March/April 2000 - Volume XV, No. II, FDA Newsletter

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CVM's Office of New Animal Drug Evaluation acted on 5,968 submissions for new animal drug applications (NADAs), abbreviated new animal drug applications (ANADAs), investigational new animal drug files (INADs) and generic investigational new animal drug (JINADs) files in FY 99 compared to 6,513 in FY 98. Approximately 85 percent of these decisions were made within the statutory and internal limits of 180 days. Of the 5,968 applications, 75 were for original applications (and reactivated originals) and 873 were for supplements to previously approved applications. In addition, 385 phased data submissions were completed by the Center during FY 99. The on-time rate for these applications and substantial submissions was 75 percent.

Approvals included very significant new product approvals, i.e., 5 new chemical entities, 9 products for use in new animal species, 6 with new tolerances/withdrawal times, and 17 with new indications. In addition, other approvals included 7 original generic approvals, 5 with new formulations, and 2 with new strengths/concentrations.

The new chemical entities approved in FY 99 included are listed in the table below.

A complete list of all FY 99 animal drug approvals is available from the FDA Veterinarian. Additional information about FDA-approved veterinary drugs is included on the Center's Home Page in the Electronic Green Book.

Dr. Glenn is the Executive Vice President and Scientific Liaison of the Federation of Animal Science Societies. Previously, she was a Research Animal Scientist for the U.S. Department of Agriculture specializing in ruminant nutrition.

Dr. Keith Sterner remains the chairman of VMAC, and other members include Dr. Fred Angulo, Dr. Steven A. Barker, Dr. Oscar Fletcher, Dr. Wanda Haschek-Hock, Dr. Robert E. Holland, Dr. Ling-Jung Koong, Dr. Vernon C. Langston, and Mr. Richard R. Wood. VMAC members normally serve four-year terms.

Adapted from a January 26 presentation made at the Association of American Feed Control Officials Midyear Meeting in Phoenix, Arizona.

The Office of Surveillance and Compliance in the Center for Veterinary Medicine (CVM) is responsible for reviewing data on genetically modified plants intended for use in animal feed. The Federal Food, Drug, and Cosmetic Act, which delineates FDA's regulatory authority for foods, defines food as articles used for food or drink for man and other animals. The Act, however, does not require pre-market clearance of food and thus, many genetically modified plants do not require formal pre-market review by the FDA as they are food.

The first modified plant evaluated by the Agency was the Calgene FlavrSavr^TM tomato which has improved ripening qualities. Calgene requested FDA regulation of the inserted marker gene product, aminoglycoside 3'-phosphotransferase II, an enzyme, as a food additive due to the novelty of the technology. This enzyme is encoded for by the kan^r or APHII gene. FDA actually regulates the gene product or its intended effect, not the inserted DNA itself. Thus, it is the gene product, aminoglycoside 3'-phosphotransferase, that was approved in 1994 as a food additive for food and feed usages in tomato, oilseed rape, and cotton (21 CFR 173.170 and 573.130).

In 1992 the FDA published a Statement of Policy in the Federal Register for Foods derived from New Plant Varieties. This policy applies to both genetically modified plants and those derived through other means. The 1992 policy sets out how the developers of new plant varieties should evaluate the safety and nutritional value of these foods. This science-based evaluation process is determined by the characteristics of the food, not its method of development. One primary focus is to determine if there are any unexpected effects in the new variety due to the genetic modification. These effects could include: 1) changes in toxicant or anti-nutrient levels; 2) changes in nutrient concentrations; and 3) alterations in allergenicity, i.e., the unintended movement of an allergenic protein from one food to another. The policy also addresses how the developers assess the safety of introduced proteins and other novel substances, the safety of any modified carbohydrates, fats, or oils, and also the products coded for by marker genes. The use of antibiotic resistance marker genes is also addressed in an Agency draft guidance document, which published in 1998. Plant developers can continue to use antibiotic resistance marker genes, but the guidance urges them to consider current medical practices and whether usage of the marker gene could compromise antibiotic effectiveness.

Developers are encouraged to voluntarily consult with the Agency at any time concerning a new genetic modification and may submit a summary of their evaluation of the new variety containing the modification for Agency review. These summaries are reviewed by both the Center for Food Safety and Applied Nutrition (CFSAN) and CVM to determine if the new variety differs in a significant manner from traditional crop lines. If all issues have been satisfactorily addressed, a letter is issued by CFSAN with CVM concurrence indicating that the consultation process is complete for that particular modification event. Information pertaining to the consultation process and FDA regulation of foods derived through biotechnology is available on the Foods WWW site under Biotechnology. It can also be accessed through the CVM WWW site. This table lays out the crops, modification, and numbers of varieties that have completed the voluntary consultation process.

Many of these plants have been modified to be herbicide tolerant and/or pest resistant. Pest resistant varieties fall under the regulatory authority of the Environmental Protection Agency (EPA). EPA is responsible for evaluating the safety, including environmental safety, of the introduced pesticide and all necessary genetic material. Recently, EPA imposed new restrictions on the use of some pesticidal corn varieties, because of concerns about the development of insect resistance. In these plants, FDA’s authority is limited to an assessment of unintended effects due to the genetic modification, primarily alterations in nutrient and toxicant concentrations. Herbicide resistant varieties fall under the regulatory authority of FDA with the exception that EPA is responsible for evaluating the safety of any applied herbicides and any resultant residues or metabolites under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). FDA evaluates the variety itself including the safety of the expression product of the introduced genetic material.

