January/February 1996 - Volume XXI, No. I, FDA Newsletter

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CVM has adopted a new strategic plan which emphasizes the Center's role in enabling the availability of effective animal drugs, food additives, feed ingredients, medicated feeds, and animal devices that are safe to animals, humans, and the environment. The Center is very sensitive to veterinarians' need for effective and safe drug therapies to provide for the health and welfare of animals under their care. CVM also recognizes that veterinarians are concerned when they seem to have a shrinking supply of approved animal drugs on the market. In addition, some have questioned why certain drug products have been withdrawn from the market when there are no approved products to replace them. The following article discusses this issue.

Animal drugs, food additives, and animal devices are regulated under the Federal Food, Drug, and Cosmetic Act (the Act). The Act requires that new animal drugs be shown to be safe and effective by the sponsor before the products are approved by the Food and Drug Administration (FDA). Safety for food animal drugs covers three main areas: safety of the food products to humans, safety to the target animal, and safety to the environment. In addition, companies must show that they can consistently manufacture the drug to a specific potency and purity, and provide adequate methods for detecting drug residues or metabolites in target tissues such as muscle, liver, kidney, fat, milk, and/or eggs.

In some cases, animal drug companies choose not to go through the time and expense of having a new animal drug approved because, for certain types of drugs, the market is too small to justify the expense. Thus, the profit from a new approval does not project a favorable return on the research investment. A prime example of this problem is in the case of drugs needed for use in minor animal species or in any animal species for the control of a disease that occurs infrequently.

To help increase availability of minor use/minor species drugs, CVM has been an active supporter of the National Research Support Project (NRSP) #7 (formerly the IR-4 Program.) This program is dedicated to developing new drugs for use in minor animal species or in any animal species for the control of a disease that occurs infrequently or in limited geographical areas.

CVM supports the NRSP #7 in a number of ways. A full time employee assists the program, and CVM cosponsors various workshops and meetings with NRSP #7 to provide a forum for exchange of ideas among minor species producers, drug manufacturers, researchers, and government agencies on approaches to disease problems and drug priorities.

As a result of the NRSP #7, 20 public master files (PMFs) have been published in the Federal Register. PMFs contain target animal safety and effectiveness data and environmental assessment to be used in support of new animal drug applications (NADAs) or supplemental NADAs. These PMFs are for small ruminants (such as goats, sheep, and reindeer), game birds (such as pheasants, quail, and chukar partridge); aquatic species (such as catfish, lobster, shrimp); and for fur-bearing species (such as rabbits and foxes). Approximately 85 percent of these PMFs have led to drug approvals.

Drug companies may also be reticent to go through the approval process when they recognize that other drugs approved for different species/indications are being used in an extra-label manner. Extra-label use (ELDU) would be any use of an approved drug product in a manner other than as directed on its label. Drug companies may be aware that a drug approved for use in humans is commonly used in an extra-label manner in dogs and cats. The companies may decide not to pursue an NADA for the drug in dogs or cats because some veterinarians might continue to use a human product, rather than purchase an approved veterinary product. This is especially true if the increased production costs of short manufacturing runs for the animal drug are expected to compete in price with the human product which has longer and more efficient manufacturing runs.

CVM is improving the drug approval process to encourage more drug companies to pursue NADAs. This must be a cooperative effort by everyone associated with or affected by the use of animal drugs. CVM is completely committed to improving the availability of approved new animal drugs and can be the catalyst to bring all the appropriate parties together. In addition, the number one goal in the new CVM strategic plan is to "reengineer product evaluation, surveillance and compliance, research, and administrative processes, and promote international harmonization to increase the availability and diversity of safe and effective products."

The Center has developed a three-pronged strategy to achieve this goal as follows:

While one reason for the lack of approved products is the lack of submissions, there are other reasons why necessary drugs are not available. In some cases, drug shortages may arise from the lack of availability of raw materials or packaging components, marketing decisions, and/or enforcement issues.

CVM is aware of the problems caused by veterinary drug shortages and has developed a Policy and Procedures Guide (P&P Guide) which presents procedures for the evaluation of essential animal drug product shortage situations. This P&P Guide was developed to enable the Center to take appropriate actions promptly when shortage situations arise.

According to this P&P Guide, a product is considered to be a medically necessary veterinary product (MNVP) if it is used to treat or prevent a serious disease or condition, or if it is needed to assure the availability of safe food-animal products and there is no other available source of that product or alternative judged to be an adequate substitute. The Guide states that inconvenience and non-therapeutic uses are insufficient bases to classify a product as MNVP.

It is FDA policy to attempt to prevent or alleviate shortages of MNVPs. FDA's response to a MNVP situation will be guided, in order of priority, by protection of public health, animal health, and the environment.

Generally, the Agency is alerted to shortage situations by veterinarians, producer associations, animal health industry, the press and/or consumer groups, or through normal FDA surveillance and enforcement activities. All veterinary drug shortage situations should be reported promptly to CVM's Office of Surveillance and Compliance.

Once a bona fide shortage is confirmed, a CVM MNVP Shortage Coordinator is informed and decisions are made concerning appropriate actions to be taken. The Shortage Coordinator helps develop an action plan to prevent or mitigate a supply disruption. In addition, the Shortage Coordinator will help determine whether there are alternate products or other sources for the drug product(s), and ascertain if human food safety concerns necessitate limiting the scope of the Center's response to a MNVP shortage. Finally, the Shortage Coordinator must assure that the Agency position is defensible and documented.

If a determination is made that a shortage exists for a MNVP, special actions to alleviate the shortage will be considered. These actions may range from discussions with the industry, acceleration of NADA/ANADA review and/or, in extraordinary circumstances, enforcement discretion.

CVM has reviewed several products under the Medically Necessary Veterinary Drug Product Shortage Management program, and this has lead to the re-introduction of some of these products in the market. For example, there was a shortage of phenylbutazone paste due to the bulk supplier's Good Manufacturing Practices (GMP) problems, change in the manufacturing site of the active ingredient, and the unavailability of an injectable form of phenylbutazone at the time. Phenylbutazone paste was classified as a MNVP, and an expedited review of the supplemental application was recommended. The supplement was reviewed and approved.

