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Approval of Drugs
for Public Fish Production by INTRODUCTION In 1994, the National Biological Service (NBS), U.S. Fish and Wildlife Service (FWS) and International Association of Fish and Wildlife Agencies (IAFWA), on behalf of the 50 states, developed an initiative to work cooperatively to fund and carry out the research required to gain approval of high priority drugs (therapeutants and anesthetics) and to demonstrate the concept of crop grouping. This unprecedented partnership is one of the largest and most important agreements ever forged on behalf of fish management, production, and disease control. The IAFWA Project began July 1, 1994 (Year 1) and presently is envisioned to extend until June 30, 1999 (Year 5). At its inception, 39 states agreed to contribute $20,000 each to the initiative for five years for a total of $ 3.9 million while NBS was to contribute $867,000 per year for a total of $4.3 million. In Year No. 2, 36 states contributed $20,000 annually. Additionally, the NBS contribution was reduced from $867,000 to $767,000. In Year No. 3 (July 1, 1996 to June 30, 1997), it is anticipated that 37 states each will contribute $20,000 to this effort. After an assessment of the remaining data requirements and the funding available through June 30, 1999, the IAFWA Project, as originally envisioned, has a shortfall of $1.4 million and two years of time. The specific objectives of the IAFWA Project are to develop data to (1) extend and expand existing New Animal Drug Applications (NADAs) for two high priority drugs, (2) gain NADA approvals for five therapeutants and one anesthetic/sedative to support public fish production in the United States, and (3) develop data to support the crop grouping concept. The IAFWA Project includes efforts to: (1) extend the NADA approval of formalin to additional fish species and their eggs;(2) expand the existing NADA approval for oxytetracycline to include other diseases and extend the label to include other species, (3) gain NADA approvals for all important public aquaculture species for use of benzocaine, chloramine-T, copper sulfate, hydrogen peroxide, potassium permanganate, and sarafloxacin hydrochloride (sarafloxacin); and (4) develop research data to support the acceptance of a crop grouping concept by the Center for Veterinary Medicine (CVM). Based on the data generated, CVM will assess whether a few selected fish species can be used as surrogates for all or most of the cultured fishes in the United States. The chronological midpoint of the IAFWA Project presents a good opportunity to reflect on the progress that has resulted over the last two and one-half years. Substantial progress toward approvals have been made in virtually every study area. Major successes in gaining approvals, such as formalin for the treatment of parasites on fish and for the treatment of saprolegniasis on eggs of all freshwater fish species, are perhaps the most representative examples of tangible achievements. However, additional successes have been realized by having certain critical studies accepted by CVM that will contribute to the approvals for copper sulfate, chloramine-T, oxytetracycline, hydrogen peroxide, and benzocaine. In a larger sense, however, the more important, but intangible successes, for the IAFWA Project continue to be made on a daily basis. These successes are reflected in the cooperative and partnering interactions of the participants associated with the IAFWA Project. Participant interaction has taken on a variety of forms in the last two and one-half years. Most of the partnering and cooperation revolve around the development of efficacy assessments of therapeutants being evaluated within the project. Alliances between Federal, State and private aquaculture concerns have been forged on five of the eight therapeutants under investigation by the IAFWA Project. The U.S. Fish and Wildlife Service (FWS) established a national Investigational New Animal Drug (INAD) office in Bozeman, MT in 1994 that is coordinating all FWS-INAD related activities (e.g., protocol development, data collection and analysis). These activities involve 12 individual INAD exemptions, including 9 INADs for IAFWA Project therapeutants (one each for chloramine-T, copper sulfate, potassium permanganate, two for formalin, and 3 for oxytetracycline), 90 facilities, and approximately 300 INAD units. In November 1993, the Western Regional INAD Project was established as a government-private sector partnership to sponsor and manage clinical field trials