or by calling or writing the FDA Veterinarian.
Interested persons may submit written comments on the final guidance documents to the Policy and Regulations Team (HFV-6), Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855.
Further information about Guidance Document #63 is contained in the July 28, 1999, Federal Register, and about Guidance Document #64 is contained in the August 4, 1999, Federal Register. Information on these final guidance documents is also available from William G. Marnane (HFV-140), Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-827-6966, e-mail firstname.lastname@example.org.
Further information on VICH is available from Dr. Sharon R. Thompson (HFV-3), Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-594-1798, e-mail: email@example.com and from Dr. Robert C. Livingston, Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Place (HFV-1), Rockville, MD 20855, 301-594-5903, e-mail: firstname.lastname@example.org.
FDA's Center for Veterinary Medicine announced the availability of a draft guidance document entitled: "Guidance for Industry, Good Clinical Practices Draft Guidance" (#85) in the August 3, 1999 Federal Register. This draft guidance document was developed by the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (VICH). It is intended to provide a unified standard as well as an international ethical and scientific quality standard for designing, conducting, monitoring, recording, auditing, analyzing and reporting clinical studies evaluating veterinary products.
Copies of this draft guidance document may be obtained from the Guidelines and Guidances Page or by calling or writing the FDA Veterinarian.
Further information about this document is contained in the August 3, 1999, Federal Register notice and from Dr. Herman M. Schoenemann (HFV-120), Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-827-0220, e-mail: email@example.com. Further information on VICH is available from Dr. Sharon R. Thompson (HFV-3), Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-594-1798, e-mail: firstname.lastname@example.org and from Dr. Robert C. Livingston, Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Place (HFV-1), Rockville, MD 20855, 301-594-5903, e-mail: email@example.com.
On May 14, the Food and Drug Administration (FDA)/Association of American Feed Control Officials (AAFCO) Bovine Spongiform Encephalopathy Feed Regulation Team was honored with Vice President Al Gore's Hammer Award. The BSE Feed Regulation Team is comprised of employees from FDA's Center for Veterinary Medicine (CVM) and Office of Regulatory Affairs (ORA), and AAFCO, an organization that includes officials from all States and the Federal government who are responsible for enforcing the laws regulating the production, labeling, distribution, and/or sale of animal feeds.
The Award was presented by Yetta Lyle who represented the Vice President's National Partnership for Reinventing Government at CVM's 1999 Honor Awards Ceremony. The award citation reads, "For making a significant contribution to reducing the possibility of bovine spongiform encephalopathy (BSE, or 'mad cow disease') becoming established and spread in the U.S." The Team used an innovative education-oriented partnership program to enforce a FDA regulation designed to control BSE. Compliance rates for the first inspections of all but one industry segment equaled or exceeded 75 percent. Compliance rates at follow-up inspections should approach the goal of 100 percent compliance, based on the enforcement strategy developed and updated jointly by the partners. Independent research has shown that major industry adjustments have been made to facilitate compliance with the regulations. FDA and State inspectors have conducted an unprecedented number of education-oriented inspections; a reinvented approach to doing inspections that has resulted in 70 percent savings in the cost of inspections, amounting to $1.3 million in Fiscal Year 1999.
The Hammer Award is the down-to-earth symbol of the National Partnership for Reinventing Government, a five-year old, major initiative to make the government work better for less. The program honors Federal employees and their partners who have joined forces to streamline procedures, put consumers first, and help build a better and more cost-effective government.
In addition to a plain carpenter's hammer, the award includes a ribbon and the Vice President's note of appreciation, all set in an aluminum frame. Also, every Team member will receive a personal certificate of appreciation with Al Gore's signature and a lapel hammer pin.
by Joanne M. Kla
The Center for Veterinary Medicine is the first Center within the Food and Drug Administration to publish a regulation using the "Plain Language" question and answer format in the codified section. Our proposed rule implementing the Veterinary Feed Directive (VFD) portion of the Animal Drug Availability Act of 1996 published in the Federal Register on July 2, 1999.
What got CVM started with Plain Language?
The President’s Memorandum for the Heads of Executive Departments and Agencies on "Plain Language in Government Writing" issued on June 1, 1998. This memo required that any proposed and final rulemakings published in the Federal Register after January 1, 1999 be in Plain Language (unless the original proposal had published before January 1, 1999). We expected the proposed rule on VFDs to publish after January 1, 1999, so we knew we needed to write it in Plain Language.
We observed that it was mainly scientists and lawyers who read and interpret our regulations for others in the regulated industries. This resulted in documents that were very technical in nature and not necessarily understandable.
An increasing number of CVM’s regulations are not intended for regulatory specialists, but rather for veterinarians, the feed industry, and animal producers.
The Small Business Regulatory Enforcement Fairness Act of 1996 requires federal agencies to publish a simplified interpretation of all major regulations.
