by Karen A. Kandra
The Food and Drug Administration (FDA) reached a major milestone on October 21, 1996, as the new home of FDA's Center for Veterinary Medicine (CVM), Office of Research was dedicated by FDA Commissioner, Dr. David Kessler, and other dignitaries who played important roles in bringing the project to fruition.
In October 1994, a group of people gathered in Calverton, MD, and made a commitment to work together to produce a state-of-the-art research facility, destined to become one of the foremost large animal research centers in the world. Congressman Steny Hoyer, Senator Paul Sarbanes, and Senator Barbara Mikulski (all from Maryland) each provided strong support and were instrumental in getting the project off the ground. A team of qualified professionals was headed up by Jag Bhargava, Development Director for the General Services Administration (GSA), who cooperated with the contractor, William M. Schlosser Company, Inc., design architects of S3E, and Parsons Brinkerhoff, and officials from CVM and other parts of FDA to complete this challenging project six months ahead of schedule as well as under budget. The unprecedented success of this project is the result of a partnering effort involving hard work, dedication, and personal sacrifices of many individuals with the same goal.
The new animal research center will serve the entire Agency's large animal needs and will provide the opportunity for collaborative efforts with the University of Maryland, the United States Department of Agriculture, and other scientific organizations to conduct critical research so vital to the protection of the Nation's food supply.
The MOD II complex encompasses 60 acres on Muirkirk Road in Laurel, Maryland. There are 18 buildings on the site including the main building, which contains office and administrative support space, laboratories, and multipurpose animal rooms. There are 31 laboratory rooms which are designed for chemistry, biochemistry, microbiology, pharmacology, immunology, nutrition, and toxicology. Laboratory rooms include a radioactive materials lab, mass spectrometry lab, walk-in cold room, and an analytical instrument room. Equipment includes 49 chemical fume hoods, 5 radiation fume hoods, and 4 biological safety cabinets.
The facility includes small and large animal clinics, each with exam rooms; surgery rooms; recovery rooms; X-ray suites; and necropsy areas. The large animal clinic is equipped with a walk-in refrigerator and freezer and is served by an overhead monorail system.
There are separate animal buildings to house beef cattle, horses, lactating cattle, calves, sheep, and swine. Animal holding areas contain fully adjustable pens to offer flexibility in research study design. The dairy building can accommodate 14 lactating cows in the milking parlor and 10 veal calves. There is also a dog building with individual pens and sheltered outside runs. The feed processing facility has the capability to prepare customized animal rations, and conduct feed processing research. The site also includes 38 acres of pasture.
An aquaculture building provides approximately 5,700 net square feet of usable space to accommodate a variety of fresh water aquatic species. Water flow rates and temperature are adjustable to each of the twelve 500 gallon insulated tanks, and twenty-four 100 gallon tanks available. One room is equipped to conduct metabolism studies and can incorporate radiolabeled compounds.
The animal research buildings are all environmentally controlled (temperature and humidity). All animal research buildings contain an animal holding area, an office/lab room, and a feed storage area. Research buildings are supported by the heating and cooling plant, which is also equipped with generators to provide emergency power.
The Office of Research at MOD II will carry out the following important functions:
conduct studies evaluating the safety and efficacy of drugs, feed additives, diagnostic agents and devices used in animals.
review tissue residue and animal feed methods for drugs in support of new animal drug approvals and other regulatory activities.
develop and validate analytical methods for drug residues, additives, and contaminants in animal tissues and feeds.
develop databases on the pharmacokinetics of drugs and feed additives in animals including fish.
conduct depletion studies of residues of animal drugs, feed additives, and contaminants (natural and industrial) in food animals including fish.
conduct metabolism studies in food animals, including fish, which identify other residues of concern from the use of drugs.
The Government Printing Office has informed us that the subscription price for the FDA Veterinarian has been increased to $9.00 per year domestic and $11.25 per year for foreign subscriptions. These price increases are due to increased costs of printing and mailing. While we regret that these increases were necessary, we believe that these prices still represent a good value for a newsletter full of information you can use right away. Subscription order forms are available through the FDA Veterinarian. In addition, credit card subscription orders may be placed by telephone (202) 512-1800 or by fax (202) 512-2250. VISA, MasterCard, and Discover cards are accepted.
FDA AND AVMA SPONSOR SATELLITE BROADCAST
The Food and Drug Administration/Center for Veterinary Medicine and the American Veterinary Medical Association (AVMA) announce a National Interactive Satellite Broadcast:
"The AMDUCA Regulations"
Wednesday, February 12, 1997
1:00 p.m. to 4:00 p.m. EST*
* Test signal will be broadcast: 12 noon to 1:00 p.m. Eastern Standard Time
This national interactive broadcast via satellite is targeted to veterinary practitioners who have specific questions regarding the use and prescription of drugs in an extra-label manner. The final regulations implementing the Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA), were published in the Federal Register of Nov. 7, 1996; copies are available from the Communications Staff, FDA/CVM, 7500 Standish Pl., HFV-12, Rockville, MD 20855; phone (301) 594-1755; or on the FDA/CVM Web Site.
The program will feature a panel including CVM Director Dr. Stephen Sundlof and AVMA President Dr. Mary Beth Leininger, and an interactive studio audience, direct-to-the-studio telephone call-in or fax-in questions for response by the panel. This program will be broadcast free of charge.
The Satellite Coordinates are:
C-Band Satellite: Galaxy 9
Transponder: 22
Location: 123 degrees West longitude
Polarity: Horizontal
Downlink Frequency: 4140 MHz
Phone Numbers During Broadcast Hours ONLY
Q&A call in: (800) 527-1401 on Feb. 12, 1997
FAX: (888) 361-4011 on Feb. 12, 1997
Broadcast Trouble: (301) 827-3251 on Feb. 12, 1997
(at downlink sites)
Note: Any unforeseen changes regarding this broadcast will be posted immediately on the Internet at: CVM's Home Page and http://www.avma.org/.
Tune in via home satellite dish receiver or locate the nearest open downlink by contacting either your State Veterinary Medical Association, your State Veterinary Medical College (where applicable), or your State USDA Cooperative State Research, Education, and Extension Service Veterinarian.
If you have specific questions regarding the AMDUCA regulations that you would like to have answered and wish to submit them in advance of the broadcast, please forward your question(s) to either:
Dr. Bernadette Dunham, AVMA
Phone: (800) 321-1473 x611
FAX: (202) 842-4360
E-mail: 74232.57@compuserve.comJoanne M. Kla, FDA/CVM
Phone: (301) 594-1771
FAX: (301) 594-4512
E-mail: jkla@bangate.fda.gov
NEW RULES FOR "LITE" PET FOODS
by David A. Dzanis, D.V.M., Ph.D., DACVN
As Americans become more health conscious with respect to food for their own consumption, they are reading food labels and choosing products more carefully. Many people are extending this scrutiny to food for their pets as well. Pet food labels are regulated by different rules than are foods for human consumption, but reading and understanding a pet food label will enable consumers to make proper food choices for their pets, too.
Pet food labeling is regulated at two levels. The Federal regulations, enforced by FDA's Center for Veterinary Medicine (CVM), establish standards applicable for all animal feeds: proper identification of product, net quantity statement, manufacturer's address, and proper listing of ingredients. Some States also enforce their own labeling regulations. Many of these follow the model pet food regulations established by the Association of American Feed Control Officials (AAFCO), which establishes other labeling requirements such as the guaranteed analysis, nutritional adequacy statement and calorie content statement. CVM works very closely with AAFCO on developing the model regulations.
