[Federal Register Volume 61, Number 217 (Thursday, November 7, 1996)]
[Rules and Regulations]
[Pages 57732-57746]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-28662]
[[Page 57731]]
_______________________________________________________________________
Part II
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
21 CFR Part 530
Extralabel Drug Use in Animals; Final Rule
Federal Register / Vol. 61, No. 217 / Thursday, November 7, 1996 /
Rules and Regulations
[[Page 57732]]
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: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule
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 rule will provide veterinarians greater flexibility for
using approved drugs for animal use.
DATES: This final rule is effective December 9, 1996.
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:
I. Background
On October 22, 1994, the President signed into law the AMDUCA (Pub.
L. 103-396). Prior to enactment of the AMDUCA, section 512 of the
Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 360b) had
provided that a new animal drug (NAD) was deemed unsafe unless it was
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
forth 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 of the act
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 the 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 the 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 the 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 there is an approved 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. The AMDUCA amends section
301(e) of the act to provide that failure to maintain records or
provide access to records of veterinarians, as provided by general
regulations, 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 final rule, any amount
of residue that may present a risk to the 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
provisions of the AMDUCA are effective upon adoption of a final rule
implementing the statute. The AMDUCA requires publication of a final
rule within 2 years of the date of enactment.
As noted in the preamble to the proposed rule, until publication of
a final implementing rule makes the AMDUCA effective, extralabel use of
drugs in animals continues to be a violation of the act. FDA's existing
enforcement policies relating to extralabel use have been described in
two FDA Compliance Policy Guides (CPG's) entitled ``Extralabel Use of
New Animal Drugs in Food-Producing Animals'' and ``Human-Labeled Drugs
Distributed and Used in Animal Medicine.'' The extralabel CPG's were
issued to provide information and direction to FDA personnel in the
field about the circumstances in which FDA would ordinarily take
regulatory action against extralabel use of approved NAD's and human
drugs in animals and those situations in which the agency would
ordinarily exercise its regulatory discretion and not take action.
The scant legislative history of the AMDUCA includes evidence that
the AMDUCA was intended to codify policies similar to those in FDA's
CPG's . The agency has generally followed policies similar to those in
the existing CPG's in this final rule. It is anticipated that these
CPG's will be withdrawn after this final rule is published. FDA may, as
necessary, issue additional CPG's or other guidance related to
extralabel use of animal and human drugs.
II. The Proposed Rule
A. Summary of the Proposed Rule
In the Federal Register of May 17, 1996 (61 FR 25106), FDA
published a notice of proposed rulemaking to implement the AMDUCA. The
rule as proposed 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.
Consistent with the policies expressed in the CPG's, the proposed
rule limited 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. The proposal asked for comment on
requests
[[Page 57733]]
to permit extralabel drug use for some nontherapeutic uses, but did not
provide for such uses.
The proposed rule included a number of definitions, including
definitions for the phrases ``a reasonable probability that a drug's
use may present a risk to the public health,'' ``use of a drug may
present a risk to the public health,'' and ``use of a drug presents a
risk to the public health.'' In defining these phrases, the agency
considered the common meaning of the words in these phrases, and other
regulations in which FDA has defined similar concepts.
The proposed rule reiterated the statutory prohibition against the
advertising and promotion of extralabel drug uses. It provided for the
inspection of veterinary records by FDA investigators, including
records required under the act and regulations and State veterinary
practice and pharmacy acts, to ascertain any extralabel use that the
agency has determined may present a risk to the public health. The
proposed rule specified particular extralabel uses that are not
permitted, i.e., extralabel use by a lay person (except when under a
veterinarian's supervision), extralabel use in or on an animal feed,
extralabel use resulting in any residue which may present a risk to the
public health, and extralabel use resulting in any residue above an
established safe level or tolerance. The proposal also included
labeling requirements. In addition, it provided conditions for
compounding of approved NAD's and approved human drugs.
The proposal would require the prescribing or dispensing
veterinarian to: (1) Diagnose and evaluate the conditions; (2)
establish a substantially extended withdrawal period prior to marketing
of milk, meat, or eggs supported by appropriate scientific information;
(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. The proposal included some
additional conditions for permitted extralabel uses in food animals of
a human drug, or of an NAD approved only in use in nonfood animals.
The proposal also stated that FDA may prohibit the extralabel use
of an approved new animal or human drug in food-producing animals if
FDA determines that an acceptable analytical method needs to be
established and this method has not been established or cannot be
established, or use of the drug presents a risk to the public health.
It added that 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.
The proposed rule also included procedures for establishing and
announcing safe levels, for developing analytical methods, and for
issuing orders prohibiting extralabel uses of drugs in food-producing
animals. The proposed rule also included provisions regarding
extralabel drug use in nonfood animals.
In addition to publishing the proposed rule in the Federal
Register, FDA gave notice of the publication of the proposed rule by
various additional means and invited comments. The comment period for
the proposed rule lasted 75 days, closing July 31, 1996. Several
requests for an extension of the comment period were denied to enable
the agency to meet the statutory deadline for publishing the final
rule.
B. Discussion of Comments
FDA received approximately 110 comments on the proposed rule. A
discussion of the comments and FDA's responses follows:
1. Issues on Which FDA Requested Comment
(1) The agency invited comment as to whether extralabel use should
be permitted when an approved drug is found by the veterinarian to be
ineffective in a particular clinical situation. 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 animal drug CPG contains an
exception that permits an extralabel use where the veterinarian finds,
within the context of a valid veterinary-client-patient relationship,
that an approved NAD is clinically ineffective for its intended use.
However, neither the statute nor the proposed rule contained a similar
provision.
A large number of comments contended that the regulations should
provide such an exception. The comments stated that veterinarians
frequently encounter clinical situations in which an approved drug is
ineffective. One comment observed that approved drugs are effective
under labeled conditions in most circumstances, so that it would not be
inconsistent with the approval provisions of the act to provide for
extralabel use in specific situations in which a drug is ineffective
under labeled conditions. The comment asserted that the AMDUCA is
intended to codify policies similar to those in the CPG's, such as the
``clinically ineffective'' provision.
FDA recognizes that the AMDUCA does not provide any explicit
exceptions to its prohibition against extralabel drug use when an
approved NAD with the same active ingredient in the same dosage form
and concentration exists for that use. The agency believes, however,
that not allowing extralabel drug use in situations in which the
approved NAD is clinically ineffective would produce an absurd result.
Under established principles of statutory construction, a statute
should be construed to avoid an absurd result. (See e.g., Rowland v.
California Men's Colony, 113 S. Ct. 716, 720 (1993).)
Under the act, an NAD can be found to be effective even though the
drug may not be effective in treating all target animals for the
labeled indication. The statute requires that there be substantial
evidence that an NAD is effective for its labeled indications. The
legislative history of the 1962 Amendments, which added the
effectiveness standard to the act, indicated that evidence sufficient
to meet the ``substantial evidence'' standard could be met where ``the
studies * * * show that the drug will help a substantial percentage of
patients in a given disease condition but will not be effective in
other cases.'' (See S. Rept. 1744, 87th Cong. 2d sess., Part 1 at 16
(1962).) For those cases in which an approved NAD is not clinically
effective, it is as if the drug does not exist for that condition.
Under the AMDUCA, if there is no approved NAD for a particular
condition, veterinarians are allowed to use a drug extralabelly;
however, veterinarians would not be allowed to use a drug extralabelly
in essentially the same situation, that is, when the approved NAD is
clinically ineffective.
Therefore, the agency has concluded that, under the AMDUCA,
allowing extralabel drug use when the approved NAD is clinically
ineffective is legally supportable. The agency cautions, however, that
veterinarians must have a basis for determining that the use of the
approved NAD is clinically ineffective in the animal or animals
involved. Unsupported claims of clinical ineffectiveness will not be
allowed to circumvent the statutory prohibition against extralabel drug
use when an approved NAD for that condition exists. Proposed
Sec. 530.20(a)(1) has been amended to provide for extralabel drug use
in the case of an approved NAD that is clinically ineffective.
(2) The agency asked for comment as whether extralabel use of
animal and
[[Page 57734]]
human drugs should be permitted for nontherapeutic uses such as
improved reproductive responses in terrestrial and, especially, in
aquatic food-producing animals.
