Submitted by: 

Axcentive bv, through its U.S. representative, held a meeting with CVM on October 31, 2001 to discuss the genotoxicity concerns that CVM has on marker residue of its chloramine-T product Halamid™. Resolution to mammalian safety issues is possible if Axcentive bv provides acceptable evidence that p-TSA is not genotoxic.

The Upper Midwest Environmental Sciences Center (UMESC) submitted to CVM: (1) data on an analytical method for para-toluenesulfonamide (p-TSA) for tissues of multiple fish species on September 28, 2001 and (2) depletion of p-TSA from tissues of rainbow trout on October 19, 2001.

CVM accepted as supporting efficacy data for treatment of external parasitic infestations in fish on July 18, 2001 and target animal safety data for a variety of fish exposed to hydrogen peroxide on October 4, 2001.

On May 15, 2001, CVM accepted residue depletion studies for walleye and northern pike fed OTC medicated feed and established zero withdrawal times in juvenile northern pike and juvenile walleye at water temperatures down to 14 C and 16 C, respectively.

UMESC obtained funding for an OTC EA from the Wallop-Breaux Sport Fish Restoration Funds on July 25, 2001. The project includes measurement of OTC in water and sediment in and around a hatchery with a typical treatment for a disease episode.

On October 5, 2001, UMESC submitted a response to CVM regarding data to support human food safety technical section for an analytical method for oxytetracycline in the edible tissue of fish used in residue depletion studies.

In September 2001, the Multi-State Conservation Grant Program indicated it will fund UMESC to develop: (1) a model to infect fish with external columnaris disease, (2) data toward oxytetracycline immersion therapy, and (3) a determinative analytical method for the marker residue for AQUI-S™.

In September 2001, the Multi-State Conservation Grant Program indicated it will fund a study in Arkansas on the environmental fate and effect of potassium permanganate.

The Joint Subcommittee on Aquaculture (JSA) Aquaculture Effluents Task Force met on October 17-18, 2001 to discuss the status of EPA’s Effluent Guidelines Plan for aquaculture facilities.

On August 2-3, 2001, nine sponsors or potential sponsors attended a meeting of the Federal-State Aquaculture Drug Approval Partnership Project to learn about the potential for development of their products for United States aquaculture.

A bill entitled "Minor Animal Species Health and Welfare Act of 2000" was introduced in the U.S. Congress into the House on June 27, 2000 (HR-4780) and into the Senate on October 5, 2000 (S-3169). The bill was renamed Minor Use and Minor Species Animal Health Act of 2001 and was reintroduced into the House as HR-1956 on May 23, 2001 and as S-1346 into the Senate on August 2, 2001.

CVM awarded a contract on the risk assessment of drugs and chemicals used in foreign aquaculture on September 28, 2001 to ICF Consulting.

The National Coordinator for Aquaculture New Animal Drug Applications had two publications, one manuscript in press, presented three papers, and wrote 15 reports.

The overall goal of this project is for the National Coordinator for Aquaculture New Animal Drug Applications (National Aquaculture NADA Coordinator) to coordinate activities for investigational new animal drug exemptions (INADs) and new animal drug applications (NADAs) to expedite approval for the use of various drugs in aquaculture. Specific objectives related to that goal are to:

Serve as an information conduit between INAD/NADA applicants and the U.S. Food and Drug Administration’s Center for Veterinary Medicine (CVM);

Identify and encourage prospective INAD participants to become involved in specific investigational studies and NADA approval-related research;

Seek the support and participation of pharmaceutical sponsors for INAD studies and NADAs and coordinate with INAD/NADA sponsors to achieve CVM approval more quickly;

Guide prospective and current INAD holders on the format for INAD exemption requests and related submissions to CVM;

Identify existing data and remaining data requirements for NADA approvals;

Review, record, and provide information on the status of INADs and NADAs;

Provide liaison and coordination among all the federal agencies involved in the INAD/NADA process; and

Provide public education related to training and guidance in obtaining INAD exemptions and pursuing NADA approval.

The National Aquaculture NADA Coordinator provided many information transfers from May 15, 2001 to November 9, 2001and worked to obtain INADs, NADAs, and approvals for a number of drugs that are considered to be of high priority for approval by the public and private aquaculture communities.

Amoxicillin (oral antibacterial)—Status: Early development stage; antimicrobial resistance issue needs to be addressed.

Kent SeaFarms Corporation, the new United States representative GB Research, Inc. for the development of its amoxicillin product, has recently interacted with CVM and the National Coordinator for Aquaculture NADA to write a development plan.

The Harry K. Dupree Stuttgart National Aquaculture Research Center (HKD-SNARC) has been making good progress on working with isolates of streptococcus.

Chloramine-T (external antibacterial)—Status: Sponsor (Axcentive bv; formerly Akzo Nobel Chemicals, Inc.) committed to INAD/NADA; one label claim close to approval.

Axcentive bv, through its U.S. representative, held a meeting with CVM on October 31, 2001 to discuss the genotoxicity concerns that CVM has on marker residue of its chloramine-T product Halamid™. Resolution to mammalian safety issues is possible if Axcentive bv provides acceptable evidence that p-TSA is not genotoxic.

The Upper Midwest Environmental Sciences Center (UMESC) submitted to CVM: (1) data on an analytical method for para-toluenesulfonamide (p-TSA) for tissues of multiple fish species on September 28, 2001 and (2) depletion of p-TSA from tissues of rainbow trout on October 19, 2001.

Progress on Technical Sections on chloramine-T:

Product Chemistry—The sponsor, Axcentive bv (a 100% daughter company of PNP Holding bv, Barneveld, The Netherlands) is committed to developing the product chemistry technical section and submitting it to CVM into INAD #8086.

