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• ANTIMICROBIAL RESISTANCE DOCUMENTS AVAILABLE

• PROTECTING PETS IN A DISASTER

• UPDATE ON CVM's ANTIMICROBIAL RESISTANCE WORKSHOP

• Expanded-Spectrum Cephalosporin Resistance in E. coli Isolates Associated with Bovine Calf Diarrheal Disease

• What is VICH?

• CVM DEVELOPS METHOD TO DETECT FLUOROQUINOLONE RESIDUES IN EGGS

• FDA PUBLISHES FINAL RULE ON MEDICATED FEED MILL LICENSING

• UPDATE ON RIMADYL®

• FDA's Regulation of Pet Food

• CVM AND CFSAN JOINTLY SPONSOR FOOD SAFETY INITIATIVE RESEARCH CONFERENCE

• REGULATORY ACTIVITIES

• NEW ANIMAL DRUG APPROVALS

• ABBREVIATED NEW ANIMAL DRUG APPROVALS

• SUPPLEMENTAL NEW ANIMAL DRUG APPROVALS

ANTIMICROBIAL RESISTANCE DOCUMENTS AVAILABLE

FDA has made available three documents on antimicrobial resistance in food-producing animals. The first document is a draft "Risk Assessment on the Human Health Impact of Fluoroquinolone Resistant Campylobacter Associated with the Consumption of Chicken." To assist in evaluating the human health impact of antimicrobial use in animals, the Center contracted with a risk assessment expert to develop a risk assessment model. The risk assessment was intended to determine the feasibility of estimating risk to human health from resistant food borne pathogens associated with the use of antimicrobials in food-producing animals. Specifically, a mathematical model was derived to relate the prevalence of fluoroquinolone resistant Campylobacter infections in humans associated with the consumption of chicken to the prevalence of fluoroquinolone resistant Campylobacter in chickens.

The concern exists for several reasons. First, chickens carry foodborne pathogens, including Campylobacter and Salmonella. An estimated 20 percent of broiler chickens in the U.S. are contaminated with Salmonella, and more than 80 percent are contaminated with Campylobacter. Second, Campylobacter is the most common known cause of bacterial foodborne illness in the United States. Epidemiological investigations have found that chicken is the most common source of human infection. Third, Campylobacter apparently can develop resistance quickly when fluoroquinolones are used in both human and veterinary medicine. Fourth, fluoroquinolones are used in human medicine to treat gastrointestinal infections, such as campylobacteriosis and are important for use in many other therapeutic indications in human medicine. The risk assessment model could become a regulatory tool for assessing such risks in the future. This document is on CVM's Home Page.

The second document is a revision of the "Guidance for Industry: Consideration of the Human Health Impact of the Microbial Effects of Antimicrobial New Animal Drugs Intended for Use in Food-Producing Animals" (CVM guidance document 78.) This guidance document now states that FDA believes it is necessary to consider the potential human health impact of the microbial effects associated with all uses of all classes of antimicrobial new animal drugs intended for use in food-producing animals. To assess this impact, it may be necessary to evaluate two separate, but related aspects (1) the rate and extent of development of antimicrobial drug resistant enteric bacteria formed in the animal's intestinal tract following exposure to the antimicrobial new animal drug (resistance), and (2) changes in the number of enteric bacteria in the animal's intestinal tract that cause human illness (pathogen load.) Copies of the revised guidance document may be obtained from CVM's Home Page.

The third document is "FDA Response to Comments on A Proposed Framework for Evaluating and Assuring the Human Safety of the Microbial Effects of Antimicrobial New Animal Drugs Intended for Use in Food-Producing Animals." FDA had published a notice of availability of "A Proposed Framework for Evaluating and Assuring the Human Safety of the Microbial Effects of Antimicrobial New Animal Drugs Intended for Use in Food-Producing Animals," also known as the Framework Document, in the January 6, 1999, Federal Register. FDA made the Framework Document available to the public to initiate discussions with the scientific community and other interested parties on the agency's thinking about appropriate underlying concepts to be used to develop microbial safety policies protective of the public health. On January 25 and 26, 1999, the FDA held a meeting of the Veterinary Medicine Advisory Committee (VMAC) on the Framework Document to allow members to publicly consider answers to specific questions.

FDA stated that it would review the transcript of the VMAC meeting and any comments on the Framework Document that were submitted to FDA Dockets Management Branch (Dockets) and publish an analysis. This document is the Agency analysis of the transcript from the VMAC meeting and more than 50 comments to the Docket on Guidance Document #78 and the Framework Document. Copies of this analysis are on CVM's Home Page .

Readers interested in these documents who do not have access to the internet may receive single copies of these documents by calling or writing the FDA Veterinarian.

PROTECTING PETS IN A DISASTER

By Karen A. Kandra and Mary Cacia Masser, D.V.M.

The following article provides information on protecting pets in a disaster. Veterinarians may wish to duplicate this article and provide copies to their interested clients. As always, material which appears in the FDA Veterinarian is free of copyright and may be reproduced without permission.

When we think of "disasters" we usually envision large-scale emergencies, such as earthquakes, floods, tornadoes, etc. However, much more common are personal disasters, which could be just as devastating to individual families as a huge cataclysmic event. House fires, extended power outages, car accidents, or sudden hospitalization are examples of events that may call for alternative care of our pets.

Preparation

It is best to prepare an emergency response plan prior to any crisis to avoid suffering to our four-legged friends. The American Red Cross provides excellent materials that will also help you and your family to develop an emergency plan. You should decide ahead of time who will be responsible for pet care if any emergency strikes. Choose the best room in the house to leave your pet if necessary. Make arrangements with neighbors. Be sure they have keys to your home along with specific information as to what pets are there, where they are located, and instructions for any medication needed. It also helps if your pets are familiar with your neighbors ahead of time, so they will not be dealing with strangers, and adding to the stress. Train your pet to a crate. In a crisis, he may need to be transported, and the ordeal will be less stressful if the crate is a comfortable and familiar place. Always keep pet's vaccinations current.

