Drug Needs for Southern US Marine Aquaculture

1
Drug Needs for Southern US Marine Aquaculture
Fisheries Industries

• Rosalie A. Schnick
• National Coordinator for Aquaculture New Animal
  Drug Applications (NADA)
• Michigan State University
• 3039 Edgewater Lane, La Crosse, Wisconsin
  54603-1088
• Phone [phone] Fax [phone]
• E-mail RozSchnick_at_centurytel.net
• Website http//ag.ansc.purdue.edu/aquanic/jsa/aq
  uadrugs/index.htm
• Presented at the Workshop on Marine Aquaculture
  Drug and Chemotherapeutant Issues and Needs in
  Southern United States, Sarasota, Florida,
  November 16, 2004 (revised after Workshop)

2
Background

• Drug approval efforts for freshwater aquaculture
  fisheries (public private)
• Initial drug approval efforts for started in 1964
• Major drug approval project in place since 1994
• Federal-State Aquaculture Drug Approval
  Partnership Project

3
Background

• This Workshop
• Initial scoping effort for drug approval needs
  for southern US marine aquaculture fisheries
  industries (public private)
• Marine interests to benefit from freshwater
  efforts
• Initial effort to identify potential resources
  for marine drug approvals

4
Background (continued)

• Initially thought
• All US marine aquaculture fisheries
• All cultured finfish, shellfish, molluscs
• Sanity prevailed thanks to
• Kevan Main, Mote Marine Laboratory
• Opportunity through connecting with Public
  Aquarium Marine Fish Health Seminar in FL
• Resultlimited to southern US marine aquaculture
  fisheries industries

5
WORKSHOP GOAL 1ALERT SOUTHERN US MARINE
AQUACULTURE FISHERIES INDUSTRIES TO LACK OF
DRUG APPROVAL IMPACTS POTENTIAL SOLUTIONS
6
LAWS REGULATIONS AFFECTING USE OF DRUGS
7
The Term Drug Means

• (A) Articles recognized in the official United
  States Pharmacopoeia, official Homoeopathic
  Pharmacopoeia of the United States, or official
  National Formulary, or any supplement
• (B) Articles intended for use in the diagnosis,
  cure, mitigation, treatment, or prevention of
  disease in man or other animals
• (C) Articles (other than food) intended to affect
  the structure or any function of the body of man
  or other animals and
• (D) Articles intended for use as a component of
  any article specified above

8
Drug Regulatory AgencyCenter for Veterinary
Medicine (CVM)

• Office of New Animal Drug Evaluation (ONADE)
• Division of Therapeutic Drugs for Food Animals
• Aquaculture Drugs Team
• Division of Therapeutic Drugs for Non-Food
  Animals
• Aquaculture Drugs Team from above also handles
  drugs for non-food aquatic animals
• Division of Manufacturing Technologies
• Division of Human Food Safety

9
Drug Regulatory AgencyCVM (continued)

• Office of Surveillance Compliance
• Division of Surveillance
• Division of Compliance
• Office of Research
• Division of Residue Chemistry
• Division of Animal Research
• Aquaculture Drug Research

10
General Drug Laws

• Federal Food, Drug Cosmetic Act (FFDACA)
• 21CFR511New Animal Drugs for investigational use
• 21CFR514New Animal Drug Applications
• FDA Modernization Act of 1997 (FDAMA)
• All foreign establishments required to register
  with FDA if products are imported into US

11
Animal Drug Laws

• Animal Medicinal Drug Use Clarification Act of
  1994 (AMDUCA)
• Extra-label use (ELU) under certain conditions
  but not medicated feed
• Animal Drug Availability Act of 1998 (ADAA)
• Substantial evidence of effectiveness
• Increase availability of drugs for minor uses and
  minor species
• Veterinary Feed Directive

12
Animal Drug Laws (continued)

• Animal Drug User Fee Act of 2003 (ADUFA)
• Intended to expedite approvals
• No fees for minor uses or minor species
• Fees to help with review of all drug submissions

13
Animal Drug Laws (continued)

• Minor Use Minor Species Animal Health Act of
  2004 (MUMS)all fish shellfish are minor
  species
• Conditional approval
• Indexing
• Non-food speciesnot likely to be consumed
  directly or indirectly by humans for food
• Early life stages on food animals (details to be
  determined)
• Diversion concernspackaging requirements

14
Animal Drug Laws (continued)

• Minor Use Minor Species Animal Health Act of
  2004 (MUMS)all fish shellfish are minor
  species (continued)
• Designation of sponsor
• MUMS Office within CVM
• Grants possible

15
RegulationsCompliance Policy Guide (CPG)

• CPG 615.115Extra-label use (ELU) of medicated
  feeds for minor species
• Extra-labeled use of medicated feed in
  aquaculture is limited to medicated feed products
  approved for use in aquatic species

16
RegulationsCPG (continued)

• CPG654.300Chloramphenicol as an unapproved new
  animal drug
• Causes aplastic anemia that is usually
  irreversible fatal onset of condition not dose
  dependent
• Not to be used in food animals
• Oral use revoked due to illegal use in food
  animals
• Non-food use (only cats dogs) must be under
  NADA veterinarian
• Drug seized if intended for unapproved use (i.e.,
  no NADA exists)any aquaculture use

17
RegulationsProgram Policy Procedures Manual

• 1240.4200 - Drug Use in Aquaculture Enforcement
  Priorities
• Part ANon-Food Fish
• Part BFood Fish Shellfish
• Definitions
• Regulation of drug use
• Regulated if classified as drug
• Regulatory statusNADA, Investigational New
  Animal Drug (INAD) exemption, ELU, or Regulatory
  Discretion

18
RegulationsProgram Policy Procedures Manual
(continued)

• 1240.4200 - Drug Use in Aquaculture Enforcement
  Priorities (continued)
• Part CEnforcement priorities
• Low Regulatory Priority (LRP) Aquaculture Drugs
  see list below
• Regulatory action deferredcopper sulfate
  potassium permanganate
• High Enforcement Prioritychloramphenicol,
  nitrofurans, fluoroquinolones quinolones,
  malachite green, steroid hormones