While some veterinary drugs are unavailable due to problems with raw materials, others are unavailable because manufacturers decide to discontinue the production because of low sales volume, or other business reasons unrelated to the safety and effectiveness of the product. These companies voluntarily request that FDA withdraw the approval of their New Animal Drug Application (NADA). Occasionally, this action can leave the impression that FDA initiated the withdrawal, rather than correctly attributing it to the business reasons involved. Customers who are concerned about the lack of availability of a drug may wish to consult the Federal Register where information on the reasons for drug withdrawals is announced. In addition, the FDA Veterinarian regularly includes information on the reasoning behind an action to withdraw a drug from the market.

Other animal drugs are withdrawn from the market because they have never been shown to be effective. These drugs were approved before the legal requirement for effectiveness. Prior to passage of the drug amendments of 1962, drug sponsors only needed to prove that their products were safe. However, in 1962 Congress passed the Kefauver-Harris Drug Amendments to the Act which required drug manufacturers to prove to FDA the effectiveness of products before marketing them. Under the Drug Efficacy Study Implementation (DESI) review process, NADAs approved prior to 1962 were reviewed to determine the drugs' effectiveness for labeled claims.

While many of the DESI-reviewed products were found to be effective for one or more indications, typically, the DESI review required labeling changes for those products. Some products were found to be less than effective. In most cases, sponsors of these products were required to submit additional data to establish effectiveness. While some drug sponsors submitted such information, others chose to withdraw non-finalized NADAs. This was the case for non-finalized NADAs providing for combination products containing penicillin and streptomycin or dihydrostreptomycin for injection, and the penicillin and streptomycin combination in feed.

Although procaine penicillin and streptomycin or dihydrostreptomycin combination products had been on the market for many years, sponsors had never provided scientific evidence that they were effective. Non-finalized NADAs providing for combination products containing penicillin and streptomycin (or dihydrostreptomycin) for injections and feed use were reviewed under the DESI review process. FDA concluded, based upon an evaluation of effectiveness by the National Academy of Sciences/National Research Council Drug Efficacy Study Implementation Group, that these products had not been shown to be effective as combination drug products for any purpose. FDA informed the sponsors that they must either withdraw these NADAs or the Center would issue a Notice of Opportunity for a Hearing on a proposal to withdraw them. All of the sponsors requested voluntary withdrawal of approval of their applications, and waived their opportunity for a hearing.

Other animal drug products were withdrawn from the market because of safety concerns which occurred after the drug had been approved. Pretesting by the manufacturer and review of the data by the government does not guarantee absolute safety and effectiveness. The chief limitations are imposed by testing methods and the restricted number of animals on which tests can be conducted. Furazolidone and nitrofurazone were drugs once approved for food animals, but later deemed unsafe for this use.

Nitrofurans (furazolidone and nitrofurazone) had been approved for antiprotozoal and other uses for a wide variety of conditions in poultry and swine. FDA took action to remove nitrofurans from the market because of concerns about the carcinogencity of these products, and the effect residues in animal-derived food might have on human health. A full public hearing on nitrofurans was held in 1986. The judge concluded from the hearing that furazolidone was an animal carcinogen and should be withdrawn from the market. In addition, he stated that nitrofurazone was a suspect carcinogen that should be withdrawn. Also, the sponsors of the drug had not provided a reliable method for residue detection, and available methodology did not show carcass residues to be below the level of concern.

After this decision, the sponsors of these products filed briefs and exceptions, and the record was subsequently reopened by the FDA Commissioner. The evaluation of this information led to the final rule withdrawing approval of both furazolidone and nitrofurazone.

The sponsors of the nitrofurazone products entered into an agreement with FDA. In the agreement, the sponsors waived their right to request judicial reconsideration of the Commissioner's decision, and agreed to cease all manufacturing and shipment by September 4, 1991.

ELDUs where drugs approved for one species have been used in others have created concerns about the safety of these products. In some cases, such as with chloramphenicol, drugs approved for use in nonfood-producing animals have been used in animals raised for human food. Other drugs approved for a specific use in one species of food-producing animal have been used in another, creating concern about the safety of the food products.

Chloramphenicol was a new animal drug approved for use only in nonfood-producing animals, specifically, cats and dogs. However, chloramphenicol was used widely and illegally in food-producing animals. FDA was concerned about this use of chloramphenicol because of potential adverse human health effects such as aplastic anemia, severe gastrointestinal distress, and neurotoxic and hypersensitivity reactions. Because of misuse in food animals, which primarily involved the use of one formulation of chloramphenicol that had been approved for nonfood animals, the chloramphenicol oral solution was banned from the market on January 23, 1986.

Dimetridazole was approved for use in turkeys for the prevention and treatment of blackhead (histomoniasis, infectious enterohepatitis), and for growth promotion and improved feed efficiency. CVM had documented evidence that dimetridazole medicated premix and dimetridazole soluble powder had been used widely for the treatment and prevention of swine dysentery. This use of dimetridazole in swine was not approved, and FDA was concerned about the human food safety of this use.

On December 16, 1986, FDA published a Notice of Opportunity for Hearing on a proposal to withdraw approval of dimetridazole. The approval for dimetridazole was revoked in a Federal Register document dated July 6, 1987. In this document FDA said that the Agency was taking the action because the drug was not shown to be safe for use (1) because new evidence provided a reasonable basis from which serious questions about the ultimate safety of dimetridazole and the residues that may result from its use could be inferred, (2) because new evidence showed that dimetridazole was no longer shown to be safe by adequate tests by all methods reasonably applicable, and (3) because new evidence showed that the labeled directions for use were not being followed in practice and were not likely to be followed in the future.

CVM is committed to increasing the availability of needed safe and effective veterinary drugs to treat both food and companion animals. Under the new strategic plan, the Center has defined specific tasks to accomplish this goal. However, CVM cannot unilaterally accomplish all the actions that will be necessary to increase animal drug availability. The Center looks forward to working with veterinarians, animal owners, drug manufacturers and other interested parties associated with or affected by the use of animal drugs to ensure that needed drugs are available.

Since there are only five approved drugs for use in aquaculture, many producers use other drugs under investigational new animal drug (INAD) exemptions. An INAD exemption is an exception from the requirements of the Federal Food, Drug, and Cosmetic Act (the Act) which allows the shipment of an approved drug for an unapproved use, or the shipment of a drug that has never been approved for any purpose. An INAD exemption is necessary to:

Typically, drugs used in a clinical setting under an INAD are administered to animals solely for the purpose of gathering data on safety and efficacy, and relatively few animals receive the drug. This type of investigation is an experiment in the traditional sense.