These factors suggested an obvious need for the use of simplified language so the average citizen could read, understand, and follow our regulations.
How did we get started?
The Center’s Policy and Regulations Team discussed the need for clearer writing in CVM documents. We raised the idea of drafting a regulation in Plain Language and asked for volunteers. Ron Scherzberg was eager to try with his in-process draft VFD regulation. Surfing the Internet, he found a wealth of guidance including plainlanguage.gov, a site sponsored by Vice President Gore’s National Partnership for Reinventing Government (NPR). In addition, all CVM Policy and Regulations Team members attended Plain Language training.
How did we write this regulation in Plain Language?
We began by defining our audience and deciding on the most useful plain language tools and techniques. We did not write the proposed rule for other government employees or lawyers. We wrote it for those we regulate:
- members of the animal feed industry
- animal producers, and
- members of the pharmaceutical industry
We used a question and answer format to explain the requirements, i.e., §558.6 (c) "What are the VFD recordkeeping requirements?"
We used personal pronouns in the regulation (such as "we" and "you").
We used the more mandatory "must" rather than "shall" for the requirements, i.e., §558.6 (d)(1) "The distributor must notify the FDA only once, by letter, that it intends to distribute animal feed containing a VFD drug."
We used simpler, more straightforward language.
We tried to streamline the regulation by removing unnecessary language, and using short sentences and the active voice.
How did CVM deal with roadblocks and challenges?
We initially met with some resistance, because the regulation in plain language did not look like what people were accustomed to seeing. Once we explained what we were doing and the strong Presidential mandate for the use of plain language, we gained support from those who had previously been skeptical.
What are CVM’s next steps?
We plan to use plain language in future regulations, when it is appropriate.
FDA has approved the first topical drug -- RevolutionTM, Selamectin, for the prevention of heartworm disease in dogs and cats six weeks of age and older. RevolutionTM is also the first drug to combine heartworm prevention as well as the prevention and control of adult fleas and their eggs. Although heartworms and fleas are the most significant parasites that RevolutionTM has activity against, the drug is also effective against ear mites in cats and dogs, sarcoptic mange (also known as scabies) in dogs, and intestinal roundworm and hookworm infections in cats.
The drug is applied topically once a month. The duration of treatment depends on the type of parasitic infection. In clinical trials, RevolutionTM was shown to be safe and effective, with minimal side effects, and was well tolerated by healthy dogs and cats. Caution must be used when treating sick, debilitated or underweight animals. RevolutionTM will be sold by Pfizer Inc. of New York, N.Y. beginning this fall. It will be available only on the order of a licensed veterinarian.
On April 13, 1999, the U.S. District Court for the Western District of Wisconsin accepted and entered a Consent Decree of Permanent Injunction between the United States, and Radix Laboratories, Inc. and its President, Premchand Girdhari. Radix is a manufacturer of injectable animal drugs, as well as other dosage forms, located in Eau Claire, Wisconsin.
The government’s Complaint for Preliminary and Permanent Injunction alleged that, among other things, Radix manufactured veterinary drug products with significant deviations from Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. Under the Federal Food, Drug, and Cosmetic Act, a drug manufactured in violation of CGMP regulations is deemed adulterated.
Negotiations between the government and Radix resulted in a settlement in which the firm neither admitted nor denied the allegations of the complaint. In the Consent Decree of Permanent Injunction, the firm agreed to be restrained and enjoined from manufacturing, processing, packaging, labeling, holding and distributing drugs unless and until it is in compliance with the CGMP regulations. Radix has also agreed to hire an independent expert who will inspect the firm and certify in writing to the FDA that the firm is in compliance with the CGMP regulations. Further, the firm agreed to revise and correct any inaccuracies on the label of a product known as Multi-B Super. Violation of this consent decree may carry civil or criminal penalties.
FDA's Minneapolis District Office conducted all investigative work for this case. CVM’s Division of Compliance, FDA's Office of the Chief Counsel and the U.S. Department of Justice's Office of Consumer Litigation were in charge of the case processing, litigation and negotiation.
The following firms/individuals received warning letters for offering animals for slaughter that contained illegal drug residues:
Dwight O. Oliver, Westville, OK
Richard J. Lee, Booneville, AR
Robert Nierman, Bob & Rodney Nierman Farm, Hoyleton, IL
Robert Duckworth, Phillpsburg, NJ
Lester Meyers, Nashville, IL
Mitch DeGroot, Sanhill Dairy, Portales, NM
Egidio M. Almeida, Egidio M. or Maria Almeida Dairy, Hilmar, CA
Donald A. Vogt, Telview Farms, Erie, PA
David W. Lemstra, Westview Dairy, Tulare, CA
Reed A. Luce, Rockwood, PA
These violations involved illegal residues of streptomycin and amprolium in rabbits, streptomycin and terramycin in rabbits, gentamicin in cows, penicillin in a cow, oxytetracycline in a cow, sulfadimethoxine in a cow, sulfadimethoxine and penicillin in cows, oxytetracycline and sulfadimethoxine in a cow, and sulfamethazine in a cow.