It is a good idea to prepare a disaster kit for your pet which should include: collars, tags, and leashes, a muzzle or gauze bandage, two-week supply of dry food, water, bowls, paper towels, and plastic bags for waste clean-up, and copies of pet's medical and vaccination records. Your pet's crate should be labeled with the pet's name, your name, and where you may be reached, or an out-of-area phone contact, if phone lines are down, and any specific medical instructions for the animal. Prepare a telephone tree, with numbers of family, friends, veterinarian, local animal control, or shelter, local hotels which accept pets, etc.

IT IS VERY IMPORTANT TO LEAVE PERTINENT INFORMATION ABOUT THE PET INCLUDING:

o Your name and whereabouts including phone number (cell phones especially),

o Pet's name, age, vaccination status,

o Name and phone number of family veterinarian,

o Pet insurance papers (if applicable),

o Any health issues or information about recent diagnoses, i.e., diabetic, epileptic, spayed/neutered, special diet, medications, heart disease, cancer, etc.,

o Behavior characteristics, i.e., fearful, aggressive w/children, other animals.

In addition, please leave some type of signed authorization sheet, outlining your wishes (include financial parameters and humane and compassion guidelines) for your pet's care. Examples are:

Please sign and date these instruction sheets. Often pet owners can leave their wishes in written form with their veterinarian to be included as part of the permanent patient record. Family veterinarians can be a valuable reference to emergency doctors trying to make decisions for pets and people they do not know. Many times they will consult with the family veterinarian in serious treatment matters or if euthanasia is being considered.

If there are financial considerations, please note them. Veterinarians want to comply with owners' wishes whenever possible. Veterinarians' goals are to save and care for family pets, not deplete your bank account! Unfortunately, unless you have pet insurance, expert care has a price. If you have a pet insurance policy be sure to leave it with the pet. Without knowing your personal choices for care of your sick or injured pet, emergency personnel are stuck between providing basic care and extended care for a pet, whose condition may only worsen as time passes, possibly lowering survival rates. Often the good neighbors who are left to care for your pets cannot or will not be financially responsible for extensive veterinary care. Most emergency veterinary practices do not offer billing services.

During the Disaster

Animals can sense danger, and may panic and try to hide when fearful. To avoid injury and escape, crate the pet immediately, if a crisis is imminent. In certain emergencies it may be necessary to temporarily evacuate the area. This may include evacuation of animals. For pets, veterinary hospitals, boarding kennels or fairgrounds may be utilized as holding facilities, where it is not possible for animals to accompany their owners to emergency shelters.

Under no circumstances should you ever leave your pet tied up or loose to fend for themselves. It is best to leave them in a room without windows, such as a bathroom, to prevent them from escaping or being injured from broken glass, in certain situations. If they will be left for several days, leave thick newspapers to absorb waste, and warm bedding. Remember, there may be extended power outages. Unplug all electrical appliances, and cover all electrical outlets with plastic or duct tape to avoid electrocution. If you have two of the same type of animals who get along well, leave them together for company. Keep exotic pets in separate rooms, since many reptiles can be dangerous to disaster personnel who do not know how to handle them. Post signs on door indicating what is in the room.

Be sure to provide a large supply of water in a heavy bowl which will not tip over, or leave water in tubs, or sinks, where the animal has access to it. Remove all flammable and poisonous chemicals from the room, and turn off all electricity.

After the Disaster

The behavior of pets often changes following a disaster. Normally quiet cats and dogs may become aggressive or defensive. Recovery from the disaster may take several days, weeks, or months. During the period of adjustment here are some recommendations:

Hopefully, you will never face a major disaster, but it pays to remember your pets as part of your household disaster planning. If you must evacuate your home, it is best to take your pets with you. However, if you must leave them behind, advance plans for their care will ensure their health and safety. These suggestions are important, not only in times of disaster, but also during a brief family vacation.

UPDATE ON CVM's ANTIMICROBIAL RESISTANCE WORKSHOP

CVM's third public meeting to discuss important issues related to antimicrobial resistance (AR) in food-producing animals will be held for three days instead of two and will include an additional topic -- pathogen load. The workshop will be held on Tuesday, Wednesday, and Thursday, February 22 – 24, 2000, from 9:00 a.m. to 5:00 p.m. at the Double Tree Hotel, 1750 Rockville Pike, Rockville, MD 20852.

This workshop will be held to discuss the appropriate design of pre-approval studies in food-producing animals to model the rate and extent of resistance development and changes in the number of enteric bacteria in the animal's intestinal tract that cause human illness (pathogen load). CVM will seek scientific input from experts at the meetings on these issues.

Registration for the workshop is free, however registration is required. Space is limited, and early registration is encouraged. For general information regarding the workshop, please contact Lynda W. Cowatch, FDA/Center for Veterinary Medicine (HFV-150), 7500 Standish Place, Rockville, MD 20855, 301-827-5281. For technical inquiries, please contact Dr. William Flynn on 301-827-7570. Interested readers may wish to visit the CVM Home Page for further information concerning this meeting, including the agenda. When making reservations with the DoubleTree Hotel, please refer to the "CVM Antimicrobial Resistance Public Meetings", to receive the group discount rate.

Expanded-Spectrum Cephalosporin Resistance in E. coli Isolates Associated with Bovine Calf Diarrheal Disease

by David G. White, Ph.D. (FDA/CVM, Office of Research) and Patricia A. Bradford, Ph.D. (Wyeth-Ayerst Research, Pearl River, NY)

Pathogenic Escherichia coli are one of the most important groups of bacteria causing diarrhea and extraintestinal infections in humans and animals.¹ There have been many recent reports of morbidity and mortality due to outbreaks of disease-causing E. coli which have been attributed to foods of bovine origin or other foods cross-contaminated by beef products or cow manure.² The occurrence of toxigenic E. coli strains in humans and calves with diarrhea is well documented and cattle have been considered an important reservoir of Shiga-like toxin (SLT) producing E. coli strains involved in human disease.³Toxigenic E. coli are also frequently implicated as the primary bacterial cause of scours in neonatal calves.⁴ Bovine calf scours is a severe form of diarrhea which is thought to cause more financial loss to cow-calf producers than any other disease-related problem. The most important aspect in treatment of calf scours is directed at correcting the accompanying electrolyte losses, dehydration, and acidosis. Antimicrobial therapy is often implemented at the same time in an attempt to treat and prevent further occurrences. However, strains of E. coli (animal and human origin) have become increasingly resistant to most frontline antimicrobials, including third generation cephalosporins, aminoglycosides, and even fluoroquinolones. Infections caused by antibiotic resistant bacteria are a major and costly animal health problem. These infections can lead to prolonged illness and if not treated in time with more expensive, alternate antimicrobial agents, can lead to increased mortality. This potential problem will continue to have a large impact on the animal industry in terms of both animal health and food safety if not investigated.

