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Flavobacterial Infections For use on all freshwater fish in the families Ascipenseridae, Centrarchidae, Esocidae, Ictaluridae, Percichthyidae, Percidae, Polydontidae, and Salmonidae. Indications: For the control or prevention of mortalities associated with external bacterial infections caused by flavobacters. Directions for Use: Control: Treat fish by immersion for 1 hr in a static bath or in a flow-through system for no more than one week per epizootic up to 4 times on consecutive or alternate days at concentrations from 10-20 mg/L. Prevention: Treat only early life stage fish by immersion for 1 hr in a static bath or in a flow-through system no more than once per day up to 3 times per week at concentrations from 10-20 mg/L. The important points gained from the meeting with CVM on October 30, 1996 were presented to the Workshop group regarding the design and major elements of pivotal study protocols. Computer diskettes were provided to the group that included (1) the protocols for the FWS compassionate INAD for chloramine-T (from Dr. Dave Erdahl, FWS), pivotal control study (from Jim Bowker, FWS), and pivotal prevention study (from Tom Cochran, PA), (2) the analytical method for chloramine-T (from UMSC), and (3) label claims (from UMSC). The group was also provided paper copies of the CVM document "Protocol development guideline for clinical effectiveness and target animal safety trials" as a guide to the format and elements considered by CVM to be important for pivotal study design. The suggestion was made to use a version of a compassionate chloramine-T INAD protocol as a template and add the elements needed for a pivotal study so that the investigator would not have to start from scratch. The second day of the Workshop centered on (1) gaining commitments to conduct pivotal clinical field trials on chloramine-T, (2) determining how to coordinate development of an initial efficacy protocol that could be used as a template for others, and (3) consideration of the types of secondary supporting data that should be collected in concert with the pivotal studies. The group made several commitments to perform pivotal clinical field trials on chloramine-T. Those commitments are provided in the list available from UMSC entitled "Summary of potential facilities volunteering to conduct pivotal chloramine-T efficacy studies to prevent or control fish mortality resulting from external flavobacterial infections." The list includes the contact person/INAD sponsor, facility/participation confirmed (yes/no), species, time of year, size of fish (inches), and type of study (prevention/control). Progress: Bridging Study to Support Chloramine-T Pivotal Efficacy Studies UMSC identified a need to develop a simple, rapid, accurate analytical procedure to quantify chloramine-T in water that could be used in lieu of the currently accepted HPLC method. The method would be used on site by hatchery personnel to monitor chloramine-T concentrations in water during pivotal efficacy trials. The analytical method selected is used to determine total and free chlorine concentrations and by difference the concentration of bound chlorine which is converted to the concentration of chloramine-T. In a preliminary review of the more common methods for analysis of chlorine, a colorimetric method appeared to produce the sensitivity, accuracy, and precision necessary to fulfill the study objectives. Additional criteria that were considered while selecting the analytical method were ease of use, analysis time, and cost. A test kit based on colorimetric determination of chlorine was selected for initial evaluation and is commercially available from the Hach Company (Loveland, CO). Current Status: Dr. Dave Erdahl and Jim Bowker offered to host the next meeting of the pivotal study group in conjunction with their annual FWS-INAD Workshop. The meetings are scheduled for August 6-8, 1997 in Bozeman, MT. Several pivotal efficacy studies should have been performed by August 1997 so UMSC should have a clear idea where future efforts will need to be focused to conduct pivotal efficacy studies that will be used to satisfy the efficacy label claims for chloramine-T as a therapeutant to control or prevent mortalities associated with BGD and external flexibacteriosis on cultured fish. Research is underway to evaluate the performance of the Hach test kit to determine chloramine-T concentrations in a variety of water conditions that might be encountered in public aquaculture. The performance of the test kit under a variety of water quality conditions remains to be evaluated including selected ranges of pH, temperature, hardness, organic content/chlorine demand, and fish load densities. A final report comparing the two methods will be submitted to CVM in early February 1997. UMSC is optimistic that this new method will be acceptable to CVM as an alternative to quantification of chloramine-T by HPLC. When this method has been validated against the accepted HPLC method, it will allow fish culturists to routinely monitor chloramine-T treatment concentrations to assure that the treated fish have received the correct concentration. When the method has been accepted by CVM, UMSC will provide test kits and training materials for the method to each participating hatchery. Job No. 4: Residue chemistry studies to support the approval of chloramine-T as a drug. Progress: No activity July 1, 1996 to December 31, 1996. Current Status: Progress in this work unit has been delayed by lack of available personnel to work on an acceptable regulatory/confirmatory method for p-TSA. When work is complete on the study to bridge the colorimetric method for chlorine with the HPLC method accepted by CVM (see project in Job No. 3 above), work will progress on development of an analytical method that will satisfy the marker residue requirements for regulatory and confirmatory identification. Job No. 5: Target animal safety studies in freshwater fish to support the approval of chloramine-T as a drug. Progress: No activity July 1, 1996 to December 31, 