National Pet Week, which will be celebrated May 5-11, 1996, is sponsored by the American Veterinary Medical Association, American Animal Hospital Association, and the Auxiliary to the AVMA. Since nearly 50 percent of all United States residents own companion animals, it is appropriate that this year's theme is "Animals Complete the Circle of Love." This is the ideal time to remember the contribution that pets make to our lives, with their unconditional love and devotion.
Promotional material such as buttons, balloons, stickers, magnets, bookmarks, and T-shirts are available from the Auxiliary to the AVMA. Activities such as open houses, and health and safety clinics are planned by veterinarians throughout the United States to promote responsible pet ownership and encourage preventive health care for all animals. This is an opportunity to increase community awareness about the impact animals have on people's lives, and also to emphasize the importance of regular veterinary attention to ensure a long and happy life for our four-legged friends.
The FDA Veterinarian is proud to support the National Pet Week campaign and its goals. The Center for Veterinary Medicine is committed to working together with our customers, i.e., consumers, veterinarians, the animal health industry, and other Government agencies, to protect the health of humans and animals alike.
The following article provides information on pet birds and provides suggestions on their care. 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.
PET BIRDS -- PRESCRIPTION FOR LONG-TERM COMPANIONSHIP
by Edward L. Spenser, M.S., D.V.M.
Some of this material has been adapted from a series of client education brochures developed by the Association of Avian Veterinarians.
There are approximately 31 million pet birds in the United States. The most popular birds are parakeets (11 million), finches (5.7 million), cockatiels (4.9 million), canaries (2 million), and other parrots (1.2 million). Birds can be a wonderful source of companionship, but since they are totally dependent on the owner for their welfare, ownership carries with it a responsibility to provide the proper housing, feed, and health care for a long and happy life.
HOUSING
The cage you choose for your pet bird should be large and roomy, since the bird will be confined most of the time. It must be strong enough to resist bending, and made of non-toxic material, absent of sharp edges, and designed for ease of cleaning. Perches should be placed to prevent droppings from contaminating the food or water. Food bowls should be wide rather than deep to encourage eating. It helps to place the food and water bowls on opposite ends of the cage, to ensure exercise between eating and drinking. Newspapers, paper towels, or any other plain paper cage liner are preferred over wood chips, chopped corn cobs, kitty litter, sandpaper, or gravel so the appearance and amount of the droppings may be closely monitored. Daily cage cleaning allows the owner to notice any abnormal condition of the droppings, which may warn of possible illness. Smaller birds often like to have a place available for retreat, such as a paper bag, towel, or nesting box.
Since birds are intelligent, active animals, locate the cage near a family area, where they can enjoy the company of humans. If allowed outside the cage, wings should be clipped by a competent professional, and be aware of ceiling fans, large windows, hot pans on the stove, mouse traps, sticky fly strips, open doors, or unfriendly four-legged animals! Beware of environmental hazards, such as cigarette smoke, pesticides, overheated non-stick coatings (e.g., teflon) and extremes in temperature.
Provide safe toys as diversions from boredom. Many birds can entertain themselves by tearing paper or cardboard. A corn cob or pomegranate, or non-toxic leaves also provide "occupational therapy."
FEEDING
Unfortunately, marketed seed mixes do not provide complete nutrition. Other foods, such as those comprising a lean, vegetarian-type human diet, must be supplemented to balance the nutrients missing in seeds.
Approximately 60 percent of the daily food consumption should be selected from whole grain products, such as various bird seeds, cooked brown rice, oats and oatmeal, dry corn, barley, wheat, and whole grain bread. Many common bird "seeds" such as sunflower, safflower, or peanuts are very high in fat, and amounts should be limited. Vegetables provide some essential vitamins and minerals. The most valuable vegetables are dark green and leafy or dark yellow, those with high vitamin A content, such as beets, broccoli, carrots, parsley, pumpkin, winter squash, and sweet potatoes. Fruits should be offered in limited amounts, since most birds do not need outside sources of vitamin C except during illness or stress. High vitamin A-containing fruits are most desirable, such as papaya, cantaloupe and apricots. In addition, mature legumes (e.g., cooked beans, such as navy, kidney, lentils, or peas) may be offered up to 25 percent of the diet to provide a valuable source of protein. Calcium can be provided by cuttlebone, oyster shell, or mineral blocks. Of course, fresh water must always be available. Grit may be provided in limited amounts, but large intakes can cause impaction. Formulated diets are available and afford a convenient way of feeding the primary ration. These diets may be purchased as pellets, nuggets, crumbles, or hand-feeding premixes.
YOUR BIRD'S HEALTH
Birds are experts at hiding their symptoms of disease. This is a defense mechanism developed to insure their survival in the wild. They often do not appear ill until their disease state is advanced. Birds have a high metabolic rate and consequently require frequent influxes of energy (nutrients) to survive. They usually have minimum body fat and other reserves. Therefore, if they get sick, they tend to go downhill very rapidly.
Signs of serious illness which should alert the owner to contact a veterinarian include the following:
It is the opinion of expert avian veterinarians that most available over-the-counter products do more harm than good. These (with a couple of lesser known exceptions) are not approved by FDA and are manufactured to unknown standards of quality. If you experiment with over-the-counter medicines for too long, by the time you realize the bird is really in trouble and seek a veterinarian's advice, it is often too late. This is one reason why traditionally, many veterinarians have been reluctant to treat pet birds. Advances in avian medicine as well as in education of bird owners is changing this, however.
For example, birds do not get "simple colds." Respiratory symptoms in birds are not colds at all, but frequently bacterial or chlamydial infections that can be quite serious if untreated. Allergic disease has also been implicated in some respiratory conditions. The use of the term "cold" on the label of a bird medicine implies a self-limiting disease that is not life-threatening. Regardless of the cause, these animals require veterinary attention and, when appropriate, antibiotic therapy. Some conditions can be life-threatening. Psittacosis ("parrot fever") can occur as a respiratory syndrome. This disease is transmissible to humans and symptomatic therapy dismissing the disease as a "cold" can have adverse consequences for the bird, its owner, and members of the household.