Obesity in pets is probably the most common nutritional problem today. Thus, it is not surprising that more and more "lite" pet food products are now available. However, the new FDA regulations governing the use of these types of terms for human food products do not apply to pet foods. Thus, there have been problems with how some pet food manufacturers were using the term and how consumers were perceiving these claims. For example, even if one manufacturer's "lite" pet food was lower in calories than its regular product, the calorie contents of products vary widely. Thus, one company's "lite" product could actually be higher in calories than another's regular product. Also, some claims were made based on volume, not weight, so a pet food could be "lite" simply by "puffing up" the food with more air. Finally, calorie content statements as stipulated in the AAFCO model regulations were only voluntary, and in practice rarely appeared on pet food labels. These facts made it difficult for the pet owner to fully assess and compare the calorie content of products and determine whether a "lite" product was truly "lite."
In August, new AAFCO model regulations governing the use of descriptive terms such as "lite" and "low fat" were passed by the membership at its annual meeting in San Diego. These new rules represent several years of hard work by the AAFCO Pet Food Committee and input from the industry to develop a means to allow for non-misleading use of these terms on pet food labels. As a result of the new regulations, some firms will be required to modify either their labels or formulas for some products.
Terms such as "lite" and "low calorie" convey a very strong message to consumers. In FDA regulations for human foods, "lite" foods must be a set percentage lower in calories and fat compared to an industry average for each category of food (for example, snack foods, bakery products, breakfast cereals). Few people would expect a "lite" ice cream to be as low in calories as "lite" ketchup, but it is not unreasonable to expect a "lite" ice cream to be lower in calories than the average regular ice cream on the market. The comparison must be based on an equal amount of both products. In most cases, the amounts are based on equivalent weights. For example, all snack food claims are based on a 30-gram (approximately one-ounce) serving size, whether popcorn, pretzels, or cheese puffs. The use of smaller serving sizes or a comparison on volume was deemed inherently misleading. Thus, a product cannot be "lite" simply because the product is offered in one-half ounce pieces instead of one ounce. Instead, the serving size is "two pieces." Also, a cheese puff is not "lite" even if a cup of it contains less calories than a cup of pretzels.
Although the specifics are different, the rationale used for human foods were also employed in the new AAFCO regulations. Three different categories of pet foods, based on moisture content, were established (see Table 1). The criteria the product must meet is in terms of weight, not volume, and an AAFCO calorie content statement must also be on the label. The maximum calorie allowances for "lite" pet foods reflect a percentage reduction in calories relative to the average calories found for products on the market under each category. The percentage reduction compared to the average is 15 percent for dog foods, and 10 percent for cat foods. These percentages are less stringent than those required for human "lite" products (33 percent) to accommodate the different nature of pet foods. Also, unlike for human foods, where a "lite" claim refers to both calorie and fat reduction, a "lite" claim for a pet food only means it is lower in calories (see "lean," below).
For products that cannot meet the criteria to be called "lite," comparative claims (for example, "less" or "reduced" calories) are still allowed. However, "less" claims must include the percent reduction and the product of comparison. An example would be "Brand X Special Cat Food has 25 percent less calories than Brand X Original Formula." Again, these comparisons should be made on the basis of weight, not volume. Comparing products between categories (e.g., a canned vs. a dry food) is misleading. Any product bearing a "less" claim must make a valid AAFCO calorie content statement as well.
The fat-related claims mirror those for calories. The term "lean" to describe low fat is assumed equivalent to "lite" as an alternative to low calorie. Instead of a calorie content statement, products bearing fat-related claims must state a maximum fat content in addition to the required minimum guarantee. Table 2 shows the maximum fat contents allowed for various categories of pet food bearing a "lean" claim.
The new regulations won't become effective before January 1998, although some products may bear revised labels before that time. Regardless, simply feeding a pet a "lite" product will not address its problems with weight control all by itself. Proper portion control, elimination of snacks, and a sound exercise program are all important components to helping the pet achieve a healthy weight.
Table 1: "LIGHT," "LITE," "LOW CALORIE," ETC.
Moisture Category Maximum kcal ME / kg Maximum kcal ME / kg
(dog food) (cat food)
<20% 3100 3250
20% or more, but <65% 2500 2650
65% or more 900 950
Table 2: "LEAN," "LOW FAT," ETC.
Moisture Category Maximum Crude Fat (%) Maximum Crude Fat(%)
(dog food) (cat food)
<20% 9 10
20% or more, but <65% 7 8
65% or more 4 5
VMAC ENDORSES POST-APPROVAL MONITORING PROGRAM FOR POSILAC®
The Veterinary Medicine Advisory Committee (VMAC) met on November 20, 1996 to consider the issue of bovine somatotropin (bST). FDA approved Monsanto Company's Posilac® in November 1993, following an extensive and comprehensive review of the product's safety and efficacy, including human food safety. Posilac® is currently the only recombinant bovine somatotropin product approved for increasing milk production in dairy cattle in the U.S. Prior to approval, the Center for Veterinary Medicine (CVM) determined that use of Posilac® caused a small increase in the incidence of mastitis and an increase in the use of medications for mastitis and other health problems. At a meeting held in March 1993, the VMAC concluded that the increased potential for drug residue in milk could be managed by practices currently in use by the dairy industry.
At the time of commercial introduction of Posilac®, the Monsanto Company initiated a Post-Approval Monitoring Program (PAMP) to determine if mastitis incidence and antibiotic use was manageable under actual use conditions and to determine if label directions were adequate. The key components of the PAMP were:
1. A proactive system of collecting Adverse Drug Experience Reports,
2. A program of tracking milk residues by key dairy States before and after the approval of Posilac®,
3. A 28-herd study to evaluate Posilac® under actual conditions of use.
This PAMP is the most extensive post-approval study ever conducted for any animal product. The herd component involved 28 herds representing 1213 cows in key dairy producing States. The results of this study reflect the general good health of dairy cattle given Posilac® for a single lactation under commercial conditions. Stringent requirements were placed on the participants regarding data collection, recordkeeping, veterinary consultation, daily observations, etc. Throughout the entire program, FDA closely monitored all PAMP activities. Special drug experience reports were submitted to CVM every 90 days, including status reports, units of product sold, etc. FDA conducted on-site inspections of the PAMP components five times during the Program. During these visits investigators reviewed raw data, interviewed clinical investigators, reviewed the firm's Quality Assurance Standard Operating Procedures for the herd study, and reviewed test article storage and inventory. In addition, CVM scientists conducted farm inspections of 10 herds selected from the 28 herds. They interviewed herd managers and veterinarians, reviewed the recordkeeping systems, and observed drug administration and inspected drug storage areas and inventories. No significant problems were found. Data integrity was acceptable, and farm records from data entry to data analysis showed excellent fidelity. CVM concluded from data collected in the PAMP that the effects of the use of Posilac® in this study were in close agreement with the effects observed in the preclearance studies.
Monsanto officials presented information from their State tracking program showing that there have been no changes in the percentage of milk discarded due to violative residues attributable to the use of Posilac®.
