PROFESSIONAL FLEXIBLE LABELING GUIDANCE RELEASED FOR PUBLIC COMMENT
NEW METHOD AVAILABLE FOR DETECTION OF BOVINE MATERIAL IN FEED
FDA REQUESTS COMMENTS ON VALIDATION DRAFT GUIDANCE DOCUMENTS
PROFESSIONAL FLEXIBLE LABELING GUIDANCE RELEASED FOR PUBLIC COMMENT
by John D. Baker, D.V.M. and William T. Flynn, D.V.M.
On January 22, 1998, the Center for Veterinary Medicine (CVM), announced in the Federal Register, the availability for public comment of a draft Guidance for Industry on "Professional Flexible Labeling of Antimicrobial Drugs." This document is intended to provide specific guidance on the development of Professional Flexible Labeling (PFL) for therapeutic veterinary prescription and veterinary feed directive (VFD) antimicrobial drugs.
In the past, CVM has approved veterinary prescription product labels with single fixed dosages that carry indications against a narrow range of specific diseases and organisms. As a result of using this approach, the label did not reflect many current uses for therapeutic agents in veterinary medicine. Specifically, for antimicrobial products, narrowly approved uses fail to address the fact that, while some specific bacteria do produce repeatable, recognized disease, many organisms are either opportunistic or are known to produce a variety of clinical manifestations.
Such restricted labeling has led to veterinary prescription products that have limited practical usefulness if administered strictly according to their approved conditions of use and has served as an impetus to development of the PFL concept. Workshops on PFL, cosponsored by the Food and Drug Administration/Center for Veterinary Medicine, the American Academy of Veterinary Pharmacology and Therapeutics, the Animal Health Institute, and the American Veterinary Medical Association were held in Rockville, MD in April and December, 1995. A summary of the discussions and opinions expressed in the April, 1995 workshop were published in the Journal of the American Veterinary Medical Association (JAVMA), October 1, 1995. Following the December, 1995 workshop, a task force was assembled to prepare a report on PFL concepts. The task force report, which included a model drug label, was published in the JAVMA, July 1, 1996.
The basic concept of PFL is to provide prescription veterinary products that carry useful prescribing information for the range of clinical situations included within their approved conditions of use. Implementation of PFL is based on the recognition that veterinarians, as a function of their medical training, possess the knowledge, skills, and abilities to interpret diagnostic and prescribing medical information and to develop these data into appropriate therapeutic regimens. The document should prove valuable in the process of developing and labeling prescription veterinary antimicrobial drugs and should render a greater service to practitioners and their clients by providing for current, accurate information in product labeling. Ultimately, products labeled as described in the PFL guidance will be consistent with and better reflect how veterinarians utilize animal drugs in the course of their professional practice.
Though this document represents FDA's current thinking on the development and labeling of therapeutic veterinary prescription antimicrobial drugs, it does not bind the agency or the public. As with any Center guidance, pharmaceutical companies may decide to follow alternate procedures or practices. In that event, CVM suggests that they discuss the matter with the agency a priori to prevent an expenditure of money and effort on activities that may later be determined to be unacceptable to the FDA. CVM also recognizes that the general concepts of PFL expressed in the guidance on antimicrobial drugs may not be equally applicable to other classes of therapeutic prescription products (e.g., antiparasitics, physiologics). Therefore, it is CVM's intention to develop PFL guidances that are specific to various classes of drugs.
Copies of the guidance document may be obtained from CVM's Internet Home Page or by contacting the FDA Veterinarian. Individuals are encouraged to submit written comments on the draft guidance to the Dockets Management Branch (HFA-305), Food and Drug Administration, Room 1-23, 12420 Parklawn Dr., Rockville, MD 20857. Comments should be identified with the full title of the draft guidance and docket number 98D-0016 and be submitted by April 22, 1998. Comments received on the draft guidance may be seen at the Dockets Management Branch between 9 a.m. and 4 p.m., Monday through Friday. After review of these comments, FDA will finalize the guidance document with any appropriate changes.
NEW METHOD AVAILABLE FOR DETECTION OF BOVINE MATERIAL IN FEED
by Michael J. Myers, Ph.D.
Bovine spongiform encephalopathy is a member of the transmissible spongiform encephalopathy (TSE) disease family. Other TSE diseases include Kuru, Creutzfeldt-Jakob Disease (CJD) which are human diseases, chronic wasting syndrome (elk) and scrapie, a disease found in sheep. These conditions cause a progressive degeneration of the central nervous system, which is always fatal.
Bovine spongiform encephalopathy (BSE) was first detected in the United Kingdom in 1986. As a consequence of epidemiological surveys, an association developed between the outbreak of BSE and the use of cattle feed containing protein derived from sheep infected with scrapie. In addition, the practice of feeding cattle protein derived in part from other cattle infected with BSE served to amplify this disease and permit further dissemination.
On June 5, 1997, the Food and Drug Administration published the final regulation prohibiting the use of mammalian protein in the manufacture of animal feeds destined to be given to ruminant animals, including cattle, sheep, and goats ( Ref.1). Products believed to pose minimal risk, including blood, blood products, gelatin, milk and milk products, protein derived solely from swine or equine sources, and inspected meat products offered for human consumption were exempted from the ban.
In the course of preparing the final regulation, several existing methods for detecting the presence of bovine derived proteins were examined, including the feed microscopic method (Ref. 2) and the ELISA method developed by the British government (Ref. 3). However, the microscopic method was determined to be very technically demanding and lacking in sensitivity. Likewise, the ELISA method, despite being used by the British government for regulatory purposes, was also determined to be inadequate, principally because of a propensity for false positive responses. In addition, this method was also found to require a high degree of technical competence which might not readily transfer to field situations.
Recently, the Center for Veterinary Medicine (CVM) became aware of another method developed by Dr. Marco Tartaglia at the Instituto Superiore di Sanita in Rome, Italy. This method is a polymerase chain reaction-based (PCR) method (Ref. 4) capable of detecting bovine DNA isolated from complete feed. The method relies on the capacity of the PCR reaction to enzymatically amplify a short segment of DNA, resulting in a method that allows the detection and amplification of a bovine-specific mitochondrial sequence from complete feedstuffs.
This method permits the detection of bovine mitochondrial DNA in feed containing as little as 0.125 percent bovine meat and bone meal. Using the bovine specific PCR primers, this method will only detect material of bovine origin. It will not detect materials of either ovine, swine, equine, avian (turkey and chicken), or lapine origin. The specificity of the PCR reaction is determined by the oligonucleotide sequence of the two PCR primers used for the polymerase chain reaction. These two regions show species specificities for all animals examined to date. No cross reactivity between PCR primers has been observed (Ref. 4). That is, a set of primers specific for swine will only detect material of swine origin, bovine-specific primers only detect material of bovine origin, etc. In addition, the method is relatively rapid, with completion in approximately 24 hours.
Species specificity/identity can also be confirmed using the oligonucleotide product generated by the PCR reaction. Within the PCR product generated from DNA of bovine origin are DNA endonuclease restriction sites for two enzymes, called SspI and DpnII. DNA endonucleases are enzymes that will cleave, or "cut" DNA at internal sites. Each endonuclease recognizes a unique set, or arrangement, of DNA base pairs.
The PCR product generated from bovine DNA is 271 base pairs in length. Endonuclease cleavage of this product by DpnII produces two fragments 57 and 217 base pairs in length. SspI produces three fragments 69, 84 and 118 base pairs in length. This cleavage pattern is unique to the PCR product derived from bovine DNA. DNA derived from ovine, swine, equine, avian, or lapine origin will not produce this cleavage pattern.
