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• MESSAGE FROM THE FORMER EDITOR

• FDA HOLDING MEETING ON ESTABLISHING RESISTANCE AND MONITORING THRESHOLDS

• REVISED FEEDS PROGRAM ISSUED

• ACCOUNTABILITY BY WAY OF: "THE GOLD STANDARD" -- AAALAC

• SHEEP RECLASSIFIED AS MINOR SPECIES FOR ALL DATA COLLECTION PURPOSES

• COMPANION ANIMAL ANALGESICS: ASSESSMENT OF PAIN

• WORKING TO PROMOTE JUDICIOUS USE OF ANTIMICROBIALS

• CVM OFFICIALS ATTEND ICEID

• CVM CO-SPONSORS SYMPOSIUM

• FINAL VICH GUIDANCE ON IMPURITIES AVAILABLE

• NEW TEAMS FORMED IN ONADE

• TAMPERING CONVICTION

• REGULATORY ACTIVITIES

• Pet Treats Can Make You Ill

MESSAGE FROM THE FORMER EDITOR

I would like to introduce you to Karen A. Kandra, the new editor of the FDA Veterinarian. Many of you will recognize her name from her many bylines and photography credits in the newsletter. She has also been managing editor since March 1999. Ms. Kandra has been with FDA for 23 years and with the Center for Veterinary Medicine for 21 years. Please do not hesitate to call Ms. Kandra if you have suggestions or comments about the FDA Veterinarian.

I have enjoyed editing the FDA Veterinarian for the past 11 years. Thank you for your encouragement and support. I am still with CVM's Communications Staff, and I may be reached at the FDA Veterinarian address and telephone number.

Linda Grassie

FDA HOLDING MEETING ON ESTABLISHING RESISTANCE AND MONITORING THRESHOLDS

FDA's Center for Veterinary Medicine (CVM) will convene a public meeting to discuss the Establishment of Resistance and Monitoring Thresholds in Food-Producing Animals. The meeting will be held on Tuesday and Wednesday, October 10-11, 2000, from 8:30 a.m. to 5 p.m. at the DoubleTree Hotel, 1750 Rockville Pike, Rockville, MD, 20852. The meeting will discuss the Center's current thinking on the establishment of resistance and monitoring thresholds in food-producing animals. CVM will seek scientific input from experts at the meeting on these issues as well as suggestions for alternative approaches.

Background information about this issue is available in the following documents 1) transcripts of the three previous CVM public meetings on antimicrobial resistance; 2) related public comments; 3) the Draft Risk Assessment on the Human Health Impact of Fluoroquinolone Resistant Campylobacter Associated with the Consumption of Chicken (Revised as of February 9, 2000); 4) A Proposed Framework for Evaluating and Assuring the Human Safety of the Microbial Effects of Antimicrobial New Animal Drugs Intended for use in Food-Producing Animals; and, 5) Draft Public Health Action Plan to Combat Antimicrobial Resistance. These documents are available on CVM's Antimicrobial Resistance page.

Registration for this meeting is free and required. Limited space is available, and early registration is encouraged. Logistics for the meeting as well as the registration form are available on the CVM Antimicrobial Resistance page. Additional information about the meeting is contained in a July 28, 2000, Federal Register notice. The agenda will be posted on the website at a future date. For general inquiries about the meeting and registration, please contact: Lynda W. Cowatch, CVM (HFV-150), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-827-5281. Technical inquiries should be directed to Aleta Sindelar, CVM (HFV-6), at (301) 827-0148. If you need special accommodations for a disability, please contact the DoubleTree Hotel at least 7 days in advance. When making reservations with the DoubleTree Hotel, please refer to the "CVM Antimicrobial Resistance Public Meetings" to receive the group discount rate.

Transcripts of the meeting will be posted on the CVM Home Page. Interested persons may submit written comments regarding this meeting for consideration until December 11, 2000. They should be directed to Docket #98D-0969 and submitted to: Dockets Management Branch, (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD, 20852; or faxed to (301) 827-6870 with the appropriate identification number. Questions about your submission of comments may be directed to HFA-305 at (301) 827-6860.

REVISED FEEDS PROGRAM ISSUED

By Patsy Gardner

The Division of Animal Feeds has published a revised compliance program for animal feeds. The program has undergone a complete rewrite, and now carries a new name, the Feed Manufacturing Compliance Program (7371.004).

Compliance Programs are formally written plans which direct and specify the work that is done by the FDA=s field personnel. They generally provide specific guidance to ensure a uniform approach for regulatory/administrative action; to accumulate data on a known problem to determine long-range trends on a statistically valid basis; and to gather product or industry information within a specific time frame to determine the existence or extent of a problem.

In the past the Medicated Feeds Compliance Program has been limited to medicated feed manufacturing. The name was changed to incorporate inspectional and regulatory coverage for non-medicated and medicated feed manufacturing as needed. This change was in response to the growing concern over feed ingredients and their impact on public health.

The enactment of the Animal Drug Availability Act of 1996 (ADAA) amended Section 512 (m) of the Federal Food, Drug, and Cosmetic Act to require a single facility license rather than multiple medicated feed mill applications (MFAs) for each feed mill as previously required. Firms using Category II Type A Medicated Articles to make medicated feeds are required to register with FDA and hold an approved medicated feed mill license. The compliance program contains information on the Medicated Feed Mill License as well as guidance on the current good manufacturing practice regulations; it also contains a list of definitions for terms used in it. The Program also contains information on verifying compliance with Veterinary Feed Directive (VFD) requirements and information for those who wish to distribute feed containing VFD drugs.

Because of the concern with the use of mammalian protein in feed for ruminants and the possible transmission of the causative agent for Bovine Spongiform Encephalopathy (BSE), the program contains information on assessing a firm=s compliance with 21 CFR 589.2000.

The Feed Manufacturing Compliance Program contains a completely revised Form FDA 2481, Medicated Feeds Inspection Report. The form contains questions that relate to 21 CFR 225, BSE, and VFDs.

For a copy of the revised program, please contact Patsy Gardner at 301-827-0187, or by e-mail at pgardner@cvm.fda.gov.

Patsy Gardner is an Industry Compliance Analyst in CVM’s Division of Animal Feeds.

