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 MID-YEAR SUMMARY OF ACTIVITY HIGHLIGHTS FOR THE NATIONAL COORDINATOR FOR AQUACULTURE NEW ANIMAL DRUG APPLICATIONS

(May 15, 2000 to November 9, 2000)

PROJECT OBJECTIVES

The overall goal of this project is for the National Coordinator for Aquaculture New Animal Drug Applications (National 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.

PROGRESS AND PRINCIPAL ACCOMPLISHMENTS

The National NADA Coordinator provided many information transfers from May 15, 2000 to November 9, 2000 and 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 community.

THERAPEUTANTS

Amoxicillin (oral antibacterial) — Status: Two sponsors submitted INAD/NADA letters of intent; early development stage; antimicrobial resistance issue needs to be addressed.

GB Research, one of the sponsors of an INAD, selected Kent SeaFarms Corporation to be the new United States representative for the development of its amoxicillin product.

Harry K. Dupree Stuttgart National Aquaculture Research Center (HKD-SNARC) has agreed to help develop data to gain approval of amoxicillin in aquaculture.

Chloramine-T (external antibacterial) — Status: Sponsor (Axcentive bv; formerly Akzo Nobel Chemicals, Inc.) committed to INAD/NADA. BOTTOM LINE: All submissions should be completed by 2002 for control of mortalities associated with flavobacterial infections on gills of salmonids.

On April 25, 2000, the National NADA Coordinator was informed that Akzo Nobel Chemicals, Inc. had sold its chloramine-T product (Halamid™) to two of its employees and the new company's name is Axcentive bv. All contacts, agreements, and timetables will remain the same. A letter was sent to CVM to change the sponsorship of INAD #8086 on October 23, 2000.

A meeting was held on October 16-18, 2000 at UMESC to discuss the draft labels for chloramine-T, hydrogen peroxide, and OTC in preparation for a December 14, 2000 meeting with CVM to identify any remaining data gaps for the label claims. These draft labels were sent to the persons who responded to the environmental survey last year for their comments and suggestions.

A meeting was held on August 31, 2000 with CVM and B.L. Mitchell, Inc. concerning the potential development of Actamide™, a chloramine-T product.

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 — Axcentive bv signed an amended Cooperative Research and Development Agreement (CRADA) with the U.S. Geological Survey (USGS) for the Upper Midwest Environmental Sciences Center (UMESC) on October 19, 2000. Axcentive bv completed genotoxicity studies that are proprietary to Axcentive to be submitted soon to CVM into INAD #8086. Funds to pay for the completed studies to be transferred from USGS for payment of funds originally provided to UMESC back to Axcentive under the amended CRADA with USGS.

Environmental Safety — An environmental assessment (EA) will be written by UMESC after a November 29, 2000 meeting with CVM on proprietary environmental data in Axcentive's INAD file and elsewhere and with funds from Axcentive under the CRADA; EA to contain both publicly available data and proprietary data owned by Axcentive; EA to be sent from UMESC to Axcentive to be submitted to CVM into INAD #8086. A model was developed by UMESC to estimate discharged environmental concentrations of chloramine-T based on UMESC’s hatchery survey and a point source dilution model from USGS.

Residue Chemistry — 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.

Work is underway for a regulatory (determinative) method for all freshwater fish at UMESC. UMESC completed validation of the analytical method to determine p-TSA concentrations in the edible tissues a coldwater fish species (rainbow trout). Method accuracy and precision data were within the range of acceptance established by FDA. UMESC also 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 data developed with the outdated method indicating that the two methods were successfully bridged.

UMESC is currently negotiating with CVM for CVM researchers or through an interagency agreement with CVM to develop data for the confirmatory method for p-TSA in fish tissue. UMESC is setting this study up to cover all species of freshwater fish publicly cultured in the United States. This work will be funded with money UMESC originally set aside with CVM for doing work on another drug, benzocaine.

A residue depletion study recently initiated at UMESC with p-TSA in rainbow trout indicates that residue levels measured so far (48, 24, and 12 hours after the 4 days of exposure) for fish exposed to 20 mg/L chloramine-T for 1 hour on 4 consecutive days are well below the 1 mg/L proposed tolerance for p-TSA.

Target Animal Safety — UMESC and the U.S. Fish and Wildlife Service (FWS) at Bozeman, Montana developed or are developing data that will soon be submitted to CVM on the toxicity of chloramine-T to several species of fish

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: Sponsor has an acceptable product chemistry technical section. BOTTOM LINE: All submissions should soon be completed for control Ichthyopthirius on catfish. The claims for control of Ichthyopthirius 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.