The procedure solubilizes 0.5 grams of feed in 4.5 mls of extraction buffer (5M guanidine thiocyanate; 0.05M Tris-Cl, pH 6.4; 0.02M EDTA, pH 8.0, 1.3 percent Triton X-100) with an overnight incubation at 60 C (about 15-16 hours). The following morning, the mixture is admixed, incubated for an additional 30 minutes, then centrifuged at 3000 x g for 10 min. to precipitate the gelatin. The supernatant is removed; 0.5 ml is used for DNA extraction, the remainder is stored at -20°C. The solubilized feed is mixed with an equal portion of extraction buffer (0.5 ml) and 0.040 ml of a silica suspension. This mixture is mixed, then allowed to incubate for 10 minutes at room temperature. During the incubation, the mixture is frequently admixed to keep the silica in suspension. At the end of the incubation period, the silica is removed from suspension by centrifugation. The supernatant is then discarded. The silica is washed two times with wash buffer (extraction buffer without EDTA or Triton X-100), followed by two washes with 70 percent ethanol and one final wash with acetone. The washing serves to remove any protein that precipitated with the silica. The silica pellet is allowed to dry. The DNA is extracted from the silica using 0.050 ml TE buffer (10 mM Tris-CL, pH 8.0; 0.1 M EDTA, pH 8.0).
The PCR reactions performed using 0.005 ml of the extracted DNA sample. The reaction conditions use 12.5 pmole of each primer, 50 µM of each dNTP, 1.5 mM MgCl2, 2.5 units of Taq, and Perkin-Elmer reaction buffer, all in a final volume of 50 µl. The mixture is subjected to 30 cycles at 94°C for 60 sec, 58°C for 60 sec, and 72°C for 60 sec. Upon completion of the PCR process, 20 µl of the PCR reaction is subjected to agarose gel electrophoresis using a 2 percent agarose gel. The results are visualized using ethidium bromide.
This method is currently being evaluated at CVM's Office of Research. Laboratories at FDA's National Center for Toxicological Research and Office of Regulatory Affairs are also participating in this effort. Part of this effort will include a method validation trial to determine the performance characteristics of this method for feedstuffs typically used in this country. In addition, the laboratories at the Office of Research and the National Center for Toxicological Research will be participating in an international method validation trial that is being coordinated by the Joint Research Institute, Environment Institute, Food and Drug Analysis at Ispra, Italy. This effort is tentatively planned to begin in the fall of 1998.
References
1. Substances Prohibited From Use in Animal Food or Feed; Animal Proteins Prohibited in Ruminant Feed. Federal Register 62 (108):30935.
2. Microscopy of Animal Feed. In: Official Methods of Analysis of the AOAC. Ed: Kenneth Helrich. AOAC, Arlington VA. 1990, pp 88-90.
3. Ansfeld, M. 1994. Production of a sensitive immunoassay for detection of ruminant proteins in rendered animal material heated to >130°C. Food and Agricultural Immunology 6:419-433.
4. Tartaglia M, Saule E, Pestalozza S, Morelli L, Antonucci G, Battaglia PA. A procedure for bovine mitochondrial DNA detection in animal feeds: a molecular approach to check for the presence of bovine-derived materials in ruminant feedstuffs. J Food Protection (in press).
The author was CVM's 1997 nominee for the FDA Excellence in Laboratory Science Award.
FDA REQUESTS COMMENTS ON VALIDATION DRAFT GUIDANCE DOCUMENTS
In a January 27, 1998, Federal Register notice, FDA announced the availability for comment of draft Guidance for Industry (GFI) documents on "Validation of Analytical Procedures: Definition and Terminology" and "Validation of Analytical Procedures: Methodology." These draft documents have been adapted for veterinary use by the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (VICH). These are the first documents developed under the VICH process. They are intended to provide guidance on characteristics that should be considered during the validation of analytical procedures included as part of registration applications for veterinary medicinal products submitted for approval to the European Union, Japan, and the United States.
Copies of these documents may be obtained from CVM's Internet Home Page or by contacting the FDA Veterinarian.
In recent years, many important initiatives have been undertaken to promote the international harmonization of regulatory requirements. FDA has participated in VICH efforts to enhance harmonization and has expressed its commitment to seeking scientifically based harmonized technical procedures for the development of pharmaceutical products. One of the goals of harmonization is to identify and reduce the differences in technical requirements for drug development among regulatory agencies. At a meeting held on August 20 and 21, 1997, the VICH Steering Committee agreed that these draft GFI documents should be made available for public comment.
The draft "Validation of Analytical Procedures: Definition and Terminology," discusses the characteristics that should be considered during the validation of analytical procedures. This "Definition and Terminology" document is not intended to cover testing requirements or procedures, rather it is to serve as a collection of terms and definitions. These common definitions such as "analytical procedures," "specificity," "precision," "accuracy," etc., are meant to bridge the differences that often exist among various compendia and requirements of the European Union, Japan, and the United States.
The draft "Validation of Analytical Procedures: Methodology," discusses common analytical procedures and provides guidance and recommendations on how to consider various validation characteristics for each analytical procedure. It also indicates the data that should be included in an application for registration.
Interested parties are encouraged to submit written comments on the draft guidances to the Dockets Management Branch (HFA-305), Food and Drug Administration, room 1-23, 12420 Parklawn Dr., Rockville, MD 20857. Comments should be identified with the full title of the draft guidance and docket number 98D-0017. Comments should be submitted by March 30, 1998.
Comments received on the draft guidances may be seen at the Dockets Management Branch between 9 a.m. and 4 p.m., Monday through Friday. After review of these comments, FDA will finalize the guidance document with any appropriate changes.
Further information about this draft guidance document is contained in the January 27, 1998, Federal Register notice. Information on the draft guidance documents is also available from William G. Marnane, Center for Veterinary Medicine (HFV-140), Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855, 301-594-0678. E-mail: wmarnane@bangate.fda.gov. Further information on VICH is available from Dr. Sharon Thompson, Center for Veterinary Medicine (HFV-3), Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855, 301-594-1798. E-mail: sthompso@bangate.fda.gov.
BIOTECHNOLOGY: PUTTING CLONES IN CONTEXT
by John Matheson
Cloning of mammals using somatic cells is big news in biotechnology. A nucleus from a diploid, mammalian cell culture derived from an organ other than the gonads has been substituted for the nucleus of a mammalian egg, the egg implanted into a surrogate mother and a viable offspring produced. This article will examine cloning in the context of how it might relate to products regulated by CVM.
News media attention to cloning reached new heights in February 1997 with the announcement from the Roslin Institute in Scotland that they had successfully created Dolly, a clone from a somatic cell derived from cultured mammary gland cells of an adult sheep. Instead of evaluating the impact of this advance upon animal biotechnology, the media and the public leaped ahead to consider the bioethical and social implications of cloned humans. The President's National Bioethics Advisory Commission last June proposed a 5-year moratorium on cloning directed at creating a human child, but not the cloning of human or other DNA in cell lines or the cloning of animals.
In an interview with The Washington Post published January 20, 1998, the Acting Commissioner of FDA, Dr. Michael Friedman, stated "Through the Food, Drug, and Cosmetic Act we do have the authority to regulate human cloning, and we are prepared to assert that authority." He added that human cloning is a form of cellular or genetic therapy that requires prior FDA approval. The same article goes on to further cite Dr. Friedman as saying that anyone wanting to attempt human cloning legally must file a formal application with FDA which would undertake a lengthy review. The FDA would initiate legal action against anyone failing to file that application.
