Joint Committee on the Use of Antibiotics in Animal Husbandry and Veterinary Medicine, Her Majesty 's Stationery Office London 1969.

Garbutt, J. M., Ventrapragada, M., Littenberg, B., and Mundy, L. M. Association between resistance to vancomyin and death in cases of Enterococcus faecium bacteremia.

Salyers, A.A., Shoemaker, N.B., Stevens, A.M., Li, L.Y. Conjugative transposons: an unusual and diverse set of integrated gene transfer elements. Microbiol Rev. 1995 Dec;59(4):579-90. Review.

The team has completed testing of two drugs in the model system. The results have attracted interest and support from the FDA’s Office of Women’s Health (OWH). Through the intramural research grant program, the OWH has agreed to fund additional development of the model to evaluate drugs of specific interest to women’s health.

Dioxins are a family of about 30 compounds that accumulate in the fat of humans and animals. They produce a broad range of adverse effects including, but not limited to, enhanced tumorigenicity, enzyme induction, immune suppression, and a wasting syndrome.

In a 1994 draft risk assessment, the U.S. Environmental Protection Agency (EPA) estimated that the diet was the primary source of dioxin exposure. EPA estimates that 95 percent of dioxin intake for a typical person comes through dietary intake of animal fats. Small amounts of exposure occur from breathing air containing trace amounts of dioxin on particles and in vapor form. Very little dioxin exposure occurs through water.

The issue of dioxin in foods is not new, and it is not unique to the U.S. food supply. To date, the primary Federal government effort regarding dioxin exposure through the food supply has been to reduce the level of dioxins released into the environment. EPA has pursued the control and management of dioxin through each of its major program areas. These actions have placed strict regulatory controls on all of the major well-defined industrial sources of dioxin. As a result of EPA's efforts, along with effort by State government and private industry, known industrial emissions will be reduced by more than 90 percent by 2002.

Another effort has been a multi-Agency endeavor to look for and eliminate special instances of food contamination by dioxin. For example, in 1997 dioxin monitoring by the Federal government found unusual levels of dioxin in some farm-raised fish and poultry products. Once discovered, an investigation was launched immediately, which revealed that a particular food additive (a clay called ball clay used as an anti-caking agent in some soybean meal) was responsible. Through the regulatory authority of FDA, this food additive was immediately prohibited for use in any animal feed. Another example of an effort to eliminate special instances of food contamination by dioxin was when elevated levels of dioxin and PCBs were discovered in some Belgian animal products in 1999. FDA stopped import of those products into the United States.

In June 2000, EPA released an Integrated Summary and Risk Characterization for dioxin and related compounds and a new technical chapter on dioxin Toxicity Equivalence Factors (TEF) for independent scientific peer review. In their draft reassessment, EPA concludes that dioxin is a "human carcinogen", and states that while emissions of dioxin have decreased from their peak levels in the 1970s they still may pose a significant cancer threat to some people who ingest the chemical through foods in a normal diet. EPA's draft Dioxin Reassessment is not considered finished until it goes through a review process including several levels of scientific evaluation and stakeholder comment.

In the past, FDA testing for dioxin has been limited to a few hundred samples a year, primarily of fish and dairy products from grocery stores and distribution centers. In addition, USDA and EPA have recently examined dioxins in a similar number of beef, pork, and poultry samples from across the country. FDA limited monitoring to these foods because dioxins occur at levels that are so low that they are hard to detect, and until recently, the methods used to detect dioxins were very expensive. Recent improvements in the science and cost of dioxin analysis have enabled FDA to broaden monitoring. FDA is now examining dioxins in 200 of the most commonly eaten foods, through the Total Diet Study. In addition, both FDA and USDA are developing plans to increase monitoring of the foods and animal feeds most likely to contain dioxins.

⁴ The number of NADAs currently marketed divided by the number of NADAs currently approved, expressed as a percentage.

The approval rate has fluctuated when comparing the number of approvals across decades. The fewest approvals occurred during the 1990s. Many factors may account for differences in approval activity. Some decades may be associated with industry investments in certain products, such as medicated feeds. Other decades may reflect various regulatory activities, such as enactment of the animal drug amendments of 1968 and NAS-NRC Drug Efficacy Studies of the 1970s.

Similarly, NADA withdrawals may reflect either disinterest in certain types of drugs by the veterinary community or disfavor because of safety or environmental concerns, or because of the availability of newer and better drugs. The majority of NADAs approved during the 1930-1960 decades have been voluntarily withdrawn by the drug sponsor, while to date no approvals from the 1990s have been withdrawn. FDA-identified safety or efficacy issues may sometimes result in an NADA being withdrawn, but this number is small. A number of NADAs in the STARS database are not associated with an approval date. These NADAs represent old approvals and all, except for one, have been withdrawn. Not surprisingly, the more recently a drug has been approved, the more likely it is to be marketed.

