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January/February 1998, Volume XIII, No. I, FDA Veterinarian Newsletter

 

FDA PUBLISHES SUBSTANTIAL EVIDENCE PROPOSED RULE

FDA PUBLISHES SUBSTANTIAL EVIDENCE PROPOSED RULE

In the November 5, 1997, Federal Register, FDA published a proposed regulation to amend the definition of substantial evidence of effectiveness of new animal drugs. The purpose of this proposed regulation is to encourage the submission of new animal drug applications (NADA's) and supplemental NADA's for single ingredient and combination new animal drugs. The proposal also encourages dose range labeling. The proposed rule implements, in part, the Animal Drug Availability Act of 1996, which amended the Federal Food, Drug, and Cosmetic Act to provide for improvements in the process of approving and using animal drugs, and for other purposes.

The Federal Register notice for this proposed rule is available for review or downloading on CVM's Internet Website at http://www.fda.gov/cvm. Paper copies are available from the FDA Veterinarian.

Written comments on the proposed rule must be submitted by February 3, 1998. All comments should be sent to the Dockets Management Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Drive, Room 1-23, Rockville, MD 20857. Please identify comments with the Docket Number 97N-0435.

Questions about this rule may be directed to Herman M. Schoenemann, Center for Veterinary Medicine (HFV-126), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-594-1638.

 

UPDATE ON DRUG APPROVALS IN FY 97

The Center for Veterinary Medicine announced 102 new animal drug-related approvals for Fiscal Year 1997 (FY 97), up from 80 in FY 96.

Thirty-seven (37) of these approvals were for generic drugs. Seven (7) approvals were for new species, and one was for new minor species, in this case sheep. Nine (9) approvals were for new production class, 6 were for new chemical entities, 2 new formulations, 3 DESI-finalizations, 2 new tolerances, 1 new combination, 6 new indications, and 2 new routes. CVM classifies 76 of the 102 approvals as "significant" new animal drug approvals. The Center defines as "significant" those approvals involving new chemical entities (first time for use in animals), new species, new indications, new combinations, new tolerances, generic drugs, minor species, new production classes, and DESI-finalizations. For FY 96, CVM had 66 "significant" approvals out of 80 new animal drug approvals.

The new chemical entities approved in FY 97 included the ones listed in the table below.

A complete list of all FY 97 animal drug approvals is available from the FDA Veterinarian.

 

Drug
(Trade Name)		 Species Sponsor NADA Number
Carprofen Dogs Pfizer 141-053
Propofol Dogs Mallinckrodt 141-070
Fomepizole Dogs Orphan Medical 141-075
Eprinomectin Cattle Merck 141-079
Selegiline Hydrochloride Dogs Deprenyl Animal Health 141-080
Orbifloxacin Dogs Schering Plough 141-081

APPLYING PHARMACOKINETICS IN VETERINARY PHARMACEUTICALS REGULATION
by Marilyn N. Martinez, Ph.D.

Pharmacokinetics is the study and characterization of the time course of drug concentrations within the body. These concentrations are a function of drug absorption, distribution, metabolism, and excretion (ADME). In turn, each of these variables is a function of a drug's physico-chemical properties and patient physiology. Thus, pharmacokinetics is a science that integrates mathematics, biochemistry, physiology, and pharmacology.

Clinical pharmacokinetics deals with the application of pharmacokinetic principles to the safe and effective therapeutic management of patients. It examines the relationship between pharmacokinetic processes and the intensity and time course of a clinical response. With the advent of clinical pharmacokinetics, practitioners have acquired a tool for individualizing dosage regimens to accommodate interpatient variability in dose/systemic drug concentration/drug response. For an excellent review on this subject, readers may consult an article by Peck, et al., in Pharm. Res., 1992;9:826-833.

Within the Center for Veterinary Medicine (CVM), pharmacokinetic study data have been submitted to meet a broad range of objectives. These include:

For the most part, the fundamental study objectives of CVM pharmacokinetic studies parallel those encountered by the Agency's human drug counterpart. Accordingly, many of the tenets governing the evaluation of these pharmacokinetic studies are comparable across FDA Centers. However, the very nature of veterinary medical practice necessitates differences between the types of pharmacokinetic studies submitted in support of veterinary versus human drug applications. Some of the unique aspects of veterinary pharmacokinetic submissions include:

The incorporation of pharmacokinetic principles into the regulation and labeling of veterinary pharmaceuticals affords a tremendous improvement in animal health care. It can be used to guide the practitioner in choosing the most effective and economic dosage regimen. In this age of the Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA), pharmacokinetics allows CVM to develop alternative approaches to drug regulation and, through an understanding of the kinetics of dose-ranged products, enables CVM to provide practitioners with the guidance needed to assure a safe and abundant food supply.

 

QUALITY STANDARDS FOR THE MANUFACTURE OF ANIMAL DRUGS -- A REPORT FROM VMAC
by Richard E. Geyer, Esq. Deputy Director, CVM Office of Surveillance and Compliance, Executive Secretary, VMAC

INTRODUCTION

In recent years, FDA's Center for Veterinary Medicine has engaged in extensive discussions with the animal drug industry and the veterinary profession regarding the Agency's drug manufacturing requirements. Some have contended that those requirements unnecessarily limit the availability of approved animal drugs because of their effect on the cost of manufacturing the drugs. Concern has also been expressed about the procedures the Agency follows in establishing, communicating, and applying the requirements. The issues relate to drug quality standards, which are implemented through chemistry, manufacturing and control (CMC) information submitted in new animal drug applications. The issues also involve interpretation of the Agency's current good manufacturing practice (CGMP) regulations, which are pertinent prior to approval but become especially significant in the post-approval context.

Drug quality issues have a pivotal role in CVM's mission. Because of this, and because this area has been characterized by controversy, the Center decided to obtain independent advice from the Veterinary Medicine Advisory Committee (VMAC). The committee and several consultants met in May, 1997 to listen to presentations from the Center for Veterinary Medicine and other FDA components, the Animal Drug Alliance, the Animal Health Institute, the American Veterinary Medical Association, and other organizations. The committee and consultants met again in November, 1997 to make recommendations on five specific issues related to animal drug manufacturing standards.

Summary of VMAC Comments

Following is a brief summary of the committee's comments on each of the issues. A more complete summary will appear in the official minutes of the November meeting, which will be available on CVM's Internet Home Page (http://www.cvm.fda.gov/) and through FDA's Freedom of Information Office (FDA, FOIA Staff, 5600 Fishers Lane, HFI-35, Rockville, MD 20855.)

ISSUE: When CVM decides whether to adopt a particular drug quality standard, should it weigh the benefits against the costs of adopting, or not adopting, the standard? If so, how should such benefits and costs be assessed? What factors should be considered?

The committee consensus was that CVM should weigh the benefits against the costs when it makes decisions on drug quality standards, but that in doing so it should not reduce drug safety, effectiveness and quality. The committee also concurred that drug availability should be considered when the Center makes drug manufacturing decisions. The committee emphasized that use of FDA-approved drugs is preferred over use of unapproved drugs. Several members stated that when CVM decides whether to adopt a particular drug quality standard, there should be an internal process for consideration of information that reflects costs and benefits related to that standard. Several members also stated their understanding that CVM is currently making an effort to consider costs and benefits, especially concerning the availability of a drug to treat a disease for which no approved drug exists.