The Veterinary Medicine Advisory Committee was asked to consider the following two questions prior to the start of the meeting:
1. Does the proposed revised labeling for Posilac® provide adequate directions for actual conditions of use?
2. Do the results of the Post-Approval Monitoring Program adequately address the safety of the milk supply as it relates to the use of Posilac®?
At the end of the meeting each VMAC member affirmatively responded to these questions. The VMAC concluded that the labeling of Posilac® provides adequate directions for actual conditions of use. In addition, the VMAC endorsement of the final results of the PAMP confirms that bST is indeed safe and has no adverse effect on the milk supply.
FDA management also agrees that Monsanto Company's Post-Approval Monitoring Program adequately addressed the safety of the milk supply as related to Posilac®. Recently, Dr. Michael A. Friedman, FDA's Deputy Commissioner for Operations, told the Monsanto Company, "The issues surrounding this highly visible product are in many ways a microcosm of the science and public policy challenges that industry and the Agency face in bringing new products to the market place that offer potential benefits to society...I believe the outstanding quality of your studies and your commitment to working closely with the Agency in meeting your PAMP goals establish a model for successfully dealing with challenging approval issues."
FDA PUBLISHES FINAL RULE ON EXTRALABEL DRUG USE IN ANIMALS
In the November 7, 1996 Federal Register, FDA published a final rule to allow veterinarians to prescribe extralabel uses of certain approved animal drugs and approved human drugs for animals under certain conditions. This action implements the Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA). This regulation provides veterinarians with greater flexibility in the use of approved drugs in animals. These regulations put AMDUCA into effect on December 9, 1996.
The notice of proposed rulemaking published in the Federal Register on May 17, 1996. FDA received and considered approximately 110 comments in preparing the final rule.
Prior to the enactment of AMDUCA, the Federal Food, Drug, and Cosmetic Act (the Act) required users of approved new animal drug products to follow the exact directions on the labeling of the drug. This extralabel use restriction precluded use of an approved drug in species or for indications (disease or other conditions) not listed in the labeling, use of an approved drug at dosage levels higher than those stated on the label, and other extralabel purposes. In addition, the Act did not provide for the use of human drugs for treating animals.
Because of AMDUCA, the Federal Food, Drug, and Cosmetic Act will now permit veterinarians, like physicians, to prescribe extralabel uses of approved drugs for their patients. Although certain restrictions have been placed on veterinarians prescribing animal and human drugs in an extralabel manner, these restrictions generally apply only to the use of drugs extralabelly in food-producing animals. The key constraints are that any extralabel use must not result in violative residues in food-producing animals, the use must be by or on the order of a veterinarian within the context of a veterinarian-client-patient relationship, and the use must be in conformance with the new regulations.
AMDUCA includes a number of provisions that permit the Agency to restrict extralabel use in certain circumstances. For example, if there is a finding that there is a reasonable probability that an extralabel use may present a risk to public health from drug residues in animal-derived food, the Agency may establish a safe level for a residue for such extralabel use by regulation or order and may require the development of analytical methods for residue detection. If, after affording an opportunity for public comment, FDA finds that an extralabel animal drug use presents a risk to public health or that no analytical method has been developed and submitted, the Agency may prohibit such extralabel use. The following prohibitions currently apply to the uses of drugs in food-producing animals:
Chloramphenicol
Clenbuterol
Diethylstilbestrol (DES)
Dimetridazole
Ipronidazole
Other nitroimidazoles
Furazolidone (except for approved topical use)
Nitrofurazone (except for approved topical use)
Sulfonamide drugs in lactating dairy cattle (except approved use of sulfadimethoxine, sulfabromomethazine and sulfaethoxypyridazine)
Neither AMDUCA nor the implementing regulations are intended to lessen the responsibility of the manufacturer, the veterinarian, or the food producer with regard to drug residues. Under AMDUCA, any amount of residue resulting from an extralabel use would constitute a violation of the Act if a safe level or tolerance has not been established.
Title 21 of the Code of Federal Regulations is now amended to add a new part 530, titled "Extralabel Drug Use in Animals." A link to the text of the rule is available for review or downloading on CVM's Internet Website. The document as it appears in the Federal Register is also available in PDF format from the U.S. Government Printing Office's Access search screen at:
http://www.access.gpo.gov/su_docs/aces/aces140.html (Search on extralabel).
Additional information is available from Richard L. Arkin, Regulatory Counsel, Center for Veterinary Medicine (HFV-238), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301- 594-1737.
MAJOR CONCERNS FOR MINOR SPECIES
by Karen A. Kandra
On September 12-13, 1996, FDA cosponsored the eighth NRSP-7/FDA workshop titled, "Drug Availability for Minor Species in the 21st Century." Animal producers, veterinarians, scientists, and regulators attended the workshop to exchange ideas on approaches to disease problems and drug priorities.
The USDA/Cooperative State Research, Education, and Extension Service National Research Support Project No. 7 (NRSP-7) is designed to address the shortage of minor use animal drugs by funding and overseeing the efficacy, animal safety, human food safety research and the environmental assessment required for drug approval. Minor animal drug uses are analogous to human orphan drug uses, for which the market is insufficient to justify the costly research expenditures by a pharmaceutical firm necessary to obtain FDA approval. Minor species are defined by exclusion. That is, any that are not major species. Major species are horses, cattle, swine, turkeys, chickens, dogs, and cats. Minor species include sheep, goats, fish, gamebirds, rabbits, ratites, and deer among others. Minor uses also include certain diseases in major species that occur infrequently or in limited geographical locations.
Projects are prioritized from Animal Drug Requests which originate from a variety of sources: producer groups, academicians, and pharmaceutical companies. The regional coordinators, principal investigators, and CVM collaborate to determine what data is required to support safety and efficacy claims for the product requested, and then to develop protocols for any necessary studies. Results of these studies are reviewed by CVM, and ultimately are placed in a Public Master File, which may be used by a pharmaceutical company to support an original or supplemental New Animal Drug Application (NADA).
In the past 10 years, NRSP-7 has received over 280 requests. The majority of these requests are not feasible for one reason or another. However, the data necessary to support approvals for 24 of these requests have been published as Public Master Files. Of these, 19 have been used to support supplemental NADA's, and have been approved. Two complete files have not been acted upon by the company. Three requests have been recently completed and are waiting for filing of supplemental NADA's. These are formalin for fish, sulfadimethoxine/ormetoprim for chukar partridges, and ivermectin injection for bison. NRSP-7 has several additional public master files nearing completion. There are currently more than 30 other projects in development for more than 17 drugs and 10 species.
At the September workshop, introductory comments were made by Dr. Alistair I. Webb, University of Florida, and Drs. Stephen Sundlof and Andrew Beaulieu of the Center for Veterinary Medicine (CVM). Dr. Andres de la Concha from the Texas Agriculture Experiment Station followed with a discussion of the lack of drugs to treat diseases of sheep and goats. Internal parasites and pneumonia are the most important diseases of sheep and dairy goats. Dr. de la Concha cited antibiotics and anthelmintics as the most needed drugs.
Dr. Lowell Wilson, Pennsylvania State University, addressed the medical needs of veal calves. He stated that the average slaughter age is now 19-20 weeks, doubling in the last 10 years. He sees the following drug needs for veal calves: amoxicillin, ampicillin, penicillin, and decoquinate.
Dr. Barry Marshall, New Zealand Embassy, spoke about farm raised deer. He said that about 1.5 million deer are farmed in the United States on 4,500 farms. The market for New Zealand venison exports is about $144 million, and live deer about $600,000.