Of notable interest is the percentage (by decade) of currently approved new animal drugs that are being currently marketed (percentage of number of currently approved currently marketed). Categorized by the decade of approval, only 30 to 47% of the currently approved NADAs are being marketed. Conversely, this means that 53 to 70% of the currently approved NADAs are not being marketed. Several factors influence whether a drug remains actively on the market. The drug sponsor or manufacturer bases their decision to distribute any one product on economic and market considerations. At present only 38% (535) of current NADAs (those available for marketing [1415]) are marketed. Even for the 1990's, approximately only half of approved NADAs are being marketed. Ultimately, for the vast majority of NADAs, it is the drug industry, and not the FDA, who determines whether an approved NADA is marketed. In order to reduce the administrative burden on the FDA and industry for maintaining NADAs, the FDA/CVM encourages the animal drug industry to voluntarily withdraw NADAs that have been inactive for several years.

²The number of NADAs with non-food animal species indications divided by the number of NADAs currently marketed, expressed as a percentage.

Presented in Table 3 is the number of NADAs currently marketed classified by their intended therapeutic uses by decade of approval. Certain approved drugs may have more than one type of indicated use, so that the sum of each therapeutic category within a decade does not total the number of currently marketed drugs. Industry product development interest has remained relatively constant over the decades with regard to several therapeutic categories. Systemic antimicrobials have usually been the most active category, followed by antiparasiticides. Analgesic, growth promotant, central nervous system, hormone and dermatologic drug categories have also remained active, although to a lesser extent.

Current and future company mergers, economic constraints and drug utilization profiles could create an animal pharmaceutical marketplace that is substantially different. Considering these factors and the current regulatory issues involving animal health and agriculture, the profile of the marketed animal drug inventory may change over time.

Table 3.
Label indications of approved marketed animal drugs^1,2.

¹# -- The number of labeled indications for each therapeutic category.
²%Mktd is the number of labeled indications divided by the number of NADAs currently marketed.

Last year, a new Division of Epidemiology was created in the CVM's Office of Surveillance and Compliance (OS&C.) Most of the Division staff members previously had been part of OS&C's Division of Epidemiology and Surveillance. William S. Calvert, M.P.H. joined as Division of Epidemiology Director in January 2000.

Over the last ten to fifteen years, there has been increasing recognition of the need for epidemiological expertise within the Center. This new Division was established to be a major contributor to CVM's mission by providing technical and epidemiological support for the regulatory and research activities of the Center. Division scientists serve as consultants to FDA and other Federal and State agencies regarding epidemiological issues such as antimicrobial resistance and tissue residues. Also, the Division of Epidemiology assists in developing regulatory policy and study protocols, overseeing study execution, analyzing and evaluating findings, and training and mentoring epidemiologists for the future. Other Division activities include evaluating surveillance and post-marketing data and initiating appropriate public health actions.

The Division of Epidemiology is unique in CVM since its current funding comes completely from the President's Food Safety Initiative. This is a reflection of the increasing importance of epidemiologic expertise in addressing food safety issues. For example, the Division's growth is linked to the expansion of the National Antimicrobial Resistance Monitoring System for enteric bacteria (NARMS-EB). NARMS-EB is an interagency collaboration established between FDA, CDC, and USDA to prospectively monitor trends in antimicrobial resistance of human and animal enteric pathogens. The NARMS-EB program provides descriptive data on the extent and temporal trends of antimicrobial susceptibility in salmonella and other enteric organisms from human and animal populations, facilitates the identification of resistance in humans and animals as it arises, provides timely information to veterinarians and physicians, prolongs the life span of approved drugs by promoting the prudent use of antimicrobial drugs, and identifies areas for more detailed investigation.

In addition to NARMS-EB, other Division activities include working on tissue residues, microbial ecology, and microbiology issues; implementing the concepts laid out in the "Framework" Document ("A Proposed Framework For Evaluating And Assuring The Human Safety Of The Microbial Effects Of Antimicrobial New Animal Drugs Intended For Use In Food-Producing Animals"); and reviewing various regulatory documents and related actions. The Division also is participating in formal risk assessment projects (such as the risk assessment on fluoroquinolone resistance in Campylobacter from poultry); post-approval monitoring programs; committee work at multiple levels, including international efforts; and contributing to the FDA response to foodborne disease outbreaks.

Before joining CVM, Mr. Calvert held a variety of positions both within and outside the government. From late 1989 until he came to CVM, Mr. Calvert was with FDA's Center for Drug Evaluation and Research where he directed a staff that developed information technology solutions and infrastructure in support of pharmacovigilance and pharmacoepidemiology efforts. He received his M.P.H. degree in epidemiology and biostatistics from the University of South Carolina. In an interview with the FDA Veterinarian, Mr. Calvert said that he "looks forward to meeting the many challenges and public health issues that confront us." He continued by saying that "as a new Division we will first have to develop our 'culture' and infrastructure so that it will continue to support the quality tradition of our roots, while still allowing us to increase our numbers and grow into our new responsibilities. Over the next year we will continue with many of our current activities. We will be looking for more and better sources of data, such as the expansion of NARMS-EB, and we will continue to develop and share epidemiological expertise. Finally, we will be looking for new ways to work with others who share our public health goals."