ISSUE: Should CVM tailor its interpretation and application of quality standards in the regulation of drugs for minor uses and minor species? If so, what are the factors that most directly impact on the decision as to how to tailor the interpretation or application?

The committee generally agreed that CVM should tailor its interpretation and application of quality standards in the regulation of drugs for minor uses and minor species. The factors that most directly impact on the decision as to how to tailor the interpretation or application should include: species or species involved, e.g., human food safety needs to be considered in the case of drugs for use in food animal species; the availability of alternative drugs; the effects of applying current or alternative standards on cost, quality, and safety; availability of sponsors to manufacture and market the drug; size of the population of animals involved, and the likely percentage of the population to receive the drug; economic importance to the producer and consumer groups; and potential extralabel use of the drugs.

ISSUE: Can sterility validation be reduced without increasing the risk of microbiological contamination?

This is an important issue because of the belief by some that current sterility validation requirements establish higher standards than necessary to assure that drugs are not contaminated during the manufacturing process. On the other hand, CVM representatives told the committee that it has already substantially reduced the validation data required for the manufacture of animal drugs; that the Center currently relies on minimal data for such products; but that the Center is willing to review data that would support further reduction in the requirements.

Generally, the committee concluded that it did not have enough information, e.g., on the incidence of problems occurring as a result of different levels of sterility validation, to provide a basis for specific advice as to changes. However, several members concluded that CVM's current direction and standards are acceptable. Others suggested that requirements could be reduced somewhat in light of drug availability needs and the absence of reported problems due to lack of sterility. Several members stated that CVM should provide the maximum flexibility in evaluating the validation processes, accepting new data from firms which show that they can meet or exceed the current standards.

ISSUE: Should CVM change its administrative review process for adopting new drug quality standards to provide for review by the Center Director?

The committee supported the concept that CVM's following the Agency's Good Guidance Practices would alleviate concern about adoption of policy without review at the highest levels in CVM. Most committee members stated the opinion that review at the Office level in CVM would be sufficient. Additional views expressed included the following: The Center Director is expected to be aware of sensitive issues in policy that are under development and, in any event, should have the right to review any given policy document; the review process within CVM should provide for careful and thoughtful review of proposed policies; and the policy review process should not be so cumbersome that approvals are held up.

ISSUE: Should a process be developed that would involve representatives from the animal health industry and its regulators, to review and identify inconsistencies in the application and interpretation of quality standards for animal drug manufacturing and to prioritize the identified issues? Or are current mechanisms sufficient to meet the need for communication between FDA (headquarters and field) and industry?

CVM personnel listed a number of CVM initiatives in recent years involving communication with the drug industry on manufacturing issues. Industry representatives stated that they believe that there is now adequate means for communication between industry and CVM. Based on these statements and the adoption of the Good Guidance Practices, the committee concluded that existing mechanisms are adequate to provide for communication, and that a new process is not needed.

One of the committee members summarized his view of the November meeting as follows: The committee does not expect to see any lowering of the quality standards, or reinterpretation of what is required by the CGMPs in the manufacture of animal drugs. FDA will communicate more, both internally and externally. And the Agency will be more flexible in its interpretation of methods and processes. But, the committee still expects that safety, quality and effectiveness will be the highest points of the Center's considerations.

Additional Issues Raised in May, 1997

Additional issues, besides the five addressed by VMAC in the November meeting, were raised in the May meeting. At the November meeting, Dr. Stephen F. Sundlof, CVM Director, presented an overview of all the issues raised in the May meeting. He also summarized CVM's response to issues raised in May but not included in November's discussion. Among the topics he addressed were:

Conclusion

CVM will take VMAC's advice, and the entire record of the May and November meetings, into consideration as it makes decisions in the drug manufacturing area. The outcome of future deliberations, within the Center and the Agency, could include changes in policy, new guidance documents, new partnership arrangements with industry, positions on proposed legislative changes and the like. The Center intends to respond as fully as it can to the significant drug manufacturing issues that the animal drug industry, and the veterinary profession, have raised in recent years.

Dr. Sundlof stated that CVM places great importance on the availability of approved animal drugs to meet the needs of veterinary medicine. At the same time, CVM is very conscious of the need to meet statutory standards for drug quality.

 

GOOD GUIDANCE PRACTICES
by Carol Haley, Ph.D.

Written guidance, in the form of "guidelines", compliance policy guides, "question and answer documents", letters, etc., help FDA staff, regulated industry, and the field offices keep abreast of changing policies. Guidance can be used for a variety of purposes, such as explaining new regulations, conveying a change in policy about regulatory discretion for a class of products, or explaining how reviewers evaluate studies submitted in support of new animal drug applications. Obviously, guidance is meant to be helpful. Unfortunately, confusion about how guidance can be used led the Indiana Medical Devices Manufacturers Council to file a citizen petition with FDA and to bring the matter up with Congress in 1995. The industry felt that FDA misused guidance and that guidance document development needed improvement. FDA's eventual response to these concerns was the publication of its policy regarding "Good Guidance Practices" (GGPs) in the Federal Register on February 27,1997.

The GGP policy was developed to ensure that FDA addressed the main concerns expressed by regulated groups and others who commented on FDA's use of guidance. The policy requires that guidance 1) not be applied as legally binding requirements, 2) be developed with adequate public participation, and 3) be readily available to the public. FDA staff are expected to abide by GGPs, and the policy states that staff involved in the development of guidance must receive training in GGPs.

The Good Guidance policy stresses that guidance documents are not legally binding on the public or the Agency. A guidance document represents the Agency's current thinking on the subject discussed in the document. Because guidance documents are not legally binding, FDA staff or industry may deviate from a guidance document with appropriate justification. FDA staff must get supervisory concurrence before they deviate from a guidance document.

FDA staff who are developing guidance are strongly encouraged to find ways to get as much public input as possible. Public participation in the development of guidance can take a number of forms, including workshops and meetings. In addition, a two-tiered system ensures that certain types of guidance documents (e.g., those that deal with highly controversial issues or are first interpretations of regulations), called Level 1 guidance, be made available for public comment before they are implemented. A notice of availability of the draft document will be placed in the Federal Register, and comments will be sent to the Dockets Management Branch of FDA. Level 1 guidances may be implemented without prior public comment in certain special circumstances, for example, if there is a public health reason for immediate implementation.

Other guidances are called Level 2 guidance and may be implemented without prior public input. However, the public may comment on both Level 1 and Level 2 guidances at any time after implementation.

The Good Guidance Practice policy requires Centers to make all their guidance documents available to the public. Also, FDA will maintain a list of all guidance documents on its homepage and regularly publish in the Federal Register a list of new guidance documents and a list of guidance documents that have been withdrawn.

The public is welcome to request new guidances or revisions of old guidances at any time. Periodically, FDA will publish in the Federal Register a list of possible topics for guidance document development or revision during the next year. The agency will request comment from the public on this list.