The labeling of food derived from genetically modified plants is a matter of some controversy. FDA does not consider the method of production, including genetic modification, to be meaningful information which is required to be on product labeling unless the modification results in a significant material change in the food product. For example, a variety of canola which supplies a significant amount of phytase activity has a proposed feed ingredient definition as phytase canola to reflect the presence of the desired enzyme. However, the majority of the plants which have completed the consultation process have not triggered any labeling requirement. FDA recently held 3 public listening sessions across the United States to solicit comments on labeling, the type of FDA's review process, public disclosure of information, and other issues associated with these products. Transcripts of these sessions are available on the FDA WWW site. FDA will evaluate this information and determine if changes are needed in its policy. More information about FDA's policy concerning food obtained from genetically modified organisms is available at www.fda.gov/oc/biotech/default.htm.

The Food and Drug Administration (FDA), Center for Veterinary Medicine (CVM) is announcing the availability of research funds for fiscal year (FY) 2000 to study the microbiological hazards associated with the food animal production environment. Approximately $600,000 will be available in FY 2000. FDA anticipates making 3 to 6 Cooperative Agreement awards at $100,000 to $200,000 per award per year (direct and indirect costs combined). Support for these agreements may be for up to 3 years.

FDA is mandated to assure the microbiological safety of foods, including those derived from animals. The President's Food Safety Initiative (FSI) of 1997 calls for increased allocation of resources for research by FDA to identify and investigate microbiological hazards associated with food produced by animal agriculture. The goal of the FSI is to further reduce the incidence of foodborne disease to the greatest extent possible. Specifically, FSI mandates research be conducted to develop the means to: (1) identify and characterize more rapidly and accurately foodborne hazards, (2) provide the tools for regulatory enforcement, and (3) develop interventions that can be used as appropriate to prevent hazards at each step from production to consumption of food.

The role of FDA's CVM in this research relates to microbial hazards associated with pre-harvest phases of food animal production, including aquaculture. The FSI specifically identifies a need for research addressing the effect(s) of therapeutic and non-therapeutic antimicrobial use in food-producing animals on commensal and foodborne bacterial pathogens.

The specific objective of this research program will be to stimulate research on microbiological hazards associated with the food animal production environment. It is of particular interest to FDA that this research advance scientific knowledge of human foodborne pathogens, such as Salmonellae, Escherichia coli, and Campylobacter. Potential areas of investigation include: (1) antimicrobial resistance development and dissemination in the animal production environment, (2) approaches to mitigate or minimize antimicrobial resistance, and (3) the impact of antimicrobial drug use on the carriage of foodborne pathogens and sentinel microorganisms used for monitoring programs.

Projects that fulfill any one or a combination of the following specific objectives will be considered for funding:

FDA anticipates funding at least one cooperative agreement for each of the objectives listed above contingent upon the quality of the application submissions and the availability of fiscal year 2000 funding.

For more information regarding the programmatic aspects of this notice, contact David B. Batson, Ph.D., Office of Research, Center for Veterinary Medicine (HFV-502), Food and Drug Administration, 8401 Muirkirk Rd., Laurel, MD 20708, 301-827-8021.

To apply, submit letters of intent as soon as possible, but no later than April 3, 2000. Submit applications by April 17, 2000. Application forms are available from, and completed applications should be submitted to: Cynthia M. Polit, Grants Management Specialist, (HFA-520), Food and Drug Administration, 5600 Fishers Lane, Room 2129, Rockville, MD 20857, Tel. 301-827-7180. (Applications hand-carried or commercially delivered should be addressed to 5630 Fishers Lane, HFA 520, Rm. 2129, Rockville, MD 20857.)

FDA's Atlanta District Director, Ballard Graham, has been selected to chair CVM’s Field Committee, succeeding Mike Rogers, who retired at the end of 1999, and Charles Breen, the Interim CVM Committee Chair.

A native of Indianapolis, Mr. Graham was a Navy Hospital Corpsman aboard the U.S.S. Chicago, prior to joining FDA's Detroit District Office in 1970. He then moved to Sioux Falls, South Dakota, as the Resident Investigator In-Charge. While there, he investigated many medicated feed mills, countless tissue residue violators, and veterinarians who injected feedlot cattle with illegal drugs.

Following his stint in Sioux Falls, Mr. Graham served as Supervisory Investigator in the Newark District Office (now the New Jersey District), where he dealt with multiple pharmaceutical firms, especially in 1990, when generic drugs became one of FDA's top priorities.

A tour as Director of Investigations in the Philadelphia District provided further regulatory experience, including Chilean fruit investigations, and injunctions of a repeat tissue residue violator, and a global pharmaceutical manufacturer.

Mr. Graham moved to his present position as Atlanta's District Director in 1994. His vast experience makes him ideally suited to lead the efforts of the CVM Field Committee.

FDA Field Committees meet routinely with Center representatives to address program priorities or modifications, special assignments, resource utilization, and significant issues of concern to either party. This type of partnering offers a key mechanism in FDA's efforts to optimize consumer protection in carrying out its mission. In addition, Committee members act as liaisons with State agencies who play key roles in the enforcement of FDA's regulations. Other CVM Field Committee members include Noel Ferguson, Kansas City District; Brenda Holman, New York District; James Dunnie, Office of Regional Operations/Division of Emergency Investigational Operations; Anita McCurdy, Office of Resource Management; and Steve Solomon, Office of Enforcement.

