Extralabel Drug Use in Animals

SUMMARY: The Food and Drug Administration (FDA) is proposing to allow

veterinarians to prescribe extralabel uses of certain approved animal

drugs and approved human drugs for animals. This action implements the

Animal Medicinal Drug Use Clarification Act of 1994 (the AMDUCA). This

proposed rule will provide veterinarians greater flexibility for using

approved drugs for animal use.

DATES: Written comments on the proposed rule by July 31, 1996. Written

comments on the information collection requirements should be submitted

by June 17, 1996.

ADDRESSES: Written comments on the proposed rule to the Dockets

Management Branch (HFA-305), Food and Drug Administration, 12420

Parklawn Dr., rm. 1-23, Rockville, MD 20857.

-Submit written comments on the information collection requirements

to the Office of Information and Regulatory Affairs, Office of

Management and Budget (OMB), New Executive Office Building, 725 17th

St. NW., rm. 10235, Washington, DC 20503, ATTN: Desk Officer for FDA.

FOR FURTHER INFORMATION CONTACT: Richard L. Arkin, Center for

Veterinary Medicine (HFV-238), Food and Drug Administration, 7500

Standish Pl., Rockville, MD 20855, 301-594-1737.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background

A. The Provisions of the AMDUCA

B. FDA's Extralabel Drug Use Policies

II. Description of the Proposed Rule

A. Scope and Purpose

B. Definitions

C. Specific Issues

1. Extralabel use when approved drugs are available for intended

therapeutic purposes

2. Compounding

3. Sponsor Records, Reports, and Adverse Events

D. Advertising and Promotion Prohibited

E. Access to Veterinarian Records

F. Provision Permitting Extralabel Use of Animal Drugs

G. Limitations

H. Labeling

I. Specific Provision for New Animal Drug Extralabel Use in Food

Animals

J. Prohibitions, Safe Levels, Analytical Methods

K. Extralabel Drug Use in Nonfood Animals

III. Proposed Effective Dates

IV. Environmental Impact

V. Analysis of Impacts

VI. Paperwork Reduction Act of 1995

VII. Federalism

VIII. Request for Comments

Appendix

I. Background

A. The Provisions of the AMDUCA

FDA is proposing rules to implement the AMDUCA (Pub. L. 103-396)

which was signed into law on October 22, 1994. Prior to enactment of

the AMDUCA, section 512 of the act (21 U.S.C. 360b) provided that a new

animal drug (NAD) is deemed unsafe unless it is subject to an approved

application and the drug, its labeling and its use conform to such

approved application. Therefore, use of an NAD without an approved

application or in a manner different from that set out in an approved

application resulted in the drug being unsafe under the act. Section

501(a)(5) of the act (21 U.S.C. 351(a)(5)) provides that a drug deemed

to be unsafe under section 512 is adulterated. The AMDUCA allows

veterinarians to prescribe extralabel uses of approved animal drugs and

approved human drugs for animals.

The provisions of the AMDUCA relating to extralabel use of approved

NAD's provide that such use must be in accordance with conditions

specified by the Secretary of Health and Human Services (the Secretary)

by regulations. The animal drug provisions also include several

safeguards in allowing veterinarians to prescribe drugs for extralabel

uses: (1) If the Secretary finds there is a reasonable probability that

an extralabel use may present a risk to public health, the Secretary

may establish a safe level for a residue for such extralabel use by

regulation or order, and may require the development of analytical

methods for residue detection; (2) the Secretary may, by general

regulation, provide access to records of veterinarians to ascertain any

use or intended use that the Secretary determines may present a risk to

public health; and (3) if the Secretary finds, after affording an

opportunity for public comment, that an extralabel animal drug use

presents a risk to public health or that no acceptable analytical

method has been developed and submitted, the Secretary may prohibit

such extralabel use by order. In addition, the AMDUCA provides that an

extralabel use of an approved NAD is not permitted if the label of

another animal drug with the same active ingredient, dosage form, and

concentration provides for that different use.

The AMDUCA also allows veterinarians to prescribe approved human

drugs for use in animals under conditions specified by the Secretary by

regulations. The human drug provisions do not, however, contain the

express conditions set out in the statute for extralabel use of

approved NAD's.

The AMDUCA adds a new section 301(u) to the act (21 U.S.C. 331(u))

which provides that failure to comply with the regulations or orders

implementing the AMDUCA is a prohibited act. In addition, the AMDUCA

amends section 512(l) of the act to require drug sponsors to keep

records and make reports regarding extralabel uses.

Neither the AMDUCA nor the implementing regulations are intended to

lessen the responsibility of the manufacturer, the veterinarian, or the

food producer with regard to violative drug residues or other adverse

impact on human health. Under the act and this proposal, any amount of

residue that may present a risk to public health resulting from an

extralabel use would constitute a violation of the act subject to

enforcement action, if a safe level or tolerance has not been

established. Residue exceeding an established safe level would also

constitute a violation of the act, as would residue resulting from an

extralabel use where the residue exceeds an established tolerance.

The AMDUCA requires that the Secretary issue final rules

implementing the statute within 2 years of the enactment date. The

provisions of the AMDUCA are effective upon adoption of the final

rules.

B. FDA's Extralabel Drug Use Policies

Under the current statute, extralabel use of drugs in animals is a

violation of the act, therefore, FDA set out its enforcement policies

regarding such use in two FDA Compliance Policy Guides (CPG's). The

first of these was issued on March 9, 1984, as CPG 7125.06,

``Extralabel Use of New Animal Drugs in Food-Producing Animals,'' and

was revised most recently on July 20, 1992. In March 1995, CPG 7125.06

was published as Section 615.100 of Chapter

[[Page 25107]]

6 in a new agency compilation of CPG's entitled the ``FDA Compliance

Policy Guides Manual, first edition'' (Washington: Government Printing

Office, publication 1995-386-982-3373, 1995). The second relevant CPG,

``Human-Labeled Drugs Distributed and Used in Animal Medicine,'' was

issued as CPG 7125.35 on March 19, 1991, and was last revised on July

20, 1992. It has been published as Section 615.100 in Chapter 6 of the

CPG Manual.

-The extralabel CPG's were issued to provide information and

direction to FDA personnel in the field about the circumstances in

which FDA would take regulatory action against extralabel use of

approved NAD's and human drugs in animals and the situation in which

the agency would exercise its regulatory discretion and not take

action. The scant legislative history of the AMDUCA includes some

evidence that the AMDUCA is intended to codify policies similar to

those in FDA's CPG's. While there are no committee reports on the

AMDUCA, floor statements of individual members of Congress express this

intent. For example, Senator Pressler said in debate on the bill, ``FDA

has stated it will not institute regulatory action against licensed

veterinarians for using or prescribing any drugs legally obtained.

Thus, this bill codifies existing FDA practice.'' (140 Congressional

Record S14072 (daily ed. October 4, 1994)). Senator Coats made a

similar statement on the floor when he noted that the AMDUCA ``codifies

the practices allowed under the current compliance policy guidelines''

regarding the extralabel use of veterinary pharmaceutical products.

(140 Congressional Record S14272 (daily ed. October 5, 1994)).

-Consistent with these congressional statements, FDA has generally

followed policies similar to those in the existing CPG's in this

proposed rule. For the public's convenience, the texts of the

extralabel CPG's are included in this document in an appendix to the

preamble. It-is anticipated that the CPG's will be withdrawn after a

final rule based on this proposal has been published.

-II. Description of the Proposed Rule

--A. Scope and Purpose

-The proposed rule would apply to the extralabel use in an animal

of any approved NAD or approved human drug used by or on the lawful

order of a veterinarian within the context of a veterinarian-client-

patient relationship. Human drugs include approved new human drugs, as

well as over-the-counter (OTC) drugs marketed under OTC monographs as

safe and effective and not misbranded within the meaning of 21 CFR part

330. The proposal applies only to the extralabel use of approved NAD's

and approved human drugs and not to the use of unapproved drugs.

-Consistent with the policies in the CPG's, these proposed rules

limit extralabel uses for food-producing animals to those that provide

alternative treatment modalities when the health of an animal is

threatened, or suffering or death may result from failure to treat an

animal, i.e., therapeutic uses. FDA, however, has received increased

requests to permit extralabel drug use for certain nontherapeutic uses

such as uses related to enhanced animal reproduction. For example,

representatives of the aquaculture industry have expressed a need for

extralabel uses of drugs for spawning and gender reversal processes.

Those representatives contended that certain aquaculture industries

would not be able to survive economically without such extralabel uses,

because approved drugs have not been available for those uses. Comments

by members of the Veterinary Medicine Advisory Committee (VMAC) and

others at the April 1995 VMAC meeting generally agreed that extralabel

uses might be extended to some reproductive uses in terrestrial and,

especially, aquatic animals.

-The agency, in considering the appropriate scope of extralabel use

under the statute, is concerned about the possible deterrent effect of

such broad extralabel use on the widely-shared goal of increasing the

number of approved drugs that are available for animal use. Therefore,

the agency is interested in public comments as to nontherapeutic

extralabel uses such as reproductive uses in terrestrial and,

especially, aquatic animals and other possible uses. The agency also is

interested in public comment as to appropriate ways to balance

extralabel use with the need to preserve the goal of increased

availability of new animal drugs approved for such uses under section

512 of the act.