GGPs should help the Agency develop guidance that is more useful to all its customers and ensure that the public has ready access to guidance documents.

 

REGULATORY ISSUES IN AGRICULTURAL BIOTECHNOLOGY

This information was presented at the Conference on Urban/Rural Environmental, Food, and Agricultural Issues: Problems and Solutions for the Next Generation at California State Polytechnic University, Pomona, California, on November 14, 1997. Remarks were prepared by G.A. Mitchell, D.V.M., C. Haley, Ph.D., M. Miller, Ph.D., J. Matheson, and W.D. Price, Ph.D.

Under the provisions of the Federal Food, Drug, and Cosmetic Act (FFDCA), in part, the Secretary of HHS promotes honesty and fair dealing in the interest of consumers through regulations that establish specifications and quality standards for food intended for man or animal. Food is considered adulterated, in part, if it bears or contains any poisonous or deleterious substance which may render it injurious to the health of man, animals, or the environment. A food is also misbranded if its labeling is false or misleading in any particular, for example, if it is offered for sale under the name of another food.

The genetic modification of food-producing animals to produce a human biologic (e.g., vaccine) or human or animal drug; or to optimize the nutritional value of derived food products; or to increase growth rate, reproduction, or resistance to disease can fall under the provisions of the FFDCA.

Biological products for administration to animals are regulated under the Virus, Serum, Toxins Act (VSTA). This act was recently amended and the final regulations implementing the amendments were published in the June 9, 1997 Federal Register (62 FR 31326).

The Environmental Protection Agency regulates pesticides used in or on food or feed under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the FFDCA and controls the use of certain genetically engineered microorganisms under the Toxic Substances Control Act (TSCA).

The environmental safety of the field testing of most genetically engineered plants is regulated by the Animal and Plant Health Inspection Service (APHIS) under the authority of the Federal Plant Pest Act and the Plant Quarantine Act.

The USDA Food Safety and Inspection Service (FSIS) is responsible for ensuring the safety, wholesomeness, and accurate labeling of meat, meat food products, and poultry products under the Federal Meat Inspection Act and Poultry Products Inspection Act.

The FDA regulates drugs for use in animals. The FFDCA defines "drugs" to include, among other things, articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases in man or other animals; and articles (other than food) intended to affect the structure or any function of the body of man or other animals. Articles that are used to improve animal performance, such as increased rate of gain and improved feed efficiency, are "drugs" under the FFDCA. Section 902(c) of the FFDCA states that nothing in the FFDCA shall affect, modify, repeal, or supersede the provisions of the VSTA. FDA regulations under 21 U.S.C. 510.4 provide that an animal drug produced in full conformance with the VSTA will not be subject to the new animal drug approval requirements of the FFDCA.

Under the VSTA, the term "biological products," also refers to biologics, biologicals, or products, and shall mean all viruses, serums, toxins (excluding substances that are selectively toxic to microorganisms, e.g., antibiotics), or analogous products at any stage of production, shipment, distribution, or sale, which are intended for use in the treatment of animals and which act primarily through the direct stimulation, supplementation, enhancement, or modulation of the immune system or immune response. The term "biological products" includes, but is not limited to vaccines, bacterins, allergens, antibodies, antitoxins, toxoids, immunostimulants, certain cytokines, antigenic or immunizing components of live organisms, and diagnostic components, that are of natural or synthetic origin, or that are derived from synthesizing or altering various substances or components of substances such as microorganisms, genes or genetic sequences, carbohydrates, proteins, antigens, allergens, or antibodies.

Analogous products shall include:

(i) Substances, at any stage of production, shipment, distribution, or sale which are intended for use in the treatment of animals and which are similar in function to biological products in that they act, or are intended to act, through the stimulation, supplementation, enhancement, or modulation of the immune system or immune response; or

(ii) Substances, at any stage of production, shipment, distribution, or sale, which are intended for use in the treatment of animals through the detection or measurement of antigens, antibodies, nucleic acids, or immunity; or

(iii) Substances, at any stage of production, shipment, distribution, or sale which resemble or are represented as biological products intended for use in the treatment of animals through appearance, packaging, labeling, claims (either oral or written), representations, or through any other means.

The term "treatment" shall mean the prevention, diagnosis, management, or cure of diseases of animals.

It is now recognized in the scientific literature that the generation of stimulation of an immune response involves both antigens and certain protein regulatory factors referred to as cytokines. Some cytokines (e.g., interleukins) serve as essential components in the generation and expression of an immune response, without which the vaccine would be worthless. These cytokines may be elicited through stimulation with antigens or certain "immunomodulators". Cytokines are also produced in many body tissues and act on cell types other than those of the immune system. Cytokines of natural or synthetic origin can be prepared as products for administration to animals. Because of the diverse biological activity of the cytokines, not all products consisting of these substances would be regulated under the VSTA. Many of these cytokines intended to be used as drugs would fall under the jurisdiction of the Food and Drug Administration. In such instances, the VSTA would not apply.

Both cytokines and immunomodulators are analogous to biological products when they are used to stimulate, supplement, enhance, or modulate the immunity of animals in the treatment of disease. Products consisting of these substances that work through these immune mechanisms in the treatment of specific disease appropriately fall within the definition of "biological products".

In summary, when a cytokine modulates or stimulates an immune response in a way that is similar to that of a vaccine, bacterin, allergin, antibody, antitoxin, toxoid as outlined in the definition of a biological product the cytokine product will be regulated under VSTA. In the event that the natural or synthetic cytokine has activity which would extend beyond a single disease organism, the product would be regulated under the FFDCA.

FDA is the primary agency responsible for the regulation of food products intended for human consumption, except for meat and poultry. FDA has responsibility for the safety of milk and dairy products, fish and shellfish and animal drug products. To date, FDA has not published a formal policy statement on how the FFDCA applies to the regulation of new gene transfer technologies when applied to food-producing animals.

The FFDCA defines drugs, as described above, based upon their functional claims rather than their chemical structure or manufacturing source and thus, some transgenic animals will be regulated, in certain respects as a drug, under the animal drug provisions of the FFDCA. Most of the transgenic animal experiments conducted to date involve the introduction of the genetic material into the germ line or somatic cells. When the genetic material is introduced into somatic or germ cells to produce phenotypic change that meets the definition of a drug in the animal or its offspring, the expressed drug product would be considered to be a new animal drug. On the other hand, when a genetic procedure is used to map the genome, and phenotypic change is achieved through traditional breeding, it would not be considered to be a new animal drug.

The following material is taken from "Food Safety Evaluation of Transgenic Animals," in Transgenic Animals Generation and Use, edited by Louis Marie Houdebine:

"To date, the biotechnology products approved by CVM have been proteins produced by recombinant DNA technology using a bacterial fermentation system. The desired gene is isolated and fused with plasmid DNA. The recombinant plasmid is cloned or inserted into a gram negative bacterial host, usually Escherichia coli. Under fermentation conditions, these transformed microorganisms become factories which produce large quantities of the protein hormone at relatively low cost. The protein product is isolated and purified from the bacteria. When treated under defined conditions, the product assumes a conformation which is biologically active. In many respects, the production of recombinant protein hormones is not substantially different from the production of other new animal drugs made by the more traditional fermentation processes.