The revised Ecological Risk Assessment (ERA) for the use of copper sulfate to control certain waterborne fish diseases was submitted by HKD-SNARC to CVM on June 29, 1999. CVM requested additional references that were supplied in April 2000 by HKD-SNARC.

HKD-SNARC submitted a revised target animal safety technical section for copper sulfate to CVM on January 10, 2000 and received an informal response that limited target animal safety studies that would address histopathology were needed on several species to address insufficient data for an all fish claim. HKD-SNARC is in the process of performing such a study on channel catfish.

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 on March 3, 2000.

Environmental Safety — The revised environmental safety technical section for all fish is in review at CVM. References related to the environmental safety were submitted by HKD-SNARC to CVM at the agency's request in April 2000; no tolerances, regulatory methods, or withdrawal times are needed for finfish treated with copper sulfate.

Residue Chemistry — Accepted by CVM; FOI written on March 3, 2000.

Target Animal Safety — Additional target animal safety studies with a histopathology component are required for an all fish label claim. A study is in progress on channel catfish.

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

Efforts are underway by HKD-SNARC to conduct pivotal efficacy studies to control fungi on fish eggs. Needed are: (1) pivotal efficacy studies to control fungi on all fish, (2) control external flavobacteriosis on all fish, and (3) control external parasites (except Ichthyopthirius) on all fish

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

FOIs for efficacy and target animal safety are underway at HKD-SNARC.

When the target animal safety (in progress) and environmental safety (under review) technical sections are accepted by CVM, the data requirements will be complete for control of Ichthyopthirius on catfish.

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

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

Earth Tec Algicide/Bactericide™ (external microbicide) — Status: Sponsor submitted INAD/NADA letter of intent and met with CVM on data requirements; early development stageno recent activity.

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.

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. BOTTOM LINE: Sponsor will continue to develop data for aquaculture approval but the efforts by the IAFWA Project on florfenicol have been redirected at this time by the IAFWA Drug Approval Working Group (DAWG) to other IAFWA Project drugs.

The National NADA Coordinator and representatives from FWS, CVM, and UMESC met with Schering-Plough Animal Health on May 2, 2000 in Union, New Jersey to discuss the details on how to proceed on the development of florfenicol for public and private aquaculture in the United States.

Discussions on the development of florfenicol were held with CVM at the FWS-INAD Coordination meeting in Bozeman, Montana on August 2-3, 2000.

UMESC and FWS submitted Multi-State Grant Conservation Proposals to develop data on florfenicol for use on publicly cultured fish to International Association of Fish and Wildlife Agencies in September 2000. The funding for the Multi-State Grant Program was signed by the President on November 1, 2000. FWS was funded for two years to develop efficacy data and UMESC was funded for one year of their proposal to support the efficacy data; additional funding beyond one year for UMESC will be dependent on an assessment of the results on the data developed in the first year and the status of the antimicrobial resistance issue for florfenicol.

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. BOTTOM LINE: All submissions should soon be completed for control of mortalities associated with fungal infections on all fish.

Progress on Technical Sections on formalin:

Product Chemistry — Accepted by CVM.

Mammalian Safety — Accepted by CVM.

Environmental Safety — Accepted by CVM.

Residue Chemistry — 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 to perform pivotal efficacy studies for control of fungi on salmonids. Supporting efficacy data are needed for control of fungi on cool and warm water fish.

Fumagillin (microsporidiosis control) — Status: Sponsor submitted INAD/NADA letter of intent; 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; human food safety data requirements are met. BOTTOM LINE: All submissions should soon be completed for control of mortality from saprolegniasis on all fish eggs; by 2002, for control of mortality from saprolegniasis on all fish, for control of mortality from external flavobacterial infections on gills of salmonids, and for control of parasitic infestations on all fish.

A meeting was held on October 16-18, 2000 at UMESC to discuss the draft labels for chloramine-T, hydrogen peroxide, and OTC in preparation for a December 14, 2000 meeting with CVM to identify any remaining data gaps for the label claims. These draft labels were sent to the persons who responded to the environmental survey last year for their comments and suggestions.

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.