In December 1999, CVM posted a draft quantitative risk assessment on the Center's Home Page on the Internet. The draft risk assessment evaluates the human health impact of fluoroquinolone resistant Campylobacter associated with the consumption of chicken.

This draft risk assessment was discussed at the FDA Center for Veterinary Medicine Workshop on Risk Assessment and the Establishment of Thresholds held in Rockville, MD, on December 9-10, 1999. At the Workshop, CVM stated that a revised version of the draft Risk Assessment would be placed on the Center's Home Page to improve consistency of the document and correct typographical errors. A revised draft risk assessment is now on the CVM Home Page.

The risk assessment is still in draft form. Changes in the revised draft document are listed below:

In addition to the above revisions, two versions of the working Risk Assessment Model (Excel and @Risk versions) have been placed on the revised draft risk assessment page. These working models will allow modelers to either determine the risk using data sources other than those used in the model or allow use of different methods or distributions to model the risk.

Individuals interested in the working Risk Assessment Model who do not have access to the Internet may receive a computer disk with this information by calling or writing the FDA Veterinarian.

Questions about the risk assessment may be addressed to Dr. Nicholas Weber, FDA/Center for Veterinary Medicine, 7500 Standish Place, HFV-151, Rockville, MD 20855, 301-827-6986, e-mail: nweber@cvm.fda.gov.

The Food and Drug Administration (FDA) and the Parenteral Drug Association (PDA) are cosponsoring a public meeting on industry experience in implementing the technical provisions of Title 21, Part 11, of the Code of Federal Regulations (CFR), Electronic Records; Electronic Signatures. All interested persons are invited to participate in the meeting that will be held June 19 and 20, 2000, at the Wyndham Franklin Plaza Hotel, 17th and Race Streets, Philadelphia, PA 19103, 215-448-2000.

The purpose of the meeting is to exchange information on (1) the range of experiences persons subject to Part 11 have had in implementing the rule's technical provisions, and (2) available products and services that enable implementation of those requirements. This will not be a forum to discuss the merits of the rule, nor a tutorial on the regulation; meeting attendees should have a basic understanding of Part 11. Information presented at the event will assist FDA in developing future industry guidance documents with respect to Part 11.

FDA invites interested persons to give brief presentations about their experiences in implementing one or more of Part 11's technical provisions. Likewise, the Agency invites persons who provide enabling technologies specific to those requirements to give presentations addressing how they have been and can be applied to FDA regulated industries. In all cases, presentations must not exceed 20 minutes. Of particular interest would be presentations regarding modifications to electronic recordkeeping systems that were in use before August 20, 1997 (so called legacy systems.)

Individuals who would like to make a presentation at this meeting should send a brief abstract (no longer than one page), along with the speaker's name, affiliation, title, postal address, fax and phone numbers, and electronic mail address to:

Abstracts of proposed presentations must be received by March 19, 2000. FDA and PDA will jointly review the abstracts, and authors will be notified accordingly. Handouts and related presentation materials for accepted abstracts must be received by May 19, 2000.

Interested parties who wish to send their abstract and speaker information by electronic mail should send the material in Adobe® PDF (Portable Document Format), or ASCII (American Standard Code for Information Interchange) format to fischer@pda.org.

To register for the meeting, contact the PDA at the above address. Also, see the association's Internet site at http://www.pda.org. If you need special accommodations due to disability, please inform the above PDA contact person when you register.

Interested persons, including those unable to attend or speak at the meeting, may submit comments regarding their experiences in implementing Part 11's technical provisions, and their products or services that help people meet those requirements. Paper comments should be sent on or before May 19, 2000 to: Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD 20852.

Additional general information may be obtained from: Dr. Steven Solomon, Office of Enforcement, Office of Regulatory Affairs (HFC-240), FDA, 5600 Fishers Lane, Rockville, MD 20857, phone: 301-827-0386, fax: 301-827-0343, e-mail: ssolomon@ora.fda.gov.

The American Veterinary Medical Association (AVMA) celebrates National Pet Week on May 7-13, 2000. This year's theme, "Friends For Life" embraces the evolution of the pet from workhorse and yard dog to valued member of the family in the 21^st century. Along with the AVMA, the Auxiliary to the AVMA, the American Animal Hospital Association, and the North American Veterinary Technician Assocation sponsor this event.

Special events and promotions are planned by veterinarians to educate the public in the importance of responsible pet ownership, emphasizing proper health care, nutrition, exercise, and behavioral training. The sponsoring groups offer posters, brochures, videotapes, public service announcements, bookmarks, and other specialty items for celebration of this 20^th annual event. For more information about National Pet Week, please visit the AVMA's web site.

The following is a list of questions and answers CVM has developed to respond to questions we have received about transgenic fish.

A. The FDA Center for Veterinary Medicine (CVM) regulates, in whole or in part, diverse animal biotechnology products.

A. No. Most transgenic animals under development are regulated by one or more FDA Centers. There are procedures to request permission to enter transgenic animals into the food or feed supply. No approvals have been granted for entry into the human food supply.

The procedures for biopharm animals (producing drugs or biologics) are described in the 1995 Points to Consider in the Manufacture and Testing of Therapeutic Products for Human Use Derived from Transgenic Animals. For these types of animals, as well as others generated by biomedical research, the Center for Veterinary Medicine (CVM) serves as a consulting group to the other FDA Centers in the food and feed safety evaluation.