However, there are certain situations where no effective approved drugs are available, for example, when the only alternative to suffering or death is treatment with an unapproved drug. Under such circumstances, CVM is willing to permit substantial use of unapproved drugs under INADs provided that certain conditions are met. This is the purpose of a compassionate INAD exemption. Compassionate INAD exemptions are granted only if

The compassionate INAD exemption is a key mechanism whereby the aquaculture industry may overcome the scarcity of approved drugs. Because compassionate INAD exemptions for aquatic species involve widespread drug exposure to animals, the environment, and humans, a compassionate INAD exemption will only be provided when it is possible to establish safe conditions of use of the drug including human food, occupational, and environmental safety.

Once a sponsor is notified that CVM has granted a compassionate INAD exemption, the sponsor and monitors must prepare to initiate clinical trials (studies of the drug under field use conditions). The trials should be conducted according to the FDA-approved study protocol. The sponsor should have the data analyzed at the end of the study, and should submit the results/data, along with the disposition of the drug and the treated animals, to CVM.

Traditionally, CVM has granted nonemergency compassionate INAD exemptions on an annual basis. The exemption specifies a maximum number of animals allowed to be treated that year. If producers wish to use the drug the following year, or in additional animals in the same year, they need to submit to CVM a request to reassess and extend the exemption. Extension of the exemption depends, in part, on a demonstration of past adherence to the conditions of the exemption, and evidence that substantial progress is being made in pursuit of an approved NADA.

CVM initiated a project, the Aquaculture Compassionate INAD Workload Reprioritization Project, to examine issues related to the resources the Center spends on compassionate aquaculture INADs. As part of this project, CVM believed it was necessary to determine the level of industry compliance with the terms of currently authorized INAD protocols for aquaculture. The Center was particularly concerned about making sure no major residue problems exist in aquaculture products sold for human consumption. Therefore, the Center focused on industry compliance with dosing regimes and withdrawal times specified in the Center's human food safety evaluations of these aquaculture drugs.

On May 4, 1995, CVM issued a Directed Assignment to FDA's District Offices for an investigation of a number of selected facilities, representing several aquaculture compassionate INADs. Different INAD sponsors, and different investigational drugs from a cross-section of the U.S. were represented in the Center's selection of sites. All of the investigations have now been completed. No significant protocol violations were noted in these investigations, and no violations of withdrawal times or dosage regimes were documented.

The Center is encouraged that this investigation appears to indicate the aquaculture industry is making a substantial effort to comply with the INAD regulations and compassionate INAD policies. While this very positive finding does not preclude future monitoring of compassionate INADs, it does provide CVM some assurance that reprioritizing our efforts in the aquaculture INAD area is justified. Effective October 1, 1995, the Center changed its priorities away from annual reviews of INADs and on-site monitoring, toward procedures which will more fully encourage the industry to develop data necessary for approval of drugs for aquaculture use.

The following are excerpts from a presentation made by Center Director Stephen F. Sundlof, D.V.M., Ph.D. at the 39th Annual Educational Conference of the Food and Drug Law Institute held on December 13, 1995 in Washington, D.C.

In June 1995, CVM published our Strategic Plan, "Planning for the Future, 'Shifting the Paradigm.' " The Center is making progress in carrying out the objectives of our Strategic Plan. For example, in 1996 most CVM employees will have a team-work element. We believe that this emphasis on team work will improve the timeliness and quality of CVM decisions. In addition, there has been some progress in reengineering of our processes. For example, one group within CVM has made recommendations on improving the consulting and specialty review processes associated with pre-approval product review, and another group has recommended improvements to the process for evaluating research ideas and needs. While these recommendations have not yet been implemented, these are examples of how the CVM Strategic Plan is being applied and how benefits are starting to show. The Center is committed to the principle that the only way to have more efficient processes in the future is to invest in reengineering today. It is taking resources to reengineer now, but we believe that it is a vitally important effort for achieving our vision of CVM for tomorrow.

We have noted a deficiency in the June 1995 Strategic Plan and have taken steps to correct that shortcoming regarding international harmonization. Goal I has been revised as follows:

We will reengineer product evaluation, surveillance and compliance, research, and administrative processes, and promote international harmonization, to increase the availability and diversity of safe and effective products.

We will promote science-based harmonization of international standards by initiating and participating in discussions and the sharing of information with foreign regulators of animal drugs, veterinary medical devices, food additives, and feed ingredients.

Objectives will be developed to accomplish this strategy. Specifically, these will address the processes in our efforts to harmonize pre-approval registration requirements and post-approval regulatory reporting requirements.

During 1995, CVM also invested time in learning the principles of the Government Performance and Results Act (GPRA). The purpose of GPRA is to improve the internal management of the Federal government. GPRA defines an outcome measure as an assessment of the results of a program activity compared to its intended purpose. An output measure is a tabulation, calculation, or recording of activity or effort and can be expressed in a quantitative or qualitative manner. A performance indicator means a particular value or characteristic used to measure output or outcome.

The Strategic Plan and our active engagement in adopting GPRA are two good examples of the culture changing at CVM. The Strategic Plan is focusing our attention on increasing the availability of new animal drugs, and GPRA is helping focus our attention on meeting the needs of our customers by improving the timeliness and quality of our services both within CVM and for our external customers.

The changes taking place inside CVM are only part of what is affecting us. We are also affected by many external factors, such as proposed legislative changes for medicated feed applications and drug availability as well as the professional flexible labeling initiative.

CVM is supporting legislative change that would eliminate the need for medicated feed applications (MFA) on a product by product basis, and require feed mills manufacturing certain medicated animal feeds to apply for and obtain a single license. While the MFA requirement is a small resource expenditure for FDA, we estimate that it costs industry more. In addition, the Center has concluded that the MFA program no longer benefits society beyond identifying the sites where most concentrated medicated feed drugs are used. The same objective can be accomplished by adding the requirement that a currently registered mill simply be licensed.

The need for CVM to be pro-active in increasing the availability of safe and effective animal drugs is a central principle of the Center's Strategic Plan. Legislative proposals to increase the availability of new animal drugs have been introduced in both the House and Senate. In general, these proposals maintain human health requirements and change the effectiveness requirements to enable CVM to expand the number of approved drugs, especially those used in combination. The legislation would also facilitate approval of drugs for minor species and modify the export laws to allow U.S. companies to locate their facilities in the U.S. CVM is providing technical assistance to Congressional staffers in response to their requests in respect to these proposals to change the law.