More than a dozen organizations and several individuals advocated
extralabel use for all reproductive purposes. One comment objected to
the concept, several comments could be interpreted to be in opposition,
and one other comment urged the agency to be extremely judicious in
granting such an exception. Reasons advanced for allowing reproductive-
related extralabel uses included: All reproductive uses are
therapeutic; drugs used for reproductive purposes pose little human
food safety threat, and in fact some broodstock (e.g., broodfish) can
be considered nonfood animals; reproductive use of drugs is especially
important in minor species (e.g., aquaculture) and other limited
situations (e.g., contraceptive uses in nuisance animals and free
ranging wildlife) for which few drugs are approved; and extralabel use
of reproductive drugs conserves animal resources, and allows
application of new technology (e.g., embryo transfer and artificial
insemination).
The agency agrees that the comments have identified some important
reasons for extralabel use of drugs for nontherapeutic reproductive
purposes. The agency believes that some, but not all, reproductive-
related drug uses are therapeutic and would be permitted under the
final rule. However, after further consideration the agency has
concluded that the statute is not intended to provide for extralabel
use of drugs for nontherapeutic purposes. For example, Senator Coats
identified the problem of the AMDUCA was intended to address as ``too
few approved animal health products to treat all animal illnesses,'' as
such:
in order to treat animals adequately and to alleviate animal
suffering, veterinarians must use some products in an extra-label
fashion * * * [AMDUCA] is at best a short-term solution to a long-
term and larger problem-the lack of drugs available to treat
animals. The legislation, as it passed, will not address this
problem * * * [W]e must address the larger and increasingly urgent
problem of animal drug availability.
(140 Congressional Record S14272 (daily ed. October 5, 1994).)
The agency believes that including nontherapeutic uses in these final
rules is beyond the scope of the AMDUCA's intent to allow the legal use
of drugs extralabelly to treat animal illnesses. Allowing
nontherapeutic uses would extend the AMDUCA's scope into the animal
drug availability issues, issues that Congress reserved to address at
another time. In this regard legislation was recently enacted, the
Animal Drug Availability Act of 1996 (Pub. L. 104-250), that is
intended to streamlime the animal drug approval process to increase the
availability of approved animal drugs. The new legislation should
decrease the need for extralabel use of drugs as more animal drug
products for both therapeutic and nontherapeutic uses are approved. The
agency also notes that it anticipates examining extralabel use which is
not covered by the AMDUCA, such as nontherapeutic extralabel drug use,
in the context of determining regulatory priorities. The agency will
either issue another CPG or determine on a case-by-case basis those
situations, if any, which fall outside the scope of the AMDUCA that
would be of low regulatory priority.
(3) One comment, from the American Association of Swine
Practitioners (AASP), advocated extralabel use for what the association
called ``therapeutic preventative medicine.'' An example would be
extralabel use for medicated early weaning and segregated early weaning
of pigs, to avoid morbidity or death loss that can be quite high among
weaned pigs if treatment is delayed until clinical signs appear. AASP
noted that the preventive extralabel use is appropriate in those
clinical situations in which the veterinarian is well acquainted with
the production system, the profile of the animals and the diseases
present or likely to occur. The agency agrees that as long as the
health of the animals is threatened, extralabel uses for preventive
purposes is acceptable. The proposed rule did not include the word
``immediately,'' which had appeared before the word ``threatened'' in
the CPG. This change was made to make it clear that preventive uses
when the health of the animal is threatened are permitted. However, the
agency cautions that the veterinarian must have a rational basis, such
as that cited by AASP in the case of weaned pigs, for determining that
the health of the animals is actually threatened. Also, preventive
extralabel use would be subject to other restrictions in the
regulations, such as restrictions on extralabel use of drugs
administered in feed.
(4) The agency asked for comment on appropriate ways to balance
extralabel use with the need to preserve the goal of increased
availability of NAD's approved for such uses under section 512 of the
act. Although the agency made the request in connection with its
discussion of nontherapeutic extralabel uses, the comments addressed
the issue more generally.
The American Veterinary Medical Association (AVMA) stated that
Congress, by permitting use of a less expensive approved human drug in
companion animals when an approved NAD is available, placed higher
priority on reducing costs to consumers and pet owners than on
incentives for drug manufacturers. The comment stated that this
emphasis is appropriate because ``the real problem of animal drug
availability pertains to approved animal drugs for use in food
animals.'' With regard to food animals, AVMA and AASP emphasized the
need for extralabel uses for which the market is extremely small and
therefore would provide little financial incentive to drug
manufacturers even if extralabel use were restricted. The Animal Health
Institute (AHI), which represents a number of animal drug
manufacturers, focused on what it called a double standard created by
the proposed regulations. According to AHI, the regulations allow the
veterinarian to determine whether a drug is safe, until FDA determines
otherwise; on the other hand, a drug that goes through the approval
process is considered unsafe until the sponsor proves it to be safe.
The comment concluded that, ``given this scenario, a company may
conclude that it doesn't make business sense to expend the considerable
resources necessary to prove safety (and efficacy) for new label
claims.'' Other comments suggested that the agency should create
incentives for drug manufacturers to submit new animal drug
applications (NADA's), for example, by revising the approval
requirements.
The agency recognizes the need for increased availability for
animal drugs and has provided for such availability as allowed under
the AMDUCA in these regulations. In addition, as indicated above,
recent legislation the Animal Drug Availability Act of 1996 has been
enacted to increase the availability of approved animal drugs. The
legislative history indicates Congress' concern about the availability
of approved drugs and discussed its intention to deal with the drug
availability issue separately. With regard to the ``double standard''
comment, the regulation does not create
[[Page 57735]]
the standard but merely implements the statute that allows
veterinarians, under regulations issued by FDA, to prescribe drugs for
animals that have not undergone the full complement of studies required
for the approval process. The changes requested are not within the
scope of this rulemaking.
(5) The agency asked for comment with respect to a policy that
would allow or encourage sponsors to provide extralabel drug use
information, regarding significant adverse events, on product labeling.
A number of comments supported the inclusion of information on
significant adverse events related to extralabel use on a drug's
labeling. The agency is continuing to explore its legal and policy
options in this regard and will consider these comments during that
process. Several related comments suggested that FDA should provide
more publicity on the need to report adverse reactions related to
extralabel use, through the existing reporting procedures for reporting
adverse drug events. FDA's Center for Veterinary Medicine (CVM) has
developed and distributed widely a brochure which answers a number of
frequently asked questions about CVM's adverse drug experience (ADE)
reporting system. The brochure specifically addresses reporting of
extralabel use-associated ADE's. CVM will take other similar proactive
measures as resources permit.
2. General Comments
(6) One comment suggested that although CPG 7125.06 makes a
distinction between extralabel drug use in food animals versus
companion animals, the proposed regulations do not appear to make this
distinction. The agency believes that the regulations clearly
distinguish between the extra-label requirements for food-producing
animals and companion animals, and that the differences are extensive;
that is part 530, subpart C contains detailed and specific provisions
relating to extralabel drug use in animals intended to provide human
food. On the other hand, part 530, subpart D provides minimal
conditions related to extralabel drug use in animals not intended for
human consumption.
(7) One comment suggested that target animal safety should be an
important consideration when prescribing extralabel use of a drug. The
comment suggested that the target animal safety profile of a drug
should be established so that the animal being treated is not unduly
exposed to risk. While considerations of target animal safety are not
specifically addressed in the AMDUCA, as is food safety, the agency
believes that the veterinarian is responsible for exercising
professional judgment regarding animal safety in prescribing extralabel
drug use. For that reason, both the CPG and the final rule require a
valid veterinary-client-patient relationship to ensure that animal
safety is properly taken into consideration. Therefore, the agency has
not conditioned extralabel drug use on the establishment of a safety
profile for the target animal.
(8) Several comments questioned FDA's conclusion that the AMDUCA
does not permit the agency to restrict use of a human drug in nonfood
animals even though an approved NAD may exist for the same uses. One
comment pointed out that the agency found authority in the act to
require use of an approved NAD in a food-producing animal before use of
a human drug is permitted, and the comment argued that the agency could
use the same authority to provide a similar restriction for drug use in
nonfood animals. The comment stated that it would be prudent for FDA to
do so to protect the safety of the target animal, because an approved
NAD will bear labeling for the safe use of the NAD in the target
animal, while a human drug will not have such labeling. Several
comments noted that restricting use of a human drug in nonfood animals
will maintain an important incentive for animal drug sponsors to pursue
such approvals, especially in minor species. One comment stated that
FDA's economic impact analysis does not consider the impact on small
animal drug companies of allowing use of human drugs when approved
animal drugs are available.