Residue Chemistry — 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 was submitted by UMESC to CVM. The safety data was accepted for a dose range of 500–1,000 mg/L for northern pike, lake trout, and common carp. A target animal safety study on rainbow trout eggs and eggs of most sensitive warm water species will be completed in 2000. The target animal safety technical section on all fish will soon be submitted to CVM by UMESC.

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

CVM accepted efficacy data for the following: (1) a 15-minute treatment at 500 mg/L with hydrogen peroxide to control mortalities associated with saprolegniasis on all salmonid eggs, and (2) a 60-minute treatment at 50 mg/L or 30-minute treatment at 100 mg/L with hydrogen peroxide to control mortalities associated bacterial gill disease on salmonids reared in freshwater. More data were needed for an all fish egg claim: (1) pivotal efficacy studies in progress by UMESC to support a claim for control of mortality from saprolegniasis on cool and warm water fish eggs, and (2) supporting efficacy studies still needed to support a claim for control of mortality from saprolegniasis on cool and warm water fish eggs.

Pivotal efficacy studies have been conducted or are planned by UMESC to support a label claim to control mortality from saprolegniasis on all fish; supporting data are needed to support a claim for control of mortality from saprolegniasis on all fish.

Supporting efficacy data are needed for control of mortality from external flavobacteriosis and control of external parasites on salmonids and both pivotal and supporting data for control of mortality from external flavobacteriosis and for control of external parasites on cool and warm water 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 salmonid eggs.

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. BOTTOM LINE: All submissions are considered complete for otolith marking on all fish by immersion; by 2002, for control of Aeromonas sp. in cool water fish, for systemic coldwater disease in salmonids, and for control of mortalities associated with systemic columnaris disease in salmonids and walleye.

Pfizer Inc., sold its oxytetracycline medicated feed products to Philbro Animal Health (Fort Lee, New Jersey) on September 28, 2000. Philbro Animal Health has expressed an interest in expanding and extending its NADAs for aquaculture.

A meeting was held on October 16-18, 2000 at UMESC to discuss the draft labels for chloramine-T, hydrogen peroxide, and OTC in preparation for a December 14, 2000 meeting with CVM to identify any remaining data gaps for the label claims. These draft labels were sent to the persons who responded to the environmental survey last year for their comments and suggestions.

Progress on Technical Sections on OTC:

Product Chemistry — Accepted by CVM.

Mammalian Safety — Accepted by CVM.

Environmental Safety — Accepted by CVM.

Residue Chemistry — CVM had previously approved certain label claims for OTC for cold water species above 9 C and warm water species above 16 C. Residue chemistry studies were submitted by UMESC to CVM for use of OTC below the label claim limit of 9 C. The HPLC method developed by UMESC was accepted to detect product in feed and fish tissue. The bridging study by UMESC from the HPLC method to the microbial assay method was accepted. Residue depletion studies were completed in two cool water species by UMESC.

Target Animal Safety — Accepted by CVM for catfish, salmonids, and lobsters. Studies may be needed on cool water fish.

Efficacy — The efficacy technical section developed by UMESC from a data call-in was accepted as supporting data 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 and systemic flavobacteriosis in salmonids. Both pivotal and supporting efficacy data are still needed for control of systemic flavobacteriosis in cool and warm water fish.

Several pivotal efficacy studies were completed by FWS to control systemic flavobacteriosis in salmonids and an efficacy technical section was submitted to CVM; however, more studies are still needed.

All technical sections except for portions pivotal and supporting efficacy are complete for new label claims to extend to other fish species and to expand its use to other diseases not on the current label.

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.

Potassium Permanganate (external microbicide) — Status: Sponsor recently submitted a product chemistry technical section and a request for categorical exclusion for environmental safety. BOTTOM LINE: All submissions should be completed by 2002 for control of Ichthyopthirius on all fish, 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.

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 — Data requirements are dependent upon results of residue chemistry review 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. The sponsor is working on developing a contract for an environmental assessment with HKD-SNARC but the company needs further information on data requirements from CVM.

Residue Chemistry — The residue chemistry technical section for all fish was submitted by HKD-SNARC to CVM and an informal response from CVM indicated that there is no increase in manganese content as a result of exposure.

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 in early 2001.

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

Staff at UMESC has prepared a study protocol 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 Ichthyopthirius) 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.

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.

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.

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. BOTTOM LINE: Early development stage for extensions and expansions.

NADA sponsorship was transferred in April 2000 from Hoffmann-LaRoche to Alpharma Animal Health and the new sponsor is interested in expanding and extending its NADA.