1996. Current Status: No progress has been made on this job because of the high priority need to develop a bridging method to support work in Job No. 3 above. After work on target animal safety studies are completed for hydrogen peroxide (see Study No. 8), UMSC will select representative cool- or warmwater species and initiate target animal safety studies for both rainbow trout and a second cool- or warmwater species sensitive to chloramine-T. STUDY NUMBER 5: APPROVAL OF SARAFLOXACIN HYDROCHLORIDE AS A DRUG TO CONTROL FLEXIBACTERIOSIS AND FURUNCULOSIS IN FRESHWATER FISH Objectives: To develop efficacy, target animal safety, and total residue and metabolism data required for the use of sarafloxacin to control furunculosis and flexibacteriosis in freshwater cold-, cool-, and warmwater fish. Expected Products: Approval of a NADA for sarafloxacin for control of enteric septicemia in catfish (ESC) by 2000 based on NADA sponsor and NRSP-7 data submissions; extension and expansion of the expected label can only occur with an extension of the IAFWA Project for a minimum of two years. Progress: Development of data on sarafloxacin has been given low priority since FDA decided to severely restrict the development of all fluoroquinolones for food animals. On October 30, 1996, the National NADA Coordinator and Dr. William Gingerich met with Dr. Meg Oeller, CVM liaison to NRSP-7, to determine the status of sarafloxacin within CVM, NRSP-7, and the Centers for Disease Control. When the current sponsor (Abbott Laboratories) decided not to pursue the completion of the NADA for channel catfish as a business decision, NRSP-7 agreed to assist in completing the NADA package; however, NRSP-7 needs Abbott Laboratories to request assistance from NRSP-7. Once this request is received, the remaining requirements will take from eight to twelve months to complete. Current Status: NRSP-7 will work to complete the requirements on sarafloxacin to control ESC. When sarafloxacin is approved, it is possible that expansions and extensions of the label through an amended NADA could be gained for other diseases and fish species. Conditions placed on the use of sarafloxacin under an amended NADA would be: (1) extra-label use would be prohibited; (2) efficacy must be established for each disease for each species; (3) no efficacy data development would be possible under a compassionate INAD as currently exists for all aquaculture drugs including IAFWA Project drugs; and (4) use of the drug would be possible only under the prescription of a veterinarian. While the conditions for use appear to be somewhat more restrictive, sarafloxacin is such a broad spectrum antibacterial that its availability to public fish production would be very advantageous. STUDY NO. 6: APPROVAL OF POTASSIUM PERMANGANATE TO CONTROL EXTERNAL PROTOZOA AND METAZOAN PARASITES AND BACTERIAL AND FUNGAL DISEASES OF CULTURED FOOD FISH. Objectives: To gain approval of potassium permanganate as a therapeutant to control external protozoan and metazoan parasites and bacterial and fungal diseases of cultured food fish. Expected Products: Approval of an NADA for potassium permanganate as a microbicide for all fish by 2000. Job No. 1: Develop research protocols for determining distribution of residual manganese in organs and tissues of fish exposed to potassium permanganate. Progress: A protocol prepared by SNARC personnel on accumulation of manganese in edible muscle of channel catfish following exposure to waterborne potassium permanganate was submitted to NCTR and CVM for review. The protocol was approved by NCTR and CVM on September 17, 1995. Current Status: Job No. 1 is complete. Job No. 2: Conduct studies of manganese residues in organs and tissues of cultured channel catfish exposed to potassium permanganate at therapeutic levels. Progress: The exposure phase of the residue study on potassium permanganate was completed by SNARC personnel on June 6, 1996. Tissue analyses to quantify manganese residues in fish tissues is nearly complete. Preliminary data suggests that the concentrations of manganese in edible tissues are not affected by the potassium permanganate exposures employed in the study. Current Status: Tissue analyses to quantify manganese residues in fish tissue after exposure to potassium permanganate should be completed early in 1997. Job No. 3: Prepare an environmental assessment of the fate and effects of release of potassium permanganate treated water. Progress: A preliminary search of the literature on the fate and effects of potassium permanganate has been completed. A reference file containing 400 entries has been compiled and is in review. Current Status: The literature review on the fate and effects of potassium permanganate will be prepared and used to support an EA. Job No. 4: Conduct studies of manganese residues in organs and tissues of cultured food fish other than channel catfish exposed to potassium permanganate at therapeutic levels. Progress: Preliminary arrangements have been made by SNARC staff with Dr. Randy MacMillan of Clear Springs Food Co. (Buhl, ID) to expose rainbow trout to potassium permanganate and transfer samples from Clear Springs Food Co. to SNARC for residue analysis. Sample preparation for manganese analysis has begun. Quality assurance practices were developed at NCTR and implemented at SNARC to insure proper documentation of chain of custody when samples are transferred for final analysis. Current Status: A cooperative project with a private aquaculture concern is underway and could result in fulfillment of the residue chemistry data requirements for fish other than channel catfish. SNARC expects to receive samples for manganese analysis by March 1, 1997. STUDY NUMBER 7: (REVISED TITLE) APPROVAL OF BENZOCAINE/AQUI-S AS AN ANESTHETIC AND SEDATIVE FOR FISH Objectives (REVISED OBJECTIVES): To develop efficacy, target animal safety, and residue depletion data required for the approval of benzocaine/Aqui-S as an anesthetic/sedative with a short withdrawal time for several species of freshwater fish. The original objectives of this work have been changed to