As stated in the preamble to the proposed rule, the AMDUCA's human
drug provisions do not contain an express provision similar to the one
that requires use of an approved animal drug as a prerequisite to
extralabel use of another approved animal drug. The agency reiterates
its belief that because of the broad public health implications in the
treatment of food animals, it is prudent to require the use of an
approved NAD if one exists. Because such broad public health
implications do not apply to nonfood animals, the agency does not
believe the statute supports a similar restriction for nonfood animals.
With regard to the comment concerning the economic impact analysis,
the requirement that the agency analyze a proposal's economic impacts
on small businesses is intended to disclose the economic burden that
would be imposed on small business by the imposition of a new
government regulation. Because FDA's analysis of the rule's impacts
concludes with a certification that it will not have a significant
economic impact on a substantial number of small entities, no further
analysis is required.
(9) One comment, from AHI, advocated that FDA vigorously enforce
the new regulations. A number of other comments, mostly from
veterinarians' groups, indicated that enforcement against extralabel
drug use should be minimal. A number of comments asked how specific
provisions of the regulations would be enforced.
The agency expects that its enforcement activities related to
extralabel use outside the scope of the statute will continue at
approximately the same level as actions under the CPG's in the past. As
in the past, the agency expects to identify areas for highest priority
enforcement attention, such as prohibited uses and situations in which
violative drug residue occurs in human food. Enforcement instructions
to FDA's field offices will be available as they are developed in the
future.
(10) A number of State and university wildlife departments asked
that use of drugs in free-ranging wildlife be exempted from the AMDUCA
(i.e., be allowed unrestricted extralabel use) because free-ranging
feral animals are not generally classified as food animals, and because
it is generally impractical to maintain the veterinary-client-patient
relationship provided for in the regulation. Several comments also
asked that wildlife biologists be allowed to make extralabel uses
because veterinarians are not always available.
The agency understands that some free-ranging wildlife may be
harvested for human food, and therefore they are considered to be food
animals. Accordingly, extralabel drug use in such animals must be in
conformity with the provisions of the regulation applicable to food
animals. In addition, the agency believes that the timing of extralabel
drug use should take into consideration periods of harvest (e.g.,
hunting seasons). The provisions of the regulation related to nonfood
animals would apply to free-ranging wildlife that are not harvested for
human food. The agency recognizes the unique applicability of the
veterinary-client-patient relationship to free-ranging wildlife. The
agency believes that Congress intended that veterinarians be
responsible for overseeing the extralabel use of drugs. However, the
agency also recognizes the significant role of wildlife biologists,
typically State or Federal employees, in administering drugs to free-
ranging wildlife under the general supervision of a veterinarian
[[Page 57736]]
who may also be a government employee and intends that such situations
fall within the scope of a valid veterinary-client-patient
relationship. In view of the above, the agency believes that changes to
the regulations are not necessary.
(11) One comment requested confirmation from the agency that it
will not delay approvals or withdraw approvals of existing NADA's, if
analytical methods are not developed for detection of extralabel use.
It is not the intention of the agency to delay approval of a NADA, or
take action to withdraw an approved NADA, if such methods are not
developed. The agency notes, however, that section 512(e)(1) of the
act, as amended by the AMDUCA, provides for withdrawal of an approval
of a drug as unsafe under the condition of extralabel use as authorized
under section 512(a)(4)(A).
(12) One comment questioned the economic assessment on two bases:
(1) Whether the costs of method development included the cost of method
validation, and (2) whether the assessment included the cost of
developing toxicology data in order to establish a safe level. Methods
validation costs, which would range from $20,000 to $40,000 for each
trial, were not included in the cost estimates in the proposal's
economic assessment. Thus, the total cost for developing a method would
range from $110,000 to $390,000, with an intermediate level of about
$200,000 for each study. Assuming that two methods would be developed
during an average year, and that one method would require a metabolism
study costing $100,000, the annual cost impact would be $500,000 rather
than $440,000 as estimated in the proposal. This comparatively small
increase in estimated costs does not materially affect the conclusions
of the economic assessment under Executive Order 12866 and the
Regulatory Flexibility Act. The agency does not expect to require the
development of new toxicology data in order to establish a safe level,
but may rely on available data for that purpose.
(13) One comment suggested that one means of reducing the risks to
public health attributed to extralabel use of drugs in animals is for
the agency to proactively determine, through use of a prioritized list,
the extralabel use of drugs that may cause a higher risk. The comment
suggested that the regulations contain provisions for developing
methods, conducting tissue residue studies, and assessing toxicity of
those drugs considered most likely to present public health concerns.
FDA agrees with this comment, and believes that the AMDUCA and the
final regulations essentially conform to the comment's request. The
agency will continuously evaluate information relating to extralabel
uses. If FDA should have concerns regarding a particular extralabel use
(i.e., if the agency finds that there is ``a reasonable probability
that a drug's use may present a risk''), the agency may establish a
safe residue level or require the development of a practical analytical
method. This decision would be reached by assessing toxicity data,
among other information. Similarly, FDA may take additional actions if
the agency finds that an extralabel use ``may present a risk'' or
``presents a risk.'' The effect of this procedure would be to establish
FDA's ``priority list,'' as requested in the comment. Accordingly, the
agency believes that it is unnecessary to revise the regulations.
(14) Comments from several organizations and individuals stated
strong concern about the implications of extralabel use for the
development and transfer of antimicrobial resistance. In general, the
comments asserted that extralabel use in food animals can increase risk
of drug resistance to human pathogens because studies show that
antimicrobial resistance can be transmitted to humans through
consumption of animal products and through contact with livestock;
extralabel uses of drugs in food and water (``environmental uses'')
should be prohibited; extralabel use of fluoroquinolines and
glycopeptides (such as vancomycin) should be prohibited; and
antimicrobials approved only for use in humans should not be permitted
for extralabel use in food animals. One comment also suggested
prohibiting herd or flock treatment, when only a few animals exhibit
symptoms.
Specifically, the Centers for Disease Control and Prevention (CDC)
stated that the proposed rule does not provide adequate public health
safeguards to prevent the emergence of antimicrobial resistance to
agents that are important in human medicine. CDC stated that the use of
antimicrobial agents in animals presents a risk to the public health as
defined in the proposed rule, and noted that the proposed rule does not
address the hazard caused by use of antimicrobials at low doses and for
prolonged periods. CDC proposed that the extralabel use of
antimicrobials be based on the results of culture and sensitivity
testing, and that more stringent criteria should be applied to the
extralabel use of antimicrobial drugs that are approved only for human
use including approval for such use only on a compassionate basis. CDC
also commended CVM for its commitment to safeguards for the prevention
of increased antimicrobial resistance including CVM's establishment and
continued sponsorship of the collaborative FDA, CDC, and U.S.
Department of Agriculture's (USDA's) National Antimicrobial Resistance
Monitoring System.
The Center for Science in the Public Interest (CSPI) stated that
CVM has acknowledged that bacteria resistant to fluoroquinolones could
emerge even in therapeutic uses of the drugs, that cross-resistance
occurs in the drugs, and that extralabel use of fluoroquinolones will
be restricted. CSPI also recommended that subtherapeutic extralabel use
be prohibited in aquaculture. The current chair of FDA's Anti-Infective
Drugs Advisory Committee and of the Antimicrobial Use and Clinical
Trials Committee for Infectious Disease Society of America commented
that recent presentations have suggested that less drug usage can
result in a reduction of resistance. That comment, and several others,
referred to general recommendations that have been made to the medical
profession for prudent use of antimicrobials to reduce resistance.
The agency has spent many years studying the effect of
antimicrobial drug use in animals on the selection of resistant
bacteria and acknowledges the concerns expressed for the public health.