-B. Definitions

-Proposed Sec. 530.3 includes definitions of relevant terms. The

term ``extralabel use'' means the actual or intended use of a human or

animal drug in an animal in a manner that is not in accordance with the

approved labeling. This includes, but is not limited to, use in species

or for indications (disease or other therapeutic conditions) not listed

in the labeling, use at dosage levels, frequencies, or routes of

administration other than those stated in the labeling, and deviation

from the labeled withdrawal time. Any deviation from labeled withdrawal

time based on these different uses must be supported by appropriate

scientific information.

-The proposed rule defines the term ``residue'' to mean any

compound present in edible animal tissues that results from the use of

a drug, and would include the drug, its metabolites, and any other

substance formed in or on food because of the drug's use.

-The proposal defines a ``safe level'' as a conservative estimate

of a drug residue level in animal tissue derived from toxicology and

metabolism data or other scientific information. This level would be

established so that concentrations of residues in tissue below the safe

level will not raise human food safety concerns.

-Under the proposal, a safe level would not be either a safe

concentration or a tolerance and would not indicate that an approval

exists for the drug in that species or category of animals from which

the food is derived. If FDA establishes a safe level and a tolerance is

later established through an approval for a particular species or

category of animals, the safe level would be superseded by the

tolerance for that species or category of animals, and would be

revoked. -

-The term ``veterinarian'' is defined as a person licensed by a

State or Territory to practice veterinary medicine, and who holds a

degree of Doctor of Veterinary Medicine (D.V.M.), Veterinary Medical

Doctor (V.M.D.), or the equivalent, from an accredited institution.

-A ``valid veterinarian-client-patient relationship'' is defined as

one in which: (1) A veterinarian has assumed the responsibility for

making medical judgments regarding the health of an animal and the need

for medical treatment, and the client (the owner or other caretaker of

the animal or animals) has agreed to follow the instructions of the

veterinarian; (2) there is sufficient knowledge of the animal(s) by the

veterinarian to initiate at least a general or preliminary diagnosis of

the medical condition of the animal(s); and (3) the veterinarian is

readily available for followup in case of adverse reactions or failure

of the regimen of therapy. Such a relationship can exist only when the

veterinarian has recently seen and is personally acquainted with the

keeping and care of the animal(s) by virtue of examination of the

animal(s), and/or by medically appropriate and timely visits to the

premises where the animal(s) are kept. This definition is consistent

with the American Veterinary Medicine

[[Page 25108]]

Association's definition of a ``valid veterinarian-client-patient

relationship.''

The proposed rules, for purposes of establishing a safe level and

requiring the development of analytical methods to detect residues,

define the phrase ``a reasonable probability that a drug's use may

present a risk to the public health''as a circumstance in which FDA has

reason to believe that use of a drug may be likely to cause a potential

adverse event. The proposal, for purposes of providing access to

veterinarians' records, would define the phrase ``use of a drug may

present a risk to the public health''to mean a circumstance in which

FDA has information that indicates that use of a drug may cause an

adverse event. In addition, under the proposal, the phrase ``use of a

drug presents a risk to the public health,''for purposes of prohibiting

an extralabel use, means a circumstance in which FDA has evidence that

demonstrates that the use of a drug has caused or is likely to cause an

adverse event.

In defining these phrases regarding risk, the agency considered the

common meaning of the words in these phrases, and other regulations in

which FDA has defined similar concepts (e.g., 21 CFR 7.3(m), 7.41, and

803.3(r). The statute provides for an increased level of FDA activity

as evidence of public concern becomes more substantial, and as the

connection between specific extralabel uses and effect on the public

health becomes more apparent. The final step may be prohibition of

specified extralabel uses.

A finding that there is a reasonable probability that ``a drug's

use may present a risk to the public health'' could be based on

relevant information--assessed in the light of the education and

experience of an agency staff member or other qualified person--that

there may be a connection between a use and a potential adverse event.

This would differ from a finding that ``use of a drug may present a

risk to the public health,'' which would normally be based on some

greater level of information that demonstrates that there may be some

more concrete link between the use and an adverse event. In contrast, a

finding that ``use of a drug presents a risk to the public health''

would require strong evidence of a direct link between the use and the

risk.

FDA intends that harm that results from chronic low level or repeat

exposure that is not high enough to cause acute toxicity but that could

cause toxicity over long periods of time is included within the meaning

of ``adverse event.''

C. Specific Issues

1. Extralabel Use When Approved Drugs are Available For Intended

Therapeutic Purposes.

FDA's discretionary policies have precluded extralabel use of an

animal or human drug in food-producing animals when an approved drug

for the intended use exists. A similar limitation has not applied in

the case of animal and human drugs used in animals not intended for

human consumption; the agency has exercised broad enforcement

discretion with regard to extralabel use in those species.

The AMDUCA provides that an extralabel use of an approved animal

drug is not permitted if an approved NAD with the same active

ingredient in the same dosage form and concentration exists for that

use. The statute does not limit this provision to food-producing

animals as FDA did in its CPG. Therefore, proposed

Sec. Sec. 530.20(a)(1) and 530.30(a) limit the extralabel use of

approved animal drugs in all animals to circumstances in which there is

no approved NAD in the needed dosage form and concentration. The CPG

contains an exception that permits an extralabel use where the

veterinarian finds, within the context of a valid veterinarian-client-

patient relationship, that an approved NAD is clinically ineffective

for its intended use. The proposed rule does not include a similar

provision. However, the agency invites comment as to whether the agency

should permit such an exception.

The AMDUCA does not restrict extralabel use of approved human drugs

in a similar manner. However, these proposed rules include the same

limitation for extralabel use of human drugs in food-producing animals.

FDA believes that, because of the broad public health implications

inherent in the treatment of animals that will become food, it is

prudent to require the use of an approved NAD if one exists before the

extralabel use of a human drug is appropriate.

2. Compounding

FDA considers compounding from an approved drug to be an extralabel

use. Thus, the agency views the language of the AMDUCA as giving

statutory authorization to the compounding of finished drug products

from approved human or approved animal drugs, within limits, under the

same conditions as for any other extralabel use. FDA has certain

concerns relative to compounding and the use of compounded drugs that

can be distinguished from those issues associated with simple

extralabel use of an approved finished drug product.

In view of the above, the proposed rule includes several major

factors in addition to the general criteria set forth elsewhere in this

proposed rule applicable to the extralabel use by compounding from

approved drugs. The proposal provides that such extralabel use is

permissible if: (1) All relevant portions of proposed part 530 have

been complied with; (2) there is no marketed or approved human or new

animal drug that, when used as labeled or in conformity with criteria

established in this part, will, in the available dosage form and

concentration, appropriately treat the condition diagnosed; (3)

compounding is performed by a licensed pharmacist or veterinarian

within the scope of a professional practice; (4) adequate processes and

procedures are followed that ensure the safety and effectiveness of the

compounded products; (5) the scale of the compounding operation is

commensurate with the established need for compounded products (e.g.,

similar to that of comparable practices); and (6) all relevant State

laws relating to the compounding of drugs for use in animals are

followed.

The AMDUCA does not authorize compounding from bulk drugs or

unapproved drugs. Compounding by or for veterinarians from bulk drugs

or unapproved drugs results in the production of an unapproved NAD that

may be subject to regulatory action. Accordingly, proposed Sec. 530.13

provides that allowable extralabel use by compounding applies only to

compounding of a product from approved drugs by a veterinarian or a

pharmacist on the order of a veterinarian within the practice of

veterinary medicine, and that nothing in proposed part 530 is to be

construed as permitting compounding from bulk drugs or unapproved

drugs.

Additional guidance on the subject of compounding may be provided

in guidance documents to be issued by FDA.

3. Sponsor Records, Reports, and Adverse Events

FDA is concerned that the enactment of the AMDUCA could have the

unintended effect of reducing the information that has heretofore been

provided to the agency by sponsors regarding their products.

Information that helps FDA assure the safe and effective use of

approved drugs comes from two sources, among others. First, sponsors

submit data and information on adverse events resulting from extralabel

uses. Second, sponsors submit supplemental applications to extend the

product labels to provide for new uses. The agency's concerns are

[[Page 25109]]

that under the AMDUCA the sponsors might have less incentive to submit

supplemental applications, and might also be reluctant to report

extralabel use adverse events that FDA could require to be stated in

the labeling. FDA believes that neither result was intended by

Congress. For example, the AMDUCA specifically requires the reporting

of adverse events related to extralabel uses.

-Section 512(l) of the act requires sponsors to maintain records of

and report experiences ``and other data and information'' regarding a

drug. Under 21 CFR 510.300 et seq., ``Records and Reports,'' adopted

under section 512(l) of the act, sponsors are currently required to

report on extralabel drug uses. Section 2 of the AMDUCA amended section

512(l) of the act by adding new language specifically requiring

maintenance of records and reports of experiences related to extralabel

drug uses. Accordingly, the sponsor is required to maintain records of

and report to the agency all information the sponsor has that pertains

to extralabel drug uses, including adverse drug experiences.