reflect the original desires of public aquaculture to have an efficacious anesthetic with a zero withdrawal time. Change In Status: In January 1996, IAFWA Project coordinators learned of a new anesthetic, Aqui-S, that is approved with a zero withdrawal time in New Zealand. Because Aqui-S might be effective for use in public fish production in the United States, UMSC decided to evaluate and compare efficacy and regulatory requirements needed for approval of Aqui-S and benzocaine. Expected Products: A decision on whether to pursue an NADA for benzocaine or Aqui-S and identification of a sponsor for benzocaine, if it is the selected anesthetic/sedative, will be made in Year No. 3. Approval of Aqui-S as the candidate anesthetic/sedative may be possible for at least one species of fish in Year No. 5. Job No. 1 (REVISED TITLE): Develop a compassionate INAD request to evaluate benzocaine/Aqui-S as an anesthetic/sedative for fish cultured on public hatcheries. Progress: Work to gain approval on benzocaine was stopped in January 1996 when UMSC became aware of the new anesthetic, Aqui-S. Until a candidate anesthetic is selected, no additional effort will be made to seek a sponsor or conduct additional research on benzocaine. A protocol was prepared by UMSC staff and preliminary data on efficacy and toxicity of Aqui-S were collected. Current Status: Efficacy and toxicity studies of Aqui-S on several fish species in two size classes will be completed in Year No. 3. A determination will also be made of remaining regulatory requirements for Aqui-S. After consulting with member states in the IAFWA Project and the FWS, a decision will be made whether to proceed with approval efforts for benzocaine or Aqui-S. Aqui-S contains an ingredient that is similar to a major component in clove oil that also has anesthetic qualities in fish. The National NADA Coordinator recently learned that CVM has no intention of granting LRP status to clove oil, even though it has a Generally Recognized As Safe (GRAS) designation as a food additive. Approval of clove oil would require data on efficacy and target animal safety at a minimum, and, unlike Aqui-S, clove oil does not have a sponsor. Job No. 2 (REVISED TITLE): Conduct residue chemistry studies in freshwater fish to support the use of benzocaine/Aqui-S. Progress: The final report from the study to define the effects of temperature on the loss of benzocaine and acetylated benzocaine in rainbow trout fillet was archived at UMSC. Current Status: Submission of a report on the effect of temperature on the loss of benzocaine and acetylated benzocaine in rainbow trout to CVM has been delayed until a decision has been made on which anesthetic will be pursued under the IAFWA Project. If benzocaine is selected as the candidate anesthetic, the rainbow trout residue report will be submitted with a request for a regulatory decision from CVM to determine the marker residue and the need for additional data. No effort has been expended by the UMSC to determine the residue chemistry requirements for Aqui-S; however, the sponsor of Aqui-S is seeking to identify a contractor to perform a total residue depletion and metabolism study. Job No. 3 (REVISED TITLE): Conduct target animal safety studies with benzocaine/Aqui-S in rainbow trout and a second species (cool-or warmwater). Progress: No activity July 1, 1996 to December 31, 1996. Current Status: Target animal safety studies will be initiated when a candidate anesthetic is selected and after similar studies are completed for chloramine-T and hydrogen peroxide. Preliminary information on the toxicity of Aqui-S is being developed for several fish species. Job No. 4 (REVISED TITLE): Coordinate mutagenicity testing in support of the approval of benzocaine/Aqui-S. Progress: Based on discussions with CVM officials at a meeting on November 15, 1994, CVM will not require mutagenicity data to support the approval of benzocaine as an anesthetic/sedative in cultured freshwater fish. Current Status: All mutagenicity testing for benzocaine is considered complete and no further studies are planned at this time. Data requirements on mutagenicity for Aqui-S are not known at this time. Job No. 5 (REVISED TITLE): Coordinate subacute mammalian toxicity studies to support the approval of benzocaine/Aqui-S. Progress: CVM officials have indicated that only 90-day rodent and 90-day non-rodent feeding studies will be required for benzocaine to complete this data requirement. An interagency agreement with CVM has been executed that will allow Office of Science personnel to administer and monitor external contract studies related to benzocaine and other fishery chemicals. UMSC is withholding authority to initiate these studies until a decision is made to pursue an approval of benzocaine or Aqui-S. Current Status: UMSC staff worked with staff of the CVM's Office of Science to draft and implement an interagency agreement to contract for these studies. No work will be initiated on these studies until a decision is made whether to pursue the approval of benzocaine or Aqui-S. Job No. 6 (REVISED TITLE): Prepare an environmental assessment of the fate and effects of the release of benzocaine/Aqui-S. Progress: No activity July 1, 1996 to December 31, 1996. Current Status: Environmental fate and effects information is not currently available for either Aqui-S or benzocaine but may be available from a pharmaceutical sponsor or NRSP-7 in the form of an EA. Environmental fate and effect data requirements will be identified when a candidate anesthetic is selected. STUDY NO. 8: DEVELOPMENT OF HYDROGEN PEROXIDE TO CONTROL FUNGAL INFECTIONS, EXTERNAL BACTERIAL INFECTIONS, AND EXTERNAL PARASITIC INFESTATIONS OF FRESHWATER FISHES. Objectives: To develop efficacy and target animal safety data to provide fish culturists with effective, safe treatment regimens for hydrogen peroxide to control fungal infections on fish and fish eggs and potentially, for controlling external parasitic infestations and external bacterial infections on freshwater fish. Expected Products: Approval of an NADA for hydrogen peroxide to control