ACCOUNTABILITY BY WAY OF: "THE GOLD STANDARD" -- AAALAC

By Jerrold Boone, B.A. and Mack Holt, D.V.M

The U.S. Food and Drug Administration (FDA) ensures that safety standards are met for foods, human and veterinary drugs, human biological products, medical devices, cosmetics, and consumer products emitting radiation. The agency verifies that products are honestly, accurately, and informatively represented to the public. Additionally, the agency also guarantees that regulated products are in compliance with FDA regulations and guidelines. If there are any instances of non-compliance, regulated products are identified and corrected, and any unsafe or unlawful products are thus removed from the marketplace.

FDA-regulated decisions are quality science-based decisions in the best interest of human and animal health. To facilitate this process, FDA has research programs that use in vivo and in vitro methodologies in the derivation of supportive data. All the operative units in FDA that have animal care and use programs conduct their research under the oversight of fully constituted and functional Institutional Animal Care and Use Committees (IACUCs). These committees execute all the duties and responsibilities prescribed by the Animal Welfare Act (AWA) and Public Health Service Policy (PHS) on Humane Care and Use of Laboratory Animals. Of the utmost importance to the IACUCs is the salient understanding that "quality animal care is critical to quality science."

FDA strives to be accountable for its laboratory animal programs. Since 1965 the Association for the Assessment and Accreditation of Laboratory Animal Care International (AAALAC) has been promoting high standards of animal care through its voluntary accreditation program. Achievement of full-accredited status through AAALAC is considered to be the "Gold Standard" in laboratory animal care. The symbol of AAALAC represents to the laboratory animal community and the public that a program is operating at standards that exceed the Federal rules and regulations. It shows that the program provides and promotes optimal care and use for its laboratory animals. Full accreditation by AAALAC should be the goal of every research, testing, and academic institution because it demonstrates responsibility to the care, use, and welfare of laboratory animals. What better way to show that you are committed to your laboratory animal program and its operation?

Current Accredited Status of FDA Programs

Four out of the seven FDA Centers are currently AAALAC accredited. These four Centers are the National Center for Toxicological Research (NCTR), Center for Veterinary Medicine (CVM), Center for Biologics Evaluation and Research (CBER), and Center for Drug Evaluation and Research (CDER). The Center for Devices and Radiological Health (CDRH) was site visited by AAALAC on July 31, 2000. Upon conclusion of the visit, an indication by the site visitors was made that "Full Accreditation" would be recommended. This will mean that there are five Centers that are now "Fully Accredited." The Center for Food Safety and Applied Nutrition (CFSAN) and Office of Regulatory Affairs (ORA) are now in the process of preparing for AAALAC accreditation. It is a worthy goal for the FDA to have all of its Centers accredited by AAALAC because it says to the research community that FDA is committed to the highest quality of care and use for animals beyond what is stated in the Public Health Service Policy, Animal Welfare Act (AWA), the Guide for the Care and Use of Laboratory Animals, and other applicable regulations and guidelines. Basically, by having all of its Centers AAALAC accredited, FDA will signify the importance of meeting the "Gold Standard" in regulatory decision making.

FDA Accreditation Process

The first step in applying for accreditation is to request an application by either contacting the AAALAC International office or by downloading from the Web. The application packet contains an outline that will guide one through the application process, the "rules of accreditation", a copy of the Guide for the Care and Use of Laboratory Animals, plus any additional resources. The next and arguably most important step is to prepare and submit the Program Description. This includes the animal care and use policies and responsibilities, the animal environment, housing and management, veterinary medical care, and information on the physical plant. The Program Description states how you run your program on a daily basis.

The second step in the FDA process, which is optional, is to have an intramural review of your program and facilities. The Office of Animal Care and Use (OACU) with the approval of the Food and Drug Research Animal Council (FRAC), has developed an intramural review process that has been 100 percent effective for aiding Centers in gaining "Full Accreditation" from AAALAC. This intramural review process parallels that of the formal AAALAC site visit procedures. This process is an integral part because it helps a Center identify areas of deficiency prior to a visit from AAALAC and provides instructive recommendations for corrections. The Office of Animal Care and Use has maintained a 100 percent success rate in helping Centers achieve "Full Accreditation." Dr. Mack Holt, Director of OACU, provides leadership for the intramural review process.

The formal site visit team is made up of two or more AAALAC representatives. One member of the team is always a member of the AAALAC Counsel on Accreditation. It is important that all members of the IACUC be present for the site visit. The actual site visit involves an in-briefing interview where AAALAC representatives sit down and go over the Program Description with the unit seeking accreditation. The interview will be interactive in that the team members will ask questions about the program and possibly request some additional documents. Following the in-briefing interview, there is a tour of the facilities. The site visit team may choose to review selected policies and experimental procedures to assure the IACUC’s performance is consistent with regulatory guidelines. The exit-briefing interview, following deliberation by the team members, is where the site visit team members share commendations, recommendations for program improvement, and accreditation recommendation that will be made to the AAALAC Council.

Accreditation Status

The first and foremost goal of FDA is to have every Center achieve "Full Accreditation." The formal AAALAC site visit will frequently identify program improvement recommendations, which can usually be fixed in a short period of time. As previously stated, NCTR, CVM, CBER, and CDER have all been granted "Full Accreditation" by AAALAC and a recommended "Full Accreditation" for CDRH. CFSAN and ORA are in various final stages of preparation for making application for accreditation. Because AAALAC’s mission involves helping research institutions maintain excellence in the animal care and use program, they have developed different categories of accreditation. The ultimate goal of every animal care and use program is to achieve "Full Accreditation" on the initial site visit and to be granted "Continued Full Accreditation" with each subsequent triennial site visit. When "Full Accreditation" is granted, an annual program update is required along with site visits by AAALAC every three years. The site visit every three years follows the same process as if the institution was applying for the first time. With the maintenance of good records and strict adherence to the program, continued full accreditation following a three-year review is very rarely a problem.

Why Organizations Value Accreditation, "The Gold Standard"

AAALAC made recent inquiries of more than 600 accredited organizations. The organizations’ responses that are cited below reflect some salient benefits of AAALAC accreditation.

• "It assures the credibility of our program among funding sources."
• "It provides the public with a positive image and validates that our program meets or exceeds high standards for animal care and use."
• "It helps convince our administrators and upper management of the need to commit resources to maintain a high quality program."
• "It coveys a high level of professionalism about our program to the scientific community."
• "The application of AAALAC standards assures high-quality research and animal care, resulting in better science."
• "Completing the Program Description [part of the accreditation process] helps us identify weaknesses and deficiencies and self-correct them."
• "Pressure to stay accredited makes us more diligent in rechecking the basics on a regular basis."
• "The rigorous peer-review evaluation ensures that we’re doing things right."