Mammalian Safety—The sponsor is addressing this technical section and met with CVM on October 31, 2001 to discuss the resolution of the genotoxicity studies.

Environmental Safety—An environmental summary was written by UMESC and is under review in November 2001. The environmental summary developed on public literature and data will be made available to any chloramine-T sponsors in Public Master File Number 5637.

Human Food Safety—CVM accepted two residue chemistry studies by UMESC for total residue depletion and metabolism of chloramine-T in rainbow trout; para-toluene sulfonamide (p-TSA) was established as the major metabolite in fish and declared as a marker residue for chloramine-T in juvenile rainbow trout. CVM accepted simple colorimetric procedure by UMESC for use in efficacy studies for determining chloramine-T concentrations in treatment waters. UMESC completed research to bridge the proposed analytical method for p-TSA with an outdated, labor intensive method previously used to quantify p-TSA in fish tissue. Data developed with the proposed method for p-TSA were similar to analytical data developed with the outdated method indicating that the two methods were successfully bridged. UMESC completed an interagency agreement with CVM’s Office of Research to develop the confirmatory method for p-TSA in fish tissue to satisfy an all fish label claim. This work will be funded with money UMESC originally set aside in another interagency agreement with CVM to conduct work on another drug, benzocaine.

Target Animal Safety—U.S. Fish and Wildlife Service (FWS) at Bozeman, Montana submitted a report to CVM on the toxicity of chloramine-T to salmonids. UMESC developed toxicity data on fish species except salmonids and the histopathology review is nearly complete.

Efficacy—Efficacy data requirements are met for chloramine-T for control of mortalities associated with flavobacterial infections on gills of salmonids reared in freshwater at 12 to 20 mg/L for one hour. Pivotal and supporting efficacy data are needed to support a label claim for control of external flavobacteriosis on cool and warm water fish. In a recent commitment, the North Central Regional Aquaculture Center is providing funds to Iowa for pivotal efficacy studies on percids for control of external flavobacteriosis

Copper Sulfate (external microbicide)—Status: All submissions should soon be completed for control of Ichthyophthirius on catfish in ponds.

Progress on Technical Sections on copper sulfate:

Product Chemistry—Accepted by CVM from the sponsor, Phelps Dodge Refining Corporation.

Mammalian Safety—Accepted by CVM; a Freedom of Information (FOI) summary written by CVM on March 3, 2000.

Environmental Safety—The revised environmental safety technical section for all fish was reviewed by CVM in 2000 and CVM is requiring an additional study. A study at HKD-SNARC addressed the use of copper sulfate in ponds was completed and will be incorporated into a revised EA and submitted to CVM by January 1, 2002.

Human Food Safety—Accepted by CVM; FOI written by CVM on March 3, 2000--no tolerances, regulatory methods, or withdrawal times are needed for finfish treated with copper sulfate.

Target Animal Safety—Additional target animal safety studies with a histopathology component are required for an all fish label claim. HKD-SNARC performed such a study on channel catfish and will submit it to CVM by the end of November 2001.

Efficacy—Accepted by CVM for control of Ichthyophthirius on all fish.

HKD-SNARC conducted pivotal efficacy studies to control fungi on catfish eggs. Needed are pivotal efficacy studies to control: (1) fungi on cool- and warmwater fish eggs, (2) fungi on all fish, (3) external columnaris disease on all fish, and (4) external parasites (except Ichthyopthirius sp.) on all fish

Supporting efficacy data considered to be sufficient by HKD-SNARC include the control of: (1) fungi on all fish, (2) external columnaris disease on all fish, and (3) external parasites (including Ichthyopthirius sp.) on all fish. Needed are supporting efficacy studies to control fungi on all fish eggs.

The claims for control of Ichthyophthirius on all fish and other external microbes on all fish would be based on additional efficacy and target animal safety studies that would be completed in 2002 if stakeholders were interested. FOI document preparation for efficacy, target animal safety, and environmental safety for the control of Ichthyophthirius sp. on catfish in ponds by copper sulfate is underway at HKD-SNARC. When the target animal safety and environmental safety technical sections are accepted by CVM, the data requirements will be complete for control of Ichthyophthirius on catfish in ponds.

Cutrine-Plus™ (external microbicide)—Status: Some interest by potential sponsor; early development stage, no recent activity.

Diquat Dibromide (external microbicide)—Status: No commitment as yet by potential sponsor; early development stage.

The potential sponsor, Syngenta, has expressed an interest in developing their diquat product for use as a drug in aquaculture. The National Aquaculture NADA Coordinator provided information on diseases, fish species, and potential market from August to October 2001.

Earth Tec Algicide/Bactericide™ (external microbicide)—Status: No recent activity by sponsor; early development stage.

Enrofloxacin (oral antibacterial)—Status: INADs inactive in the United States because of fluoroquinolone and antimicrobial resistance issues; no sponsor interest.

Erythromycin (oral antibacterial)—Status: Sponsorship needs to be resolved; all technical sections except sponsor product chemistry submitted; risk assessment needed on potential for disease resistance in humans; near NADA approval for bacterial kidney disease in salmonids if can gain sponsor and resolve the antimicrobial resistance issue.

University of Idaho researchers recently submitted to CVM a summary addressing antimicrobial resistance issues by discussing the effects of erythromycin and other antimicrobials on the bacterial load, species composition, and resistance patterns in salmonid gastrointestinal tracts.

A potential sponsor for erythromycin has been identified.