In addition to providing assistance to Congress, we are taking actions on our own to the extent possible within the existing statute. For example, the Center has been involved in two public meetings on professional flexible labeling. The professional flexible labeling (PFL) initiative represents the effort of regulators, drug sponsors, academics, scientists, and practitioners to better meet the needs of the veterinary medical community. These groups hope to accomplish this goal through increased (enhanced) drug availability; the marketing of dose ranged products; facilitating the approval of product supplements for such things as expanded indications, new dosage forms (routes of administration), and product use in minor species; and having a broader range of labeled indications.

In addition to meeting the needs of the veterinary medical practitioner, flexible labels will also enable sponsors to legally and properly promote the drug's spectrum of potential uses. Through this initiative, CVM hopes to encourage better use of scientific principles and "state of the art" technology in an attempt to minimize drug development costs.

Another area of Center concern is regulation of new antimicrobial drugs. The Center considers the regulatory status of new antimicrobial drugs on a case-by-case basis. When a dosage form drug is restricted to prescription status, then a medicated feed containing the same drug for similar use indications should be restricted as well. In order to facilitate the feed use of these drugs, CVM is working with industry and consumer groups to devise a unique system which is now known as the Veterinary Feed Directive (VFD). This new system requires a change in the law. A legislative change is important to prevent VFD feed and feed products from being disruptive and causing delay and confusion in the availability of new antimicrobial drugs for use in feed. It is becoming urgent that the statute be modified soon to accommodate the VFD new animal drug because new antimicrobial submissions which might qualify for VFD are under evaluation.

The Center is also interested in the issue of antimicrobial susceptibility. CVM has recently established a program to monitor antimicrobial susceptibility, and salmonella was selected as the sentinel organism for this program. The goals of the monitoring program are to use the information in a timely way to guide practitioners in each arena (human and veterinary medicine), to prolong the lifespan of drugs that are approved, to facilitate the identification of resistance in the human and animal populations, and to identify areas for more detailed investigation by the appropriate group. CVM is collaborating with the USDA's Agricultural Research Service's National Animal Disease Center (NADC) to conduct susceptibility testing of animal Salmonella isolates to establish baseline profiles. The samples are representative of isolates originating from healthy farm animals, the carcasses of food-producing animals at slaughter plants, and clinical specimens.

CVM has established an Interagency Working Group on Antimicrobial Susceptibility Monitoring to provide guidance and technical expertise on the broad array of activities that comprise the monitoring effort, to periodically review the results of the monitoring system, and to discuss the need for more detailed information from additional studies. The Working Group membership consists of experts from the FDA, the Centers for Disease Control and Prevention, and the U.S. Department of Agriculture. We anticipate that the Working Group will identify governmental programs, initiatives and research related to the issue of antibiotic susceptibility in both veterinary and human medicine and their public health significance, evaluate the relevance and merit of research proposals, identify pivotal unanswered questions for future research, identify redundancy of effort among the agencies, and suggest ways to improve coordination, collaboration, and exchange of research information among departments and agencies.

In addition to our efforts in the area of antimicrobial susceptibility, CVM is also reviewing our inspection programs to try and focus use of our limited resources on violative conditions or other areas of concern which may involve significant potential risks to public or animal health. CVM has structured guidance in our inspection programs toward making firms aware of any observed deficiencies and providing them with an opportunity to make voluntary correction. We are well aware that this is generally the quickest and most cost effective means of protecting public and animal health. We support GPRA-oriented outcomes such as improving the safety and wholesomeness of animal derived foods and ensuring the safety and quality of animal drugs. The Center views enforcement actions as one mechanism for helping to achieve such outcomes, but we do not view enforcement actions as meaningful outcomes unto themselves.

Under the Public Health Service Act, the Food and Drug Administration (FDA) and the States administer the Interstate Milk Shippers Program, a voluntary Federal/State program established to ensure the safety and wholesomeness of fresh milk in the United States. Under this program, the FDA publishes the Grade A Pasteurized Milk Ordinance (PMO), a model regulation used in voluntary, cooperative interstate milk safety programs in which all 50 States, the District of Columbia, and Puerto Rico participate. The PMO specifically requires that all bulk milk pickup tankers be tested for the presence of beta-lactam drug residues.

Prior to 1991, the PMO recognized only one official test method for detecting drug residues in milk, the Bacillus stearothermophilus Disc Assay (BSDA). Changes to the PMO in 1991 required intensified testing of milk for beta-lactam residues and created the need for additional rapid, reliable screening tests that "have been evaluated through AOAC and accepted by FDA." (AOAC International, formerly known as the Association of Official Analytical Chemists, is a scientific organization whose primary objective is to validate and improve analytical methods.) As a result of this change to the PMO, 17 screening tests for beta-lactam antibiotics, one test for chloramphenicol, and one test for sulfonamide drugs have been evaluated and accepted by FDA. These tests are accepted for the monitoring of truck tanker loads of raw, commingled, bovine milk in accordance with Appendix N of the PMO and from bulk tank producer samples in accordance with Section 6 of the PMO.

The reliability of these tests to monitor the nation's milk supply has been questioned by some individuals. This article addresses these issues and clarifies the role of screening tests for monitoring raw milk.

The accepted screening tests have met a standard for a low incidence of false positive and false negative findings. Combined with these standards, there are important principals of use which must be considered. These are:

The percentage of truck tankers found positive in 1994 (National Milk Drug Residue Third Party Data Base) was 0.063 percent. This low incidence of positive truck tankers supports our standard for selectivity (false positive test result). Further, this low incidence also demonstrates that the majority of the milk producers are using drugs in a responsible manner. The FDA has found no evidence which would indicate that the use of approved beta-lactam drugs in accordance with label directions will cause a violative or non-violative residue in a truck tanker. The FDA has concluded that despite the inherent limitations of screening tests, the issue remains one of proper drug use. The FDA believes the use of the accepted tests under the provisions of Appendix N, PMO, has reduced the amount of positive milk entering the food supply.

The FDA recognizes the economic losses to the milk producer which would result from false violative and false positive test results. With this issue in mind, the NCIMS and the FDA agreed to retest all original positive truck tanker samples using the same test when the initial test is conducted by an industry analyst. Only after the results from retesting indicate a positive finding is a truck tanker rejected. Retesting increases the probability of acceptance of a non-violative milk tanker and decreases the number of non-violative truck tanker rejections. The FDA must also be concerned with the incidence of false negative results to ensure the public health.