Mr. Bill MacFarlane of MacFarlane Pheasant Farm, Janesville, Wisconsin, addressed problems associated with the production of game birds. About 25 to 50 million birds are produced annually. These birds are raised outdoors, and stress is a concern. Gapeworm and blackhead are common diseases. Medications provided in drinking water are not practical since birds drink from puddles during rainy seasons. The need for approved medicated feeds is critical since extra-label use does not apply to medicated feeds.
Dr. Thomas Nickerson, Weaverville, CA, discussed drug availability for ratites. Emus are popular for their meat and leather; ostriches for meat, feathers, and hide; and rheas for body fat on the tail used to make oil for moisturizing skin. Drugs are needed to treat diseases such as avian influenza, external parasites, flukes, and equine encephalitis in emus. Most diseases attack young birds under 3 months of age, and the birds are not slaughtered until approximately 10 months of age. The ratites have a renal-portal system which carries drugs directly to the kidney, causing more toxicity, which is a unique problem.
Dr. William Lance, Wildlife Pharmaceuticals, Inc., discussed the needs of zoologic species. This is a focused market, since only about 10,000 animals are included. Major needs are reproductive modifiers, long-acting neuroleptics, sustained-release antibiotics, and anthelmintics.
Dr. John Pitts, Quicene, WA, addressed the problems of aquaculture. The aquaculture industry has successfully cooperated with CVM and the pharmaceutical industry in prioritizing the drug needs of the industry and assisting with studies to support future approvals. The need for medicated feeds is also paramount in this industry.
Dr. Ruth Francis-Floyd, University of Florida, discussed the problems of the ornamental fish industry. This is an industry worth over fifty million dollars per year where there are no approved drugs. Aquarium fish are growing in popularity and the biggest problems facing the species are external parasites, bacterial infections, and fungal infections.
Dr. Chris Hayhow, Hoechst Roussel, addressed the drug availability issues for rabbits, a species which has a growing market in fur, exhibition, pets, and laboratory areas. He estimated that 2.3 million households have rabbits, with pet ownership increasing rapidly. Special challenges facing rabbit enthusiasts are disease, parasites, and production problems in their animals. There are currently only three approved products: sulfaquinoxaline, lasalocid, and tetracycline.
Dr. Brad Smith, Oregon State University, reported on the growing popularity of llamas. With about 100,000 in North America, they are increasing at a rate of about 25 percent per year. Now used as companion animals, as well as for guarding sheep, they are prone to P. tenuis, a gastrointestinal nematode, liver flukes, and bacterial diseases like tuberculosis, Johne's disease, and brucellosis. The alpaca is a smaller animal, similar to llamas, very popular for its quality fur. Both llamas and alpacas are gaining in popularity and long-term growth of the industry is expected.
On the second day of the workshop, speakers from the pharmaceutical industry presented their perspective on the problem. There was common agreement that firms adding minor species claims to their labels increase legal liability. This potentially places the company's assets and major species claims at risk. Despite these risks, several companies have gone through the process of supplementing their approved labels with minor species claims.
In order to successfully expand the availability of minor use therapeutants, there is a need for NRSP-7, pharmaceutical companies, and CVM to collaborate early in the product development planning, including the design of study protocols. These cooperative efforts benefit all parties and expedite the process.
The workshop concluded with a lively panel discussion chaired by Dr. Robert Ringer, the National Coordinator of the NRSP-7 program. Members of the panel included Dr. Joe Gloyd of AVMA, Dr. James Wilkerson, a lawyer and veterinarian, Dr. Harold Hafs of Rutgers University, Dr. Kurt Mann, a veterinary advisor to the House Committee on Agriculture, Dr. Michael Blackwell, Deputy Director of the FDA Center for Veterinary Medicine, and Dr. Richard Carnevale of the Animal Health Institute. The discussion touched on many issues introduced throughout the 2-day workshop. Most comments concentrated on how to improve the program so as to increase availability of therapeutic drugs labeled for minor species, and means to address the problems facing specific industries.
NRSP-7 will publish the proceedings from this workshop by the summer of 1997. Anyone interested in receiving a copy can contact Dr. Alistair Webb at the College of Veterinary Medicine at the University of Florida. His telephone number is (352) 392-4700, extension 3828.
CVM also has recently finalized a revision of the Minor Use Guidance Document: A Guide to the Approval of Animal Drugs for Minor Uses and for Minor Species. The availability of this publication will be announced in the Federal Register and the FDA Veterinarian in the near future.
VETERINARY CODEX HOLDS TENTH SESSION IN COSTA RICA
by Karen A. Kandra
The Codex Committee on Residues of Veterinary Drugs in Foods held its Tenth Session from October 29 to November 1, 1996 in San Jose, Costa Rica, at the invitation of the U.S. Government in cooperation with the Government of Costa Rica and the Inter-American Institute for Cooperation on Agriculture (IICA). The Session was chaired by Dr. Stephen Sundlof, Director, FDA, Center for Veterinary Medicine. Attendees represented 34 member countries and 12 international organizations.
An important role of Codex is working to improve food quality and safety while facilitating international trade and harmonization. There was a major discussion concerning elements of risk assessment for the determination of veterinary drug residues in food. The Committee identified seven areas requiring further work:
better delineation of the respective roles of the Committee and Joint FAO/WHO Expert Committee on Food Additives (JECFA);
improvement of transparency of the process;
recognition that the application of safety factors and other conventions to address uncertainty were not strictly scientifically based and therefore, introduced an element of risk management into the risk assessment process;
consideration of the benefits of the use of veterinary drugs as well as risks, for animals as well as humans;
problems in relation to animal studies and the potential of using in vitro studies as alternatives for such studies;
problems related to the generation of residue data for minor species;
problems related to old substances which had not been evaluated under modern criteria, but which were still in use in many countries, and substances on the so-called "inactive list."
The recommendations of the Joint Expert Committee on Food Additives (JECFA) for thirteen veterinary drugs were evaluated. Acceptable Daily Intakes (ADI's) and Maximum Residue Limits (MRL's) were allocated/confirmed for clenbuterol, abamectin, moxidectin, chlortetracycline, oxytetracycline, tetracycline, neomycin, spiramycin, cypermethrin and -cypermethrin, and tilmicosin. MRL's for cypermethrin, -cypermethrin, and tilmicosin in sheep milk were made temporary pending further information. A temporary ADI and temporary MRL's were established for thiamphenicol. The JECFA could recommend neither an ADI nor MRL's for xylazine.
A working paper on procedures for assessing the effects of antimicrobial veterinary drug residues in food on the human intestinal microflora was reviewed.
The International Office of Epizootics reported on the progress of the "International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products" (known as VICH). In the short term, it was decided to establish five working groups which would consider the following topics: Guidelines on Quality, Safety, Good Clinical Practice, Efficacy of Anthelmintics, and Ecotoxicology.
Another important issue discussed was Guidelines on Residues at Injection Sites. The intention of the proposed guidelines was to ensure consumer safety, enhance residue monitoring practices, and to assist in trade facilitation. There was general support that the calculation of risk from consumption of residues at the injection site should be based on the principles of acute reference dose. The Committee invited JECFA to examine the issues raised in the paper and in the present discussion. It also requested that the paper be revised in light of this advice and be circulated for comments prior to submission for consideration at its next Session.