Florfenicol (oral antibacterial)—Status: Sponsor recently allowed the development of florfenicol for approval in U.S.; approved in Canada in August 1997 to control furunculosis in Atlantic salmon. Sponsor will continue to develop data for aquaculture approval but the efforts by the IAFWA Project on florfenicol have been redirected by the IAFWA Drug Approval Working Group (DAWG) to other IAFWA Project drugs.

The florfenicol INAD exemption (INAD 10-697) has been granted by CVM to FWS. The INAD stipulates a 21-day withdrawal period. The first pivotal efficacy study was completed in June 2001 evaluating the effectiveness of florfenicol to control mortality caused by furunculosis in coho salmon.

A UMESC scientist was trained by Schering-Plough Animal Health (SPAH) personnel on the analytical method for determination of florfenicol in fish feed to support efficacy studies through the INAD held by FWS. Two UMESC scientists analyzed fortified and unknown fish feed samples for florfenicol that were simultaneously analyzed at SPAH. Based on the results of these analyses, the analytical method was deemed successfully transferred to UMESC and the scientists were certified to conduct analyses of fish feed for florfenicol.

Multi-State Conservation Grant Proposal "Analytical Support of Pivotal Efficacy Trials for Use in Public Fisheries" was funded under the Federal Aid in Sport Fish Restoration Act on May 16, 2001. The proposal provides for analyses of fish feed for florfenicol content from pivotal efficacy trials conducted under the INAD held by FWS. In addition, the proposal includes validation of the analytical method on fish feeds not previously completed by the sponsor and used in pivotal trials.

Discussions on the development of florfenicol were held with CVM and the sponsor at the FWS-INAD Coordination meeting in Bozeman, Montana on August 1-3, 2001.

A proposal was submitted in April 2001 to the Initiative for Future Agriculture and Food Systems to fund studies on both florfenicol and Romet-30® needed for approval in cool and warm water scaled fish to help modest-sized farms diversify for more profitability and efficiency. The proposal was not funded.

A Cooperative Research and Development Agreement (CRADA) between SPAH and USGS was signed on April 10, 2001. UMESC completed the in-life phase of a target animal safety study for florfenicol in channel catfish under that CRADA.

Formalin (external microbicide)—Status: Supplemental NADA approved on June 18, 1998 for control of certain fungi on the eggs of all finfish and certain external protozoa and monogenetic trematodes on all finfish. All submissions should soon be completed for control of mortalities associated with fungal infections on all fish.

Natchez Animal Supply Company submitted a supplemental NADA to CVM on June 5, 2001 for its formalin product, Formalin-F®, to control certain fungi on the eggs of all fish and certain external protozoa and monogenetic trematodes on all fish.

Progress on Technical Sections on formalin:

Product Chemistry—Accepted by CVM.

Mammalian Safety—Accepted by CVM.

Environmental Safety—Accepted by CVM.

Human Food Safety—Accepted by CVM.

Target Animal Safety—Accepted by CVM.

Efficacy—Fungal disease model developed for efficacy studies by UMESC.

CVM informally accepted supporting efficacy for control of fungi on salmonids from FWS and UMESC efforts. Plans are underway by CVM and UMESC to perform pivotal efficacy studies for control of fungi on salmonids and channel catfish.

Fumagillin (microsporidiosis control)—Status: No recent sponsor activity; several efforts to collect efficacy data in public and private sector; early development stage.

Hydrogen peroxide (external microbicide)—Status: Currently considered as a low regulatory priority drug for use as a fungicide on fish and fish eggs but CVM has encouraged the development of a NADA; three label claims nearing completion for approval.

On July 18, 2001, CVM accepted as supporting efficacy data for treatment of external parasitic infestations in fish.

On October 4, 2001, CVM accepted target animal safety data at concentrations from 50 to 100 mg/L for a variety of fish exposed to hydrogen peroxide from 30 to 60 minutes.

In September 2001, the Multi-State Conservation Grant Program indicated it will fund UMESC to develop a model to infect fish with external columnaris disease.

UMESC has continued to expand its coordination and collaboration to develop additional efficacy data to support the use of hydrogen peroxide by initiating three compassionate INADs. Participation in the three INAD protocols has increased immensely over the past year from 24 INAD cooperators in 2000 to 115 in 2001.

UMESC is drafting a report providing additional efficacy data at the low end of the proposed hydrogen peroxide dose range for the eggs of cool and warm water fish. No further laboratory testing of hydrogen peroxide on freshwater fish eggs is planned.

Progress on Technical Sections on hydrogen peroxide:

Product Chemistry—Sponsor, Eka Chemicals, Inc., submitted product chemistry technical section on July 12, 1999; additional data are required that the sponsor is committed to provide.

Mammalian Safety—Accepted by CVM. The FOI summary was written by CVM on March 22, 2000.

Environmental Safety—A model was developed by UMESC to estimate discharged environmental concentrations based on UMESC hatchery survey and a point source dilution model from the U.S. Geological Survey. UMESC wrote an environmental assessment to support an all fish label claim and submitted it to CVM on March 14, 2000 and was under review by a contractor in the summer of 2001.

Human Food Safety—Accepted by CVM. The FOI summary was written by CVM on March 22, 2000--no tolerances, regulatory methods, or withdrawal times are needed for finfish and their eggs treated with hydrogen peroxide.

Target Animal Safety—Target animal safety technical section on all fish eggs submitted by UMESC to CVM was accepted for a dose range of 500–1,000 mg/L for northern pike, lake trout, and common carp. A target animal safety technical section on all fish from UMESC was accepted on October 4, 2001 by CVM.