The agency believes that several factors will provide the basis to
adequately safeguard the public health: (1) Responsible therapeutic
drug use by veterinarians, as described in this regulation; (2)
provisions for adequate recordkeeping, including the requirement for
specifying dose and duration of treatment; and (3) resistance
monitoring efforts. FDA, CDC, and USDA have implemented a national
surveillance program to monitor changes in antimicrobial
susceptibilities of zoonotic pathogens from human and animal clinical
specimens, from healthy farm animals, and from carcasses of food-
producing animals at slaughter plants. This has been done in response
to recommendations from a 1994 joint FDA advisory committee meeting
regarding fluoroquinolones as well as a 1995 American Society for
Microbiology Task Force on Antibiotic Resistance. The monitoring system
will provide descriptive data on the extent and temporal trends of
antimicrobial susceptibility in Salmonella from the human and animal
populations. The goals are to use the information in a timely way to:
(1) Guide veterinarians
[[Page 57737]]
and physicians; (2) prolong the lifespan of drugs that are approved;
(3) facilitate the identification of resistance in either population as
they arise; and (4) identify areas for more detailed investigation by
the appropriate group. Moreover, the monitoring system will provide
direction to initiate studies designed to answer some of the more
vexing scientific questions regarding the resistance issue. The early
identification of emerging resistance will allow agencies to focus
educational efforts in the human and veterinary medical communities on
the appropriate use of antimicrobial agents.
The agency believes that the selection of resistant human pathogens
could be a basis for restricting extralabel drug use provided that
these organisms can be shown to present a risk to the public health.
The agency will allow extralabel use of drugs administered in drinking
water only for therapeutic purposes, and information on resistance will
be evaluated in relation to individual drugs and classes of drugs that
might be administered by this means. Subtherapeutic use of drugs in
animals is typically accomplished by adding drugs to feed at a low dose
and over a long-term period. Such uses are ordinarily for
nontherapeutic or production purposes. As explained elsewhere
extralabel use of drugs in feeds and for production purposes are not
allowed under the AMDUCA. Therefore, this should not be a factor in any
resistance issues arising from extralabel drug use.
The agency has decided to initiate the process specified by the
AMDUCA to prohibit extralabel use of approved fluroquinolones and
glyecopeptides, for animal or human use, in food producing animals. An
order to this effect will be published in the Federal Register, in the
near future. The agency does not have information that meets the
statutory requirement (that such extralabel use presents a risk to the
public health) for across-the-board prohibition of the extralabel use
of antimicrobial drugs that are approved only for use in humans. The
agency has not determined what, if any, authority it has to require
sensitivity testing but the agency believes that such testing is part
of the responsible practice of veterinary medicine. Finally, as to
treatments of groups of animals when only a few are sick, the agency
believes that this is not likely to occur because of cost
considerations.
(15) One comment suggested that the agency needs to expand the
scope of the regulations to include environmental concerns, and animal
health and well-being, as well as human health. The agency agrees that
environmental and animal well-being are included in the term ``public
health,'' and intends to interpret the term broadly in making
determinations under this regulation. Of course, consistent with the
language of the AMDUCA and the underlying purposes of the act, the
major public health consideration is human health.
(16) One comment requested that extralabel drug use criteria and
precautions address environmental safety questions. The agency believes
that veterinarians should take environmental impacts into account when
they make an extralabel use of an animal drug. They are expected to
comply with any applicable Federal or local requirements, and to report
environmental problems to CVM through the ADE reporting system.
(17) One comment suggested that the regulations be modified to
suggest that good management practice, preventative health management
plans, and quality assurance programs be used to minimize the need for
extralabel (and routine) drug use in livestock systems. The agency
agrees that these are important steps in minimizing risk to the public
associated with extralabel drug use in food animals. However, the
agency does not believe the regulations need to be modified because
these measures are part of normal veterinary and animal management
practices.
3. Comments on Specific Sections
a. Scope (Sec. 530.1)
(18) One comment, apparently assuming that the regulations apply
only to OTC drugs and expressing concern about illegal OTC sale of
prescription drugs directly to farmers, suggested that the regulations
should apply to veterinary prescription drugs. The agency confirms that
the regulations apply to all approved drugs, whether prescription or
OTC. OTC sale of prescription drugs is illegal under the act, and that
status is not changed in any way by the enactment of the AMDUCA or the
publication of this regulation.
b. Purpose (Sec. 530.2)
(19) One comment suggested that the proposed regulation's stated
purpose did not adequately recognize the importance of minimizing
animal pain and suffering in permitting extra-label use. The agency
considers the clause ``when the health of animals is threatened,'' in
Sec. 530.2, to include the concept of minimizing animal pain and
suffering.
c. Definitions (Sec. 530.3)
(20) One comment stated that the regulations do not define the term
``food producing animal,'' and asked if this term would include species
that are used for food in other countries but not in the United States.
As an example the comments cited horses that are to be exported from
the United States for food. Another comment suggested that the
definition of food-producing animals should not include food-producing
animals that are in early life stages. Another comment stated that
dairy heifer calves should be considered nonfood, since they will not
be used to produce food (milk) for 2 years. The agency has not defined
the term ``food-producing animal'' in the regulation because its
meaning (i.e., those animals that are intended to provide food for
human consumption) is the same for purposes of this rule as it is for
any other purpose under the act. Thus, horses may be food or nonfood
animals, depending on their intended use. If they are intended to be
exported for human consumption, they would be considered to be food-
producing animals. Further, the agency does not ordinarily distinguish
food-producing from nonfood-producing animals based on life-stages or
production classes.
(21) One comment suggested that the term ``drug sponsor'' be
defined. The terms ``drug sponsor'' and ``sponsor'' are used to refer
to the person who holds the approved NADA. We have not provided a
definition of ``drug sponsor'' or ``sponsor'' in Sec. 530.3, because
these terms are not used in the regulations in new part 530.
(22) A number of comments requested clarification of the phrase
``adverse event'' as used in the definitions of risk to the public
health (Sec. 530.3(c), (d), and (e)). One comment suggested defining
the term in relation to the preservation of animal health, while
recognizing any science-based risk to the public health. One comment
suggested that the term ``adverse event'' be replaced by ``adverse
public health event.'' Another comment suggested that the
interpretation of ``adverse event'' was too narrow when confined to
those events currently considered reportable adverse drug reactions
required by 21 CFR 510.300 and 510.301. The agency's use of the phrase
``adverse events'' in these sections is related to the public health.
As explained above, the agency intends to interpret the term ``public
health'' to include animal and environmental safety in addition to
human health. The agency did not intend for the term ``adverse event''
to be interpreted as related only to animal ``adverse drug reactions.''
In fact, the primary focus will be on human health.
(23) One comment concluded that the description of the agency's
means of determining risk as defined in
[[Page 57738]]
Sec. 530.3(c), (d), and (e) suggested that one agency's employee would
make this decision or recommendation. The comment suggested that the
agency involve FDA's Veterinary Medicine Advisory Committee (VMAC) in
making risk determinations. Several comments proposed that the agency
have defined and open processes for determining whether the statutory
criteria are met. Many comments requested that the definition of these
terms incorporate the concept that the determinations would be based on
documented or reliable scientific information. Several comments
suggested that the thresholds be more rigorous, e.g., ``may be likely
to cause,'' ``may cause,'' and ``has a direct causative link'' to an
adverse public health consequence, respectively, for Sec. 530.3(c),
(d), and (e). Several comments insisted that FDA was applying a double
standard, i.e., by holding veterinarians to strict scientific
requirements (see Sec. 530.20) while requiring only minimal scientific
information in making the threshold findings.
It was not the intention of the agency to suggest that decisions
would be made by an FDA employee. Any decision regarding the risk to
the public health would be an agency decision made by the appropriate
agency official acting under the authority of Secretary as delegated or
redelegated under the act.
FDA will consider seeking advice from VMAC, as appropriate, on
issues relating to the implementation of the AMDUCA. As explained
elsewhere in the preamble, and as reflected in the regulations, the
agency will use defined processes, provide opportunity for public
comment, and provide for public information on its risk determinations.
FDA believes that the risk determinations, especially the determination
that leads to prohibition of a particular extralabel use, typically
will involve documented scientific information. However, the agency
believes that it is not limited to making risk determinations based
solely on documented scientific information, but may use other suitable
information as appropriate. Finally, the agency believes that its
interpretations of the statutory criteria in Sec. 530.3(c), (d), and
(e) are consistent with the plain meaning of the words, past agency
interpretations of similar words, and the overall congressional
purpose, and therefore has not adopted the suggested changes to
Sec. 530.3(c), (d), and (e).
With regard to the ``double standard'' comment, the agency believes
that both the requirements for threshold determinations and those for
veterinarian use of extralabel drugs in food animals are consistent
with the AMDUCA and the agency's responsibility to protect the public
health.
(24) Some comments sought clarification of the term ``safe level.''