The National NADA Coordinator met with the product manager for Romet-30™ and UMESC on November 1-2, 2000 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. 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. BOTTOM LINE: 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.

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.

ANESTHETICS

Aqui-S™ — Status: Sponsor (Aqui-S New Zealand Ltd.) proceeding with worldwide drug approval. BOTTOM LINE: All submissions should be completed by 2002 for zero or low withdrawal time anesthetic for all fish.

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.

Residue Chemistry — On July 7, 1999, the sponsor signed a CRADA with UMESC (in progress).

Target Animal Safety — Preliminary toxicity studies have been completed at UMESC on a variety of fish species. Pivotal target animal safety studies are in progress at UMESC. 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 are in progress at UMESC. The sponsor is ready to submit efficacy studies on salmonids completed in Canada to CVM. The sponsor submitted existing residue depletion rates to CVM in December 1999 that gained a 21-day experimental withdrawal time. An INAD number was established for FWS to collect supporting efficacy data at limited sites but experimental withdrawal time and slaughter authorization is pending CVMs access to sponsor’s data via a "Right of Reference" letter.

The IAFWA Drug Approval Working Group on Aqui-S™ decided on March 26, 2000 to continue to support current research on an active ingredient in Aqui-S™ whose status as a potential carcinogen will not be known until July 2001 but whose sponsor concluded that the active ingredient is safe based on: (1) an understanding of metabolic pathways that support safety, (2) agreement on safety by independent experts, (3) supportive preliminary results of a parallel NTP study, (4) similar results on a related active ingredient, eugenol, and (5) similar toxicological studies showed no adverse effect.

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.

SPAWNING AND GENDER MANIPULATION AIDS

Common Carp Pituitary (CCP) — Status: Sponsor and interested parties proceeding toward NADA approval. BOTTOM LINE: All submissions should be completed in 2000 for use on all fish.

Progress on Technical Sections on CCP:

Product Chemistry — With the help of the National NADA Coordinator, the sponsor, Stoller Fisheries, 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.

Residue Chemistry — 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 has completed needed target animal safety studies on CCP and is in the process of preparing a submission 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. BOTTOM LINE: Early development stage.

An INAD (#10-673 was obtained for 17 -estradiol to gender manipulate American eels and summer flounder to all female populations. A draft efficacy protocol was developed and submitted to CVM for review.

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. BOTTOM LINE: All technical section submissions should be into CVM by the end of 2000.

The National Aquaculture NADA Coordinator, INAD sponsor (Auburn University), and a CVM official met on July 18, 2000 to discuss the status of the environmental assessment of MT for its use as a gender manipulation aid.

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.

Residue Chemistry — Accepted by CVM.

Target Animal Safety — Target animal safety study completed on percids by Southern Illinois University and resent to Auburn for submission to CVM; 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. BOTTOM LINE: Early development stage.

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

A meeting was held with the sponsor and CVM on June 6, 2000 to discuss the development of ReproBoost™ as a spawning aid for finfish species.

CHEMICAL MARKING AGENTS

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. BOTTOM LINE: All the technical section submissions for OTC are assumed to be completed for a supplemental NADA approval as a marking agent for all fish by immersion.

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

PUBLIC INFORMATION, WORKSHOPS AND PRESENTATIONS

Federal-State Aquaculture Drug Approval Partnership Program (IAFWA Project)

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, Montana on August 2-3, 2000. Discussions centered particularly on the status of chloramine-T, Aqui-S™, and florfenicol and the general progress of the IAFWA Project.

The Drug Approval Working Group (DAWG) formed to aid the federal-state aquaculture drug approval partnership program (a project of the International Association of Fish and Wildlife agencies=IAFWA Project) to achieve its goal of obtaining drug approvals for U.S. public aquaculture held a meeting in Indianapolis, Indiana on September 15, 2000 to: (1) discuss the progress being made on the IAFWA Project drugs, (2) support the extension of the IAFWA Project until at least 2002, and (3) discuss the new funding proposal on florfenicol.

Crop grouping — Status: Studies of crop grouping for the water borne drug benzocaine have been completed in four species and the results have been analyzed. UMESC presented the results of crop grouping research to CVM in the form of a seminar/meeting on August 30, 2000 at CVM’s Office of Research. A terminal completion report for this phase of the crop grouping research is being prepared and will be formally submitted to CVM. UMESC scientists met with representatives from CVM’s Office of Research and NRSP-7 on September 26-27, 2000.