Over-the-counter antibiotics for birds are available at most pet stores. Most are intended for use in the drinking water and can include the tetracyclines and erythromycin. There are many reasons why treating your pet bird with these products may be detrimental. Following are just a few:
You will find many products labeled to treat "diarrhea" in pet birds. Most of them are based on a kaolin-pectin combination, similar to those sold for use in humans. There are several problems with this. First, diarrhea in pet birds is rarely the self-limiting, uncomplicated condition that it is frequently in humans. True diarrhea (other than transitory changes in bird's stools due to certain fresh foods) or changes in the droppings, is actually considered rare in pet birds and is a symptom of a systemic illness. Second, it is common for a pet owner to observe excess liquid in the droppings and call this "diarrhea." Most of the time the problem is actually a condition called "polyuria", which is an over-production of urine and urates from the kidneys. This is easily confused by an inexperienced bird owner. Polyuria is much more common and also is usually a symptom of an underlying disease. In EITHER diarrhea or polyuria, a symptomatic remedy for "diarrhea" is usually ineffective. This is because:
1. True diarrhea is usually indicative of an underlying disease that requires more than symptomatic treatment, and
2. If the bird really has polyuria, which is kidney-related and also has many possible underlying causes, then obviously treating the gastrointestinal tract symptomatically alone will not be sufficient. Appropriate diagnosis and treatment by a veterinarian are usually required.
CONCLUSION
Your bird is important to you, so line up a qualified avian veterinarian before you need one. Pet store personnel, although they have good intentions, are not trained in veterinary medicine and should not be dispensing medical advice except to refer you to a professional. Avian medicine has come a long way in the past 15 years. There are now "board-certified" avian specialists in the U.S., with numbers growing yearly. Equally important, organizations like the Association of Avian Veterinarians (AAV) and other regional associations have very been active in educating veterinarians in all aspects of avian medicine and surgery. For further information about the care of birds, you may contact the Association of Avian Veterinarians, P.O. Box 618372, Orlando, FL 32861-8372.
With proper care and management, your pet bird will live a long and healthy life, providing years of companionship to you.
REVIEW OF THE VETERINARY DRUG APPROVAL PROCESS
by Linda A. Burgos, D.V.M.
The following article is provided for those readers interested in the approval process for veterinary drugs.
The term "new animal drug" means any drug intended for use for animals other than man, including drugs intended for use in animal feed. The approval of a new animal drug is a multi-stage process. The first stage involves the accumulation of the data that will support the safety and efficacy of the product. This phase, where pertinent preliminary and supportive studies are conducted, is developed as an Investigational New Animal Drug (INAD). Once investigational studies have been completed and a data base has been established that addresses both the safety and efficacy of the product, this information may be submitted in a new animal drug application (NADA) along with the other items discussed under 21 CFR 514.1 (such as the manufacturing and environmental information and labeling). If the NADA is complete and the information satisfactory, the NADA is approved and the drug may be legally marketed.
INAD Stage
Sponsor's responsibilities:
A drug company or other sponsor pursuing approval of a new animal drug must first establish an INAD with CVM so that they may legally ship their new animal drug to investigators to conduct studies. Often a sponsor will request a meeting with CVM to discuss their developmental plan for their product and get initial feedback and guidance from CVM. CVM encourages these "pre-INAD" meetings, especially for innovative drugs.
Studies demonstrating the safety and efficacy of the new animal drug are required to support approval of the product. According to the regulations (21 CFR 514.111), at least two well-controlled efficacy studies, including a clinical field trial, are needed to provide substantial evidence that the drug is effective for the purpose(s) indicated on the labeling. The types of studies generally done to demonstrate efficacy are dose determination, dose confirmation, and clinical field trial. The dose determination study is conducted to determine an effective dose that does not cause toxicity. The dose confirmation study is done to confirm that the therapeutic dose (determined from the dose determination study) is effective. Both of these studies are typically conducted on laboratory animals. The clinical field trial is performed to demonstrate that the drug is effective under conditions of actual use, i.e., using client-owned animals. Important safety data is also collected from this trial.
The types of studies needed to demonstrate the safety of the new animal drug include drug tolerance test, margin of safety, and reproductive safety. The drug tolerance test characterizes the target animal's response to a toxic dose(s) (usually up to 10 times the maximum proposed dose for the proposed maximum duration of use or up to 21 days). The study is done to determine what a potential overdose would cause clinically and what organ systems are affected. The margin of safety study is usually conducted at 0, 1x, 3x, and 5x the proposed therapeutic dose for at least 3 times the recommended duration of treatment. Reproductive safety studies are performed on both sexes to evaluate possible drug effects in the target species on general reproductive performance (i.e., fertility), teratogenesis, and postnatal factors. A sponsor may opt for a label disclaimer in lieu of conducting reproductive studies.
CVM's responsibilities:
CVM's responsibilities during the INAD stage include being available for pre-INAD meetings with sponsors and explaining the requirements for obtaining approval of their product. This involves input from the applicable drug evaluation division, the division of chemistry (regarding manufacturing requirements), the environmental staff, and possibly the division of toxicology (regarding human safety issues).
During the study development phase, CVM is often requested by the sponsor to review their study protocols. CVM strongly encourages this practice to prevent firms from conducting inadequate studies which waste time, money, and animal lives.
Once studies are completed, CVM has the responsibility of reviewing all of the raw data generated from each study and deciding if the data truly demonstrate what they were supposed to. This review of data usually involves the expertise of several people. Safety and efficacy data are primarily reviewed by a veterinary medical reviewer. At the veterinary medical reviewer's discretion, selected data may be reviewed by specialists in other divisions in the form of "consulting reviews." For example, statisticians may be requested to review the statistical analyses of the data or a toxicologist may be asked to review histopathologic data. (CVM mathematicians, toxicologists, immunologists, pharmacologists, etc. may be consulted during the review of study protocols as well.)
Another important responsibility of CVM and FDA is to evaluate the integrity of the raw data. Specifically, FDA determines if the data have been collected in conformance with the Good Laboratory Practices Regulations for safety studies and acceptable standards for the conduct of clinical investigations in animals. This is done by performing an inspection of the study. Each pivotal study in support of drug approval may be inspected. Trained FDA field investigators go to the study site and conduct a routine inspection of the study including the facility, investigator(s) and study records. When possible, the veterinary medical reviewer may also participate in the inspection. Results of the inspection (Establishment Inspection Report) are submitted to the primary reviewer, who reviews the inspection results and draws conclusions about the integrity of the data.