The food safety evaluation for recombinant protein hormones is similar to that performed for other protein products approved as animal drugs. On the other hand, the toxicology studies conducted to demonstrate the human food safety of protein products are considerably different from drug products. With the consent of the drug's sponsors, CVM has published a comprehensive review of the food safety evaluation for bovine somatrotropin describing the studies required for this recombinant protein hormone product (Guyer and Juskevich, 1990).

The statutory food safety requirements for animal drug residues in genetically modified animals are the same as those for other animal drugs. Basically, the food products produced from genetically modified animals must be as safe as those from nontransgenic animals; and the sponsor of the transgenic animals must demonstrate safety of the animal products before the animal can enter the food supply. The standard battery of toxicology studies used to establish the safety of "traditional" animal drugs are not appropriate for assessing the safety of a transgene in genetically modified animals. Also, the "traditional" withdrawal period may not apply to transgenic animals. Although it may be possible to "turn-off" the expression of the transgene, and thereby limit exposure to the expression product; it will not eliminate the transgene from the animal. In cases where there are food safety concerns for the expression products and not the transgene, a tolerance approach could apply.

Biopharm animals have been genetically modified to manufacture a human or veterinary drug, biologic, a food additive, or other product of commercial value. The substance is then harvested from milk, blood or other tissue of the biopharm animal. The genetic modification can be a germ line, heritable modification, or a somatic cell or gene therapy involving the introduction of the modified genes into cells of a particular tissue of an individual. The main emphasis of these efforts is on harnessing the metabolic capabilities of the animal to produce a product in lieu of using, for example, chemical synthesis, fermentation, or extraction from a dilute natural source.

Transgenic animals may also be modified to include food or color additives intended to affect the quality of animal-derived human food. Examples might include cattle that produce more nutritionally complete milk, fish that produce more omega-3 fatty acids, or trout with pink muscle tissue.

In summary, many of the product claims being anticipated for transgenic animals, for example, improved growth, improved feed efficacy, improved carcass characteristics, and improved disease resistance, are the same as animal drug claims. Any regulation of transgenic animals under the FFDCA will require demonstration of human food safety. The food safety evaluation under the animal drug provisions of the FFDCA is science-based and its inherent flexibility can accommodate the additional products and animals carrying or sold with animal drug claims."

In respect to genetically engineered plants, on June 26, 1986, FDA published a coordinated framework for the regulation of biotechnology in the Federal Register (FR). It stated the intention by FDA to regulate foods and feeds that are produced by rDNA technology under existing laws and regulations. The FR indicated that, in some instances, whole food derived from a new plant variety including a food from a genetically modified plant might fall within the scope of a food additive. FDA received comments requesting clarification of the regulatory status of foods such as, fruits, vegetables, grains, and byproducts from plants developed by use of rDNA technology.

FDA reviewed the comments and published the FR Notice entitled "Statement of Policy: Food Derived from New Plant Varieties" on May 29, 1992. This statement laid out the issues that individuals should consider during the development of new plant varieties including those using rDNA techniques. FDA noted in its response that the safety of a food is regulated primarily under its post-market authority in Section 402(a)(1) of the FFDCA. It also stated that it is the transferred genetic material and the expression product that might be subject to the food additive regulations, if they are not generally recognized as safe (GRAS). It further stated that the Notice was being published to ensure that the relevant scientific, safety, and regulatory issues are resolved prior to the commercial sale of the products.

After the publication of the policy, the Center for Food Safety and Applied Nutrition (CFSAN) and the Center for Veterinary Medicine (CVM) developed a document to outline the consultation process for a developer of a new plant variety to follow in consulting with the Agency about the safety and regulatory issues prior to the marketing of the new product. Typically, the developer initiates dialog with FDA and then can submit summary information about the safety and nutritional assessment of each plant transformation event. The Agency may then conclude the consultation process by issuing a letter to the developer which indicates that there are no unresolved issues associated with that variety (event). The consultation procedures are described in detail on CFSAN's WWW site (http://vm.cfsan.fda.gov/~lrd/consulpr.html). Please make reference to that site for specific details.

The use of antibiotic resistance marker genes in the development of biotech plants has been a concern. Plant breeders have indicated in the consultation process with FDA that kanamycin (kanr), lactam, chloramphenicol and amino glycoside antibiotics have been used in the development of modified plant varieties. To date, only the Kanr expression product, amino glycoside 3'-phosphotransferase II (NPT), has been shown to be expressed in modified plant varieties. A food additive regulation was established to allow the use of NPT II in canola, cotton, and tomatoes. In other cases the gene coding for antibiotic resistance is present in the plant, but the expression product is not, because the gene does not have the right regulatory sequences for expression in the plant. The known mechanisms for gene transfer lead us to believe that it is highly unlikely that a functional copy of these genes would be transferred from the plant to rumen, environmental, or gut microflora.

A list of plant varieties which have completed the consultation process is maintained at the CFSAN WWW site (http://vm.cfsan.fda.gov/~lrd/biocon.html).

The FDA role is to assure the safety of the products it regulates.

 

INVESTIGATING DRUG TRANSFER INTO EGGS
by Dan J. Donoghue, Ph.D.

The Center for Veterinary Medicine (CVM) commits significant resources towards protecting the human food supply by evaluating and eliminating potentially toxic levels of veterinary drug residues and contaminants which may be deposited in edible animal tissues. As part of this goal, CVM's Office of Research has ongoing laboratory research programs which investigate the transfer and uptake of drug residues and other contaminants in food products. As a member of this team, our laboratory evaluates the kinetics of contaminant transfer into eggs and has recently proposed a model to predict the pattern of residue transfer into egg yolks. The importance of this type of work has recently been highlighted by the recent reports of contamination of poultry feed with chlordane in the midwest and dioxin in the south and the potential for transfer into edible poultry products.

Eggs are an extremely important human food commodity. Each year, approximately 220 eggs are consumed, on average, by each individual in this country. Many of these eggs are eaten as further processed foods such as ice cream, bakery products, etc. Residues in eggs may be produced by exposing laying hens to drugs or contaminants in a number of ways. These include: 1) illegal or extra-label uses of drugs, 2) use of feed unintentionally cross-contaminated during feed mixing, 3) use of mislabeled feed and 4) pesticide, chemical or heavy metal contamination of feed ingredients or water.

Our laboratory's strategy to investigate contaminant transfer into eggs has taken a three-pronged approach. These approaches are: 1) use of traditional feeding studies to investigate transfer of an individual drug into eggs, 2) development of models to predict the pattern of contaminant transfer for a number of different chemical compounds, and 3) collaborative efforts to develop methods to identify if contaminant transfer is taking place.