Conclusion

The enormous benefit for having an animal care and use program AAALAC accredited goes without saying. The benefit of having all the Centers within the FDA AAALAC accredited is more than just having a sticker in the window; it holds FDA accountable to the public, its workers, and the entire research community. FDA will be making a statement in the research community that is everlasting.

Jerrold Boone is a fourth-year veterinary student attending Tuskegee University, Tuskegee, AL. This is his second year as a summer intern in the Office of Animal Care and Use (OACU). Dr. Mack A. Holt is the Director of CVM’s OACU.

SHEEP RECLASSIFIED AS MINOR SPECIES FOR ALL DATA COLLECTION PURPOSES

FDA's Center for Veterinary Medicine (CVM) published a final rule to reclassify sheep as a minor species for all data collection purposes in the August 3, 2000, Federal Register. This reclassification allows sponsors of new animal drug applications to extrapolate human food safety data from a major species such as cattle to sheep. In particular this rule will allow the extrapolation of the tolerances for residues of new animal drugs in cattle to sheep.

A copy of this final rule may be obtained from CVM's Home Page on the Internet or by calling or writing the FDA Veterinarian.

In the Federal Register of July 26, 1999, FDA published a proposed rule to revise the definition of minor species in Title 21, Part 514.1 of the Code of Federal Regulations by deleting the following language: "Sheep are a minor species with respect to effectiveness and animal safety data collection requirements; sheep are a major species with respect to human safety data collection requirements arising from the possible presence of drug residues in food." This change makes sheep a minor species for all data collection purposes.

The benefit of this final rule will be to lessen the pre-approval study requirements of New Animal Drug Approvals (NADAs) for animal drugs to be used in sheep. It is expected to lower research expenses and provide an impetus for drug sponsors to submit NADAs for minor use species rather than rely on extra-label use of animal drugs on sheep. The rule went into effect on September 5, 2000.

Further information about this final rule may be obtained from Dr. Meg Oeller, Center For Veterinary Medicine (HFV-130), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-827-7581

COMPANION ANIMAL ANALGESICS: ASSESSMENT OF PAIN

Animal pain models are used in laboratory studies in companion animals (dogs, cats and horses) to test the effectiveness of various analgesics used to control acute and chronic pain. Clinical field trials evaluate short-term perioperative pain or long-term osteoarthritic pain in client-owned animals.

Veterinarians and pet owners want to avoid causing pain to animals in their care. One way of reducing pain is to administer safe and effective analgesics. Pain assessment models are used to measure the effectiveness of an analgesic. FDA approval decisions are based on data obtained from some pain assessment models. Many steps are taken to avoid inducing unnecessary pain in the use of these models. Information contained in this article briefly describes some of these models and the criteria used for the assessment of analgesic effectiveness.

1. LABORATORY MODELS FOR ANIMAL PAIN:

Arthroscopic transection of the cranial cruciate ligament induces canine osteoarthritis. This model is probably the best characterized and most commonly used laboratory model for experimental osteoarthritis in dogs. It has been repeatedly used in studies to evaluate analgesia following treatment with NSAIDs, opioids and alpha-₂- agonists in the acute perioperative period. Transection of the cranial cruciate ligament results in a mechanically unstable femoropatellar (stifle) joint that reproducibly mimics osteoarthritis. Osteoarthritic changes with osteophyte formation occur in approximately 8 weeks and are progressive. Arthroscopic transection is preferred over the percutaneous stab incision technique because articular surfaces can be carefully examined for any signs of existing osteoarthritis, full ligament transection is assured, and inadvertent iatrogenic damage is minimized. The arthroscopic technique is preferred over arthrotomy because it requires less extensive tissue dissection that results in damage to periarticular soft tissue and articular neurons.

Chronic articular inflammation is commonly modeled using intraarticular Freund’s Complete Adjuvant, carragheenan or sodium urate in dogs and horses. Adjuvant-induced synovitis is characterized by an acute response during the first 24 hours, followed by a subacute response approximately 3 weeks later, that persists for several weeks. However, lameness induced by chemical injection can yield inconsistent results, especially during the acute phase of the inflammatory response. The placebo injected animals may be indistinguishable from the treated animals because rapid self-healing may occur and responses vary among individual lame animals.

Polyvinyl alcohol particles in the equine metacarpophalangeal joint (fetlock) have recently been used in a model of acute synovitis/capsulitis to study the effects of therapeutic analgesics. The inflammatory response is comparable to clinical cases of acute primary synovitis as demonstrated by acute lameness, inflammation of the synovium and joint capsule, increased synovial effusion, and changes in synovial fluid variables. Moderate lameness remains constant for several days after an initial peak. On necropsy, the condition of the articular cartilage was not obviously affected by a single injection of polyvinyl alcohol particles.

Tendinitis (bowed tendon), a common clinical diagnosis in horses, has been modeled by injecting collagenase into the superficial digital flexor tendon of the equine forelimb. The resultant pathophysiology does not closely mimic the clinical condition and the horse’s lameness response is variable.

Visceral analgesia is evaluated in horses when abdominal pain (colic) is induced by inflation of a balloon placed in the lumen of the cecum through a surgically prepared fistula. Rectal balloons have been used similarly in cats.

A lameness model uses force plate data to evaluate the gait of horses after inducing lameness by tightening or loosening screws in modified horseshoes. The resulting pressure pain on the sole enables induction and reversal of three different degrees of lameness and the same horse may be used to generate control data.

2. PAIN MODELS USED IN CLINICAL FIELD TRIALS:

Standardized mechanical and electrical nociceptive stimuli have been adapted from rat and rabbit methodology for the assessment of analgesia in dogs and cats. A mechanical device produces pain without tissue damage and is secured to one hind leg with fiberglass cast material. Using a pneumatic control, a 4 mm pin is gradually extended from within a cuff over the medial, proximal tibia. Stimulation continues to the minimum pressure (mm Hg) that causes an avoidance response (leg movement or vocalization). Similarly, a computer controlled system delivers an electrical stimulus to the tail by an attached electrode for set periods of time. Stimulation increases over time to the minimum intensity (voltage) that produces an avoidance response (tail movement or vocalization).