Classical compartmental pharmacokinetic models are being developed in five phylogenetically diverse species. UMESC is using physiologically based pharmacokinetic models developed in channel catfish and rainbow trout to support work on florfenicol. Work on florfenicol in the crop grouping work plan is constrained by the inability to obtain supplies of radiolabeled florfenicol. Once radiolabeled florfenicol is obtained, the crop grouping work will continue.

BOTTOM LINE: Acceptance of the crop grouping concept by CVM will reduce residue chemistry data requirements and costs of approvals for all aquaculture drugs.

Need for efficacy studies — Additional efficacy studies are needed for IAFWA Project drugs for at least one label claim for all eight IAFWA Project drugs. UMESC, HKD-SNARC, and FWS are making efforts to fill both pivotal and supporting efficacy data needs but not enough to cover all the needs. The solutionsSolutions are as follows: (1) a nationwide initiative entitled "The Shortest Yard" to mainly private aquaculture sector implemented by National Aquaculture NADA Coordinator, (2) Drug Approval Working Group to work with National Aquaculture NADA Coordinator to obtain pivotal efficacy data from state agencies, and (3) National Aquaculture NADA Coordinator wrote article for Fish Health Section Newsletter requesting studies from the members to gain both pivotal and supporting data for IAFWA Project drugs.

Meetings and Special Activities

Dr. Joan Gotthardt was selected as the Leader of the Aquaculture Drugs Team in July 2000. The establishment of this team is important because aquaculture drug approvals now have greater stature at CVM than before.

The National NADA Coordinator attended the American Fisheries Society annual meeting in St. Louis, Missouri on August 19-23, 1999 to: (1) present a symposium on the proper use of rotenone, (2) finalize a public brochure on rotenone, and (3) discuss options on the reregistration of antimycin. Both rotenone and antimycin are used by resource agencies and private aquaculture facilities to control undesirable fish.

The Joint Subcommittee on Aquaculture (JSA) formed the Aquaculture Effluents Task Force 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. An EPA Effluent Guidelines Plan could affect the use and approval of all drugs needing environmental assessments and those currently approved for aquaculture use. JSA Aquaculture Effluents Task Force (AETF) met on June 7, 2000 to discuss the status of EPA’s plan. A white paper on drugs and chemicals was submitted to EPA on August 24, 2000. A Draft Information Collection Survey was published in September 14, 2000 issue of the Federal Register; comments are due November 13, 2000. An AETF Aquaculture Technical Information Exchange Forum was held September 20-21, 2000 where EPA distributed draft industry profiles and discussed issues related to approved analytical detection methods; industry profiles needed revisions by October 27, 2000. Frequently Asked Questions (FAQs) were completed and posted on Effluents home page (October 12, 2000).

A bill entitled "Minor Animal Species Health and Welfare Act of 2000" was introduced in the U.S. Congress by the Minor Species/Minor Use (MUMS) Coalition. The Bill was introduced into the House on June 27, 2000 (HR-4780) and into the Senate on October 5, 2000 (S-3169); there is 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. The draft Bill was reviewed by CVM in August 20, 2000 and changes need to be resolved with MUMS coalition. The bill may have to be reintroduced into the next session since it probably will not get passed this congressional session.

The National NADA Coordinator received the FDA Commissioner’s Special Citation Award at a ceremony in Rockville, Maryland on June 9, 2000 for outstanding leadership, teamwork, and sustained efforts as the National NADA Coordinator.

PUBLICATIONS, MANUSCRIPTS, PAPERS PRESENTED, AND SPECIAL REPORTS

PUBLICATIONS

Griffin, B.R., R.A. Schnick, and W.H. Gingerich. 2000. Update on the federal-atate aquaculture drug approval partnership. Aquaculture Magazine 26(3):56-68.

Schnick, R.A., and P. Smith. 1999. International harmonisation of antibacterial agent approvals and susceptibility testing. EAFP Bulletin 19(6):293-294.

Schnick, R.A. 2000. Efficacy data needed for high priority aquaculture drugs. American Fisheries Society Fish Health Newsletter 28(2):3.

MANUSCRIPTS

Schnick, R.A. In press. International harmonization of antibacterial sensitivity determination for aquaculture drugs. Aquaculture.

PAPERS PRESENTED

Schnick, R.A. 2000. Overview of NADA Coordinator activities. USFWS-INAD Coordination Workshop, Bozeman, Montana, August 2-3, 2000.