Many veterinary drugs are fed to poultry to enhance growth rates, feed efficiency, egg production or for therapeutic reasons. Our laboratory has evaluated transfer rates of some of these drugs using traditional feeding studies. By adding the compound of interest to the feed and following depletion patterns, we have quantitated residue levels in eggs for the organic arsenicals, roxarsone and arsanilic acid and oxytetracycline. Feeding laying hens various doses of arsenicals, we discovered that arsenic levels in the whole egg did exceed the 500 ppm tolerance established for whole eggs by the FDA (Donoghue et al., 1994). In addition, we determined that 95 % of the arsenic was preferentially deposited in the egg yolk. In the case of the antibiotic, oxytetracycline (OTC), the opposite pattern of transfer seems to occur. Instead of preferential deposition in the yolk, our results indicate that OTC seems to preferentially deposit in albumen (Donoghue et al., 1997, submitted). Preferential deposition into egg components has regulatory significance since a significant proportion of eggs produced are separated into either yolk or albumen and sold separately for further processing. Just consider, of the average consumption of 220 eggs a year how often are you eating whole eggs such as scrambled or poached eggs? Many consumers get their egg products in further processed foods and therefore, it would be prudent to establish tolerances on an egg component basis (albumen or yolk) and not a whole egg basis.

Although these types of traditional feeding studies have provided useful information, they are only valuable for regulatory decisions for the particular drugs and doses used in that one study. Since these studies can take years to perform, it is not conceivable to investigate all drugs and titrations necessary for future regulatory decisionmaking. In an effort to provide the FDA with timely assessment of the potential for residue contamination for a variety of chemical compounds, our laboratory is developing prediction models for residue transfer into eggs. The intent is to identify underlying physiological mechanisms responsible for regulating residue transfer and mathematically describing these relationships. Factors such as the: 1) dynamic nature of yolk or albumen formation, 2) propensity of the drug to transfer into either albumen or yolk (drugs physicochemical properties), and/or 3) a drug's plasma half-life may all contribute or interact to affect the quantity of drug transfer or the duration of time eggs are laid containing residues.

Recently, our laboratory identified the important role the ovary performs in regulating drug transfer into developing egg yolks (Donoghue et al., 1996). Yolks develop in the ovary over a period of months and, even when contaminant transfer was limited to just a 24-hour period, yolks that are weeks to months from ovulation incorporated and stored residues. Interestingly, the patterns of residue transfer into yolks were similar for different types of contaminants. In separate, replicated studies, we determined that two dissimilar classes of antibiotics (ampicillin or oxytetracycline) or the pesticide, lindane, all had similar patterns of residue uptake into developing egg yolks. This potentially universal physiological regulation of residue transfer into egg yolks has been used to develop the following mathematical prediction model for residue transfer for all types of chemical compounds. Our model is as follows:

 

I+j-1

Pk

k=I

It is beyond the scope of this article to define and give examples of our model, but for interested readers, this information can be obtained from our paper in Journal of Food Protection (Donoghue, et. al., 1997; in press) or by contacting the author.

The predictive pattern of residue uptake into developing yolks is only one consideration in evaluating transfer into whole eggs. Models factoring the availability of contaminants at the level of the ovary (plasma residue levels), degradation of residues stored in the developing egg yolks (residues' stability), influence of variable feed intakes, etc. also need to be considered. In addition, model predictions need to be developed for residue transfer into egg albumen. Studies are currently underway or completed which address these issues. For example, we recently published our results examining ampicillin transfer and depletion levels in laid eggs (Donoghue, et al., 1997).

Results of these studies have significant human food safety implications. Due to the unusual nature of egg formation, many principles of residue transfer for domestic livestock do not apply to birds. Even if hens are dosed for only one day, it is possible, laid eggs will contain varying (even increasing) levels of residues, days to a number of weeks after drug withdrawal. Each individual developing preovulatory yolk acts as its own pharmacokinetic compartment, with drug uptake and concentration independent of every other egg yolk compartment. Evaluating the pattern or duration of incurred residues in eggs based on the drug's half-life, as is done in domestic livestock, could expose the consumer to violative residues in eggs for an extended period of time. Utilization of our prediction model by producers or veterinarians would aid in making informed decisions of the components affecting residue duration in eggs and reduce the potential for unintentional contamination of this important food commodity.

Our laboratory's final area of research involves the important endeavor to develop methods to identify and quantitate contaminants in eggs. In recent years our laboratory, in collaboration with other FDA, the Department of Agriculture's Food Safety Inspection Service (FSIS) or Agricultural Research Service (ARS) laboratories have developed methods for arsenicals, sulfonamides, tetracyclines, beta-lactams, fluoroquinolones and pesticides. Without these methods, it is not possible for field personnel to monitor and alert our Agency about potential human food safety problems.

The author was CVM's 1996 nominee for the FDA Excellence in Laboratory Science Award, and would like to express his appreciation to Mr. Herman Hairston and Mr. Stuart Gaines for research and methods support and Ms. Mary Bartholomew for statistical and mathematical assistance with model development.

 

OVERVIEW OF FDA PROGRAMS AFFECTING ZOO ANIMAL FEEDS
by David A. Dzanis, D.V.M., Ph.D., DACVN

This information was presented to the American Zoo and Aquarium Association Nutrition Advisory Group, Ft. Worth, Texas, on October 19, 1997.

Introduction

The authority to regulate animal feeds in interstate commerce is granted to the U.S. Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act. This authority includes not only livestock feeds, but also feeds for pets, zoo animals, and even wildlife. Most of the regulatory functions related to animal feeds are carried out by the Center for Veterinary Medicine (CVM). The Division of Animal Feeds within CVM is divided into three teams: Nutrition and Labeling, Animal Feed Safety, and Medicated Feeds. Each team is responsible for matters that may impact foods intended for zoo animals. The Division interacts with other offices within CVM, other FDA Centers, and a wide network of FDA Field offices to achieve its goals.

Nutrition and Labeling

The Nutrition and Labeling Team, as its name implies, is responsible in assuring that animal feeds are labeled in accordance with pertinent laws and regulations, and that any claims related to nutritional value or other aspects of the product are not false and misleading. The Team also reviews Food Additive Petitions, GRAS (Generally Recognized As Safe) Affirmation Petitions and applications for new AAFCO Feed Ingredient Definitions for nutritive substances to ensure that they can be used in animal feed in a safe manner. Because manufacturers of zoo animal feeds are often less familiar with Federal and State labeling regulations than the larger volume animal feed and pet food companies, errors in the fundamental aspects of labeling are common. Mistakes with net weight declarations, statements of responsibility (manufacturer's name and address), and guaranteed analyses are not uncommon. Since ingredients not typically used in domestic animal feeds are often included in formulations, use of proper ingredient declaration terminology can be problematic. Although these aspects may appear to be mere technicalities to some, the regulations are in place to assure truthful, non-misleading information for all animal feeds.

Comparative nutritionists face formidable challenges in their attempts to provide nutritionally adequate diets to zoo animals. Commercially available products for these animals offer many potential benefits. However, there is often a paucity of reliable scientific data on the nutritional needs upon which the owner or caretaker can adequately assess the value of commercially available products specifically intended for these species. This has become an even bigger problem with the increased popularity of exotic animals as pets.