Analgesics are frequently evaluated in client-owned animals that present for elective surgery. Animal behaviors in response to pain can be difficult to interpret after mildly painful procedures. Therefore, surgeries that are suitable for the evaluation of analgesics have been categorized in dogs and cats:

EVALUATION OF ANIMAL PAIN:

In general, pain in the laboratory is subjectively scored as a response to the administration of various nociceptive stimuli, such as:

heat

cryothermia

needle pricks

toe pinch

tail clamp

carragheenan sponge tissue insertion

Pain evaluation in client-owned animals and clinical cases primarily relies on:

EEG assessments (alpha-₂-agonists)

BEHAVIORAL RESPONSES:

To include analgesia as a part of routine case management, veterinarians need to be able to accurately assess pain status in their patients. Since animals must indirectly communicate that they are in pain, veterinarians rely primarily on behavioral signs, together with blood indicators (increases in blood glucose, corticosteroid, and catecholamine concentrations) and physiological changes (increases in heart rate, respiratory rate, temperature) .

Behavioral Signs Of Pain By Species:

LAMENESS EVALUATION:

Lameness examinations are most commonly employed for the evaluation of chronic pain. Subjective lameness examinations use graded scoring systems, are very standardized and can yield meaningful results if the lameness is consistent prior to treatment with analgesics. Traditional lameness evaluations may make use of measurements of stride length using ink and paper (dogs) or hoofprints on sand (horses).

Clinical Scoring Of Lameness:

FORCE PLATE TECHNOLOGY:

Technologically complex measurements of force plate analysis have become sufficiently repeatable, reproducible and appropriate for the quantitative evaluation of lameness in dogs and horses. Vertical and craniocaudal force measurements are used for the evaluation of gait. Vertical force measurements are described as vertical peak force and vertical impulse. Craniocaudal force is divided into braking (peak force and impulse) and propulsion (peak force and impulse). Adjunctive use of computer analyzed kinematics measures joint range of motion and compares pre-treatment and post-treatment parameters. Training of both animals and investigators is required. The practical use of this complex technology may depend on the expertise of the operator. Force plate results should always be accompanied by simultaneously recorded subjective lameness scores.

ETHICAL CONSIDERATIONS:

Recent years have demonstrated an increased awareness within the veterinary profession of the necessity to provide effective pain relief for their patients. Clients now expect veterinarians to recognize and control pet both acute and chronic pain and suffering. The need to provide adequate analgesia has increased since anesthetic drugs (for example, propofol and sevoflurane) provide rapid post-operative recovery times. Rapid recovery can result in intense immediate post-operative pain. Also, the use of balanced anesthetic regimens allows, more lengthy and invasive procedures, potentially causing greater tissue damage and longer post-operative pain.

Studies that evaluate companion animal drug pain frequently take place within the university setting. Study design must comply with the Institutional Animal Care and Use Committee (IACUC). The Institutional Animal Care and Use Committee is composed of at least five members, including a veterinarian, an experienced investigator and an individual not affiliated with the institution. The committee determines that research projects are conducted in accordance with the Animal Welfare Act. The Act is administered by the United States Department of Agriculture. Some pain models may not be acceptable to these committees.

Minimizing pain and distress in well-controlled laboratory studies using research animals can enhance scientific results. Animals that experience unnecessary pain may introduce confounding variables into study design. The fewest numbers of animals that are exposed to the least noxious stimuli for the shortest period of time can still provide the clearest results in a well-controlled study.

REFERENCES:

1. Marshall, K.W., and Chan, A.D.M. "Arthroscopic Anterior Cruciate Ligament Transection Induces Canine Osteoarthritis." The Journal of Rheumatology; 23:2 (1996)
2. Cornelisson, B.P.M., et.al. "Experimental model of synovitis/capsulitis in the equine metacarpophalangeal joint." AJVR, 59:8 (1998)
3. Boatwright, C.E., et.al. "A comparison of N-butylscopolammonium bromide and butorphanol tartrate for analgesia using a balloon model of abdominal pain in ponies." Can J Vet Res, (60) 1 (1996)
4. Merkens, H.W., and Schamhardt, H.C. "Evaluation of equine locomotion during different degrees of experimentally induced lameness." Equine Vet J Suppl, 6 (1988)
5. Personal communication: William Muir, DVM, PhD, Ohio State University, College of Veterinary Medicine, 610 Tharp Street, Columbus, Ohio, USA (1999)
6. Tranquilli, W., et.al. "Factors to Consider in Selecting an Anesthetic and Pain Management Protocol in Stable Patients", Veterinary Proceedings, The North American Veterinary Conference, Orlando, Florida (1998)
7. Waterman, A.E. and Kalthum, W. in Animal Pain, ed. Short, C.E. and Van Poznak, A. (1992)
8. National Research Council, "Recognition and Alleviation of Pain and Distress in Laboratory Animals", Washington, DC, National Academy Press (1992)
9. Waterman-Pearson, A.E. "Peri-operative analgesia", Proceedings, 6^th International Congress of Veterinary Anaesthesia, Thessaloniki, Greece (1997)
10. Committee for Research and Ethical Issues of the International Association for the Study of Pain: "Ethical guidelines for investigations of experimental pain in conscious animals.", Pain 16 (1983)

Dr. Germaine Connolly is the Anesthetics Reviewer in CVM’s Division of Therapeutic Drugs for Non-Food Animals.

WORKING TO PROMOTE JUDICIOUS USE OF ANTIMICROBIALS

The American Veterinary Medical Association (AVMA) has developed principles on Judicious Therapeutic Use of Antimicrobials to help veterinarians make informed therapeutic decisions about these products. FDA's Center for Veterinary Medicine (CVM) contracted with AVMA to develop four species-specific brochures, a video, and a set of speeches to help promote these principles to veterinarians and veterinary students. The brochures are entitled, "Judicious Use of Antimicrobials for Poultry Veterinarians," "Judicious Use of Antimicrobials for Swine Veterinarians," "Judicious Use of Antimicrobials for Beef Cattle Veterinarians," and "Judicious Use of Antimicrobials for Dairy Cattle Veterinarians." CVM plans to make these brochures available this fall. Readers interested in obtaining copies may contact the FDA Veterinarian.