Gene-based modifications of animals for production or therapeutic claims fall under CVM regulation as new animal drugs. Investigational applications are filed for these modifications where, with a showing of adequate safety data, the sponsor may request disposition of animals by slaughter for food or for processing into animal feed components.

A. Non-heritable modifications (gene therapy) are still in early stages of development for animals, although this is a very active area in human medicine. These products are anticipated to be individual animal injections that would modify only some of the cells of the body to express a protein, protein hormone or enzyme. For example, individual steers could be modified to produce more muscle mass without having to modify the breeding herd, where additional muscle mass could cause calving difficulties.

Heritable modifications or germ-line transgenic animals with agronomic traits are most advanced for fish, and have already begun to receive public attention in the U.S. and abroad. Most of the modifications currently relate to improving animal productivity.

A. Yes. CVM's first recombinant DNA product - recombinant bovine somatotropin (BST) for dairy cows.

A. Most, but probably not all, gene-based modifications of animals for production or therapeutic claims fall under CVM regulation as new animal drugs. As strange as it may seem at first, many of the modifications being investigated involve the addition of new animal drug substances. For example, adding growth hormone to a cow can be accomplished through use of BST injections, through gene therapies to create BST-producing regions in the body of the cow, or through germ-line modification, making a transgenic variety that contains extra BST-coding genes in every cell of the body, including reproductive cells. It all amounts to adding an animal drug, but the conditions are different – dose, areas of the body where the drug is released, opportunity for a withdrawal time, etc. The substances being added are for the purpose of improving animal health or productivity.

A. The animal drug provisions of the Federal Food, Drug, and Cosmetic Act best fit transgenic animals that have agronomic traits now being investigated and developed. Other transgenics will no doubt come along that could be viewed as containing food additives, color additives, and vaccines. Development of site-specific gene insertion techniques and animal genome projects could change the scope of potential genetic modifications to yield a wider variety of products than are currently being investigated.

A. Transgenic fish of various species of salmon, tilapia, channel catfish and others are being actively investigated worldwide as possible new food-producing varieties. Technology developed for using transgenic fish as laboratory models to study developmental biology is being applied to food fish species with the aim of adding agronomically important traits, like improved growth rates and disease resistance.

No transgenic fish have been approved for producing food in the U.S., although a variety of transgenic fish species can be found in laboratories around the world. As there is active investigation of transgenic fish abroad, as well as in the U.S., the public and the research community are occasionally exposed to predictions of the imminent commercial release of transgenic fish into the food supply. This should not occur without the pre-market approval from CVM, for those fish that have an added gene-based animal drug.

Q. What limitations does current technology have on the production of transgenic fish?

A. The current technology has limitations that affect what types of transgenics can be developed. The "transgenes" are limited to short gene constructs and are inserted randomly and in variable numbers of copies in each individual. This creates difficulty in stabilizing genetic modifications in a breeding population. There may be uncontrolled expression of the transgene. It may be expressed all the time; it cannot be turned off. Insertion sites for the transgenes may inadvertently affect the expression of other genes by disabling them or turning them on at an inappropriate time. The incidental insertion of drug resistance genes from bacterial plasmids introduces further uncertainties as to food safety. The technology for creating transgenic animals is constantly improving and will soon begin to reduce the limitations of the current approaches and improve the competitive balance with other approaches to breed improvement.

A.?Breeding programs are needed to stabilize the transgenes in a patentable variety and to produce numbers necessary for regulatory approvals and for marketing. Biocontainment strategies, both from an engineering and biological point of view, are necessary to prevent escape of the transgene into wild fish populations and to provide a means of control over the unlicensed breeding of the patented variety. These features add to the costs of development and affect competitiveness of the approach versus other, more traditional, breeding approaches. Biocontainment needs are specific for each species and the location where it would be reared.

A. The primary environmental concerns about releases of transgenic fish, for example, include competition with wild populations, movement of the transgene into the wild gene pool, and ecological disruptions due to changes in prey and other niche requirements in the transgenic variety versus the wild populations. For example, transgenic tilapia (with cold tolerance similar to the unmodified species) might require little containment in the northern tier of the U.S., but might be excluded from the Gulf States altogether, where tilapia may be a serious exotic invader of freshwater streams and ponds. These site-specific concerns may make it necessary to control the sites where transgenic fish are reared and the level of biocontainment required might differ from site to site. Any biocontainment other than absolute containment will have to be assessed for specific proposed sites.

A. Germ-line transgenic modifications of animals, including fish and shellfish, have already begun to receive public attention in the U.S. and abroad. Public acceptance of foods derived from transgenic animals will be important to the success of any transgenic variety introduction. Approval by FDA or a food regulatory group in another country does not guarantee public acceptance. Labeling of food from transgenic animals will likely be even more important to consumers desiring a choice than has been observed for milk derived from BST-treated dairy cows or for transgenic plant varieties. Ethical concerns among the public over the appropriate use of animals are issues, not evident with transgenic plants, that may affect public acceptance of transgenic animals as food sources. There is also expected to be variation among the citizens of different countries as to their acceptance of transgenic animals. Development of a world market for a transgenic animal variety is currently fraught with difficulties owing to the varying cultural views and governments.