19
RegulationsProgram Policy Procedures Manual
(continued)

• 1240.4210 - Extra-label Use of Approved Drugs in
  Aquaculture
• ELU provided for in AMDUCA
• ELU required under supervision of veterinarian
• Under certain conditions, ELU of terrestrial
  animal drugs allowed in aquaculture
• ELU not permitted for non-therapeutic uses
• ELU in medicated feed updated in CPG 615.115

20
RegulationsProgram Policy Procedures Manual
(continued)

• 1240.4220 - Drug-Pesticide Issues
• Pesticides prevent, destroy, repel, or mitigate
  any pests as defined by EPA
• No objection if pesticide has incidental,
  concurrent therapeutic (drug) benefit if
  pesticide is used properly to control pests on
  label

21
RegulationsProgram Policy Procedures Manual
(continued)

• 1240.4220 - Drug-Pesticide Issues
• Pesticides can be used under Federal or state
  Special Local Need (SLN) registrations
  (40CFR162.153) if these conditions exist
• Use must be need within state
• Use covered by tolerances (i.e., allowed
  residues if not, not legal to use on food
  animals)
• Registration for same use not previously denied,
  disapproved, suspended, or cancelled
• Registration in accord with purposes of Federal
  Insecticide, Fungicide, Rodenticide Act

22
RegulationsProgram Policy Procedures Manual
(continued)

• 1240.4230 - Regulation of Fish Identification
  Products
• Products used for management purposes
• 2 drugs approved for marking
• Oral oxytetracycline for Pacific salmon
• Immersion oxytetracycline for all fish

23
RegulationsProgram Policy Procedures Manual
(continued)

• 1240.4240 - Safe Levels of Unapproved Drugs in
  Aquaculture
• Levels established as targets for method
  development
• FDA does not sanction use of unapproved drugs
• FDA to consider enforcement against illegal
  manufacture distribution of drugs for use in
  aquaculture
• Enforcement discretion when residue is at safe
  levels

24
RegulationsProgram Policy Procedures Manual
(continued)

• 1240.4260 - Classification of Aquaculture
  Species/Population as Food or Non- food
• Aquarium fish drug packaging must not allow for
  diversion to food fish
• Must be sized small enough so that not
  economically feasible for food fish use
• Life stage for food fish factor in enforcement
  priority
• Nonfood fish groupsbaitfish, ornamental
  aquarium species, endangered threatened
  species, some broodfish

25
RegulationsGuidance Documents

• 3General principles for evaluating the safety
  of compounds used in food-producing animals
  (1994)
• 33Target animal safety (1989)
• 53Evaluation of utility of food additives in
  diets fed to aquatic animals (1994)

26
RegulationsGuidance Documents (continued)

• 56Protocol development for clinical
  effectiveness and target animal safety trials
  (2001)
• 61FDA approval of new animal drugs for minor
  uses and for minor species, Part 2EAquatic
  species (1999)
• 85Good Clinical Practices (2001)

27
RegulationsGuidance Documents (continued)

• 89Environmental impact assessments for
  veterinary medicinal products Phase I (2001)
• 166Environmental impact assessments for
  veterinary medicinal products Phase II (2004)

28
RegulationsGuidance Documents (continued)

• 52Assessment of the effects of antimicrobial
  drug residues from food of animal origin on the
  human intestinal flora (2004)
• 152Evaluating the safety of antimicrobial new
  animal drugs with regard to their microbiological
  effects of human health concern (2003)

29
RuleAquaculture Effluents

• Effluent GuidelinesAquatic Animal Production
  Industry
• EPA signed rule (6/30/04) published in Federal
  Register (8/23/04)
• Rule requires
• Prevent discharge of drugs pesticides that have
  been spilled minimize discharges of excess feed
• Report use of experimental animal drugs or drugs
  that are not used in accordance with label
  requirements

30
NEED FOR APPROVED DRUGS
31
Why Gain Drug Approvals?

• Maintain healthy fish with proven safe
  effective drugs
• Use proven safe effective drugs for production
• Laws regulations on drugs
• Legally produce fish for food
• Legally produce fish for stocking
• Legally produce ornamental fish

32
DATA REQUIRED TO GAIN DRUG APPROVALS
33
Technical Sections

• Manufacturing, Chemistry, and Controls (i.e.,
  Product Chemistry)
• Environmental Safety
• Human Food Safety(a) Mammalian Toxicology
• Human Food Safety(b) Residue Chemistry

34
Technical Sections (continued)

• Human Food Safety(c) Microbial Safety
• Effects of drug residues on human gut flora
• Microbiological effects on bacteria of human
  health concern
• Human Food Safety(d) User Safety
• Target Animal Safety
• Effectiveness (i.e., Efficacy)
• Labeling
• All Other Information

35
RESOURCES NEEDED TO GAIN DRUG APPROVALS
36
Human Resources

• Company sponsors
• Scientists
• Toxicologists
• Research veterinarians
• Fishery biologists
• Environmental specialists
• Chemists

37
Human Resources (continued)

• Fish culturists farmers
• Disease specialists, including clinical
  veterinarians histopathologists
• Agencies, organizations, and companies

38
Facilities

• Fish hatcheries farms
• Laboratories (including research ponds
  tanks)public or private
• Chemical
• Toxicological
• Fishery
• Environmental
• Contract

39
Funding

• Company sponsor generally covers
• Product Chemistry
• Human Food Safety(a) Mammalian Safety
• Human Food Safety(d) User Safety
• Labeling
• All Other Information

40
Funding (continued)

• Agencies, organizations, companies with
  interest in a certain drug generally cover
• Environmental Safety
• Human Food Safety(b) Residue Chemistry
• Human Food Safety(c) Microbial Safety
• Target Animal Safety
• Efficacy

