[Federal Register Volume 72, Number 234 (Thursday, December 6, 2007)]
[Rules and Regulations]
[Pages 69108-69131]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E7-23580]



[[Page 69107]]

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Part IV





Department of Health and Human Services





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Food and Drug Administration



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21 CFR Parts 20, 25, 201, et al.



Index of Legally Marketed Unapproved New Animal Drugs for Minor 
Species; Final Rule

  Federal Register / Vol. 72, No. 234 / Thursday, December 6, 2007 / 
Rules and Regulations  

[[Page 69108]]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 20, 25, 201, 202, 207, 225, 226, 500, 510, 511, 515, 
516, 558, and 589

[Docket No. 2006N-0067]
RIN 0910-AF67


Index of Legally Marketed Unapproved New Animal Drugs for Minor 
Species

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Minor Use and Minor Species Animal Health Act of 2004 
(MUMS act) amended the Federal Food, Drug, and Cosmetic Act (the act) 
to authorize the U.S. Food and Drug Administration (FDA, the agency) to 
establish new regulatory procedures that provide incentives intended to 
make more drugs legally available to veterinarians and animal owners 
for the treatment of minor animal species and uncommon diseases in 
major animal species. At this time, FDA is issuing final regulations to 
implement section 572 of the act entitled ``Index of Legally Marketed 
Unapproved New Animal Drugs for Minor Species.'' These regulations 
establish administrative procedures and criteria for index listing a 
new animal drug for use in a minor species. Such indexing provides a 
basis for legally marketing an unapproved new animal drug intended for 
use in a minor species.

DATES: This rule is effective February 19, 2008.

FOR FURTHER INFORMATION CONTACT: Bernadette Dunham, Center for 
Veterinary Medicine (HFV-50), Food and Drug Administration, 7519 
Standish Pl., Rockville, MD 20855, 240-276-9090, e-mail: 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    In enacting the MUMS act (Pub. L. 108-282), Congress sought to 
encourage the development of animal drugs that are currently 
unavailable to minor species (species other than cattle, horses, swine, 
chickens, turkeys, dogs, and cats) in the United States or to major 
species afflicted with uncommon diseases or conditions (minor use). 
Congress recognized that the markets for drugs intended to treat these 
species, diseases, or conditions are so small that there are often 
insufficient economic incentives to motivate sponsors to develop data 
to support approvals. Further, Congress recognized that some minor 
species populations are too small or their management systems too 
diverse to make it practical to conduct traditional studies to 
demonstrate safety and effectiveness of animal drugs for such uses. As 
a result of these limitations, sponsors have generally not been willing 
or able to collect data to support legal marketing of drugs for these 
species, diseases, or conditions. Consequently, Congress enacted the 
MUMS act, which amended the Federal Food, Drug, and Cosmetic Act to 
provide incentives to develop new animal drugs for minor species and 
minor use, while still ensuring appropriate safeguards for animal and 
human health.
    The major incentives of the MUMS act include the following:
    (1) Designation, established by section 573 of the act (21 U.S.C. 
360ccc-2), which provides for eligibility for grants and contracts to 
defray the costs of qualified safety and effectiveness testing expenses 
and manufacturing expenses incurred in the development of designated 
new animal drugs. Designation also provides for eligibility for a 7-
year period of exclusive marketing rights to enable sponsors to recover 
costs of drug development without competition. FDA published final 
regulations implementing the designation provision of the act on July 
26, 2007 (72 FR 41010) (the designation final rule).
    (2) Conditional approval, established by section 571 of the act (21 
U.S.C. 360ccc), which provides for animal drug marketing after all 
safety and manufacturing components of a new animal drug approval have 
met the standards of section 512 of the act (21 U.S.C. 360b). For the 
effectiveness component, a reasonable expectation of effectiveness must 
be established, after which sponsors have up to 5 years to complete the 
demonstration of effectiveness by the standards of section 512 of the 
act and achieve a full approval. Regulations to implement the 
conditional approval provision will be proposed in the future.
    (3) Indexing, established under section 572 of the act (21 U.S.C. 
360ccc-1), which provides for the legal marketing of unapproved new 
animal drugs intended for use in a minor species through an integrated 
process of agency and expert panel review.
    At this time, FDA is issuing final regulations implementing the 
indexing provisions of the MUMS act. These regulations establish 
procedures and criteria for index listing a new animal drug for use in 
a minor species. They describe a process whereby the agency makes a 
determination regarding the following: (1) The eligibility of a new 
animal drug, (2) the selection of a qualified expert panel, and (3) the 
findings of the qualified expert panel.
    In the Federal Register of August 22, 2006 (71 FR 48840), FDA 
issued proposed regulations to implement section 572 of the act (21 
U.S.C. 360ccc-1). The proposed rule initially provided for a 90-day 
public comment period during which the agency received several comments 
asserting that 90 days was not an adequate amount of time to prepare 
and submit meaningful comments. In response to this, in the Federal 
Register of October 2, 2006 (71 FR 57892), FDA extended the comment 
period allowing an additional 30 days of public comment.