Data derived from such records and reports may be used in

establishing a prohibition against the use of a drug in food-producing

animals under Secs. 530.21 and 530.25, or safe levels and analytical

methods under proposed Secs. 530.22, 530.23, and 530.24. In addition,

Section 2 of the AMDUCA amended section 512(e) of the act by adding new

language specifically giving authority to the agency to withdraw

approval of a NAD based on records and reports of experience with

extralabel uses, in addition to experience with an approved use.

-FDA believes that it is important to publicize data it has

received concerning adverse events resulting from all uses, including

extralabel drug uses. This could be done through provision of this

information to professional journals, the trade press, and others,

through press releases, ``Dear Doctor letters,'' and similar documents.

FDA would be interested in receiving comments from the public with

respect to any policy that would allow or encourage sponsors to provide

extralabel drug use information regarding significant adverse events on

labeling.

-D. Advertising and Promotion Prohibited

-While the AMDUCA and the proposed rule permit extralabel uses of

approved drugs, neither the statute nor the proposed rule would permit

advertising and promotion of extralabel uses. The act does not permit

advertising and promotion of an unapproved use for a human or approved

animal drug because scientific data supporting the safety and efficacy

of a new drug use must be submitted by the sponsor and reviewed and

approved by the agency in order to permit such use to be advertised,

promoted, or included on the labeling. Advertising and promoting of any

unapproved use for a drug would be inconsistent with the act and would

subvert the entire system of drug approval and regulation because there

would no longer be any incentive for a sponsor to submit data and go

through the approval process for an unapproved use.

-Accordingly, proposed Sec. 530.4 includes a statement that the

rule shall not be construed as permitting advertising or promotion of

extralabel uses of human or new animal drugs.

E. Access to Veterinarian Records-

Section 2(a) of the AMDUCA adds a new section 512(a)(4)(C) to the

act which provides that FDA may adopt regulations providing FDA the

right of access to records maintained by veterinarians to ascertain any

extralabel use or intended use of an approved animal drug authorized by

the agency that may present a risk to the public health.

-Proposed Sec. 530.5 provides that persons designated by FDA (i.e.,

FDA investigators) would be given access to the records of

veterinarians, including records required to be maintained under the

act, State veterinary practice acts, and State pharmacy acts. Any

person who has custody of these records would be required to permit

inspection at any reasonable times, permit copying, and verify such

records.

-While the AMDUCA does not include an explicit authority for FDA to

require the creation and maintenance of records by veterinarians, the

statute clearly allows the agency to specify the conditions for

extralabel use. The agency believes that the maintenance of records is

essential to the agency's ability to implement the statute and protect

the public health and, as such, maintenance of records is a condition

of allowable extralabel use. However, it is not FDA's intention to

create new recordkeeping burdens on veterinarians who are required to

keep records under State recordkeeping requirements.

-FDA believes that these State required records will include the

type of information FDA will need to carry out its statutory

responsibilities. Records required by State veterinary practice acts or

State pharmacy acts routinely document the existence of a valid

veterinarian-client-patient relationship. These records also would

provide relevant information concerning extralabel drug uses.

Typically, these records include: (1) The name, address, and telephone

number of the veterinarian; (2) the name, address, and telephone number

of the client; (3) the complaint, or other reason for the provision of

services, including information on the patient history, physical

examination, and laboratory data; (4) the provisional or final

diagnosis and date of diagnosis; (5) identification of the animal(s)

treated (including species, breed, age, sex, color, brand, and tag or

tattoo number); (6) the date of treatment, prescribing, or dispensing

of the drug; (7) the established name of the drug and its active

ingredient, or if formulated from more than one ingredient, the

established name of each ingredient; the dosage form, strength, and

quantity of the prescribed or dispensed drug, and the dates of

administration; (8) any directions for use provided, including dose,

route of administration, and length of therapy; (9) the number of

refills authorized; (10) cautionary statements, if any; and (11) the

veterinarian's specified withdrawal, withholding, or discard time(s),

if applicable, for meat, milk, eggs, or any food that might be derived

from any food animals treated.

-Under the proposal, veterinarians would be required to maintain

individual records for each nonfood animal treated as required by State

veterinary practice and pharmacy acts. State veterinary practice acts

generally require veterinarians in large animal practices to maintain

records for food-producing animals that are adequate to substantiate

the identification of the animals and the medical care provided. Such

records in large animal practices can usually be maintained either as

individual records or on a group, herd, flock, or per-client basis.

-State veterinary practice and State pharmacy acts generally

require veterinarians to maintain complete records of receipt and

distribution of each veterinary drug. These records, which are

maintained in the form required by the appropriate State acts, may

include sales invoices, shipping records, prescription files, or

records or logs established solely for this purpose. Receipt and

distribution records usually are also required to include: (1) The name

of the drug, (2) the name and address of the person or corporation from

whom the drug was shipped, (3) the date and quantity received, and (4)

the name and address of the person to whom the drug was distributed.

[[Page 25110]]

-Under the proposed rule, drug distribution and use records would

be required to be maintained for 2 years or as otherwise required by

Federal or State law, whichever is greater.

-The proposal would require that veterinarians maintain all records

required by State veterinary practice and pharmacy acts in a legible

form, document them in an accurate and timely manner, and keep them

readily accessible to permit prompt retrieval of information.

-Refusal to provide access to such required records is a prohibited

act under section 301 of the act as amended by the AMDUCA.

-F. Provision Permitting Extralabel Use of Animal Drugs

-Proposed Sec. 530.10 provides that extralabel use of an approved

human or NAD is permitted by or under the lawful written or oral order

of a veterinarian within the context of a veterinarian-client-patient

relationship, if the extralabel use is otherwise in compliance with the

regulation.

-G. Limitations

- Proposed Sec. 530.11 sets out the following specific limitations

on extralabel use. The following uses result in the drug being deemed

to be unsafe within the meaning of the act: (1) Extralabel use in an

animal of an approved new animal or human drug by a lay person (except

under the supervision of a veterinarian), (2) extralabel use of an

approved NAD or human drug in or on an animal feed, (3) extralabel use

resulting in any residue which may present a risk to public health, and

(4) extralabel use resulting in any residue above an established safe

level or tolerance.

-H. Labeling

-The proposal at Sec. 530.12 would require that any human or animal

drug prescribed or dispensed for extralabel use by a veterinarian or a

pharmacist on the order of a veterinarian bear or be accompanied by

labeling information adequate to assure the safe and proper use of the

product. The phrase ``be accompanied by'' is intended to permit

shipment of drugs by a veterinarian or pharmacist on the order of a

veterinarian in case quantities. The minimum information required under

the proposal is the same as that currently required by CPG and

includes: (a) The name and address of the veterinarian; (b) the

established name of the drug, or if formulated from more than one

active ingredient, the established name of each ingredient; (c) any

directions for use specified by the veterinarian, including the class/

species or identification of the animal in which it is intended to be

used; the dosage, frequency, and route of administration; and the

duration of therapy; (d) any cautionary statements; and (e) the

veterinarian's specified withdrawal, withholding, or discard time for

meat, milk, eggs, or any food that might be derived from the treated

animal.

-I. Specific Provision for New Animal Drug Extralabel Use in Food

Animals

-Proposed Sec. 530.20(a)(2) requires as a condition for extralabel

use that a veterinarian be required to take a number of affirmative

actions before prescribing or dispensing an animal or human drug for an

extralabel use in food animals. The veterinarian must do the following:

(1) Make a careful diagnosis and evaluation of the conditions for which

the drug is to be used; (2) establish a substantially extended

withdrawal period prior to marketing of milk, meat, or eggs supported

by appropriate scientific information, if applicable; (3) institute

procedures to assure that the identity of the treated animal or animals

is carefully maintained; and (4) take appropriate measures to assure

that assigned timeframes for withdrawal are met and no illegal drug

residues occur in any food-producing animal subjected to extralabel

treatment.

-Because extralabel use of drugs in food-producing animals

engenders an increased potential for illegal drug residues in meat,

milk, and eggs, which are consumed in significant amounts by the

American public, the proposed rule would also set forth additional

conditions for extralabel drug use in food-producing animals.

-One restriction, contained in proposed Sec. 530.20(b), applies to

the extralabel use of either an approved human drug, or an animal drug

approved only for use in animals not intended for human consumption. In

such instances, records maintained by the veterinarian must reflect the

medical rationale for such use. In addition, if there is no published

scientific information on public health aspects of the use of the

nonfood animal drug in food-producing animals, the veterinarian must

determine that the animal and its food products will not enter the

human food supply.

-A second restriction would apply only to the use of human drugs in

food animals. As discussed in section II.C. of this document, proposed

Sec. 530.20(a)(1) would not allow such use if an approved animal drug

is available for such use (with certain exceptions). Section 530.20(c)

requires the additional step of consideration of extralabel use of

approved food-animal drug before use of a human drug or drug approved

for use in animals not intended for human consumption. In addition,

records maintained by the veterinarian must reflect this consideration.

-J. Prohibitions, Safe Levels, Analytical Methods

-Section 512(a)(4)(B) and (a)(4)(D) of the act as added by the

AMDUCA grants FDA the authority to prohibit extralabel drug uses,

establish safe levels and require the development of analytical

methods. These provisions are included in section 512(a)(4) of the act

which addresses approved NAD's and are not specified in section

512(a)(5) which addresses approved human drugs. Nevertheless, FDA

believes that, under the general authority in section 512(a)(5) of the

act to set the conditions for extralabel use of approved human drugs in

animals, the agency may also set safe levels, require development of

analytical methods, and prohibit extralabel uses of human drugs when

necessary to protect the public health. Thus, the proposed rule applies

these safeguards to human drugs as well as animal drugs.