Warning letters were sent to the following firms/individuals for violations from Good Manufacturing Practices (GMPs):
John D. Moyer, Moyer & Son, Inc., Souderton, PA
Dean Beyer, Western Consolidated Cooperative, Holloway, MN
Robert C. McKernan, Hess & Clark, Inc., Ashland, OH
A warning letter was sent to Scott A. Sanders, SAS Dairy, Modesto, CA, for consigning a dairy heifer to be slaughtered for human food with illegal residues of sulfamethazine and for having a history of offering animals for sale for human food use which were adulterated with drug residues.
Lois M. Lochary, Riverbend Rabbitry, Oilton, OK, received a warning letter for offering rabbits for sale with violative residues of streptomycin, for failing to use amprolium in conformance with its approved labeling, and for using sulfaquinoxaline to treat rabbits even though this product is not approved for this use. Also, the warning letter noted that the firm had a supply of furazolidone on the premises. The use of nitrofuran drugs such as furazolidone or nitrofurazone has been banned in food-producing animals.
A warning letter was sent to Dr. Marc A. Puleo, Petmed Express, Fort Lauderdale, FL, for dispensing prescription veterinary drugs without obtaining a lawful order from a licensed veterinarian within the course of the veterinarian's professional practice.
Dr. William R. Lance, Wildlife Pharmaceuticals, Inc., Fort Collins, CO, received a warning letter because the firm has been commercially marketing veterinary drugs without approval of supplemental new animal drug applications for a change in manufacturing facilities and for revisions in manufacturing procedures as required by Title 21, Code of Federal Regulations, Part 514.8.
|Company||Generic and Brand Names||Indications||Routes/Remarks|
|Carprofen (Rimadyl®) Rx||Dogs. For the relief of pain and inflammation associated with osteoarthritis.||ORAL: The chewable tablets are scored so that a half-tablet may be easily given. Amount to be administered is 1 milligram per pound of body weight twice daily. Tablets contain either 25, 75, or 100 milligrams of carprofen. This approval qualifies for three years of marketing exclusivity.|
Federal Register: 06/16/99
|Schering-Plough Animal Health Corp.
|Diclazuril (Clinacox™)||Broiler chickens. For the prevention of coccidiosis in broiler chickens.||MEDICATED FEED: The NADA provides for use of a Type A medicated article containing diclazuril for use in manufacturing a Type C medicated feed. Such feed indicated for prevention of coccidiosis caused by Eimeria tenella, E. necatrix, E. acervulina, E. brunetti, E. mitis (mivati), and E. maxima. A tolerance for diclazuril is established as is an ADI.|
Federal Register: 07/02/99
|Selamectin (Revolution™) Rx||Dogs and Cats. For use as a topical parasiticide.||TOPICAL: Selamectin kills adult fleas and prevents flea eggs from hatching for 1 month, and it is indicated for the prevention and control of flea infestations, prevention of heartworm disease caused by Dirofilaria immitis, and treatment and control of ear mite infestations in dogs and cats; in dogs for treatment and control of sarcoptic mange and in cats for treatment of intestinal hookworm and roundworm infections. The approval qualifies for 5 years of marketing exclusivity.|
Federal Register: 07/12/99
|Marbofloxacin (Zeniquin™) Rx||Dogs. For treatment of infections associated with bacteria susceptible to marbofloxacin.||ORAL: The drug is limited to veterinary prescription use and prohibited from extra-label use in food-producing animals. This approval qualifies for 5 years marketing exclusivity.|
Federal Register: 07/23/99
|Company||Generic and Brand Names||Indications||Routes/Remarks|
|Nystatin Neomycin Thiostrepton Triamcinolone acetonide (Derma-Vet Cream) Rx||Dogs and Cats. For topical management of dermatologic disorders.||TOPICAL: The ANADA is a generic copy of Solvay's NADA 96-676 for Panalog® Cream. The dermatologic disorders are characterized by inflammation and dry or exudative dermatitis, particularly those caused, complicated, or threatened by bacterial or candidal infections.|
Federal Register: 08/06/99
|Company||Generic and Brand Names||Indications||Routes/Remarks|
|Pharmacia & Upjohn Co.
|Neomycin sulfate (Neomix® AG 325) (Neomix® 325)||Turkeys. For the control of mortality associated with Escherichia coli organisms susceptible to neomycin sulfate in growing turkeys.||ORAL: The supplement is to add the additional species, turkeys, to the cattle (not veal calves), swine, sheep, goats already approved. In addition, a tolerance and an ADI are provided. This approval qualifies for 3 years marketing exclusivity.|
Federal Register: 06/11/99