II. Major Changes to the Proposed Rule

    After considering public comments FDA has made the following 
changes to the proposed rule:
    In Sec.  516.123, paragraph (b) has been revised to read: ``The 
written notice will include information for scheduling the informal 
conference and state that a written request for a conference must be 
made within 60 days of the date FDA sends its notice.'' Also, paragraph 
(c) has been revised to read: ``Within 45 days of receiving a request 
for an informal conference, FDA will schedule and hold the informal 
conference at a time agreeable to both FDA and the person making the 
request.''
    In Sec.  516.123, proposed paragraphs (j) and (l)(3) have been 
deleted and paragraph (k) has been revised to read: ``The presiding 
officer will prepare a written report regarding the subject of the 
informal conference that states and describes the basis for his or her 
findings. Whenever time permits, the parties to the informal conference 
will have 30 days to review and comment on the report.''
    In section 516.141, paragraph (b)(1) has been revised to read: ``A 
qualified expert panel member must be an expert qualified by training 
and experience to evaluate a significant aspect of target animal safety 
or effectiveness of the new animal drug under consideration.''
    In addition, FDA has made two technical corrections to the proposed 
rule. The first one is in part 25 (21 CFR part 25). An amendment to 
Sec.  25.33 was proposed as a conforming change to add index listed 
drugs to the list of actions for animal drugs which may be 
categorically excluded from the preparation of an environmental 
assessment. However, the agency neglected to propose a corresponding 
amendment to Sec.  25.20 to also add index

[[Page 69109]]

listed drugs to the list of actions requiring preparation of an 
environmental assessment. Therefore, this final rule contains a 
conforming change to Sec.  25.20(m) to correct this omission. The 
second technical correction is in part 207 (21 CFR part 207). 
Amendments to Sec. Sec.  207.21 and 207.35 were proposed as conforming 
changes to include index listed drugs under the drug registration and 
listing provisions of part 207. However, the agency neglected to 
propose a corresponding amendment to Sec.  207.20(c) which describes 
who must register and submit a drug list. Therefore, this final rule 
contains a conforming change to Sec.  207.20(c) to correct this 
omission.

III. Comments

    The agency received comments from six organizations on the August 
22, 2006, proposal. Comments were received from a trade organization 
representing new animal drug manufacturers, a trade organization 
representing pet product manufacturers, an animal feed manufacturer, a 
professional association representing veterinarians, an aquaculture 
trade association, and a U.S. Government agency.
    All of the comments supported the purpose of the proposed 
regulations. Four comments generally supported the structure and scope 
of the proposed regulations. Four comments expressed concern regarding 
the apparent complexity of the proposed regulations and encouraged the 
agency to demonstrate considerable flexibility in their implementation. 
The issue of greatest concern in these four comments involved the 
formation and functioning of the qualified expert panels proposed in 
the regulations--particularly the application of the conflict of 
interest provisions to potential panel members.
    The agency understands the time and effort involved in providing 
comments on the proposed regulations and greatly appreciates this 
effort. The general issues noted previously, as well as a number of 
more specific issues raised in the comments, are addressed as follows:
    (Comment 1) As noted, four comments expressed considerable concern 
over the apparent complexity of the process described in the proposed 
regulations. While most apparently accepted the need for this 
complexity as a direct consequence of the statutory requirements of 
section 572 of the statute, these comments uniformly expressed a desire 
that the agency be as flexible as possible in implementing the 
potentially more burdensome aspects of the regulations and encouraged 
the agency to provide as much guidance as possible to potential 
sponsors regarding their implementation.
    (Response) The agency agrees that it should be flexible, to the 
extent allowable under the law, in implementing the indexing program. 
In order to further clarify the indexing process and assist requestors 
and potential requestors, the agency intends to develop guidance 