41
DRUGS POTENTIALLY AVAILABLE FOR DEVELOPMENT
42
Approved Aquaculture Drugs

• Existing approvals gained only through
  partnerships with sponsors
• Developed from crisisforerunner of CVM requested
  approvals (1964)
• First partnershipUS Fish and Wildlife Service
  with some help from states (MN, MI, WI)
• Other partnerships followed
• 7 drugs
• 3 antibacterials (1 also marking aid), 1
  fungicide parasiticide, 1 anesthetic, 1 marking
  aid, 1 spawning aid

43
Approved Drugs for Use in Aquaculture

• Antibacterials
• Terramycin for Fish (oral oxytetracycline)NADA
  038-439 008-804
• Romet-30 (sulfadimethoxine ormetoprim)NADA
  125-933
• Sulfamerazine in Fish Grade (sulfamerazine)NADA
  033-950 (currently not commercially available)

44
Approved Drugs for Use in Aquaculture

• Fungicides parasiticides
• Formalin-F (formalin)NADA 137-687
• Paracide-F (formalin)NADA 140-831
• Parasite-S (formalin)NADA 140-989

45
Approved Drugs for Use in Aquaculture (continued)

• Anesthetics
• Finquel (MS-222 or tricaine methanesulfonate)NAD
  A 042-427
• Tricaine-S (MS-222 or tricaine
  methanesulfonate)ANADA 200-226

46
Approved Drugs for Use in Aquaculture (continued)

• Marking spawning aids
• Terramycin for Fish (oral oxytetracycline)NADA
  038-439 008-804marking aid for Pacific salmon
• OXYMARINE (immersion oxytetracycline)NADA
  130-435
• Oxytetracycline HCI Soluble Powder-343
  (immersion oxytetracycline)NADA 200-247
• Chorulon (human chorionic gonadotropin)NADA
  140-927

47
Low Regulatory Priority Drugs

• Acetic acid
• Calcium chloride
• Calcium oxide
• Carbon dioxide gas
• Fullers earth
• Garlic
• Hydrogen peroxide
• Ice
• Magnesium sulfate

• Onion
• Papain
• Potassium chloride
• Povidone iodine
• Sodium bicarbonate
• Sodium chloride
• Sodium sulfite
• Thiamine hydrochloride
• Urea tannic acid

48
Generally Recognized As Safe (GRAS)

• No drugs are considered GRAS for any specific use
  in aquaculture
• GRAS designation requirements as difficult to
  meet as drug approval requirements

49
Investigational New Animal Drug (INAD) Exemptions

• Hydrogen peroxide
• LHRHa
• 17 a-methyltestosterone
• Ovaprim Ovaplant
• Oral oxytetracycline
• Immersion oxytetracycline
• Potassium permanganate
• Pyceze
• Slice
• Strontium chloride

• Amoxicillin
• AQUI-S
• Calcein
• Chloramine-T
• Copper sulfate
• Crude carp pituitary
• Erythromycin
• Florfenicol
• Formalin

50
SUCCESSFUL DRUG APPROVAL PROGRAMS PATNERSHIPS
FOR THE FRESHWATER AQUACULTURE FISHERIES SECTOR
51
Success Story in the MakingFederal-State
Aquaculture Drug Approval Partnership
ProjectIAFWA Project

• Entities involved
• International Association of Fish and Wildlife
  Agencies (IAFWA)
• 3 Federal agencies
• US Geological Survey
• US Fish Wildlife Service
• US Agriculture Research Service
• 38 state natural resources agencies
• 10 sponsors
• National Coordinator for Aquaculture New Animal
  Drug Applications
• Private aquaculture sector involvement

52
Success Story in the MakingIAFWA Project
(continued)

• 8 years, formal project ended September 2002
  effort continues to complete initial label claims
  under pending Memorandum of Agreement
• 12 million combined federal state funds
• 9 drugs AQUI-S?, chloramine-T, copper sulfate,
  florfenicol, formalin, hydrogen peroxide, oral
  oxytetracycline, immersion oxytetracycline,
  potassium permanganate

53
Success Story in the MakingIAFWA Project
(continued)

• Approvals
• Formalin/1 label claim/all fish eggs
• Formalin/1 label claim/all fish
• Immersion oxytetracycline/1 label claim/all fish
• Nearing completion
• 17 Label claims/7 drugs/various fish species
• September 2003-49 drugs 23 label claims
• Submissions27
• Acceptances23

54
Definitions

• Label Claim
• Disease to be controlled or production situation
  to be managed
• Label claims Nearing Completion
• IAFWA Project work submitted or completed except
  for parts of 1 or 2 technical sections

55
Definitions (continued)

• Label claims Proceeding Toward Completion
• IAFWA Project work planned funded but several
  technical sections remain to be competed
• Label claims with Immediate Potential NADA
• All technical sections covered for approval
  except mainly pivotal efficacy studies
• Label claims with Distant Potential NADA
• Few technical sections covered for approval but
  anecdotal efficacy information

56
Federal IAFWA Project Partners

• AADAPPAquatic Animal Drug Approval Partnership
  Program, Bozeman, MT (Dave Erdahl
  Dave_Erdahl_at_fws.gov)
• SNARCHarry K. Dupree Stuttgart National
  Aquaculture Research Center, Stuttgart. AR (Dave
  Straus DStraus_at_spa.ars.usda.gov)
• UMESCUpper Midwest Environmental Sciences
  Center, La Crosse, WI (Bill
  Gingerich bill_gingerich_at_usgs.gov)

57
1. AQUI-S (isoeugenol Sponsor, AADAPP, UMESC)

• Research Data to Be Conducted Submitted
• Product Chemistry Environmental Safety Human
  Food SafetyMammalian Safety Human Food
  SafetyResidue Chemistry/Salmonids, Coolwater,
  Warmwater Fish Target Animal Safety/Rainbow
  Trout, Coolwater, Warmwater Fish
  Efficacy/Coolwater Warmwater Fish
• Label claims1. Short-exposure handling
  anesthetic on all salmonids2. Short-exposure
  handling anesthetic on all coolwater warmwater
  fish