INFORMATION ON APPROVAL OF SUPPLEMENTAL APPLICATIONS FOR NEW ANIMAL DRUGS AVAILABLE

As required by the Food and Drug Administration Modernization Act of 1997 (FDAMA), the FDA's Center for Veterinary Medicine (CVM) is making available information regarding the approval of supplemental applications for approved new animal drugs. As part of this process, CVM has made available for comment a draft guidance document for industry entitled "Development of Supplemental Applications for Approved New Animal Drugs" (Guidance Document #82). This draft guidance, announced in the February 8, 2000 Federal Register, explains how drug sponsors can use existing data contained within an original application to support category II supplemental applications.

Copies of this draft guidance document may be obtained from CVM's Guidelines and Guidances Page or by calling or writing the FDA Veterinarian. Written comments on this draft guidance document should be submitted by May 8, 2000, to the Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD 20852.

In addition to this draft guidance, CVM is publishing standards for the prompt review of supplemental applications and referencing an existing guidance that describes how supplemental applications may qualify for priority review. This existing guidance (CVM Program Policy and Procedures Guide 1240.3135) outlines the circumstances in which CVM may make a determination that a product represents an important advance in animal health. Upon rendering this determination, FDA may expedite the review of original and supplemental applications.

Copies of this existing guidance document "Animal Drug Applications; Expedited Review Guideline" may be obtained from CVM's Home Page or by calling or writing the FDA Veterinarian. Comments on this CVM Program Policy and Procedures Guide may be submitted at any time to the Policy and Regulations Team (HFV-6), Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855.

CVM is also designating an individual within the Center who is responsible for encouraging the prompt review of supplemental applications and for working with sponsors to facilitate the development and submission of data to support supplemental applications. Further, CVM is describing its efforts to collaborate with other organizations and persons to identify published and unpublished studies that may support supplemental applications and to encourage sponsors to submit supplemental applications based on such studies.

Additional information on this subject may be found in the February 8, 2000, Federal Register. Information about draft guidance #82 may be obtained from Dr. Marilyn N. Martinez, Office of New Animal Drug Evaluation (HFV-130), Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-827-7577. Additional information about other parts of this Federal Register notice may obtained from Dr. Carol Haley, Office of the Director (HFV-6), CVM, FDA, 7500 Standish Place, Rockville, MD 20855, 301-594-1682.

The Maryland Veterinary Medical Association (MVMA) announces the following continuing education course for veterinarians: 2000 Mid-Atlantic Conference for Bovine Practitioners, March 30-31, 2000, at the Holiday Inn, Frederick, Maryland. The two-day seminar will include lectures from nationally recognized experts, interactive case studies, practice tips, and opportunities for fellowship. Meals are included in the registration. Topics include transition diets, calf health, heifer nutrition, selecting and using antimicrobials, and resistance issues.

The pre-registration deadline is March 20, 2000, however, registration will be accepted at the door for one or both days. Cost (including meals) is $140 for both days, or $80 for one day. Veterinary students or technicians may attend at half price. Spouses are admitted free, but must pay for meals. The course is cosponsored by the Maryland Veterinary Medical Association, the Maryland Department of Agriculture, the American Association of Bovine Practitioners, District II, the Western Maryland Veterinary Medical Association, the Pennsylvania State University, and the Virginia-Maryland Regional College of Veterinary Medicine. For further information, please contact the MVMA office at (888) 884-6862.

The United States Department of Agriculture (USDA) is co-sponsoring the first National Animal Disaster Conference, March 22-24 at the Hilton Orlando/Altamonte Springs Hotel in Orlando, Florida. Other sponsors are the Humane Society of the United States (HSUS), the Florida Department of Agriculture and Consumer Services, and the Florida Division of Emergency Management.

USDA Under Secretary for Marketing and Regulatory Programs, Michael V. Dunn, will be the keynote speaker. Dozens of workshops and training sessions on aspects of animal disaster management will be offered including:

Attendance is limited. Advance registration is $90 until February 22. Late registration is $120. For more information, please call the HSUS, Southeast Regional Office, 850-386-3435. For hotel information, please call 800-445-8667.

Several CVM officials attended AQUACULTURE AMERICA 2000, held in New Orleans, Feb. 2-5. Kim Young from CFSAN's Office of Seafood presented HACCP: Lessons Learned Related to Aquaculture and Dr. Joan Gotthardt presented Drug Approvals for Aquaculture - Progress and Proposed Initiatives, in the Encouraging Aquaculture Development in the U.S. - Critical Needs and National Initiatives session.

Other than the standard updates on drug issues from state, federal and industry attendees, the most popular topic was Minor Use Minor Species (MUMS). In a session titled "Future Drug Approval Process: MUMS Opportunities," Dr. Carol Haley gave a presentation on how and why the MUMS document was developed.

Randy MacMillan, President of the National Aquaculture Association, discussed the status of the proposed MUMS legislation, and the benefits it would have on different parts of the aquatic animal industries.

Dr. Renate Reimschuessel and Chuck Eirkson attended the Joint Subcommittee on Aquaculture (JSA) Aquaculture Effluents Study Task Force meeting on Feb. 5. EPA is beginning to collect information to develop a proposed rule for regulating aquaculture effluents by June 2002. The final rule is scheduled to be released June 2004. The Task Force is set up to provide input from other government agencies, industry and non-government organizations.

Fran Pell, Dr. John Machado, Dr. Joan Gotthardt and Kim Young attended the Joint Subcommittee on Aquaculture (JSA) Working Group on Quality Assurance for Aquaculture held February 2, the day before the Conference.

