Legal and Judicious
Use of Drugs and Therapeutants
in Aquaculture
Presented at:
Illinois and Indiana Veterinary Aquatic Medicine Workshop
Funded by: Illinois-Indiana Sea Grant College Program
Purdue University School of Veterinary Medicine
Lafayette, Indiana
September 24 & 25, 2010
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Background information
• Prior to the 1990s FDA chose not to regulate drug and chemical
use in MUMS (fish) – “regulatory discretion”
• Unfortunately, in the early 1990s FDA decided that the time had
come when aquaculture needed to be regulated like major
species.
• FDA’s decision to regulate left aquaculture with only
3 therapeutants and a single anesthetic approved for use in all
fisheries programs
• Use of these approved drugs was limited by species, life stage,
specific pathogen, and use pattern
• Effect of decision was exacerbated by FDA’s broad definition of
a “drug”…… that included even apparently innocuous
compounds such as ice, salt, onion, and garlic ??!!
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
USFWS AADAP Program
• Established in 1994
– National INAD Office (2.5 FTEs)
– Initially to ensure USFWS fish culturists could be compliant
with FDA regulations – administered INADs
• Expanded in 2003
– National INAD Program
– Research team
• Effectiveness
• Safety
– New Animal Drug Application Coordinator
– Information dissemination
• Website and Newsletter
• Quick reference guides
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Important acronyms and
definitions
• NADA = new animal drug application (approval)
– A formal application submitted to FDA’s Center for Veterinary
Medicine by a drug company to demonstrate that its new drug is
safe and effective
– 10 – 15 yrs and >$10M to gain FDA approval
– Public data necessary due to low profit incentive for drug
companies
• INAD = investigational new animal drug exemption
– Exemption issued by CVM to allow use of an unapproved drug
under strict conditions
– Permits the legal use of the drug and release or slaughter of food
animals treated with the drug
– Permits the legal interstate transport of the drug
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Important acronyms and
definitions
• Withdrawal period
– Period of time between last administration of a drug and the time
when a food animal may be released or slaughtered
• Extra-label use
– Veterinary prescription for the use of an approved drug for a
disease condition and/or species not on the approved label
– Veterinarian must assume all responsibility for residues
• Veterinary Feed Directive (VFD)
– Written statement (prescription) issued by a vet that allows the use
of a VFD feed drug
– VFD can only be written if a valid vet-client-patient relationship
exists
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
“Mechanisms” currently available for
legal use of drugs in aquaculture

FDA-approved drugs (full and conditional approvals)

Low Regulatory Priority drugs

Drugs with Deferred Regulatory Status

Extra-label drug use policy

Compassionate INAD exemptions

Federally-listed T&E fish species – letter of non-enforcement
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Judicious

Definition: Having or exhibiting good judgment or
sound thinking
•

Synonyms: wise, sensible, prudent
AVMA Judicious Antimicrobial Use Principles
• Accept responsibility for helping client design management,
immunization, production unit, and nutritional programs to
reduce the incidence of disease and the need for
antimicrobial treatment
• CVM Guidance Document (draft) #209
• The judicious use of medically important antimicrobial
drugs in food-producing animals
•
Needs clarification (antimicrobial vs. antibiotic, etc.)
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Judicious Use of Therapeutants

Treat as a last resort

Match “diagnosis” with situation; or utilize historical
data for a given facility/fish species/time of year

Establish/maintain a valid veterinarian-client-patient
relationship with the fish culturist and fish health
specialist

Select appropriate therapeutant to control mortality

Deliver appropriate treatment by following all use
guidelines (i.e., dose + duration + frequency) conduct a
small bioassay trial if you’re unsure
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Judicious Use of Therapeutants

Fate of treated fish (possible human consumption, not
harvestable, aquarium fish, etc.)

Food fish - adherence to withdrawal period before
release or slaughter

“More is not necessarily better”

Adherence to discharge requirements (NPDES –
Federal and state agencies)

Familiar with EPA Hatchery Effluent Guidelines
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Approved Drugs
(full drug approval)
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
How does a drug
get FDA approval?