As the species-specific brochures state, "Whenever an animal or human host is exposed to antimicrobials, there will be some degree of selection for a resistant bacterial population. Selection will depend upon the type of antimicrobial used, the number of individuals treated, the dosage regimen, and the duration of treatment. Therefore, it is vital to limit therapeutic antimicrobial use in animals and humans to those situations where they are needed.

"The veterinary profession shares the concerns of the public, governmental agencies, and public health community regarding the broad issue of antimicrobial resistance and specifically the potential risk of resistance developing in animals with subsequent transfer to humans."

The brochures continue, "The overarching position of the AVMA is, 'When the decision is reached to use antimicrobials for therapy, veterinarians should strive to optimize therapeutic efficacy and minimize resistance to antimicrobials to protect public and animal health." The objectives of the AVMA are to:

• support development of a scientific knowledge base that provides the basis for judicious therapeutic antimicrobial use,
• support educational efforts that promote judicious therapeutic antimicrobial use,
• preserve therapeutic efficacy of antimicrobials, and
• ensure current and future availability of veterinary antimicrobials."

AVMA has developed fifteen general principles that emphasize preventive actions to avoid disease, other options before choosing to use antimicrobials, or the use of drugs, when possible, that are less important to human and animal needs. The principles are as follows:

1. Preventive strategies, such as appropriate husbandry and hygiene, routine health monitoring, and immunizations, should be emphasized.

2. Other therapeutic options should be considered prior to antimicrobial therapy.

3. Judicious use of antimicrobials, when under the direction of a veterinarian, should meet all the requirements of a valid veterinarian-client-patient relationship.

4. A veterinarian is required to direct the use of prescription antimicrobials or antimicrobials being used in an extralabel manner. This direction may take place only within the context of a valid veterinary-client-patient relationship (VCPR). A valid VCPR exists when all of the following conditions have been met:
   
   

   1. The veterinarian has assumed the responsibility for making clinical judgments regarding the health of the animal(s) and the need for medical treatment, and the client has agreed to follow the veterinarian’s instructions.
   2. The veterinarian has sufficient knowledge of the animal(s) to initiate at least a general or preliminary diagnosis of the medical condition of the animal(s). This means that the veterinarian has recently seen and is personally acquainted with the keeping and care of the animal(s) by virtue of an examination of the animal(s) or by medically appropriate and timely visits to the premises where the animal(s) are kept.
   3. The veterinarian is readily available for follow-up evaluation, or has arranged for emergency coverage, in the event of adverse reactions or failure of the treatment regimen.

      When it is not possible to make a direct clinical evaluation, the diagnosis should be based on past experience, on knowledge of the farm epidemiological status, and historical and/or on-going susceptibility testing.
      

5. Prescription, Veterinary Feed Directive, and extra-label use of antimicrobials must meet all the requirements of a VCPR.

6. Extralabel antimicrobial therapy must be prescribed only in accordance with the Animal Medicinal Drug Use Clarification Act amendments to the Food, Drug, and Cosmetic Act and its regulations (21 CFR Part 530).

7. No drug can be marketed unless its quality, safety, and efficacy have been demonstrated. Therefore, the first line of choice should be based on the products approved for the species and the indication concerned. When no suitable product is approved for a specific condition or species, or the approved product is considered to be clinically ineffective, the choice of an alternative product should be based, whenever possible, on the results of valid scientific studies and a proven efficacy for the condition and species concerned.

   1. For food animals, extralabel drug use (ELDU) is not permitted if a drug exists that is labeled for the food animal species and contains the needed ingredient, is in the proper dosage form, is labeled for the indication, and is clinically effective.

   2. ELDU is permitted only by or under the supervision of a veterinarian.

   3. ELDU is allowed only for FDA approved animal and human drugs.

   4. ELDU is permitted for therapeutic purposes only when an animal’s health is suffering or threatened. ELDU is not permitted for production drugs (e.g., growth promotion).

   5. ELDU in feed is prohibited.

   6. ELDU is permitted for preventative purposes when an animal’s health is threatened.

   7. ELDU is not permitted if it results in a violative food residue, or any residue that may present a risk to public health.

   8. ELDU requires scientifically based drug withdrawal times to ensure food safety.

   9. The record and labeling requirements must be met.

   10. The FDA prohibits specific ELDU. For example, the following drugs are prohibited for extralabel use in food animals: chloramphenicol, clenbuterol, diethylstilbestrol, dimetridazole, ipronidazole, other nitroimidazoles, furazolidone (except for approved topical use), nitrofurazone (except for approved topical use), sulfonamide drugs in lactating dairy cows (except approved use of sulfadimethoxine, sulfabromomethazine, and sulfaethoxypyridazine), fluoroquinolones, and glycopeptides (example is vancomycin).

8. Veterinarians should work with those responsible for the care of animals to use antimicrobials judiciously regardless of the distribution system through which the antimicrobial was obtained.

9. Regimens for therapeutic antimicrobial use should be optimized using current pharmacological information and principles.

10. Antimicrobials considered important in treating refractory infections in human or veterinary medicine should be used in animals only after careful review and reasonable justification. Consider using other antimicrobials for initial therapy.

11. Use narrow spectrum antimicrobials whenever appropriate.

12. Utilize culture and susceptibility results to aid in the selection of antimicrobials when clinically relevant.

13. Therapeutic antimicrobial use should be confined to appropriate clinical indications. Inappropriate uses such as for uncomplicated viral infections should be avoided.

14. Therapeutic exposure to antimicrobials should be minimized by treating only for as long as needed for the desired clinical response.

15. Limit therapeutic antimicrobial treatment to ill or at risk animals, treating the fewest animals indicated

16. Minimize environmental contamination with antimicrobials whenever possible.

17. Accurate records of treatment and outcome should be used to evaluate therapeutic regimens.

CVM OFFICIALS ATTEND ICEID

Drs. Marcia Headrick, Charlotte Spires, Kathy Hollinger, Charles Eastin (Division of Epidemiology) and Linda Tollefson (OSC), attended the recent International Conference on Emerging Infectious Diseases (ICEID). The conference was hosted by the Centers for Disease Control (CDC) and the American Society of Microbiology (ASM) in Atlanta, Georgia. There were several presentations and posters at the conference using National Antimicrobial Resistance Monitoring Program (NARMS) data. Oral presentations were given by Shannon Rossiter of CDC on "High prevalence of fluoroquinolone-resistant Campylobacter jejuni in the FoodNet sites" and by Fred Angulo of CDC on "Enterococci study: monitoring for the seeds of antimicrobial resistance in the food supply."