58
2. CHLORAMINE-T (Sponsor, AADAPP, UMESC)

• All Research Data Submitted Except
• Product Chemistry Microbial Safety
• Label claims
• 1. Bacterial gill disease on all
  freshwater-reared salmonids
• 2. External columnaris disease on walleye

59
3. COPPER SULFATE (Sponsor SNARC)

• All Research Data Submitted Except
• Revised Environmental Assessment
• Label claim
• 1. Ichthyophthirius on channel catfish in
  earthen ponds with no outflows

60
4. FLORFENICOL (Sponsor, AADAPP, Mississippi
State University, UMESC)

• All Research Data Submitted Except
• Furunculosis/Salmonids Systemic Columnaris
  Disease/Salmonids Catfish Efficacy Studies
• Label claims
• 1. Enteric septicemia in catfish2. Coldwater
  disease in freshwater-reared salmonids3.
  Furunculosis in freshwater-reared salmonids4.
  Systemic columnaris disease in freshwater-reared
  salmonids catfish

61
5. FORMALIN (Sponsors UMESC)

• All Research Data Submitted Except
• Saprolegniasis/Rainbow Trout Efficacy Study
• Label claims1. Saprolegniasis on all fish eggs
  (Completed Approved 2 supplemental NADAs)2.
  External protozoans and monogenetic trematodes
  (now Monogenea) on all fish (Completed
  Approved 2 supplemental NADAs)3. Saprolegniasis
  on all fish

62
6. HYDROGEN PEROXIDE (Sponsor UMESC)

• All Research Data Submitted Except
• Daphnia Study, Revised Environmental Assessment,
  Microbial Safety Saprolegniasis/Rainbow Trout
  Efficacy Study
• Label claims1. Saprolegniasis on all
  freshwater-reared fish eggs2. Saprolegniasis on
  all freshwater-reared fish3. Bacterial gill
  disease on all freshwater-reared salmonids4.
  External columnaris disease in all coolwater fish
  channel catfish

63
7. OXYTETRACYCLINE (ORAL) (Sponsor, AADAPP,
UMESC)

• All Research Data Submitted Except
• Amended Product Chemistry, Amended Environmental
  Assessment, Microbial Safety, Systemic
  Columnaris Disease/Salmon Efficacy Studies
• Label claims1. Systemic coldwater disease in all
  freshwater-reared salmonids2. Systemic
  columnaris disease in steelhead trout

64
8. OXYTETRACYCLINE (IMMERSION) (Sponsors UMESC)

• All Research Data Submitted Except
• Human Food Safety Studies All Efficacy Studies
  For Label Claims
• Label claims (2-3 years to generate)
• 1. Otolith marking of all finfish (APPROVED
  12/24/03)
• 2. Bacterial gill disease on coolwater
  warmwater fish
• 3. External columnaris disease on coolwater
  warmwater fish
• 4. Systemic columnaris disease on coolwater
  warmwater fish

65
9. POTASSIUM PERMANGANATE (Sponsor, Arkansas
State University, SNARC)

• Research Data To Be Conducted Submitted
• Product Chemistry Environmental Safety Target
  Animal Safety Efficacy
• Label claim1. Ichthyophthirius on channel
  catfish in earthen ponds with no outflows
  (questions on efficacy toxicity considering
  external columnaris disease control)

66
Strategic Plan for End Point to IAFWA Project

• 1. Determine status of IAFWA Project label claim
  progress toward completion
• 2. Determine remaining unmet IAFWA Project label
  claim needs

67
Strategic Plan for End Point to IAFWA Project
(continued)

• 3. Prioritize the remaining unmet IAFWA Project
  label claim needs
• 4. Identify prioritize any new drug label claim
  needs NOT covered by the IAFWA Project

68
Re-establish National Conservation Need (NCN)

• Survey stakeholders for unmet label claim needs
• Therapeutants
• Anesthetic (i.e., AQUI-S)
• Spawning aids
• Chemical marking aids
• Write National Conservation Need (NCN) for drug
  approvals
• Contact federal state natural resources
  agencies to support NCN for drug approvals

69
NON-IAFWA PROJECT DRUG PROGRAMS PARTNERSHIPS
70
Programs Partnerships

• Amoxicillin (Streptococcushybrid striped bass
  tilapia)
• Sponsor, Kent SeaTech, National Research Support
  Project-7 (NRSP-7), SNARC
• Calcein (chemical marking aid)
• Sponsor AADAPP
• Crude carp pituitary (spawning aid)
• NRSP-7 (Southern Illinois University) others

71
Programs Partnerships (continued)

• Erythromycin (bacterial kidney diseasesalmon)
• Bonneville Power Administration, NRSP-7,
  University of Idaho
• Fumagillin (whirling diseasetrout
  proliferative gill diseasecatfish)
• Sponsor, AADAPP, Mississippi State University,
  others
• Luteinizing Hormone-Releasing Hormone analogue
• Sponsor Auburn University

72
Programs Partnerships (continued)

• 17 a-methyltestosterone (gender manipulation
  aidtilapia other species including ornamental
  fish species)
• Sponsor, North Central Regional Aquaculture
  Center (Southern Illinois University University
  of Wisconsin-Madison), AADAPP, University of
  Florida, Cornell University, Auburn University

73
Programs Partnerships (continued)

• Oral oxytetracycline (vibriosissummer flounder
  shrimp)
• Sponsor NRSP-7 (Cornell University University
  of Arizona)
• Strontium chloride (chemical marking aid)
• Sponsor NRSP-7 (Alaska Fish Game)

74
MODEL FOR POTENTIAL DRUG APPROVAL PROGRAMS FOR
SOUTHERN US MARINE AQUACULTURE FISHERIES
INDUSTRIES
75
IAFWA Project Model