It takes:
• An active sponsor (traditional sponsor – Pharmaceutical/drug
company; non-traditional sponsor – chemical company)
• Time and a lot of resources




Coordinators
Researchers
$$
Completion of Major Technical Sections
•
•
•
•
•
Human Food Safety
Environmental Safety
Efficacy
Target Animal Safety
Product Chemistry
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Aquaculture Drug Approvals
• “Pie-in-the-Sky” Goal
– To get as many drugs approved for use in
aquaculture as possible…as quickly as
possible:
• Approvals for all finfish
• Approvals for all disease claims
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Aquaculture Drug Approvals
• A more realistic Goal
– To get as many drugs approved for use in
aquaculture as possible…as quickly as
possible:
• Approvals for specific species or “groups” of
species (i.e., coolwater finfish)
• Approvals for specific disease claims
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Approved drugs

Romet 30® and TC®
•
•

Terramycin® 200 for Fish
•
•
•

Catfish – enteric septicemia
Salmonids – furunculosis
Catfish – HS, and pseudomonas
disease
Salmonids – ulcer disease,
furunculosis, HS, coldwater
disease, and pseudomonas
disease
Rainbow and Steelhead trout –
columnaris disease

(four families of fish)

Catfish – ESC
FW salmonids – CWD
FW salmonids - furunculosis
35% PEROX-AID®
•
•
•


Parasiticide – all FW fish
Fungicide – all FW eggs
Oxytet (skeletal marking)



Fungicide – All FW eggs
BGD – FW salmonids
Ex. Col. – coolwater fish/CCF
Formalin
•
•
Aquaflor® - VFD Drug
•
•
•
MS–222
Immersion - (all finfish fry and
fingerling)
Feed – Pacific salmon
Chorulon® (HCG)
(all fish)
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
----Soon to be---Approved drugs

Aquaflor® - VFD Drug
Warmwater fish – Streptococcal
disease (S. iniae)
• Warmwater fish – Columnaris
disease
• FW salmonids – Columnaris
disease
• FW salmonids – Bacterial kidney
disease
 Terramycin® 200 for Fish
• FW salmonids – mark skeletal
tissue

•
35% PEROX-AID®
•

Formalin
•

Cool- and warmwater fish External Columnaris
FW fish - Fungicide
Chloramine-T
•
•
•
FW salmonids – bacterial gill
disease
Walleye – external columnaris
Warmwater fish – external
columnaris
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Approved Drugs - Summary

There is a shortage of approved drugs
….…particularly if you are feeling poorly and you are
not a salmonid or a catfish!!