A "complete and balanced" commercial food can offer many advantages to the owner or caretaker in terms of convenience and assurances of adequate nutrient intake. However, a product intended to be offered as the sole source of nutrition that is not, in fact, nutritionally adequate is both misbranded and unsafe. For domestic animals such as dogs and cats, there are standards (AAFCO Dog and Cat Food Nutrient Profiles) which products must meet in order to substantiate nutritional adequacy. There are also some zoo species where the recommendations of the National Research Council may apply (e.g., primates, rodents). For most exotic species, there is no unbiased authority upon which these claims of nutritional adequacy can be validated. Lacking such abilities to verify a claim's truthfulness, some regulators have required companies to remove the claims from the labels. Although this helps protect the consumer from false claims, it can also be a disservice for those products that are truly "complete and balanced."

To help remedy the problem, the Association of Avian Veterinarians has established an ad hoc committee to attempt to set a rudimentary nutrient profile for the most common pet psittacine and passerine birds. Unfortunately, for many other commonly kept exotic animals (e.g., iguanas, other reptiles, many small mammals), establishment of minimum nutrient standards is not in the foreseeable future. Owners or others charged with the responsibility of providing food to exotic animals are advised to view any claim of nutritional completeness for these species with due scrutiny.

Under FDA law, an expressed or implied claim that a product will treat, prevent, or otherwise affect a disease or condition identifies the intent to offer that product as a drug. Furthermore, unless that product has been shown to be safe and effective for its intended use via a New Animal Drug Application (NADA) approval, it is unsafe. Many commercial exotic animal feed labels bear "health" claims that could make them "drugs" under the law. These include references to specific conditions, such as "treats metabolic bone disease" or "cures feather picking," or more generalized promises (e.g., "reduces stress" or "improves health"). When made aware of certain products, FDA has required the manufacturer to remove the claims if the product was to be regulated solely as a food. However, many products bearing unproven drug claims are still prominent on the market. Thus, comparative nutritionists must use their expertise to carefully evaluate the merit of any label health claim before using or recommending the product.

Animal Feed Safety

The Animal Feed Safety Team is responsible for review of Food Additive Petitions, GRAS Affirmation Petitions and AAFCO definition applications for substances that are not intended for their nutritive value (e.g., preservatives, anti-caking agents). It also deals with cases of adulteration, such as chemical or microbiologic contamination, and develops policies regarding food/feed safety issues.

Many commercial diets designed for carnivorous species are comprised of raw meat or by-products obtained from animals that may have died from means other than slaughter (i.e., "4-D meat"). By their very nature, these products have a high risk of containing potentially pathogenic organisms. Depending on handling both before and after sale, the bacteria may proliferate and pose a risk to both the animal and caretaker. Purchasers of such products must be aware of the potential risks, and handle raw meat diets appropriately. "Safe handling" instructions on raw meat product labels would also be a prudent measure.

An important aspect related to animal feed safety is the risk of Bovine Spongiform Encephalopathy (BSE) entering and proliferating in the United States. New regulations designed to help minimize the risk will impact zoo animal feeds. Under the new rules, any feed containing non-exempt mammalian proteins cannot legally be fed to ruminants (including cattle, deer, elk, bison, and antelope). Exempt protein sources include milk and milk products, blood and blood products, and gelatin from all species, meat, meat and bone meal and other proteins derived exclusively from swine and horses, and plate waste. If a product contains any non-exempt proteins, it must carry a warning statement not to feed it to ruminants. Pet foods are excluded from carrying a warning statement under this rule, but zoo animal feeds are not.

Medicated Feeds

The Medicated Feeds Team is responsible for ensuring that an animal feed containing a drug is properly formulated and labeled to comply with the requirements set out in the drug's approval. Medicated feeds are drugs under the law, and they must be subject to an approved NADA before they can be used legally. The NADA specifies the species, conditions, and other restrictions of use necessary to ensure that they are used in a safe and effective manner. Medicated feeds must be manufactured in accordance with current Good Manufacturing Practice regulations (cGMPs) to assure that a uniform product meets the declared potency and is not contaminated with unwanted drug ingredients. FDA's Field investigators conduct routine inspections of medicated feed manufacturers to assure they are meeting these requirements.

A feed containing a drug that is not subject to an approved NADA, or intended for a species or condition not specified by the approval is an adulterated drug. The Animal Medicinal Drug Use Clarification Act (AMDUCA) grants some leeway for veterinarians to use approved drugs in an "extra-label" manner, that is, use the drugs at different dosages or for different species or diseases not specified by the NADA. However, AMDUCA also states that medicated feeds are not covered under the Act. Thus, the extra-label use of medicated feeds is not legally permitted.

Conclusion

CVM works in concert with FDA Field personnel and State feed control officials to ensure that all animal feeds are safe and properly labeled. Anyone who suspects that a feed is potentially unsafe by virtue of adulteration or misbranding should contact the appropriate State feed control official and/or FDA District Office.

 

ELECTRONIC FOI READING ROOM NOW AVAILABLE

FDA has widely expanded its current internet capabilities by including a new electronic Freedom of Information Act (FOI) "reading room." This feature allows users to access and download a variety of Agency documents and records.

Internet users can now directly access warning letters, inspection operation manuals, monthly import detention lists, medical device reports and other often-requested material without the time and paperwork involved with filing a traditional FOI request. The Electronic FOI Reading Room contains an index with links to all current listings, and can be reach directly from the FDA Home Page at http://www.fda.gov.

The Electronic FOI Reading Room is one of the latest features to be added to the FDA website to enhance its value to internet users, in keeping with the Electronic Freedom of Information Act Amendments of 1996. In addition, FDA has revised the Home Page to provide new options and specific "menu" selections for consumers, journalists and other user groups. These menus will help users to access information on a given subject from throughout the Agency, regardless of the FDA Center or office that published it.

For further information concerning FDA's website, contact Bill Rados at 301-443-3220 (or e-mail wrados@bangate.fda.gov).

 

CVM SENDS EPIDEMIOLOGIST TO U.K. TO RESEARCH SALMONELLA TYPHIMURIUM DT104
by Kathy Hollinger Godon, D.V.M., MPH

Earlier this year, I was fortunate to spend 4-1/2 months on temporary duty assignment at the Epidemiology Department, Central Veterinary Laboratories (CVL) of the Veterinary Laboratories Agency, an Executive Agency of the Ministry of Agriculture Fisheries and Food (MAFF) in the United Kingdom (U.K.) As an epidemiology training fellow at CVM in the, Division of Epidemiology and Surveillance, this was an excellent opportunity to work with scientists at the Epidemiology Department at CVL, a research agency within MAFF. The work contracted by the Epidemiology Department is varied and reflects public health, animal health, and animal welfare concerns related to animal production in the U.K. Activities of the Department include the monitoring of animal disease, the proposal, design, and conduct of research studies and risk assessments, the participation in education programs directed at veterinary practitioners, animal producers, and the public, and the reporting of findings to the Minister, the public, and in the scientific literature.