• Developed from crisis
• FDA inspected fish farms found unapproved drugs
  chemicals (1989-1990)
• US Fish Wildlife Service developed directives
  on proper legal use of drugs
• US Fish Wildlife Service continued drug
  approval work on limited budget at UMESC

76
IAFWA Project Model

• Public private entities formed Joint
  Subcommittee on Aquaculture Working Group on
  Quality Assurance in Aquaculture Production
  (November 1990)
• Identified drug approval priorities
• Developed producer quality assurance programs
• Developed guides to approved drugs laws

77
IAFWA Project Model (continued)

• UMESC searched for funding sources (1991-1993)
• Applied to US Fish and Wildlife Service (FWS) but
  agency requested shared state contributions
• State departments of natural resources agreed to
  cost share
• UMESC developed IAFWA project proposal (1993)
• Based drug approval priorities (drugs potential
  label claims) on state survey (1992)

78
IAFWA Project Model (continued)

• Agency administrators agreed to proposal for drug
  approvals
• Proposal signed by FWS, US Geological Survey,
  IAFWA representing states (March 1994)
• Agencies committed funds to project
• Research started July 1, 1994

79
IAFWA Project Model (continued)

• Oversight by IAFWA Drug Approval Working Group
• Determined any changes in drugs
• Sarafloxacin to florfenicol
• Benzocaine to AQUI-S
• Determined any adjustments in label claims
• Advocated for completion of all formalin label
  claims
• Advocated for at least initial NADA approvals for
  each drug
• Advocated for as broad approvals as possible

80
IAFWA Project Model (continued)

• Oversight by IAFWA Drug Approval Working Group
  (continued)
• Suggested any adjustments in responsibilities
• Reduced efforts on florfenicol
• Redirected funds from AQUI-S to others
• Championed three-year extension
• Searched for additional funds when needed
• Multi-State Conservation Grants (based on
  National Conservation Need)

81
IAFWA Project Model (continued)

• Benefits to southern US marine aquaculture
  fisheries industries
• Major data generated for universal coverage on 9
  drugs
• Researchers knowledgeable in drug approval
  process available
• Research protocol templates in place

82
IAFWA Project Model (continued)

• Benefits to southern US marine aquaculture
  fisheries industries (continued)
• Good working relationship developed with CVM
• Company sponsors available
• Structure successful for achieving approvals

83
WORKSHOP GOAL 2 DEVELOP STRATEGIC PLANS TO GAIN
DRUG APPROVALS FOR SOUTHERN US MARINE AQUACULTURE
FISHERIES INDUSTRIES
84
IDENTIFY DRUG APPROVAL NEEDSCODE?Drugs
available(NA)No drugs available or very
difficult to treat or find drugs for that
indication(?)Possible drugs available
85
Label Claim Extensions for Marine Fish Species

• In most cases, these Technical Sections will need
  to be completed
• Revised or new environmental assessment for
  marine applications
• Human Food SafetyResidue Chemistry (for food
  fish species only)
• Target Animal Safety for species or group
• Efficacy for each disease indication

86
Potential Therapeutant NeedsBacterial Fish
diseases

• Vibriosis ?
• Winter ulcers (?)
• Cold water vibriosis ?
• Furunculosis ?
• Tenacibaculum maritimum infections ?

• Enteric redmouth disease ?
• Bacterial kidney disease ?
• Fish mycobacteriosis (NA)
• Piscirickettsiosis ?
• Epitheliocystis (NA)
• Streptococcosis ?

87
Potential Oral Antibacterials

• Oral oxytetracycline
• Approvedulcer disease, furunculosis, bacterial
  hemorrhagic septicemia, pseudomonas diseaseall
  salmonids
• Approvedbacterial hemorrhagic septicemia
  pseudomonas diseasecatfish
• ApprovedGaffkemiaLobster
• Nearing completionsystemic columnaris
  diseasesteelhead trout
• Nearing completioncoldwater diseaseall
  freshwater-reared salmonids

88
Potential Oral Antibacterials (continued)

• Romet-30
• Approvedfurunculosisall salmonids
• Approvedenteric septicemiacatfish
• Immediate potential NADAsystemic columnaris
  diseaseall salmonids
• Immediate potential NADAcoldwater diseaseall
  salmonids
• Romet-TC
• Improved palatability for top coating (11/03)

89
Potential Oral Antibacterials (continued)

• Florfenicol nearing completion for
• Coldwater diseasefreshwater-reared salmonids
• Furunculosisfreshwater-reared salmonids
• Systemic columnaris diseasefreshwater-reared
  salmonids catfish
• Enteric septicemiacatfish

90
Potential Oral Antibacterials (continued)

• Erythromycin
• Nearing completion (except for microbial
  environmental safety)bacterial kidney
  diseasesalmon
• Amoxicillin
• Very distant potential NADA (work
  underway)Streptococcushybrid striped bass
  tilapia

91
Potential Immersion Antibacterials

• Oxytetracycline immersion nearing completion for
• Systemic columnaris diseaseall coolwater
  warmwater fish (potentially all freshwater-reared
  salmonids)
• External columnaris diseaseall coolwater
  warmwater fish (potentially all freshwater-reared
  salmonids)
• Bacterial gill diseaseall coolwater warmwater
  fish (potentially all freshwater-reared salmonids)

92
Potential Immersion Antibacterials (continued)

• Chloramine-T nearing completion for
• Bacterial gill diseaseall freshwater-reared
  salmonids (potentially all coolwater warmwater
  fish)
• External columnaris diseasewalleye (potentially
  all freshwater fish)

93
Potential Immersion Antibacterials (continued)

• Hydrogen peroxide nearing completion for
• Bacterial gill diseaseall freshwater-reared
  salmonids (potentially all coolwater warmwater
  fish)
• External columnaris diseaseall coolwater fish
  catfish (potentially all freshwater fish)

94
Potential Immersion Antibacterials (continued)

• Copper sulfate
• Distant potential NADAexternal columnaris
  disease bacterial gill diseasechannel catfish
  (potentially all freshwater fish)
• Potassium permanganate
• Distant potential NADAexternal columnaris
  disease bacterial gill diseasechannel catfish
  (potentially all freshwater fish)
• Pyceze (bronopol)
• Distant potential NADAexternal bacteria

95
Potential Therapeutant NeedsParasitic Fish
diseases

• Monogenea ?
• Digenea (control hosts)
• Cestoda ?
• Copepoda ?
• Isopoda ?