and prevent mortalities associated with saprolegniasis on all fish and fish eggs, and completion of an assessment of its efficacy as an external antibacterial and parasiticide on fish by the end of Year No. 5. Change in status: Hydrogen peroxide will retain its current LRP status to control and prevent saprolegniasis on fish and fish eggs; however, as a result of a request by Eka Nobel Inc. (Marietta, GA) in January 1996, an NADA for hydrogen peroxide will be pursued. CVM stated in June 1995 that LRP status would not apply to external antibacterial or parasiticide uses. Job No. 1: Conduct efficacy studies on the use of hydrogen peroxide to control fungal infections of freshwater fish and fish eggs. Progress: Studies to identify methods to systematically and uniformly induce saprolegniasis in channel catfish are complete and those for rainbow trout are nearly complete. Infection models will be used to produce fish with saprolegniasis for evaluating the efficacy of hydrogen peroxide to control and prevent mortalities associated with saprolegniasis. A pilot study to determine the efficacy of hydrogen peroxide for treating saprolegniasis in channel catfish was conducted. The final report on a study to determine the safety of hydrogen peroxide for treating saprolegniasis on the eggs of eight cool- and warmwater fish species is in review at the UMSC and will be submitted to CVM in Year No. 3 for inclusion in the hydrogen peroxide public master file (PMF). This study also contains information on the efficacy of hydrogen peroxide for treating saprolegniasis on fish eggs. A study comparing the efficacy of several hatchery egg incubation systems to deliver hydrogen peroxide treatments was completed. Results indicate that expected treatment concentrations were often not realized throughout different egg incubation systems. Mc Donald egg jar incubators accurately delivered treatment concentrations whereas treatment concentrations delivered in Clark-Williamson and Heath Incubators were diluted. Researchers and fish culturists should periodically verify the accuracy of treatment dosing methods to ensure that expected concentrations are met. Current Status: Hydrogen peroxide efficacy studies on eggs are complete and efficacy studies on fish will continue in the second half of Year No. 3. Hydrogen peroxide appears to be an effective drug to control mortalities associated with saprolegniasis on fish and their eggs. Job No. 2: Conduct efficacy studies on the use of hydrogen peroxide to control external parasitic infestations and external bacterial infections of freshwater fish at public hatcheries. Progress: A study protocol to assess the control of external parasitic infestations and mortalities associated with external bacterial infections by hydrogen peroxide treatment has been drafted and is in review by UMSC staff. In Year No. 3, pivotal dose titration studies testing three concentrations of hydrogen peroxide will be conducted on fish infected with external bacteria or infested with external parasites at hatcheries near UMSC. Current Status: Pivotal dose titration studies to determine the efficacy of hydrogen peroxide to control external parasitic infestations and the mortalities associated with external bacterial infections will begin in Year No. 3. Preliminary observations indicate that hydrogen peroxide may control mortality associated with external bacterial infections and control external parasitic infestations on freshwater fish. Job No. 3: Conduct target animal safety studies on fish and fish eggs with hydrogen peroxide in support of its intended use as an antifungal agent and therapeutant to control external parasitic infestations and external bacterial infections on cultured freshwater fish. Progress: Target animal safety studies on the eggs of channel catfish, common carp, lake sturgeon, northern pike, paddlefish, walleye, and white sucker were completed. Previously, on February 29, 1996, a report was submitted to CVM in support of a request to amend the current LRP status of hydrogen peroxide. This report requests an increase in the maximum allowable treatment concentration from 500 ppm to 1000 ppm for fish eggs with saprolegniasis. No response has been received from CVM to date. Target animal safety studies on the eggs of rainbow trout were completed. Based on the results of this study, rainbow trout eggs may be safely treated with hydrogen peroxide at <1000 uL/L. The most sensitive egg stage to hydrogen peroxide treatment is blastopore formation through closure (Day 6-8 at 12°C) for rainbow trout. Steelhead rainbow trout eggs were more sensitive to hydrogen peroxide than non-steelhead rainbow trout eggs, especially those eggs from a strain with a history of Early Mortality Syndrome. Current Status: Target animal safety data on hydrogen peroxide for cool- and warmwater fish eggs are complete and a report is being prepared to submit in Year No. 3 to CVM for inclusion into the hydrogen peroxide PMF. Data from these studies are also being used to support amending the current LRP status of hydrogen peroxide to allow use of concentrations up to 1,000 ppm on most fish eggs. Based on the data gathered in rainbow trout egg target animal safety studies, UMSC does not recommend treatment of steelhead rainbow trout eggs above 500 uL/L during the sensitive stage (blastopore formation through closure). A protocol to determine the most sensitive representative species of fish to evaluate the safety of hydrogen peroxide to fish is in review by UMSC staff. Data from acute toxicity studies on fish will be submitted to CVM to support the concept of using a most sensitive representative species as a surrogate for other species to satisfy target animal safety data requirements for an NADA approval of hydrogen peroxide. STUDY NO. 9: DEVELOPMENT AND EXECUTION OF STUDIES TO ADDRESS THE CONCEPT OF CROP GROUPING Objectives: (1) To develop cooperative studies with CVM scientists and university investigators that will result in a reasonable approach to solving problems related to developing extensive residue chemistry data for minor species drug