The low incidence of positive truck tanker results do not appear to be caused by unreliable tests. Based on reports from the States, the FDA has concluded that misuse of animal drugs is the cause of most positive test results from truck tanker testing even when residue concentrations are below the tolerance/safe level. The FDA has found no evidence which indicates that treating lactating cows in accordance with labeled directions will cause a positive truck tanker. The follow-up by the State regulatory agencies on positive truck tankers indicates that the positive test results are primarily the result of misuse of animal drugs.

It has been suggested by some individuals that testing under the provisions of Appendix N, PMO, with the FDA and NCIMS accepted screening tests be discontinued. The FDA takes the position that discontinuing tanker truck testing is not consistent with a commitment to a safe milk supply, and therefore would be unacceptable to the Agency. Prior to the implementation of Appendix N, PMO, the Government Accounting Office concluded that there was no comprehensive strategy to ensure the safety of the milk supply. The State regulatory agencies and FDA are committed to maintaining a safe milk supply and have developed a comprehensive strategy for ensuring a safe milk supply. The strategy adopted by FDA and NCIMS includes monitoring of truck tankers in accordance with Appendix N, PMO, monitoring producer bulk tanks in accordance with Section 6, PMO, participation in the ten point Milk and Dairy Beef Quality Assurance Program in the event of a violation, monitoring the use and labeling of drugs through the PMO Farm Inspection Program, and individual cow testing.

Although research indicates that some screening tests may produce false positive test results in milk from individual cows, the FDA is not aware of any data which supports the conclusion that unique factors in the milk from individual cows produce false positive findings in truck tanker milk samples. The FDA maintains the view that the misuse of animal drugs causes a majority of screening test positives at the truck tanker. Despite the inherent limitations of screening tests, the issue remains one of proper drug use.

No screening test has been evaluated by the Center for Veterinary Medicine or the AOAC International Research Institute for use on milk from individual cows. Nine of the currently accepted tests for testing truck tanker milk are being evaluated for this use.

FDA has prepared a document entitled "Evaluation and Use of Milk and Antimicrobial Drug Screening Tests" which provides a detailed discussion of the evaluation and use of the screening tests as well as related issues regarding the monitoring for animal drug residues in milk. Copies of this document may be obtained from the FDA Veterinarian. Comments or questions on this issue may be addressed to Dr. Norris E. Alderson, HFV-500, CVM/FDA, 7500 Standish Place, Rockville, MD 20855. Phone 301-594-1702; email alderson@a1.cvm.fda.gov.

The following is an update of an article on FDA's tissue residue program which appeared in the March/April 1991 issue of the FDA Veterinarian (pp. 7-9).

Consumers are more health conscious than ever before. There is significant consumer concern about the safety of the food supply. FDA has primary responsibility in the Federal government for food safety in the U.S. Under the Federal Food, Drug, and Cosmetic Act, FDA is responsible for ensuring that human foods and animal feeds are safe and, among other things, do not contain illegal residues of drugs, pesticides, environmental contaminants, or microorganisms that might be harmful to public health.

Among other duties, FDA's Center for Veterinary Medicine (CVM) is responsible for protecting the public health through pre-approval evaluations and acceptance of sponsor-submitted safety and effectiveness studies for regulation of animal drugs, medicated feeds, and food additives. CVM also regulates veterinary devices to ensure that the labeling is not false or misleading and that directions for use are adequate. In addition, CVM regulates the levels of chemical, mycotoxin, and bacterial contaminants in animal feeds to ensure that food for man and animals is safe and free of illegal drugs, industrial chemical and pesticide residues, and harmful bacteria. When an animal drug is intended for use in food-producing animals, the safety of food products derived from the treated animals must be established before approval for marketing is granted. The pre-market approval process ensures that foods derived from properly treated animals will not contain potentially harmful drug residues. The preslaughter withdrawal period and milk discard times are based upon the time necessary for drug residues in the animal to deplete to levels that have been shown to be safe.

Protecting the public health, while permitting food animal producers to realize the economic benefits of safe and effective drugs are responsibilities shared by several Federal and State agencies. FDA works closely with the United States Department of Agriculture's (USDA's) Food Safety Inspection Service (FSIS) in both preharvest and postharvest initiatives to control illegal tissue residues of veterinary drugs. In addition to FSIS, FDA also works with the USDA's Grain Inspection Packers and Stockyards Administration (GIPSA) and Animal and Plant Health Inspection Service (APHIS), and the Environmental Protection Agency (EPA). The mechanism for interagency interaction between these Federal agencies is the Interagency Residue Control Group (IRCG). IRCG's objective is to attempt to solve the complex problem of tissue residue violations through communication and cooperative efforts in investigation and enforcement.

The FSIS is charged under the Federal Meat Inspection Act and the Poultry Products Inspection Act with ensuring that meat and poultry sold in interstate commerce in the U.S. is safe, wholesome, and free of adulterating residues. FSIS reports violative residues of drugs, pesticides, and other contaminants in meat or poultry to FDA for followup.

GIPSA works closely with FSIS in regulating animal marketing practices. GIPSA enforces the Packers and Stockyards Act through economic regulation to assure fair marketing practices. GIPSA also assists FDA in securing producer identification when sales are through auctions, sales barns, or dealers.

APHIS carries out programs to protect the Nation's livestock and poultry resources, to prevent the entry of dangerous animal diseases by assuring that only healthy animals are imported, and to enhance the export of livestock and poultry. Also, APHIS cooperates with, and provides technical assistance to States in disease control and eradication programs.

As mentioned above, the FDA evaluates and decides on the approval of animal drugs and medicated feeds. This includes establishing tolerances for residues of animal drugs in edible tissues. FDA also conducts followup inspections of producers or others involved in the production or marketing of food animals or poultry which have tissue residue violations.

FSIS monitoring programs currently indicate a low rate overall of violative residues in animal products. This was not always the case, for instance, in 1979 sulfamethazine residues exceeded 10 percent in some slaughter classes. During Fiscal Year 1994, FSIS reported 2514 animals containing violative residues. This was a decrease from the level in Fiscal Year 1993 of 3809 animals. Despite this reduction, USDA and FDA recognize the need for continued vigilance to ensure that current levels do not increase and the need for continued work towards a zero level of illegal tissue residue violations.

CVM's Tissue Residue Program is a public health program with the goal of assuring that consumer exposure to drug residues in edible tissues of food animals is minimized. The program focuses on prevention and regulatory enforcement in eliminating illegal residues. FDA's Tissue Residue Program has been emphasized in recent years because of the Agency's increasing concern about consumer exposure to drug residues in the edible tissues of food animals.