• Protozoa ?
• Microspora
• Rhizopoda ?
• Myxosporea ?
• Metazoa ?

96
Potential Parasiticides

• Formalin
• Approvedexternal protozoa monogenetic
  trematodes (now Monogenea)all fish
• ApprovedExternal protozoaPenaeid shrimp

97
Potential Parasiticides

• Copper sulfate
• Nearing completionIchthyophthiriuschannel
  catfish
• Potassium permanganate
• Distant potential NADAexternal protozoa
  Monogeneachannel catfish

98
Potential Parasiticides (continued)

• Slice (emamectin benzoate)
• Nearing completionsea licesaltwater salmon
• Very distant potential NADAother copepoda
• Fumagillin
• Very distant potential NADA myxosporea (whirling
  diseasetrout proliferative gill
  diseasecatfish)

99
Potential Parasiticides (continued)

• Praziquantel
• Very distant potential NADAtrematodes cestodes
• Pyceze (bronopol)
• Distant potential NADAprotozoa Monogenea

100
Potential SLN Pesticides to Control Pests or
Hosts of Parasites on Non-Food Fish

• Bayluscide (niclosamide)snails
• Baytex (fenthion)larval dragonflies
• Dimilin 25W (diflubenzuron)Lernaea
• Dylox 80 (trichlorfon)predacious zooplankton

101
Potential Therapeutant NeedsFungal Fish Diseases

• Exophiala salmonis (NA)
• Ichthyophonus ?

102
Potential Fungicides

• Formalin
• Approvedsaprolegniasisall fish eggs
• Nearing completionsaprolegniasisall fish
• Hydrogen peroxide
• Nearing completionsaprolegniasisall fish all
  fish eggs

103
Potential Fungicides (continued)

• Copper sulfate
• Distant potential NADAsaprolegniasisall
  freshwater fish all freshwater fish eggs
• Potassium permanganate
• Distant potential NADAsaprolegniasisall
  freshwater fish all freshwater fish eggs
• Pyceze (bronopol)
• Distant potential NADAsaprolegniasis

104
Other Potential Drug NeedsSpawning Aids

• Chorulon (human chorionic gonadotropin)
• Approvedall fish
• Crude carp pituitary
• Almost complete except no Product Chemistry
  Potentially Low Regulatory Priority drug

105
Other Potential Drug NeedsSpawning Aids
(continued)

• Luteinizing Hormone-Releasing Hormone analogue
  (LHRHa)
• Under developmentvariety of fish
• Ovaprim (salmon GnRH analogue dopamine
  inhibitor)
• Ovaplant (Salmon GnRH analogue)
• Very distant potential NADA (work
  underway)variety of fish

106
Other Potential Drug NeedsGender Manipulation
Aids

• 17 a-methyltestosterone
• Proceeding to completiontilapia potentially
  other freshwater fish

107
Other Potential Drug NeedsChemical Marking Aids

• Immersion oxytetracycline
• Approvedall fish
• Oral oxytetracycline
• ApprovedPacific salmon
• Calcein
• Distant potential NADAall fish
• Strontium chloride
• Distant potential NADA

108
Other Potential Drug NeedsAnesthetics

• MS-222 (Finquel Tricaine-S)
• Approved with 21-day withdrawal time for food
  fish
• Approved for limited food fish species other
  cold-blooded animals
• Ictaluridae
• Salmonidae
• Esocidae
• Percidae
• Other fish other cold-blooded animalshatchery
  or laboratory use only
• Approved for all non-food fish other
  cold-blooded animals

109
Other Potential Drug NeedsAnesthetics

• Isoeugenol (AQUI-S)
• Proceeding to completionshort-exposure handling
  with zero withdrawal timeall freshwater fish
  saltwater salmonids

110
Need for Zero Withdrawal Anesthetic

• American Fisheries Society (AFS), Task Force on
  Fishery Chemicals, Aquaculture Chemicals
  Subcommittee
• Conducted Roundtable August 22, 2004 at AFS
  Annual Meeting, Madison, Wisconsin
• Fact Sheet out to agencies, organizations, and
  companies November 2004
• Article for AFSs Fisheries under development

111
What is a Zero Withdrawal Anesthetic?

• Time between last treatment of fish with an
  anesthetic potential consumption through
  slaughter or immediate release
• Circumstances in greatest need for a zero
  withdrawal anesthetic marked in red

112
Short-Exposure Procedures Needing Zero Withdrawal
Anesthetics

• Rested harvestfood-size cultured fish
• Artificial spawningfood-size captured fish
  cultured fish (carcasses or immediate live fish
  release)

113
Short-Exposure Procedures Needing Zero Withdrawal
Anesthetics

• Marking, tagging, measuring, sexingfood-size
  captured cultured fish
• Grading sortingfood-size cultured fish
• Vaccinationfood-size cultured fish

114
High Concentrations or Long-Exposure Procedures
Needing Zero Withdrawal Anesthetics

• Transportfood-size captured cultured fish
  shellfish (for immediate slaughter or live fish
  release)
• Research, surgery, veterinary
  practicefood-size captured cultured fish
  shellfish

115
Who Needs a Zero Withdrawal Anesthetic?

• All private fish shellfish aquaculture
  industries involved with
• Fish shellfish culture
• Fisheries stock restoration
• Commercial recreational fisheries
• All federal state agencies involved with
• Fisheries stock restoration
• Commercial recreational fisheries
• Fish shellfish culture
• Threatened endangered aquatic species

116
Anesthetics Considered

• Carbon dioxide gas sodium bicarbonate
• MS-222 (Finquel or Tricaine-S)
• Benzocaine
• Clove oil eugenol
• Isoeugenol (AQUI-S?)