There was an extensive discussion regarding the methods of analysis and sampling for residues of veterinary drugs at the Ninth Session held in 1995. The Committee recalled the decision that if no method of analysis acceptable to the Committee was available to monitor an MRL, that the MRL should not be advanced beyond Step 7 to full acceptance by the Committee. Noting that its Terms of Reference required the Committee "to determine criteria for analytical methods used for the control of veterinary drug residues in foods" but did not extend to the consideration of methods of analysis, the Committee agreed that all MRL's currently retained at Step 7 should be considered for acceptance by advancement to Step 8.
The Committee also discussed a paper prepared by the Delegation of Australia and other delegations on the validation of analytical methods. Many of the issues raised in the paper were of potential concern in other areas of the Commission's work, including pesticide residues, contaminants, and microbiological analysis. The Committee proposed that the Commission request FAO, together with WHO, to give consideration to convening an Expert Consultation on the question of methods validation for food control purposes.
The delegation of the United States, with assistance from other delegations, presented a paper on the evaluation of residues of veterinary drugs in milk and milk products. The Committee noted that the proposals contained in the document were directed towards the prevention and monitoring of veterinary drug residues. Drug monitoring programs should be undertaken at an early point in the milk collection system. Problems such as the dilution of affected milk from individual cows or herds with other milk could be addressed this way. It was proposed that an integrated test system, drawing on the principles of the Hazard Analysis/Critical Control Point (HACCP) System, would be effective in combining screening and more investigatory tests at Critical Control Points.
The Committee noted the need for more data on the fate of residues during milk processing, e.g., pasteurization, spray drying, and cheese-making. The Committee also suggested the need for further data on the distribution of residues between different milk components (milk fat, whey, protein) following the administration of veterinary drugs by different routes (e.g., intramuscular use compared to intramammary use).
NEW COMMITTEE MEMBERS FOR VMAC
Two new members have been selected to join FDA's Veterinary Medicine Advisory Committee (VMAC). The new members are Oscar J. Fletcher, Jr., D.V.M, Ph.D. and Keith E. Sterner, D.V.M. They replace retiring members Dr. Bernard Curran, and Dr. Stanley Kleven.
Dr. Fletcher is Dean of the College of Veterinary Medicine at North Carolina State University. He received his D.V.M. and M.S. degrees from the University of Georgia, and his Ph.D. from the University of Wisconsin. As a specialist in avian medicine, Dr. Fletcher is the author of more than 125 scientific papers and a contributor to four text books. In addition, he is a member of the American College of Veterinary Pathologists and a Founder Diplomate of the American College of Poultry Veterinarians.
Dr. Sterner is a graduate of Michigan State University, and is co-owner of a mixed animal practice in Ionia, Michigan treating mainly food animals. He represents the large animal specialty, principally bovine. In 1991 the American Association of Bovine Practitioners honored Dr. Sterner as "Bovine Practitioner of the Year", and Michigan State University College of Veterinary Medicine presented him with the Distinguished Alumnus Award.
Dr. Donald Lein remains the chairman of VMAC, and other members include Dr. George Cooper, Sue Hudson Duran, Dr. Diane Gerken, Dr. Gary Koritz, Dr. Alice Wolf, Dr. Steven Barker, Col. Nancy Jaax, and Dr. Ling-Jung Koong. VMAC members normally serve four-year terms.
FEED MILL LICENSING NOW A REALITY
by Dr. W. D. Price, Dr. Malcolm Thomas, and James Tessmer
Medicated Feed Applications (MFA's), or 1900's are now a thing of the past. On October 9, 1996, the President signed the Animal Drug Availability Act of 1996 (ADAA), which amends Section 512(m) of the Federal Food, Drug, and Cosmetic Act (the Act) to require a single facility license rather than multiple MFA's for each feed mill as previously required. FDA intends to revise its regulations to clarify that a license will be required for the manufacture of feeds using Category II, Type A medicated articles, the manufacture of free choice feeds, and the manufacture of liquid Type B feeds where the formula or specifications are not published in the 21 CFR 558 regulations.
Following are some frequently asked questions concerning licensing:
What are the advantages of Feed Mill Licensing?
This amendment streamlines the paper work process for the approval to manufacture medicated feeds. Now any feed manufacturing facility which currently holds one or more approved MFA's automatically holds a transitional license. The transitional license is valid up to 18 months, and will terminate unless converted by CVM to a license upon receipt (within the 18-month period) of a license application accompanied by a copy of an approved MFA.
If I have an approved MFA, how do I submit a license application?
License applications will be accepted in letter form, and should include the following:
full statement of the business name, address, and FDA registration central file number (CFN) of the specific manufacturing site;
the name and signature of the responsible individuals for that facility;
the certification statement that the animal feeds bearing or containing new animal drugs are manufactured and labeled in accordance with the applicable regulations published pursuant to 512 (i) of the Act; and
the certification statement that the methods used in, and the facilities and controls used for, manufacturing, processing, packaging, and holding such animal feeds are in conformity with good manufacturing practice as described in 21 CFR 225.
If I do not have an approved MFA, how do I submit a license application?
Register with FDA and submit a license application as outlined above.
What happens when a feed mill license application is filed?
It is checked for completeness. If it is incomplete, it will be returned to the applicant. If it is complete, CVM will request a feed mill inspection of the facility by FDA Field unless the mill is covered under the transitional provisions of the October 9, 1996 act, in which case a license will issue. Upon completion of the inspection, a license will issue if the facility is found to be in substantial compliance with CGMP requirements. If the result of the inspection is classified Official Action Indicated (OAI), the license will not be approved unless FDA and the applicant agree on an extended review time (beyond 90 days) so that the applicant has time to correct the deficiencies and FDA has reinspected.
What is required prior to shipment of a Type A Medicated Article for use in medicated feeds?
Prior to shipment of a new animal drug intended for use in the manufacture of medicated animal feed, the seller must have a written statement from the buyer that the buyer has a feed mill license and possesses current approved Type B and/or C feed labeling for the drug, unless FDA has exempted by regulation manufacturers of animal feed bearing or containing such drug from the requirement to hold a license. In the event that the buyer is not the feed manufacturer, the buyer must provide the seller with a statement that the drug will be sold only to feed mill license holders. The source of the labeling is the approved labeling in the new animal drug application (NADA), and is available from the Type A article manufacturer or the distributor.
How does licensing affect the records and assay requirements?
Licensees are required to establish and maintain all records and make such reports as required by regulation or order issued under 512 (m)(5)(A) of the Act and as now published in 21 CFR 510.301. They are also required by good manufacturing practice regulations to establish and maintain a program of sampling and analysis of at least three representative samples of the medicated feed collected at periodic intervals during the calendar year. The program must provide for sampling and assay of the first batch manufactured. If a medicated feed contains a combination of animal drugs, only one of the drugs need be subject to analysis each time, provided the one tested is different from the one(s) previously tested. Reports of assays shall be kept on the premises for not less than 1 year after the date of manufacture of the medicated feed.
Do licensees still have to register and be inspected?
Licensees are required to register every year with the FDA. Licensees will be subject to biennial inspections, the same as MFA holders, and if regulatory action is indicated, will be subject to the same regulatory procedures as MFA holders were.
Where do feed mills get approved Type B and C medicated feed labels?