Tissue residue investigations may reveal problems associated with a variety of CVM program areas including the illegal sale of veterinary prescription drugs, illegal distribution and use of bulk drugs, cross-contamination of animal feeds due to poor Good Manufacturing Practices, failure to follow good animal husbandry practices or withdrawal requirements, the misuse of drugs in medicated animal feeds, the marketing of treated/medicated animals intended for pet food or rendering purposes being diverted to slaughter for human consumption, and inadequate animal identification.

Due to resource constraints, FDA cannot investigate all of the initial tissue residue violations reported by FSIS. State regulatory bodies have stepped in to help carry out followup investigations. FDA has Memoranda of Understanding (MOUs), contracts, and informal agreements with30 State agencies to conduct these investigations. Under these various agreements, States trace and identify producers who market animals with illegal residues. They investigate auction barns, trucking companies, feedlots, and animal dealers, as well as collect and analyze feed and other materials to determine the source of the violations.

Improper use of drugs can result in illegal residues which can cause carcass condemnation at slaughter. In addition, involved parties are subject to various regulatory actions by the FDA.

FDA can take regulatory action against a producer or other responsible person(s) when it has been documented that the animals offered for slaughter in interstate commerce resulted in illegal residues in edible tissue. For example, regulatory action can be taken against a producer who sells animals containing illegal drug residues to an intermediate party, that in turns sells them at an auction, where they are purchased by a buyer who in turn sells them to a slaughter plant doing interstate business. In such circumstances, the producer can be charged with causing the delivery for introduction into interstate commerce of adulterated food, even if the producer has no specific knowledge of the ultimate destination of the animals.

The other parties involved in the scenario may also be charged with causing the delivery for introduction into interstate commerce of adulterated food, or they may be charged with offering for introduction into interstate commerce. Additionally, "caused to be introduced" charges may be brought against veterinarians, animal dealers, buyers, vendors, auction barns, or other persons who are responsible for having caused the residue or having introduced animals into interstate commerce without first assuring that the animals were free of illegal residues.

When illegal residue investigations uncover suspected criminal activity such as use of false names, knowingly purchasing medicated animals for immediate slaughter, purchasing animals with the understanding that they will be sold for rendering or other non-human food, the matter is referred to FDA's Office of Criminal Investigations (OCI).

Persons involved in handling, transporting, holding, and marketing food-producing animals are encouraged to establish systems to ensure that if they administer drugs to animals in their control or care, those drugs are used properly, and to establish systems to prevent potentially hazardous drug residues in edible animal products.

Persons who do not administer medications, but who acquire animals for sale for slaughter (such as livestock dealers) should also establish and implement a record keeping system. This system should include information on the source of the animal and whether the animal has been medicated (when, with what drug, and the withdrawal period) to preclude the marketing of edible animal tissues containing violative residues.

Meat, poultry, milk, and egg producers also must be sensitive to consumer concerns about residues. Adequate quality assurance programs must be in place, and responsibility for the safety of the edible product must be assumed at all levels of the food distribution chain, including the producer, veterinarian, auction/sales barn, dealer/hauler, feed manufacturer, packer, wholesaler, retail store, and consumer. All parties involved in livestock marketing should make a concerted public relations effort to foster consumer confidence, but this must be backed up with a solid quality assurance program. Maintaining high standards for products will maintain and perhaps improve market share.

The following information is derived from a report prepared by CVM's Division of Voluntary Compliance and Hearings Development on illegal drug residues during FY 94.

Under the Meat and Poultry Inspection Act, USDA's Food Safety and Inspection Service (FSIS) has the authority to perform inspections of animals offered for slaughter for human food. As part of their inspection program, FSIS may collect samples of edible tissues from the animals to be analyzed for chemical contaminants, as well as for other adulterants. When FSIS finds levels of drugs or pesticides in edible animal tissues which are above tolerances set by FDA or the Environmental Protection Agency, FDA is notified so that a follow-up may be made. Based on a number of criteria, which include the toxicity of the chemical, the level found, permitted uses of the chemical, and manpower availability, FDA or a State may conduct a follow-up investigation. The purposes of the follow-up investigations are to determine the cause of the residue and the responsible individuals, prevent future occurrences of residues by that person, and establish documented notification and warning of the violation if future legal action is necessary.

During Fiscal Year 1994, FSIS reported 2,514 animals containing violative residues. FDA, in cooperation with participating States, followed up on 1,076 (approximately 45 percent) of the reported violations.

CVM's Division of Voluntary Compliance and Hearings Development has reviewed the 1,049 Fiscal Year 1994 Establishment Inspection Reports (EIRs) containing data captured during field investigations conducted by FDA/CVM and State veterinarians. The remaining 37 reports were excluded from the study because they were incomplete.

The drugs most frequently identified as causing antibiotic residues included the following: penicillin (21 percent), oxytetracycline (10 percent), sulfamethazine (10 percent), streptomycin (6 percent), tetracycline (5.2 percent), neomycin (4.1 percent), gentamicin (3.7 percent), and sulfadimethoxine (3.4 percent). Sulfamethazine was the most frequently cited sulfonamide. Thirty percent of the reported violative residues were Calf Antibiotic and Sulfonamide Test (CAST) positive samples (see Table I).

In Fiscal Year 1994, the animal slaughter classes most often associated with residues were bob veal calves, culled dairy cows, other cows (both beef and cull cows, and market hogs) (see Table II). Residues associated with injectable drugs were investigated most frequently. Injectable drugs accounted for approximately 42 percent of the violations. This was followed by unknown, and the oral route (feed additive, bolus, and water). Intramammary infusion accounted for 2.2 percent of the violations investigated (see Table III).

Most of the drugs that caused the residues were purchased from a feed/farm supply store or veterinarian. They accounted for 31.2 percent and 20.4 percent of the drug purchases respectively.

The primary cause of residue violations was failure to adhere to the approved withdrawal time. Other causes included failure to keep proper animal identification and treatment records or poor husbandry practices, and exceeding recommended dosage (extra-label use) (see Table IV).

The total number of residues has decreased each year since 1991 (see Table V). There have been no major changes in the drug classes, slaughter classes, and drug use patterns which have contributed to violative residues. Ignoring labeled withdrawal times continues to be a major source of drug residue violations.

Copies of the complete "Tissue Residue Annual Report - FY 94" are available from the FDA Veterinarian.