-Proposed Sec. 530.21 addresses food-producing animals and states

that FDA can prohibit the use of a drug or class of drugs in food-

producing animals if the agency determines that: (1) An acceptable

analytical method needs to be established and such method has not been

established or cannot be established, or (2) the use of the drug or

class of drugs presents a risk to public health. Under the proposal, a

prohibition may be a general ban on the use of the drug or class of

drugs in all food-producing animals, or may be limited to a specific

species, indication, dosage form, route of administration, or

combination of factors.

-Under proposed Sec. 530.22, FDA could establish a safe level for

extralabel use of a drug upon a finding that there is a reasonable

probability that an extralabel use may present a risk to the public

health. To accomplish this, the agency may: (1) Establish a finite safe

level based on residue and metabolism information (i.e., toxicological

data) from available sources; (2) establish a safe level based on the

lowest level that can be measured by a practical analytical method; or

(3) establish a safe level based on other appropriate scientific,

technical, or regulatory bases.

-The proposal allows FDA to require the development of an

acceptable analytical method for the quantification or detection of

residues. If FDA requires such a method, the agency would

[[Page 25111]]

announce that requirement in the Federal Register. If development of an

acceptable analytical method is required and a method is not developed,

submitted, and accepted, the agency could, under the proposal, prohibit

the extralabel use of the drug in food-producing animals.

-The proposed rule provides, however, that if the agency

establishes a safe level and a tolerance is later established through

an approval for a particular species or category of animals, the safe

level is superseded by the tolerance for that species or category of

animals.

-The proposed rule contemplates that FDA: (1) Will establish safe

levels and publish them in the Federal Register, and (2) may establish

specific analytical methods for drug residue detection for those drugs

for which safe levels have been established. The safe levels and the

availability of an analytical method will be codified at proposed

Sec. 530.40.

-Proposed Sec. 530.23 states that FDA will publish a document

establishing a safe level in the Federal Register. This document would

include a statement setting forth the agency's finding that there is a

reasonable probability that extralabel use in animals of the human drug

or animal drug may present a risk to public health, and would request

public comments.

-Under the proposed rule, FDA would codify in proposed Sec. 530.40

the following: (1) A current listing of those drugs for which a safe

level for extralabel drug use in food-producing animals has been set,

and (2) the specific safe levels, and the availability, when one has

been developed, of a specific analytical method or methods for drug

residue detection.

-Proposed Sec. 530.24 provides that copies of analytical methods

would be made available upon request from the Center for Veterinary

Medicine's Communications and Education Branch (HFV-12), 7500 Standish

Pl., Rockville, MD 20855, and that acceptable analytical methods will

be incorporated by reference.

-While the agency does not intend to engage in prior notice and

comment rulemaking for the establishment or acceptance of analytical

methods or safe levels, interested persons will have the opportunity to

make public comment to the agency as these actions are announced and

published that could, if appropriate, result in modifications to the

actions.

-Proposed Sec. 530.25 provides that FDA could issue an order

prohibiting extralabel use of a drug in food-producing animals if the

agency finds, after providing an opportunity for public comment, that:

(1) An acceptable analytical method has not been developed, submitted,

and found to be acceptable by FDA; or (2) an extralabel use in animals

of a particular human drug or animal drug presents a risk to the public

health.

-After making a preliminary determination that a required

analytical method has not been developed and submitted, or an

extralabel use in food-producing animals of a particular human drug or

animal drug presents a risk to the public health, FDA would, under the

proposal, publish an order of prohibition with a 90-day delayed

effective date in the Federal Register. Such order would specify the

nature and extent of the order of prohibition and the reasons for the

prohibition, and provide a period of not less than 60 days for

comments.

-The order of prohibition would become effective 90 days after the

date of publication of the order of prohibition unless FDA publishes a

Federal Register document before that date revoking the order of

prohibition, modifying it, or extending the period of public comment.

-The proposed rule would permit the agency to publish an order of

prohibition with an abbreviated comment period and/or delayed effective

date in exceptional circumstances (e.g., where there is immediate risk

to the public health), provided that the order of prohibition states

that the comment period and/or effective date have been abbreviated

because there are exceptional circumstances, and sets forth the

exceptional circumstances and the agency's rationale for taking such

action.

-Under the proposal, a current listing of drugs prohibited for

extralabel use in food-producing animals would be codified in new

Sec. 530.41.

-The proposed rule would also note that the agency could, after

publishing a Federal Register document, remove a drug from the

prohibited list after the submission of appropriate information, such

as adequate safety and effectiveness data, an acceptable method,

approval of a new animal drug application for the prohibited drug and

use, or information demonstrating that the prohibition was based on

incorrect data.

-K. Extralabel Drug Use in Nonfood Animals

-Because the same public health implications do not exist in the

treatment of nonfood animals as for food animals, the proposed rule

does not include the same level of detail for such extralabel use.

Specifically, proposed Sec. 530.30 provides that veterinarians can make

extralabel use or dispensing of drug products in nonfood-producing

animal practice except when such use may threaten the public health.

One other limitation, as discussed earlier in the preamble, is that, if

an approved NAD for such use exists, an extralabel use of an approved

animal or human drug is not permitted. (See proposed Sec. 530.30(a).)

-The proposal adds that the agency may publish a document in the

Federal Register prohibiting a particular extralabel drug use in

nonfood animals if the agency determines that it presents a risk to the

public health. This provision is consistent with the agency's authority

to establish conditions for extralabel use of human drugs under the

AMDUCA.

-III. Proposed Effective Dates

-Under Section 2(d) of the AMDUCA, the amendments to the act

permitting the extralabel use of certain approved animal drugs and

approved human drugs for animals become effective upon the adoption of

final rules implementing the amendments. FDA intends that any final

rule that may issue based on this proposal become effective 30 days

after the date of publication in the Federal Register.

-IV. Environmental Impact

-The agency has determined under 21 CFR 25.24(a)(8) that this

action is of a type that does not individually or cumulatively have a

significant effect on the human environment. Therefore, neither an

environmental assessment nor an environmental impact statement is

required.

-V. Analysis of Impacts

-FDA has examined the impacts of the proposed rule under Executive

Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354).

Executive Order 12866 directs agencies to assess all costs and benefits

of available regulatory alternatives and, when regulation is necessary,

to select regulatory approaches that maximize net benefits (including

potential economic, environmental, public health and safety, and other

advantages; distributive impacts; and equity). The agency believes that

this proposed rule is consistent with the regulatory philosophy and

principles identified in the Executive Order. In addition, the proposed

rule is not a significant regulatory action as defined by the Executive

Order.

-Most of the requirements in this proposed rule have already been

implemented by regulated industry,

[[Page 25112]]

veterinarians, and pharmacists in response to the existing Compliance

Policy Guides relating to extralabel drug use in animals and the

passage of the AMDUCA, FDA guidance, and industry trade associations'

recommendations, as well as the requirements of State veterinary

practice acts and as customary elements of good veterinary medical

practice.

-The actual cost to industry and the public associated with this

proposal will be quite minimal. The AMDUCA was enacted to decriminalize

extralabel use of most approved new human and animal drugs in

veterinary medicine, and to provide FDA with specific regulatory tools

to assure food safety. Congress intended that the new legislation

codify FDA's discretionary enforcement policies that have permitted

extralabel use of approved new human and animal drugs by veterinarians

in specified circumstances.

-FDA is likely to require the establishment of a safe level for one

to two drugs per year after the proposed rule is finalized. An

analytical methodology for drug residue detection will be required for

each of these drugs. The sponsor may be willing to provide the

methodology in some cases, while in others, FDA, the sponsor, and,

perhaps, a third party, may negotiate a cooperative arrangement for

methodology development. The range of costs for development of

methodologies is likely to range from about $90,000 for a drug for

which there are few problems in developing a procedure, upward to about

$350,000 for a drug which presents significant problems in methodology

development, with an additional $100,000 required for a drug metabolism

study. Methodology development costs for a drug presenting an

intermediate level of difficulty would be about $170,000. The agency

estimates that the average year would see the development of two drug

methodologies presenting an intermediate level of development

difficulty, with one of those drugs requiring a metabolism study, for

an annual cost impact of about $440,000. The proposal does not impose

any new extralabel drug use recordkeeping and reporting requirements

for sponsors or veterinarians which are not currently required under

other sections of the act or under State veterinary practice acts.

-The Regulatory Flexibility Act requires agencies to analyze

regulatory options that would minimize any significant impact of a

proposed rule on small entities. Because the proposed rule clarifies

existing FDA policy, and because most of the requirements in this

proposed rule have already been implemented by regulated industry,

veterinarians, and pharmacists in response to the existing Compliance

Policy Guides relating to extralabel drug use in animals and the

passage of the AMDUCA, FDA guidance, and industry trade associations'

recommendations, the agency certifies, in accordance with section

605(b) of the Regulatory Flexibility Act, that the proposed rule will

not have a significant economic impact on a substantial number of small

entities. Therefore, under the Regulatory Flexibility Act, no further

analysis is required.