But . . . the list is growing!
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Conditional Drug Approval
(under MUMS legislation)
• Provides for animal marketing after all
safety and manufacturing components
have been met.
• Only component missing is effectiveness.
• Sponsor has 5 yrs to complete
effectiveness component (for each claim)
to achieve full drug approval
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Aquaflor®-CA1
• News Flash – April 18, 2007!!: Sponsor (ISP) gained
a conditional approval -- the first of its kind for any
food-animal therapeutic -- for use of Aquaflor®- CA1
to control mortality in catfish caused by Columnaris.
• Sponsor may seek conditional approval for:
• Salmonids - Enteric Redmouth, etc.
• Conditional approvals - VFD drug
• CVM requires separate product labeling and
separate “lots” for each claim
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Why VFDs
• To more closely control new therapeutic products
(primarily antibiotics) and their use in food animals
– New classification applies only to new therapeutants
approved after 1999 and administered in feed
– All products approved before 1999 – still Over-the-Counter
• Obtain VFD drugs through normal feed distribution
channels – but orders require a signed VFD from a
licensed veterinarian.
• Falls somewhere between Over-the-Counter and
prescription drugs…but probably closer to a
prescription.
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Control???
• VFD regulations – developed by a coalition of animal
health experts.
• Help reduce antibiotic resistance and prolong
effectiveness of new antimicrobials through
judicious use.
• Feed mill holding a Medical Feed Mill License – need
to file a notification with FDA that it will be
distributing VFD drugs in feed.
• No extra-label use allowed!
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Steps to obtain
and feed VFD drugs
• Veterinarian performs/coordinates diagnosis.
• Veterinarian works within veterinarian-client-patient
relationship to determine need for VFD drug.
• Veterinarian issues a signed VFD form to hatchery &
feed mill.
• Hatchery uses VFD form to order medicated feed.
• All parties retain copies of signed VFD order for 2
yrs.
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Does the VFD process work?
• Works well when:
– Veterinarian w/ fish experience is on-hand; large quantities of
medicated feed are needed (catfish)
• Doesn’t work so well when:
– Veterinarian w/ fish experience is not on-hand; small quantities of
medicated feed are needed; medicated feed is needed quickly
• FDA requested public comments on all aspects of
the VFD regulations
– To identify possible changes to the regulations to improve
efficiency
– Electronic comments submitted via the Federal eRulemaking
Portal (go to http://www.regulations.gov and follow the
instructions for submitting comments)
– Reference - Docket No. FDA-2010-N-0155
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Low Regulatory Priority
(LRP) Drugs
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
LRP Drugs

Consideration for LRP status originates from a
request from outside of CVM

Candidate drugs are typically quite innocuous (e.g.,
salt, ice, onion, etc.)

FDA made determination based on review of all
available data

16 drugs are currently on the LRP list
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
LRP drugs


LRP status does not mean carte blanche use of a
particular compound
1.
Must be used for indication listed
2.
Must be used according to good management practices
3.
Must be used at the prescribed level
4.
Must be of appropriate grade for use in food animals
5.
Use only if an adverse effect on the environment is unlikely
LRP drug use is not considered to be “approved”
drug use, but rather low enforcement
priority….regulatory action unlikely
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
LRP Drugs





Acetic acid
Calcium oxide
Garlic
Magnesium sulfate
Onion








Potassium chloride
Sodium chloride



Calcium chloride
Fuller’s earth
Papain
Urea and Tannic acid
Povidone Iodine
Sodium Sulfite
Ice
Carbon dioxide gas
Sodium bicarbonate
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
LRP Drugs





Acetic acid
Calcium oxide
Garlic
Magnesium sulfate
Onion








Potassium chloride
Sodium chloride



Calcium chloride
Fuller’s earth
Papain
Urea and Tannic acid
Povidone Iodine
Sodium Sulfite
Ice
Carbon dioxide gas
Sodium Bicarbonate
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Deferred Regulatory Status
(DRS) Drugs
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Deferred Regulatory Status

Very little specific, written guidance available

…..verbal translation is that FDA chooses not to
regulate….period!….. at this time

For all practical purposes…..use can be carte
blanche

Ongoing efforts to gain FDA approval of DRS drugs
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
DRS Drugs
Copper sulfate (CuSO4)


Proposed approved uses
•
•
For use to control mortality cause by Ich on catfish reared in
earthen ponds
For use to control fungus on channel catfish eggs
Potassium permanganate (KMnO4)


Proposed approved uses
•
For use to control mortality caused by columnaris in
freshwater finfish

hybrid striped bass
Channel catfish

Freshwater-reared salmonids

Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Extra-Label Drug Use Policy

AMDUCA (signed into law in Oct. 1994) outlines
provisions relating to extra-label use of approved New
Animal Drugs (NAD)

Is a reflection of FDA’s recognized need for
veterinarians to be able to treat disease conditions for
which there may not be an effective, approved drug

Applies to the extra-label use of any approved NAD or
human drug by a veterinarian within the context of the
veterinarian-client-patient relationship in a manner not
in accordance with label directions.