Efficacy—A fungal disease model was developed for efficacy studies with fish by UMESC.

CVM accepted pivotal efficacy data for treatment of salmonid eggs to control mortalities associated with saprolegniasis by a 15-minute treatment at 500 mg/L of hydrogen peroxide; and a 60-minute treatment at 50 mg/L or 30-minute treatment at 100 mg/L of hydrogen peroxide to control mortalities associated with BGD on salmonids. CVM accepted the following as supporting data: (1) 60-minute treatments to control mortalities associated with external columnaris disease in yellow perch and (2) treatment of external parasitic infestations in fish.

Protocols for supporting efficacy studies under an INAD at UMESC were submitted to CVM for review for: (1) control of mortality from saprolegniasis on cool and warm water fish eggs and all fish, (2) control of mortality from external flavobacteriosis on all fish, and (3) control of external parasites on all fish.

When target animal safety technical section on salmonid eggs and the environmental assessment are accepted and the FOIs completed for efficacy and target animal safety, the data requirements will be completed for the control of mortality from saprolegniasis on all fish eggs, saprolegniasis on all fish, and bacterial gill disease on salmonids reared in freshwater.

MelaFix (external microbicide)—Status: Early development stage

Neomycin sulfate (vibriosis control)—Status: No activity on this drug.

Oxytetracycline (OTC, oral antibacterial)—Status: Currently approved for control of certain bacterial diseases in catfish, salmonids, and lobsters and as a marking agent in Pacific salmon. Almost all submissions are considered complete for otolith marking on all fish by immersion and for control of mortalities associated with systemic columnaris disease in all salmonids and systemic coldwater disease in all salmonids.

On May 15, 2001, CVM accepted residue depletion studies for walleye and northern pike fed OTC medicated feed and established zero withdrawal times in juvenile northern pike and juvenile walleye at water temperatures down to 14 C and 16 C, respectively.

UMESC obtained funding for an OTC EA from the Wallop-Breaux Sport Fish Restoration Funds on July 25, 2001. The project includes measurement of OTC in water and sediment in and around a hatchery with a typical treatment for a disease episode.

In September 2001, the Multi-State Conservation Grant Program indicated it will fund UMESC to develop data toward oxytetracycline immersion therapy.

On October 5, 2001, UMESC submitted a response to CVM regarding data to support human food safety technical section for an analytical method for oxytetracycline in the edible tissue of fish used in residue depletion studies.

Progress on Technical Sections on OTC:

Product Chemistry— Previously accepted by CVM under original NADA from Pfizer, Inc. (now owned by Philbro Animal Health).

Mammalian Safety—Previously accepted by CVM under original NADA from Pfizer, Inc. (now owned by Philbro Animal Health).

Environmental Safety—Previously accepted by CVM under original NADA from Pfizer, Inc. (now owned by Philbro Animal Health). CVM is requiring a new EA for any new label claims. UMESC is in the process of writing the EA.

Human Food Safety—Previously accepted by CVM for certain label claims under original NADA from Pfizer, Inc. for OTC for cold water species above 9 C and warm water species above 16 C. Recently, CVM accepted: (1) residue chemistry studies submitted by UMESC for use of OTC below the label claim limit of 9 C which established a withdrawal time of three days for juvenile salmonids, (2) residue depletion studies submitted by UMESC for the use of OTC in juvenile cool water species with a zero withdrawal time, (3) an HPLC method developed by UMESC to detect OTC in feed and fish tissue, and (4) a study completed by UMESC bridging the HPLC OTC detection method to the official microbial assay method. UMESC petitioned CVM to shorten the withdrawal time for OTC in all freshwater fish species based on its residue depletion data and the new tolerance of 2 ppm. Efforts on this technical section are considered complete.

Target Animal Safety—Previously accepted by CVM for catfish, salmonids, and lobsters under original NADA from Pfizer, Inc. Target animal safety studies conducted according to Good Laboratory Practice regulations will be required for cool water fish, unless there are adequate pivotal and supporting efficacy studies on these additional species to demonstrate that OTC is safe. At this point in the IAFWA Project, only one efficacy study on a cool water species (northern pike) has been accepted by CVM as supporting data for efficacy.

Efficacy—Previously accepted by CVM under original NADA from Pfizer, Inc. for OTC use on catfish, salmonids and lobsters to control certain systemic bacterial diseases. CVM accepted the use of OTC at 3.75 g/100 lbs of fish for 10 days as effective in reducing mortalities from: (1) systemic columnaris disease in steelhead trout and (2) systemic coldwater disease in fingerling coho salmon. The efficacy technical section developed by UMESC from a data call-in was accepted as supporting data for control of: (1) Aeromonas sp. in cool water species and (2) systemic columnaris disease in salmonids. Both pivotal and supporting efficacy data are still needed for control of systemic columnaris disease in cool and warm water fish.

The efficacy technical section developed by UMESC from a data call-in was accepted as supporting data by CVM for: (1) control of Aeromonas sp. in cool water species and (2) systemic flavobacteriosis in salmonids. Pivotal efficacy data are still needed for control of Aeromonas sp. in cool water species.

UMESC researchers collaborated with the state of Iowa (Rathbun Research Facility, Moravia, Iowa) to conduct a pivotal efficacy trial to control mortalities associated with systemic columnaris disease in walleye (Stizostedion vitreum). The efficacy trial was inconclusive.

Pet Fish Therapeutants (various drugs and pesticides)—Status: Major effort to resolve non-food fish issues for these drugs through Minor Use/Minor Species legislation.