In recent years, bacterial resistance to ß-lactam antimicrobials has risen dramatically among human bacterial pathogens. The use of expanded-spectrum cephalosporins in health institutions contributes to the emergence of such resistance. However, there is limited knowledge concerning the incidence and prevalence of extended-spectrum ß -lactamases (ESBLs) among pathogenic veterinary strains of E. coli incriminated in animal disease. Therefore, a survey was initiated to collect data on the occurrence of multiple antibiotic resistance and virulence factors among E. coli strains associated with bovine calf scours in the state of North Dakota, USA. As a result of this survey, it was noted that about 13% of E. coli strains implicated in bovine calf scours displayed decreased susceptibilities to ceftiofur, an expanded-spectrum cephalosporin used in veterinary medicine. Ceftiofur, a veterinary expanded-spectrum cephalosporin, is active against a variety of animal pathogens, including microorganisms associated with bovine and swine respiratory disease.⁵ Although this antimicrobial is not approved for treatment of bovine calf scours, ceftiofur is sometimes used in an extralabel manner to treat bacterial diarrheal diseases when these pathogenic strains are resistant to other less efficacious veterinary antimicrobials. This study was performed to characterize the nature of bacterial resistance to expanded-spectrum cephalosporins and to determine if ESBLs were present among these isolates.

E. coli isolates were selected from primary agar cultures of either bovine feces from diarrheic animals, or intestinal tissue from septicemic animals taken post mortem from scours cases submitted to the North Dakota State University Veterinary Diagnostic Laboratory during 1996 and 1997. Isolates were further examined for antimicrobial susceptibility according to NCCLS methodologies.^6,7

Thirty-two strains exhibiting varying degrees of resistance to ceftiofur were chosen for further study. All of the isolates tested were resistant to ampicillin and had reduced susceptibility to ticarcillin and piperacillin which suggested the presence of a $ –lactamase. The addition of a ß-lactamase inhibitor to these penicillins restored susceptibility to some, but not all of the strains. In addition, 27 of the 32 strains tested displayed increased resistance to the expanded-spectrum cephalosporins, aztreonam and cefoxitin. None of the strains were resistant to imipenem. All of the isolates were resistant to kanamycin, streptomycin, sulfisoxazole and tetracycline. In addition, most of the strains were also resistant to trimethoprim-sulfamethoxazole (84%), chloramphenicol (59%), and gentamicin (53%). Four strains were nalidixic acid resistant, and two strains were ciprofloxacin-resistant.

Using established iso-electric focusing (IEF) techniques, the ß -lactamases of the pathogenic bovine E. coli isolates were further characterized.⁸ Five isolates produced only the plasmid mediated TEM-1 $ –lactamase, 17 isolates produced only the chromosomal AmpC ß-lactamase and 10 isolates produced the AmpC ß -lactamase in combination with either the plasmid mediated TEM-1 or TEM-2 ß -lactamase. Pathogenic veterinary E. coli isolates that produced only the TEM-type enzymes were all susceptible to expanded-spectrum ß -lactams. Increased resistance to the expanded-spectrum cephalosporins, aztreonam, cefoxitin and ceftiofur correlated with overexpression of the E. coli chromosomal AmpC ß -lactamase.

In this study, many of the E. coli strains associated with bovine calf scours were found to be resistant to several antimicrobial classes including expanded-spectrum ß-lactam antimicrobials. Resistance to the expanded-spectrum ß-lactam antimicrobials was most likely due to the hyperproduction of the chromosomally-encoded AmpC ß -lactamase naturally found in E. coli, but usually not expressed at high levels. Although there is no direct correlation between the occurrence of the cephalosporin-resistance with the use of ß -lactams in veterinary medicine, these results suggest that the use of these antimicrobials may have contributed to the in vivo selection of E. coli strains which hyperproduce this enzyme. No extended-spectrum ß -lactamases were found among this population of isolates which suggests that extended-spectrum ß -lactamases do not routinely play a role in expanded-spectrum cephalosporin resistance among veterinary isolates of E. coli. However, identification of several TEM-type ß -lactamases among these isolates suggests that the emergence of ESBLs in this population of pathogens is possibly only a matter of time. The somewhat surprising finding of so many E. coli isolates that over express their ampC gene constitutes a serious threat to veterinary ß -lactam therapy of E. coli related diseases, as well as serving as a potential reservoir for drug resistant human and veterinary pathogens.

The results from this study demonstrated that resistance to front line antimicrobials is present among E. coli strains incriminated in bovine calf scours. This combination of virulence coupled with multi-drug resistance is an increasing threat to successful treatment of E. coli related veterinary diseases in the near future.

This work was published in the Journal of Antimicrobial Chemotherapy, 1999, Vol. 44:607-610.

References

What is VICH?

by Robert C. Livingston, Ph.D.

VICH is a trilateral (EU-Japan-U.S.) program aimed at harmonizing technical requirements for veterinary product registration. Australia and New Zealand participate as active observers. Its full title is the International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products. VICH was officially launched in April 1996. The scope of the VICH program includes both pharmaceutical and biological veterinary medicinal products.