for three therapeutants (oxytetracycline, chloramine-T, and formalin) at 218 facilities operated by six state conservation agencies, three tribal groups, and 24 private fish producers in Alaska, California, Idaho, Montana, Oregon and Washington. Twenty states have 61 individual INAD exemptions for eight therapeutants, one anesthetic, and three spawning aids. Many states have offered to consolidate their INADs with other states, and in some cases, with the private sector. More importantly, the groups are communicating, solving common problems, and sharing work-loads while working toward a common goal. Hopefully, this spirit of cooperation and involvement will continue after the initial project is completed. The balance of this document reports on the progress and current status of each study element, identifies expected products for the project, and anticipates project shortfalls. As you read about the progress that has been made, reflect back on the spirit of cooperation that has made much of this progress possible. It is likely you will come to appreciate just how fully this project has benefitted public aquaculture in the last two and one-half years. Acronyms used in this report:
HIGHLIGHTS: (July 1, 1996 to December 31, 1996) Copper Sulfate (microbicide): A revised environmental assessment of copper sulfate was completed and submitted to CVM on December 20, 1996. Based on a previous review of the data that indicated the lack of hazard to the environment, CVM determined on July 11, 1996 that there are no environment safety concerns over the use of copper sulfate as a therapeutant, making approval of a New Animal Drug Application (NADA) relatively easy to obtain. A final evaluation and determination of environmental concerns by CVM is forthcoming. Formalin (microbicide): CVM placed a notice in the October 18, 1996 issue of the Federal Register inviting NADA sponsors of formalin to amend their labels to include the extended claims for both the fungicide uses (based on UMSC studies) and parasiticide uses (based on studies at Auburn University, Auburn, AL). When one formalin sponsor amends its NADA and label, formalin use will be extended to include treatments for the control and prevention of saprolegniasis (fungal infections) on the eggs of Cypriniformes, Perciformes, Siluriformes (1,000 to 2,000 ppm) and Ascipenseriformes (concentrations < 1,500 ppm) for 15 minutes daily. Hydrogen Peroxide (microbicide): Studies to develop methods to uniformly and systematically induce saprolegniasis on channel catfish are complete and those for rainbow trout are nearly completed. Infected fish will be used in pivotal efficacy studies of hydrogen peroxide to control or prevent mortalities resulting from saprolegniasis. A pilot study to test the efficacy of hydrogen peroxide for treating saprolegniasis in channel catfish was conducted. Negotiations and Contract Coordination: A meeting was held with CVM on October 30, 1996 to clarify the design of protocols to conduct pivotal efficacy studies on chloramine-T. A chloramine-T pivotal study meeting was held in Kansas City, MO on November 7-8, 1996 with chloramine-T INAD coordinators to coordinate efforts on pivotal efficacy studies, finalize label claims, design protocols for pivotal clinical field trials, and identify pivotal study sites for chloramine-T. Commitments were obtained from several INAD coordinators to conduct these studies within the next year. Oxytetracycline (microbiocide): The tolerance for the amount of residues of tetracyclines (including oxytetracycline) in meats and seafoods was increased from 0.1 ppm to 2.0 ppm in edible muscle tissue by CVM on December 23, 1996 (21CFR Part 556). This new ruling should also reduce the withdrawal times for approved uses of oxytetracycline. Oxytetracycline (microbiocide): Data generated at the UMSC on the analytical method (HPLC) for oxytetracycline in the edible tissue of fish were reviewed by CVM and recommended as acceptable for use in a bridging study with the official microbial inhibition assay. The CVM has initiated steps to have the Denver FDA laboratory conduct the microbial inhibition assay portion of the bridging study. UMSC staff will coordinate the study and conduct the analytical phase. NOTE: The Fish Farming Experimental Laboratory in Stuttgart, AR, recently transferred from the U.S. Department of the Interior to the Agricultural Research Service, U.S. Department of Agriculture, has been renamed the Stuttgart National Aquaculture Research Center (SNARC). The UMSC was transferred to the Biological Resources