Schnick, R.A. 2000. Aquaculture drug approval progress. Office of New Animal Drug Evaluations, Center for Veterinary Medicine, Rockville, Maryland, August 29, 2000.

Schnick, R.A. 2000. Aquaculture drug approval progress and need for efficacy studies. American Fisheries Society/Fish Health Section 2000 Annual Meeting, Pensacola Beach, Florida, September 6-8, 2000.

Schnick, R.A. 2000. Update on federal-state aquaculture drug approval partnership. Annual Meeting of the International Association of Fish and Wildlife Agencies, Indianapolis, Indiana, September 15-16, 2000.

Schnick, R.A. 2000. Highlights of National NADA Coordinator Activities. NRSP-7 Fall 2000 Meeting, Gaithersburg, Maryland, October 23-24, 2000.

SPECIAL REPORTS

Schnick, R.A. 2000. National Coordinator for Aquaculture New Animal Drug Applications (NADAs). Fifth annual report of activities, May 15, 1999 to May 14, 2000. Submitted to Ted Batterson, North Central Regional Aquaculture Center, East Lansing, Michigan. May 18, 2000. 20 pp.

Schnick, R.A. 2000. Status of technical sections for joint minor use/minor species drug approvals coordinated through the National Aquaculture NADA Coordinator and NRSP-7 as of April 21, 2000. Submitted to NRSP-7. Revised June 28, 2000. 4 pp.

Schnick, R.A. 2000. 2000 annual report of the AFS Task Force on Fishery Chemicals. Submitted to the Governing Board and AFS President, Christine Moffitt, Bethesda, Maryland. July 21, 2000. 4 pp.

Schnick, R.A. 2000. Minutes to meeting on ReproBoost™ with the Center for Veterinary Medicine, VeriPharm, International LLC, and the National Coordinator for Aquaculture New Animal Drug Applications. Submitted to the Center for Veterinary Medicine. July 21, 2000. 5 pp.

Gingerich, W.H., G.R. Stehly, V.K. Dawson, M.P. Gaikowski, J.R. Meinertz, J.J. Rach, R.A. Schnick, and B.R. Griffin. 2000. Approval of Drugs for Public Fish Production: Sixth annual report of progress [performance period: July 1, 1999 to June 30, 2000]. Biological Resources Division, USGS, Upper Midwest Environmental Sciences Center, La Crosse, Wisconsin. August 21, 2000. 54 pp.

Schnick, R.A., Charles E. Eirkson, and others. 2000. Aquaculture effluents containing drugs and chemicals. Submitted to the Joint Subcommittee on Aquaculture, Aquaculture Task Force, for transmittal to the U.S. Environmental Protection Agency. August 24, 2000. 8 pp.

Gingerich, W.H., G.R. Stehly, V.K. Dawson, M.P. Gaikowski, J.R. Meinertz, J.J. Rach, and R.A. Schnick. 2000. Florfenicol as an antibacterial for cool and warm water fish: a Multi-State Grant Conservation Proposal. Submitted to the International Association of Fish and Wildlife Agencies. September 8, 2000. 55 pp.

Schnick, R.A. 2000. Executive summary of the Federal-State Aquaculture Drug Approval Partnership Project on September 15, 2000. Submitted to the International Association of Fish and Wildlife Agencies. September 15, 2000. 3 pp.

Schnick, R.A. 2000. Minutes to meeting on Actamide™ with the Center for Veterinary Medicine and B.L. Mitchell, Inc. Submitted to B.L. Mitchell, Inc., sponsor of Actamide™. September 29, 2000. 6 pp.

Schnick, R.A. 2000. National Aquaculture INAD/NADA Coordinator. Project termination report. Part 1 (September 1, 1992 to August 31, 2000). Submitted to North Central Regional Aquaculture Center, East Lansing, Michigan. October 27, 2000. 15 pp.

Schnick, R.A. 2000. Progress report for Contract #99-116 (April 1, 2000 through October 1, 2000). Submitted to the Center for Tropical and Subtropical Aquaculture, Waimanalo, Hawaii. October 30, 2000. 18 pp.

Schnick, R.A. 2000. Status of the technical sections for a New Animal Drug Application (NADA) for Halamid™ (as of November 1, 2000). Submitted to Axcentive bv (The Netherlands), sponsor of Halamid™. November 1, 2000. 1 pp.