documents regarding various parts of the process as soon after 
finalization of implementing regulations as resources permit.
    (Comment 2) One comment stated that the proposed indexing process 
is overly complex and too similar to the new animal drug approval 
process. This comment suggested that the proposed process be discarded 
and replaced with an alternative process that would emphasize general 
compounds rather than specific drug products.
    (Response) The indexing process established by the MUMS act is for 
drug products rather than general compounds. For example, section 
572(c)(1) of the act describes how to make a request for a 
determination of whether ``a new animal drug'' may be eligible for 
indexing. Moreover, that provision requires that the requestor submit 
information specific to a new animal drug, rather than for general 
compounds, such as information regarding the components and composition 
of the new animal drug and a description of the methods, facilities, 
and controls used for manufacturing the new animal drug. A request for 
addition to the index under section 572(d)(1) of the act is made ``with 
respect to a new animal drug for which [FDA] has a made a determination 
of eligibility.'' Additionally, in considering a request for 
eligibility for indexing, the statute requires that the request not 
involve the same drug in the same dosage form for the same intended use 
as a drug that is already approved or conditionally approved.
    Based on this and similar language in the statute, the agency 
believes, with respect to the indexing of new animal drugs, that 
indexing should follow the product-specific model of new animal drug 
approval.
    However, the agency notes that this basic statutory construction 
does not necessarily preclude information supporting the indexing of 
one product from being used to support the indexing of other products, 
provided the information is relevant to such products, and provided the 
party or parties gathering the information allow its use for that 
purpose if such information is proprietary.
    (Comment 3) Four comments expressed concern about the formation and 
operation of qualified expert panels and, in particular, the 
application of the conflict of interest provisions of the regulations.
    (Response) The agency is aware of the potential scarcity of experts 
to serve on some expert panels. It also wants to assure the integrity 
of this fundamental part of the indexing process, so that the agency 
can have confidence in the information and recommendations it receives 
from the expert panel and the public can trust the agency's decisions 
based on that information and recommendations.
    The purpose of obtaining information regarding potential experts is 
to enable the agency to make an informed judgment, on a case-by-case 
basis, regarding whether a financial or other interest could impair the 
person's objectivity in serving on the panel or could create an unfair 
competitive advantage for a person or organization. Under the proposal, 
and not changed in the final rule, even if there is an otherwise 
disqualifying financial interest, FDA has discretion to nonetheless 
allow the person to serve as a member of the expert panel.
    In making its determinations on the subject of conflicts of 
interest, the agency will be cognizant of both the need to assure the 
integrity of the expert panel process and the need to attract qualified 
experts to serve on these panels.
    (Comment 4) Three comments suggested that the agency needs to 
consider the expertise of the entire panel as a whole, and not each 
panelist individually, when implementing the requirement that a panel 
be composed of ``experts qualified by training and experience to 
evaluate the safety and effectiveness of the new animal drug under 
consideration.''
    (Response) It is the intention of the agency to consider the 
expertise of the entire panel as a whole, as suggested in the comment. 
Proposed Sec.  516.141(b)(5) says that the ``panel, as a whole, is 
qualified by training and experience to evaluate the safety and 
effectiveness of the new animal drug under consideration.'' However, 
paragraph (b)(1) of the same regulation could be read as requiring that 
each individual member of a panel must meet this requirement, that is, 
each member of an expert panel is expected to be qualified to 
independently assess all aspects of a particular product's target 
animal safety and effectiveness. This was not the agency's intention 
and, therefore, the language of Sec.  516.141(b)(1) has been revised to 
read: ``A qualified expert