approvals and (2) to develop a course of study to demonstrate similarities and differences in the metabolism and residue chemistry of aquaculture drugs by a broad range of cultured freshwater fish. Expected Products: By Year No. 5 demonstrate to CVM that crop grouping is a viable concept in developing residue chemistry data for aquaculture drugs, thus reducing future data requirements and associated costs. Job No. 1: Development of comparative pharmacokinetics and metabolism data for sarafloxacin in rainbow trout and channel catfish. Progress: Studies were initiated to adapt existing analytical methods for HPLC analysis of sarafloxacin to rainbow trout tissues. An HPLC method for analysis of sarafloxacin in the plasma of rainbow trout and channel catfish has been refined and the accuracy and precision determined. Similar studies for an analytical method for sarafloxacin in the edible fillet of channel catfish and rainbow trout have been initiated. Current Status: A protocol to study the pharmacokinetics of sarafloxacin in channel catfish and rainbow trout is in review and should be initiated in Year 3. Job No. 2: Development of comparative pharmacokinetics and metabolism data for sarafloxacin in phylogenetically diverse aquaculture species. Progress: No activity July 1, 1996 to December 31, 1996. Current Status: Work on this job will be initiated after development of information on the pharmacokinetics and metabolism of sarafloxacin in rainbow trout and channel catfish. Work should be initiated in Year No. 4. Job No. 3: Develop comparative pharmacokinetics and metabolism data for benzocaine in rainbow trout and channel catfish. Progress: Work in this job focuses on (1) development and implementation of methods to collect reliable pharmacokinetic data from channel catfish and rainbow trout using benzocaine as a waterborne test drug and (2) development of accurate and representative models of the accumulation, metabolism, and loss of benzocaine in fish. Initial work with channel catfish has been promising. To establish the details of benzocaine disposition, initial work has utilized the intraarterial administration of benzocaine. Benzocaine pharmacokinetics and metabolism were characterized in channel catfish as a part of the effort toward approval of benzocaine for use as an anesthetic for fish. Catfish at 21C were administered benzocaine (1, 10, and 50 mg/kg) intraarterially over 30 minutes at a constant rate of infusion. Blood samples were collected over 48 hours and the plasma concentrations of benzocaine and its metabolites were determined by HPLC. Benzocaine, acetylated benzocaine, p-amino benzoic acid, and acetylated p-amino benzoic acid were observed, but there was no evidence of p-amino hippuric acid as is seen in mammalian species. At 48 hours, the fish were sacrificed, and several tissues were removed for analysis of benzocaine and its metabolites. The benzocaine plasma-time profile appeared to be triexponential and a three compartment model (WinNonlin software) was used to characterize its pharmacokinetics. The relatively long biological half-life (about 20 hours) was due to a large volume of distribution rather than the total body clearance, which was roughly equal to the cardiac output. A Physiologically-Based Pharmacokinetic (PBPK) model (ACSL software) was also developed that included six distributive tissue groups (gills, slowly perfused, rapidly perfused, fat, liver, and kidney), and three elimination and/or metabolism tissue groups (liver, kidney, and gill). In another attempt to model benzocaine loss from catfish, the data collected from the compartmental analysis studies were compared with the prediction of a simple PBPK model using physiological parameters determined for channel catfish by other investigators. The model for benzocaine in channel catfish was refined since its original testing in early July 1996. Simulations were run to determine the goodness of fit of the model to analytical data collected in these studies from plasma, kidney and muscle tissues. These profiles agree with the experimentally determined concentrations observed after intraarterial administration of benzocaine to catfish, particularly for the plasma. Refinement of this model is underway. This model will permit examination of the behavior of benzocaine in fish of different size and at different temperatures and will help to identify the physiological and biochemical characteristics of fish that influence the pharmacokinetics and metabolism of benzocaine. Initial simulations indicate that temperature-induced changes in cardiac output have major impact on tissue concentration-time profiles. Other physiological parameters may prove important; only cardiac output has been examined thus far. Current Status: Data from this job will continue to be collected and developed into a database that can be accessed for use in development of pharmacokinetic models and for the establishment of metabolite residues in trout and catfish. Job No. 4: Develop comparative pharmacokinetics and metabolism data in phylogenetically diverse species to support or refute a crop grouping concept for fish. Progress: Work in this portion of the project is contingent upon the establishment and evaluation of reasonable compartmental and PBPK models in channel catfish and rainbow trout. Much of the work being undertaken in the project at this time is to develop the model in channel catfish and rainbow trout. Work for refinement of the model being developed for channel catfish and reported in Job No. 3 above was applied to diverse species including sturgeon, catfish, carp, and trout. Initial simulations indicate that both cardiac output and gill surface areas of different species provide evidence for substantial species differences in clearance of benzocaine. With a more refined model, the impact of interspecific differences in blood flows, tissue volumes, elimination clearances, tissue-to-plasma distribution coefficients and differences in metabolism can be quantitatively assessed. This should demonstrate that benzocaine pharmacokinetics are similar among diverse