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Potassium Permanganate (external microbicide)—Status: Sponsor is committed to revising a product chemistry technical section; one label claim possible in 2003

In September 2001, the Multi-State Conservation Grant Program indicated it will fund a study on the environmental fate and effect of potassium permanganate.

HKD-SNARC completed a target animal safety study on channel catfish and plans to submit the study to CVM in March 2002.

HKD-SNARC completed pivotal efficacy studies that demonstrated efficacy to prevent Ichthyophthirius sp. on channel catfish and tilapia and plans to submit the study to CVM in March 2002.

Progress on Technical Sections on potassium permanganate:

Product Chemistry—The sponsor, Carus Chemical Company, submitted product chemistry technical section for all fish to CVM on December 8, 1998; additional data are still needed.

Mammalian Safety—Accepted by CVM.

Environmental Safety—The sponsor submitted a request for a categorical exclusion from an environmental assessment for all fish to CVM on February 23, 1998; CVM is requiring an environmental assessment. Effort will begin soon on environmental fate and effects studies with funding from the Multi-State Conservation Grant Program

Human Food Safety—Accepted by CVM.

Target Animal Safety—HKD-SNARC completed a target animal safety study on channel catfish (except for histopathology) and plans to conduct a target animal safety on rainbow trout.

Efficacy—HKD-SNARC completed pivotal efficacy studies that demonstrate efficacy to prevent Ichthyophthirius on channel catfish and tilapia. HKD-SNARC is initiating a pivotal efficacy study for control of Ichthyophthirius on channel catfish and a scaled species.

Staff at UMESC has begun a study to determine the efficacy of potassium permanganate for control of mortality from saprolegniasis on channel catfish.

Supporting efficacy data are considered to be sufficient by HKD-SNARC for: (1) control of mortality from saprolegniasis on fish, (2) control of mortality from external flavobacteriosis, and (3) control of external parasites (including Ichthyophthirius) on all fish. Needed are supporting efficacy studies for control of mortality from saprolegniasis on all fish eggs.

HKD-SNARC will decide whether to address adding other label claims. Interested parties will need to help gain data for control of mortality from external fungal infections on all fish and for control of mortality from external flavobacteriosis and control of parasitic infestations on all fish.

Praziquantel (trematode and cestode control)—Status: Some interest on the part of potential sponsor in a NADA approval in the United States but needs positive marketing information; has approval in several countries.

The potential sponsor of praziquantel expressed an interest in developing their product for United States aquaculture at a meeting in August 2001 in Bozeman, Montana.

The National Aquaculture NADA Coordinator met with Betty L. Mitchell, Inc. on May 17, 2001 in Stoneville, Mississippi to discuss the development of her praziquentel product.

Pyceze™ (external microbicide)—Status: Sponsor submitted an INAD/NADA letter of intent and summary of all major technical sections; met with CVM on development of data; early development stage.

Vericore Limited sold its Pyceze™ to Novartis Animal Health LTD who is interested in moving forward more rapidly in developing their product for our domestic aquaculture as stated at a meeting in August 2001 in Bozeman, Montana.

On November 1, 2001, Novartis Animal Health announced that Pyceze™ was approved in the United Kingdom for the control of fungal infections on salmonid eggs.

Quinine (internal microbicide—Status: Some interest on the part of potential sponsor in a NADA approval in the United States but needs positive marketing information.

Romet-30™ (oral antibacterial)—Status: Romet-30™ has limited approvals for catfish and salmonids. Early development stage for extensions and expansions.

The National Aquaculture NADA Coordinator met with the product manager for Romet-30™ and UMESC in August 2001 in Bozeman, Montana to discuss potential extensions and expansions of the NADA for publicly cultured finfish.

Sarafloxacin (oral antibacterial)—Status: Previously, most of the NADA technical sections were submitted by Abbott Laboratories and accepted by CVM for control of enteric septicemia in catfish with sarafloxacin. However, CDC presented concerns about the use of all fluoroquinolones in animal health because of the perceived potential for developing pathogen resistance to drugs used in humans. It is doubtful that a new NADA on sarafloxacin or any fluoroquinolone will be allowed for aquaculture uses by CVM. Sarafloxacin was replaced by florfenicol as the oral antibacterial and model drug for crop grouping research in January 1998 by a unanimous vote of the IAFWA Project stakeholders.

Sea Lice Control (various drugs and pesticides)—Status: Various drugs and pesticides (azamethiphos or Salmosan™, cypermethrin or Excis™) are being pursued by the United States and Canada and are at various stages of registration and approval.

Various drugs and pesticides (azamethiphos or Salmosan™, cypermethrin or Excis™) are being pursued by the United States and Canada and are at various stages of registration and approval. These uses are being challenged on the East coast, particularly in Maine. An INAD for Slice™ (emamectin benzoate) was allowed by CVM as a result of great need for a control that could not be challenged to the extent that the others have been.

Trichlorfon (external parasite control)—Status: Some interest on the part of potential sponsor in a NADA approval in the United States; has approvals in several countries; several Special Local Need registrations obtained in 1998 for control of predaceous insects.

The SLN registration in California is in jeopardy because the state wants more data.

AQUI-S™ — Status: Sponsor (AQUI-S New Zealand Ltd.) proceeding with worldwide drug approval.

The sponsor, AQUI-S New Zealand LTD., reversed a business decision to reformulate their product. The product to be developed in the United States is the same formulation that the company has approved as a fish anesthetic in several countries.

At their meeting at Bozeman, Montana on August 2-3, 2001, members of the DAWG verbally agreed to the redirection of Year 8 funds originally intended for efficacy and target animal safety studies to conduct studies necessary to determine the marker residue of AQUI-S™.