Division, U.S. Geological Survey, U.S. Department of the Interior on October 1, 1996. SUMMARY OF PROGRESS BY RESEARCH STUDY PLAN A summary follows on the progress made during the period from July 1, 1996 to December 31, 1996 for each of the ten research study plans in the IAFWA Project. STUDY NO. 1: EXTENSION OF FORMALIN LABEL FOR USE AS A FUNGICIDE ON FISH AND THEIR EGGS PRODUCED AT PUBLIC AQUACULTURE FACILITIES. Objectives: To develop suitable efficacy and target animal safety data to extend the current New Animal Drug Application (NADA) for formalin to include its use to control fungal infections on eggs and adults of publicly cultured freshwater fish. Expected Products: Approval of an amended NADA for formalin to control and prevent saprolegniasis (fungal infections) on all fish eggs and control external parasitic infestations on all fish by the end of Year No. 3. Approval of an amended NADA for formalin to control and prevent saprolegniasis on all fish by the end of Year No. 5. Job No. 1 : Coordination of formalin compassionate Investigational New Animal Drug (INAD) exemptions and NADA submissions. Progress: Upper Mississippi Science Center (UMSC) staff continued to monitor the progress of six formalin compassionate INADs held by the states of Illinios, Pennsylvania, Texas, the Western Regional INAD Project, and the National Research Support Project 7 (NRSP-7). INAD coordinators have gathered efficacy data, discussed results with UMSC staff, and submitted annual reports to the Center for Veterinary Medicine (CVM). The study protocols for all six formalin INADs were revised and approved by CVM in 1996 for five additional years. Current Status: Six formalin INADs were revised in 1996 and approved for five additional years. All INADs for prevention of saprolegniasis on fish eggs will terminate when the amended NADA for use of formalin to prevent saprolegniasis on all fish eggs becomes effective in 1997. The INADs for use of formalin to control saprolegniasis on fish will continue until efficacy data are accepted by CVM. Job No. 2: Conduct controlled laboratory studies on a variety of fish species to evaluate the efficacy of formalin as a fungicide on cultured freshwater fish and their eggs. Progress: Studies to develop methods to uniformly and systematically induce saprolegniasis in channel catfish are complete and those for rainbow trout are nearly completed. Pivotal efficacy study protocols for treating saprolegniasis in fish are being developed for channel catfish and rainbow trout. Current Status: The data on fish eggs are considered complete and no further studies are planned at this time. The protocols being developed to study the efficacy of hydrogen peroxide for treating saprolegniasis on channel catfish and rainbow trout will also be used to study the efficacy of formalin for treating saprolegniasis in channel catfish and rainbow trout when work with hydrogen peroxide is complete (see Study No. 8). Job No. 3: Conduct target animal safety studies on fish and fish eggs with formalin in support of its extended use as an antifungal agent in public aquaculture. Progress: CVM accepted the data and conclusions of a target animal safety study on the safety of formalin to warm- and coolwater fish eggs that was submitted along with a proposed formalin label on December 15, 1995. These data will allow for the eminent extension of the current formalin label, under an amended NADA, to control and prevent saprolegniasis in the eggs of warmwater and other coolwater species of the orders Acipenseriformes (<1,500 ppm), Cypriniformes, Perciformes, and Siluriformes (1,000 to 2,000 ppm). Current Status: All target animal safety data on formalin are considered complete and no further studies are planned at this time. Data to support the extension of the formalin NADA to control external protozoa and monogenetic trematodes on all finfish, and saprolegniaisis on the eggs of all finfish were placed in Public Master File (PMF) 5228 and announced as accepted by CVM in the Federal Register (volume 61, number 203, pages 54445-54446). Sponsors need to submit amended or new NADAs to complete the approval process. STUDY NO. 2: EXPANSION OF OXYTETRACYCLINE FEED ADDITIVE FOR CONTROL OF BACTERIAL DISEASES AND OTOLITH MARKING ON FISH. Objectives: To extend the feed additive label for treatment of certain bacterial diseases on cool-and warmwater fish species of importance to public fish production and to cover marking of fish species not covered by the current label. To expand the feed additive label for control of flexibacteriosis on cold-, cool-, and