Type A medicated article manufacturers are required to have Type B and C Blue Bird labeling (model labeling) approved as part of the New Animal Drug Application (NADA) approval procedure. The seller, Type A medicated article manufacturers or the distributor, is required to furnish Type B and/or C medicated feed labels to the feed mill prior to shipment of the Type A medicated article.
How will licensing affect the Veterinary Feed Directive?
CVM is working on regulations to implement the Veterinary Feed Directive drug provisions of the ADAA. In accordance with Congress' directive, FDA will not delay any approvals of veterinary feed directive drugs pending the publication of implementing regulations.
CVM is available to answer questions during the transition to a feed mill licensing system. For additional information, please contact the Division of Animal Feeds, Office of Surveillance and Compliance, Center for Veterinary Medicine, 7500 Standish Place, Rockville, MD 20855, telephone 301-594-1724.
by Dr. M. Alewynse and Dr. W. D. Price
On May 29, 1992, the FDA published a Statement of Policy: Foods Derived from New Plant Varieties in the Federal Register. This statement laid out issues that individuals should consider during the development of new plant varieties which includes those developed using rDNA techniques. After publication of the policy, FDA's Center for Food Safety and Applied Nutrition (CFSAN) and Center for Veterinary Medicine (CVM) initiated a voluntary consultation process where the developer of a new plant variety consults with the Agency about safety and regulatory issues prior to marketing. In June 1996, these procedures were formalized. Included in the procedures are the CVM concerns published in the FDA Veterinarian by Price and Alewynse (September/October 1995). Typically, the developer submits summary information about the safety and nutritional assessment of the plant to FDA. The Agency may then conclude the consultation process by issuing a letter to the developer which indicates that there are no unresolved issues associated with that variety. The consultation procedures are described in more detail on CFSAN's WWW site (http://vm.cfsan.fda.gov/~lrd/consulpr.html).
Twenty-five consultations involving eight different crops, including both human foods, such as tomatoes, and traditional animal feedstuffs, like the soybean, have been completed. In 1994, the Agency and plant developers concluded eight consultations. During 1995, seven consultations were concluded; and by November, 1996, another ten had completed the process. Some of the consultations involved several different plant lines. In 1996, the first multiple trait plant, corn to be marketed for both its insect protection and herbicide tolerance qualities, completed the consultation process.
At the present time, five different consultations have been concluded for tomatoes which exhibit modified ripening or softening behavior. Several potatoes which contain the cryIIIA gene product to confer insect protection have also been examined. In addition, virus resistant squash has completed the process.
For crops such as corn and soybeans which have traditionally been used in animal feed, the primary focus of trait development has been to improve insect resistance and plant tolerance to herbicide application. Insect resistance has been accomplished by plant expression of insecticidal proteins. At the present time, genes obtained from Bacillus thuringiensis have been utilized to obtain the insecticidal trait. This characteristic has been incorporated into both cotton and corn. In corn, the desired effect, a reduction in European corn borer infestations, has been the subject of five consultations. These insecticidal proteins are classified as pesticides by the Environmental Protection Agency (EPA) which is responsible for licensing these genetically modified crops. However, FDA is still responsible for the wholesomeness of the plants.
Herbicide tolerance is also a trait of interest to plant breeders and has been the subject of nine consultations. Many herbicides can not be used on or have a limited time when they can be applied to crops. By engineering a gene into the plant which allows herbicide application without injury or yield reduction, firms hope to aid farmers in the control of field weeds. With herbicide tolerant crops, weeds can be treated anytime they become a problem which allows more freedom in the timing of herbicide application. Corn, cotton, canola, and soybeans have all been modified to be tolerant to different herbicides. FDA has the sole responsibility for the safety of these genetically modified crops, while EPA regulates the use of the herbicide.
In addition, several consultations have dealt with modifications to aid traditional plant breeding, such as male sterility in corn, and hybridization in oilseed rape. Plant composition has also been changed using rDNA techniques. Canola has been modified to produce oil containing an increased level of laurate, making its composition similar to coconut oil which is used in nondairy whipped toppings.
The use of antibiotic resistance marker genes in the development of biotech plants has been a concern. Plant breeders have indicated in the consultation process that kanamycin (kanr), ß lactam, chloramphenicol, and aminoglycoside resistance genes have been used in several modified plants released thus far. Only the kanr gene produces a product in the plant. Calgene Inc. filed a Food Additive Petition (FAP) for aminoglycoside 3' phosphotransferase II (NPT II) encoded by the kanr gene. This gene product appears in small quantities in the Flavr Savr™ tomato, and cotton, rape (canola) and potato varieties. The FAP was approved after a thorough review which substantiated that NPT II would not raise a safety concern. It was also concluded that NPT II would not significantly affect the stability of neomycin in animal feed.
Genes encoding resistance to kanamycin, ß lactam, chloramphenicol, and aminoglycoside antibiotics have been used in the development of other modified plant varieties, but these genes are not expressed in those plants. These genes have bacterial promoters to target expression in bacteria where the total gene construct to be inserted in the crop is cloned, and are used only as a gene detection tool. Convincing arguments have been made by the plant developers that it is highly unlikely that a functional copy of these genes would be transferred from the plant to rumen or gut microflora. However, the use of antibiotic resistance marker genes continues to be an issue on the international scene.
CFSAN and CVM in cooperation with USDA's Foreign Agricultural Service have participated in several international meetings, including those with Japan and the European Union (EU) in an attempt to harmonize preclearance requirements. CVM has worked with Canada, Japan, and the EU on guidance for animal feed use of Novel (biotech) Foods. Labeling of food and feed derived from new plant varieties appears to be an issue within the EU. In the U.S., labeling has only been suggested for high laurate canola oil because of the compositional changes. Feed or food labeling would be required in the U.S. if there is a safety issue, such as the presence of an allergen or a significantly higher level of a toxic factor, such as gossypol in cottonseed, or if the product would be misbranded, due to changes in composition, such as occurred in high laurate canola.
The following table lists plant varieties which have completed the consultation process as of December 6, 1996. The table includes the name of the developer, the crop, the trait, and the source of the genetic material conferring the trait. An updated version of the table is maintained at the CFSAN WWW site (http://vm.cfsan.fda.gov/~lrd/biocon.html).
Firm Crop and Trait Responsible Gene Gene Source
Agritope Inc. Modified fruit S- hydrolase gene E. coli
ripening tomato adenosylmethionine bacteriophage T3
Dekalb Genetics Glufosinate Phosphinothricin Streptomyces
Corp. tolerant corn acetyl transferase hygroscopicus
gene
Dupont Sulfonylurea Acetolactate tobacco
tolerant cotton synthase gene
Monsanto Co. Insect protected CryIIIA gene Bacillus
potato thuringiensis
Monsanto Co. Insect protected CryIA(b) gene Bacillus
corn thuringiensis
subsp. kurstaki
Monsanto Co. Insect protected CryIA(b) gene Bacillus
corn thuringiensis
subsp. kurstaki
Monsanto Co. Glyphosate Enolpyruvylshikimate Agrobacterium sp.