Cloning of humans has long been recognized as an ethical and social challenge. Westerners have been conditioned by books like Brave New World and movies like Boys from Brazil to reject human cloning. Our society will probably still be debating the permissibility of cloning humans long after cloning becomes technically and economically feasible.
On the other hand, clones of plants have long been prominent members of agriculture and horticulture. Genetic uniformity is an important agricultural plant trait that, among other things, facilitates efficient machine harvesting of crops and helps standardize product quality. For example, each apple tree of a single variety is genetically identical to every other individual of the same variety apples and many other fruits are cloned through vegetative propagation, i.e., stem cuttings, because they do not "breed true". In other words, the reshuffling of genes that occurs during sexual reproduction of apples results in apple offspring that are too dissimilar from the parents to be reliable for propagation of apples for commercial production. However, there is no movement afoot to ban the cloning of apples or to consider the bioethical dilemmas posed by cloned apples on the fabric of human society. Cloned plants are accepted as a normal part of human society.
Aside from Dolly the sheep, clones of domesticated animals are rare compared to clones of plants in our everyday environment. One might well argue that this is only because clones of animals are more difficult to establish than plants. The goals of many selective breeding programs, many of which feature repetitive back-crossing and inbreeding, include establishing a population of animals, e.g., dogs, horses, cattle, fish, etc., that possesses desirable traits that "breed true." Selective breeding reduces genetic diversity in "breeds of domesticated animals. The extreme case of this selective breeding can be found in the many strains of laboratory rats and mice used for product testing. These strains are so genetically homogeneous that there is no tissue rejection when tissue from one mouse is transplanted to another of the same strain. They are practically genetically identical. This uniformity is important for animal testing because statistically powerful testing may be conducted with small numbers of test individuals. There is less statistical "noise" caused by individual variation. Since the results are similar, cloning of animals could be looked upon as an alternative to selective breeding, especially useful where selective breeding is not practical.
So, is Dolly the logical extension of sheep selective breeding, possessing all the desirable traits sought by sheep breeders of the past? Well, no. Dolly is proof that the process of cloning apparently can work in sheep. Why were sheep selected to clone? Economics. Sheep have shorter generation times than cattle and they still produce milk in reasonable quantities. Why the interest in milk? The mammary gland is a marvelous protein synthesis and secreting organ whose products cannot always be duplicated by bacterial fermentation or chemical synthesis. Domesticated strains of transgenic sheep or cattle might be used to secrete bioactive proteins in milk that can be used as drugs, biologics and animal drugs.
Transgenic animals are genetically modified to contain a grouping of inserted genes (transgenes) from practically any species or combination of species. One application of transgenic animals is for the expression of proteins or enzymes that are not normally present or for the expression of higher concentrations of proteins that are normally present. Expression may be throughout the animal or directed to a specific organ, for example, the mammary gland. Transgenic animals have already been created through various genetic modification techniques that secrete proteins of great value in their milk, e.g., drugs that can be extracted and purified. The only trouble has been that, like the apple, most transgenic animals do not breed true. A major application for the technique of cloning will be in reproducing, in one generation, copies of transgenic animals that yield a high value product.
January 20, 1998, also brought a report from the University of Massachusetts that transgenic Holstein calves had been cloned and born in Texas as part of a project sponsored by Advanced Cell Technology, Inc., and Genzyme Transgenics Corporation. The stated goal of the project is producing recombinant human albumin in cows milk. (This can be purified for use as a human blood product.) Like Dolly, these calves are clones and test models, rather than production animals. Unlike Dolly, the calves are genetically modified. They contain only a marker gene, however, instead of a human albumin gene. Then, too, they are a male clone. Dairy cattle are also capable of more efficient milk production than sheep, so the experiment is an advance toward commercial production in this respect, too.
Cloning of somatic cells in animals is more a tool to reproduce valuable animals, like transgenic animals that produce drugs or biologics, or endangered species, or the best results of selective breeding programs, like the dairy herd improvement plan. The societal benefit to cost ratio for cloning of animals is decidedly different from the ratio for cloning humans, and the use of cloning in animals deserves to be considered separately.
Will the successful somatic cell cloning of mammals open the product floodgates from animal biotechnology companies? Like almost everything in the field of biotechnology, this is hard to predict. For the time being, the answer is "probably not." Cloning will probably always be an expensive way to reproduce mammals compared to sexual reproduction and so will be limited to extremely valuable animals producing high value products.
Does CVM plan to regulate cloning of animals under the Food, Drug, and Cosmetic Act? The answer is probably yes and no. CVM regulates products. Cloning is a process. In the sense that cloning is a means to "manufacture" more transgenic animals and if those transgenic animals are producing an animal drug, then CVM could be involved in examining cloning carried out as part of the production process for the animal drug. CVM also regulates the drugs used on animals as part of the cloning process, for example, drugs for super-ovulation and estrus regulation. Other FDA Centers could similarly be indirectly regulating the cloning process as it is applied to transgenic animals producing a human drug or biologic.
Still under consideration is whether CVM should play a role in determining the safety of food derived from cloned animals that are not genetically modified, for example, clones of a high-producing dairy cow. Does the process of cloning have the potential to introduce changes in the quality of milk or meat derived from clones of normal dairy cows? While clones of food-producing animals are now starting to be developed, there are not yet enough of them to answer this question with hard data. Strictly on a theoretical basis, clones of normal animals should be indistinguishable from their parent in nearly all respects and, therefore, present no food safety concern.
John Matheson works in the Office of Surveillance and Compliance where, among other duties, he follows biotechnology developments for CVM.
BSE -- PREVENTION IS EVERYONE'S RESPONSIBILITY
Preventing Bovine Spongiform Encephalopathy (BSE) should be a high priority for anyone who has a role to play in food safety or animal health, whether it is the renderer of slaughtered animals, livestock producer, feed manufacturer, or any person in between. One way to help ensure that BSE does not occur in the U.S. is to make everyone acutely aware of their individual responsibility in protecting the public health. It is an educational initiative which must involve all levels of FDA's internal and external customers.
BSE has had a devastating effect on the cattle and rendering industries in the United Kingdom where it was first diagnosed in 1986. BSE poses a serious risk to human health, as well as animal health, since recent evidence has shown a strong link between BSE and the occurrence of new variant Creutzfeldt-Jacob Disease. On August 4, 1997, the regulation published under 21 CFR 589.2000 became effective. This regulation is designed to prevent the establishment and amplification of undetected BSE, often referred to as "Mad Cow Disease," through animal feed by prohibiting the use of certain proteins derived from mammalian tissue in feeding ruminant animals.
FDA is expecting 100 percent compliance with this new regulation, which affects renderers, protein blenders, feed manufacturers including FDA-licensed manufacturers, all other commercial feed manufacturers, distributors including retailers, on-farm feed mixers, and ruminant feeders. On January 29, 1998, CVM issued a nationwide assignment to all FDA field offices to implement our enforcement approach of education, a strong inspectional presence, and taking selected enforcement actions for repeated and/or egregious violations. State governments will cooperate in this effort, and in many cases, have already undertaken educational initiatives related to this regulation.
The assignment includes: 1) inspecting firms in each affected segment of the industry, and 2) tracing shipments forward and backward in the chain from renderer to producer, to verify that prohibited material is properly labeled and used. FDA expects that as close to 100 percent of the affected parties as possible will be inspected in the next two years. These inspections will provide an opportunity to educate the affected industries, measure the extent of compliance, and identify areas that may need additional educational focus.
by Tania Woerner, V.M.D.