NADA Stage
Sponsor's responsibilities:
When a sponsor has collected data that adequately demonstrate the safety and efficacy of their new animal drug and has the other information needed to support NADA approval, they file a New Animal Drug Application, or NADA. An original NADA consists of the following: Form FDA 356V, identification of the drug, table of contents and summary, labeling, components and composition of the drug, manufacturing methods, facilities and controls, samples (if requested by CVM), analytical methods for residues, evidence to establish safety and effectiveness, environmental assessment, and Freedom of Information Summary.
CVM's responsibilities:
According to the Regulations, if a NADA is determined not to be acceptable for filing, the sponsor must be notified within 30 days of receipt of the application. However, if the application is found to be acceptable for filing, CVM has up to 180 days to review the NADA. For the primary veterinary medical reviewer, usually the safety and efficacy data have already been reviewed under the INAD stage. At the NADA stage, the labeling may be reviewed since all of the data used to write the label have been completed and reviewed. Components which correspond to divisions outside of the primary review branch are reviewed by the respective division, i.e., the environmental assessment is reviewed by the Environmental Sciences Staff. If the application is complete and satisfactory, the NADA is approved and a regulation regarding the approval is published in the Federal Register and subsequently in the Code of Federal Regulations. If the NADA is not satisfactory, either an incomplete letter is issued to the sponsor, or, if the unsatisfactory items are minor, the issues may be resolved over the telephone with the sponsor.
Special Requests for Use of Unapproved Substances
CVM occasionally receives requests from private practitioners, zoo veterinarians, etc. to obtain investigational drugs, unapproved drugs, or chemical substances for use in treating animals in special situations. These requests are resolved on a case-by-case basis. If the situation is urgent in that the patient's condition is life-threatening, then the INAD request is handled with special priority as an Expedited Compassionate Investigational New Animal Drug Exemption. If the situation is not an emergency, the exemption should be requested in writing.
The category of Expedited Compassionate Investigational New Animal Drug (ECINAD) Exemption (with respect to non-food animals) is reserved for treatment of life-threatening conditions in which there is no animal or human drug approved in the U.S. When a request is restricted to a single occurrence for emergency treatment to save an animal's life, the Center may allow shipment under the following specified conditions:
1. The sponsor submits to FDA a Notice of Claimed Investigational Exemption for a New Animal Drug and a copy of the appropriate investigational labeling. The shipper (drug supplier) must keep a record of the shipment and the practitioner a record of receipt and disposition of the drug for two years and make the record available for FDA inspection.
2. For requests involving exotic animals in zoos where a drug may be needed but the situation may not be life-threatening, permission may be considered for multiple shipments, if indicated, under the same controls, i.e., submissions to FDA and retention of records.
3. The sponsor provides additional information.
If the above issues are satisfactorily addressed, an INAD file is established and an Investigational Exemption is granted.
Emergency INAD requests are generally taken by telephone. The CVM employee records the information requested on the ECINAD form and then a decision to grant the exemption or not is made by CVM. If the exemption is granted, the CVM employee notifies the practitioner and gives him/her an INAD number. Two copies of the ECINAD form are then mailed to the practitioner--one to be signed by the practitioner and returned to CVM, and the other for the practitioner to keep for his/her records. The completed and signed ECINAD form serves as the Notice of Claimed Investigational Exemption.
UPDATE ON DRUG APPROVALS IN FY 95
The Center for Veterinary Medicine announced 51 new animal drug-related approvals for Fiscal Year 1995 (FY 95). Twenty-three of these approvals were for generic drugs. In addition, 9 were for new species, 6 new sub-species (class), 4 were for new chemical entities, 3 new strength, 2 DESI-finalization, 2 new tolerances, and one each for a new combination and for a new indication. CVM classifies 49 of the 51 approvals as "significant" new animal drug approvals. The Center defines as "significant" those approvals involving new chemical entities (first time for use in animals), new species, new indications, new combinations, new tolerances, generic drugs, minor species, new production classes, and DESI-finalizations. For FY 94, CVM had 36 "significant" approvals out of 60 new animal drug approvals.
The new chemical entities approved in FY 95 included the ones listed in the table below:
A complete list of all FY 95 animal drug approvals is available from the FDA Veterinarian.
| Drug(Trade Name) | Species | Sponsor | NADA Number |
|
Lufenuron (Program ®) |
Dogs | Ciba-Geigy | 141-035 |
| Melarsomine (Immiticide ®) | Dogs | Rhone Merieux | 141-042 |
| Cyclosporine (Optimmune ®) | Dogs | Schering-Plough | 141-052 |
| Sarafloxacin Hydrochloride (SaraFlox ® WSP) | Chickens (broilers) | Abbott Labs | 141-017 |
FDA approved Monsanto Company's recombinant bovine somatotropin (rbST) product, Posilac ® , in November 1993 after a comprehensive review of the product's safety and efficacy, including human food safety. Posilac ® is the only rbST product approved for increasing milk production in dairy cattle. The product has been commercially available since February 4, 1994.
During the first year of commercial use of Posilac ® , a total of 806 reports of adverse effects were reported to Monsanto and submitted to FDA. The November/December 1995 issue of the FDA Veterinarian, included information on 509 reports of adverse effects reported in the next seven months from February 1 to August 25, 1995.
The following is an update on the adverse experiences to Posilac ® reported to FDA from August 26, 1995 through February 3, 1996. During this period, FDA received 144 adverse experience reports (see table below.) It is important to note that a report of an adverse effect in relation to a drug does not itself establish that the effect was caused by the drug. FDA believes that 83 of the 144 reports were possibly associated with the use of Posilac ®, and that the other 61 reports were not related to treatment with Posilac ® . Also, all of the reported clinical manifestations are known to occur in dairy cattle not supplemented with Posilac ® .
Of the 83 reports possibly related to the use of Posilac ® , 18 included reproductive disorders, 10 involved digestive disorders, 23 included mastitis, 19 included injection site reactions, 12 included swelling of the udder or abnormal milk, 9 included foot or leg problems, and 17 involved increased somatic cell counts. In some cases, a single report contained multiple conditions.
The number and severity of the reported conditions raise no new animal health concerns about the safety of Posilac ® . There is no indication that the drug is any less effective than labeled. In addition, FDA and State regulatory officials have found no indication of a change in the incidence of violative drug residues in milk associated with the commercial use of Posilac ® .