[[Page 69110]]

panel member must be an expert qualified by training and experience to 
evaluate a significant aspect of target animal safety or effectiveness 
of the new animal drug under consideration.''
    (Comment 5) Two comments suggested that the scope of review of the 
expert panel might be expanded to include elements of food safety and/
or environmental safety.
    (Response) The MUMS act clearly established several distinct steps 
in the review process for indexing new animal drugs. One step is the 
determination of eligibility for indexing, which involves an evaluation 
of most of the indexing criteria, including food, user and occupational 
safety and environmental impacts. This evaluation is to be performed by 
the agency prior to the formation of a qualified expert panel. After 
the agency makes its determination regarding eligibility, a subsequent 
step is the formation and operation of a qualified expert panel. The 
responsibilities of the expert panel are set forth in section 572(d)(2) 
of the act: Evaluate and make findings regarding target animal safety 
and effectiveness; provide information from which labeling can be 
written; and recommend whether the new animal drug should be over the 
counter, prescription, or veterinary feed directive.
    Given this statutory construction, it would not be feasible or 
appropriate for the qualified expert panel to review or to comment upon 
aspects of product safety outside the scope of target animal safety and 
effectiveness. However, sponsors are free to involve experts, not 
serving in the capacity of qualified expert panel members, in the 
preparation of information submitted to the agency in support of a 
determination of eligibility for indexing.
    (Comment 6) Several comments stated that 30 days is not a 
sufficient amount of time for a sponsor to submit a written response to 
the denial of a request for determination of eligibility for indexing 
or a denial of a request for indexing and indicated that this time 
period should be extended to 90 days.
    (Response) While the agency agrees that 30 days may not be an 
adequate period for a written response to a denial, the agency also 
notes that the proposed regulation did not explicitly limit a sponsor 
to 30 days for a written response. Instead, it proposed that a sponsor 
must inform the agency within 30 days that it wishes to avail itself of 
the opportunity for an informal conference. Within 30 days of receipt 
of such a request, the agency would schedule such a conference at a 
time agreeable to both the agency and the sponsor, and the sponsor 
would be required to submit a written response at least two weeks prior 
to the scheduled meeting.
    The agency continues to believe that it is appropriate to have a 
two-step process for scheduling an informal conference. This would 
involve an initial period of time during which a sponsor must signify 
their desire to have an informal conference followed by a second period 
of time during which the conference will actually be scheduled. The 
agency also continues to believe that it needs to receive the written 
response from a sponsor a minimum of two weeks prior to an informal 
conference.
    However, the agency has extended the initial period during which 
sponsors must request an informal conference from 30 days to 60 days to 
permit sponsors additional time to consider the need for such a 
conference. The agency has also extended the second period of time 
during which the agency will schedule a requested informal conference 
from 30 days to 45 days. With these revisions, a sponsor may take as 
long as 60 days to request an informal conference, may request that the 
conference not be held until 45 days after such a request and need not 
submit the written response in support of the conference until two 
weeks before the conference. This process will generally permit 
sponsors to have as much as 90 days to prepare a written response, if 
they feel they need it.
    Accordingly, the language of Sec.  516.123(b) and (c) is revised to 
read as follows:
    (b) The written notice will include information for scheduling 
the informal conference and state that a written request for a 
conference must be made within 60 days of the date FDA sends its 
notice.
    (c) Within 45 days of receiving a request for an informal 
conference, FDA will schedule and hold the informal conference at a 
time agreeable to both FDA and the person making the request.
    (Comment 7) Two comments stated that the language of Sec.  516.123 
indicated that informal conferences were, in fact, rather formal and 
one commentor asked for clarification of the reason for using the term 
``informal'' in this context.
    (Response) The statute and the proposed and final regulation use 
the phrase ``informal conference.'' The agency believes that the 
purpose of the statutory use of the term ``conference'' in section 572 
of the act is to be distinct from the term ``hearing'' which is used in 
the context of similar denial or withdrawal decisions regarding 
products involved in the new animal drug approval process under section 
512 of the act. The hearing referred to in section 512 of the act has 
been clarified by regulation to be a formal evidentiary hearing under 
21 CFR part 12. The agency believes that the purpose of the statutory 
use of the word ``informal'' in section 572 of the act is to draw a 
further distinction between the formal evidentiary hearing under 512 of 
the act and the informal conference under section 572.
    FDA believes that the process for the informal conference set forth 
in Sec.  516.123 is appropriately tailored. While much less formal than 
the part 12 hearings, it still ensures that there is a meaningful 
opportunity for parties to express their views, a neutral decision 
maker, and an administrative record for judicial review if the final 
agency decision is challenged in court. Moreover, by describing the 
process in a regulation, the parties in the informal conference will 
have a common understanding of how it will operate, fostering an 
orderly operation and reducing the potential for disagreements over the 
process.
    (Comment 8) One comment questioned the inclusion of the requirement 
for an estimation of annual product distribution in proposed Sec.  
516.129(c)(6).
    (Response) In accordance with section 572(c)(1)(A) of the act, the 
request for determination of eligibility for indexing must include the 
anticipated annual distribution of the new animal drug. This 
information would be useful, for example, in estimating the extent of 
environmental and user exposure in the process of determining 
environmental and user safety.
    (Comment 9) One comment suggested that requestors of an informal 
conference have an opportunity to read and respond to the minutes of an 
informal conference within 30 days.
    (Response) This comment raises two issues which the agency needs to 
address and clarify in the final regulation. The first issue relates to 
whether the person requesting an informal conference should have the 
opportunity to review and comment on a summary of the informal 
conference. The agency believes that the requestor should have such an 
opportunity. In framing the comment in the context of the ``minutes of 
an informal conference,'' the comment also raises an issue regarding 
what sort of a summary of the informal conference the person requesting 
an informal conference should have an opportunity to review and comment 
on. In this context, the agency has reconsidered the requirement in the 
proposed regulation for the preparation of both a ``written summary'' 
of the conference and a

[[Page 69111]]