The globalization of the human and veterinary pharmaceutical industries led to the obvious conclusion that harmonization of registration requirements would have favorable impacts, not only on the industries but also on the consumers of pharmaceuticals. The increased trade in animal-derived food further emphasized the need for harmonization. Harmonization has the potential for decreasing developmental costs, decreasing the number of research animals required, reducing potential trade barriers and, most importantly, increasing the number of safe and effective drugs available to the consumer. Early initiatives in harmonization of animal drugs were the adoption in Europe in 1981 of standard requirements for veterinary product registration and the formation in 1985 by Codex Alimentarius of a Committee on Residues of Veterinary Drugs in Foods. Following the first International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1991, the Organization of International Epizootics (OIE) in 1994 set up an ad hoc group to discuss the harmonization of veterinary medicinal products. That group recommended that the organizational structure of ICH be used for veterinary medicinal products and proposed the membership and objectives of the VICH. Under the auspices of OIE, the Steering Committee of the VICH held its first meeting in April 1996, at which the membership and the working procedures were agreed and a work program established. The OIE, through its Collaborating Centre for Veterinary Medicinal Products, has recently been made an associate member of the VICH Steering Committee. The World Federation of the Animal Health Industry (COMISA) serves as the secretariat of VICH.

The objectives of VICH are included in its organizational charter:

The Steering Committee has the responsibility for managing the VICH process. This committee selects the topics for harmonization on the basis of a concept paper proposed by one of the parties to VICH or by a VICH Working Group. The Steering Committee establishes the appropriate Working Groups and appoints topic leaders and WG chairpersons. The Steering Committee approves the draft recommendations of the Working Groups prior to release for worldwide consultation and subsequent approval by the competent authorities of the EU, Japan and the U.S. The Steering Committee is composed of two delegates of the regulatory authorities and two delegates of representative industry associations from the three regions. Australia/New Zealand has observer status with one delegate representing government authorities and one delegate representing industry associations from the two countries. Each region has two coordinators, one from the regulatory authorities and one from the representative industry associations. The Steering Committee meets twice a year on a rotational basis. The host region appoints the chairperson.

The draft guidelines from the Working Groups must pass a 9-step approval process (see Table below.) The U.S. uses the notice and comment procedure to ensure a transparent process in the development of guidance documents. Notices of availability of draft and final guidance documents are published in the Federal Register at Steps 4 and 7, respectively. The guidance documents are considered implemented when the notice of availability of the final document is published or on the date specified if one is given. CVM guidance documents are available on our home page . The VICH documents are available on our home page. There may be slight differences in the language used in the documents to reflect FDA’s policies on guidance documents. These differences do not impact on the technical requirements described in the documents. For example, VICH uses the term guideline, but the U.S. uses the term guidance document.

The Steering Committee initially established five working groups: Efficacy requirements for anthelmintics, Ecotoxicity/environmental impact assessments, Good clinical practices, Quality, and Safety. Two additional working groups were subsequently formed: Biologicals and Pharmacovigilance. The results of these seven working groups were presented at the First Conference on International Harmonization of Veterinary Medicinal Products held November 16-18, 1999, in Brussels, Belgium. Over 300 people attended VICH-1.

The Anthelmintic Working Group has completed four final guidelines (general, bovine, ovine and caprine) and three draft guidelines (equine, swine, canine). The WG also has two future guidelines (feline and poultry) under development. The Quality WG has completed eight final documents and 2 draft documents. The Good Clinical Practice WG has a final document pending sign-off by the Steering Committee. Both the Quality and Good Clinical Practice WGs have essentially completed their work. The Ecotoxicity WG has completed a Phase I document (pending SC sign-off) and expects to complete the Phase II document in 2000. The Safety WG expects to have a draft guideline recommending studies required for the determination of an ADI (Acceptable Daily Intake) of residues of an animal drug in 2000. Additionally, the SC authorized a task force to make recommendations on testing requirements for the determination of ADIs using microbiological endpoints.

As two of the Working Groups have essentially completed their work, the Steering Committee has authorized the formulation of two additional Working Groups: Antimicrobial Resistance and Target Animal Safety. The Antimicrobial Resistance WG, which will be chaired by the EU, will recommend the design of pre-approval studies to assess the rate and extent of resistance development when antimicrobials are used in food-producing animals. The specific scope of work for the Target Animal Safety WG will be defined on the basis of a concept paper to be prepared by Japan.

A nine-step procedure will be followed in developing, implementing, and revising guidelines:

Step 1

The Steering Committee defines a priority item from a concept paper prepared by a member and appoints a working group if needed. A topic leader is given a mandate to draft a recommendation.

Step 2

The expert working group drafts a recommendation.

Step 3

The draft is submitted to the Steering Committee for approving its release for consultation.

Step 4

Following adoption by the Steering Committee, the draft recommendation is circulated for consultation.

Step 5

The working group takes comments into consideration in preparing a revised draft. The topic leader must be a representative of a regulatory authority at this stage.

Step 6

The revised draft recommendation is submitted to the Steering Committee for approval.

Step 7

A final recommendation and proposed implementation date are circulated to the relevant regulatory authorities.

Step 8

Steering Committee members report back on the implementation progress in their regions.

Step 9

Recommendations may be revised at the request of a member to take into account new scientific evidence.

CVM DEVELOPS METHOD TO DETECT FLUOROQUINOLONE RESIDUES IN EGGS

Fluoroquinolones, such as enrofloxacin and sarafloxacin, are antimicrobial drugs approved for the control of early mortality in growing turkeys and broiler chickens. However, these drugs are not approved for use in laying hens. Failure to observe the label directions for these drugs and unintentional contamination of feed for laying hens could cause violative residues in eggs for human consumption. In recent years, the public has become more concerned about the emergence of strains of bacteria resistant to fluoroquinolones, as these drugs are increasingly used in treatment of human bacterial diseases.

The Office of Research in FDA's Center for Veterinary Medicine (CVM) has recently conducted a radio-tracer study on sarafloxacin. The findings indicate that residues are transferred into eggs, and that residues stay in the egg yolk for a longer time than in egg albumen. CVM's Office of Research (OR) has developed an analytical method for quantifying and monitoring sarafloxacin residues in eggs. Currently, the OR is expanding the single-analyte method to include two other fluoroquinolones, namely ciprofloxacin and enrofloxacin. Once the development of the multi-residue method is completed, CVM plans to conduct a national survey for fluoroquinolones in table eggs.