Based on the these reports of adverse reactions to Posilac ®, FDA finds no cause for concern. However, it is important for dairy farmers to continue to report all adverse reactions associated with the use of rbST. They may report such reactions to Monsanto, to FDA through their veterinarian, or directly to FDA's Center for Veterinary Medicine. CVM accepts collect calls during working hours, and an answering machine is available to record after-hours calls. The telephone numbers are (301) 594-1751 for collect calls during working hours, and (301) 594-0797 to leave a message on evenings and weekends.
UPDATE ON EQUINE PROTOZOAL MYELOENCEPHALITIS
by Joseph J. Bertone, D.V.M., MS, Diplomate ACVIM
This article summarizes conclusions drawn from a recent symposium concerning Equine Protozoal Myeloencephalitis sponsored by the Grayson-Jockey Club Research Foundation, held March 5 through 8, 1996, in Lexington, Kentucky. Attendees were invited as experts in this or related areas. The Grayson-Jockey Club Foundation and the American Association of Equine Practitioners invited Dr.JosephBertone to attend this symposium as a regulatory representative, taking into account his clinical expertise.
Equine protozoal myeloencephalitis (EPM) is a progressive debilitating neurologic disease of horses associated with migration of Sarcocystis falcatula (neurona). It can affect any portion of the central nervous system. Clinical signs are related to focal (single site) or multifocal (many sites) neuropathology. Varied clinical signs may be present depending on the neural anatomic location of parasite migration and the ensuing inflammatory process.
Distribution
EPM occurs in much of the Western Hemisphere. Over 3000 horses have been diagnosed with the condition, by immunologic analysis of cerebral spinal fluid samples, since 1992. The number of affected horses is most likely greater. Surveys in Kentucky, Pennsylvania, Ohio, and Oregon identified that 50 to 60 percent of horses are seropositive for this organism (identifies exposure). The incidence of clinical disease involving the spinal cord is far lower. Climatic factors may affect exposure rates. The frequency of seropositive horses appears to be less in areas with greater numbers of freezing days, or with hot, dry climates. EPM is often sporadic (individual cases), but herd outbreaks have been reported in Kentucky, Ohio, Indiana, Michigan, Florida, and Maryland.
Life Cycle
The clinical disease and associated pathology have been recognized for over 20 years. However, the organism was not successfully cultured until recently (J.P.Dubey, et al. 1991). Once cultured, the organism was titled Sarcocystis neurona. Strong evidence suggests that the organism is Sarcocystis falcatula. The definitive host of this organism is the opossum, and various birds (brown headed cowbird, boat tailed grackle, and probably others) act as intermediate hosts. The horse is a dead-end, aberrant host. Infectious forms of the parasite are not passed from horse to horse, or from horse to the definitive or true intermediate hosts. Recent investigation indicates that opossum feces is the major source of infection. Opossums acquire the infection by eating infected birds. Birds and insects may contribute to feed contamination, but the importance of this to equine infection is unclear. Aberrant migration of Sarcocystis falcatula has been described in free-range chickens.
Signalment and Clinical Signs
EPM often progresses to loss of neural and musculoskeletal function and may lead to death. In many cases, the abnormal neurologic deficit is so subtle that abnormal function is attributed to other causes. EPM can affect any breed or sex. To date, the youngest horse identified was 2 months of age, and the oldest was over 30years old. Clinical signs may be triggered or worsened by physiologic stress (e.g., shipping), or the administration of corticosteroids.
Clinical signs associated with neuropathology of any sort relate to the specific site (neural anatomic location) of pathology. Neurologic control of musculoskeletal activity can be divided into 3 general categories that include the upper and lower motor neuron and proprioceptive functions. Lower motor neurons directly stimulate muscle contraction. Upper motor neurons are inhibitory and control the extent of lower motor neuron induced muscle activity. Proprioceptive neurons provide for limb and trunk positional awareness. An example of proprioceptive dysfunction is the inability to touch one's nose when blind-folded (loss of positional awareness) in association with alcohol consumption. Since EPM can affect all 3 of these systems (separately or in combination), the disease may present as any gait or function deficit. Clinical signs of EPM include weakness (lower or upper motor neuron deficit), hypermetria (upper motor neuron deficit), poor limb position awareness (proprioceptive deficit), muscle atrophy (lower motor neuron deficit), and various cranial nerve deficits. In addition, many horses whose presenting chief complaint is poor performance, lameness, weakness, and/or behavioral changes may have this condition. In many cases, horses with EPM are lame secondary to musculoskeletal pathology. This is believed to be secondary to neurologic gait abnormalities that place these animals at higher risk for injury. Therefore, any horse that is demonstrating neurologic and/or musculoskeletal abnormalities of any kind may have EPM.
Abnormal behavior and seizures have been associated with EPM. Severely affected horses may be recumbent and unable to rise. In most cases, affected horses are bright and alert, with a normal appetite. Hematological and biochemical blood values are usually within reference ranges.
Diagnosis
Diagnosis of EPM is based on clinical signs, and cerebrospinal fluid (CSF) positive for antibodies to the organism (western-blot analysis) or organism DNA (polymerase-chain reaction, PCR). The PCR analysis appears to be most useful in very early, or late stages of the disease when the western-blot analysis may be negative. False positive CSF samples most commonly occur with blood admixture during CSF collection. Blood admixture can be confidently excluded by use of protein electrophoresis and protein indices. The commercial laboratory performing the western-blot and PCR analyses will perform the analysis for blood contamination (Equine Biodiagnostics, Lexington, Kentucky). The meeting attendees strongly suggest that to be confident of the results of CSF testing, the analysis for blood contamination must be performed to guarantee that the CSF sample has not been contaminated regardless of the gross appearance or of the cytologic analysis of the CSF sample. False negatives (horses with EPM and a negative test) are extremely rare.
Treatment
Currently, treatment of EPM includes a combination of antimicrobials that inhibit folic acid metabolism. Antimicrobial treatment simply clears the organisms and their associated inflammation. It does not guarantee return to function (see prognosis). Pyrimethamine, administered orally at 1 mg/kg, once per day, acts by inhibiting dihydrofolate reductase. The most common form of this drug used for EPM is a tablet approved for use in people. However, pharmacokinetic data, which is the basis for the dose, was collected by evaluating oral administration of bulk chemical and relating that information to the effects of this drug on other similar pathogens (C.R. Clark, et al. 1992). This drug is combined with sulfamethoxazole (oral, 12.5 to 25 mg/kg, once or twice per day) or sulfadiazine (oral, 20 mg/kg, once per day). The doses of these drugs are based on pharmacokinetic analysis as well. The only veterinary formulations of the two sulfonamides are in combination with trimethoprim. Trimethoprim is not useful for treatment of this condition and may contribute to increased risk of adverse drug reactions. Folic acid metabolism inhibitors should be administered 1 hour prior to feeding hay.