For example, one comment asked for clarification of the third sentence
in proposed Sec. 530.3(g), which distinguishes ``safe level'' from
other concepts such as ``safe concentration'' and ``tolerance.'' The
latter two terms are applied to approved drugs. A ``safe level'' within
the meaning of the AMDUCA is one that presents essentially no human
food safety concern.
(25) Several comments suggested adding the word ``edible'' before
``animal tissues'' in the first sentence of Sec. 530.3(g). The agency
agrees, and it has made the change.
(26) Many comments suggested that the definition provided in
proposed Sec. 530.3(h) for ``veterinarian'' and ``veterinary-client-
patient relationship'' was adequate for individual practitioners, but
needed to be amended to provide for group practices, in which several
veterinarians may provide for the veterinary needs of an individual
client or patient. The agency agrees with this comment, and it will
interpret the regulation accordingly.
(27) Comments stated that graduation from an accredited institution
should not be a prerequisite for a veterinarian to make extralabel
uses, as stated in the preamble. The agency agrees, but no change is
required in the regulation because the regulation did not state an
accreditation requirement.
(28) One comment suggested that the veterinarian is responsible for
determining the appropriate timeliness of visits, a concept that is
included in the definition of veterinary-client-patient relationship in
Sec. 530.3(h). The agency agrees that timeliness is ordinarily
determined by generally accepted standards of veterinary medicine
practice, and it has not specified a timeliness standard in the
regulation.
d. Advertising and promotion (Sec. 530.4)
(29) Several comments suggested that the section of the regulation
prohibiting advertising and promotion of extralabel uses, Sec. 530.4,
be modified to permit the mere listing of human labeled drug products
in price sheets and catalogs that are distributed to veterinarians. The
agency agrees that this practice is acceptable because we do not
consider mere listing of human labeled drug products in price sheets
and catalogs distributed to veterinarians to be advertising and
promotion of extralabel use. However, the agency does not believe that
it is necessary to modify the regulation as suggested.
e. Records (Sec. 530.5)
(30) Approximately two dozen organizations and individuals
expressed objection to one or more provisions of the section related to
recordkeeping and access to records. Only one comment favored the
provision. The comment suggested a uniform Federal requirement and
additional records besides those specified in the regulations,
including dates of administration and use of a form specified by FDA.
Generally, the comments characterized the requirement as confusing,
excessive, and burdensome. The comments stated that notwithstanding
FDA's preamble statement to the contrary, States do not uniformly
require the records listed in the proposed regulation; in fact, the
comments asserted, some States have no recordkeeping requirements at
all. Several comments said, in contrast, that veterinarians keep and
are encouraged to keep adequate records in accordance with generally
accepted standards of practice and AVMA Guidelines for Prescription
Drugs. The comments also stated that FDA should not mandate
recordkeeping; the agency should specify the records that are directly
related to extralabel use and access should be limited to those
records; inspection should be preceded by procedural restrictions
(e.g., an open process for determining when the statutory threshold of
``may present a risk to the public health'' is met, along with evidence
that a particular veterinarian is engaged in the extralabel use in
question before records are requested); and client confidentiality
should be respected under State confidentiality laws. In addition,
comments questioned FDA's use of the records as an enforcement tool.
FDA acknowledges that the comments are correct in their assertion
that not all States require the records listed in the proposed
regulation. The agency wishes to clarify the main purpose of records
inspection, that is, to ascertain the extent and nature of an
extralabel use that the agency has determined may present a risk to the
public health information gathered in the inspection may lead to
prohibition of the particular extralabel use. The main purpose of the
inspection, therefore, is not enforcement of these regulations as
apparently understood by the comments. The agency believes that most
veterinarians keep records that would be adequate for FDA's
information-gathering purposes, whether by State law or standard
veterinary practice. Such records would
[[Page 57739]]
include identification of the drug, condition treated, species, dosage,
duration, number of animals treated, and withdrawal time. However, the
agency has concluded that it should specify minimal recordkeeping
requirements in order to accomplish the purposes of the act. Congress
has clearly provided authority for such requirement.
The agency emphasizes that the requirement to keep the records
applies only to extralabel uses, and the records access provisions
apply only after the agency has determined that a particular use may
present a risk to the public health. As discussed in response to the
next comment, the agency will give public notice of such
determinations.
The agency will consider a system using notification and
appointments when it develops its procedures for records inspections.
The agency's personnel who collect and review records will be
instructed to protect client confidentiality. As suggested by one
comment, veterinarians will be allowed to copy or reformulate records
to provide inspectors with only information required by the
regulations.
The regulation has been modified in accordance with this
discussion.
(31) A number of comments suggested that FDA give public
notification of a ``determination'' that an extralabel use in animals
``may present a risk to the public health,'' and that such notice be
provided prior to initiating record inspections related to the
particular use. The agency will provide informal public notification
(e.g., articles or notices in the CVM Update or on the CVM Homepage
(http://www.cvm.fda.gov) on the Internet World Wide Web) when it has
determined that a particular use ``may present a risk to the public
health.'' It is likely that in most cases, this informal public
notification will be prior to FDA initiating inspections of
veterinarian records related to a particular use.
f. Feed use drugs (Sec. 530.11(b))
(32) Several comments addressed the provision of the AMDUCA
(Section 4(a)) and the regulation, Sec. 530.11(b), that prohibits
extralabel use of a drug ``in or on an animal feed.'' The American Feed
Industry Association commented that the proposed regulation is correct,
that it would clearly prohibit--without limitation or exception--the
extralabel use of drugs administered in or on feed. The National Grain
and Feed Association strongly supported the prohibition. Comments from
organizations representing aquaculture, pheasant growers, and wildlife
interests requested exceptions for their species. These groups
contended, for example, that extralabel uses should be permitted of
medicated feeds that are properly formulated and labeled in accordance
with regulations. Several groups suggested that there should be
exceptions for use of feed to administer drugs to individual animals.
FDA believes that the act as amended by the AMDUCA does not allow
extralabel use of a feed use drug (Type A article) in medicated feed or
an extralabel use of the medicated feed. As stated earlier, the agency
anticipates examining extralabel use which is outside the scope of
AMDUCA in the context of determining regulatory priorities. In this
regard, the agency notes that in the past, as a matter of enforcement
discretion, the agency generally has not objected to mixing a drug with
an individual animal's feed, and does not expect to change its
regulatory priorities in this regard.
g. Labeling (Sec. 530.12)
(33) One comment sought clarification of the agency's intention, as
stated in the preamble discussion of Sec. 530.12, to allow labeling of
case quantities of drugs. The agency believes case-labeling is
appropriate when large numbers of animals need to be treated in an
extralabel manner for a short period (e.g., feedlot use).
(34) Several comments objected to the provision in Sec. 530.12(c),
which requires that labeling identify ``the animal'' in which the drug
is to be used. The comments proposed that the regulation allow for
identification of a group of animals, i.e., a herd, where appropriate.
Suggestions included requiring pen number, pasture, lot number, or
other defining characteristic. The agency agrees, and it has modified
the regulation accordingly.
(35) One comment suggested that the labeling requirements in
Sec. 530.12(a) be modified to allow the labeling to display either the
name and address of the veterinarian, or the name of the veterinarian
and the name and address of the dispensing pharmacy. The comment stated
that most State pharmacy acts require the name and address of the
pharmacy to appear on the labeling, while the pharmacy keeps the
address of the veterinarian in its files. The comment stated that in
many cases, the label is too small to include both addresses. The
agency agrees, and it has modified the regulation accordingly.
h. Compounding (Sec. 530.13)
(36) One comment suggested that rules implementing the AMDUCA
should not include regulations regarding compounding. The comment
suggested that the regulation merely state that the AMDUCA does not
authorize compounding from bulk drugs or unapproved drugs, and refer to
separate guidance on compounding. Compounding for use in food animals
raises unique concerns with respect to drug residues. The detailed
regulations for extralabel use of finished products, while generally
applicable to compounding, do not fully address these unique concerns.
Therefore, the agency believes that regulations specific to
compounding allowed as a result of the AMDUCA are necessary.