Some current areas of study in the Department include BSE predictive modeling, determination of scrapie prevalence at slaughter, pre-slaughter and farm-based predictors of zoonotic pathogen carriage in food animals, tuberculosis control and eradication, the effectiveness of biosecurity for the prevention of campylobacter in poultry, conditions promoting the growth of listeria in baled silage, risk assessment for the transmission of bovine leukosis, and the prevalence of E. coli in cattle, among many others.

In the U.K. there is an epidemic of Salmonella Typhimurium DT104 (StmDT104) occurring in humans and a diverse range of animal species. The epidemic strain is resistant to five antimicrobials (ampicillin, chloramphenicol, streptomycin, sulphonamides and tetracycline), and this resistance is unique as it is chromosomally borne. Currently StmDT104 is the second most commonly isolated cause of human salmonellosis, after S. enteriditis, and is the predominate salmonella isolated from cattle. Recently resistance in StmDT104 has been identified to two additional classes of drugs: trimethoprim and fluoroquinolones. The organism has been isolated from a diverse range of wild and domestic animal species in the U.K. and more recently identified in the U.S. Transmission from animals to man has been demonstrated in the U.K. to occur primarily via foodborne routes, as well as through direct and indirect contact with animals, especially ill farm animals.

Concern about the existence and evidence of the spread of the organism in the U.S. prompted CVM to send an epidemiologist to assist CVL with the description of the U.K. epidemic and the construction of a study to determine factors associated with recurrent clinical disease in cattle caused by StmDT104. The proposed study of StmDT104 was to follow-up a case control study of cattle herds with StmDT104 done by Dr. Sarah Evans in 1994-1995.

Upon arrival and orientation to the various databases, I carried out a descriptive analysis of the epidemic detailing the seasonality and temporality of the epidemic, including projections into the next year. A historical review of the StmDT104 isolates, from laboratory day books, gave me an opportunity to experience "shoe-leather" epidemiology, though my eyes and fingers, not the soles of my shoes, were worn after leafing through 7 years of day books for StmDT104 listings. Results of this research provided new information about the early StmDT104 isolates. Early isolates of the epidemic strain (R type ACSSuT) between 1984-1988 were identified primarily from birds; both seagulls and exotic imported psitticines. The early cattle epidemic was described and appeared sporadic due to the low incidence and geographic distribution of isolates from 1988 to 1991. In 1991, the isolation rate in cattle increased dramatically and continued to increase through 1996. Also, the index herd from which the epidemic strain was isolated in 1988 was identified and characterized.

In addition to the historical data, the susceptibility profiles from the bacteriology database were tabulated for food animal species. The proportion of isolates that were the epidemic strain appeared to be increasing through 1996 in most species, with a concurrent decrease in other phage types of Salmonella Typhimurium. Cattle isolates with nalidixic acid resistance, an indicator of fluoroquinolone resistance, have increased from 0.3 percent in 1994 to 9.7 percent in preliminary 1997 data. Trimethoprim resistance has also shown an increase from 3.6 percent in 1994 to 11.9 percent in preliminary 1997 cattle data.

Calculation of the incidence of StmDT104 in cattle herds was complicated by the lack of a valid denominator, as census data was considered to overestimate the number of cattle herds in the U.K. A sample population, using the control herds from the previous 1994-1995 case control study, was used to estimate the incidence and disease recurrence rates. Other animal and herd characteristics such as age of the index case in an affected herd, morbidity, and severity of disease were described.

After researching the literature and describing the epidemic using the database available information, we began planning and designing the study. The case and control definition, the sample size, power, and potential biases and many other factors were considered in the design of the study and the construction of the questionnaire.

The questionnaire was piloted in the field in ten on-farm visits throughout the southern and western regions of England. Three of the farms visited had episodes of human disease on the farm following the illness in the cattle. On one farm the organism was isolated from the family dog, which was the proposed route of exposure to an ill child. One farm was also able to isolate the organism from the bulk milk tank for four months after the episode of clinical disease in the herd. These farm visits were informative resulting in improvements in clarity and construction of the questionnaire. In addition to the farm visits, the questionnaire was tested in two separate mailings to develop strategies that would improve the response rate and structure of the questionnaire. Strategies that improved response rate included mailing the questionnaire on a Friday for a Saturday delivery, mailing the questionnaire when farmer harvest activity level was low, when the weather was wet, and the inclusion of a handwritten note. Incorporation of these strategies for the second mailing resulted in an improved response rate from 55 percent to 70 percent.

The protocol for the case control study of recurrent disease in cattle was completed in mid-August. Currently, the questionnaire is being mailed and data entry of returned questionnaires is ongoing. I look forward to participating in the data analysis of this study. While in the U.K., I also visited sister agencies, including the Veterinary Medicines Directorate and the European Medicines Evaluation Agency, representing the U.K. and the EU drug evaluation agencies, establishing valuable contacts with the staff of these agencies.

 

PUBLICATIONS

NRC Chromium Publication

The National Research Council (NRC), Board on Agriculture, Committee on Animal Nutrition has published The Role of Chromium in Animal Nutrition. This report begins with a discussion of the absorption, transport, and deposition of chromium in humans and animals. It also includes chapters on current knowledge of the role of chromium in metabolism of humans and animals, and a comprehensive review of data describing the effects of supplemental dietary chromium on cattle, sheep, swine, poultry, horses, rabbits, and fish.

Copies of The Role of Chromium in Animal Nutrition are available for purchase from the National Academy Press, 2101 Constitution Avenue, NW, Lockbox 285, Washington, DC 20055. Credit card orders may be placed by calling 1-800-624-6242 or 202-334-3313 in the Washington, DC metropolitan area; Internet, http://www.nap.edu.

1996 ADE Summary

Copies of the complete 1996 Veterinary Adverse Drug Experience Summary, which was contained in two inserts in the September/October and November/December issues of the FDA Veterinarian, are available. This summary includes all domestic adverse drug reaction reports submitted to CVM for calendar year 1996 that the Center has determined to be at least possibly drug related. Readers who wish to obtain copies of the complete report may call or write the FDA Veterinarian.

 

TECHNICAL AMENDMENT

FDA published a technical amendment concerning the use of animal drugs in medicated feeds [Title 21, Section 558.4(d) of the Code of Federal Regulations] to reflect the correct assay limits for lasalocid in Type A medicated articles. These assay limits are 95 to 115 percent of the labeled amount. Although the original approval for new animal drug application (NADA) 96-298 provided for a 10 percent overage (an assay limit of 100 to 120 percent), a supplemental approval dated August 25, 1992, revised that overage to 5 percent (95 to 115 percent). The regulation in Section 558.4(d) is amended in the table entitled "Category I" in the entry for "Lasalocid," accordingly. Federal Register, November 12, 1997.

 

REGULATORY ACTIVITIES

The following firms/individuals received warning letters for offering animals for slaughter that contained illegal drug residues:

These violations involved illegal residues of oxytetracycline in a dairy cow, oxytetracycline and penicillin in a calf, oxytetracycline in a beef cow, sulfadimethoxine in a cow, and gentamicin in a dairy cow.

Indexx Veterinary Services, Inc., Westbrook, ME received a warning letter for violations of Good Laboratory Practices.