FDA PUBLISHES FINAL RULE ON MEDICATED FEED MILL LICENSING

In the November 19, 1999, Federal Register, the Food and Drug Administration (FDA) published a final rule amending the new animal drug regulations to implement the medicated feed mill licensing requirements of the Animal Drug Availability Act of 1996 (ADAA).

Prior to the passage of the ADAA, the Federal Food, Drug, and Cosmetic Act (the Act) required an approved medicated feed mill application (MFA) for the manufacture of medicated feed. The Act required a feed mill to submit a separate MFA for each medicated feed manufactured at each site. The ADAA eliminates this requirement, and provides for feed mills to be licensed. It allows licensed facilities to manufacture any approved medicated feed. In addition, the ADAA amendments to the Act provide the Agency with the authority, to the extent consistent with the public health, to exempt facilities that manufacture certain types of medicated feed from the requirement of obtaining a medicated feed mill license.

The final rule takes all the medicated feed procedural regulations from Title 21, Part 514 of the Code of Federal Regulations (CFR), and places them in a new section, Title 21, Part 515 of the CFR. This new Part includes sub-sections on applications (515.10), supplemental applications (515.11), administrative actions on licenses (515.20 - 515.26), hearing procedures (515.30 - 515.31), and judicial review (515.40).

The final rule formalizes in Part 515.10 the licensing application approved by OMB with one minor modification. That modification clarifies that a licensed feed mill only needs to maintain current approved "Blue Bird" labels for each Type B and/or Type C medicated feed to be manufactured from a Type A medicated article they have in their possession, rather than for all possible medicated feeds that could be manufactured. "Blue Bird" labels are the only medicated feed labels approved by FDA, and, serve as the model label for feed mills in generating the actual medicated feed labels. All Type A medicated article NADA holders must have Type B and Type C medicated feed "Blue Bird" labels approved with their NADA. The "Blue Bird" feed labels are also on file with CVM in the NADA and as a part of the Freedom of Information approval package. CVM also concluded that the home office of multi-mill operations may maintain the Blue Bird labels for all of its satellite mills since the home office generates the actual labels for the satellite mills.

The final rule in Part 515.21 sets forth the criteria to be used in the CVM review of license applications. The application shall be refused if:

(1) The application is incomplete, false, or misleading in any particular; or

(2) The feed mill is deficient in their good manufacturing practices (GMP); or

(3) The facility has or is manufacturing feeds containing unapproved animal drugs, and/or has/is mislabeling feeds containing animal drugs.

The final rule provides an opportunity for a feed mill to voluntarily withdraw its license without prejudice to a future filing. This provision was not allowed for under the old MFA regulations, and should simplify paperwork for voluntary withdrawals.

The final rule maintains the general scheme for categories and types of medicated feeds, and provides that those feeds exempted from the MFA requirement would now be exempt from being required to be manufactured in a licensed feed mill. The possession of NADA approved Type B and Type C medicated feed labeling (Blue Bird) by a licensee satisfies the feed labeling requirements of the statute.

FDA made no substantive changes to the scope of the registration exemption. Registration, unlike medicated feed mill licensing, is required annually by Title 21, Part 207.22 of the CFR. FDA has found that firms comply with this requirement and provide annually the numbers and locations of registered facilities. This requirement allows FDA to update the information on feed mills.

The final rule allows drug sponsors to learn if a facility is licensed to manufacture medicated feed either by receiving written confirmation of the feed mill license number from the feed mill or by identifying the feed mill’s license status on the FDA website. The confirmation and/or identification of a feed manufacturing facility’s license number shows that the firm possesses current approved Blue Bird labeling, because the firm must commit to the possession of such labeling in the medicated feed mill license application. The drug sponsor’s identification from the FDA website of a facility’s license number would constitute "notice from the Secretary" that the feed mill possesses a license and the current approved feed labeling.

To assist drug sponsors and feed manufacturers in the distribution of Blue Bird labels and to allow parties to determine more easily whether a feed mill is licensed, FDA has created a database of medicated feed mill licensing information, available to the public on the Center for Veterinary Medicine’s website. Included in this information is a database of medicated feed mill licensees and CVM intends to post periodic updates.

The final rule will become effective on December 20, 1999. Additional information about the final rule is included in the November 19, 1999, Federal Register, and may be obtained from Dr. William D. Price, Center for Veterinary Medicine (HFV-200), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-827-6652.

UPDATE ON RIMADYL®

FDA's CVM received a substantial number of adverse drug experience (ADE) reports for carprofen (trade name Rimadyl^®) in 1998. As mentioned in the last issue of the FDA Veterinarian, CVM has released the "1998 Annual Adverse Drug Experience (ADE) Summary" which includes information about ADEs to all veterinary drugs, including Rimadyl®. This ADE summary is on the Center's Home Page on the Internet.

FDA approved Rimadyl® for dogs on October 25, 1996, after a comprehensive review of the product’s safety and efficacy. Rimadyl® is a non-steroidal anti-inflammatory drug (NSAID) indicated for use in relief of pain and inflammation associated with osteoarthritis in dogs. NSAIDs are commonly used in human medicine for relief of pain and include such drugs as aspirin, ibuprofen, and naproxen. Rimadyl^® is one of two NSAID products currently approved for use in dogs. The active ingredient in Rimadyl®, carprofen, is not approved for use in humans. The drug is available by veterinary prescription only. The approved drug sponsor is Pfizer Animal Health of Exton, PA.

Pre-approval studies for Rimadyl^® included a clinical trial involving 297 dogs administered either the drug or a placebo for 14 days. Similar adverse clinical signs were observed in both the carprofen and placebo-treated groups. These signs included an increase in vomiting, diarrhea, lethargy, behavioral changes, constipation, and an increase in liver enzymes. Safety studies revealed no remarkable side effects associated with long-term drug administration. Based on the studies submitted to CVM, the risk of Rimadyl^® was thought to be negligible.