TABLE I--DRUGS CAUSING RESIDUES IN MEAT EXPRESSED AS A PERCENTAGE OF ALL RESIDUES--Fiscal Year 1994

Drug	Number of Residues	Percentage
CAST* General	880	30
Penicillin	629	21
Oxytetracycline	304	10
Sulfamethazine	293	10
Streptomycin	177	6
Tetracycline	154	5.2
Neomycin	120	4.1
Gentamicin	108	3.7
Sulfadimethoxine	101	3.4
Chlortetracycline	63	2.1
Erythromycin	43	1.4
Ivermectin	10	0.3
PCBs	9	0.3
Levamisole	7	0.2
DDT & Metabolites	7	0.2
Arsenic	6	0.2
Sulfaquinoxaline	4	0.1
Sulfathiazole	3	0.1
Carbadox	3	0.1
Unidentified	3	0.1
Sulfachlorpyridazine	2	0.07
Tylosin	2	0.07
Berenil	2	0.07
Other (1 Each)	7	0.20
TOTAL	2,937

TABLE II--VIOLATIVE ANIMALS BY FREQUENCY OF VIOLATIONS--Fiscal Year 1994

Slaughter Class	Number	Percentage
Bob Veal	893	35.5
Dairy Cows	523	20.8
Cows	476	18.9
Barrows & Gilts	187	7.4
Beef Cows	120	4.8
Steers	60	2.4
Heifers	53	2.1
Sows	43	1.7
Roaster Pigs	24	1.0
Formula Fed Veal	21	0.8
Bulls/Stags	20	0.8
Non-Formula Fed Veal	18	0.7
Boars/Stags	16	0.6
Horses	15	0.6
Heavy Calves	13	0.5
Young Turkeys	8	0.3
Calves	7	0.3
Lambs & Yearlings	7	0.3
Mature Sheep	6	0.2
Young Chickens	5	0.2
Mature Turkeys	4	0.2
Goats	4	0.2
Ducks	1	0.04
TOTAL	2,514

TABLE III--RESIDUE VIOLATIONS BY ROUTES OF ADMINISTRATION--Fiscal Year 1994

Route of Administration	Number of Follow-ups	Percentage
Injectable	438	42.0
Unknown/Other	229	21.8
Oral	181	17.2
Feed Additive	(90)	(8.6)
Bolus	(87)	(8.3)
Water	(4)	(.3)
Intrammary Infusion	24	2.2
Blank or Unanswered	177	16.8

TABLE IV--PRIMARY CAUSES OF RESIDUE VIOLATIONS--Fiscal Year 1994

Causes	Total Number of Cases	Percentage
Failure to Adhere to Approved Withdrawal Time	455	43.4
Unable to Determine	180	17.2
Other	140	13.3
No Answer	65	6.2
Failure to Keep Proper
ID and Treatment	64	6.1
Records or Poor
Husbandry Practices
Exceeded Recommended Dosage	51	4.9
Drugs Administered by Mistake	47	4.5
Feeding Colostrum with Residues	37	3.5
Drug Carryover/Cross Contamination	5	0.5
Unapproved Use	4	0.4
Mistakenly Given Medicated Feed	1	0.1
Total	1,049

This issue of the FDA Veterinarian contains the second in a series of questions and answers that are frequently asked about CVM's Veterinary Adverse Drug Experience (ADE) program.

A. FDA's 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 (such as rabies vaccines) are regulated by the U.S. Department of Agriculture 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 under the Federal Insecticide, Fungicide, and Rodenticide Act.

The U.S. Pharmacopeia 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. The identity of the person reporting will be withheld if they wish to remain anonymous. This program has the support and endorsement of the American Veterinary Medical Association. The USP program is not affiliated with FDA.

A. 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.

A. Approximately 95 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.

A. Veterinarians at CVM evaluate about two thousand reports annually. This estimate includes reports of product defects.

CVM is announcing that all dipyrone products must have an approved new animal drug application (NADA) to remain on the market. The Center is taking this position because a recent survey of dairy farms found evidence of extra-label use in food-producing animals. Use of the drug in dairy animals has never been shown to be safe or effective. In addition, CVM is concerned that these unapproved dipyrone products unfairly compete with other drugs which have been approved.

Dipyrone injectables have been sold as prescription products for use in certain non-food animals. While these dipyrone animal products have never been the subject of approved NADAs, FDA has permitted their sale under regulatory discretion. The labeled use of dipyrone has been as an injectable analgesic/antipyretic for horses, dogs, and cats. The label of these marketed products specifically prohibits use in food animals.

The use of dipyrone has been associated with bone-marrow toxicity, severe agranulocytic anemia, dose independent teratogenicity, induction of the microsomal enzyme system, and a tendency to increase bleeding times by suppressing the formation of prothrombin. Toxicity concerns led FDA to withdraw approval of all dipyrone-containing products for use in humans in 1977.

In addition to these safety concerns, qualified experts have questioned the effectiveness of dipyrone animal products for their labeled claims for use as a spasmolytic agent to aid in treating equine colic. Therefore, these products are not considered to be generally recognized as safe and effective for their labeled uses. Also, the scientific literature contains no information on pharmacokinetics, and no regulatory method exists for assay of dipyrone or its metabolites in milk or meat.

Dipyrone products are in violation of the Federal Food, Drug, and Cosmetic Act. In letters to all known manufacturers and distributors of dipyrone, CVM has advised that these products now must be approved. Regulatory discretion for marketing these products will no longer be granted because of concerns about safety, effectiveness, and fairness to other approved drug products.

Additional information on this subject is available from FDA, Center for Veterinary Medicine, Office of Surveillance and Compliance, HFV-200, 7500 Standish Place, Rockville, MD 20855, (301) 594-1761.

Annual Maryland Conference for Bovine Practitioners--March 28-29, 1996, Frederick, Maryland.

The Virginia-Maryland Regional College of Veterinary Medicine, Maryland Campus; the Maryland Cooperative Extension Service; and the American Association of Bovine Practitioners, District II are sponsoring a two-day conference for bovine practitioners at the Holiday Inn, Francis Scott Key Mall, Route 85, Frederick, Maryland.

The conference begins at 10:30 a.m. on Thursday, March 28, 1996. Topics for the first day of the conference include troubleshooting the use of recombinant bovine somatotropin in dairy cows, managing and feeding cows during heat stress, roles and responsibilities of veterinarians and others in the dairy industry when a tanker tank is positive for residues, and computer-based practice tips. The second day of the conference will feature a four-hour workshop on assessing critical financial and production success factors for a dairy farm, and a session on troubleshooting pasture management systems for dairy cattle.