species and should permit rational identification of "crop groups". Current Status: Development of the PBPK model for benzocaine pharmacokinetics is continuing in channel catfish (warmwater) and rainbow trout (coldwater). Physiological parameters for minor species are being collected. Along with the model development work, laboratory studies in white sturgeon, striped bass, and walleye will be used to validate and refine the model. Subsequent work is likely to proceed rapidly once the methods are in place for channel catfish and rainbow trout. STUDY NO. 10: NEGOTIATIONS AND CONTRACT COORDINATION Objectives: To ensure that all data required by CVM for approval through NADAs are developed for the eight priority drugs in a timely, logical, and efficient manner. To coordinate the administration of all contracts by CVM's Office of Science to ensure efficiency, timeliness, and acceptability of data to CVM. To track and report the progress of all studies and ensure that they are proceeding toward approval in a timely, logical, and efficient manner. To assemble and submit NADAs for approval by CVM. Job No. 1: Determine data requirements for approval of each candidate drug. Progress: General Several discussions were held between the National NADA Coordinator, UMSC staff, SNARC staff and CVM regarding the status and direction for chloramine-T, copper sulfate, formalin, hydrogen peroxide, and oxytetracycline. In addition, UMSC staff and the National NADA Coordinator have negotiated with CVM regarding label claims and regulatory requirements for pivotal efficacy study sites. Three recent events will have an impact on the approval process and data requirements for IAFWA Project drugs. The Animal Drug Availability Act of 1996 (ADAA), signed into law on October 9, 1996, provides clearer definition of the "substantial evidence" required for NADA approvals, streamlines the consideration process by CVM, establishes a new drug category of a "veterinary feed additive", and simplifies licensing procedures for feed mills. These changes in the Food, Drug, and Cosmetic Act should help the IAFWA Project gain approvals for its priority drugs. The IAFWA Project will work with CVM for any additional clarification of ADAA rulings. CVM released its new draft "A guide to the approval of animal drugs for minor uses and for minor species" in September 1996. This guide provides suggested protocols for drug approvals for multiple species at one time, simplifies requirements for approvals, and increases flexibility. CVM held a Joint Canadian-United States Workshop on Jurisdiction of Sea Lice Treatment and Control in September 1996 that will impact IAFWA Project drug approvals. One of the action items resulting from the Workshop is the strategies and mechanics to institute forums for harmonization activities, i.e., the establishment of a joint Canada and United States Aquaculture Working Group. This means that data could be shared and certain requirements for all drugs could be harmonized so that there could be joint submissions leading to approvals being granted simultaneously in both countries. Progress: Specific Drugs Aqui-S -- Jan Holland, representative for the NADA sponsor of Aqui-S (Crop & Food Research, Nelson, New Zealand) met with the National NADA Coordinator and UMSC staff on August 20, 1996 in La Crosse, WI to discuss the research developed on Aqui-S in New Zealand, efficacious range of concentrations for various aquatic species, and potential for development of Aqui-S in the United States under the IAFWA Project. The National NADA Coordinator contacted CVM to determine whether oil of cloves could be considered under a LRP status. CVM responded on December 6, 1996 that the agency will not consider clove oil to be a LRP drug when used as a fish anesthetic. Therefore, sponsors interested in fish anesthetic/sedative INADs/NADAs can continue to pursue them without concern for competition from unapproved clove oil products. Benzocaine -- Nine potential sponsors of benzocaine were sent letters on September 4, 1996 requesting an indication of continued interest in being kept informed on benzocaine or becoming an NADA sponsor of benzocaine. Two pharmaceutical firms expressed an interest in becoming sponsors if the IAFWA Project selects benzocaine as the candidate anesthetic. Chloramine-T -- The National NADA Coordinator, INAD coordinators, and a representative of UMSC met 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 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. Copper Sulfate -- CVM met July 11, 1996 and determined that there are no human food or environmental safety concerns over the use of copper sulfate as an therapeutant, thus making its approval relatively easy to obtain. A meeting was held July 15, 1996 in Memphis, TN with a potential NADA sponsor, Phelps Dodge Refining Corporation (El Paso, TX), to discuss their interest in sponsoring an INAD/NADA on copper sulfate, data requirements for approval, and coordination activities. A follow-up meeting with CVM and Phelps Dodge Refining Corporation was held on August 5, 1996 to develop an action plan needed to obtain approval of copper sulfate as a microbicide.
`Formalin -- 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 use on eggs (based on UMSC studies) and parasiticide use (based on studies at Auburn University, Auburn, AL). These extensions of the formalin NADA to additional species will remove the need for INADs on formalin for these claims. On October 28, 1996, the NADA Coordinator sent letters to the three current NADA sponsors of formalin inviting them to amend their NADAs and change their labels to reflect the extended claims granted by CVM. The INADs on formalin's use as a fungicide on fish will remain in effect until data are submitted to cover this use. Hydrogen Peroxide -- The National NADA Coordinator and UMSC staff sent a letter and supporting documentation on August 27, 1996 to CVM summarizing the preliminary data and information on the safety and efficacy of hydrogen peroxide. Hydrogen peroxide has potential to be safe and effective at exposures up to 250 L/L for 