The average duration of treatment is 90 to 120 days, and may exceed 6 months in some instances. The appropriate length of treatment and the methods to determine adequate treatment duration are unknown. Negative western-blot analysis, or PCR on CSF may be useful to determine the time to withdraw treatment. Premature withdrawal of treatment often leads to relapse, which is often associated with a poorer prognosis for improvement or recovery. Sub-optimal dosing or intermittent therapy (for treatment or prophylaxis) has no proven efficacy and may lead to increased resistance of the organisms within the treated individual. If resistant organisms develop, they will most likely reside in that affected horse, since they cannot multiply in aberrant hosts.
Adverse side effects of drug therapy may include anemia, abortion, diarrhea, and leukopenia (low white blood cell counts). In some cases, the initiation of therapy may be associated with worsened signs. This response is believed to be associated inflammation, secondary to death of organisms within the spinal tract. Administration of a nonsteroidal anti-inflammatory drug in the initial stage of treatment has been recommended to alleviate this situation. Folic acid supplementation, administered at 40 mg orally, once a day, may help prevent adverse side effects associated with bone marrow suppression and may also reduce the risk of abortion. This quantity of folic acid supplementation will not inhibit the effect of the absorbed drug. Supra-pharmacologic concentrations of folic acid are required to overcome the effects of drug-inhibited folic acid metabolism. Folic acid should not be administered at the same time as the antimicrobial drugs as it may inhibit antimicrobial drug absorption.
In cases with severe neurologic signs, nonsteroidal anti-inflammatory medications (labeled doses), dimethylsufoxide (intravenous, diluted 5 to 1 in saline solution), and supportive care are often added to the treatment regimen.
Prognosis
Antimicrobial treatment simply clears the organism and its associated inflammation and does not guarantee return to function. The specific site and extent of the lesion, the horse's use, duration of disease, and physical therapeutics are the most important contributors to prognosis once the organism has been cleared. Early detection and treatment increases the chance of success. Response to treatment is highly variable. Many treated horses return to their original level of function; however, many respond incompletely. It is estimated that approximately 10 percent of cases relapse after treatment is discontinued.
CVM Response
CVM is aware of the severity and prevalence of this condition, and intends to act in response to the needs of horse owners and veterinarians. CVM has contacted the American Association of Equine Practitioners (AAEP) and suggested that they submit a request for Investigational New Animal Drug status for the above drug combinations, which are now being compounded. This will allow continued data collection for this drug formulation. In addition, CVM has suggested that the AAEP encourage the pharmaceutical industry to sponsor these drug combinations. Since there is no approved therapy for this severe, debilitative disease, CVM will grant expedited review status to such applications and otherwise work with NADA sponsors to facilitate the data generation and review process. In addition, a great deal of information is available to support efficacy and safety of the therapeutic combination to provide for an expedient development plan. For further information, please contact Dr. Joseph J. Bertone, at 301-594-1692.
UPDATE ON PYTASE AND CHROMIUM FOR USE IN ANIMAL FEED
by Sharon A. Benz, Ph.D., PAS
Recently, CVM reviewed requests from industry for the use of phytase and chromium picolinate in animal feed. Phytase is an enzyme that hydrolyzes phosphorus bound to phytate in plant-derived feedstuffs. Phosphorus is a critical mineral element required in the diet of all livestock species. Since two-thirds of the phosphorus from cereal grains and forages is in the form of phytates, which is unavailable to non-ruminant animals (e.g., swine and poultry), inorganic phosphates are commonly added to diets to satisfy the animals' phosphorus requirement. Recent studies have shown that the addition of the enzyme, phytase, to swine and poultry diets can release the phosphorus bound to phytate and increase the amount of phosphorus available to the animal. The addition of phytase to the diet should allow producers to reduce the amount of inorganic phosphorus added to animal diets and also reduce the amount of phosphorus in the manure and entering the environment.
On November 17, 1995, CVM stated it would not object to BASF marketing a microbial-derived phytase enzyme, which was obtained from bioengineered Aspergillus niger. This product was already marketed in other countries by BASF under the trade name, Natuphos ® . CVM reviewed information to show that Natuphos ® increases the digestibility of phytin-bound phosphorus in swine and poultry diets. Current recommended use levels are 100 g/ton for swine, 60 g/ton for laying hens, and 120 g/ton for other classes of poultry. Based on information to date it is recommended that use of phytase could replace 0.1 - 0.12 percent of phosphorus in the diet.
Chromium is a trace element generally present in diets in very small quantities. It serves as a cofactor for insulin and is involved in carbohydrate and lipid metabolism. Although the animal's requirement for trace elements can often be met from amounts present in the diet, because of wide variations in concentrations of trace elements in feedstuffs, trace elements are often supplemented to ensure an adequate intake. Chromium has been recognized as an essential trace element by humans for many years, but chromium supplementation to animal diets has only recently received attention. Information submitted to CVM by Prince Agri shows that chromium picolinate can serve as a bioavailable source of chromium for swine; and on January 11, 1996, CVM notified Prince Agri Products, Inc., Quincy, IL that they would not object to the marketing of chromium picolinate in swine diets at a level of 200 ppb. The chromium picolinate premix will be marketed under the trade name of Chromax ® and the amount of chromium from chromium picolinate will be guaranteed on the labeling.
In its decision, CVM considered only chromium picolinate. Presently, there is not sufficient information available to demonstrate the safety and utility (1) for supplementation of other sources of chromium in swine diets or (2) for the use of any source of chromium in diets for species other than swine.