(37) In contrast, several comments requested that CPG 608.400,
``Compounding of Drugs for use in Animals,'' be issued under notice and
comment procedures so that the entire content of CPG would be made part
of the regulations. CPG's, which set out FDA's regulatory priorities
are intended to provide information and guidance. Because such policies
are discretionary, they are not binding either on the agency or the
public and can be changed from time to time. Notice and comment
rulemaking and resulting regulations, on the other hand, establish
policies which have the force and effect of law. Therefore, the use of
such procedures is not appropriate for CPG's. The agency notes that it
followed its usual practice and published a Federal Register notice
that announced the availability of the CPG (61 FR 34849, July 3, 1996)
which included the entire text of the CPG and specifically provided
opportunity for comment.
(38) One comment suggested that all cutaneously administered
compounds (e.g., foot bath preparations) be exempted from the
compounding restrictions. The agency believes that the comment may
refer to the use for compounding of drug products that have not been
approved. Because the AMDUCA applies only to approved drugs, the agency
does not have authority in its implementing regulations to exempt
extralabel use, including compounding, of unapproved drugs. If the
comment intended to address compounding from approved drugs for a
specific use (i.e., cutaneous administration), such compounding must be
consistent with these final rules. As stated above, further detailed
guidance for compounding is provided in its compounding CPG.
(39) One comment recommended that Sec. 530.13 be modified to be
consistent with Sec. 530.20 to state that, if available, an approved
animal drug must be utilized for compounding before using a human drug
for compounding. The agency agrees, and it has made the appropriate
modification of Sec. 530.13. To be consistent with Sec. 530.30,
however,
[[Page 57740]]
the restriction will apply only to drugs compounded for use in food
animals.
(40) One comment suggested that the recently issued CPG on
compounding contradicts the second sentence in Sec. 530.13(a), and that
this sentence should be deleted. The sentence states that the
regulations shall not be construed as permitting compounding from bulk
drugs. On the other hand, the CPG states that the agency will generally
exercise enforcement discretion in very limited circumstances with
regard to compounding from bulk substances. The comment suggests a
misunderstanding of the difference in scope and purpose between the
AMDUCA and its implementing regulations, and the compounding CPG. The
AMDUCA applies only to approved products, therefore, compounding from
bulk drugs could not be permitted under the AMDUCA regulations.
However, limited compounding from bulk substances may be subject to
FDA's enforcement discretion as expressed in the CPG. Thus, the second
sentence in Sec. 530.13(a) is not in conflict with the CPG.
i. Conditions for extralabel use in food animals (Sec. 530.20)
(41) One comment suggested it would be appropriate to add language
to Sec. 530.20 to state that an animal owner administering an
extralabel drug under a valid veterinary-client-patient relationship
shall be responsible for maintaining animal identification and
observing the established withdrawal periods. The agency agrees that
the animal owner as well as the veterinarian has responsibility to
assure that steps are taken to avoid the occurrence of unsafe drug
residues. However, the agency does not believe that the regulations
need to be amended to state the animal owner's responsibility because
the responsibility is emphasized elsewhere, e.g., in CPG 615.200,
Proper Drug Use and Residue Avoidance by Non-Veterinarians.
(42) Comments suggested that Sec. 530.20(a) should be revised by
deleting the words ``and human drugs'' at the end of the sentence. The
comments asserted that the deletion would provide for compliance with
the specific language in the AMDUCA, and would conform to the language
contained in the CPG 7125.35. The agency disagrees with the suggestion,
which would mean that safeguards that would be applied to extralabel
use of animal drugs in food animals would not be applied when human
drugs are used in food animals. The agency believes that Congress did
not intend a lesser standard of protection for the public when human
drugs are used in food animals, and that the AMDUCA provides the
necessary authority to apply the standards to use of human drugs.
(43) Approximately two dozen organizations and individuals
commented on the provisions in Sec. 530.20(b) that would require
veterinarians to: (1) Document the medical rationale for use of a human
or nonfood animal drug in food animals, and (2) if there is no
published scientific information on the public health implications,
determine that the animal and its food products will not enter the
human food supply. A large number of comments opposed these provisions.
Comments stated that the provisions would essentially preclude
extralabel use in food animals and exotic animals; that the provisions
are inconsistent with standards elsewhere in the regulation (e.g.,
``reasonable probability of risk''); and that there is no serious drug
residue problem (related to extralabel use by veterinarians) to be
solved. Specifically, the comments stated that: (1) The requirement for
published scientific information would exclude extralabel use of some
60 therapeutic agents, now permitted by the CPG's; (2) the regulation's
requirement for published scientific information is unclear; (3) the
regulation places unreasonable responsibility on the veterinarian, and
it may result in substandard care for food animals; and (4) the
regulation contradicts the agency's past position that there are no
nonfood food animals. Most of those commenting suggested deleting these
provisions from the regulation. Several suggested that the scientific
information should be specified to include pharmacokinetic and
toxicological information and data from sources such as the Food Animal
Residue Avoidance Database, sponsors, etc. in addition to peer reviewed
journals. One comment suggested that the restriction on food animal use
should apply only if there is scientific information that identifies a
problem. Several suggested that the regulation should require a 6
months withdrawal period, instead of permanent prohibition from food
use.
The agency is primarily concerned that the veterinarian have a
scientific basis for an extralabel use, and is especially concerned
where the veterinarian is using in a food animal a drug that is not
approved for food animal use. The agency notes that the human drug CPG
contains several restrictions in addition to those contained in the
animal drug CPG, and that the human drug CPG states that use of human
drugs in food animals is expected to be rare. Thus, the agency believes
that there is not only a rational basis but also precedential policy
that applies to the provisions of Sec. 530.20(b).
The agency believes that the rationale for restricting use of human
drugs in food animals applies as well to use in food animals of drugs
approved only for nonfood animals. Such drugs often contain the same
active ingredients as approved human drugs. Thus, the agency expects
the veterinarian to have scientific information on which to base such
use, but has deleted the requirement that the data be ``published.''
Essentially, the agency expects that the veterinarian will have a
scientific basis for using in food animals a drug that is not approved
in any food animal, but that scientific information could be derived
from a variety of sources, and that the veterinarian's rationale will
be recorded in appropriate records. Accordingly, the agency has
retained in Sec. 530.20(b)(1) of the final rule the requirement for a
medical rationale (i.e., a rational basis for using the drug), but has
removed from the regulation the proposed requirement for documentation.
With respect to the veterinarian's responsibility for keeping
animals out of the food supply, the agency believes that this
obligation can be met by informing the client of the client's
responsibility not to allow an animal to enter the human food supply.
The agency has revised the regulation accordingly.
With the changes described above, FDA believes that the AMDUCA
regulation will not preclude the use of approved drugs that previously
have been available for extralabel use. Nor does the regulation
contradict the agency's general policy that certain classes of animals
are food animals regardless of circumstances.
(44) One comment suggested that the requirement in Sec. 530.20(c)
for a veterinarian to ``consider'' the extralabel drug be clarified to
state that a veterinarian must utilize an animal drug, if one is
available to treat the condition. The agency agrees and has revised the
language accordingly. The agency has also deleted the requirement for
documenting consideration of an approved animal drug (Sec. 530.20(c)).
In these cases, however, a veterinarian will be expected to be able,
upon request, to explain and support the use of a human drug or nonfood
animal drug in food animals.
j. Prohibitions for food animals (Sec. 530.21)
(45) A few comments suggested that Sec. 530.21(a), (a)(2), and (b)
be modified by adding the term ``extralabel'' prior to the word ``use''
to clarify the prohibition
[[Page 57741]]
is for the ``extralabel use''' of a drug. The agency agrees, and it has
made the appropriate changes.
(46) One comment asked who would be responsible for conducting and
paying for the development of analytical methodology for drug residue
detection. The comment suggested that this research could be done by
USDA and a public master file established as is presently done for
minor species claims. The AMDUCA does not specify who has the
responsibility for method development. Methods may be developed under a
variety of scenarios. The drug sponsor, FDA, USDA, States, or a
consortium of interested parties are all possible participants. The
agency is willing to work in partnership with the private and public
sectors to ensure that the methods are developed when needed.