Animal Medicinal Drug User Clarification Act of 1994
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Extra-Label Drug Use Policy

Extra-label drug use is limited by the following very specific
restrictions:
1.
Applies only to NAD’s approved for use in other species
2.
Available only thru practicing veterinarians, and mandates a valid
veterinarian-client-patient relationship
3.
No effective approved drug is available for use in target animal
4.
Permits the use of approved over-the-counter drugs mixed in feeds
(veterinarian order to treat a different fish species than that described on the label
or for a different disease condition)
5.
Not permitted for VFD drugs!
6.
Does not permit the use of drugs to prevent disease, or for enhanced
production (e.g., growth promotion, induced spawning)
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Investigational New
Animal Drugs
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Good ol’ INADs
“The Upside”

Provide access to a variety of drugs…and drug uses….that are
not yet approved by FDA (and that we would otherwise not have
at our disposal)

Contributes “valuable” efficacy and safety data that can be used
to support broadening new approvals

Treatment objectives written to be as inclusive as possible (e.g.,
“…..to control mortality caused by susceptible pathogens in
freshwater fish”)

……we have been able to assemble quite a few!!
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Good ol’ INADs
“The Downside”
 Not just “use permits” like many folks initially believed
 Paperwork (and accountability) necessary for ALL involved
 Cost to participate….in either $$’s and/or time
 Under constant scrutiny by FDA……as many within the “Big
FDA” would like to see them go-away
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
INADs
Antibiotics
Microbicides





Marking agents







 SE-MARK® (calcein)
 Oxytetracycline (feed – marking)
Spawning hormones
Aquaflor® (florfenicol)
Oxytetracycline (feed – therapy)
Oxytetracycline (injection – therapy)
Oxytetracycline (immersion – therapy)
Erythromycin (feed – therapy)
Gender manipulation
 17-α MT
Anesthetics




35% PEROX-AID® (35% hydrogen peroxide)
REWARD® (diquat)
Chloramine-T
SLICE® (0.2% emamectin benzoate)
Formalin
Copper sulfate
Potassium permanganate
Common Carp Pituitary
LHRHa (injection)
Ovaplant® (implant)
Catfish pituitary
 Eugenol (AQUI-S E®)
 Benzocaine (BENZOAK®)
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Use of Unapproved Drugs on
Federally-Listed T & E Species

CVM letter dated December 4, 1995

Includes USFWS and Collaborators

Use of unapproved drugs in federally-listed T & E
species will be considered to be of low enforcement
priority

Requires completion and submission to AADAP:

Drug receipt form

Drug use inventory form
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Federally-Listed T & E Species
regulatory action will not ordinarily
be considered if:

Treated species are not subject to legal harvest

Service assumes responsibility with NEPA
compliance

Used only as conservation action necessary for
protection and recovery of listed species

CVM’s enforcement discretion will apply to the
USFWS and contract facilities utilized by the USFWS
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Summary of Legal Drug Use Options
Extra-label Drugs
+
LRP Drugs
T&E
Drugs
+

+
Approved Drugs
+
Deferred Regulatory
Drugs
+
INAD Drugs
+
…thankfully….the utility of the sum is greater than
that of the individual parts

….a variety of options do exist

……but we certainly have a long way to go with
respect to our goal of approved drugs
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Drugs most likely to be
used illegally

Clove oil (eugenol)


MS-222 (used off-label)



CVM Guidance Document #150
Approved for 4 families of freshwater finfish
21 d withdrawal period
Drugs purchased from sources other than
the sponsor


Over the internet or from supply catalogues
Lower quality (cheaper) grade
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Regardless of the “classification” of the
accessible drugs, all drugs should be used
judiciously

Treat as a last resort

Know what you’re treating for…don’t guess

Use the appropriate drug correctly – more is not
necessarily better

Adhere to established withdrawal periods and
hatchery discharge requirements

Establish a valid veterinarian-client-patient
relationship to provide VFD drug(s)
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals
Questions??
Aquatic Animal Drug Approval Partnership: In Pursuit of Aquaculture Drug Approvals