``written report'' of the conference. The latter was intended to 
parallel the written report associated with a 21 CFR part 16 informal 
hearing, and was intended to be more comprehensive than simply a 
``written summary of the conference'' or the ``minutes of an informal 
conference'' as expressed in the comment. The agency believes that the 
requestor of an informal conference should have an opportunity to 
review and comment on the written report of the informal conference. We 
have revised Sec.  516.123(k) to provide for such a review whenever 
time permits. That being the case, the agency believes that a written 
summary of the informal conference is superfluous and this requirement, 
which was proposed by means of Sec. Sec.  516.123(j) and 516.123(l)(3), 
has been removed from the final regulation.
    (Comment 10) Two comments requested clarification of different 
aspects of the early, non-food life-stage provision of the proposed 
regulations.
    (Response) As stated in the preamble to the proposed regulations, 
the early, non-food life-stage provision of the statute and 
implementing regulations will be applicable only in limited 
circumstances, and the safety of food eventually derived from such 
animals will be determined in accordance with the safety standards of 
512(d) of the act.
    The agency has currently identified only early, non-food life 
stages of some aquatic species, such as certain fish eggs and mollusc 
larvae, as likely to be able to meet this standard. There is no 
explicit statutory restriction of this provision to aquatic minor 
species, although the statutory restriction to products intended only 
for use in a hatchery, tank, pond or other similar contained man-made 
structure tends to exclude terrestrial species. The agency has yet to 
identify a terrestrial species that it feels is likely to qualify under 
this provision of the statute, but has not ruled out the possibility 
that some terrestrial minor species could qualify.
    The agency is unable at this time to establish any general criteria 
regarding ages, sizes, amount of time between early, non-food life 
stages and later food life stages, or biological developmental 
processes that can predict the applicability of this provision of the 
act. Nor is the agency able to make any general statements regarding 
how much information of what sort will be necessary to meet the 
requirements of 512(d) of the statute. These issues depend upon the 
drug and the minor species involved in each particular case.
    (Comment 11) One comment asserted that the revenue to be expected 
from some segments of the minor species market may not justify the 
estimated administrative costs for indexing cited in the proposed rule. 
The comment is concerned with needed medicated feeds, especially for 
zoo and laboratory animals. The comment proposes that an ``exemption'' 
should be provided in cases where sales will not offset these costs. 
Specifically, the comment suggests that a threshold sales level should 
be set ($100,000 is recommended) above which indexing would be 
required, but below which an expanded policy of regulatory discretion 
would be provided.
    The comment also notes that the inability to alter the nutrition 
and physical form of an approved medicated feed to suit use in a minor 
species limits the utility of the existing regulatory discretion policy 
(Compliance Policy Guide (CPG) 615.115) for the extra-label use of 
medicated feed in minor species. Therefore, it is suggested that a new 
policy of regulatory discretion based on customer formulated feeds be 
incorporated into the MUMS indexing rule for the intended uses that 
fall below the proposed sales threshold.
    (Response) The lack of medicated feeds legally available to minor 
species is recognized by the agency. The Animal Medicinal Drug Use 
Clarification Act of 1994 (AMDUCA) (Pub. L. 103-396) provides for 
certain extra-label uses of new animal drugs by veterinarians, but 
specifically prohibits extra-label use of medicated feeds. The CPG is 
intended to be a limited exercise of regulatory discretion regarding 
access to needed medicated feeds for some minor species. The indexing 
provision was included in the MUMS act partly to address this concern. 
It is intended to provide legal means for sponsors to provide these 
much-needed formulations to non-food minor species animals, like the 
zoo species cited in this comment. The agency recognizes that indexing 
will not provide for the legal availability of drugs for minor species 
under all circumstances. However, the exercise of regulatory discretion 
does not provide legal access under any circumstances.
    The administrative cost of indexing, as cited in the proposed rule, 
is an estimate of the average cost of indexing a new animal drug. The 
enormous variety of species and products will be reflected in the range 
of complexity of indexing these products. Variables such as the number 
of species to be included in the intended use, the availability of 
scientific literature and experts, whether or not the drug has already 
been approved in other species or formulations, etc. will have a 
significant effect on the cost of completing a request for indexing. 
Simple requests for indexing can be expected to require less time to 
prepare and, therefore, will be less costly than the estimate, while 
others may be more involved and will require more time.
    The agency will nonetheless continue to consider the exercise of 
regulatory discretion under appropriate circumstances and, as it gains 
experience with the indexing process, will consider whether it should 
make any changes to CPG 615.115.
    (Comment 12) One comment was received in regard to the proposed 
conforming changes to parts 201 and 202 (21 CFR parts 201 and 202). 
This comment stated that the addition of indexing references to these 
parts of 21 CFR will add very specific requirements to the labeling and 
advertising process for an unapproved drug.
    (Response) Part 201 pertains to drug labeling. The proposed 
conforming changes to part 201 are in subpart D which is entitled 
``Exemptions for Adequate Directions for Use.'' The regulations in this 
subpart describe situations where new drug and new animal drug labeling 
would be exempt from the misbranding requirements of section 502(f)(1) 
of the act or provide clear descriptions of specific labeling 
information required to avoid misbranding under section 502(f)(1) of 
the act. Specifically, Sec.  201.105 describes what information must 
appear on prescription new animal drug labeling and Sec.  201.122 
describes what information must appear on drugs for processing, 
packing, or manufacturing. The agency believes these same exemptions 
and clear descriptions should be available for index listed drugs and 
does not believe that the specific labeling requirements described in 
this subpart for approved new animal drugs are overly burdensome for 
index listed drugs. Furthermore, the labeling requirements for 
prescription new animal drugs described in Sec.  201.105 are necessary 
for the safe and effective use of such drugs whether they are approved 
or index listed.
    Part 202 pertains to prescription drug advertising. The conforming 
change to Sec.  202.1 will require that prescription drug advertising 
for index listed drugs shall not recommend or suggest any use that is 
not in the labeling accepted in such index listing and that the 
advertisement shall present information from labeling granted in the 
listing relating to each specific side effect and contraindication in 
such labeling that relates to the uses of the advertised drug dosage 
form(s). Section 202.1 currently contains this same provision for new 
animal drugs that are approved under section 512 of the act and for new 
drugs