CVM and CFSAN shared a booth and participants were available to answer questions from conference attendees.

In April 1998, FDA issued a level two guidance for industry (GFI) entitled, "Use of Human Chorionic Gonadotropin (HCG) as a Spawning Aid for Fish" (GFI #71.) This guidance stated that the Center for Veterinary Medicine (CVM) is not likely to object to the use of HCG as a spawning aid for fish if certain conditions are met.

CVM has determined that now it does object to the use of HCG products as a spawning aid for fish if such products have not been approved for that purpose. Therefore, GFI #71 is rescinded. Distribution and use of any HCG product as a spawning aid other than a product approved for that purpose would cause that HCG to be adulterated under section 501(a)(5) of the Federal Food, Drug, and Cosmetic Act. Extralabel use of a HCG product as a spawning aid is not permitted under the Animal Medicinal Drug Use Clarification Act (AMDUCA) because this is a production rather than a therapeutic use.

CVM notes that there is a new animal drug HCG approved for use as a spawning aid in fish (NADA 140-927.) That product, Chorulon Human Chorionic Gonadotropin, is sponsored and marketed by Intervet, Inc., Millsboro, DE.

Additional information on this subject is available from Frances Pell, Center for Veterinary Medicine, (HFV-235), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-827-0188.

Ketamine hydrochloride officially became a schedule III controlled substance on August 12, 1999. Schedule III labels will appear on commercial containers after April 15, 2000. Control of ketamine was considered necessary due to years of abuse, diversion, and robberies related to both the human and veterinary products. Ketamine is approved for anesthesia or restraint in cats and restraint in subhuman primates by intramuscular injection. The dissociative cataleptoid state, somatic analgesia, and altered consciousness are rapidly induced. To eliminate many of the typical side effects associated with its use (extreme muscle tone, exuberant spontaneous movement, violent recovery, and occasional convulsions), ketamine is combined with sedatives and tranquilizers; its use as a monoanesthetic is limited.

For those veterinarians who are unwilling or unable to make use of scheduled drugs, there are FDA-approved veterinary alternatives. Propofol, an injectable anesthetic for intravenous administration in dogs and cats is approved for induction and maintenance of anesthesia. Its rapid effect and rapid recovery make it suitable for procedures requiring restraint, and anesthesia can be extended by repeated doses and concomitant sedation. Volatile anesthetics such as isoflurane (approved in dogs and horses), sevoflurane (approved in dogs), and halothane (approved in dogs, cats and horses) are labeled for the induction and maintenance of anesthesia.

Many unscheduled approved veterinary sedatives and tranquilizers are available to provide restraint and analgesia. Alpha₂-adrenergic agonists such as xylazine (approved for dogs, cats, horses), detomidine (approved for horses), and medetomidine (approved for dogs) can be administered intramuscularly, provide deep sedation and their effects are reversible using alpha₂-antagonists. Acepromazine, a phenothiazine neuroleptic tranquilizer, is approved for use in dogs, cats, and horses.

Veterinarians using the above unscheduled approved veterinary drugs can adequately provide restraint and anesthesia to their patients. These resources when combined with schedule III controlled substances like ketamine and tiletamine/zolazepam and schedule II narcotics provide an ample variety of veterinary approved anesthetic and preanesthetic agents.

The Center for Veterinary Medicine is engaged in a continuous performance improvement initiative. Offices and Divisions within CVM are examining the effectiveness and efficiency of their work. They are asking questions such as: Are there services that we are not providing in which we need to be engaged? When we provide a service or product, does it meet the needs of our stakeholders?

Our goal is to have our Divisions function as integrated strategic business units, each aligned with the mission of their respective Office and with the mission of the Center. Divisions meet on a regular basis, typically biweekly or monthly, to discuss complex and important long-term issues. Division members work together to address these issues in an effort to improve the quality and quantity of their work. They also discuss concerns of a more interpersonal nature, for example, improving working relationships and the overall work culture of their organizations and the Center, in general. Examples of areas of concern that specific Divisions have either addressed or are currently discussing include:

CVM's high performance organization initiative has been a part of the life of the Center for the past 2 years. The initial focus of this change process has been on improving our work culture. While that aspect of the process will continue, we are beginning a more focused examination of our core work and work processes.

A key aspect of our emphasis on high performance is our recognition of the need to engage all CVM employees and stakeholders in this initiative. Ultimately, it is our "customers" and stakeholders that determine whether or not we are a high performance organization, i.e., is CVM doing the right things in the right way? CVM is asking its many stakeholders to help answer that question by providing the Center with their feedback. What do we do well? Where would you like to see our performance improve? What services would you like to see or see more of? What recommendations could you make to help us be more effective and efficient? Our Stakeholder meetings are one aspect of our effort to engage in dialogue with those we serve. This high performance initiative is still evolving, and while it has been mostly internal, in the future there will be aggressive outreach to solicit even more Stakeholder input.

We invite you to share your thoughts in answer to the questions previously stated. You may do so by contacting the FDA Veterinarian. Thank you for your continued support as we endeavor to improve our organization and provide the highest quality service with the current level of resources available.

In response to the article entitled "Protecting Pets in a Disaster" that appeared in the January/February 2000 FDA Veterinarian, the editors received a letter from the Humane Society of the United States (HSUS). In the letter HSUS states that "...under no circumstances should pets be left behind; the only way to protect pets is to evacuate them with their owners... Leaving pets behind could result in their loss or injury."