(47) A number of comments suggested that the agency exceeded its
authority when it proposed to allow the prohibition of extralabel-label
drug use of a class of drugs. The agency disagrees. Where a class of
drugs has one or more common elements that cause a particular risk, FDA
believes the statute authorizes prohibition of the entire class of
drugs. Examples of situations where the agency has prohibited
extralabel use of a class of drugs are the sulfonamide and
nitroimidazole drug classes, which are excluded from extralabel use in
the animal drug CPG. One comment suggested that as safer new analogs of
drugs are being developed it is inappropriate to prohibit a class of
compounds. The agency agrees. If safer analogs are developed for a drug
that is in a prohibited class of drugs, the agency may amend the
prohibited list as appropriate.
k. Safe levels and analytical methods (Sec. 530.22)
(48) One comment expressed concern over the perception that the
agency has in the regulations developed two standards of safety
concerning human food safety in food animals, i.e., safe levels and
tolerances. The comment asserted that establishment of a safe level
without complete toxicology data implies that FDA is willing to accept
a lower standard of safety for extralabel use of drugs in food animals.
The comment recommended that safe levels should be established based on
drug metabolism and toxicology data. It also stated the criteria used
by FDA to establish human food safety for extralabel use should be made
public. The agency notes that the AMDUCA clearly directs the agency to
permit extralabel uses that have not gone through the rigors of testing
provided by the NADA process. The law directs the agency to develop
regulations that provide veterinarians the latitude to practice
veterinary medicine, while protecting public health. As specific
criteria for establishing human food safety are developed, information
relating to those criteria will be provided to the public.
The agency has also added the words ``safe concentration'' in
addition to the word ``tolerance'' in Secs. 530.11 and 530.22. This is
because the term ``safe concentration'' is used in some instances to
describe safe levels of approved products.
(49) Several comments questioned the appropriateness of setting a
safe level on the basis of the lowest level that can be measured by a
practical analytical method. The comments stated that this is not a
sound scientific basis for protecting the public health. The agency
notes that where a safe level cannot be established on the basis of
toxicological and other scientific information, it may require the
development of an analytical method having state-of-the-art residue
detection capability. Such methods can be used in an empirical strategy
to minimize risk, i.e., to control or limit public exposure to residues
of animal drugs for which toxicological safety information is lacking.
However, the agency will not establish a safe level on this basis
unless it has concluded that the lowest level of measurement
sufficiently protects the public health. All relevant scientific
information will be reviewed before doing so.
l. Safe levels (Sec. 530.23)
(50) A number of comments suggested that the agency modify
Sec. 530.23(a)(1) to include the basis for the agency's finding in the
notice that establishes a safe level, and that CVM should invite the
public to comment before that safe level becomes final. One comment
suggested that the procedure described in Sec. 530.22 be followed. The
agency agrees with the suggestion as to the basis for the finding, and
it has amended Sec. 530.23(a), accordingly. However, the agency
believes that it is not necessary to have additional procedural
provisions because the regulation provides an opportunity for public
comment after the safe level is established. If comments received after
the safe level is established bring new information to light, the
agency may revoke or modify the safe level as appropriate.
m. Analytical methods (Sec. 530.24)
(51) On its own initiative, the agency has modified proposed
Sec. 530.24 to include a specific process for issuance of an order
announcing a specific analytical method or methods for the
quantification of extralabel use drug residues above the safe levels
established under Sec. 530.22 for extralabel use of an approved human
drug or an approved animal drug. This process is the same as that in
Sec. 530.23 for setting a safe level. Under the modified procedure, the
agency will publish in the Federal Register a notice of the order,
including the name of the specific analytical method or methods and the
drug or drugs for which the method is applicable.
n. Prohibited uses (Sec. 530.25)
(52) One comment requested that Sec. 530.25(h) be reworded to
require FDA to publish a safe level, whenever possible, rather than
prohibit an extralabel use. The regulations do not require publication
of a safe level first because the statute provides the agency with
flexibility through use of the word ``may.'' It is FDA's intention,
however, to consider establishing a safe level prior to prohibiting a
drug's extralabel use unless the agency finds it necessary to protect
public health to prohibit the extralabel use of a drug without first
establishing a safe level.
The agency has also inserted a provision in Sec. 530.25(b) that an
order of prohibition may be issued if the agency determines that an
analytical method cannot be established. This provision was included in
Sec. 530.21 of the proposed rule but left out of corresponding
Sec. 530.25. This would apply in situations in which the agency has
determined, based on information available to it, that development of a
practical method related to the particular extralabel use is not
technically feasible. This determination would be subject to comment
during the comment period on the prohibition order. This allows the
agency to protect the public health by eliminating the time that would
elapse if the agency were to follow the procedure specified in
Sec. 530.22 for requiring development of an analytical method, in cases
where the agency believes that an acceptable method cannot be
developed.
The agency understands that Congress expected the agency to
prohibit those extralabel uses that were prohibited under the animal
drug CPG, without following the prohibition procedures prescribed by
the AMDUCA. For example, Senator Heflin stated, ``This bill authorizes
FDA to incorporate in its initial regulations the list of prohibited
extralabel uses of drugs specifically listed by name in the current
compliance policy guide. Any new restrictions would have to go through
the procedures established in this law prior to being prohibited.''
(140 Congressional Record S14071 (daily ed.
[[Page 57742]]
October 4, 1994).) Accordingly, Sec. 530.41 in the final regulations
includes a list prohibiting extralabel uses as specified in the CPG.
o. Nonfood animal drugs (Sec. 530.30)
(53) A number of comments pointed out an inconsistency between the
preamble statement (61 FR 25106 at 25111) and the regulation
(Sec. 530.30(a)) regarding extralabel uses in nonfood animals of human
drugs where an approved NAD exists. The agency notes that the
regulation is correct, but the preamble incorrectly stated that use of
human drug is not permitted if an approved NAD for such use exists,
i.e., the words ``or human drug'' were inadvertently added to the
preamble.
(54) Many comments suggested that a new Sec. 530.30(c) be added to
read ``Extralabel use of a drug approved for human use is permitted in
nonfood-producing animals even if there is an identical approved new
animal drug.'' Although the agency agrees that this statement is
correct, the agency does not believe that the statement is necessary in
the regulation because of the broad language in Sec. 530.30(a).
III. 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. This final rule becomes
effective December 9, 1996.
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 final rule under Executive
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354) (5
U.S.C. 601 et seq). 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 final rule is consistent with
the regulatory philosophy and principles identified in the Executive
Order. In addition, the final rule is not a significant regulatory
action as defined by the Executive Order.
Most of the requirements in this final rule have already been
implemented by regulated industry, veterinarians, and pharmacists in
response to the existing CPG's 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
final rule will be quite minimal. The AMDUCA was enacted to legalize
extralabel use of certain approved new human and animal drugs in
veterinary medicine, and to provide FDA with specific regulatory tools
to assure food safety. The scant legislative history of the AMDUCA
includes evidence that the AMDUCA was intended to codify policies
similar to those in FDA's CPG's.
FDA is likely to require the establishment of a safe drug residue
level for one to two drugs per year after the final rule becomes
effective. An analytical methodology for drug residue detection may 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. In the proposal, FDA estimated the cost for
development of methodologies 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. One comment to the proposal concerned the inclusion of the costs
of methods validation in the above costs. FDA did not include these
costs, which range from about $20,000 to $40,000 for each trial, in its
proposal. Adding the midpoint of this range to the previous estimate of
$170,000 for a drug presenting an intermediate level of difficulty, FDA
estimates methodology development costs for the final rule to be about
$200,000 for each of these drugs. The agency estimated in its proposal
that the average year would see the development of two of these
intermediate level drug methodologies, with one of those drugs
requiring a metabolism study. FDA did not receive any comments about
this estimate and retains it for use in the final rule. Thus, total
cost impacts for development of two methodologies and one metabolism
study are estimated at $500,000 per year. The agency believes that the
final rule does not impose any significant new extralabel drug use
recordkeeping requirements for sponsors or veterinarians that are not
currently required by other sections of the act or under State
veterinary practice acts, or that are not kept by veterinarians as part
of customary veterinary practice.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. The final rule, for the most part, implements
existing FDA policy, and most of the requirements in this final rule
have already been implemented by regulated industry, veterinarians, and
pharmacists in response to the existing CPG's relating to extralabel
drug use in animals and the passage of the AMDUCA, FDA guidance, and
industry trade associations' recommendations. Further, because FDA
estimates that only two entities will incur economic impacts annually,
the agency certifies, in accordance with section 605(b) of the
Regulatory Flexibility Act, that this final 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. Federalism
FDA has analyzed this final rule in accordance with the principles
and criteria set forth in Executive Order 12612 and has determined that
this final rule does not have sufficient federalism implications to
warrant the preparation of a federalism assessment.