tolerant/insect -3-phosphate strain CP4
protected corn synthase gene and
glyphosate Ochrobactrum
oxidoreductase anthropi
gene in the
glyphosate tolerant
lines
Bacillus
CryIA(b) gene thuringiensis
in lines that are subsp. kurstaki
insect protected
Northrup King Insect protected CryIA(b) gene Bacillus
corn thuringiensis
subsp. kurstaki
Plant Genetic Male Male sterile oilseed Bacillus
Systems sterile/fertility rape contains the amyloliquefaciens
restorer oilseed barnase gene
rape
Fertility restorer Bacillus
lines express the amyloliquefaciens
barstar gene
Plant Genetic Male sterile corn Barnase gene Bacillus
Systems amyloliquefaciens
AgrEvo Inc. Glufosinate Phosphinothricin Streptomyces
tolerant canola acetyltransferase viridochromogenes
gene
AgrEvo Inc. Glufosinate Phosphinothricin Streptomyces
tolerant corn acetyltransferase viridochromogenes
gene
Calgene Inc. Laurate canola 12:0 acyl carrier California bay,
protein thioesterase Umbellularia
gene californica
Ciba-Geigy Corp Insect protected CryIA(b) gene Bacillus
corn thuringiensis
kurstaki
Monsanto Co. Glyphosate Enolpyruvylshikimate Agrobacterium sp.
tolerant cotton -3-phosphate strain CP4
synthase gene
Monsanto Co. Glyphosate Enolpyruvylshikimate Agrobacterium sp.
tolerant canola -3-phosphate strain CP4
synthase gene
Monsanto Co. Insect protected CryIA(c) Bacillus
cotton thuringiensis
subsp. kurstaki
Asgrow Seed Virus resistant Coat protein genes watermelon
Co. squash mosaic virus 2 and
zucchini yellow
mosaic virus
Calgene Inc. Flavr Savr™ Antisense tomato
tomato polygalacturonase
gene
Calgene Inc. Bromoxynil Nitrilase gene Klebsiella
ozaenae
tolerant cotton
DNA Plant Improved ripening Fragment of the tomato
Technology tomato aminocyclopropane
carboxylic acid
synthase gene
Monsanto Co. Glyphosate Enolpyruvylshikimate Agrobacterium sp.
tolerant soybean -3-phosphate strain CP4
synthase gene form
Monsanto Co. Improved ripening Aminocyclopropane Pseudomonas
tomato carboxylic acid chloraphis strain
deaminase gene 6G5
Monsanto Co. Insect protected CryIIIA gene Bacillus
potato thuringiensis sp.
tenebrionis
Zeneca Plant Delayed softening Fragment of the tomato
Science tomato polygalacturonase
gene
In the November 18, 1996 Federal Register, FDA published a notice stating that the Agency is withdrawing approval of a new animal drug application (NADA 125-226) for tylosin Type A medicated articles to make tylosin Type C medicated feeds. This NADA was held by Countrymark Cooperative, Inc. (formerly Indiana Farm Bureau Cooperative). The sponsor requested the withdrawal of approval because it no longer makes Type A medicated articles for use in Type C medicated feeds.
In the November 20, 1996 Federal Register, FDA published a notice that the Agency is providing an opportunity for a hearing on a proposal to withdraw approval of a new animal drug application (NADA) for Protamone-D (iodinated casein tablets) for dogs, held by Agri-Tech, Inc., because the applicant has failed to submit required periodic reports.
Milwhite, Inc., has filed a petition proposing that the food additive regulations be amended to provide for the safe use of hydrated sodium calcium aluminosilicate as a binder of aflatoxins in feeds and drinking water. Additional information is included in the November 20, 1996 Federal Register (page 59101) and from Dr. Henry E. Ekperigin, Center for Veterinary Medicine (HFV-222), FDA, 7500 Standish Place, Rockville, MD 20855, (301) 594-1724.
SENTENCING IN DRUG RESIDUE CASE
On October 10, 1996, Eugene Gorr and Jeffrey Lee Gorr of Petersburg, Michigan, were fined $25,000 each and sentenced to three years probation as a result of their guilty pleas to conspiracy to introduce adulterated food into interstate commerce with the intent to defraud and mislead. During the probation period, the Gorrs must perform 50 hours of community service per year. The defendants were also ordered to comply with the terms of the plea agreement.
The Gorrs were livestock dealers, buying, selling, and transporting livestock, including cattle, obtained from farmers and auction markets, to meat packers for slaughter for food for human consumption. The Gorrs had been identified by the U.S. Department of Agriculture's Food Safety and Inspection Service as the source for more than 30 animals containing illegal levels of drugs. Also, on three separate occasions, the Gorrs purchased from undercover FDA agents animals which they were told were medicated, and subsequently sold those animals for human food.
During their sentencing, Judge Nancy Edmonds commented that the Gorr's practice of selling cattle adulterated with drug residues was not a crime of negligence, but of overreaching and greed on the part of the defendants.
INDICTMENTS IN VEAL DRUG CASES ANNOUNCED
On November 21, 1996, U.S. Attorney, Thomas P. Schneider, Milwaukee, Wisconsin, announced Federal indictments in the ongoing nationwide investigation into the smuggling, distribution, and use of illegal drugs in the veal industry.
Gerard Hoogendijk of the Netherlands has been indicted as the principal supplier of these black market drugs. Hoogendijk is the owner of Pricor, B.V., the Dutch animal premix company which owns a majority of Vitek, a firm previously convicted on twelve counts of conspiracy, smuggling and distribution of unapproved animal drugs into and throughout the United States. The new indictment charges Hoogendijk with nine Federal offenses including conspiracy to defraud the United States and to smuggle and distribute misbranded and adulterated animal drugs. Hoogendijk is also charged with six smuggling counts. Both the conspiracy and smuggling charges each carry a prison term of up to five years, a fine of up to $250,000, or both. In addition, Hoogendijk is charged with two counts of introducing the drug clenbuterol into interstate commerce, an offense which carries a maximum prison term of three years, a fine of up to $250,000, or both. Arrangements are continuing with the Dutch government for the extradition of Hoogendijk, who is a Dutch citizen.
Additional indictments were returned against Travis Calf Milk, Inc., and its President, Gerald R. Travis; and VIV, Inc. (aka Hying America), and its operators Jan Van Den Hengel and Hennie Van Den Hengel. They are charged with conspiracy to smuggle and distribute unapproved, adulterated and misbranded animal drugs. Each of the defendants is also charged with five additional counts of violating food and drug laws prohibiting the distribution or receipt of unapproved and adulterated animal drugs. In addition, VIV and the Van Den Hengels are accused of smuggling various chemicals into the U.S., resulting from a seizure of animal drugs found concealed in a container destined for Vitek in February, 1994.
The indictments allege that both VIV and Travis Calf Milk, Inc., received over 200,000 and 150,000 pounds, respectively, of Vitek veal feed supplements containing clenbuterol, zinc bacitracin, and/or avoparcine. Travis Calf Milk, a Wisconsin feed company, is accused of using the unapproved drugs in its veal feed. VIV, a Pennsylvania veal grower, is accused of using the unapproved drugs on veal raised in its own facilities.
If convicted, the corporate defendants face fines of up to $500,000 on each count, totaling $3,500,000 for VIV and $3,000, 000 for Travis Calf Milk, Inc. Jan and Hennie Van Den Hengel face fines of up to $250,000 for each count, up to five years in prison for each of the smuggling and conspiracy counts, and up to three years in prison for each of the adulterated drug charges.