117
Carbon Dioxide Gas Sodium Bicarbonate

• Low Regulatory Priority drugs but
• Unapproved drugs
• No drug sponsor
• No investigations for approval
• No formulation properly manufactured for this use
• Inconsistent results
• Difficult to use
• Easily toxic to fish

118
MS-222 (Finquel Tricaine-S)

• Only approved anesthetic
• Has 21-day withdrawal time
• Not all fish species covered (see above)
• Temperature limitations (
• To reduce 21-day withdrawal time
• 800,000 for mammalian safety studies
• Probably other studies would need to be repeated
  (e.g., target animal safety studies)

119
Benzocaine

• Initially had potential for approval but
• No sponsor
• No investigations for approval
• No formulation for this use
• Two 90-day mammalian feeding studies required
  (300,000)
• May not have been able to achieve zero withdrawal
  based on previous residue results

120
Clove Oil Eugenol

• Considered Generally Recognized as Safe (GRAS)
  when used as a direct food additives
• To use as anesthetics on fish
• Must be approved by CVM for that purpose
• Sponsors required no sponsors
• No known drug approval activities underway
• No properly manufactured formulations
• Equivocal carcinogens

121
Clove Oil Eugenol (continued)

• Declared as unapproved drugs by CVM
• Illegal to use as anesthetics on fish even if the
  treatment occurs in laboratory settings (Guidance
  Document 150)
• Only exception for useINAD exemption (none in
  place)
• Treatment authorization required
• Investigational withdrawal timeat least 21 days
• Isoeugenol (AQUI-S)potential substitute zero
  withdrawal time possibilities

122
Why Isoeugenol (AQUI-S)?

• Only candidate zero withdrawal anesthetic under
  development
• Immediate funding availableshort-term exposure
  handlingall salmonids
• Active drug company sponsorfunding some of the
  data generation

123
Why AQUI-S? (continued)

• Product formulation to met Good Manufacturing
  Practices
• Preliminary resultssafe to fish, humans,
  environment
• Effectivenessproven through controlled clinical
  tests accepted by FDA

124
Why AQUI-S? (continued)

• Technical Sections for non-marine studies covered
  by sponsor UMESC
• Only three Technical Sections to be covered by
  marine researchers
• Human Food Safety (only for marine food fish
  shellfish)
• Target Animal Safety
• Efficacy
• INAD in place for efficacy studies by marine
  researchers
• Under AADAPP (contact Dave Erdahl
  Dave_Erdahl_at_fws.gov)

125
Key to Color Coding
126
Abbreviations For Technical Sections
127
AQUI-SZero withdrawal anesthetic All
exposures/all fish shellfish
128
AQUI-SZero withdrawal anesthetic
Short-exposure/marine fish (not salmonids)
shellfish
129
AQUI-SZero withdrawal anesthetic
Long-exposure/all fish shellfish
130
PRIORITIZE DRUG APPROVAL NEEDS FOR SOUTHERN US
MARINE AQUACULTURE FISHERIES INDUSTRIES
131
Prioritization Process

• Survey marine aquaculture fisheries industries
• Select several priority drugs for approval
• Determine feasibility immediate possibility for
  approvals
• Identify resources available to gain approvals
• Develop Research Development Plans

132
IDENTIFY COMPANIES, AGENCIES, ORGANIZATIONS
THAT COULD HELP THE DRUG APPROVAL PROCESS FOR
SOUTHERN US AQUACULTURE FISHERIES INDUSTRIES
133
CompaniesPotential Drug Sponsors

• AQUI-S (isoeugenol)Representative in the United
  States Thomas Goodrich, 15110 NE 108th Place,
  Redmond, Washington 98052 Phone [phone]
  Fax [phone] E-mail res0099k_at_gte.net 
• Sponsor Don Bell, AQUI-S New Zealand Limited,
  PO Box 44-269, Lower Hutt, New Zealand Phone
  011-644-569-3852 Fax [phone] E-mail
  FishTrans_at_Compuserve.com

134
CompaniesPotential Drug Sponsors

• Chloramine-T (Halamid)Technical consultant in
  the United States Edwin Bisinger, Akzo Nobel
  Chemicals, inc., 300 South Riverside Plaza,
  Chicago, Illinois 60606 Phone [phone]
  Fax [phone] E-mail Edwin.c.Bisinger_at_akzo-n
  obel.com 
• Sponsor Paul Raadsen, Director of Axcentive
  SARL, Chemin de Champouse, Quartier Violesi,
  13320 Bouc Bel Air, France Phone [phone]
  090 Fax [phone] E-mail
  p.raadsen_at_axcentive.com

135
CompaniesPotential Drug Sponsors

• Copper sulfate (Triangle Brand Copper
  Sulfate)David Fisher, Phelps Dodge Refining
  Corporation, PO Box 20001, El Paso, Texas 79996
  Phone [phone] Fax [phone] E-mail
  dfisher_at_PhelpsDodge.com
• ErythromycinPotential sponsor Paul Rice,
  Bimeda-Osborn, Le Sueur, Minnesota 56058 Phone
  507-665-3316, extension 35 Fax [phone]
  E-mail paul.rice_at_bimedadaus.com

136
CompaniesPotential Drug Sponsors

• Florfenicol (Aquaflor)Dr. Richard Endris,
  Schering-Plough Animal Health, 1095 Morris
  Avenue, Union, New Jersey 07083-1982 Phone
  908-629-3133 Fax [phone] E-mail
  Richard.Endris_at_SPCorp.com