Foxes are one of the most widespread species, covering six of the seven continents and many different countries and climate zones. Foxes did live in North America before the European Discovery in 1491; however, it was the importation by the British of foxes (mainly for hunting and fur trapping) that established the population of foxes in North America and Australia. The fox prefers gently rolling farmland with sparsely wooded areas and running streams, but the fox is remarkably adaptable and manages to survive and prosper in urban and suburban areas, living in culverts, basements and garden sheds and eating human refuse.
The beautiful russet-coated red fox is a full member of the dog (Canidae) family; however, because of the way it stalks and pounces on its prey, many people think of foxes as more cat-like. Foxes will bury their food much like a dog and return for it later when food supplies are limited. Like humans, foxes are omnivorous and feed on fruit, berries, birds, mice, voles, insects and other invertebrates, especially earthworms! A study conducted on urban foxes living around London found that foxes had even consumed the discarded remains of various ethnic human foods!
The average life span of a fox is about 3 years with a maximum known lifespan of 12 years. Predators of foxes are coyotes, cougars, wolves and wild dogs; however, the most vicious predator is man. In the past foxes were considered vermin and killed for sport and fur. Now humans threaten foxes in a more indirect fashion by over-development. Man's destruction of the foxes' natural habitat has forced foxes to move into more urban areas, where the threat of traffic is greater, and residents often call upon the animal control authorities to eliminate them.
Courtship for foxes begins in mid to late December. When courtship begins, foxes will often be seen traveling in pairs or sometimes groups of three. Mating usually takes place in January or February; however, it can extend into April if the food supply is adequate. Since the gestation period is 52 days, fox kits are typically born in March through April. A typical red fox family consists of the dog fox and a vixen, plus up to four "helper" females which may or may not breed and are subordinate to the breeding vixen. Often these younger foxes are the vixen's daughters. Each family of foxes needs several safe den sites in which to raise their cubs in addition to safe resting spots outside the den. The family domain is established by the dog fox by marking his territory. The scent of the dog fox alerts other foxes to stay clear of this territory. It is common for a family to have several dens within their territory. Prior to parturition, the mated pair selects a den, called the natal den, in which to bear the kits. This den is usually larger than the other available dens and always has several exits.
Fox litters can be as small as one kit, or as large as thirteen, but the average is five. If a mother and an older daughter produce a litter at the same time, the daughter will often surrender her kits to her mother, and all the kits are raised together as a litter, with the older daughter assisting in rearing the kits.
Kits are born blind, with short grey fur. Within ten days, their eyes are open, and by three weeks they are playing outside the den. It is not uncommon for urban and rural foxes to move their kits to alternate den sites several times while the kits are maturing. Fox kits are playful and affectionate, and by five weeks of age they begin to explore outside of the den. By two months of age the fox kits are less dependent on their parents and begin to hunt on their own. Typically, October is the month when they begin to leave the den to find a domain of their own. Interestingly, not all fox kits leave in their first year; females are more likely to "stick around," sometimes until they are about two years old. Population density and food supply determine the timing of the dispersal of fox kits. When the population is dense and the food supply is scarce, they will strike out on their own at an earlier age and travel greater distances.
Once the kits have dispersed, the adults and remaining kits hunt on the same territory, but hunt and travel alone. The male and female foxes do not associate regularly until courtship begins again in December.
FDA PUBLISHES GUIDANCE ON INDUSTRY-SUPPORTED ACTIVITIES
In the December 3, 1997, Federal Register, FDA announced the publication of "Final Guidance on Industry-Supported Scientific and Educational Activities." This guidance document was prepared by FDA's Intra-Agency Working Group on Advertising and Promotion.
FDA is providing this guidance to describe the Agency's enforcement policy with regard to scientific and educational activities supported by industry. The guidance seeks to clarify the distinction the Agency draws between scientific and educational activities that FDA considers nonpromotional and those that the Agency considers promotional, and to provide guidance on how industry may support such activities without being subject to the labeling and advertising provisions of the Federal Food, Drug, and Cosmetic Act (the Act). This jurisdictional line is important because the constraints on advertising and labeling, when applied to scientific and educational activities, can restrict the freedom of participants to discuss their data or express their views in promoting the use of a drug. In particular, promotional discussions of unapproved uses, which can be an important component of scientific and educational activities, are not permissible in programs that are or can be subject to substantive influence by companies that market products related to the discussion. The Agency recognizes that industry-supported activities can be both nonpromotional and educational.
FDA does not intend to regulate, under the labeling and advertising provisions of the Act, industry-supported scientific and educational activities that are independent of the influence of the supporting company. Companies and providers who wish to ensure that their activities will not be subject to regulation should design and carry out their activities free from the supporting company's influence and bias, based on factors FDA considers in evaluating activities and determining independence. These factors are listed in the guidance document.
Copies of "Final Guidance on Industry-Supported Scientific and Educational Activities" (CVM number 65) may be obtained from the on-line library at CVM's Internet Home Page or by calling the FDA Veterinarian at 301-594-1755.
Comments on this document may be submitted at any time to the Dockets Management Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Drive, Room 1-23, Rockville, MD 20857. Questions regarding this guidance in regard to prescription animal drugs may be directed to Dr. Edward L. Spenser, FDA/Center for Veterinary Medicine, HFV-216, 7500 Standish Place, Rockville, MD 20855, 301-594-1722.
PERSONNEL CHANGE IN CVM'S ONADE
In January 1998, the Center for Veterinary Medicine announced that Dr. Robert Livingston, who has been Director of the Office of New Animal Drug Evaluation (ONADE), changed positions within the Center to focus his efforts on preparing for upcoming Codex Alimentarius Commission (Codex) meetings, and to work with Dr. Sharon Thompson, CVM Special Assistant for International Affairs, on international drug harmonization issues.
Dr. Andrew Beaulieu, ONADE Deputy Director for Therapeutic and Production Drug Review, was named acting ONADE Director for 90 days starting on January 4, 1998. Following that period, Dr. Margaret Miller, ONADE Deputy Director for Human Food Safety and Consultative Services, will be acting Director for 90 days. CVM has begun nationwide recruitment to permanently fill the vacancy.
According to CVM Director Dr. Stephen Sundlof, "There is a considerable amount of work to be done in the area of international veterinary drug harmonization, and I am pleased that Dr. Livingston has accepted the assignment." Dr. Livingston is ideally suited both professionally and through his experience to contribute to CVM's international effort, Dr. Sundlof added.
In a July 7, 1997 Federal Register notice, the Food and Drug Administration said it is studying the possibility of amending its regulations so the U.S. could consider standards established by the Codex for food safety and veterinary drug residues. Codex is an international body that establishes food safety standards under the joint auspices of the United Nations' World Health Organization and Food and Agriculture Organization.
Dr. Livingston's expertise also will help in supporting the U.S. science-based system of food safety rules at a Codex meeting in May. The Codex Committee on General Principles will meet in Paris to define the "other legitimate factors" that could be used as a basis for establishing Codex standards. Codex currently uses scientific data in setting standards pertaining to public health. The U.S. is concerned that, if non-science factors are introduced into the standard-setting process, it would have an undermining effect on the Codex system and could lead to an increase in non-tariff trade barriers. Dr. Livingston will serve a critical role in helping to prepare the U.S. Codex delegation for the General Principles meeting.
Also, under the Animal Drug Availability Act, passed in 1996, Congress ordered FDA to consider data from foreign governments or international bodies in establishing tolerance levels for veterinary drugs in imported food. The Act directs FDA to consider, in establishing such tolerances, data submitted to the appropriate regulatory authority of any country where the new animal drug is lawfully used or data available from a relevant international organization.