Staff members of the Division of Epidemiology include: Dr. Charles E. Eastin II, Dr. Marcia L. Headrick, Ms. Kathy S. Hemming, Dr. Roger A. Jones, Dr. Joseph C. Paige, Dr. Terry Proescholdt, Dr. Linda E. Silvers, and Ms. Teresa R. Thomas. There are two additional staff members currently on temporary duty assignments within CVM: Dr. Katherine A. Hollinger and Dr. Charlotte D. Spires.

In a notice published in the May 12, 1998, Federal Register, FDA announced that FAP 2238 had been filed by Alltech Biotechnology Center, Nicholasville, KY. FDA has concluded that the data submitted by the firm establish the safety and utility of selenium yeast for use in feeds for chickens. The petition and the documents that FDA considered and relied upon in reaching its decision to approve it are available for inspection at FDA's Center for Veterinary Medicine by appointment with Dr. Nelson Chou. Dr. Chou may be reached at Center for Veterinary Medicine (HFV-228), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-827-0161. The Agency will delete any materials that are not available for public disclosure before making the documents available for inspection.

Additional information about this approval is contained in the June 6, Federal Register and from Dr. Nelson Chou. Written objections to this approval and requests for a hearing should be submitted by July 6, 2000 to: Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD 20852.

The Food and Drug Administration (FDA) announced today plans to refine its regulatory approach regarding foods derived through the use of modern biotechnology. The initiatives unveiled stem in part from input received during FDA's public outreach meetings held late last year and build upon programs already underway at FDA to help ensure the safety of all foods.

"FDA's scientific review continues to show that all bioengineered foods sold here in the United States today are as safe as their non- bioengineered counterparts, "said Jane E. Henney, MD, Commissioner of Food and Drugs. "We believe our initiatives will provide the public with continued confidence in the safety of these foods."

FDA will publish a proposed rule mandating that developers of bioengineered foods and animal feeds notify the agency when they intend to market such products. FDA also will require that specific information be submitted to help determine whether the foods or animal feeds pose any potential safety, labeling or adulteration issues.

Although the current consultative process has worked well, and the agency believes it has been consulted on all bioengineered foods and feeds currently on the market, FDA will propose to strengthen this process by specifically requiring developers to notify the agency of their intent to market a food or animal feed from a bioengineered plant at least 120 days before marketing. After reviewing the company's submission, FDA will issue a letter to the firm describing its conclusion about the regulatory status of the food or animal feed. To make sure that consumers also have access to product information, FDA will propose that submitted information and the agency's conclusions be made available to the public, consistent with applicable disclosure laws, by posting them on the FDA Web site for easy viewing.

In a related step, the agency will augment its food and veterinary medicine advisory committees by adding scientists with agricultural biotechnology expertise. FDA will use these committees to address over-arching scientific questions pertaining to bioengineered foods and animal feed.

FDA also announced today plans to draft labeling guidance to assist manufacturers who wish to voluntarily label their foods being made with or without the use of bioengineered ingredients. The guidelines will help ensure that labeling is truthful and informative. To receive maximum consumer input, FDA will develop the guidelines with the use of focus groups and will seek public comment on the draft guidance.

These violations involved illegal residues of gentamicin and penicillin in dairy cows; gentamicin in cows; penicillin in a dairy cow; sulfadimethoxine in a dairy cow; tilmicosin and sulfamethazine in a steer; tilmicosin and sulfamethazine in a heifer; tilmicosin, sulfamethazine, and gentamicin in a steer; sulfamethazine and gentamicin in a steer; gentamicin in a steer; and tilmicosin in a dairy cow.

Warning letters were also sent to the following firms/individuals that also had offered animals for sale for human food in the past that were adulterated with drug residues. These warning letters stated that these individuals/firms had offered animals for slaughter that contained illegal drug residues:

These violations involved illegal residues of penicillin in dairy cows and illegal residues of penicillin, tilmicosin, and neomycin in cows.

Warning letters were sent to the following firms/individuals for violations from Good Manufacturing Practices (GMPs):

A warning letter was sent to Dr. Douglas A. Tuthill, Noah's Ark Animal Hospital, Goshen, NY, for prescribing and dispensing gentamicin sulfate for the treatment of cows that were later offered for sale for human food with illegal residues of gentamicin. There is no permitted level for residues of gentamicin in edible tissue of cattle. Veterinarians who prescribe drugs for extra-label use in the treatment of disease conditions in food-producing animals assume added responsibility. The warning letter said that veterinarians who prescribe drugs for these types of uses must establish a substantially extended withholding period supported by appropriate scientific information. It also said that veterinarians must assure the identity of a treated animal is carefully maintained, and they must take appropriate measures to assure that assigned timeframes for withdrawal are met and no illegal residues occur.

A warning letter was sent to Dr. Howard F. Terrill, Manchester Veterinary Clinic and Supply, P.C., North Manchester, IN, for prescribing veterinary drugs for veal farms in Pennsylvania without a valid veterinarian/client/patient relationship. The warning letter stated that Dr. Terrill was selling drugs for extra-label use which do not meet the conditions of the Animal Medicinal Drug Use Clarification Act for legal extra-label use.