Registration, which includes meals, may be made for one or both days. The cost is $140.00 for both days or $80.00 for one day. Half price registration is available for veterinary students or animal health technicians. Registration for spouses is free, but this does not include meals. The registration deadline is March 15, 1996. Checks for payment of the registration should be made out to the University of Maryland. Conference participants may receive reduced nightly room rates at the conference hotel. Reservations for the hotel must be made directly with the hotel by calling (301) 694-7500.

Additional information and registration is available from Dr. Douglas K. Carmel, Livestock Extension Veterinarian, VMRCVM, University of Maryland, College Park, MD, 20742, phone (301) 935-6083 extension 118 or fax (301) 935-6079, or electronic mail at dc9@umail.umd.edu.

CVM has published a new consumer flier entitled "Information on Marketing a Pet Food Product" which may be of interest to firms or individuals interested in this endeavor. Single copies of the flier are available free of charge from the FDA Veterinarian.

FDA has announced that the "Report of the Fluoroquinolone Working Group" is available. This report addresses issues and contains recommendations regarding policies and procedures related to approval of fluoroquinolone (FQ) antimicrobial drugs in food animals. The report of the Fluoroquinolone Working Group is in response to concerns that approval of FQ drugs for use in food animals may result in increased development of FQ resistance in zoonotic organisms harbored by food animals that are transmitted to humans and cause disease. Single copies of the report are available free of charge from the FDA Veterinarian.

SEMDURAMICIN (Aviax (TM)), Pfizer, Inc. (NADA 140-940). FDA is amending the animal drug regulations that reflect approval of a new animal drug application (NADA). The previous amendment provided for making a semduramicin Type A medicated article used to make a Type C medicated broiler chicken feed for the prevention of coccidiosis. The Agency has since realized it needs to more accurately reflect both the assay limits for semduramicin Type A articles and the limitation for its use. This action is being taken to ensure the accuracy and consistency of the regulations. Federal Register, November 24, 1995.

On December 6, 1995, a Grand Jury issued a 12-count indictment against Jannes (John) Doppenberg, Sherry Steffen, and the Vitek Corporation for conspiracy and smuggling unapproved drugs into the U.S., and adding these drugs to feed mixtures sold to veal producers. Vitek Supply Corporation, located in Oak Grove, Wisconsin, imports, manufactures and distributes animal drugs, feed, feed supplements, and feed premixes for food-producing animals, primarily veal calves. Jannes Doppenberg is the president and owner of Vitek, and Sherry Steffen is employed as Vitek's office manager.

It is alleged in the indictment that the unapproved drugs were added by Vitek to its feed premix products and shipped to feed companies and growers in Kansas, Nebraska, Wisconsin, Minnesota, Pennsylvania, and Illinois. It also is alleged that between 1988 and April 1994, Vitek sold over 1.7 million pounds of products containing unapproved drugs, valued at almost $1.3 million dollars. The unapproved drugs listed in the indictment include:

The indictment charges a conspiracy to defraud the U.S. by circumventing the lawful functions of the Food and Drug Administration and the U.S. Customs Service, five counts of smuggling, four counts of shipping misbranded drugs, and two counts of shipping adulterated drugs. Vitek Corporation and Doppenberg are charged in all twelve counts of the indictment. If convicted, the corporation faces fines up to $500,000 on each of the first six counts and fines up to $10,000 for the other six counts. In addition, both Doppenberg and Steffen face up to five years incarceration, a $25,000 fine, or both, if convicted of the conspiracy alleged in the indictment (count one) . The five smuggling-related offenses charged in the indictment (counts two through six) carry up to five years incarceration, a $250,000 fine, or both. Doppenberg is charged in each of these counts, while Steffen is charged only in one. Counts seven through twelve each carry up to three years incarceration, a $10,000 fine, or both. Doppenberg is charged in all these counts, while Steffen is charged only in one. If convicted of all counts and given the maximum sentence, the corporation could be fined $3,060,000; Doppenberg could be sentenced to 48 years in jail and a fine of $1,335,000; and Steffen could be sentenced to 13 years in jail and a fine of $285,000.

The indictment is the result of a cooperative investigation conducted by investigators from U.S. Customs, the FDA, and the U.S. Department of Agriculture. The investigation is ongoing.

Day-old Broiler Chickens. For control of early mortality associated with E.coli organisms susceptible to sarafloxacin.

INJECTABLE: Provides for a single subcutaneous 0.2 milliliter injection in the neck. Dilute 1 milliliter of SaraFlox® with 100 milliliters of sterile water or physiologic saline to provide 0.1 milligram sarafloxacin in a 0.2 milliliter dose. Federal Register 11/22/95.

Weanling Calves and Breeding Beef Cattle. For prevention and treatment of selenium/tocopherol deficiency.

INJECTABLE: ANADA 200-109 is a generic copy of SCHERING- PLOUGH'S MU-SE ® (selenium/vitamin E injection) in NADA 30-314. Federal Register 11/22/95.

Horses. For relief of inflammatory conditions associated with the musculo-skeletal system.

INJECTABLE: ANADA 200-126 is a generic copy of Coopers Animal Health's NADA 011-575 for Butazolidin ®. Federal Register 10/16/95.

MEDICATED FEED: The supplemental NADA expands the use of Type A medicated article to make a 113-g/t Type C medicated feed for rabbits. Federal Register 11/24/95.

MEDICATED FEED: The firm filed two supplemental NADAs. One supplement provides for the addition of certain lasalocid-containing Type A medicated articles to dry, powdered milk replacer before reconstitution. The reconstituted Type C medicated feed is used to control coccidiosis in non-veal calves. Additionally, FDA is amending the regulations to reflect approval of another supplemental NADA which changes "feed continuously" to "hand feed" for lasalocid-containing (68 to 113 g/t), Type C medicated feeds to cattle for control of coccidiosis caused by E. bovis and E. zuernii. Federal Register 10/20/95.

Cattle. For treatment of acute bovine interdigital necrobacillosis (foot rot, pododermatitis) associated . with certain bacteria.

INJECTABLE. Provides for equivalent of 50 milligrams of ceftiofur per milliliter used at 0.5 to 1.0 milligrams per pound of body weight once daily for up to 5 days. Federal Register 10/3/95.

MEDICATED FEED: Provides for the use of decoquinate Type A medicated articles to make Type C medicated feeds. Federal Register 10/17/95.

Fiscal Year	Violative Animals	Violative Residues

1991	4339	5072
1992	4325	4960
1993	3809	4283
1994	2514	2937