Definitions for both microbially-derived phytase and chromium picolinate will be established in the Official Publication of the Association of American Feed Control Officials (AAFCO). Any manufacturer of microbially
by Karen A. Kandra
Objectives of CVM Research Programs
The Center for Veterinary Medicine's Office of Science (OS) initiates research programs, both intramural and extramural, designed to provide a scientific basis for FDA decisionmaking. The objectives of these research activities are to provide the following:
Intramural Research
Intramural research is conducted in response to a variety of needs such as, a) to develop, improve, or validate analytical methods and techniques; b) to develop better research methodology, procedures, or models to support the evaluation of the safety or efficacy of new animal drugs; c) to provide qualitative or quantitative assessments of risks associated with animal drugs, feed additives, or other xenobiotics; or d) to provide information for dissemination to the general public under the Center's education initiatives. In addition, OS provides a source of scientific expertise in specialized disciplines. Personnel engage in cooperative research studies with other research facilities, such as U. S. Department of Agriculture (USDA), FDA's National Center for Toxicological Research (NCTR), and the Animal Drug Research Center (ADRC) in Denver, CO. OS scientists are recognized by their peers, and often are requested to collaborate on research projects with scientists from institutions such as Georgetown University Medical Center, University of Maryland at Baltimore, and Auburn University. OS experts often serve as Project Officers and reviewers for scientific publications, or participate on scientific committees relating to their specific area of expertise.
In FY 95, method trials of determinative procedures for gentamicin, ceftiofur, and thionin in milk were completed, and trials for spectinomycin, tilmicosin, pirlimycin, and phenylbutazone in milk were initiated. OS scientists expanded their efforts in evaluating applications for commercially available milk residue screening tests. The evaluations consist of intensive review and a 100 percent audit of all of the data submitted by the manufacturers and the independent laboratories. Approval of the tests by the AOAC-RI and CVM will gain acceptance of the use of the screening test by the National Conference on Interstate Milk Shipments and State regulatory laboratories. Since more than 4 million tests are used to evaluate the potential presence of beta-lactams in milk, the validity of the screening test results is critical for the milk industry to ensure the safety of the Nation's milk supply.
During FY 95, intensive reviews were completed for screening tests for beta-lactams. Two specific tests for cloxacillin and one multiresidue sulfonamide test were evaluated and accepted, and evaluations of two additional beta-lactam tests were still ongoing at the end of the Fiscal Year. In addition, OS scientists addressed problems that arose with already marketed tests, due to complaints received. Intensive evaluations of screening tests for cow-side testing were continued under an interagency agreement with USDA's Agricultural Research Service.
The ability to quantify sulfonamide residues in milk was developed at OS several years ago. In FY 95, a multiresidue confirmatory procedure capable of confirming the identity of all nine sulfonamides quantified by the official determinative procedure was developed at OS. Included in the nine sulfonamides are the four major ones detected by screening tests accepted by FDA for use on tanker truck milk. This provides the Agency with the most specific tool for identification, mass spectrometry, in a system that most regulatory laboratories already possess, GC/MS. This tool uses a well-defined extraction system that minimizes hazardous waste.
Extramural Research
Programs in extramural research are initiated to extend the intramural capability or develop new areas of research for which intramural resources are not available. This may be accomplished via contracts, grants, conference grants, cooperative agreements, and interagency agreements with universities, other government agencies, or private laboratories. In FY 95, the extramural research program consisted of 18 research-related projects, with a total budget of $1,410,412.
The highest priority program areas in FY 95 were analytical methods development and drug metabolism/residue studies in aquatic animal species. Another high priority area involved the development of models for evaluating the effects of antimicrobials on human intestinal microflora. The primary objectives of the analytical methods program are: a) to develop multiresidue procedures that can reliably quantitate and confirm the identity of classes of drug residues, b) to develop methods for residues of unapproved drugs that may be used illegally in food-producing animals, and c) to develop chemical-based methods of analysis that can be used to confirm analytical results obtained with currently available antimicrobial screening assays for several approved classes of antibiotics used in food-producing animals.
For FY 95, there were 6 projects in the analytical methods development program. There were also 4 projects in the aquatic animal species research program.
Methods Development Program
This research program is a coordinated effort involving intramural resources of FDA, USDA, and State regulatory agencies. The Methods Development Program conducts research on the development of regulatory methods of analysis for residues in animal-derived human food. Laboratories utilized are from Universities, FDA District offices, USDA's Agricultural Research Service and Food Safety Inspection Service, animal drug sponsors, and the Department of Health and Welfare in Canada.
For FY 95, two mass spectrometric confirmatory procedures for tetracyclines and sulfonamides were developed. In addition, method trials of determinative procedures for gentamicin, ceftiofur, and thionin, were completed, and trials for spectinomycin, tilmicosin, pirlimycin, and phenylbutazone were initiated.
These are just a few of the many scientific accomplishments by OS in FY 95. OS is looking forward to moving into its new state-of-the-art large animal research facility early in FY 97. Information about this new facility will be included in a future issue of the FDA Veterinarian.
This issue of the FDA Veterinarian contains the fourth in a series of questions and answers that are frequently asked about CVM's Veterinary Adverse Drug Experience (ADE) program.
Q. What happens after I report an ADE?
A. Each ADE report is evaluated by a veterinarian and entered in a computer database. The reviewer assigns codes to items that describe the drug(s) and animal(s) involved. These items become separate fields of information. The reviewer also enters a brief clinical description of the ADE, and makes an assessment of whether the event is judged to be drug related using an algorithm scoring system.
CVM publishes an annual summary of ADE reports. The summary provides the number of reports and the clinical signs associated with each drug in the database. The information is limited to those reports that were assessed as at least "possibly drug related". The publication is available from the FDA Center for Veterinary Medicine. CVM also anticipates providing the ADE annual summary on a World Wide Web Internet server.
Other information and reports from the database can be requested on an individual basis by filing a written Freedom of Information (FOI) request. For more information about filing a request, you can contact the CVM Communications and Education Branch at (301) 594-1755.
Q. What actions result from reports of ADEs?
A. A group of similar reports submitted in a short period of time may alert CVM and the drug company to a problem with a particular lot of drug. This may result in a product recall of the affected lot.
Another outcome would be for a label change to include new information gleaned from reported ADEs. The changes may include new warnings, contraindications or human safety information. In very rare instances, a drug may be removed from the market due to problems discovered by ADE reporting.
At times, CVM may require the involved drug company to issue a "Dear Doctor" letter to veterinarians informing them of the type of actions that had resulted from ADE reports.
HOW TO COMMENT ON PROPOSED REGULATIONS AND SUBMIT PETITIONS
The following information is provided for those readers who want to know how to comment on FDA regulations or file petitions to influence the Agency.