The editors appreciate receiving these comments from HSUS. The HSUS, in cooperation with the American Red Cross, has prepared a booklet on this subject. To receive a copy, please call the HSUS at 202-452-1100, and ask for "Pets and Disasters: Get Prepared."

A topical index for the 1999 FDA Veterinarian is now available on the CVM Internet Home Page. Readers who wish to obtain a paper copy of the Index may call or write the FDA Veterinarian.

At the FDA's Scientific Achievement Awards Ceremony held February 15, 2000, the following awards were announced for CVM scientists:

The Center for Veterinary Medicine is proud of these accomplishments and congratulates all FDA award winners.

CVM PLANS TO MODIFY GUIDANCE ON MICROBIOLOGICAL SAFETY OF DRUG RESIDUES IN FOOD

In January 1996, CVM made available a guidance document entitled "Microbiological Testing of Antimicrobial Drug Residues in Food" (Guidance for Industry #52.) This guidance document describes when antimicrobial drugs would be exempt from additional microbiological testing and when additional testing would be required. According to this guidance document, a maximum acceptable daily intake (ADI) of 1.5 mg of microbiologically active residues per person per day is established for antimicrobial drug residues. This threshold ADI was based on the best information available at that time and was believed to produce no adverse effects on the human intestinal microflora of the consumer.

In a workshop sponsored by FDA on September 20 and 21, 1999, in Rockville, Maryland, information from two FDA-funded research contracts was presented on the effect of low doses of different classes of antimicrobials on several microbiological endpoints of the human intestinal microflora. The purpose of these studies was to determine effects of antimicrobials in two types of model systems that could be used, once properly validated, for regulatory purposes. The model systems studied were an in vitro model (continuous flow one-chambered chemostat) and an in vivo model [human flora associated (HFA) mice]. Both systems were inoculated with human intestinal microflora.

From reviewing the data generated by these contracts, workshop participants concluded that the threshold ADI established by CVM is not appropriate for all classes of antimicrobials. Microbiological endpoints that could be of public health concern are affected to different degrees by different classes of antimicrobials. Research performed with the fluoroquinolone drug ciprofloxacin showed that low levels of this drug, even dose levels equivalent to the traditional threshold ADI of 1.5 mg/person/day, altered the ecology of the intestinal microflora in both of the model systems. The microbiological endpoints most adversely affected were the development of resistant strains, disruption of the barrier effect, and changes in bacterial populations.

Based on this information, the Center plans to modify its current Guidance No. 52, and in the near future plans to publish in the Federal Register a notice of availability for comment of a modified guidance document. The Center will implement this modified guidance in accordance with the Agency's good guidance practices. This guidance might be further revised to reflect agreement with the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (VICH) guidance for antimicrobial residues in food.

Until such time as CVM implements a revised guidance document on this issue, sponsors of new antimicrobial drug applications should contact the Center concerning microbiological testing for

On November 22, 1999, Bradley J. Rabe D.V.M. was sentenced in U.S. District Court, District of Nebraska. Dr. Rabe was charged with the intentional misbranding of the prescription veterinary drug Baytril (enrofloxacin). The product was labeled as "Vitamin B1 - No Withdrawal" and distributed to food animal producers.

Enrofloxacin is in a group of drugs called fluoroquinolones. Initially approved for treating disease conditions in dogs, enrofloxacin is now approved in some food animals. However, the FDA has prohibited its extra-label use in animals due to concerns for antibiotic resistance, potentially transferred to humans from meat, poultry, eggs, and dairy products.

Dr. Rabe was sentenced to one-year probation, two hundred hours of community service, a one thousand dollar fine, and a one hundred dollar special assessment. The terms of Rabe's probation include that he must provide court access to his financial records; that he must provide the Food and Drug Administration (FDA) access to his place of business and veterinary practice records upon request; that he must comply with all Nebraska Department of Health Veterinary license requirements; and that he must comply with all FDA rules, regulations and policies.

Rabe’s sentencing stems from a Federal Grand Jury indictment on March 16, 1999, after FDA's Office of Criminal Investigations (OCI) determined that he was relabeling Baytril and selling it to local food animal producers both with and without the producer’s knowledge of what the product contained. The indictment charged Rabe with 5 counts of Title 21, intent to defraud by adulterating and misbranding Baytril after receipt in interstate commerce. The indictment also charged Title 18, Aiding and Abetting. At the time of Rabe's Baytril distribution, the drug was not approved for use in food-producing animals.

Between the time of Rabe's plea agreement and sentencing, the Nebraska Department of Agriculture reported to OCI that they had evidence that Rabe was continuing to misbrand prescription veterinary drugs which resulted in the adulteration of two loads of Grade A milk.

On January 3, 2000, Arie C. Van Leeuwen pled guilty in U.S. District Court for the Eastern District of California to a three-count Information charging him with introduction into interstate commerce of adulterated food with intent to defraud and mislead, in violation of 21 U.S.C. sections 331(a) and 333(a)(2); and two counts of criminal contempt, in violation of 18 U.S.C. section 401(3).

Van Leeuwen, owner and operator of a dairy farm in Modesto, California, had been permanently enjoined under a consent decree entered by the Court in 1995, prohibiting him from selling or consigning cattle for slaughter until he established and implemented certain record-keeping and other systems to control the use and administration of drugs to his cattle.