Posters on NARMS data included:

• Emergence of a multidrug-resistant strain of Salmonella serotype Newport in the United States -- NARMS 1997-1999

• Antimicrobial resistance patterns of Escherichia coli O157:H7 - NARMS 1996-1999

• Fluoroquinolone-resistance in Campylobacter from chicken and the human health impact: a quantitative risk assessment using data from FoodNet and NARMS

• Fluoroquinolone-resistant Campylobacter causes longer duration of diarrhea than fluoroquinolone-susceptible Campylobacter strains in FoodNet sites

• High prevalence of antimicrobial resistance among Shigella isolates to agents commonly used for treatment - NARMS 1999

• Phage type and antimicrobial resistance trends among human Salmonella serotype Typhimurium isolates in NARMS 1997-1998 - continued dominance of DT-104 R-type ACSSuT

• Emerging antimicrobial resistance among human Salmonella isolates to clinically important antimicrobial agents -- NARMS 1996-1999

Following is an abstract presented by Dr. Katherine Hollinger:

Fluoroquinolone Resistance in Campylobacter from Chickens and Human Health Impact; A Quantitative Risk Assessment using FoodNet and other sources of Data

K. Hollinger¹, M. Bartholomew¹, D. Vose², M. Miller¹, S. Thompson¹, D. Vugia³, T. Fiorentino⁴, J. Benson⁵, J. Johnson⁶, K. Smith⁷, E. DeBess⁸, F. Angulo⁹, and the EIP FoodNet Working Group⁹

¹FDA, Rockville, MD; ²D. Vose Consultancy, Ltd., Dordogne, FRANCE; ³California Dept. of Health Services, Berkeley, CA; ⁴Connecticut Emerging Infections Program, New Haven, CT; ⁵Georgia Emerging Infections Program, Decatur, GA; ⁶Maryland Dept. of Health and Mental Hygiene, Baltimore, MD; ⁷Minnesota Dept. of Health, Minneapolis, MN; ⁸Oregon Health Div., Portland, OR; ⁹CDC, Atlanta, GA

Background: Emerging antimicrobial resistance, due to use of antimicrobials, is a public health concern in human and animal medicine worldwide. Animals serve as reservoirs for many foodborne pathogens, including Salmonella and Campylobacter. Antibiotic resistant organisms may be present in or on animals as a result of drug use. These resistant foodborne pathogens can contaminate a carcass during slaughter or processing. When these resistant bacteria cause illness in a person who needs treatment, medical therapy may be compromised if the pathogenic bacteria are resistant to the drug(s) used for treatment. Fluoroquinolones are effective against most bacterial enteric pathogens and are often used to treat Campylobacter infections. Campylobacter is the predominant bacterial cause of enteric infections. Fluoroquinolones were approved for treatment of colibacillosis in poultry in 1995. The FDA Center for Veterinary Medicine (CVM) developed a risk assessment model that evaluates the risk of fluoroquinolone resistant Campylobacter infections from consumption of chicken that are attributed to use of fluoroquinolones in chickens.

Methods: A mathematical model was developed to relate the prevalence of resistant Campylobacter infections in humans, due to consumption of chicken, to the prevalence of resistant Campylobacter in chickens. The model uses data from recently initiated surveillance systems (FoodNet and NARMS) that monitors incidence of foodborne disease, and prevalence of fluoroquinolone resistance, as well as data from the published literature.

Results: The model estimates a mean of 2 million cases of Campylobacter for 1998 in the US. Approximately 50 to 70 percent of Campylobacter infections were attributed to exposure to chicken. Of these chicken associated infections seeking care and receiving treatment, 55 percent received a fluoroquinolone. An estimated 5000 people (5 –95 percent confidence interval 2600 to 8600) became ill with a fluoroquinolone resistant Campylobacter infection associated with consuming chicken and received fluoroquinolones for their illness. The risk assessment also described data gaps and data limitations and gives detailed assumptions where data were lacking.

Conclusions: This risk assessment indicates that approximately five thousand people who are ill with fluoroquinolone resistant infections could be treated with a fluoroquinolone and that treatment is potentially compromised due to resistance. Surveillance data can be used to update the model annually and will indicate changes in level of resistance and incidence of campylobacteriosis. These changes may reflect alterations in food animal production, processing or may indicate changes in bacterial virulence or a change in the susceptibility of the human population. Forecasting potential changes in level of resistance in chickens could provide a means to mitigate the human health impact.

Dr. Katherine Hollinger is an Epidemiologist in CVM’s Division of Epidemiology.

CVM CO-SPONSORS SYMPOSIUM

CVM cosponsored a symposium on the use of herbs and botanicals in livestock diets. The symposium was held July 25, 2000, in conjunction with the ADSA-ASAS Joint Annual Meeting, Baltimore, Maryland. The meeting was intended to raise awareness on this important issue, since, in the past few years, the explosion in sales of botanicals and herbs, has brought many products to the marketplace that do not conform to the standards of safety and efficacy expected. Approximately 200 people attended the meeting.

Introductory comments were provided by Drs. G. L. Cromwell, Chair of FASS Committee on Food Safety, Animal Drugs, and Animal Health and C.B. Ammerman, University of Florida. Also, as part of the opening session, Dr. Sharon Benz (Division of Animal Feeds) spoke on the regulation of botanical and herbal substances in animal feeds. Dr. Benz provided an overview of the FDA’s regulation of animal feed products and highlighted the differences of the animal feed and feed supplement regulations compared to the regulations for dietary supplements intended for humans. Specifically, she addressed why Congress did not intend DSHEA (Dietary Supplement Health & Education Act) to apply to products for use in animals. Before finishing, she expressed the safety concerns FDA has regarding the use of botanical and herbal ingredients that are not recognized for use in animal diets.