As ONADE director, Dr. Livingston developed a reputation for leading a highly productive and professional organization. As evidence of this, in 1997 ONADE approved a record large number of animal drug applications.
"Dr. Livingston is perhaps the most ardent supporter of my belief that the animal drug approval process is the most powerful regulatory tool we have for assuring the safety of the food supply. Under his leadership, ONADE has become a focused, efficient, entrepreneurial, service-oriented organization, which has earned the respect of FDA, the animal health industry, and the Congress," Dr. Sundlof said.
CVM TO COSPONSOR FOOD SAFETY SYMPOSIUM AT AVMA CONVENTION
The Center for Veterinary Medicine will cosponsor a one-day Food Safety Symposium entitled "Post-Harvest: Foodborne Disease Issues." The Symposium will be presented in conjunction with the annual meeting of the American Veterinary Medical Association (AVMA) to be held July 25-29, 1998, in Baltimore, Maryland. This symposium will offer a comprehensive review and analysis of emerging foodborne issues, i.e., residues, resistance, and foodborne pathogens. Leaders from Public Health organizations, regulatory agencies, and medical practitioners will speak, and moderators will direct panel discussions focusing on criteria for prevention and resolution of these foodborne issues. Other sponsors include AVMA, American Association of Food Hygiene Veterinarians, and the American College of Veterinary Preventive Medicine. The symposium will be held on July 25, and a full agenda will appear in the next issue of the FDA Veterinarian.
National Pet Week, which will be celebrated May 3-9, 1998, is cosponsored by the Auxiliary to the American Veterinary Medical Association (AVMA), the AVMA, the American Animal Health Association, and the North American Veterinary Technician Association. This year's theme is "People and Animals Need Each Other," which emphasizes the human-animal bond, as well as the importance of veterinary health care professionals. This is the ideal time to stress the contribution that pets make in our lives.
Promotional materials are available from the Auxiliary to the AVMA. For more information concerning materials and resources, you may access the AVMA's Internet Web site at www.avma.org. The AAHA Web site is www.healthypet.com.
The FDA Veterinarian is proud to support the National Pet Week campaign and its goals. The Center for Veterinary Medicine is committed to working together with our customers, i.e., consumers, veterinarians, the animal health industry, and other Government agencies, to protect the health of humans and animals.
TRANSITIONAL MEDICATED FEED MILL LICENSES WILL EXPIRE SOON
CVM officials have sent out more than 400 letters to feed manufacturers reminding them that after April 9, 1998, they can no longer manufacture and distribute any feed that contains drugs requiring an approved Medicated Feed Mill License unless they have obtained an approved permanent medicated feed mill license.
The Animal Drug Availability Act (ADAA) of 1996 eliminated the need for feed manufacturers to have multiple Medicated Feed Applications (MFAs) by allowing them instead to obtain a single license for their facility. The intent of this change was to reduce the paperwork imposed on manufacturers of medicated feed and FDA, while maintaining sufficient safeguards for the manufacture of medicated feed. When ADAA was enacted (October 9, 1996), holders of MFAs were granted transitional licenses. These transitional licenses will expire on April 9, 1998.
Transitional license holders who wish to continue as licensed firms must submit and obtain approval of a permanent Medicated Feed License Application (Form FDA 3448) no later than April 9, 1998. More than one-fourth of the firms that previously held MFAs have not yet requested a permanent license.
Firms may obtain a copy of Form FDA 3448 from CVM's Home Page or by calling or writing CVM's Division of Animal Feeds, Medicated Feeds Team, 7500 Standish Place, Rockville, MD 20855, 301-594-1731. Please note: Annual Drug Establishment/Registration (FDA Form 2656/2656e) is still required.
ANNUAL MID-ATLANTIC CONFERENCE FOR BOVINE PRACTITIONERS
The Maryland Veterinary Medical Association (MVMA) announces the following continuing education course for veterinarians: Annual Mid-Atlantic Conference for Bovine Practitioners, March 26-27, 1998, at the Holiday Inn, Frederick, Maryland. The two-day seminar will include lectures from nationally recognized experts, interactive case studies, practice tips, a good and welfare session and opportunities for fellowship. Meals are included in the registration. Topics include Laminitis and Nutrition, Investigating Herd Lameness in a Dairy Herd, Pasture Management and Lameness, Calf Diarrheas: Causes and Treatments, Neospora Caninum-Like Species Infection in Dairy Cattle, Johnes Disease, Practical Procedures for Control, Etiology of Foot Disease, Treatment, Control and Surgical Procedures, Epidemiology of Foot Problems and Lameness, and Management of Upper Leg Lameness. Pre-Registration deadline is March 20, 1998, however, registration will be accepted at the door for one or both days. Cost (including meals) is $140 for both days, or $80 for one day. Veterinary students or technicians may attend at half price. Spouses are admitted free, but must pay for meals. The course is cosponsored by the Maryland Veterinary Medical Association, the Maryland Department of Agriculture, the American Association of Bovine Practitioners, District II, the Western Maryland Veterinary Medical Association, the Pennsylvania State University, and the Virginia-Maryland Regional College of Veterinary Medicine. For further information, please contact Buzz Thomas at the MVMA office at (888) 884-6862.
CVM MAKES THE ANALYSIS OF COMMENTS ON THE FLUOROQUINOLONE AND GLYCOPEPTIDE PROHIBITION AVAILABLE TO THE PUBLIC
The Center for Veterinary Medicine has made available to the public its analysis of comments on the prohibition of the extralabel use of fluoroquinolone and glycopeptide antibiotics in food-producing animals. Copies of this analysis may be obtained from CVM's Internet Home Page or by contacting the FDA Veterinarian.
In the May 22, 1997 Federal Register, FDA published a prohibition against the extralabel use in food-producing animals of fluoroquinolone and glycopeptide antibiotics. Enrofloxacin and vancomycin are examples of antibiotics in each of these classes. The prohibition is based on a finding by the FDA that the extralabel use of these antibiotics in food-producing animals presents a risk to the public health. These extralabel uses are capable of increasing the antibiotic resistance of the bacteria that can cause human illness and that are present in treated animals at the time of slaughter.
The Animal Medicinal Drug Use Clarification Act (AMDUCA) authorizes the issuance of an order of prohibition. The AMDUCA of 1994 amended the Federal Food, Drug, and Cosmetic Act to allow licensed veterinarians to prescribe extralabel uses of approved animal drugs and human drugs in animals. The implementing regulations for AMDUCA were published in the Federal Register on November 7, 1996, and codified in the Code of Federal Regulations (CFR) in Title 21, Part 530. The AMDUCA regulations provide an opportunity for public comment, and that the order of prohibition becomes effective 90 days after the date of publication, unless FDA revokes or modifies the order, or extends the period of public comment.
FDA did not revoke or modify the order, or extend the period for public comment. Accordingly, the prohibition on the extralabel use in food-producing animals of fluoroquinolone and glycopeptide antibiotics became effective on August 20, 1997.
FDA received 15 comments relating to this action. These comments and the analysis are available for review in the Public Reading Room of the Dockets Management Branch (HFA-305), Room 1-23, 12420 Parklawn Drive, Rockville, MD 20857, between 9 a.m. and 4 p.m., Monday through Friday. Questions about the order of prohibition and the analysis of comments may be directed to Richard L. Arkin, Center for Veterinary Medicine (HFV-6), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-827-0141.