15 to 45 minutes to control mortalities associated with external bacterial infections and to control external parasitic infestations on certain species of freshwater fish. This treatment regimen is well below the LRP concentration of 500 L/L allowed for the control of mortalities associated with saprolegniasis on all fish species and life stages. Detailed information was provided to the NADA sponsor (Eka Nobel Chemicals Inc., Marietta, GA) on the status of hydrogen peroxide under the IAFWA Project. Oxytetracycline -- The National NADA Coordinator and UMSC staff continued to coordinate the activities related to oxytetracycline as an antibacterial through the IAFWA Project, especially concerning the development of pivotal efficacy data. They have interacted with Jim Warren (Western Regional INAD Project, Portland, OR) regarding his discussions with CVM on September 19, 1996 concerning the use of voluminous efficacy data as "historical controls" and placebo feeds to gain early extension and expansion of the current oxytetracycline label. A private fish producer was helped in their efforts to gain access to the oxytetracycline INAD held by the State of Texas. The National NADA Coordinator has reviewed the protocol being developed for control of strep infections in tilapia and largemouth bass. Sarafloxacin -- The National NADA Coordinator and Dr. William Gingerich (UMSC) met with the CVM liaison to NRSP-7 on October 30, 1996 to discuss ways to complete the approval process for sarafloxacin to control ESC. The NADA for sarafloxacin is held by Abbott Laboratories (North Chicago, IL). Current Status: Progress has been made on interactions with current or potential sponsors of NADAs for Aqui-S, benzocaine, chloramine-T, copper sulfate, formalin, and hydrogen peroxide. Progress has been made on coordinating the INADs and determining how and where pivotal efficacy studies will be performed. Negotiations and discussions continue with CVM regarding data requirements for all IAFWA drugs. Job No. 2: Coordinate the administration of contracts. Progress: A memorandum of need was developed and an interagency agreement entitled "Drug toxicity studies for the support of drug approvals in aquatic animal species" was initiated on May 1, 1996 between CVM and UMSC. This agreement encumbers $200,000 and allows CVM's Office of Science to administer and monitor external contracts to support the approval of drugs for public fish production. This contract was extended to September 30, 1997 to allow for identification and implementation of external contracts that may be required for the approval of the therapeutants/anesthetics under study. A cooperative research and development agreement is being developed between UMSC and the New Zealand Institute for Crop and Food Research Limited to cover cooperative efforts on Aqui-S. Current Status: Three contracts were negotiated in Year No. 2 and UMSC anticipates these will continue in Year No. 3. One contract is being negotiated in this reporting period. Job No. 3: Track the progress of all studies and summarize and report the data. Progress: The following report was written and distributed in this reporting period to all IAFWA Project participants and stake holders: The second annual report of progress ( July 1, 1995 to June 30, 1996). Products (NADA submissions, study protocols, publications, special reports, and presentations) that are a part of the IAFWA Project are reported to December 31, 1996 in Appendix I. In the future, the products will first be reported in Job No. 3 and then placed in the accumulative Appendix. Major advances were made toward communication and coordination of INAD/NADAs of high priority drugs important to public fish production at a workshop held by the FWS in Bozeman, MT on August 14-15, 1996. Discussions centered on developing the pivotal data needed to complete the efficacy portion of the NADAs. The Working Group on Quality Assurance in Aquaculture Production met on September 20, 1996 in Washington, DC and developed a five-year strategic plan that includes the IAFWA Project drugs. The National NADA Coordinator and Dr. William Gingerich (UMSC) met on October 30, 1996 in Rockville, MD with Dr. Meg Oeller, CVM Liaison to NRSP-7, to discuss coordination of the mutual projects that NRSP-7 and the IAFWA Project have in common. Both projects are working on chloramine-T, copper sulfate, hydrogen peroxide oxytetracycline, potassium permanganate, and sarafloxacin. Current Status: Appropriate progress reports have been and will continue to be presented to the IAFWA Project participants and stake holders. Continuing efforts will be made to inform the entire aquaculture community of the progress being made on IAFWA Project drugs and the crop grouping research. The IAFWA Project will be featured at a special session entitled "Partnerships for aquaculture drug approvals: models for success" to be held at World Aquaculture '97, Seattle, WA, February 19-23, 1997. A Workshop on International Harmonization for Aquaculture Drugs and Biologics is scheduled to be held in Seattle, WA on February 24, 1997 to create an educational forum to exchange information and identify issues among public and private sectors and international organizations with the goal of initiating follow-up strategies to advance harmonization of drug maximum residue levels, aquaculture drug approval standards and biologics licensure. Job No. 4: Assemble and submit NADA packages to FDA for approval. Progress: From July 1, 1996 to December 31, 1996, IAFWA Project personnel submitted two NADA packages to CVM and received one response as follows: Copper sulfate submission. Environmental assessment: effect of copper sulfate used as a therapeutant in aquaculture. December 20, 1996. Formalin, CVM response. Based in part on the December 15, 1995 submission from UMSC on the safety of formalin treatments on fish eggs, the CVM placed a notice in the October 18, 1996 issue of the Federal Register inviting 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). Hydrogen peroxide submission. Schnick, R.A., and J.J. Rach. 1996. Summary of data and information on the use of hydrogen peroxide to control bacterial infections and external parasite infestations on freshwater fish. Submitted to the Center for Veterinary Medicine, Rockville, MD. August 27, 1996. 