Dr. Caspar Wenk, a distinguished speaker of the Institute of Animal Sciences, ETH Zurich, Switzerland, spoke on the use of herbs and botanicals in European livestock nutrition. Depending on the intended use, herbs are regulated in Europe as feedstuffs, feed additives or medical drugs. Typical uses discussed were as flavoring agents, antioxidants, endocrine stimulants, antimicrobial agents, or anthelmintic agents. Herbs that have shown antimicrobial activities in livestock and poultry include oregano, laurel, rosemary, coriander, and sage. Herbal feed antioxidants include rosemary, sage, thyme, and oregano. Rosemary is the most used herbal antioxidant in Europe. Dr. Wenk emphasized that, with the ban of antibiotics in Europe, the use of herbs has become an important alternative.

Professor Peter Cheeke, Oregon State University, Corvallis, Oregon, provided the results of recent research on the use of herbs in livestock nutrition. Prof. Cheeke discussed the results of poultry and swine studies which tested yucca as an odor and ammonia control agent. In addition, due to their possible role in lowering blood cholesterol, yucca saponins are also being tested for this and other therapeutic uses.

Dr. Kyle E. Newman, Venture Laboratories, Lexington, Kentucky, addressed the chemistry of herbs and botanicals with regard to the safety for animals. For instance, chaparral contains the antibiotic nordihydroguaiaretic acid (NDGA) which has shown to be effective against skin infections; however, this compound causes allergic contact dermatitis. In addition, although a potent antioxidant, the hepatotoxic effects of chaparral have been demonstrated in animal studies. During his closing remarks, Dr. Newman pointed out the importance of standardization (proper processing) of the "active" ingredients to prevent contamination (heavy metals, pesticides).

FINAL VICH GUIDANCE ON IMPURITIES AVAILABLE

The Food and Drug Administration (FDA) announced in the July 7, 2000, Federal Register, the availability of two final guidances for industry entitled "Guidance for Industry: Impurities In New Veterinary Drug Substances, VICH GL10 (#92) " and "Guidance for Industry: Impurities In New Veterinary Medicinal Products, VICH GL11 (#93)." These guidance documents were developed by the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (VICH).

These guidance documents represent current thinking and do not create or confer any rights for or on any person and do not operate to bind FDA or the public. Alternative methods may be used as long as they satisfy the requirements of the applicable statute and regulation.

Guidance #92 on impurities in new veterinary drug substances provides guidance for registration applications (referred to as registration applications or marketing authorisation in this final guidance) on the content and qualification of impurities in new veterinary drug substances intended to be used for new veterinary medicinal products, produced by chemical synthesis and not previously registered in the European Union, Japan, and the United States.

Guidance #93 on impurities in new veterinary medicinal products provides guidance recommendations for new animal drug applications (referred to as registration applications or marketing authorisation in this final guidance) on the content and qualification of impurities in new veterinary medicinal products, produced by chemical synthesis and not previously registered in the European Union, Japan, and the United States.

Copies of these documents may be obtained from CVM's Guidelines and Guidances Page on the Internet or by calling or writing the FDA Veterinarian.

Interested persons may submit written comments and suggestions on the guidance documents at any time to the Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD 20852. Comments should be identified with the full title of the guidance document and with the appropriate Docket number -- 99D-2215 (for Guidance #92) or 99D-2145 (for Guidance #93).

Further information about these guidance documents is contained in the July 7, 2000, Federal Register. Information on guidance documents #92 and #93 is also available from Dr. Kevin Greenlees, Center for Veterinary Medicine, (HFV-153), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-827-6977.

Further information on VICH is available from Dr. Sharon R. Thompson (HFV-3), Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-594-1798, e-mail: sthompso@cvm.fda.gov, or from Dr. Robert C. Livingston, Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Place (HFV-1), Rockville, MD 20855, 301-594-5903.

NEW TEAMS FORMED IN ONADE

The reorganization package for three new teams in CVM’s Office of New Animal Drug Evaluation (ONADE) has been approved. The official names, placement in the office, and functions are as follows:

1. Risk Analysis Team -- The Risk Analysis Team is located under the Office of the Director, ONADE. The Team consists of specialized scientific appointments and is responsible for implementing the President’s Food Safety Initiative and providing risk analysis capabilities for the Office and Center. Staffing for this Team is ongoing at this time.

2. Aquaculture Drugs Team -- The Aquaculture Drugs Team is part of the Division of Therapeutic Drugs for Food Animals. The formation of this Team recognizes a specialized scientific function that is performed within the Division. The Team oversees the CVM aquaculture program and evaluates the safety and effectiveness of new animal drugs for use in aquaculture. Dr. Joan Gotthardt has been appointed as Team Leader, and current members include Dr. Donald Prater, and Mr. Ben Puyot.

3. Microbial Food Safety Team -- The Microbial Food Safety Team is part of the Division of Human Food Safety. The formation of this Team recognizes a new specialized scientific function within that Division. The Team’s primary function is to review pre-approval protocols and studies designed to evaluate the potential microbiological hazard posed by antimicrobial residues in food and the development of resistant organisms in food animals. In addition, the Team provides expertise and input into broader issues dealing with microbial safety and antibiotic use. Staffing for this team is ongoing at this time.

TAMPERING CONVICTION

On September 14, 1999, Brian W. "Skip" Lea was indicted by a Federal Grand Jury in the Eastern District of Wisconsin on two counts of product tampering in violation of Title 18, U.S.C., 1365(b). The indictment alleged that on two occasions, Lea contaminated consumer products intended as ingredients in animal feed processed by the National By-Products, Inc. The contamination forced the company to recall products and to destroy raw material. According to NBP, its losses stemming from the contamination exceeded $2.5 million.

This investigation began in January 1997, after the Berlin Police Department, Berlin, Wisconsin, received a letter of sabotage. In this first tampering incident, several hundred pounds of the banned pesticide (Chlordane) was placed in tallow and bone meal produced by National By-Products (NBP). In a second tampering incident, another pesticide was put in grease containers owned by NBP. During the course of this investigation, special agents of FDA’s Office of Criminal Investigations conducted approximately 200 interviews and executed three Federal search warrants.

On April 3, 2000, Lea’s trial began in the Eastern District of Wisconsin, Milwaukee, WI. On April 13, 2000, the jury returned a guilty verdict to the charge of tampering.

Brian Lea was sentenced on July 28, 2000, to 3 years incarceration, to be followed by one year supervised release, and a restitution of $2.2 million to be paid at a minimum of $100 a month.