-VI. Paperwork Reduction Act of 1995

-This proposed rule contains reporting requirements that are

subject to public comment and to review by OMB under the Paperwork

Reduction Act of 1995 (Pub. L. 104-13). Therefore, in accordance with 5

CFR 1320, a description of reporting requirements is given below with

an estimate of the annual collection of information burden. Included in

the estimate is the time for reviewing instructions, gathering and

maintaining the data needed, and completing and reviewing the

collection of information.

-With respect to the following collection of information, FDA is

soliciting comments on: (1) Whether the proposed collection of

information is necessary for proper performance of FDA's functions,

including whether the information will have practical utility; (2) the

accuracy of FDA's estimate of the burden of the proposed collection of

information, including the validity of the methodology and assumptions

used; (3) ways to enhance the quality, utility, and clarity of the

information to be collected; and (4) ways to minimize the burden of the

collection of information on respondents, including through the use of

automated collection techniques, when appropriate, and other forms of

information technology.

-Title: Extralabel Drug Use in Animals.

-Description: This proposed rule provides that FDA may require the

development of an acceptable analytical method for the quantification

of residues above an established safe level. FDA estimates that it will

likely establish safe levels for one to two drugs per year if the rule

is finalized, and that an analytical methodology for drug residue

detection will be required for each of these drugs. If no method is

provided, the Secretary may prohibit the extralabel use. This

requirement may be fulfilled by any interested person. FDA believes

that the sponsor may be willing to provide the methodology in some

cases, while in others, FDA, the sponsor, and perhaps a third party may

negotiate a cooperative arrangement for method development.

-Description of Respondents: Persons, sponsors, States, or Federal

Government.

ESTIMATED ANNUAL REPORTING BURDEN

----------------------------------------------------------------------------------------------------------------

Annual

21 CFR Section No. Of Frequency per Total Annual Hours per Total Hours

Respondents Response Responses Response

----------------------------------------------------------------------------------------------------------------

21 CFR 530.22(b) 2 1 2 4,160 8,320

----------------------------------------------------------------------------------------------------------------

There are no operating and maintenance or capital costs associated with

this information collection. The agency recognizes that the time and

expense of method development is highly variable dependent on the

difficulty of the development. The agency estimates that two methods of

intermediate difficulty would be developed and these methods may take

up to 2 person-years to develop.

-The agency has submitted a copy of this proposed rule to OMB for

its review and approval of this information collection. Interested

persons are requested to send comments regarding this information

collection, including suggestions for reducing this burden to the

Office of Information and Regulatory Affairs, OMB, New Executive Office

Building, 725 17th St. NW., rm. 10235, Washington, DC 20503, Attn: Desk

Officer for FDA. Written comments on the information collection should

be submitted by June 17, 1996.

-VII. Federalism

-FDA has analyzed this proposal in accordance with the principles

and criteria set forth in Executive Order 12612 and has determined that

this

[[Page 25113]]

proposal does not have sufficient federalism implications to warrant

the preparation of a federalism assessment.

-VIII. Request for Comments

-Interested persons may, on or before July 31, 1996, submit to the

Dockets Management Branch (HFA-305), Food and Drug Administration,

12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857, written comments

regarding this proposal. Two copies of any comments are to be

submitted, except that individuals may submit one copy. Comments are to

be identified with the docket number found in brackets in the heading

of this document. Received comments may be seen in the office above

between 9 a.m. and 4 p.m., Monday through Friday.

List of Subjects in 21 CFR Part 530

-Administrative practice and procedures, Advertising, Animal drugs,

Animal feeds, Human drugs, Labeling, Prescription drugs, Promotion,

Reporting and recordkeeping requirements.

-Therefore, under the Federal Food, Drug, and Cosmetic Act, and

under authority delegated to the Commissioner of Food and Drugs, it is

proposed that Title 21 of the Code of Federal Regulations be amended to

add a new part 530 to read as follows:

PART 530--EXTRALABEL DRUG USE IN ANIMALS

Subpart A--General Provisions

Sec. 530.1 Scope.

Sec. 530.2 Purpose.

Sec. 530.3 Definitions.

Sec. 530.4 Advertising and promotion.

Sec. 530.5 Veterinary records.

Subpart B--Rules and Provisions for Extralabel Uses of Drugs in Animals

Sec. 530.10 Provision permitting extralabel use of animal drugs.

Sec. 530.11 Limitations.

Sec. 530.12 Labeling.

Sec. 530.13 Extralabel use from compounding approved new animal and

approved human drugs.

Subpart C--Specific Provisions Relating to Extralabel Uses of Animal

and Human Drugs in Food-Producing Animals

Sec. 530.20 Conditions for permitted extralabel animal and human

drug use in food-producing animals.

Sec. 530.21 Prohibitions for food-producing animals.

Sec. 530.22 Safe levels and analytical methods for food-producing

animals.

Sec. 530.23 Procedure for setting and announcing safe levels.

Sec. 530.24 Procedure for announcing analytical methods for drug

residue quantification.

Sec. 530.25 Orders prohibiting extralabel uses for drugs in food-

producing animals.

Subpart D--Extralabel Use of Human and Animal Drugs in Animals Not

Intended for Human Consumption

Sec. 530.30 Extralabel drug use in nonfood animals.

Subpart E--Safe Levels for Extralabel Use in Animals and Drugs

Prohibited for Extralabel Use in Animals

Sec. 530.40 Safe levels and availability of analytical methods.

Sec. 530.41 Drugs prohibited for extralabel use in animals.

-Authority: Secs. 4, 5, 6 of the Fair Packaging and Labeling Act

(15 U.S.C. 1453, 1454, 1455); Secs. 201, 301, 501, 502, 503, 505,

507, 512, 701, and 721 of the Federal Food, Drug, and Cosmetic Act

(21 U.S.C. 321, 331, 351, 352, 353, 355, 357, 360b, 371, 379e).

-Subpart A--General Provisions

Sec. 530.1 Scope.

-This part applies to the extralabel use in an animal of any

approved new animal drug or approved new human drug by or on the lawful

order of a veterinarian within the context of a valid veterinarian-

client-patient relationship.

Sec. 530.2 Purpose.

-The purpose of this part is to establish conditions for extralabel

use or intended extralabel use in animals by or on the lawful order of

veterinarians of approved new animal drugs and approved new human

drugs. Such use is limited to treatment modalities when the health of

an animal is threatened or suffering or death may result from failure

to treat. This section implements the Animal Medicinal Drug Use

Clarification Act of 1994 (the AMDUCA) (Pub. L. 103-396).

Sec. 530.3 Definitions.

-(a) Extralabel use means actual use or intended use of a drug in

an animal in a manner that is not in accordance with the approved

labeling. This includes, but is not limited to, use in species not

listed in the labeling, use for indications (disease or other

conditions) not listed in the labeling, use at dosage levels,

frequencies, or routes of administration other than those stated in the

labeling, and deviation from the labeled withdrawal time based on these

different uses.

-(b) FDA means the U.S. Food and Drug Administration.

-(c) The phrase a reasonable probability that a drug's use may

present a risk to the public health means that FDA has reason to

believe that use of a drug may be likely to cause a potential adverse

event.

-(d) The phrase use of a drug may present a risk to the public

health means that FDA has information that indicates that use of a

drug may cause an adverse event.

-(e) The phrase use of a drug presents a risk to the public health

means that FDA has evidence that demonstrates that the use of a drug

has caused or likely will cause an adverse event.

-(f) A residue means any compound present in edible tissues that

results from the use of a drug, and includes the drug, its metabolites,

and any other substance formed in or on food because of the drug's use.

-(g) A safe level is a conservative estimate of a drug residue

level in animal tissue derived from food safety data or other

scientific information. Concentrations of residues in tissue below the

safe level will not raise human food safety concerns. A safe level is

not a safe concentration or a tolerance and does not indicate that an

approval exists for the drug in that species or category of animal from

which the food is derived.

-(h) Veterinarian means a person licensed by a State or Territory

to practice veterinary medicine.

-(i) A valid veterinarian-client-patient relationship is one in

which:

(1) A veterinarian has assumed the responsibility for making

medical judgments regarding the health of (an) animal(s) and the need

for medical treatment, and the client (the owner of the animal or

animals or other caretaker) has agreed to follow the instructions of

the veterinarian;

(2) There is sufficient knowledge of the animal(s) by the

veterinarian to initiate at least a general or preliminary diagnosis of

the medical condition of the animal(s); and

(3) The practicing veterinarian is readily available for followup

in case of adverse reactions or failure of the regimen of therapy. Such

a relationship can exist only when the veterinarian has recently seen

and is personally acquainted with the keeping and care of the animal(s)

by virtue of examination of the animal(s), and/or by medically

appropriate and timely visits to the premises where the animal(s) are

kept.

Sec. 530.4 Advertising and promotion.

-Nothing in this part shall be construed as permitting the

advertising or promotion of extralabel uses in animals of approved new

animal drugs or approved human drugs.

Sec. 530.5 Veterinary records.