Of all the ADE reports CVM received in 1998, thirty-nine percent (39 percent) or 3626 involved Rimadyl^®. The number of ADE reports received by CVM for Rimadyl^® is considerably more than that received for other animal drugs. For any one ADE report, there is no absolute certainty that the suspected drug caused the effect. The adverse effects in these reports are consistent with those expected for NSAIDs. They typically involve the gastrointestinal system, renal/urinary system, hematopoietic (blood) system, neurological system, and the liver. Approximately 13% of the 1998 Rimadyl^® ADE reports for dogs involved death of the dog, either on their own or by means of euthanasia.

In spite of the high standards for safety and effectiveness that exist for FDA approval, not everything is known about a drug when it is first marketed. Due to the limited number of animals and controlled nature of pre-marketing clinical trials, only the most common adverse effects will be observed. Uncommon effects or problems may not be discovered until after the drug has been widely used.

Based on adverse experience reports received since Rimadyl^® was marketed, a number of actions have been taken to provide the most current product safety information to veterinarians and dog owners. In 1997, shortly after Rimadyl® was marketed, CVM began receiving ADE reports involving the drug. In May 1997, CVM asked Pfizer to change the adverse reaction section of the label.

CVM also asked Pfizer to send a "Dear Doctor" letter to veterinarians informing them of the adverse effects reported with product use. In August 1997, Pfizer mailed a "Dear Doctor" letter to all veterinarians who had purchased the product. By September 1997, Pfizer had revised Rimadyl^® labeling to include an extensive adverse reaction section. The possibility of a fatal outcome was mentioned elsewhere on the label, but death was also added to the adverse reactions section in the spring of 1999. In addition, at CVM’s request, Pfizer developed and distributed an information sheet containing safety information for veterinarians to give to owners at the time Rimadyl^® is dispensed.

A number of factors might contribute to the high number of ADE reports received for Rimadyl^®:

Most of the ADEs reported by owners directly to CVM involved owners of dogs who said they were not aware of the potential adverse effects associated with Rimadyl® use. Adequate communication between the veterinarian and client should result in an awareness of the risk and benefit of drug use and alternate therapies that are available. Additionally, communication should establish the importance of evaluation of the dog prior to Rimadyl^® initiation and the necessity of periodic follow-up evaluations if drug use is continued long-term. Animal owners have told CVM that adequate communication is not occurring in many instances.

CVM will continue to evaluate ADE reports received for Rimadyl^® compared to the benefits of NSAID therapy. In many dogs, the use of NSAIDs is not an elective therapeutic choice, but the primary therapy available for maintaining an acceptable standard of life due to the long-term debilitating effects of osteoarthritis. As an NSAID with potentially serious side effects, however, the use of Rimadyl^® should be carefully considered before being incorporated in any therapeutic plan. Moreover, dog owners should have an active role in making that decision. CVM, along with drug sponsors, is actively pursuing a number of avenues to improve the management of NSAID safety issues in order to minimize the risks and maximize the benefits of using these products in dogs.

FDA's Regulation of Pet Food

by Sharon Benz, Ph.D., P.A.S.

Adapted from a presentation made at the Fifth Educational Workshop in Pet Food Labeling and Regulations, November 14, 1999, St. Louis, Missouri.

This article describes the role of the Food and Drug Administration (FDA) in the regulation of pet food. FDA is charged with the enforcement of the Federal Food, Drug, and Cosmetic Act (the Act.) Under the Act, a part of FDA's responsibility is to ensure that human and animal foods are safe and properly labeled. Within FDA, the Center for Veterinary Medicine is responsible for the regulation of animal drugs, medicated feeds, food additives and feed ingredients. The regulations based, in part, on this law are found in the Code of Federal Regulations, Title 21, Food and Drugs, Part 500.

The Act is this country's basic food and drug law. It defines food as "articles used for food or drink for man or other animals…and articles used for components of any such article." There is no requirement that pet foods have pre-market approval by FDA. The Act does require that pet foods, like human foods, be pure and wholesome, contain no harmful or deleterious substances, and be truthfully labeled. Additionally, canned pet foods must be processed in conformance with low acid canned food regulations (Title 21, Code of Federal Regulations, Part 113, abbreviated as 21 CFR 113).

In the Act a "drug" is, in part, an article intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease, or an article intended to affect the structure or function of the body other than food (Sec. 201 (g)(1)). In the drug definition, the courts have interpreted "food" as something that provides nutrition, taste or aroma. If a food affects the structure or function of the body, it does so by these properties (for example, a food may provide nutrients such as calcium for proper bone structure or taurine for healthy heart function in cats.) However, if a product affects the structure or function of the body apart from its nutritive value, such as urine acidification or improvement in joint function, it may be considered a drug. Structure/function effects extending beyond the "food" umbrella also include claims for improved or increased production and performance, or alteration or improvement in function.

When a substance, including one considered food, is intended to be used for the treatment or prevention of disease or "non-food" structure/function effect, it "becomes" a drug. Under the law, a new animal drug must be shown to be safe and effective for its intended use by adequate data from controlled scientific studies as part of an New Animal Drug Application (21 CFR, Part 514). If a product on the market is not approved, it may be deemed an adulterated drug and subject to regulatory action.

In 1958, in response to public concern about the increased use of chemicals in foods and food processing, Congress amended the Act to require the pre-marketing clearance of additives whose safety was not generally recognized. The Act was also amended to deem food unsafe and adulterated if it contains an unapproved food additive. Under the definition for food additive in Sec. 201 (s) of the Act, it provides that substances added to food which qualified scientists generally recognize as safe (GRAS) under the conditions of their intended use are not "food additives" and as such are exempt from pre-clearance approval.

A food additive petition is the pre-clearance mechanism developed by the FDA for demonstrating that a food additive is safe for its intended use and has utility. If the FDA agrees with the petition, a regulation is published in the Federal Register and 21 CFR, Part 573, Food Additives Permitted in the Feed and Drinking Water of Animals, is amended. The information needed in a food additive petition is described in Part 571 of Title 21. Briefly, a petition contains a description of the chemical identity, manufacturing process and controls, analytical methods, utility data, human food safety data, target animal safety data, product labeling, and in some cases an environmental assessment.