137
CompaniesPotential Drug Sponsors

• Formalin
• Parasite-SRon Secor, President, Western
  Chemical Inc., 1269 Latimore Road, Ferndale,
  Washington 98248 Phone [phone] Fax
  206-384-0270 E-mail WCI_at_Premier1.net has NADA
  and amended NADA 
• Formalin-FDr. Alton J. Hall, Natchez Animal
  Supply, 201 John Junkin Drive, Natchez,
  Mississippi 39120 Phone [phone] Fax
  800-647-6762 E-mail amcnas_at_iamerica.net has
  NADA and amended NADA 
• Paracide-FDr. Eliot Lieberman, Argent Chemical
  Laboratories, 8702-152nd Avenue N.E., Redmond,
  Washington 98052 Phone [phone] Fax
  425-665-2112 has NADA

138
CompaniesPotential Drug Sponsors

• Hydrogen peroxide (Perox-Aid)Dr. David Lovetro,
  Eka Chemicals Inc., 1519 Johnson Ferry Road,
  Marietta, Georgia 30062 Phone [phone]
  Fax [phone] E-mail DLovetro_at_EkaChem.com

139
CompaniesPotential Drug Sponsors

• 17a-methyltestosterone (Masculinizing Feed for
  Tilapia Masculinizing Feed for Fish)Dr.
  David Brock, Rangen, Inc., PO Box 706, Buhl,
  Idaho 83316-0706 Phone [phone] Fax
  208-543-4698 E-mail Rangenaq_at_magiclink.com

140
CompaniesPotential Drug Sponsors

• Oral oxytetracycline (Terramycin for Fish)Paul
  F. Duquette, Director, Global Regulatory Affairs,
  Phibro Animal Health, 710 Route 46 East, Suite
  401, Fairfield, New Jersey 07004 (has NADA)
  Phone [phone] Fax [phone] E-mail
  paul.duquett_at_phibroah.com has NADA

141
CompaniesPotential Drug Sponsors

• Immersion oxytetracycline (OXYMARINE)formerly
  Alpharma Animal Health, now Pharmaq, ASP.O.Box
  267 Skøyen, N-0213 Oslo, Norway Phone 47 23 29
  85 00
• Immersion oxytetracycline (Oxytetracycline HCI
  Soluble Powder-343)Phoenix Scientific, Inc.,
  3915 South 48th Street Terrace, St. Joseph,
  Missouri 64503 Phone [phone]

142
CompaniesPotential Drug Sponsors

• Potassium permanganate (Cairox)John Boll, Carus
  Chemical Company, 315 Fifth Street, PO Box 599,
  Peru, Illinois 61354-0599 Phone [phone]
  Fax [phone] E-mail John.Boll_at_caruschem.co
  m

143
CompaniesPotential Drug Sponsors

• Romet (Sulfadimethoxine ormetoprim)formerly
  Alpharma Animal Health, now Pharmaq AS, P.O.Box
  267 Skøyen, N-0213 Oslo, Norway Phone 47 23 29
  85 00

144
Potential Agencies Organizations

• Agricultural Research Service (ARS)
• National Aquaculture Program DirectorLewis Smith
  (lws_at_ars.usda.gov)
• Aquaculture fisheries organizations
• IAFWA Resource DirectorEric Schwaab
  (eschwaab_at_sso.org)
• 23 Marine state natural resources departments

145
Potential Agencies Organizations

• NRSP-7cooperative project for approval of drugs
  for minor species and minor uses in other species
  (http//www.nrsp-7.org)
• Southern Regional Aquaculture Center
  (http//www.msstate.edu/dept/srac)
• Universities (e.g., Mississippi State University,
  University of Florida, Auburn University)

146
Potential Agencies Organizations

• National Marine Fisheries Service (NMFS)
• Aquaculture CoordinatorMike Rubino
  (Michael.Rubino_at_NOAA.gov)

147
NMFS Aquaculture Policy

• Goals by 2025
• Increase value of domestic aquaculture
  production900 million to 5 billion
• Increase number of jobs180,000 to 600,000
• Develop technologies methods to improve
  products safeguard the environment

148
NMFS Aquaculture Policy (continued)

• Goals by 2025 (continued)
• Double value of non-food products services
  produced by aquaculture
• Enhance depleted wild fish stock through
  aquaculture
• Increase exports of US aquaculture products
  services500 million to 2.5 billion

149
NMFS Aquaculture Policy (continued)

• NMFS support of marine aquaculture
• Provide assistance associated with need of marine
  aquaculture
• Capital investment programs
• Information
• Research
• Provide sensible regulation surveillance
• Provide cooperation in monitoring

150
NMFS Strategic Plan for Fisheries Research

• Goals objectives
• Deployment of advanced innovative sampling
  technologies
• Use of stock assessments of greater
  sophistication accuracy
• Develop of cooperative research efforts
• Enhance data collection to address cultural
  diversity of fisheries
• Establish inventory of marine resource habitats

151
IDENTIFY POTENTIAL PUBLIC PRIVATE RESEARCHERS
FACILITIES FOR DRUG APPROVALS FOR SOUTHERN US
MARINE AQUACULTURE FISHERIES INDUSTRIES
152
Potential Researchers Facilities

• Company sponsors
• Those active in freshwater fish projects
• Researchers veterinarians at
• Universities (e.g., Mississippi State University,
  University of Florida, Auburn University)
• Federal agencies (e.g., NMFS ARS)
• Marine state natural resources agencies
• NRSP-7
• Private laboratories
• Fish farms
• Others?

153
IDENTIFY POTENTIAL SOURCES OF FUNDING FOR DRUG
APPROVALS FOR SOUTHERN US MARINE AQUACULTURE
FISHERIES INDUSTRIES
154
Potential Funding Sources

• NRSP-7
• Southern Regional Aquaculture Center
• Federal agencies (e.g., NMFS ARS)
• Marine state natural resources agencies
• Aquaculture fisheries organizations (e.g.,
  IAFWA)
• Universities
• Others?

155
(No Transcript)