-(a) Persons designated by FDA shall have access to the records of

veterinarians, including records

[[Page 25114]]

required to be maintained under the act, State veterinary practice

acts, and State pharmacy acts, to ascertain any extralabel use or

intended extralabel use of drugs that the agency has determined may

present a risk to the public health. -

-(b) As a condition of extralabel use permitted under this part,

veterinarians shall maintain records as required by State veterinary

practice and pharmacy acts. Such records shall be legible, documented

in an accurate and timely manner, and be readily accessible to permit

prompt retrieval of information. Such records shall be adequate to

substantiate the identification of the animals and the medical care

provided and shall be maintained either as individual records or, in

large animal practices, on a group, herd, flock, or per-client basis.

As required by the State, such records will typically include, but not

be limited to, the following information:

-(1) The name, address, and telephone number of the veterinarian;

-(2) The name, address, and telephone number of the client; -

(3) The complaint, or other reason for the provision of services,

including information on the patient history, physical examination, and

laboratory data;

-(4) The provisional or final diagnosis and date of diagnosis;

-(5) Adequate identification of the animal(s) treated;

-(6) The date or dates of treatment, prescribing, or dispensing of

the drug;

-(7) The established name of the drug and its active ingredient, or

if formulated from more than one ingredient, the established name of

each ingredient; the dosage form, strength, and quantity of the

prescribed or dispensed drug, and the dates of administration;

-(8) Any directions for use provided, including dose, route of

administration, and length of therapy;

-(9) The number of refills authorized;

-(10) Cautionary statements, if any; and

-(11) The veterinarian's specified withdrawal, withholding, or

discard time(s), if applicable, for meat, milk, eggs, or any food which

might be derived from any food animals treated.

-(c) A veterinarian shall keep all required drug distribution and

use records for 2 years or as otherwise required by Federal or State

law, whichever is greater.

-(d) Any person who is in charge, control, or custody of such

records shall, upon request of a person designated by FDA, permit such

person designated by FDA to, at all reasonable times, have access to,

permit copying, and verify such records.

Subpart B--Rules and Provisions for Extralabel Uses of Drugs in Animals

Sec. 530.10 Provision permitting extralabel use of animal drugs.

-An approved new animal drug or human drug intended to be used for

an extralabel purpose in an animal is not unsafe under section 512 of

the act and is exempt from the labeling requirements of section 502(f)

of the act if such use is:

-(a) By or on the lawful written or oral order of a veterinarian

within the context of a valid veterinarian-client-patient relationship;

and

-(b) In compliance with this part.

Sec. 530.11 Limitations.

-In addition to uses which do not comply with the provision set

forth in Sec. 530.10, the following specific extralabel uses are not

permitted and result in the drug being deemed unsafe within the meaning

of section 512 of the act:

-(a) Extralabel use in an animal of an approved new animal drug or

human drug by a lay person (except when under the supervision of a

veterinarian); -

(b) Extralabel use of an approved new animal drug or human drug in

or on an animal feed;

-(c) Extralabel use resulting in any residue which may present a

risk to public health; and

-(d) Extralabel use resulting in any residue above an established

safe level or tolerance.

Sec. 530.12 Labeling.

-Any human or animal drug prescribed and dispensed for extralabel

use by a veterinarian or dispensed by a pharmacist on the order of a

veterinarian shall bear or be accompanied by labeling information

adequate to assure the safe and proper use of the product. Such

information shall include the following:

-(a) The name and address of the veterinarian;

-(b) The established name of the drug, or if formulated from more

than one active ingredient, the established name of each ingredient;

-(c) Any directions for use specified by the veterinarian,

including the class/species or identification of the animal in which it

is intended to be used; the dosage, frequency, and route of

administration; and the duration of therapy;

-(d) Any cautionary statements; and

-(e) The veterinarian's specified withdrawal, withholding, or

discard time for meat, milk, eggs, or any food which might be derived

from the treated animal.

Sec. 530.13 Extralabel use from compounding of approved new animal -

and approved human drugs.

-(a) This part applies to compounding of a product from approved

animal or human drugs by a veterinarian or a pharmacist on the order of

a veterinarian within the practice of veterinary medicine. Nothing in

this part shall be construed as permitting compounding from bulk drugs.

-(b) Extralabel use from compounding of approved new animal or

human drugs is permitted if:

-(1) All relevant portions of this part have been complied with;

-(2) There is no approved new animal or approved new human drug

that, when used as labeled or in conformity with criteria established

in this part, will, in the available dosage form and concentration,

appropriately treat the condition diagnosed;

-(3) The compounding is performed by a licensed pharmacist or

veterinarian within the scope of a professional practice;

-(4) Adequate procedures and processes are followed that ensure the

safety and effectiveness of the compounded product;

-(5) The scale of the compounding operation is commensurate with

the established need for compounded products (e.g., similar to that of

comparable practices); and

-(6) All relevant State laws relating to the compounding of drugs

for use in animals are followed.

-(c) Guidance on the subject of compounding may be provided in

guidance documents issued by FDA.

Subpart C--Specific Provisions Relating to Extralabel Use of Animal and

Human Drugs in Food-Producing Animals

Sec. 530.20 Conditions for permitted extralabel animal and human -

drug use in food-producing animals.

-(a) The following conditions must be met for a permitted

extralabel use in food-producing animals of approved new animal and

human drugs:

-(1) There is no approved new animal drug that is labeled for such

use and that contains the same active ingredient which is in the

required dosage form and concentration.

-(2) Prior to prescribing or dispensing an approved new animal or

human drug for an extralabel use in food animals, the veterinarian

must:

-(i) Make a careful diagnosis and evaluation of the conditions for

which the drug is to be used;

-(ii) Establish a substantially extended withdrawal period prior to

marketing of

[[Page 25115]]

milk, meat, or eggs supported by appropriate scientific information, if

applicable;

-(iii) Institute procedures to assure that the identity of the

treated animal or animals is carefully maintained; and

-(iv) Take appropriate measures to assure that assigned timeframes

for withdrawal are met and no illegal drug residues occur in any food-

producing animal subjected to extralabel treatment.

-(b) The following additional conditions must be met for a

permitted extralabel use of an approved human drug, or of an animal

drug approved only for use in animals not intended for human

consumption, in food-producing animals:

-(1) Records maintained by the veterinarian must reflect the

medical rationale; and

-(2) If there is no published scientific information on the public

health aspect of the use of the drug in food-producing animals, the

veterinarian must determine that the animal and its food products will

not enter the human food supply.

-(c) Extralabel use of an approved human drug in food-producing

animals will not be permitted unless the veterinarian first considers

the extralabel use of an approved animal drug for use in food-producing

animals under the provisions of this part. Such consideration must be

documented in the veterinarians' records.

Sec. 530.21 Prohibitions for food-producing animals.

-(a) FDA may prohibit the use of an approved new animal or human

drug or class of drugs in food-producing animals if FDA determines

that:

(1) An acceptable analytical method needs to be established and

such method has not been established or cannot be established, or

(2) The use of the drug or class of drugs presents a risk to public

health.

-(b) A prohibition may be a general ban on the use of the drug or

class of drugs or may be limited to a specific species, indication,

dosage form, route of administration, or combination of factors.

Sec. 530.22 Safe levels and analytical methods for food-producing -

animals.

-(a) FDA may establish a safe level for extralabel use of an

approved human drug or an approved new animal drug when the agency

finds that there is a reasonable probability that an extralabel use may

present a risk to the public health. FDA may:

-(1) Establish a finite safe level based on residue and metabolism

information from available sources;

-(2) Establish a safe level based on the lowest level that can be

measured by a practical analytical method; or

-(3) Establish a safe level based on other appropriate scientific,

technical, or regulatory bases.

-(b) FDA may require the development of an acceptable analytical

method for the quantification of residues above any safe level

established under this part. If FDA requires the development of such an

acceptable analytical method, the agency will publish notice of that

requirement in the Federal Register.

-(c) The extralabel use of an animal drug or human drug that

results in residues exceeding a safe level established under this part

is an unsafe use of such drug.

-(d) If the agency establishes a safe level and a tolerance is

later established through an approval for a particular species or

category of animals, for a particular species or category of animals,

the safe level is superseded by the tolerance for that species or

category of animals.

Sec. 530.23 Procedure for setting and announcing safe levels.

-(a) FDA may issue an order establishing a safe level for a residue

of an extralabel use of an approved human drug or an approved animal

drug. The agency will publish in the Federal Register a notice of the

order. The notice will include:

-(1) A statement setting forth the agency's finding that there is a

reasonable probability that extralabel use in animals of the human drug

or animal drug may present a risk to public health, and

-(2) A request for public comments.

-(b) A current listing of those drugs for which a safe level for

extralabel drug use in food-producing animals has been set, the

specific safe levels, and the availability, if any, of a specific

analytical method or methods for drug residue detection will be

codified in Sec. 530.40.

Sec. 530.24 Procedure for announcing analytical methods for drug -

residue quantification.

-Copies of analytical methods for the quantification of extralabel

use drug residues above the safe levels established under Sec. 530.22

will be available upon request from the Communications and Education

Branch (HFV-12), Division of Program Communication and Administrative

Management, Center for Veterinary Medicine, 7500 Standish Pl.,

Rockville, MD 20855. When an analytical method for the detection of

extralabel use drug residues above the safe levels established under

Sec. 530.22 is developed, and that method is acceptable to the agency,

FDA will incorporate that method by reference.

Sec. 530.25 Orders prohibiting extralabel uses for drugs in -food-

producing animals.