In September 2001, the Multi-State Conservation Grant Program indicated it will fund UMESC to develop a determinative analytical method for the marker residue for AQUI-S™.

USDA did not fund the proposal submitted by the U.S. representative of AQUI-S™ for mammalian safety studies that would substitute for NTP studies that are scheduled for completion in the spring of 2002.

Progress on Technical Sections on AQUI-S™:

Product Chemistry—Accepted elsewhere; no current activity for U.S.

Mammalian Safety—The sponsor (AQUI-S New Zealand Ltd.) conducted a review of the mammalian safety literature to determine whether to continue with the original active ingredient in light of National Toxicology Program (NTP) studies to test for its potential carcinogenicity scheduled for completion in July 2001. The sponsor concluded that the active ingredient is safe and presented these conclusions to CVM on November 18, 1999 and decided to proceed with the drug approval in the U.S. for original active ingredient based on their assessment of scientific data that the active ingredient is not a carcinogen.

Environmental Safety—The sponsor submitted a summary to CVM and has completed an environmental biodegradation study in freshwater and salt water that will soon be submitted to CVM for review.

Human Food Safety—Efforts are underway to develop residue chemistry data on salmonids by July 2002.

Target Animal Safety—Preliminary toxicity studies have been completed at UMESC on a variety of fish species but UMESC will not perform any other studies because funds were diverted to fulfill the need for human food safety studies. Pivotal target animal safety studies on salmonids will be performed at FWS. The sponsor is ready to submit target animal safety and efficacy studies on salmonids completed in Canada to CVM.

Efficacy—Preliminary efficacy studies were completed at UMESC on a variety of fish species. Pivotal efficacy studies will be performed by FWS on a variety of fish species but UMESC will not perform any other studies because funds were diverted to fulfill the need for human food safety studies. The sponsor is ready to submit efficacy studies on salmonids completed in Canada to CVM. On November 29, 2000, CVM permitted the use of AQUI-S™ under FWS’s INAD to treat up to 100 million fish with 5 to 34 mg/L AQUI-S™ in a static bath for one to ten minutes.

Benzocaine—Status: Major effort by IAFWA Project for NADA approval terminated because of decision by IAFWA Project stakeholders to select AQUI-S™ as the candidate anesthetic in the U.S. public aquaculture sector; no known drug approval activities underway.

MS-222—Status: Two approved NADAs for MS-222 as an anesthetic with a 21-day withdrawal time.

Oil of Cloves—Status: Oil of cloves (eugenol) is considered Generally Recognized as Safe (GRAS) when used as a direct food additive (21CFR184.1257); however, to use eugenol as an anesthetic on fish, it must be approved by CVM for that purpose. A sponsor is required to proceed toward approval and no sponsor has come forward; no known drug approval activities underway.

Common Carp Pituitary (CCP)—Status: Sponsor and interested parties proceeding toward NADA approval. All submissions should be completed in 2001 for use on all fish.

Mississippi State University submitted a target animal safety study on grass carp to CVM. Funding has been requested from NRSP-7 to do research on walleye, catfish, and white bass.

Progress on Technical Sections on CCP:

Product Chemistry—The sponsor submitted the product chemistry technical section for CCP to CVM on September 21, 1999. The sponsor received a response on November 22, 1999 from CVM that asked for more information

Mammalian Safety—Accepted by CVM.

Environmental Safety—Accepted by CVM.

Human Food Safety—Accepted by CVM.

Target Animal Safety—A literature review on target animal safety of CCP was completed, presented on August 5, 1998 in Bozeman, Montana and submitted to CVM in summer 1999 by the Southeastern region of NRSP-7. A researcher from Mississippi State University completed target animal safety studies on CCP and submitted them to CVM.

Efficacy—A literature review on efficacy of CCP was completed, presented on August 5, 1998 in Bozeman, Montana and submitted to CVM in summer 1999 by the Southeastern region of NRSP-7.

17 -estradiol (estrogen)—Status: Sponsor established INAD #10-673) and had a meeting with CVM to determine data requirements; early development stage.

Human Chorionic Gonadotropin (hCG)—Status: September 1999 NADA approval in the United States.

Chorulon® (human chorionic gonadotropin) was approved on September 7, 1999 by CVM as a spawning aid by intramuscular injection for all fish and requires a prescription under the direction of a veterinarian. This approval is significant because it is the first original approval since 1986 when formalin was first approved for fish and because it was approved for all fish.

17 -methyltestosterone (MT)—Status: Sponsor is developing NADA package; INAD sponsors actively pursuing a NADA approval; environmental assessment reviewed, revised, and resubmitted.

Environmental Safety—Auburn University is working on a response to comments by CVM on the environmental assessment that they wrote on the use of MT for tilapia. It has been determined that an environmental study is needed and Auburn has secured a USDA laboratory to do the study. This study will be conducted in the spring of 2002. Auburn developed a study protocol that they submitted on October 4, 2001 to CVM for review and acceptance.

Target Animal Safety—Auburn is working on a TAS technical section for tilapia. Southern Illinois University (SIU) completed a TAS study on percids that was funded by NCRAC and reviewed by CVM. The TAS study was found to be inadequate by CVM; SIU needs to respond to the comments by CVM to resolve the issues so that the technical section can be declared complete for percids by CVM.

Efficacy—Auburn is working on a technical section to complete it for tilapia. The University of Wisconsin is working on developing the efficacy technical section for percids.

Progress on Technical Sections on MT:

Product Chemistry—The sponsor, Rangen, Inc., submitted a product chemistry technical section on 17 -methyltestosterone to CVM on November 8, 2000.