The Injunction required Van Leeuwen to establish and implement the following systems:

These systems are designed to ensure that cattle sold and consigned for slaughter did not contain illegal (above-tolerance) animal drug residues in their edible tissues, which can cause significant public health consequences. Consumers of the edible tissues of such animals may experience severe allergic reactions as a result of ingesting such food. Such food also poses the hazard of contributing to the creation of antibiotic-resistant strains of bacteria in humans who eat or handle the food. Under the Food, Drug, and Cosmetic Act, food is adulterated if it has been prepared, packed or held under insanitary conditions whereby it may be rendered injurious to health.

The Injunction further prohibited Van Leeuwen from introducing cattle into interstate commerce until FDA inspected the dairy's operations, and FDA notified him in writing that it was satisfied that the dairy's operations comply with the requirements set forth above.

FDA inspected Van Leeuwen's dairy in 1996 and determined that Van Leeuwen had not complied with the Injunction. As a result, the Court entered a Stipulation and Order in November 1996 holding Van Leeuwen liable for civil contempt for failing to comply with the terms of the Injunction. In June 1997, on a motion from the government, the Court assessed penalties against Van Leeuwen for his failure to eartag animals and for failure to keep records, in violation of the Injunction and Contempt Order.

In 1997 and 1998, FDA conducted additional inspections and found that Van Leeuwen still had failed to comply with the requirements of the Injunction. Accordingly, during this time period, FDA never authorized Van Leeuwen to resume the sale of cattle. The criminal charges to which Van Leeuwen pled guilty arose from an investigation into his illegal sales of cattle. During 1997 and 1998, Van Leeuwen sold cattle for slaughter at two California livestock auction yards, using fictitious names, in order to conceal his ownership of the animals.

After follow-up inspections by FDA in June and August, 1999, FDA found the dairy to be in compliance and, as of September 13, 1999, the dairy was authorized to resume the sale of cattle. Sentencing is set for March 13, 2000.

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

These violations involved illegal residues of gentamicin in dairy cows, sulfadimethoxine in dairy cows, penicillin in dairy cows, tilmicosin in a cow, and phenylbutazone in a beef cow.

Warning letters were also sent to the following firms/individuals which had a history of offering animals for sale for human food which 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 a cow, sufadimethoxine in a cow, gentamicin in a cow, gentamicin and neomycin in dairy cows.

A warning letter was sent to Bruce C. Rohde, Chief Executive Officer, ConAgra, Inc., Omaha, NE, for violations from Good Manufacturing Practices (GMPs):

S. Michael Forsythe, D.V.M., Owner, Amanda Animal Hospital, Lancaster, OH, received a warning letter for extra-label use of a drug that resulted in drug residues in edible tissue. This drug residue caused the food animal to be adulterated under the Federal Food, Drug, and Cosmetic Act (the Act.)

A warning letter was sent to Richard J. Denier, President, Universal Marketing Services, Inc., Visalia, CA, for distributing UDDERMINT and HoofTect that are new animal drugs not subject to approved New Animal Drug Applications (NADAs.) As such, these products are adulterated and misbranded drugs under the Act.

Graphic A -- Michael P. Doyle, Ph.D.
Graphic B -- Thomas L. Carson, D.V.M., Ph.D.
Graphic C -- Ballard Graham

Company	Generic and Brand Names	Indications	Routes/Remarks
Abbott Laboratories (NADA 141-103)	Sevoflurane (SevoFlo ^TM) Rx	Dogs. As an inhalant for induction and maintenance of general anesthesia.	INHALATION: The liquid, with oxygen, is to induce surgical anesthesia, and with oxygen and with or without pre-medication to maintain surgical anesthesia. Federal Register: 12/22/99
Elanco Animal Health (NADA 140-863)	Ractopamine Hydrochloride (Paylean®)	Swine. For increased rate of weight gain, improved feed efficiency, and increased carcass leanness.	MEDICATED FEED: The Type A medicated article is used to make Type B and Type C medicated swine feeds. The Type C medicated finishing feed must contain at least 16 percent crude protein. Feeds containing 4.5 grams per ton ractopamine are used for increased rate of weight gain, improved feed efficiency and increased carcass leanness. An ADI and tolerances in muscle and liver are established. Federal Register: 01/26/00

Company	Generic and Brand Names	Indications	Routes/Remarks
Pharmacia & Upjohn Co. (NADA 140-976)	Neomycin Sulfate	Cattle, swine, sheep, goats. For treatment and control of colibacillosis caused by Escherichia coli susceptible to neomycin.	MEDICATED FEED: The Type A medicated article is used to make Type B and C medicated feeds for cattle, swine, sheep and goats, and medicated milk replacers for calves, piglets, lambs, and goat kids. The products were subject to a DESI review of effectiveness. Federal Register: 12/17/99

Crop	Purpose	Number
Corn	Herbicide tolerant	3
	Male sterile	2
	Insect protected	5
	Herbicide tolerant/ Insect protected	2
Flax	Herbicide tolerant	1
Oilseed Rape	Male sterile/ Fertility restorer	2
	Herbicide tolerant	4
	Laurate canola	1
	Phytase production	1
Cotton	Herbicide tolerant	4
	Insect protected	1
	Herbicide tolerant/ Insect protected	1
Soybean	Herbicide tolerant	2
	High-oleic	1
Sugar beet	Herbicide tolerant	2
Total		32