As a regulatory Agency, FDA publishes rules that establish or modify the way that foods, human and veterinary drugs, medical devices and other products are regulated. By law, anyone can participate in the rule-making process by commenting in writing on rules that FDA proposes. FDA allows for public input and carefully considers these comments when it draws up a final rule. One way that FDA gathers public comments is through proposed rules.
When FDA plans to issue a new regulation or revise an existing one, it places an announcement in the Federal Register on the day the public comment period begins. The Federal Register, which is published every weekday, is available at many public libraries and colleges. It is also available on the Internet through the World Wide Web. Two Web addresses that include information from the Federal Register are:
http://www.access.gpo.gov/su_docs/
http:/thorplus.lib.purdue.edu/gpo/
Information on FDA issues that are open for public comment are also available through the Agency's News Page at the following World Wide Web site:
http://www.fda.gov/opacom/backgrounders/voice.html
In the Federal Register, the "notice of proposed rulemaking" describes the planned regulation and provides background on the issue. It also gives the address for submitting written comments and the name of the person to contact for more information.
Also noted is the "comment period," which specifies how long the Agency will accept public comments. Usually, the file (or docket) stays open for comments at least 60 days, although some comment periods have been as short as 10 days or as long as nine months. Weekends and holidays are included in the comment period.
There is no special form to fill out for comments, nor do submitters have to follow a certain style. But, FDA can process comments more effectively if they are presented -- either written legibly or typed -- on 8 1/2-inch by 11-inch paper. The Agency also has the following suggestions for making sure comments have the greatest impact:
Clearly indicate if you are for or against the proposed rule or some part of it and why. FDA regulatory decisions are based largely on law and science, and Agency reviewers look for reasoning, logic, and good science in comments they evaluate.
Refer to the docket number listed in the Federal Register notice.
Include a copy of articles or other references that support your comments. Only relevant material should be submitted.
If an article or reference is in a foreign language, it must be accompanied by an English translation verified to be accurate. Translations should be accompanied by a copy of the original publication.
To protect privacy when submitting medical information, delete name or other information that would identify patients.
Threats, obscenities, profanities, or material defamatory to FDA or the Federal government may be rejected or referred to law enforcement officials.
Comments must be postmarked or delivered in person by the last day of the comment period.
When FDA receives a comment, it is logged in, numbered, and placed in a file for that docket. It then becomes a public record and is available for anyone to examine in the FDA's reading room (Room 1-23, 12420 Parklawn Drive, Rockville, MD). Under the Freedom of Information Act (FOIA), visitors to the reading room can receive free copies of comments up to 50 pages if their request is for noncommercial use. After that, each page costs 10 cents. People also can send FDA an FOIA request and have copies of comments mailed to them.
Another way to influence the way FDA does business is to petition the Agency to issue, change or cancel a regulation, or to take other action. The Agency receives about 200 petitions yearly.
Petitions require careful preparation by the submitter. FDA spends considerable time and staff resources processing petitions. Individuals sometimes submit petitions, but most come from regulated industry or consumer groups. For example, a drug company might request a change in labeling for one of its products; a food company might ask that its product be exempted from some provision of a regulation; or a consumer group might petition FDA to tighten regulation of a certain product.
Petitions submitted to FDA must contain:
Action requested -- What rule, order, or other administrative action does the petitioner want FDA to issue, amend or revoke?
Statement of grounds -- The factual and legal grounds for the petition, including all supporting material, as well as information known to the petitioner that may be unfavorable to the petitioner's position.
Certification -- A statement that to the best of the petitioner's knowledge, the petition includes all information relevant to the petition, favorable or not. The petition must be signed and include the petitioner's address and phone number.
In addition, some petitions may require information on:
Environmental impact -- This information is generally required if the petition requests approval of food or color additives, drugs, biological products, animal drugs, or certain medical devices, or for a food to be categorized as GRAS (generally recognized as safe). Procedures for preparing environmental impact statements can be found in Title 21 of the Code of Federal Regulations, Sections 25.24 and 25.31. If an environmental impact statement is not required, petitions should include a statement to that effect.
Economic impact -- This information is required only if FDA requests it after review of the petition.
Petitions should be mailed or delivered to: Dockets Management Branch, Food and Drug Administration, Room 1-23, 12420 Parklawn Drive, Rockville, MD 20857.
Ultimately, FDA management decides whether to grant a petition. But first, Agency staffers evaluate it, a process that may take several weeks to more than a year, depending on the issue's complexity. After FDA grants or denies the petition, the Agency will notify the petitioner directly. If not satisfied, the petitioner can take the matter to court.
For more information on submitting petitions, consult Title 21 of the Code of Federal Regulations, Sections 10.30, 10.33, and 10.35.
Besides accepting public comments and petitions, FDA also schedules public meetings and hearings to discuss and explain its proposals. These usually are held with industry representatives or consumer groups, but anyone interested may attend and, with advance notice, may comment on a proposal. Meetings often are held in the Washington, DC area, but sometimes are set in other areas across the country. Meetings for the public to present views are announced in the Federal Register.
Questions about the comment, petition or hearing process should go to the FDA Dockets Management Branch, (301) 443-7542. Hours are 9 a.m. to 4 p.m., Eastern time, Monday through Friday.
Filing a Freedom of Information Request
Copies of comments on any given issue may be obtained through a Freedom of Information Act (FOIA) request to FDA. The request is best made by letter, specifying exactly what material is sought. Requesters usually should be specific about what comments they want, instead of asking for "all comments" received on a certain proposal, which in some cases can run thousands of pages. (Indexes of comments are available by FOIA request as well.)
FOIA requests should include an address and phone number and be sent to: Food and Drug Administration, Freedom of Information Staff (HFI-35), 5600 Fishers Lane, Rockville, MD 20857. Requests also can be faxed to (301) 443-1726. For more information, call (301) 443-6310.
FDA APPROVES FOOD ADDITIVE PETITION FOR FORMALDEHYDE
In the April 9, 1996 Federal Register, FDA announced that the Agency is amending the food additive regulations to provide for the safe use of formaldehyde (37 percent aqueous solution), at the rate of 5.4 pounds per ton (2.5 kilograms per ton) as an antimicrobial food additive for maintaining complete poultry feeds salmonella negative for up to 14 days. This action is in response to a food additive petition filed by Anitox Corp., Buford, Georgia.
Salmonella is known to cause animal disease. The effect of subclinical cases of salmonella on animal production is difficult to quantitate. However, there are circumstantial data suggesting a potential link between the organisms in feed and organisms causing human and animal salmonellosis. For this reason in 1990, FDA announced a salmonella negative goal for animal feed and feed ingredients.