20 pp. Current Status: The UMSC and SNARC were pleased with CVM's decisions to extend the formalin NADA to control and prevent saprolegniasis on the eggs of all cultured freshwater fishes, thus eliminating the need for INADs for these uses and the agency's the lack of concern over human food or environmental safety of copper sulfate making for a fairly easy NADA approval. APPENDIX I: ACCUMULATED PRODUCTS OF THE "APPROVAL OF DRUGS FOR PUBLIC FISH PRODUCTION PROJECT," A PROJECT OF THE INTERNATIONAL ASSOCIATION OF FISH AND WILDLIFE AGENCIES NADA SUBMISSIONS Benzocaine submission. Stehly, G.R., J.R. Meinertz, W.H. Gingerich, P.M. Mazik, and M.P. Gaikowski. 1995. Effects of temperature on the loss of benzocaine and acetylated benzocaine residues from edible tissues of channel catfish (Ictalurus punctatus). Contract completion report for Interagency Agreement Number 224-92-7036. Submitted to the Center for Veterinary Medicine, Rockville, MD, October 5, 1995. 121 pp. Accepted by CVM on November 5, 1995. Benzocaine submission. Stehly, G.R., J.R. Meinertz, J.A. Bernardy, and W.H. Gingerich. 1995. Final report for contract study entitled "Effects of temperature on the pharmacokinetics of benzocaine in rainbow trout Oncorhynchus mykiss, Part I: Development and validation of experimental methods and Part II: Pharmacokinetic profiles of benzocaine in temperature-acclimated fish." U.S. Food and Drug Administration, Contract number FDA 224-92-7036. Submitted to the Center for Veterinary Medicine, Rockville, MD. May 11, 1995. 193 pp. Accepted by CVM June 22, 1997. Chloramine-T submission. Dawson, V.K., W.H. Gingerich, L.J. Delaney, P.L. Vetter, and M.J. Rogazcewski. 1995. Isolation and characterization of chloramine-T metabolites in rainbow trout after use-pattern treatment with [ring-UL14C]chloramine-T. Submission of metabolite identification data to support the approval of chloramine-T to control mortalities associated with external flavobacterial infections in freshwater fish. Submitted to the Center for Veterinary Medicine, Rockville, MD, April 13, 1995. 100 pp. Accepted by CVM on July 20, 1995. Chloramine-T submission. Dawson, V.K. and W.H. Gingerich. 1991. Accumulation and clearance of chloramine-T residues in rainbow trout after use-pattern treatment with [ring-UL14C]chloramine-T. Submission of total residue depletion data to support the approval of chloramine-T to control mortalities associated with external flavobacterial infections in freshwater fish. Submitted to the Center for Veterinary Medicine, Rockville, MD. April 15, 1991. 250 pp. Accepted by CVM on July 20, 1995. Chloramine -T, CVM response. The CVM responded on July 20, 1995 to prior NADA submissions from UMSC by accepting data in two residue chemistry studies as satisfying requirements for total residue depletion and metabolism of chloramine-T in rainbow trout. They concluded from the data that p-TSA is the major metabolite that results from chloramine-T exposure in fish and that the agency has enough data to calculate a tolerance. Copper sulfate submission. Environmental assessment: effect of copper sulfate used as a therapeutant in aquaculture. Submitted to the Center for Veterinary Medicine, Rockville, MD. December 20, 1996. 20 pp. Copper sulfate submission. Hobbs, M., F. Kadlubar, D. Schlenk, B.R. Griffin, and C.D. Brand. 1996. Technical report for Experiment No. E06897.01 Accumulation of copper in edible muscle of channel catfish (Ictalurus punctatus) following exposure to waterborne copper sulfate. Submitted to the Center for Veterinary Medicine, Rockville, MD. April 4, 1996. 20 pp. Accepted by CVM June 1, 1996. Copper sulfate, CVM response. The CVM reviewed submitted data on residue chemistry and environmental safety and determined on July 11, 1996 that the agency has no human food or environmental safety concerns over the use of copper sulfate as a microbicide. Formalin submission. Rach, J.J., G.E. Howe, and T.M. Schreier. 1995. Safety of formalin treatments on fish eggs. Final report submitted to the Center for Veterinary Medicine, Rockville, MD. December 15, 1995. 128 pp. Accepted by CVM October 18, 1996. Formalin, CVM response. The 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). Hydrogen peroxide submission. Schnick, R.A., and J.J. Rach. 1996. Summary of data and information on the use of hydrogen peroxide to control bacterial infections and external parasite infestations on fresh water fish. Submitted to the Center for Veterinary Medicine, Rockville, MD. August 27, 1996. 20 pp. Hydrogen peroxide submission. Rach, J.J., 1996. Regarding an amendment to the low regulatory priority ruling of hydrogen peroxide. Submitted to the Center for Veterinary Medicine, Rockville, MD. February 29, 1996. 6 pp. Hydrogen peroxide submission. Schnick, R.A., L.L. Marking, J.J. Rach and T.M. Schreier. 1993. Request for determination of regulatory status of hydrogen peroxide. Submitted to the Center for Veterinary Medicine, Rockville, MD. August 6, 1993. 6pp + attachments. Accepted by CVM January 11, 1994. Hydrogen peroxide, CVM response. The CVM concluded on January 11, 1994 that "hydrogen peroxide, used at 250-500 mg/L to control fungi on all species and life stages of fish, including eggs, will be considered a new animal drug of low regulatory priority." Oxytetracycline submission. Stehly, G.R., J.R. Meinertz, and W.H. Gingerich. 1996. High performance liquid chromatography (HPLC) method for oxytetracycline in fish proposed for use in bridging studies with the official microbiological method. Preliminary report submitted to Dr. P. Chu, Center for Veterinary Medicine. June 17, 1996. 48 pp. Accepted by CVM November 25, 1996. Oxytetracycline Response. The CVM chemist reviewing the HPLC method, forwarded a recommendation 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. Accepted by CVM November 1996.
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