VETERINARY FEED DIRECTIVE DRUGS
The category of Veterinary Feed Directive (VFD) drugs was authorized under the Animal Drug Availability Act of 1996. VFD drugs offer an alternative to prescription status, allowing veterinarian supervision of these types of drugs while enabling the feed industry to maintain current channels of commercial feed distribution. The determination of whether a product for use in feed will be approved as a VFD drug or as an over-the-counter (OTC) drug is made by the FDA's Center for Veterinary Medicine (CVM). CVM policy is that all new antimicrobials for therapeutic use in feed will be approved only as VFD drugs.
Before a VFD drug may be used, the veterinarian, working in conformance with the veterinarian-client-patient relationship, examines and diagnoses disease conditions and determines whether the condition warrants administration of a VFD drug. If so, the veterinarian issues a signed Veterinary Feed Directive. These are available on a preprinted multi-part form. The veterinarian then provides the form to the producer who orders the VFD feed from a feed supplier. A lawful VFD form is required to distribute VFD feeds to a producer. The veterinarian who issues a VFD, the producer, and the person or company supplying the VFD feed must retain copies of the signed VFD form.
Feed manufacturers and distributors that ship a VFD feed to a retailer or distributor for inventory must receive and retain a copy of a written acknowledgment, stating that the VFD feed will be further distributed only in accordance with FDA requirements. In addition,VFD drugs and any article or feed manufactured from them must include the following cautionary statements: "Caution: Federal law limits this drug to use under the professional supervision of a licensed veterinarian. Animal feed bearing or containing this veterinary feed directive drug shall be fed to animals only by or upon a lawful veterinary feed directive issued by a licensed veterinarian in the course of the veterinarian=s professional practice."
It is important to keep in mind that VFDs are only for approved animal drugs. In addition, the Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA), prohibits the extralabel use of approved animal drugs in feed. This prohibition applies to VFD drugs as well as OTC drugs.
WE WANT YOU -- TO REPORT ADVERSE DRUG REACTIONS
The following is a list of questions and answers related to the importance of reporting adverse drug reactions to the Center for Veterinary Medicine.
What is an ADE?
In common terms, an adverse drug experience (ADE) is either an undesired side effect, or the lack of a desired effect. The Center for Veterinary Medicine (CVM) defines an ADE as "any side effect, injury, toxicity, or sensitivity reaction (or failure to perform as expected) associated with use of an animal drug, whether or not determined to be attributable to the drug."
What are the FDA Center for Veterinary Medicine's specific areas of interest?
The primary purpose of our ADE monitoring system is to detect problems, or "side effects" associated with the use of FDA approved animal drugs. During the research studies that lead to drug approval, only a limited number of animals are treated. Because of this, effects or problems that only occur rarely may not be discovered until after the drug has been more widely marketed and used in a clinical setting.
Lack of effectiveness is an adverse experience. The majority of reports of this nature involve anesthetics, tranquilizers, and anthelmintics. These reports can be difficult to evaluate, but a group of similar reports will prompt further investigation.
CVM gives careful consideration to any reports of adverse experiences occurring in humans as a direct result of using or administering an animal drug or in other situations involving accidental human exposure.
Does CVM review reports that involve extra-label use of animal drugs?
The reporting of ADEs associated with extra-label use is important to the veterinary profession. Under the Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA), veterinarians can administer drugs more freely in an extra-label manner. About one-third of the reports on file involve extra-label use. We are also interested in ADEs involving human drugs used in veterinary practice, and in ADEs involving animal drugs marketed without FDA approval.
Who monitors reports of ADEs for products used to treat animals?
The FDA Center for Veterinary Medicine monitors reports of ADEs for animal drug products, medicated feeds, and animal devices under the Federal Food, Drug, and Cosmetic Act.
Animal vaccines and most biologics (e.g., rabies vaccines) are regulated by the United States Department of Agriculture (USDA) under the Federal Virus, Serum and Toxin Act.
Most of the products used topically for the control of ectoparasites and insects on animals are regulated by the Environmental Protection Agency (EPA) under the Federal Insecticide, Fungicide and Rodenticide Act.
The United States Pharmacopeia (USP) operates an independent, non-government reporting program called the Veterinary Practitioner's Reporting Program. USP will forward reports of ADEs to the appropriate regulatory agency and the drug company, at the discretion of the person reporting. This program has the support and endorsement of the American Veterinary Medical Association. The USP program is not affiliated with FDA.
Are there any laws that require reporting of ADEs?
Reporting by veterinary medical professionals is entirely voluntary. However, Federal regulations require that drug companies send FDA all information concerning adverse drug experiences reported to, or coming to the attention of, the company. Products regulated by USDA and EPA do not have the same reporting requirements as animal drugs.
Who submits these reports?
Roughly ninety-five percent of the reports are submitted by drug companies after learning of the adverse experience from a veterinarian or animal owner. The other five percent of reports are submitted directly to CVM by veterinarians and animal owners.
How many reports does CVM receive each year?
Veterinarians at CVM evaluate about two thousand reports annually. This estimate includes reports of product defects.
If I decide to report an ADE, who should I contact?
You should first call the drug company. Inform them that you wish to report an ADE, and ask to speak to a technical services veterinarian. The technical services veterinarian should ask a series of questions about the experience, complete a form called the FDA 1932, and forward the report to CVM. We suggest the drug company as your first point of contact because many companies will also offer clinical advice or diagnostic assistance. CVM does not provide these services. Drug company phone numbers can be obtained from the publications Compendium of Veterinary Products (North American Compendiums Inc.) and Veterinary Pharmaceuticals and Biologics (Veterinary Medicine Publishing Company).
If you wish to confirm that your report was forwarded, or prefer not to call the drug company, you can contact CVM directly at (301) 827-6643 or toll-free at (888) FDA-VETS. Please ask to speak to one of the veterinarians responsible for the ADE monitoring program. We can also provide a supply of prepaid mailers (Form FDA 1932a). These mailers are available by writing or telephoning CVM and are also distributed at veterinary medicine meetings and seminars.
If the ADE involves a product other than a drug, the following numbers may be useful. The phone number to reach USDA regarding biologics is (800) 752-6255. The phone number to reach EPA regarding topical insecticides is (800) 858-7378. A third option for reporting is the Veterinary Practitioners' Reporting Network (USP PRN) sponsored by the United States Pharmacopeia. The USP PRN program is an independent, non-government reporting program. The phone number to reach USP regarding any veterinary product is (800) 4-USPPRN.
What happens after I report an ADE?
Each ADE report is evaluated by a veterinarian and entered in a computer database. The reviewer assigns codes to items that describe the drug(s) and animal(s) involved. These items become separate fields of information. The reviewer also enters a brief clinical description of the ADE, and makes an assessment of whether the event is judged to be drug-related using an algorithm scoring system.
CVM publishes an annual summary of ADE reports. The summary provides the number of reports and the clinical signs associated with each drug in the database. The information is limited to those reports that were assessed as at least "possibly drug-related." The publication is available from the FDA Center for Veterinary Medicine.
Other information and reports from the database can be requested on an individual basis by filing a written Freedom of Information (FOI) request. For more information about filing a request, contact the CVM Communications Staff at (301) 594-1755.
What actions result from reports of ADEs?
A group of similar reports submitted in a short period of time may alert CVM and the drug company to a problem with a particular lot of drug. This may result in a product recall of the affected lot.
Another outcome would be for a label change to include new information gleaned from reported ADEs. The changes may include new warnings, contraindications or human safety information. In very rare instances, a drug may be removed from the market due to problems discovered by ADE reporting.