warmwater fishes. Expected Products: Approval of an amended NADA for oxytetracycline as a marking agent on all fish in Year No. 3; approval of an amended NADA for oxytetracycline to control internal flexibacteriosis for all salmonids below and above 9°C by 2000; approval of an NADA for oxytetracycline to control internal flexibacteriosis in one representative cool-and one representative warmwater species by 2000. Job No. 1: Develop efficacy data or determine if current data are adequate on oxytetracycline to expand the label. Progress: UMSC personnel have kept abreast of the results of INADs for oxytetracycline from FWS and the Western Regional INAD projects. To date, the majority of treatments have been for flexibacteriosis: coldwater disease in coho salmon and columnaris in other salmonids. Treatments for columnaris have been at the upper end of the labeled dosage (3.75 g/100 lbs fish for 10 days) and treatments for coldwater disease have mostly been at dosages higher (7 to 12 g/100 lbs fish for 14 days) than allowed on the current label. The majority of treatments were defined as efficacious by a reduction in mortalities associated with flexibacteriosis. In the coming year, the Western Regional INAD Project has requested (through CVM) that participants under their INAD compare the 10 g/14 day and 3.75 g/10 day use patterns for efficacy in side-by-side testing. These studies will be designed to determine if the higher dosage is more efficacious and will be important in determining if other data, such as residue depletion, will be required for dosages greater than the current label claims. Jim Warren, Coordinator of the Western Regional INAD Project, met with CVM in September 1996 and discussed several items that will be important in conducting efficacy field trials for oxytetracycline. CVM suggested that data collected to date be analyzed to establish "historical controls" (i.e., multiple results of a single disease on a single fish species and hatchery). With the "historical control" information, treatments could be applied where approximately one-third would be placebos. Five requirements would have to be met for these studies to be initiated: (1) full cooperation and support of the participants, (2) standardized entrance requirements, (3) standardized success criteria for fish receiving medication in reference to those receiving the placebo, (4) procedures to determine when a placebo trial should be ended to prevent serious production losses, and (5) cooperation and support of the feed manufacturer before the start of the project. Review of data requirements to conduct pivotal efficacy studies identified the need for an analytical method acceptable to CVM for quantifying oxytetracycline in feed. A protocol was developed by UMSC scientists to address this issue and the study under that protocol is near completion. Three types of feed were tested including feed types that covered the extremes in fat and protein content. Researchers at UMSC completed studies on the accuracy and precision for recovery of oxytetracycline spiked onto three types of unmedicated fish feeds. The analytical method was also tested on medicated feeds from manufacturers. Preliminary findings suggest that some feeds can have considerably different oxytetracycline content than listed on the label. Current status: When studies on the analytical method for quantifying oxytetracycline in medicated feed and the storage stability of the samples are completed, results will be forwarded to CVM for concurrence that the method is acceptable. UMSC will use this method to quantify oxytetracycline in feed to support pivotal efficacy studies at hatcheries that agree to cooperate and coordinate their activities with the UMSC. There is a urgent need for all holders of INADs for oxytetracycline medicated feed and UMSC to meet soon to decide on new label claims, develop protocols for pivotal efficacy studies, identify pivotal study sites, coordinate activities, and to support pivotal efficacy studies. Job No. 2 (NEW TITLE): Develop residue chemistry data on oxytetracycline in cold-, cool-, and warmwater fish. Progress: Work is complete to determine the accuracy and precision of an analytical method for quantifying oxytetracycline in spiked edible tissue of rainbow trout, Atlantic salmon, walleye, lake sturgeon, and striped bass using high performance liquid chromatography (HPLC). A preliminary report of the method was forwarded to CVM for evaluation on June 17, 1996. Additional data including the complete chromatographic data for rainbow trout was also