-(a) FDA may issue an order prohibiting extralabel use of an

approved new animal or human drug in food-producing animals if the

agency finds, after providing an opportunity for public comment, that:

-(1) An acceptable analytical method required under Sec. 530.22 of

this part has not been developed, submitted, and found to be acceptable

by FDA; or

-(2) The extralabel use in animals presents a risk to the public

health.

-(b) After making a determination that the analytical method

required under Sec. 530.22 has not been developed and submitted, or

that an extralabel use in animals of a particular human drug or animal

drug presents a risk to the public health, FDA will publish in the

Federal Register, with a 90 day delayed effective date, an order of

prohibition for an extralabel use of a drug in food-producing animals.

Such order will:

-(1) Specify the nature and extent of the order of prohibition and

the reasons for the prohibition, and

-(2) Request public comments, and

-(3) Provide a period of not less than 60 days for comments.

-(c) The order of prohibition will become effective 90 days after

date of publication of the order unless FDA publishes a notice in the

Federal Register prior to that date, that revokes the order of

prohibition, modifies it, or extends the period of public comment.

-(d) The agency may publish an order of prohibition with a shorter

comment period and/or delayed effective date than specified in

paragraph (b) in exceptional circumstances (e.g., where there is

immediate risk to the public health), provided that the order of

prohibition states that the comment period and/or effective date have

been abbreviated because there are exceptional circumstances, and the

order of prohibition sets forth the agency's rationale for taking such

action.

-(e) If FDA publishes a notice in the Federal Register modifying an

order of prohibition, the agency will specify in the modified order of

prohibition the nature and extent of the modified prohibition, the

reasons for it, and the agency's response to any comments on the

original order of prohibition.

-(f) A current listing of drugs prohibited for extralabel use in

animals will be codified in Sec. 530.41.

-(g) After the submission of appropriate information (i.e.,

adequate

[[Page 25116]]

data, an acceptable method, approval of a new animal drug application

for the prohibited drug and use, or information demonstrating that the

prohibition was based on incorrect data), FDA may, by publication of an

appropriate notice in the Federal Register, remove a drug from the list

of human and animal drugs prohibited for extralabel use in animals, or

may modify a prohibition.

-(h) FDA may prohibit extralabel use of a drug in food-producing

animals without establishing a safe level.

Subpart D--Extralabel Use of Human and Animal Drugs in Animals Not

Intended for Human Consumption

Sec. 530.30 Extralabel drug use in nonfood animals.

-(a) Because extralabel use of animal and human drugs in nonfood-

producing animals does not ordinarily pose a threat to public health,

extralabel use of animal and human drugs is permitted in nonfood-

producing animal practice except when the public health is threatened.

In addition, the provisions of Sec. 530.20(a)(1) will apply to the use

of an approved animal drug.

-(b) If FDA determines that an extralabel drug use in animals not

intended for human consumption presents a risk to the public health,

the agency may publish in the Federal Register a notice prohibiting

such use following the procedures in Sec. 530.25. The prohibited drug

use will be codified in Sec. 530.41.

Subpart E--Safe Levels for Extralabel Use in Animals and Drugs

Prohibited for Extralabel Use in Animals

Sec. 530.40 Safe levels and availability of analytical methods.

-In accordance with Sec. 530.22, when the agency finds that there

is a reasonable probability than an extralabel use may present a risk

to the public health, FDA may establish by order a safe level for an

extralabel use in animals of an approved human drug or an approved

animal drug, and may establish a specific analytical method or methods

for drug residue detection. FDA will publish in the Federal Register a

notice of the order and the availability, if any, of an analytical

method or methods for drug residue detection and will codify them in

this section. This section will include the following: A current

listing of those drugs for which a safe level for extralabel drug use

in food-producing animals has been set, and the specific safe levels,

and the availability, when one has been developed, of a specific

analytical method or methods for drug residue detection.

Sec. 530.41 Drugs prohibited for extralabel use in animals. -

-In accordance with Sec. 530.25, the following drugs are prohibited

for extralabel use in animals:

Dated: May 8, 1996.

William B. Schultz,

Deputy Commissioner for Policy.

Note: The following appendix will not appear in the Code of

Federal Regulations.

Appendix

Compliance Policy Guides

Chapter 6--Veterinary Medicine

Sec. 608.100 Human-Labeled Drugs Distributed and Used in Animal ---

Medicine (CPG 7125.35)

Background

-This Compliance Policy Guide explains how FDA will exercise its

enforcement discretion with respect to distribution and use of

human-labeled drug products for use in animals. It is FDA's intent

to:

--eliminate promotion by manufacturers, distributors, and

pharmacies;

--ensure that distribution and dispensing are made only in

response to requests by veterinary practitioners (practitioner

driven);

--refrain in ordinary circumstances from enforcement actions

when human drugs are used or dispensed by veterinarians in treating

non-food-producing animals;

--take enforcement action against veterinarians who cause

illegal residues in food-producing animals;

--limit use of human-labeled drugs in treating food-producing

animals to very narrow circumstances; and

--prohibit use except by or on the order of a licensed

veterinarian in the course of his or her practice.

The key regulatory elements under this policy are determination

of whether or not (1) the distribution and dispensing are

practitioner driven and (2) the veterinary practitioners limit their

uses of human-labeled drug products to treating non-food animals,

with certain narrow exceptions. Because distribution and dispensing

are to be veterinary practitioner driven, and because distributors

and pharmacists, after properly distributing the drug, ordinarily

cannot control end uses, this policy places primary responsibility

on the veterinarian. This policy is not intended to permit the

distribution of human-labeled drug products to veterinarians where

prohibited or limited by State laws.

-FDA is aware that human-labeled drug products have been

promoted and distributed by manufacturers, distributors, and

pharmacies for use in animals and that such drugs are being

prescribed, dispensed, and administered by veterinarians for animal

use.

-Promotion of human-labeled drug products for veterinary use by

these sources has included acts such as advertising animal use in

veterinary publications; distribution of labeling and promotional

materials suggesting or recommending use of these products in

animals; or oral statements from sales personnel describing or

recommending use in animals. Such promotion causes the drugs to be

misbranded under Section 502(f)(1), or adulterated new animal drugs

under Section 501(a)(5), or both. Furthermore, such promotion may

subvert the New animal drug approval process by creating a

disincentive for drug manufacturers to seek such approvals.

-Most veterinary use of human-labeled drug products occurs in

non-food animal practice (companion, sporting, exotic, etc.). Many

of the maladies of pets and other non-food animals cannot be treated

in accordance with current standards of veterinary practice without

the use of human-labeled drugs since appropriate drug products

bearing veterinary labeling often do not exist. Because of this, FDA

has generally refrained from taking enforcement actions in this area

because there is no expected adverse impact upon the public health.

-FDA is very concerned about the use of human-labeled drugs in

food-producing animals because of the increased potential for

illegal drug residues in meat, milk, and eggs. Human-labeled drug

products have not, among other things, undergone testing for residue

depletion from edible tissues. Appropriate withdrawal times to avoid

illegal residues in food can only be estimated.

-Nevertheless, there are legitimate and important veterinary

needs for human-labeled drugs in the treatment of disease or to

prevent pain in food-producing animals in instances where there

simply are no animal drug products available that would avoid animal

suffering or death. Examples include, but are not necessarily

limited to analgesics and anesthetics for pain, sedation, and

surgery, insulin for ketosis, and antidotes for poisonings.

Policy

A. Distribution and Dispensing

-Labeling, advertising, oral representations, or any other act

by a manufacturer, distributor, or pharmacy which establishes an

intended use of human-labeled drugs for animal use is subject to

regulatory action. However, the simple listing of human-labeled drug

products in price sheets and catalogues distributed to veterinarians

will not ordinarily be subject to such action. Dispensing

pharmacists are required by Section 503(f) to label dispensed drugs

in accordance with the prescribing veterinarian's instructions,

including the name and address of the dispenser, the serial number

and date of the order or of its filing, the name of the licensed

veterinarian, and directions for use and any cautionary statements.

Providing this information does not constitute promotion against

which the agency is prepared to take action.

-High priority will be placed on actions against manufacturers,

distributors, and pharmacies who promote the substitution of human-

labeled drug products for animal drugs for economic reasons.

B. Use of human drugs by veterinarians in professional practice

-(i) Use in non-food-producing animals; e.g., dogs, cats,

horses.

Under usual circumstances, veterinary practitioners may consider

[[Page 25117]]

the use of human-labeled drug products in non-food-producing animal

practice without the threat of FDA enforcement actions. In rare

circumstances, for example, when the health of the treated animals is

harmed, regulatory attention by FDA would be considered or, preferably,

referred to the State veterinary licensing authority for investigation.

(ii) Use in food-producing animals; e.g., cattle, swine,

poultry.