At times, CVM may require the involved drug company to issue a "Dear Doctor" letter to veterinarians informing them of the type of actions that had resulted from ADE reports.
Why should veterinarians in practice care about reporting an ADE?
Veterinarians in practice depend on the information available in drug labeling to make informed choices about the risk and benefits associated with the use of a drug. The purpose of ADE monitoring is to ensure that animal drug labeling is adequate and accurate.
In spite of the highest standards for safety and effectiveness that exist for FDA approval, not everything is known about a drug when it is first marketed. Due to the limited size and controlled nature of premarketing clinical trials, only the most common adverse events will be observed and included in product labeling at the time of FDA approval. An accurate safety profile emerges only after a product is marketed and the number and spectrum of animals receiving the drug increases.
As a practicing veterinarian, you are in a unique position to observe adverse clinical outcomes associated with the use of drug products. Some of these problems may only be associated with extra-label drug use. You can assist in the development of a complete safety profile by reporting adverse experiences. Such reports are often the first signal that a problem exists. By participating in the reporting program and contributing to our knowledge of animal drugs, you provide a valuable service to animals, the public, and your colleagues in the veterinary profession.
Where can I obtain information for a specific drug concerning potential adverse reactions?
The drug manufacturer is usually the best source for this type of information. Other sources include the FDA Center for Veterinary Medicine, the FDA/CVM Internet World Wide Web server (http://www.cvm.fda.gov/), the National Animal Poison Control Center and veterinary computer networks, such as VIN (America Online) and NOAH (Compuserve).
HONEY BEES -- MORE THAN JUST HONEY
This information was presented in a seminar at CVM's Animal Research Center by Ann Harman, a certified Master Bee Keeper. Mrs. Harman is retired from the National Bureau of Standards, and currently participates as a volunteer in the Overseas Cooperative Assistance Program to access the possibility of expanding apiculture in foreign countries as a viable agricultural market.
Honey is a natural, pure food product that is produced by bees in the United States as well as other countries around the world. Honey bees are extremely intelligent and productive little insects which thrive in colonies of 20,000 to 60,000 bees. The chemistry of the honey bee colony uniquely controls the number and activities of the individuals. Beekeepers maintain colonies in wooden hives which can be transported to field sites for the pollination of food crops and the collection of honey. The primary use of the honey bee is actually for pollination of crops rather than the production of honey. One-third of our food supply is dependent, either directly or indirectly, on the honey bee. Almost no wild bees are left at this time, and growers are having difficulty finding enough beekeeper-managed colonies for pollination.
The products of the hive fall into two groups: plant products, which are substances produced by plants and simply collected by the bees with little or no change in composition, and products of the bee. The plant products are honey, pollen, and propolis. The products of the bee are beeswax, royal jelly and venom. Honey is the bees' carbohydrate food; pollen provides protein, vitamins and minerals in the bees' diet; propolis is plant resins gathered by the bee for caulking and waterproofing. Beeswax is turned into honeycomb for the storage of food and cells for raising bees; royal jelly is the food for the developing larvae and for the queen; venom makes an effective defense of the colony for its food and young. The number of chemical compounds contained in these products is very large and quite varied.
To produce honey, the bees visit flowers to obtain nectar, a dilute sugar (sucrose) solution. During transport to the hive the bees add an enzyme, invertase, to convert the sugar to the simple sugars of glucose and fructose. The bees then simply evaporate water from the nectar and when the concentration reaches about 18.6 percent water it can be considered honey. At this point the honey is capped with beeswax. The plants used by the bee are responsible for the characteristic colors and flavors of honey.
Contamination of honey can occur in several ways:
a. Spraying field crops with pesticides
b. Microencapsulated pesticides used on field crops
c. Medicines used by the beekeeper
Pesticides are usually lethal to the bees thus preventing them from contaminating the honey.
Unfortunately, two parasites are causing the death of bee colonies. These are tracheal and varroa mites. The mites can be kept in check through the use of medicines. Although these may be thought of as a source of contamination, good beekeeping practice should prevent that. For tracheal mites, menthol is used once a year, but menthol is present in many honeys, principally those from the very common mint family blossoms. Grease patties, made from granulated sugar and Crisco are used year-round but these are considered trash by the bees and removed from the hive, never stored as honey is stored. For Varroa mites, a twice-a-year treatment with fluvalinate-impregnated plastic is used. This is a contact miticide that is most effective in late autumn after nectar gathering has ceased. A second treatment can occur in early spring before surplus honey is being stored.
The only other medication used for bees is oxytetracycline. The commercial formulation is "Terramycin" which is normally used for treating domestic animals. For bee colonies affected by American foulbrood, Terramycin is a useful method of control, but does not provide a cure for this devastating disease of honey bees. The bee hive should not be medicated during the summer months when honey is being produced and stored in the honeycomb.
In the January/February 1998 FDA VETERINARIAN, the article titled "REGULATORY ISSUES IN AGRICULTURAL BIOTECHNOLOGY" by G.A. Mitchell, D.V.M., C. Haley, Ph.D., M. Miller, Ph.D., J. Matheson, and W.D. Price, Ph.D. contained the following two incorrect Internet citations: http://vm.cfsan.fda.gov/-lrd/consulpr.html, and http://vm.cfsan.fda.gov/-lrd/biocon.html. The correct citations are:
http://vm.cfsan.fda.gov/~lrd/consulpr.html and http://vm.cfsan.fda.gov/~lrd/biocon.html. We apologize for this error.
WARNING ON CONTAMINATED VETERINARY DRUGS
The Food and Drug Administration issued a national warning against the use of all large volume parenteral drugs distributed by Veterinary Pharmaceuticals, Inc., (VPI) of Hanford, California, and manufactured by its subsidiary, Sierra Pharmaceuticals, Inc., of Mexicali, Mexico. The company has recalled these drugs, commonly used to treat dairy cows, because they are contaminated with bacillus cereus bacteria -- bacteria that can cause severe injury and death in cows.
The Agency urges anyone who has these products on hand to immediately stop using them. The Agency has also issued an Import Alert to prevent the importation of these products. FDA analyses show that samples of the following drugs manufactured by this company are contaminated with bacillus cereus bacteria or related bacteria species:
Hypertonic Saline Solution
Lactated Ringer's Solution
Calcium Gluconate 23% Solution
Dextrose Solution 50%
Electrolyte Solution w/ Dextrose
Caldex CMPK
Sterile Water for Injection
Vitamin B Complex
Vitamin B Complex Fortified
Since Sierra Pharmaceuticals used common equipment, manufacturing practices, and controls for the above drugs and all other large volume parenteral products it manufactured, all large volume parenteral veterinary drugs manufactured by Sierra Pharmaceuticals, Inc., and distributed by Veterinary Pharmaceuticals Inc., are covered by this warning.
Those who may have existing stocks of these drugs should contact the distributorship from where they were purchased for instructions on what to do with these products. Purchasers may also want to consult their veterinarians if they have treated any cows with these products.