sent in response to questions by the reviewing CVM chemist on July 12, October 3, November 13, November 15, and December 5, 1996. The CVM chemist reviewing the method forwarded his recommendation to CVM on November 25, 1996 that the method was acceptable for use in a bridging study between the HPLC method and the official microbial inhibition assay method. Current status: A protocol will be developed to conduct a bridging study between the official microbial inhibition assay and the HPLC method developed at the UMSC. The CVM has initiated steps for the Denver FDA lab to conduct the microbial inhibition assay portion of the bridging study. The UMSC will conduct the HPLC portion of the bridging study and use rainbow trout edible tissue since this species is most often tested in the oxytetracycline INADs and is considered a standard salmonid species for laboratory testing. The increase in the tolerance of the residue of oxytetracycline in edible fillet tissue of fish from 0.1 ppm to 2.0 ppm should also result in reduced withdrawal times. Residue depletion studies will begin after an acceptable bridging study of the HPLC method with the official microbial inhibition assay method is completed. Job No. 3: Develop target animal safety data on oxytetracycline in cool-and warmwater fish. Progress: No activity July 1, 1996 to December 31, 1996. Current Status: The requirements for target animal safety are unclear at this time. Some studies have involved doses for marking that are higher than those allowed by the label (11.35 g/ 100 lbs for 4 days). If the higher dosages are found to be more efficacious in pivotal efficacy studies, additional data may be required. On the other hand, if the current marking label is extended by CVM to all freshwater fish, there may be no need to perform target animal safety studies for oxytetracycline. STUDY NO. 3: APPROVAL OF COPPER SULFATE TO CONTROL EXTERNAL PROTOZOAN AND METAZOAN PARASITES AND BACTERIAL AND FUNGAL DISEASES OF CULTURED FOOD FISH. Objectives: To gain approval of copper sulfate as a therapeutant to control external protozoan and metazoan parasites, bacterial, and fungal diseases of cultured food fish. Expected Products: Approval of an NADA for copper sulfate as a microbicide for all fish by Year No. 3. Job No. 1: Develop research protocols for determining distribution of residual copper in organs and tissues of fish that have been exposed to copper sulfate. Progress: A protocol on the accumulation of copper residue in edible muscle of channel catfish following exposure to waterborne copper sulfate was prepared by personnel at the Stuttgart National Aquaculture Research Center (SNARC) and approved by the National Center for Toxicological Research (NCTR) and CVM on September 30, 1994. Current Status: Job No. 1 completed. Job No. 2: Conduct studies of residues of copper in organs and tissues of cultured channel catfish that have been exposed to copper sulfate at therapeutic levels. Progress: A study report on the accumulation of copper residues in edible tissue of channel catfish following exposure to waterborne copper sulfate was submitted to CVM and NCTR on April 4, 1996. Current Status: Job No. 2 is considered complete. Based on the above report and similar research on tilapia by Tom Bell, CVM aquaculture specialist, CVM determined on July 11, 1996 that there are no human food safety concerns for use of copper sulfate as a therapeutant; thus, making an NADA approval relatively easy to obtain. Job No. 3: Prepare an environmental assessment (EA) of the fate and effects of release of treatment water containing copper sulfate. Progress: A revised EA on the effect of copper sulfate use in aquaculture was completed and submitted to CVM on December 20, 1996. Current Status: Based on preliminary analysis of the original EA, CVM determined that there are no environmental concerns for the use of copper sulfate as a therapeutant in aquaculture; thus, making an NADA approval relatively easy to obtain. Pending a final review and a positive evaluation of the EA by CVM, Job No. 3 is considered complete. Job No. 4: Conduct studies of residues of copper in organs and tissues of cultured food fish other than channel catfish that have been exposed to copper sulfate at therapeutic levels. Progress: No activity July 1, 1996 to December 31, 1996. Current Status: Based on discussions with CVM, it is unlikely that residue data will be needed on any additional fish species. STUDY NUMBER 4: APPROVAL OF CHLORAMINE-T TO CONTROL BACTERIAL GILL DISEASE ON SALMONIDS AND FLEXIBACTERIOSIS ON COLD-, COOL-, AND