[[Page 69112]]

that are approved under section 505 of the act. We do not believe this 
conformation to current regulations is unreasonable.
    (Comment 13) One comment expressed confusion regarding whether 
unapproved index listed products that are drug listed under the 
provisions of part 207 (21 CFR part 207) are subject to product user 
fees under Animal Drug User Fee Act of 2003 (ADUFA).
    (Response) Unapproved new animal drugs that are index listed under 
section 572 of the act are not subject to product user fees under ADUFA 
(Pub. L. 108-130). Unless specifically exempted, all new animal drugs 
that are in commercial distribution, whether approved or not, are 
subject to the drug listing requirements of part 207 (see Sec.  
207.20). However, to be subject to a product user fee, an animal drug 
product must not only be subject to the drug listing requirements of 
part 207, but also approved as either an animal drug application or 
supplemental animal drug application (see section 740(a)(2) of the 
act). As defined under ADUFA, these applications do not include drugs 
that are index listed under section 572 of the act (see section 739(1) 
and (2) of the act).
    (Comment 14) One comment asked for clarification on why certain 
conforming changes to the regulations in part 510 for approved drugs 
were proposed to apply to index listed drugs.
    (Response) Three sections in part 510 contain conforming changes. 
Those sections apply to new animal drugs, which means they apply to 
index listed drugs because they are new animal drugs. The conforming 
changes are needed so it is clear how these provisions apply in the 
context of index listed drugs. For example, Sec.  510.301 describes the 
reporting and recordkeeping requirements for licensed medicated feed 
mills concerning experience with new animal drugs when used in or on 
animal feeds. Previously, the regulation said the records and report 
must be appropriately identified with the new animal drug 
application(s) to which they relate. The conforming amendment adds ``or 
index listing(s)'' to which they relate. Similarly, one of the items to 
be reported is any failure of the drug to meet specifications 
established for it in the new animal drug application. This is being 
amended to include specifications established in the request for 
determination of eligibility for indexing. Conforming amendments are 
also made in Sec.  510.305, which requires licensed medicated feed mill 
operators to maintain approved labeling for each Type B and/or Type C 
feed being manufactured on the premises of the manufacturing 
establishment or the facility where the feed labels are generated, and 
Sec.  510.455, which describes the requirements for manufacturing a 
free-choice medicated animal feed.
    (Comment 15) One comment stated that due to the prohibitive cost of 
production of small quantities of separately labeled product, the 
requirement for labeling indexed drugs separately from approved drugs 
could be a deterrent for indexing useful drugs that are already 
approved in major species. The comment suggested that adequate 
distinction could be required on existing labeling to provide the 
indexed claims as well as information on the approved labeling.
    (Response) New animal drug labeling that contains information 
derived from both an application approved under section 512(b) of the 
act and from an index listing granted under section 572 of the act (572 
index listing) would be misbranded under section 502(w)(2) of the act 
and would cause the new animal drug to be unsafe under section 
512(a)(1)(A) and (C) of the act. Simply put, in this situation, the 
labeling information derived from the 512(b) approval does not conform 
with the 572 index listing, and the labeling information derived from 
the 572 index listing does not conform with the 512(b) approval. For 
example, under section 572(h) of the act, the labeling of an index 
listed drug must include the statement ``NOT APPROVED BY FDA.--Legally 
marketed as an FDA indexed product.'' Such a statement would be false 
on the labeling of a product approved under section 512(b) of the act 
because that product has been approved by FDA.
    (Comment 16) One comment requested clarification on the statement 
in proposed Sec.  516.155 to the effect that a product cannot be 
utilized in an extra-label manner once it is indexed. The comment said 
that this could be prohibitive to the veterinarian's ability to utilize 
an approved medication off label when needed if it has also been 
indexed.
    (Response) Under Sec.  516.155, the label of an indexed drug must 
state that extra-label use is prohibited. This statement is based on 
section 572(h) of the act. However, this statement prohibiting extra-
label use of new animal drugs indexed under section 572 of the act does 
not impose any restrictions, beyond those that already existed, on the 
extra-label use of new animal drugs approved under section 512(b) of 
the act.
    The extra-label use of an approved new animal drug is not permitted 
when ``the labeling of another animal drug that contains the same 
active ingredient which is in the same dosage form and concentration'' 
provides for the same use as a contemplated extra-label use (section 
512(a)(4)(A) of the act). We believe that the reference to ``another 
animal drug'' in this provision means a new animal drug that, like the 
drug to be used in an extra-label manner, has been approved under 
section 512(b) of the act, and that it does not include a new animal 
drug that has been indexed under section 572 of the act. The 
regulations implementing the extra-label use provisions of section 512 
of the act provide that one of the conditions for the extra-label use 
of an approved new animal drug is that ``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'' (Sec. Sec.  530.20(a)(1) (emphasis added) and 
530.30(a)). Based on our interpretation of the act, we do not believe 
the condition in this regulation should be broadened to reference 
indexed drugs along with approved drugs. Thus, if a new animal drug is 
index listed for intended use A, for example, and the same active 
ingredient in the same dosage form is approved for intended use B, then 
the approved drug may be used in an extra-label manner for intended use 
A, as long as all other provisions of 21 CFR part 530 have been met.
    (Comment 17) One comment noted that the preamble failed to 
explicitly state that indexed drugs may fall into one of three 
categories: Over-the-counter, prescription, and veterinary feed 
directive (VFD).
    (Response) We agree that index listed drugs may fall into one of 
these three categories. Prescription status for index listed drugs is 
provided for in section 503(f)(1)(A)(ii) of the act and VFD status is 
provided for in section 504(a)(1) of the act. The current regulations 
in title 21 of the CFR have been revised accordingly by conforming 
change in this rulemaking at Sec.  201.105, Sec.  202.1, Sec.  558.3, 
and Sec.  558.6.
    (Comment 18) One comment stated that it appears that there can be a 
number of holders of the same product listed in the index, in other 
words, there is no exclusivity associated with index listing.
    (Response) We agree. There are no exclusive marketing rights 
associated with index listed drugs, such as are provided for MUMS-
designated approved and conditionally approved drugs under section 
573(c) of the act.