VII. Unfunded Mandates Act of 1995
The Unfunded Mandates Act of 1995 (Pub. L. 104-4) (2 U.S.C. 1532)
requires an agency to prepare a budgetary impact statement before
promulgating any rule likely to result in a Federal mandate that may
result in expenditures by State, local, and tribal governments or the
private sector of $100 million or more in any 1 year. As discussed in
the preamble, the final rule essentially reflects current agency
policies with respect to extralabel drug use in animals and imposes
minimal new Federal requirements. Because this rule will not impose a
cost of $100 million or more on any governmental entity or the private
sector, no budgetary impact statement is required.
VIII. Paperwork Reduction Act of 1995
This final rule contains information collection provisions that are
subject to review by the Office of Management and Budget (OMB) under
the Paperwork
[[Page 57743]]
Reduction Act of 1995 (44 U.S.C. 3501-3520). Therefore, in accordance
with 5 CFR 1320, the title, description, and the description of
respondents of the information collection requirements are shown below
with an estimate of the annual reporting 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.
Title: Extralabel Drug Use in Animals--Final Rule
Description: This final 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\1\
----------------------------------------------------------------------------------------------------------------
Annual
21 CFR Section No. of Frequency per Total Annual Hours per Total Hours
Respondents Response Responses Response
----------------------------------------------------------------------------------------------------------------
530.22(b) 2 1 2 4,160 8,320
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital or operating or maintenance costs associated with this collection.
None of the 110 comments received had an impact on the Paperwork
Reduction Act requirements. As a result, OMB has waived its option to
review the paperwork at the final rule stage. Therefore, the
information collection provisions in the final rule are approved under
OMB Control No. 0910-0325 and are effective upon publication of this
document. OMB approval expires on July 31, 1999. An agency may not
conduct or sponsor, and a person is not required to respond to, a
collection of information unless it displays a currently valid OMB
control number.
IX. Congressional Review
This rule is not a major rule for purposes of 5 U.S.C. 801 et seq.,
Subtitle E of the Small Business Regulatory Enforcement Fairness Act of
1996 (Pub. L. 104-121). Agency reports on this final rule have been
submitted to Congress and the Comptroller General as required by 5
U.S.C. 801 et seq.
List of Subjects in 21 CFR Part 530
Administrative practice and procedures, Advertising, Animal drugs,
Animal feeds, Drugs, Labeling, Prescription drugs, Reporting and
recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act, and
under authority delegated to the Commissioner of Food and Drugs, Title
21 of the Code of Federal Regulations is 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.
530.2 Purpose.
530.3 Definitions.
530.4 Advertising and promotion.
530.5 Veterinary records.
Subpart B--Rules and Provisions for Extralabel Uses of Drugs in Animals
530.10 Provision permitting extralabel use of animal drugs.
530.11 Limitations.
530.12 Labeling.
530.13 Extralabel use from compounding of approved new animal and
approved human drugs.
Subpart C--Specific Provisions Relating to Extralabel Uses of Animal
and Human Drugs in Food-Producing Animals
530.20 Conditions for permitted extralabel animal and human drug
use in food-producing animals.
530.21 Prohibitions for food-producing animals.
530.22 Safe levels and analytical methods for food-producing
animals.
530.23 Procedure for setting and announcing safe levels.
530.24 Procedure for announcing analytical methods for drug residue
quantification.
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
530.30 Extralabel drug use in nonfood animals.
Subpart E--Safe Levels for Extralabel Use of Drugs in Animals and Drugs
Prohibited From Extralabel Use in Animals
530.40 Safe levels and availability of analytical methods.
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 licensed veterinarian within the context of a valid
veterinary-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
licensed veterinarians of Food and Drug Administration 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.
[[Page 57744]]
(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 edible 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) As a condition of extralabel use permitted under this part, to
permit FDA to ascertain any extralabel use or intended extralabel use
of drugs that the agency has determined may present a risk to the
public health, veterinarians shall maintain the following records of
extralabel uses. 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 shall be maintained
either as individual records or, in food animal practices, on a group,
herd, flock, or per-client basis. Records shall be adequate to provide
the following information:
(1) The established name of the drug and its active ingredient, or
if formulated from more than one ingredient, the established name of
each ingredient;
(2) The condition treated;
(3) The species of the treated animal(s);
(4) The dosage administered;
(5) The duration of treatment;
(6) The numbers of animals treated; and
(7) The 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.
(b) A veterinarian shall keep all required records for 2 years or
as otherwise required by Federal or State law, whichever is greater.
(c) 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 licensed
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
licensed 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 the public health; and
(d) Extralabel use resulting in any residue above an established
safe level, safe concentration 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 prescribing veterinarian. If the
drug is dispensed by a pharmacy on the order of a veterinarian, the
labeling shall include the name of the prescribing veterinarian and the
name and address of the dispensing pharmacy, and may include the
address of the prescribing 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 or herd, flock, pen,
lot, or other group of animals being treated, in which the drug 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 other food which might be
derived from the treated animal or animals.
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
[[Page 57745]]
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. Compounding from a human
drug for use in food-producing animals will not be permitted if an
approved animal drug can be used for the compounding;
(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 found 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, except where a veterinarian
finds, within the context of a valid veterinarian-client-patient
relationship, that the approved new animal drug is clinically
ineffective for its intended use.
(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 milk, meat, eggs, or other edible products 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 in food-producing animals an approved human drug, or
of an animal drug approved only for use in animals not intended for
human consumption:
(1) Such use must be accomplished in accordance with an appropriate
medical rationale; and
(2) If scientific information on the human food safety aspect of
the use of the drug in food-producing animals is not available, the
veterinarian must take appropriate measures to assure that the animal
and its food products will not enter the human food supply.
(c) Extralabel use of an approved human drug in a food-producing
animal is not permitted under this part if an animal drug approved for
use in food-producing animals can be used in an extralabel manner for
the particular use.
Sec. 530.21 Prohibitions for food-producing animals.
(a) FDA may prohibit the extralabel 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 extralabel use of the drug or class of drugs presents a
risk to the public health.
(b) A prohibition may be a general ban on the extralabel 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 criteria.
(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 for a particular species
or category of animals and a tolerance or safe concentration is later
established through an approval for that particular species or category
of animals, for that species or category of animals, the safe level is
superseded by the tolerance or safe concentration 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 the public health;
(2) A statement of the basis for that finding; and
(3) 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 established, 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.
(a) FDA may issue an order announcing a specific analytical method
or methods for the quantification of extralabel use drug residues above
the safe levels established under Sec. 530.22 for 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, including the name of
the specific analytical method or methods and the drug or drugs for
which the method is applicable.
[[Page 57746]]
(b) 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 has
not been developed, submitted, and found to be acceptable by FDA or
that such method cannot be established; 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 such method cannot be established, 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 shall state that an
acceptable analytical method required under Sec. 530.22 has not been
developed, submitted, and found to be acceptable by FDA; that such
method cannot be established; or that the extralabel use in animals
presents a risk to the public health; and shall:
(1) Specify the nature and extent of the order of prohibition and
the reasons for the prohibition;
(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) of this section 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
data, an acceptable method, approval of a new animal drug application
for the prohibited extralabel 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 the 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
extralabel drug use will be codified in Sec. 530.41.
Subpart E--Safe Levels for Extralabel Use of Drugs in Animals and Drugs
Prohibited From Extralabel Use in Animals
Sec. 530.40 Safe levels and availability of analytical methods.
(a) In accordance with Sec. 530.22, the following safe levels for
extralabel use of an approved animal drug or human drug have been
established: [Reserved]
(b) In accordance with Sec. 530.22, the following analytical
methods have been accepted by FDA: [Reserved]
Sec. 530.41 Drugs prohibited for extralabel use in animals.
The following drugs are prohibited for extralabel animal and human
drug uses in food-producing animals:
(a) Chloramphenicol;
(b) Clenbuterol;
(c) Diethylstilbestrol (DES);
(d) Dimetridazole;
(e) Ipronidazole;
(f) Other nitroimidazoles;
(g) Furazolidone (except for approved topical use);
(h) Nitrofurazone (except for approved topical use); and
(i) Sulfonamide drugs in lactating dairy cattle (except approved
use of sulfadimethoxine, sulfabromomethazine and
sulfaethoxypyridazine).
Dated: October 22, 1996.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 96-28662 Filed 11-6-96; 8:45 am]
BILLING CODE 4160-01-F