Mammalian Safety—Accepted by CVM.

Environmental Safety—Auburn University received a response from CVM on November 8, 1999 regarding the revised environmental assessment for MT that requested additional information; met on July 18, 2000 to discuss response; efforts to meet the remaining data requirements in this technical section are underway at the Aquatic Animal Health Research Unit in Auburn, Alabama..

Human Food Safety—Accepted by CVM.

Target Animal Safety—CVM found a target animal safety study on percids by Southern Illinois University to be inadequate; literature review on other species completed by Auburn University.

Efficacy—Auburn University coordinating compassionate INAD on tilapia; North Central Regional Aquaculture Center representatives coordinating compassionate INAD on percids.

Ovaplant™ and Ovaprim™—Status: Sponsor recently submitted INAD letter of intent; early development stage.

ReproBoost™ (Gonadotropin Releasing Hormone)—Status: Sponsor recently submitted INAD letter of intent; early development stage.

Calcein—Status: No sponsor; one known publication on efficacy.

Oxytetracycline—Status: FDA liaison to NRSP-7 completed a Public Master File and submitted it to CVM on November 1, 1999.

Strontium Chloride—Status: Western Chemical Inc. is the sponsor; some work completed in Alaska; some efficacy studies underway under Western NRSP-7.

Both rotenone and antimycin are used by hatcheries in resource agencies and private aquaculture facilities to control diseases in cultured fish and undesirable fish in ponds.

The National Aquaculture NADA Coordinator hosted a meeting at La Crosse, Wisconsin on May 31 to June 3, 2001 to discuss the development of reregistration feasibility on antimycin and a rotenone use survey.

The National Aquaculture NADA Coordinator met with EPA on November 15, 2001 to discuss the revised data requirements for the reregistration of antimycin based on a draft study report that was completed by the Fish Management Chemicals Subcommittee of the American fisheries Society.

The Drug Approval Working Group (DAWG) for the Federal-State Aquaculture Drug Approval Partnership Project (IAFWA Project) held a meeting in Bozeman, Montana on August 2-3, 2001 to: (1) discuss the progress being made on the IAFWA Project drugs, (2) work plans for the final year of the IAFWA Project, (3) discuss new funding proposals on florfenicol, AQUI-S™, disease model for external columnaris disease, and environmental assessment for oxytetracycline, and (4) the future of public drug approval efforts after 2002.

A special session entitled "Aquaculture and drug resistance" was convened at Aquaculture 2001 on January 25, 2001, Lake Buena Vista, Florida. Topics included: (1) biology of antibiotic resistance, (2) antibiotic resistance in the salmonids and channel catfish industries, (3) standardization of susceptibility testing, and (4) the negligible public health risk from antimicrobial use in aquaculture.

An article addressing aquaculture and drug resistance was written by Randy MacMillan and published in the June 2001 issue of World Aquaculture.

The Joint Subcommittee on Aquaculture formed the Aquaculture Effluents Task Force (AETF) to coordinate and facilitate input of science-based information to assist in the development of national effluent limitation guidelines and standards for aquaculture facilities by EPA. The AETF met on October 17-18, 2001 to discuss the status of EPA’s Effluent Guidelines Plan for aquaculture facilities. A white paper related to effluent issues for drugs and chemicals was submitted to EPA on August 24, 2000. A conference call was convened on May 30, 2001 to discuss drug and chemical issues with EPA and a response was prepared after a conference call on October 11, 2001 with AETF members.

A bill entitled "Minor Animal Species Health and Welfare Act of 2000" was introduced in the U.S. Congress into the House on June 27, 2000 (HR-4780) and into the Senate on October 5, 2000 (S-3169). The MUMS Act will facilitate and accelerate the approvals of aquaculture drugs. There is a great need for more co-sponsors. The bill includes provisions for early life stages that should help expedite the approvals of aquaculture drugs that are of interest to public and private fish production. A revised bill "Minor Use Minor Species Animal Health Act of 2001" was reintroduced into the House on May 24, 2001 (HR-1956) and into the Senate on August 2, 2001 (S-1346). The MUMS Coalition met on June 22, 2001 to coordinate the legislative effort on the bill, present information to legislative staff, and contact individual congressmen and senators for their support and sponsorship. Letters were written to follow-up on the contacts.

A session on international harmonization of sensitivity testing was held at the EAFP 9th International Conference, September 19-24, 1999 in Rhodes, Greece. A follow-up session was held in Dublin, Ireland in September 2001; an update is not available at this time. The EAFP Work Group is working with the National Committee for Clinical Laboratory Standards to develop protocols that will allow aquatic diagnostic and research laboratories to: (1) test disease-associated bacterial isolates for antimicrobial susceptibility patterns and (2) recommend appropriate therapy in a standard, internationally accepted manner. Added benefits include aiding the approval process for antibacterial agents and helping to determine the antimicrobial resistance of aquaculture pathogens worldwide.

CVM awarded a contract on the risk assessment of drugs and chemicals used in foreign aquaculture on September 28, 2001 to ICF Consulting. The objectives of this contract are to: (1) create a database containing information on drug and chemical use is foreign aquaculture and (2) perform a human food safety risk assessment for each drug and chemical listed in the database. FDA will use the results of this contract to: (1) prioritize the monitoring of drug and chemical residues in the edible tissue of imported aquaculture products, (2) prioritize the development of methods to be used in the monitoring program, and (3) provide a basis for promoting discussion with foreign countries regarding the hazard concerns identified by the risk assessment. The National Aquaculture NADA Coordinator is a subcontractor to this project.