WARMWATER FISH SPECIES Objectives: To develop data on mutagenicity, environmental fate, residue chemistry, efficacy, and target animal safety that satisfy CVM requirements to support the approval of chloramine-T to control bacterial gill disease (BGD) and external flexibacteriosis on cultured freshwater fish. Expected Products: Approval of an NADA for chloramine-T to control and prevent BGD and external flexibacteriosis on salmonids and a representative species of cool- or warmwater fish by 2000. Job No. 1: Conduct a mutagenicity study in support of the approval of chloramine-T as a drug. Progress: With the ruling that the marker residue for chloramine-T is para-toluene sulfonamide (p-TSA), CVM has identified three required genotoxicity studies with p-TSA to support the approval of chloramine-T. The National NADA Coordinator has requested that Akzo Nobel Chemicals Inc., the NADA sponsor of chloramine-T, evaluate mutagenicity studies that had been previously generated on p-TSA. Current Status: If the existing mutagenicity studies are adequate, it may be possible that no funds will be required for genotoxicity studies on p-TSA. Job No. 2: Environmental fate and effect studies in support of the approval of chloramine-T as a drug. Progress: The CVM liaison to the NRSP-7, Dr. Meg Oeller, was contacted concerning the requirements for an environmental assessment (EA) on chloramine-T and what options were available to the IAFWA Project for having the EA conducted. Dr. Oeller stated that NRSP-7 is performing the EA because chloramine-T is under an INAD with that program. Current Status: UMSC will wait until the EA has been evaluated by CVM before any requests are made to CVM concerning an opinion on any remaining data requirements. Job No. 3: Coordination of chloramine-T compassionate INAD exemptions and NADA submissions. Progress: Pivotal Efficacy Study Protocols As part of the INAD/NADA process, two meetings were held during this reporting period. The first was convened in Rockville, MD on October 30, 1996 with CVM and several representatives of the International Association of Fish and Wildlife Agencies (IAFWA) Project, the U.S. Fish and Wildlife Service, and a state participating in the IAFWA Project (Pennsylvania). The group met with CVM personnel to discuss the design of the protocols for conducting pivotal efficacy studies on aquaculture drugs (especially chloramine-T) important to public fish production. This meeting was requested to facilitate the chloramine-T pivotal study meeting that was to be held with cooperators on November 7-8, 1996 in Kansas City, MO. The major conclusions reached as a result of the meeting with CVM are as follows: (1) no dose titration studies will be required if a definitive, effective low concentration for a drug has been identified through the compassionate investigational new animal drug (INAD) process; (2) label claims must make sense for field applications; (3) design of the label claims for chloramine-T to control or prevent external bacterial infections will probably be based on either increased survival or reduced mortalities, not on the reduction of the quantity of the disease pathogens or the intensity of the infections; (4) label claims drive the study design, therefore, of the three different categories of pivotal clinical field trial studies (preventive, control, and treatment), it is likely that only the first two categories of studies would be needed for chloramine-T or other water-borne drugs to determine the efficacy of the drug to control or prevent the mortalities associated with external bacterial or fungal infections; and (5) pivotal clinical field trial protocols could be designed to develop meaningful data at production hatcheries. The second meeting was held in Kansas City, MO on November 7-8, 1996 to: (1) develop label claims for chlorneeded to support amine-T; (2) discuss the elements of the pivotal study protocols the label claims; and (3) obtain commitments to perform pivotal clinical field trials on chloramine-T. The aim of the pivotal study protocols will be to make the use of chloramine-T as broad as possible. The label claims will depend on the studies the group can perform. This workshop should provide the information needed by the investigators to design individual protocols that are suitable to the sites available to them. After much discussion and reflection on the labels developed at the meeting in Council Bluffs, IA in February 1996, the group decided on the following label claims for chloramine-T:
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