[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]]


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Part II





Department of Health and Human Services





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Food and Drug Administration



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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.

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

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

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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

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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