 

ABBREVIATED NEW ANIMAL DRUG APPROVALS

Company Generic and (Brand) Names Indications Routes/Remarks
Med-Pharmex, Inc. (ANADA 200-196) Miconazole Nitrate Lotion and Spray Dog and Cats. For use as a topical antifungal agent to treat certain infections. TOPICAL: ANADA 200-196 is a generic copy of Mallinckrodt Veterinaryšs Conofite ’ miconazole nitrate 1 percent lotion and spray -- NADA 95-184. Federal Register 10/23/97.
ALPHARMA, Inc. (ANADA 200-223) Bacitracin Zinc<.td> Cattle, Broiler Chickens, Turkeys, Pheasants, Growing Quail, and Growing and Finishing Swine for increased rate of weight gain and improved feed efficiency and for Laying Chickens for improved feed efficiency and increased egg production. ORAL: ANADA 200-223 is a generic copy of Hoffmann-LaRochešs NADA 46-920. Federal Register 10/23/97.
ALPHARMA, Inc. (ANADA 200-207) Clopidol and Bacitracin Zinc with Roxarsone. Broiler Chickens. For prevention of coccidiosis, improved feed efficiency, improved pigmentation, and increased rate of weight gain. MEDICATED FEED: ANADA 200-207 is a generic copy of Rhone-Poulenc, Inc.šs NADA 44-016. Federal Register 11/21/97.
ALPHARMA, Inc. (ANADA 200-218) Clopidol and Bacitracin Zinc Broiler Chickens. For prevention of coccidiosis, improved feed efficiency, and increased rate of weight gain. MEDICATED FEED: ANADA 200-218 is a generic copy of Rhone-Poulenc, Inc.šs NADA 49-934. Federal Register 11/20/97.
ALPHARMA, Inc. (ANADA 200-211) Monensin and Bacitracin Zinc with Roxarsone Broiler Chickens. For prevention of coccidiosis, and increased weight gain or for prevention of coccidiosis and improved feed efficiency, and improved pigmentation. MEDICATED FEED: ANADA 200-211 is a generic copy of Hoffmann-LaRochešs NADA 123-154. Federal Register 11/20/97.
ALPHARMA, Inc. (ANADA 200-205) Amprolium plus ethopabate and Bacitracin Zinc Broiler and Replacement Chickens. For prevention of coccidiosis in broiler and replacement chickens and improved feed efficiency in broiler chickens. MEDICATED FEED: ANADA 200-205 is a generic copy of Hoffmann-LaRochešs NADA 114-794. Federal Register 11/19/97.
ALPHARMA, Inc. (ANADA 200-203) Carbarsone and Bacitracin Zinc Turkeys. For prevention of blackhead, increased rate of weight gain, and improved feed efficiency. MEDICATED FEED: ANADA 200-203 is a generic copy of Hoffmann-LaRochešs NADA 136-484. Federal Register 11/14/97.
ALPHARMA, Inc. (ANADAs 200-204 and 210) Salinomycin and Bacitracin Zinc Broiler Chickens. For prevention of coccidiosis and increased rate of weight gain. MEDICATED FEED: ANADA 200-204 is a generic copy of Hoffmann-LaRoche Inc.šs NADA 139-235 and ANADA 200-210 is a generic copy of Hoechst-Roussel Vetšs ANADA 200-089. Federal Register 11/13/97.
ALPHARMA, Inc. (ANADA 200-214) Amprolium plus Ethopabate with Bacitracin Zinc and Roxarsone Broiler Chickens. For prevention of coccidiosis and improved feed efficiency or improved feed efficiency and improved pigmentation. MEDICATED FEED: ANADA 200-214 is a generic copy of Hoffmann-LaRoche Inc.šs NADA 105-758. Federal Register 11/12/97.
Phoenix Scientific, Inc. (ANADA 200-236) Chlortetracycline Hydrochloride Soluble Powder Swine, Chickens and Turkeys. In swine, for control and treatment of certain diseases caused by pathogens susceptible to chlortetracycline. In chickens and turkeys, for control of certain diseases caused by pathogens susceptible to chlortetracycline. ORAL (in Drinking Water): ANADA 200-236 is a generic copy of ADM Animal Health and Nutrition Div.šs Chlortet TM Soluble-O, NADA 65-256. Federal Register 11/12/97.

SUPPLEMENTAL NEW ANIMAL DRUG APPROVALS

Company Generic and (Brand) Names Indications Routes/Remarks
Mallinckrodt Veterinary, Inc. (NADAs 34-266, 34-697, 139-858) and PM Resources, Inc. (NADA 43-215) Famphur -- Famix Famphur Type A article (for Type C Cattle Feed) (NADA 34-266), Warbex Famphur Cattle Pour-On/Bo-Anna Famphur Cattle Insecticide (NADA 34-697), Tramisol-X-Tra (Famphur/Levamisole) Cattle Anthelmintic and Ecoparasite Paste (NADA 139-858), and Purina Grub-Kill (Famphur) (NADA 43-215) Cattle MEDICATED FEED/TOPICAL -- TOLERANCES. The animal drug regulations are amended to specify the tolerances for residues of famphur in cattle products. The residue tolerances were originally issued in FDAšs regulations under tolerances and exemptions from tolerances for pesticide chemicals in or on raw agricultural commodities, and subsequently moved to the EPA regulations for residues of pesticides. Subsequent FDA NADA approvals with the same tolerances, instead of stating the tolerances, cross- reference EPAšs regulations. This action is being taken because EPA has removed the tolerance from its regulations. Federal Register 10/23/97.
Pfizer, Inc. (NADA 141-061) Doramectin (DectomaxŽ) Swine INJECTABLE: Provides for intramuscular use in swine for treatment and control of certain infections of gastrointestinal roundworms, lungworms, kidney worms, sucking lice, and mange mites. In addition, the CFR (21 CFR 556.225) is amended to provide for a tolerance for residues of doramectin in swine tissues. A tolerance of 0.1 ppm is established for parent doramectin in liver of cattle and 0.16 ppm in liver of swine. Federal Register 11/21/97.
Hoffmann-LaRoche, Inc. (NADA 48-761) Chlortetracycline Beef and non-lactating dairy cattle. For control of anaplasmosis and other uses. MEDICATED FEED: Provides for changing the withdrawal time to zero following certain uses of chlortetracycline in Type C cattle feeds (including free-choice feeds). Federal Register 11/19/97.
Schering Plough Animal Health Corp. (NADA 141-081) Orbifloxacin Cats ORAL: Provides for prescription use in cats for management of susceptible bacterial disease. Federal Register 11/19//97.

SUPPLEMENTAL ABBREVIATED NEW ANIMAL DRUG APPROVALS

Company Generic and (Brand) Names Indications Routes/Remarks
Pharmacia and Upjohn Co. (ANADA 200-113) Neomycin sulfate Cattle (excluding veal calves), Swine, Sheep, and Goats. For treatment and control of colibacillosis. ORAL: The supplemental ANADA provides for a shorter withdrawal period following use in drinking water or in milk. Federal Register 11/12/97.

horizonal rule

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