The availability of compounds that can control re-contamination of a feed with salmonella is important to achieving the goal of salmonella negative for animal feed and feed ingredients. In the September 28, 1995 Federal Register, FDA defined salmonella negative as 10 samples, from a production lot, testing negative for salmonella using the culture procedure described in the 7th Edition of FDA's Bacteriological Analytical Manual.
FDA has evaluated the data in the food additive petition for formaldehyde and other relevant material. The Agency concluded that formaldehyde (37 percent aqueous solution) is safe when used at the rate of 5.4 pounds (2.5 kilograms) per ton of poultry feed, and that the regulations should be amended in Title 21, Part 573.460.
Additional information on this food additive approval is available in the Federal Register announcement or by contacting Dr. Daniel G. McChesney, Center for Veterinary Medicine (HFV-222), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-594-1728. Any person who will be adversely affected by this regulation may file written objections on or before May 9, 1996, with the Dockets Management Branch (HFA-305), Food and Drug Administration, Room 1-23, 12420 Parklawn Drive, Rockville, MD 20857.
NUFLOR ® (Florfenicol). Schering-Plough Animal Health filed an application requesting approval for export of NUFLOR ® to Canada. The product is used for treatment of bovine respiratory disease (shipping fever) in cattle. Federal Register 3/12/96.
ANIPRYL ® (1-selgiline hydrochloride, 1-deprenyl hydrochloride). Deprenyl Animal Health, Inc., has filed an application requesting approval for export of ANIPRYL ® to Canada. The product is used for treatment of uncomplicated canine pituitary dependent hyperadrenocorticism. Federal Register 1/26/96.
DENAGARD ® (TIAMULIN). Fermenta Animal Health Co. filed an application requesting approval for the export of DENAGARD ® to Canada. The product is used for treatment of dysentery in swine. Federal Register 1/19/96.
RALGRO ® (Zeranol). Mallinckrodt Veterinary Inc. filed an application requesting approval for the export of RALGRO ® to Canada. The product is used for increased rate of weight gain and improved feed conversion in weaned beef calves, growing beef cattle, feedlot steers, and feedlot heifers. In addition, it is used for increased rate of weight gain in suckling beef calves. Federal Register 1/19/96.
FOOD ADDITIVE REGULATIONS AMENDED
In the March 21, 1996 Federal Register, the FDA announced that the Agency is amending the food additive regulations to provide for the use of poly (2-vinylpyridine-co-styrene) as a coating agent in the preparation of rumen-stable, abomasum-dispersible nutrient products for dairy cattle and dairy replacement heifers. The additive is currently used as nutrient protectant in feed for beef cattle. This action is in response to a food additive petition filed by Rhone-Poulenc Animal Nutrition.
NICARBAZIN, Merck Research Laboratories, Division of Merck and Co. (NADA 98-378). FDA is amending the animal drug regulations regarding the use of nicarbazin in Type C broiler feeds. Because of incorrect amendatory instructions in a final rule that appeared in the Federal Register of June 5, 1995, certain uses of nicarbazin combination Type C broiler feeds were removed from the regulations. This amendment corrects those errors. Federal Register, March 29, 1996.
Coopers Animal Health, Inc. has transferred ownership of 28 approved new animal drug applications to Mallinckrodt Veterinary, Inc. Federal Register, March 6, 1996.
Syntex Animal Health, Division of Syntex Agri-business, Inc. has transferred 35 approved new animal drug applications to Fort Dodge Laboratories, Division of American Home Products. Federal Register, February 13, 1996.
The following firms/individuals received warning letters for offering animals for slaughter that contained illegal drug residues:
These violations involved illegal residues of penicillin in cows, oxytetracycline in cows, neomycin and gentamicin in a calf, DDT in a beef cow, gentamicin in a cow, chlortetracycline in a veal calf, and tetracycline in a veal calf.
The following firms/individuals received warning letters for offering animals for slaughter that contained illegal drug residues, and have a history of offering animals for sale for human food use which have been adulterated with drug residues :
These violations involved illegal residues of sulfamethoxazole, tetracycline, and gentamicin in calves; gentamicin in a dairy cow; penicillin in a dairy cow; gentamicin, tetracycline, and streptomycin in a bull calf; gentamicin in bull calves; and gentamicin in a dairy calf.
The following firms received warning letters for deviations from the Good Manufacturing Practice (GMP) regulations:
Company
Syntex Animal Health Division of Syntex Agri-business, Inc. (NADA 141-043)
Generic and (Brand) Names
Trenbolone Acetate and Estradiol Benzoate
Indications
Steers fed in confinement for slaughter. For improved feed efficiency.
Routes/Remarks
IMPLANT: Provides for use of an ear implant consisting of 8 pellets. Each pellet contains 25 milligrams (mg) of trenbolone acetate and 3.5 mg of estradiol benzoate. Federal Register 4/2/96.
Company
Planalquimica Industrial Ltda. (ANADA 200-170)
Generic and (Brand) Names
Nicarbazin with Roxarsone and Lincomycin for Type C medicated feeds.
Indications
Broiler Chickens. As an aid in preventing outbreaks of cecal and intestinal coccidiosis and for increased rate of weight gain.
Routes/Remarks
MEDICATED FEED: ANADA 200-170 is a generic copy of Merck Research Laboratories' NADA 107-997. Federal Register 4/2/96.
Company
Planalquimica Industrial Ltda. (ANADA 200-171)
Generic and (Brand) Names
Nicarbazin and Lincomycin for Type C medicated feeds.
Indications
Broiler Chickens. As an aid in preventing outbreaks of cecal and intestinal coccidiosis and for increased rate of weight gain.
Routes/Remarks
MEDICATED FEED: ANADA 200-171 is a generic copy of Merck Research Laboratories' NADA 108-116. Federal Register 4/2/96.
Company
Planalquimica Industrial Ltda. (ANADA 200-172)
Generic and (Brand) Names
Nicarbazin and Roxarsone for Type C medicated feeds.
Indications
Broiler Chickens. As an aid in preventing outbreaks of cecal and intestinal coccidiosis and for increased rate of weight gain.
Routes/Remarks
MEDICATED FEED: ANADA 200-172 is a generic copy of Merck Research Laboratories' NADA 108-115. Federal Register 4/2/96.
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