This investigation was conducted by the FDA's Office of Criminal Investigations, Chicago Field Office, and was prosecuted by the Office of the U.S. Attorney, Eastern District of Wisconsin, Milwaukee, WI. The Minneapolis District Office, in conjunction with CVM's Division of Compliance, assisted the Wisconsin Department of Agriculture, Trade, and Consumer Protection in the recall of the tainted product.

REGULATORY ACTIVITIES

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

• Frank J. Garcia, Jr. and Danny Garcia, Garcia Brothers Dairy, Tulare, CA

• Douglas G. Brunner, Edward DeJager, and Edgar DeJager, DeJager Dairy South, Chowchilla, CA

• John R. Wigle, Latrobe, PA

  These violations involved illegal residues of streptomycin in a dairy cow; penicillin in a dairy cow; and gentamicin in dairy cows.

Warning letters were sent to the following veterinarians as a result of illegal residues reported in animals treated by these individuals:

• James E. O’Shea, D.V.M., New Berlin, NY

• Benjamin F. Turner, D.V.M., Cortland, NY

• Douglas E. Evans, D.V.M., Georgetown, NY

All of these residues involved the illegal prescription and dispensing of gentamicin in dairy cows that were later offered for sale for human food. There is no permitted level for residues of gentamicin in edible tissue of cattle.

A warning letter was sent to Richard L. Lawson, President of Products Carousel, Inc., Sanger, CA. FDA analyses of Choo-HoovesPressed Sticks revealed contamination with Salmonella, a pathogenic bacteria. As a manufacturer of pet foods, it is Mr. Lawson’s responsibility to assure that his products are safe, wholesome, and not contaminated with pathogenic bacteria.

A warning letter was also sent to Dr. Praful R. Patel, President of National Biochemicals Corp., Twinsburg, OH, for violations related to the repackaging and distribution of bulk active pharmaceutical ingredients (API’s). Twenty-one Code of Federal Regulations 201.122 states that API’s used to produce new animal drugs are exempt from the requirement for adequate directions for use under 502(f)(1) if used to produce an animal drug that is covered by an approved new animal drug application. Conversely, an API that is used to produce an unapproved new animal drug is not exempt from the requirement for adequate directions for use and is therefore misbranded under 502(f)(1).

The regulation, 21 CFR 201.150, requires a written agreement between API shippers and recipients, assuring that the API’s will not be adulterated or misbranded by the end users. Distributors will be held accountable when drugs (API’s) they sell are used to manufacture unapproved drug products and they have not taken proper steps to prevent such illegal use.

Robert E. Hinckley, President/CEO of Bimeda Animal Health, Inc., Riverside, MO, received a warning letter for improper sales of veterinary prescription drugs. Sales were made without a valid veterinarian/client/patient relationship (VCPR) or to firms who are not lawfully engaged in distributing prescription drugs. Mr. Hinckley’s firm was selling prescription veterinary drugs such as Gentamicin Sulfate Solution, Cyanocobalamin Injection, Vitamin B-12, and Hypertonic Saline Solution, which are misbranded within the meaning of Section 502(f)(1) of the Federal Food, Drug, and Cosmetic Act in that they do not have adequate directions for use.

Within a valid VCPR, prescription animal drugs are exempt from adequate directions for lay use; the veterinarian’s supervision can be substituted for the legal requirement that drugs be labeled with adequate directions for use. Without supervision, prescription drugs are misbranded because they lack adequate directions for the layperson to use them safely.

Pet Treats Can Make You Ill

By Linda Bren

This article appeared in the September/October 2000 issue of the FDA CONSUMER.

Dogs love them. They're blissfully chewy and delightfully smelly to your pet--but treats made from the leftover parts of food-producing animals can make you and your family very sick.

Pet treats made from the dried ears, hooves, lungs, and bones of pigs and cows have been implicated in Salmonella poisoning in humans. In late 1999, Canadian health officials alerted the Food and Drug Administration to more than 35 human cases of Salmonella poisoning that occurred in Canada over the past year and were linked to contact with pig ears produced in that country. Some of these illnesses required children to be hospitalized.

"It's alarming to find that number of serious illnesses," says Gloria Dunnavan, the director of the Division of Compliance in FDA's Center for Veterinary Medicine. "We want to make sure there is no Salmonella in dried animal parts being sold as pet treats in the United States."

Earlier this year, FDA alerted U.S. distributors of both the suspect Canadian products and U.S.-manufactured dried animal parts. After U.S. retail store Costco tested and found Salmonella in samples of Medalist brand pig ears produced in this country, manufacturer Treat Makers L.L.C. recalled the products in May. The recall covers treats sold at Costco stores in 11 states: Washington, Oregon, California, Arizona, New Mexico, Nevada, Utah, Colorado, Idaho, Montana, and Hawaii. The products are packaged in 25-count plastic bags and stamped with lot numbers 07600EXU3 or 08300EX01 on a white sticker on the back of the bag.

In June, another U.S. manufacturer, Products Carousel, Inc., recalled its Pets Carousel 100% Choo-Hooves Pressed Sticks--Item #90010-S because of possible contamination with Salmonella. The Pets Carousel products were sold by Petsmart in Ohio and Arizona.

Although no illnesses from these products have been reported in the United States, consumers should handle dried animal parts like they would handle raw meat, according to Dunnavan. In other words, wash your hands with soap and hot water after handling, avoid putting the treats on food contact surfaces (such as kitchen countertops), and don't allow children to touch their mouths after handling until they've washed their hands. Dunnavan also advises consumers not to purchase unpackaged dried treats, which are more likely to be contaminated by Salmonella.

While healthy pets rarely become ill from the bacteria, they can become carriers of Salmonella and infect humans or other animals. This means that you could become infected if Fido licks your face after chewing a contaminated product.

Salmonella can cause vomiting, diarrhea, fever and stomach cramps in otherwise healthy individuals and can be fatal in young children, the elderly, or people with weakened immune systems.

Consumers may return the recalled Medalist and Pets Carousel products to the store where they purchased them for a full refund. Customers with questions about the recall should call Treat Makers at 1-888-250-7369 or Products Carousel at 800-231-3572. FDA continues to work with pet treat manufacturers to investigate the cause of the problem and ways to prevent it in the future.

Linda Bren is a Writer-Editor with the FDA CONSUMER.

NEW ANIMAL DRUG APPROVALS

ABBREVIATED NEW ANIMAL DRUG APPROVALS

SUPPLEMENTAL NEW ANIMAL DRUG APPROVALS

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