CVM has used regulatory discretion and not required food additive petitions for substances that do not raise any safety concerns. In this case, we ask the company to submit the information needed to list the ingredient in the Official Publication of the Association of American Feed Control Officials (AAFCO). This ingredient definition process is done to conserve agency resources, as food additive approval is time-consuming. CVM reviews the data to ensure the ingredient has utility and can be manufactured consistently to meet product specifications. Although ingredients used under regulatory discretion are still unapproved food additives, we agree we will not take regulatory action as long as the labeling is consistent with the accepted intended use, the labeling or advertising does not make drug claims, and new data are not received that raise questions concerning safety or suitability.

A GRAS substance is GRAS only for an intended purpose. For example, sodium aluminosilicate is GRAS as an anticaking agent. It has been purported to bind mycotoxins and prevent absorption from the intestinal tract but would not be GRAS for this use. A food substance also cannot be GRAS for the prevention, treatment, or mitigation of a disease. So, chondroitin sulfates cannot be GRAS to prevent or treat arthritis. For this use it would be a drug.

It is very important to recognize that general recognition of safety of a substance for an intended use may only be based on the views of experts qualified by scientific training and experience to evaluate the safety of the substance. As interpreted by FDA and the courts, there are two requirements that must be satisfied before a substance can be GRAS; general recognition and safety:

1. For general recognition, there must be an expert consensus that the substance is safe for use as a component of food, and;
   
2. This expert consensus of safety must be based on either (a) generally available data and information to show common use of the substance in animal feed prior to 1958 or (b) scientific procedures, which require the same quantity and quality of scientific data needed for FDA approval of the substance as a food additive. In addition, this information must be published in the scientific literature.

Both of these requirements, general recognition and safety, must be met for a substance to be considered as GRAS. The GRAS standard is actually more stringent than that required for a food additive approval because for a substance to be GRAS there must exist the same quality and quantity of information needed for a food additive approval, and in addition, the data must be published and there must be a consensus among qualified experts, based on the data, that the substance is safe for that use. Publication of data in a company's annual report does not meet the publication standard. For general recognition of safety to exist, the data must be available to the experts by publication in the scientific literature. The Act permits companies to make their own GRAS determination, and many times, GRAS Panels will be assembled that are comprised of scientific experts in a particular field to evaluate the safety of a substance for an intended use. However, regardless of who makes the determination, the FDA or the company, the standard for GRAS is the same.

On April 17, 1997, the Center for Food Safety and Applied Nutrition (CFSAN) and (62 FR 18938) CVM published a proposed rule in the Federal Register to amend the regulations to replace the current GRAS affirmation process with a notification procedure. Under the notification procedure, any person could notify the agency of a determination that a particular use of a substance is GRAS. The notification would include a description of the substance, the conditions of use, and the basis of the GRAS determination. The FDA would not conduct its own detailed evaluation of the data, as was done previously for GRAS Affirmation petitions. Rather, FDA would evaluate whether the notice provides sufficient basis for a GRAS determination and whether the information in the notification or otherwise available to FDA raises issues on whether the use of the substance is GRAS or not. In the proposal FDA would have 90 days to respond to the notifier. The summary of the GRAS notifications would be available on the FDA homepage, as would the FDA's responses to the person submitting the notification. CVM is not currently accepting GRAS notifications under the proposed rule; however, CFSAN is. A listing of the notifications that have been submitted can be found on our website.

Once the final rule is published, CVM will accept GRAS notifications. It is anticipated that GRAS notifications submitted for use of substances in animal feed will be posted on the CVM homepage. When a GRAS notification raises no issue of concern to CVM, the AAFCO Feed Ingredient Chair will be notified so that the substance and its use can be listed in the AAFCO publication.

The Dietary Supplement and Health Education Act

When Congress enacted the Dietary Supplement and Health Education Act (DSHEA) on October 25, 1994, it created a new category of substances and new regulatory scheme. The Act was amended to define a dietary supplement as a product intended to supplement the diet and that contains at least one or more of the following ingredients: a vitamin; a mineral; a herb or other botanical; an amino acid; a dietary substance for use to supplement the diet by increasing total dietary intake; or a concentrate, metabolite, constituent, extract or combination of any of the previously mentioned ingredients (Sec. 201 (ff) of the Act). The main effect of DSHEA was to remove certain dietary ingredients from regulation as food additives, which requires pre-market approval. On April 22, 1996, CVM published a notice in the Federal Register outlining the reasons why FDA believes that Congress did not intend DSHEA to apply to products for use in animals. This has been upheld in at least one court case. Thus, products marketed as dietary supplements for humans still fall under the pre-DSHEA regulatory scheme when marketed for animals, that is, they are considered food, food additives, new animal drugs, or GRAS depending on the intended use. For most of these types of products on the market they would be considered unapproved and unsafe food additives or new animal drugs based on current intended use.

It is important to note that DSHEA defines the term "dietary supplement" to exclude products intended for use as conventional foods. For example, St. John's Wort would not be considered a dietary supplement if it were added to soup. Soup is a conventional food and any ingredient added to conventional foods must be used in accordance with the food additive regulation or be GRAS. Similarly, if DSHEA was extended to include pet food, chondroitin sulfate added to pet food would not be permitted under DSHEA. Chondroitin sulfate would be an unapproved food additive for this use.

Health Claims

Congress also amended the Act, when it enacted the Nutrition Labeling and Education Act in 1990. This law required FDA to write regulations to permit health claims on human food. A number of these claims have been approved for various foods, the latest being the claim approved by FDA on October 26, 1999, for soy protein as follows:

Diets low in saturated fat and cholesterol that include 25 grams of soy protein a day may reduce the risk of heart disease. One serving of (name of food) provides ____ grams of soy protein.

CVM has incorporated the philosophy of NLEA in its policies in order to permit meaningful health information on pet foods. Examples are the use of urinary health tract claim on cat food diets, and development of AAFCO regulations for light, lean, less or reduced calories, lean, and less or reduced fat. Recently, CVM has been asked about complete cat foods for the control of hairballs. We would likely not take regulatory action provided the effect is achieved by ingredients already permitted for use in cat food, such as fiber sources. In this case, we ask that the firm submit information for review on the quantitative diet formulation, nutrient analysis, and labeling, and discussion on the basis for the claim, i.e. scientific studies or common knowledge of ingredients biological properties. If novel ingredients are used to achieve the effect, then we believe data demonstrating ingredient safety should be obtained prior to marketing.