[[Page 69113]]

    (Comment 19) One comment requested clarification regarding whether 
proposed Sec.  516.125(d) meant that target animal safety studies done 
under an index investigational new animal drug (INAD) were not required 
to be conducted in accordance with good laboratory practices (GLPs).
    (Response) While the agency encourages adherence to GLPs to the 
maximum extent possible, the comment is correct that target animal 
safety studies in support of an index listing are not required to be 
conducted under GLPs. Qualified expert panels may consider all 
available information in reaching their conclusions regarding target 
animal safety and effectiveness, including target animal safety studies 
that do not meet the GLP standards of 21 CFR part 58.
    (Comment 20) One comment stated that the agency's estimated costs 
to a MUMS index drug requestor appeared to be reasonable and accurate. 
However, the comment also stated that, as a result of the fees referred 
to in Sec.  516.141(g)(4), costs for complex reviews requiring 
extensive panel time may be dramatically higher than simple reviews 
that can be quickly completed. The comment suggested that, in an effort 
to contain such costs, avoid economic discrimination, and increase 
participation in the indexing process, the agency should consider, at 
least for an initial period of time, establishing a uniform fee of 
$10,000 for indexing requests.
    (Reponse) FDA anticipates that some expert panel members may charge 
requestors a fee for their professional services. Sec.  516.141(g)(4) 
recognizes this fact and states that if such professional fees are paid 
they should be no more than commensurate with the value of the time 
that the member devotes to the review process in order to avoid a 
conflict of interest or the appearance of a conflict of interest. This 
cost to requestors is also discussed in the Analysis of Economic 
Impacts section of the proposed rule and this final rule. While the 
agency supports, in principle, efforts to contain costs and increase 
efficient utilization of the indexing process, the agency believes 
that, Sec.  516.141(g)(4) notwithstanding, it should not be involved in 
establishing or otherwise regulating fees for the work expert panel 
members provide to the requestor as part of the indexing process.
    (Comment 21) One comment suggested that a requestor not necessarily 
be a particular firm, but potentially a group of individuals or 
organizations each of which could contribute to the indexing process.
    (Response) Under the new animal drug approval process, information 
gathered from multiple sources can be placed into master files from 
which the information can be referenced in support of one or more new 
animal drug applications. Master files can contain public or 
proprietary information relating to, for example, manufacturing 
processes. The indexing rule does not prevent different individuals or 
groups from contributing to the indexing of a drug product using this 
type of a master file mechanism, and FDA intends to allow for such 
master files to be used in the context of indexing.
    (Comment 22) One comment requested clarification of the post-
indexing reporting requirements for chemistry, manufacturing, and 
control (CMC) information and whether they will be the same as the 
Minor Changes and Stability Reporting (MCSR) process.
    (Response) MCSR, as required by 21 CFR 514.8(b)(4), does not apply 
to indexed drugs. Under Sec.  516.161(b)(1), changes in manufacturing 
methods or controls required to correct product or manufacturing 
defects that may result in serious adverse drug events should be made 
as soon as possible and a request to modify the indexed drug should be 
concurrently submitted to the Director, Office of Minor Use and Minor 
Species Animal Drug Development (OMUMS). Under Sec.  
516.165(c)(3)(iii), the annual indexed drug experience report must 
contain a summary of any changes made during the reporting period in 
the methods used in, and facilities and controls used for, manufacture, 
processing, and packing. This information must be presented in the same 
level of detail that it was presented in the request for determination 
of eligibility for indexing. The information is not included in this 
report, however, if it has already been submitted under Sec.  516.161.
    (Comment 23) One comment stated that proposed Sec.  516.165(a)(3) 
appeared to be inconsistent with proposed Sec.  516.165(c)(3)(iii) in 
that Sec.  516.165(a)(3) implied that indexed drugs must meet all 
``approved CMC requirements'' while Sec.  516.165(c)(3)(iii) implied 
that CMC information only needed to be reported in the level of detail 
it was originally described in the indexing request.
    (Response) The comment is correct that under Sec.  
516.165(c)(3)(iii), changes in the manufacturing process subsequent to 
product indexing need to be reported only to the level of detail that 
the manufacturing process was described in the original request for a 
determination of eligibility for indexing. However, section 
572(d)(1)(F) of the act requires, as a condition of indexing, that 
requestors affirmatively commit to manufacture the drug product 
proposed for indexing according to current good manufacturing practices 
(cGMP). Accordingly, Sec.  516.165(a)(3) reflects the requirement for 
the manufacturer of an indexed drug to meet the record-keeping 
requirements of the cGMP regulations, and that this requirement is in 
addition to annually reporting the relatively limited CMC information 
required by Sec.  516.165.
    (Comment 24) One comment indicated that, with respect to 
occupational and user safety, the proposed regulations provided ``no 
regulatory relief from the statutory requirement for an indexed drug.''
    (Response) This is an accurate observation. The regulations, 
Sec. Sec.  516.129(c) and 516.133(a), are consistent with section 
572(c)(1)(F) and (c)(2)(E) of the act in this regard. Both the 
regulations and the statutory provisions they implement require that 
this aspect of product safety be assessed in accordance with the 
requirements of section 512(d) of the act.
    (Comment 25) One comment stated that references to ``statutory 
criteria'' in the preamble were unclear, raising the question whether 
the qualified expert panel and the agency would be subject to the 
evidentiary standards of section 512 or to those of section 572.
    (Response) The comment failed to specifically identify where in the 
preamble the unclear references to statutory criteria appeared, but the 
agency presumes that it was in the introductory paragraph of section 
II. F. (71 FR 48840 at 48842 and 48843). This paragraph describes the 
two-part indexing review process established by the act, which includes 
a review of whether the new animal drug meets the statutory criteria 
regarding target animal safety and effectiveness.
    The standard for target animal safety and effectiveness is 
established, with respect to expert panels, under section 572(d)(2)(C) 
of the act and, with respect to the agency, under section 572(d)(4) as: 
The benefits of using the new animal drug for the proposed use in a 
minor species outweigh its risks to the target animal, taking into 
account the harm being caused by the absence of an approved or 
conditionally approved new animal drug for the minor species in 
question.