In the December 30, 1997 Federal Register, FDA published a notice stating that the Agency is withdrawing approval of a new animal drug application (NADA 100-903) which provided for use for chlortetracycline Type A medicated articles to make Type B or Type C medicated feeds. This NADA was held by Hoffman-La Roche, Inc. The sponsor requested the withdrawal of approval because the product is no longer being manufactured or marketed
The following firms/individuals received warning letters for offering animals for slaughter that contained illegal drug residues:
Alfred C. Bairos, DeSimas and Bairos Dairy, Oakdale, CA
Antonio M. Cabral, Galt, CA
Daniel T. Aprile, Aprile Farms, Inc., Temple Terrace, FL
Douglas Weaver, Columbiana, OH
Gary J. Van Der Geest, Van Der Geest Dairy Cattle, Inc., Merrill, WI
Greg D. Hooker, Diamond H. Dairy, Escalon, CA
James Heida, Milky Way Dairy, Escalon, CA
John D. Whiting, New Wilmington Slaughterhouse, New Wilmington, PA
Loek Van Wamerdam, Nicolaus, CA
Manuel Goncalves, Dos Palos, CA
Paul H. Codorniz, Codorniz Dairy, Tulare, CA
Peter J. DeJong, Bakersfield, CA
Petrissas Dairy, Bakersfield, CA
Sylvester Vander Tuig, Jay Vander Tuig Dairy, Strathmore, CA
Tony C. Mello, Buena Vista Dairy, Tulare, CA
Tony Dutra, Dutra Farms, Manteca, CA
William Tolsma, Cal Chris Holsteins, Turlock, CA
These violations involved illegal residues of penicillin in cows, sulfadimethoxine in dairy cows, tetracycline in a cow, gentamicin in a calf, tilmicosin in a dairy cow, sulfadimethoxine in a calf, gentamicin in a dairy cow, oxytetracycline in a cull dairy cow, oxytetracycline in a calf, tetracycline in a calf, and gentamicin and sulfamethoxazole in a cull dairy calf.
Warning letters were sent to the following firms/individuals for violations from GMPs:
Arthur W. Huguley IV, Westway Trading Corporation, New Orleans, LA
Raymond Gerringa, Carbon County Cattle Co., Boyd, MT
Thomas A. Ewing, ASAS, Inc., St. Paul, MN
William R. Cammack, C&H Chemical, St. Paul, MN
| Company | Generic and (Brand) Names | Indications | Routes/Remarks |
| Pfizer, Inc. (NADA 141-095) | Doramectin (Dectomax®) | Cattle. For treatment and control of certain worm, grub, lice, and mite infections. | TOPICAL: Provides for 0.5 percent pour-on solution for beef cattle and female dairy cattle less than 20 months of age. Federal Register 12/16/97. |
| Schering-Plough Animal Health Corp. (NADA 141-071) | Imidocarb Dipropionate (Imizol®) Rx | Dogs. For treatment of babesiosis. | INJECTABLE (SUBCUTANEOUS OR INTRAMUSCULAR): Provides for use of 120 mg/ml injectable solution to provide for using 6.6 milligrams imidocarb per kilogram (3 milligrams per pound) of body weight. Repeat the dose after 2 weeks for a total of two treatments. Do not use simultaneously with or a few days before or after treatment with or exposure to cholinesterase-inhibiting drugs, pesticides, or chemicals. Federal Register 12/23/97. |
| Pfizer, Inc. (NADA 141-066) | Semduramicin and Roxarsone | Broiler Chickens. To prevent coccidiosis. | MEDICATED FEED: Provides for using approved single ingredient Type A medicated articles containing Aviax™ (semduramicin sodium, 22.7 grams per pound) and 3-Nitro (roxarsone, 45.4, 90, and 227 grams per pound) to make combination drug Type C medicated broiler chicken feeds containing 22.7 grams per ton of semduramicin and 45.4 grams per ton roxarsone. Federal Register 12/23/97. |
ABBREVIATED NEW ANIMAL DRUG APPROVALS
| Company | Generic and (Brand) Names | Indications | Routes/Remarks |
| Alpharma, Inc. (ANADA 200-212) | Robenidine and Bacitracin Zinc | Broiler Chickens. For prevention of coccidiosis, increased rate of weight gain, and improved feed efficiency. | MED. FEED: ANADA 200-212 is a generic copy of Hoffmann-LaRoche, Inc.'s NADA 96-933. Federal Register 12/23/97. |
| Alpharma, Inc. (ANADAs 200-209 and 200-215) | Salinomycin, Bacitracin Zinc, and Roxarsone | Broiler Chickens. For prevention of coccidiosis, increased rate of weight gain, and improved feed efficiency. | MED. FEED: ANADA 200-209 is a generic copy of Hoechst-Roussel Vet's ANADA 200-143. ANADA 200-215 is a generic copy of Hoffmann-LaRoche, Inc.'s NADA 139-190. Federal Register 12/23/97. |
| Alpharma, Inc. (ANADA 200-217) | Amprolium Plus Ethopabate, with Bacitracin Zinc and Roxarsone | Broiler Chickens raised in floor pens. As an aid in the prevention of coccidiosis and increased rate of weight gain. | MED. FEED: ANADA 200-217 is a generic copy of Swisher Feed Div.'s NADA 39-284. Federal Register 12/23/97. |
| Alpharma, Inc. (ANADA 200-206) | Decoquinate and Bacitracin Zinc with Roxarsone | Broiler Chickens. For prevention of coccidiosis, increased rate of weight gain, and improved feed efficiency. | MED. FEED: ANADA 200-206 is a generic copy of Rhone Poulenc Inc.'s NADA 91-326. Federal Register 12/24/97. |
| Alpharma, Inc. (ANADA 200-213) | Decoquinate and Bacitracin Zinc | Broiler Chickens. For prevention of coccidiosis, increased rate of weight gain, and improved feed efficiency. | MED. FEED: ANADA 200-213 is a generic copy of Rhone Poulenc Inc.'s NADA 45-348. Federal Register 12/19/97. |
| I.D. Russell Co. Labs (ANADA 200-189) | Lincomycin Hydrochloride Soluble Powder | Swine and Broiler Chickens. In swine for treatment of dysentery (bloody scours). In broiler chickens for control of necrotic enteritis. | ORAL (MED. DRINKING WATER): ANADA 200-189 is a generic copy of Pharmacia & Upjohn's NADA 111-636 for Lincomix™ Soluble Powder. Federal Register 12/10/97. |
| Hoffmann-La Roche, Inc. (ANADA 200-140) | Chlortetracycline, Sulfathiazole, and Penicillin | Swine. For reduction of incidence of cervical abscesses, treatment of bacterial enteritis, maintenance of weight gain, increased rate of weight gain, and improved feed efficiency. | MED. FEED: ANADA 200-140 is a generic copy of Boehringer Ingelheim's NADA 39-077. Federal Register 12/30/97. |
| Hoffmann-La Roche, Inc. (ANADA 200-167) | Chlortetracycline, Sulfathiazole, and Penicillin | Swine. For reduction of incidence of cervical abscesses, treatment of bacterial enteritis, maintenance of weight gain, increased rate of weight gain, and improved feed efficiency. | MED. FEED: ANADA 200-167 is a generic copy of Boehringer Ingelheim Animal Health, Inc.'s NADA 39-077. Federal Register 1/15/98. |
SUPPLEMENTAL NEW ANIMAL DRUG APPROVALS
| Company | Generic and (Brand) Names | Indications | Routes/Remarks |
| Lloyd, Inc. (NADA 140-921) | Prednisolone Tablets | Dogs. For use as an anti-inflammatory agent. | ORAL. This provides for use of a 20 milligram prednisolone tablet in addition to the currently approved 5 milligram tablet. Federal Register 1/5/98. |
| Hoffmann-LaRoche, Inc. (NADA 128-686) | Salinomycin (Bio-Cox®) | Broiler, Roaster, and Replacement Chickens, and Quail | MED. FEED: The supplement provides for use of a 60-grams per pound salinomycin Type A article in addition to the currently approved 30-grams per pound product. Federal Register 2/10/98. |
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