Interaction with AAFCO

FDA also plays an active role in pet food regulation in partnership with AAFCO. A FDA representative serves on the AAFCO Board of Directors. FDA has served on the Pet Food Committee. CVM staff also serves on other standing AAFCO committees and as investigators. We believe that continued partnership with AAFCO is vital to the continued regulation of pet food products because FDA has limited enforcement resources that are focused on human food safety issues. For this reason, an important role of CVM staff is to serve as scientific resources for state regulatory officials.

Summary

In summary, within the FDA, CVM has primary responsibility for enforcing the Act to ensure that animal foods, including pet foods, are safe and labeled appropriately and animal drugs are safe and effective. While FDA has tried to incorporate some of the philosophy of NLEA to permit health claims for pet foods, we believe that DSHEA was not intended by Congress to apply to animal foods. Thus, products sold as dietary supplements for humans may not be legally distributed for use in animals unless the substances are food, approved animal food additives, GRAS or approved new animal drugs. CVM works in partnership with AAFCO to ensure continued regulation of pet foods and serves as scientific resources to State regulatory officials.

CVM AND CFSAN JOINTLY SPONSOR FOOD SAFETY INITIATIVE RESEARCH CONFERENCE

On December 7-8, 1999, the Center for Veterinary Medicine (CVM) and the Center for Food Safety and Applied Nutrition (CFSAN) jointly sponsored a conference on extramural research projects funded under the Food Safety Initiative. The purpose of this conference was to (1) review and discuss progress made during the first year of the cooperative agreements, (2) provide for formal and informal discussions between principal investigators and project officers, and update scientists in CVM and CFSAN on current extramural research project activities. Attendance at the meeting was limited to FDA scientists and principal investigators from the organizations that received funding. The results of studies from this research will be made available to the public when the data is published in peer-reviewed scientific journals. Descriptive summaries of these projects are available at http://www.foodsafety.gov.

REGULATORY ACTIVITIES

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

o Craig R. Phelps, Edgewood Farms, Groveland, NY

o Robert J. Hilarides, Sierra Cattle Company, Lindsay, CA

o Jason B. Tuls, Tuls Cattle Co., Tulare, CA

o Roger Winner, Sunnyside Farms, Inc., Mount Holly, NJ

o Robert J. Van Grouw, Visalia, CA

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

A warning letter was sent to Jose M. Xavier, Xavier Cattle-Holsteins, Merced, CA, for consigning a dairy cow for human food that was adulterated with residues of gentamicin and for having a history of offering calves for sale for human food use which were adulterated with drug residues.

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

o Leo Rutten, Hiawatha Milling Company, Beloit, KS

o William R. Cramer, Star Milling Company, Perris, CA

o Dr. F. Abel Ponce de Leon, University of Minnesota, St. Paul, MN

o Mark C. Puliafico, Webco Chemical Corp., Dudley, MA

Johnny R. Williams, Springville, CA, received a warning letter for sale and distribution of a human prescription drug for veterinary purposes.

A warning letter was sent to Edward T. Henry, D.V.M., Dairy Veterinary Services, Tulare, CA, for serious deviations of the extra-label drug use in animals regulations (Title 21, Part 530, of the Code of Federal Regulations (CFR.)

John M. Ochs, Red Bank Mills, Inc., New Bethlehem, PA, received a warning letter for significant deviations from the requirements set forth in Title 21, Part 589.2000, of the CFR (Animal Proteins Prohibited in Ruminant Feed.)

NEW ANIMAL DRUG APPROVALS

Company	Generic and Brand Names	Indications	Routes/Remarks
Lloyd, Inc. (NADA 140-908)	Sulfamethazine (Veta-Meth)	Beef Cattle, Non-lactating Dairy Cattle. To treat diseases caused by sulfamethazine sensitive organisms.	ORAL: The tablets are to treat diseases such as bacterial pneumonia, and bovine respiratory disease complex (shipping fever complex) (Pasteurella spp.), colibacillosis (bacterial scours) (Escherichia coli), necrotic pododermatitis (foot rot) (Fusobacterium necrophorum), calf diphtheria (F. necrophorum), acute mastitis (Streptococcus spp.), acute metritis (Streptococcus spp.), coccidiosis (Eimeria bovis, E. zurnii). Federal Register: 11/26/99

ABBREVIATED NEW ANIMAL DRUG APPROVALS

Company	Generic and Brand Names	Indications	Routes/Remarks
Alpharma, Inc. (ANADA 200-233)	Lincomycin Hydrochloride Soluble Powder (Linco Soluble)	Swine, Broiler Chickens. For the treatment of dysentery in swine and for control of necrotic enteritis in broiler chickens.	ORAL: The medicated drinking water preparation in the ANADA is a generic copy of Pharmacia & Upjohn’s NADA 111-636 for LincomixÒ soluble powder. Federal Register: 11/26/99
Pharmacia & Upjohn Co. (ANADA 200-244)	Trimethoprim Sulfadiazine (TucoprimÒ )	Horses. For control of bacterial infections during treatment of acute strangles, respiratory tract infections, acute urogenital infections, wound infections, and abscesses.	ORAL: The ANADA is a generic copy of Macleod Pharmaceuticals, Inc.’s ANADA 200-033 for UniprimÔ . Federal Register: 12/07/99

SUPPLEMENTAL NEW ANIMAL DRUG APPROVALS

Company	Generic and Brand Names	Indications	Routes/Remarks
Fort Dodge Animal Health (NADA 141-087)	Moxidectin (QuestÔ )	Horses and Ponies. For treatment and control of horse stomach bot Gasterophilus nasalis (3rd instars).	ORAL: The supplement provides for oral use of the 2 percent moxidectin oral gel for treatment and control of infections of certain large strongyles, small strongyles, encysted cyathostomes, ascarids, pinworms, hairworms, large-mouth stomach worms, and horse stomach bots, and for suppression of strongyle egg production for 84 days. Federal Register: 11/24/99

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