Use of human-labeled drug products in food-producing animals should

be extremely limited, primarily because of the increased potential for

illegal drug residues in meat, milk, and eggs. For example, it is

ordinarily unacceptable to use a human-labeled product for common

disease conditions in food animals because approved veterinary-labeled

drug products; e.g., antibacterials, anti-inflammatory agents, etc. are

available. The food animal veterinarian assumes greater responsibility

when he or she uses a human drug rather than a veterinary drug. Use of

human-labeled drugs may be considered by food animal veterinarians only

when they have:

--made a careful and definitive diagnosis and evaluation of the

condition for which the drug is to be used, and are otherwise

operating within the confines of a veterinarian/client/patient

relationship;

--made a deliberate determination that there is no other

appropriate veterinary-labeled therapy; i.e., there is no marketed

veterinary labeled drug product specifically labeled for the disease

condition to be treated or the veterinary drug has been found

clinically ineffective by the veterinarian in the animals to be

treated; and

--taken adequate steps to prevent the occurrence of illegal

residues in edible animal products. This should include a review of

the best available toxicological and tissue distribution and tissue

residue depletion data and establishment of an extra long drug

withdrawal period prior to marketing meat, milk, or eggs. The animal

owner or manager should be given explicit written withdrawal

instructions. The practitioner should have a high degree of

confidence that the client will follow the drug withdrawal

instruction.

-Regulatory action should be considered when an illegal residue

occurs even if the veterinarian followed the foregoing precautions.

The enforcement discretion that might be accorded to veterinarians

will not be extended to lay persons; e.g., owners, who administer

human-labeled drugs either to food-producing or nonfood animals

without the supervision of a licensed veterinarian operating within

the framework of a valid veterinarian/client/patient relationship.

-Veterinarians are expected to follow cautionary handling and

disposal provisions, if any, specified in human drug labeling to

protect handlers and the environment.

Regulatory Action Guidance

-The highest priority for regulatory attention is for follow-up

on reports of illegal tissue residues from human-labeled drugs.

Follow the instructions in Compliance Program 7371.006, Illegal

Drug Residues in Meat and Poultry and Compliance Program 7371.008,

National Drug Residue Milk Monitoring Program. Consultation with

Case Guidance Branch for guidance under this policy is indicated

when encountering other suspected violations, especially where there

is substitution of human-labeled drugs for treatment of common

disease conditions in food animals.

-The initial enforcement action of choice is ordinarily a

Warning Letter. Center concurrence is required prior to issuance.

Depending on the circumstances, one or more of the following charges

would be appropriate.

--402(a)(2)(D)-food adulterated by illegal residue from a new

animal drug;

--402(a)(2)(A)-food adulterated by illegal residue from a human-

labeled drug;

--501(a)(5)-adulterated drug (labeled for human use which is

accompanied by labeling indicating it for animal use which causes it

to be unsafe under Section 512(a) as an unapproved new animal drug);

--502(f)(1)-misbranded human drug when not used as labeled;

misbranded human drug promoted for animal use in ways other than by

labeling (see 21 CFR 201.128).

Issued: 3/19/91

Revised: 7/20/92

Sec. 615.100 Extralabel Use of New Animal Drugs in Food-Producing

Animals (CPG 7125.06)

Background

-Concern over the extralabel use of drugs in treating food-

producing animals and the possibility that human food may become

adulterated with illegal drug residues from such misuse has prompted

a revision in the Center for Veterinary Medicine (CVM) extralabel

drug use policy. Under the revised policy, a finding of illegal drug

residues no longer will be a prerequisite for initiating regulatory

action based on extralabel drug use of drugs in food-producing

animals.

-For the purpose of this policy, ``extralabel use'' refers to

the actual or intended use of a new animal drug in a food-producing

animal in a manner that is not in accordance with the drug labeling.

This includes, but is not limited to, use in species or for

indications (disease or other conditions) not listed in the

labeling, use at dosage levels higher than those stated in the

labeling, and failure to observe the stated withdrawal time.

-FDA in the past has not sanctioned extralabel uses of drugs in

food-producing animals, but the agency has stated that it would

refrain from instituting regulatory action against licensed

veterinarians for using or prescribing in their practices any drugs

they could legally obtain. Nevertheless, it has been FDA's position

that veterinarians may be subject to regulatory action for any

violative drug residues in human food resulting from their

prescriptions, recommendations, or treatments contrary to label

instructions. Similarly, anyone in the producing or marketing chain

who could be shown to have caused illegal drug residues through

extralabel use of drugs in food-producing animals has been subject

to regulatory action.

-In contrast, under usual circumstances veterinary practitioners

may consider the extralabel use of drug products in non-food-

producing animal practice without being subject to FDA enforcement

actions. In rare circumstances, for example when the health of the

treated animals is harmed, regulatory attention by FDA would be

considered or, preferably, referred to the State veterinary

licensing authority for investigation.

Policy

-The use or intended use of new animal drugs in treating food-

producing animals in any manner other than in accord with the

approved labeling causes the drugs to be adulterated under the

Federal Food, Drug, and Cosmetic Act (the Act) (sections 501(a)(5)

and (6), 512(a)(1)(A) and (B), 512(a)(2)). The agency will consider

regulatory action when such use or intended use is found, whether by

a veterinarian, producer, or other person. Regulatory actions will

also be considered against distributors and others who might cause

adulteration of approved new animal drugs. Nevertheless, extralabel

drug use in treating food-producing animals may be considered by a

veterinarian when the health of animals is immediately threatened

and suffering or death would result from failure to treat the

affected animals. In instances of this nature, regulatory action

would not ordinarily be considered provided all [at] the following

criteria are met and precautions observed:

-1. A careful medical diagnosis is made by an attending

veterinarian within the context of a valid veterinarian-client-

patient relationship;* * *

-2. A determination is made that (a) there is no marketed drug

specifically labeled to treat the condition diagnosed, or drug

therapy at the dosage recommended by the labeling has been found

clinically ineffective by the veterinarian in the animals to be

treated;

-3. Procedures are instituted to assure that identity of the

treated animals is carefully maintained;

-4. Significantly extended time period is assigned for drug

withdrawal prior to marketing meat, milk, or eggs; steps are taken

to assure that the assigned time frames are met, and no illegal

residues occur; and

-5. The prescribed or dispensed extralabel drug (prescription

legend or over the counter) bears labeling information which is

adequate to assure the safe and proper use of the product. At a

minimum, the following label information is recommended:

-a. The name and address of the veterinary practitioner.

-b.-The established name of the drug (active ingredient), or if

formulated from more than one ingredient, the established name of

each ingredient.

-c. Any directions for use specified by the practitioner

(including the class/species or identification of the animals; and

the dosage, frequency, route of administration, and duration of

therapy).

[[Page 25118]]

-d. Any cautionary statements specified by the veterinarian.

-e. The veterinarian's specified withdrawal/discard time(s) for

meat, milk, eggs, or any food which might be derived from the

treated animal(s).

-Extra-label use of drugs in treating food-producing animals may

under this policy, therefore, be considered only in special

circumstances. The ``exempting'' criteria do not include drug use in

treating food-producing animals by the layman. Lay persons cannot be

expected to have sufficient knowledge and understanding concerning

animal diseases, pharmacology, toxicology, drug interactions, and

other scientific parameters to use drugs in treating food-producing

animals in any way other than as labeled.

-Certain drugs may not be used in treating food-producing

animals even under the cited criteria. This includes

chloramphenicol. Extralabel uses of drugs in treating food-producing

animals for improving rate of weight gain, feed efficiency, or other

producing purposes, or for routine disease prevention are

inappropriate as is use for therapeutic purposes other than under

the circumstances described above. Also, the criteria cited above do

not sanction the sale and use, for any purpose, of new animal drugs

that are not approved, such as diethylstilbestrol (DES).

Furthermore, a drug (including a bulk drug) may not be mixed into

feed for any use or at a potency level not specifically permitted by

the regulations in 21 CFR Part 558, even if prescribed or ordered by

a veterinarian.

Regulatory Guidance

-The highest priorities for regulatory attention regarding

extra-label use are:

1. Instances where illegal residues occur.

2. In all food-producing animals:

-Chloramphenicol

-Clenbuterol

-Diethylstilbestrol (DES)

-Dimetridazole

-Ipronidazole

-Other nitroimidazoles

-Furazolidone (Except for approved topical use)

-Nitrofurazone (Except for approved topical use)

3. In lactating dairy cattle:

-Sulfonamide drugs (except approved use of sulfa-dimethoxine,

sulfabromomethazine and sulfaethoxy-pyridazine)

4. Manufacturers and distributors who promote extra-label use of

drugs.

5. The mixing of drugs into medicated feeds intended for extra-

label use.

6. Extra-label use by laymen at their own initiative.

* * *A valid veterinarian-client-patient relationship, as

defined by the American Veterinary Medical Association is the

following: An appropriate veterinarian-client-patient relationship

will exist when: (1) the veterinarian has assumed the responsibility

for making medical judgements regarding the health of the animal(s)

and the need for medical treatment, and the client (owner or other

caretaker) has agreed to follow the instructions of the

veterinarian; and when (2) there is sufficient knowledge of the

animal(s) by the veterinarian to initiate at least a general or

preliminary diagnosis of the medical condition of the animal(s).

This means that the veterinarian has recently seen and is personally

acquainted with the keeping and care of the animal(s) by virtue of

an examination of the animal(s), and/or by medically appropriate and

timely visits to the premises where the animal(s) are kept; and when

(3) the practicing veterinarian is readily available for follow-up

in case of adverse reactions or failure of the regimen of therapy.

Issued: 3/9/84

Revised: 5/1/84, 8/1/86, 11/1/86, 7/20/92

[FR Doc. 96-12403 Filed 5-16-96; 8:45 am]

BILLING CODE 4160-01-F