On August 2-3, 2001, nine sponsors or potential sponsors invited by the National Aquaculture NADA Coordinator attended a meeting of the Federal-State Aquaculture Drug Approval Partnership Project. These sponsors were interested in the development of their products for aquaculture. These sponsors included the major pharmaceutical firms of Alpharma, Bayer, Intervet, Norvartis, and Schering-Plough and chemical or niche companies of Akzo Nobel Chemicals Inc., AQUI-S New Zealand LTD, Phelps Dodge Refining Corporation, and Carus Chemical Company.

Schnick, R.A. 2001. International harmonization of antimicrobial sensitivity determination for aquaculture drugs. Aquaculture (3-4):277-288.

Schnick, R.A. 2001. Progress of the Federal-State Aquaculture Drug Approval Partnership Project. American Fisheries Society Fish Health Newsletter 29(4):6-7, 9.

MANUSCRIPTS

Schnick, R.A. In press. Aquaculture chemicals. Chapter in Kirk-Othmer Encyclopedia. John Wiley & Sons, Inc., New York, New York..

Schnick, R.A. 2001. New drug availability. Aquaculture Medicine Educational Program, AVMA Convention 2001, Boston, Massachusetts, July 14-16, 2001.

Schnick, R.A. 2001. Overview of progress toward aquaculture drug approvals. USFWS – 7^th Annual INAD Coordination Workshop, Bozeman, Montana, August 1-3, 2001.

Schnick, R.A. 2001. Update on the activities of the National Coordinator for Aquaculture new Animal Drug Applications. NRSP-7 Fall Meeting, Rockville, Maryland, October 22-23, 2001.

Schnick, R.A. 2001. National Coordinator for Aquaculture New Animal Drug Applications (NADAs). Sixth annual report of activities, May 15, 2000 to May 14, 2001. Submitted to Ted Batterson, North Central Regional Aquaculture Center, East Lansing, Michigan. June 15, 2001. 17 pp.

Schnick, R.A. 2001. Notes on conference call regarding AQUI-S™ on June 5, 2001, 2:45 PM. Submitted to participants in conference call, La Crosse, Wisconsin, July 10, 2001. 2 pp.

Schnick, R.A. 2001. 2001 annual report of the AFS Task Force on Fishery Chemicals. Submitted to the Governing Board and AFS President, Carl Burger, Bethesda, Maryland. July 18, 2001. 4 pp.

Gingerich, W.H., R.A. Schnick, and B.R. Griffin. 2001. Approval of Drugs for Public Fish Production: Grant proposal for Project Year 8. Biological Resources Division, USGS, Upper Midwest Environmental Sciences Center, La Crosse, Wisconsin. July 26, 2001. 13 pp.

Schnick, R.A. 2001. OTC: Federal-State Aquaculture Drug Approval Partnership Project. Submitted to Gregory Bergt, PennField Animal Health, La Crosse, Wisconsin, August 21, 2001. 2 pp.

Schnick, R.A. 2001. Estimated costs for studies to be performed at the Upper Midwest Environmental Sciences Center, La Crosse, Wisconsin (as of August 2001). Submitted to pharmaceutical firm (confidential), August 23, 2001. 2 pp.

Schnick, R.A. 2001. Rankings of proposals for Multi-State Conservation Grant Program–August 2001. Submitted to IAFWA representatives, August 29, 2001. 5 pp.

Schnick, R.A. 2001. Comments on import tolerances. Submitted to the Catfish Farmers of America, Indianola, Mississippi, September 5, 2001. 2 pp.

Gingerich, W.H., V.K. Dawson, G.R. Stehly, J.A. Bernardy, M.P. Gaikowski, J.R. Meinertz, J.J. Rach, J.J. Rach, L.J. Schmidt, C. Vue, R.A. Schnick, and B.R. Griffin. 2001. Approval of Drugs for Public Fish Production: Seventh annual report of progress [performance period: July 1, 2000 to June 30, 2001]. Biological Resources Division, USGS, Upper Midwest Environmental Sciences Center, La Crosse, Wisconsin. September 14, 2001. 50 pp.

Schnick, R.A. 2001. Draft minutes to Drug Approval Working Group meetings, Bozeman, Montana. Submitted to selected IAFWA representatives, September 20, 2001. 10 pp.

Schnick, R.A. 2001. Diquat dibromide potential in aquaculture. Submitted to Syngenta, Greensboro, North Carolina, October 3, 2001. 3 pp.

Schnick, R.A. 2001. Status of technical sections for joint minor use/minor species drug approvals coordinated through the National Aquaculture NADA Coordinator and NRSP-7 as of October 22, 2001. Submitted to NRSP-7, Rockville, Maryland, October 22, 2001. 5 pp.

Schnick, R.A. 2001. Progress report for Contract #99-116 (National Coordinator for Aquaculture New Animal Drug Applications). Center for Tropical and Subtropical Aquaculture, Waimanalo, Hawaii. October 25, 2001 (revised November 9, 2001). 9 pp.

Schnick, R.A. 2001. Confidential: Minutes to meeting on genotoxicity studies on p-TSA, the marker residue of chloramine-T with the Center for Veterinary Medicine and Akzo Nobel Chemicals, Inc. representing Axcentive bv. Submitted to Akzo Nobel Chemicals, Chicago, Illinois. November 5, 2001. 5 pp.

Schnick, R.A. 2001. National Coordinator for Aquaculture New Animal Drug Applications (NADAs). Seventh mid-year report of activities, May 15, 2001 to November 9, 2001. Submitted to Ted Batterson, North Central Regional Aquaculture Center, East Lansing, Michigan. November 21, 2001. 15 pp.