[Federal Register Volume 61, Number 97 (Friday, May 17, 1996)]
[Proposed Rules]
[Pages 25106-25118]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-12403]
[[Page 25105]]
_______________________________________________________________________
Part V
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
21 CFR Part 530
Extralabel Drug Use in Animals; Propose Rule
Federal Register / Vol. 61, No. 97 / Friday, May 17, 1996 / Proposed
Rules
[[Page 25106]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 530
[Docket No. 96N-0081]
RIN 0910-AA47
Extralabel Drug Use in Animals
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice of proposed rulemaking.
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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