A plea agreement was reached with Provimi Veal Corp., a Wisconsin corporation charged with violating food and drug laws prohibiting the distribution of adulterated and misbranded animal drugs which stem from their involvement in a 1988-89 lamb raising venture. Information provided alleges that Provimi was a half-owner of Vitek from 1988 until 1992 and purchased lambs fed with Vitek products containing clenbuterol. In early 1992, Provimi sold its interest in Vitek before the current investigation began.
These charges are the result of over three years of joint investigations conducted by criminal investigators from U.S. Customs, the Food and Drug Administration (FDA), and the U. S. Department of Agriculture (USDA). Also involved are attorneys from the Office of Consumer Litigation in the Department of Justice and the U.S. Attorney's Office in the Eastern District of Wisconsin, as well as numerous State and local agencies, including the Pennsylvania State Police. Investigations are ongoing and additional indictments are expected in the near future.
VAN LEEUWENS VIOLATE CONSENT DECREE
On November 12, 1996 in the U. S. District Court for the Eastern District of California, a Stipulation and Order was signed by the judge and filed finding defendants Arie, Clara, Arnold, Barry, and Jon Van Leeuwen had violated a Consent Decree of Permanent Injunction entered by the court on October 4, 1995, and were, therefore, liable for Civil Contempt.
The Van Leeuwens owned and operated two dairies in Modesto, California. The original injunction action against the Van Leeuwen Dairy was based on 16 reports of illegal drug residues in cull dairy cows offered for slaughter during the period from January 22, 1991 through November 17, 1994. The illegal residues included the following drugs: streptomycin, oxytetracycline, penicillin, sulfamethazine, tetracycline, sulfathiazole, gentamicin, erythromycin, and chlortetracycline. At that time the Consent Decree permanently restrained and enjoined Arie C. and Clara G. Van Leeuwen from administering to cattle any article of new animal drug and introducing or delivering for introduction into interstate commerce any article of food consisting of cattle or their edible tissues unless and until the defendants had established and implemented systems to control the use and administration of drugs to their cattle to avoid illegal drug residues, including an identification system, a written recordkeeping system, a drug inventory and accountability system, another system which ensures that each animal had been held for the proper withdrawal period, and a quarantine or segregation system for medicated animals.
After the Consent Decree was entered, FDA held a meeting with the Van Leeuwens and their attorney to discuss the requirements of the Consent Decree and conducted four inspections where the requirements were thoroughly explained to the owners. In spite of these efforts, the Van Leeuwens had failed to develop and implement adequate systems and continued to sell animals for slaughter contrary to the requirements of the Consent Decree. The Van Leeuwens failed to take the injunction seriously and continued to violate the law while making promises of compliance.
Under the Stipulation and Order, the defendants were ordered to comply with the Injunction at both dairies and to permanently identify all cattle with an ear tag and provide FDA with a list of ear tag numbers each month. The defendants will be fined $100 per day until they have demonstrated compliance with the injunction, except that fine will be purged if they demonstrate compliance within 60 days of the Order. Subsequent violations of the injunction will result in a sanction of $1,000 for each animal sold in violation of the injunction and $1,000 for any other violation of the injunction. Defendants were also ordered to pay $2,500 for costs incurred by the Government in monitoring compliance with the injunction to date.
A warning letter was sent to Brabant Farm, Verona, NY, for drug residue violations. The firm medicated cows without maintaining medication records and did not observe adequate withdrawal periods.
Russell F. Leone, a livestock dealer from Utica, NY, was sent a warning letter for drug residue violations. The firm did not implement adequate procedures to prevent medicated cows from entering the food supply.
A warning letter was sent to Foster Farms, Livingston, CA, for above tolerance levels of arsenic in poultry, failure to follow withdrawal times, failure to conduct assays of medicated feeds, and failure to review production records.
Roseland Elevator, Blomkest, MN, a firm that produces medicated feed, was sent a warning letter for not maintaining adequate daily drug records and not conducting assays of medicated feeds.
A warning letter was sent to Lindsay Farms, Masonville, IA, for deviations from the Good Manufacturing Practice (GMP) regulations for medicated feed.
Company
Bayer Corp. Animal Health Divison
(NADA 140-828)
Generic and (Brand) Names
Enrofloxacin (Baytril ®) concentrate antimicrobial solution 3.23% Rx
Indications
Chickens and turkeys. For control of mortality associated with certain bacteria.
Routes/Remarks
ORAL: The concentrate is added to drinking water to pruce a final concentration of 25 to 50 ppm.
Federal Register 11/5/96.
Company
Pfizer, Inc.
(NADA 141-061)
Generic and (Brand) Names
Doramectin (Dectomax®)
Indications
Cattle. For treatment and control of gastro-intestinal roundworms, lungworms, eyeworms, grubs, lice, and mange mites.
Routes/Remarks
INJECTABLE: Provides for the use of Dectomax 1 percent injectable solution.
Federal Register 10/11/96.
Company
Pharmacia and Upjohn Co.
(NADA 135-940)
Generic and (Brand) Names
Clindamycin Hydrochloride Liquid (Antiroe® Aquadrops) Rx
Indications
Dogs. For treatment of soft tissue infections (wounds and abscesses), dental ifections, and osteomyelitis caused by or associated with certain susceptible strains of aerobic or anaerobic bacteria. The supplement expands use of the drug to cats.
Routes/Remarks
ORAL: 5.0 to 10.0 milligrams per pound of body weight every 24 hours for a maximum of 14 days for cats.
Federal Register 11/20/96.
Company
Merck Research Labs, Division of Merck & Co., Inc.
(NADA 140-971)
Generic and (Brand) Names
Ivermectin with Pyrantel Pamoate (Heartgard™ Plus) Rx
Indications
Dogs. To prevent heartworm disease and to treat and control ascarid and hookworm infections.
Routes/Remarks
ORAL: The supplement provides for expanding the use for the treatment and control of an additional adult hookworm infection.
Federal Register 11/20/96.
Company
Luitpold Pharmaceuticals, In., Animal Health Division
(NADA 140-901)
Generic and (Brand) Names
Polysulfated glycosaminoglycan (Adequan®)
Indications
Horses. For treatment9f noninfectious degenerative and/or traumatic joint dysfunction and associated lameness of the carpal joint. The supplement provides for use for treatment of the same conditions of the hock joint.
Routes/Remarks
INJECTABLE.
Federal Register 10/18/96.
Company
Phoenix Scientific, Inc.
(ANADA 200-126)
Generic and (Brand) Names
Phenylbutazone Rx
Indications
Dogs. For relief of inflammatory conditions associated with the musculo-skeletal system.
Routes/Remarks
INJECTABLE: The supplement provides for use in dogs. The ANADA was approved for use in horses. The supplemental ANADA is a generic copy of Cooper's NADA 11-575 for Butazolidin® Injectable 20 percent.
Federal Register 10/18/96.
Company
Phoenix Scientific
(ANADA 200-146)
Generic and (Brand) Names
Oxytetracycline hydrochloride soluble powder
Indications
Chickens, turkeys, swine, cattle, and sheep. For either control or control and treatment of certain diseases of these animals.
Routes/Remarks
ORAL (in drinking water): The supplement provides for the drug product in a 5-pound pail in addition to the previously approved 2-pound pail. In addition, the regulations are amended to specify the withdrawal period for use of medicated drinking water made from the subject sponsor's drug and to add certain warning statements required on the label.
Federal Register 10/8/96.
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