IV. Conforming Changes

    Conforming changes to certain applicable sections of title 21 of 
the Code of Federal Regulations (CFR) can be found in:
    Sec.  20.100 Applicability; cross-reference to other regulations.

[[Page 69114]]

    Sec.  25.20 Actions requiring preparation of an environmental 
assessment.
    Sec.  25.33 Animal drugs.
    Sec.  201.105 Veterinary drugs.
    Sec.  201.115 New drugs or new animal drugs.
    Sec.  201.122 Drugs for processing, repacking, or manufacturing.
    Sec.  202.1 Prescription-drug advertisements.
    Sec.  207.21 Times for registration and drug listing.
    Sec.  207.35 Notification of registrant; drug establishment 
registration number and drug listing number.
    Sec.  225.1 Current good manufacturing practice.
    Sec.  225.35 Use of work areas, equipment, and storage areas for 
other manufacturing and storage purpose.
    Sec.  225.135 Work and storage areas.
    Sec.  226.1 Current good manufacturing practice.
    Sec.  500.25 Anthelmintic drugs for use in animals.
    Sec.  500.26 Timed-release dosage form drugs.
    Sec.  510.301 Records and reports concerning experience with animal 
feeds bearing or containing new animal drugs for which an approved 
medicated feed mill license application is in effect.
    Sec.  510.305 Maintenance of copies of approved medicated feed mill 
licenses to manufacture animal feed bearing or containing new animal 
drugs.
    Sec.  510.455 Requirements for free-choice medicated feeds.
    Sec.  511.1 New animal drugs for investigational use exempt from 
section 512(a) of the act.
    Sec.  515.10 Medicated feed mill license applications.
    Sec.  515.21 Refusal to approve a medicated feed mill license 
application.
    Sec.  558.3 Definitions and general considerations applicable to 
this part.
    Sec.  558.5 Requirements for liquid medicated feed.
    Sec.  558.6 Veterinary feed directive drugs.
    Sec.  589.1000 Gentian violet.

V. Legal Authority

    FDA's authority for issuing this final rule is provided by the MUMS 
act (21 U.S.C. 360ccc et seq.). When Congress passed the MUMS act, it 
directed FDA to publish implementing regulations (see 21 U.S.C. 360ccc 
note). In the context of the MUMS act, the statutory requirements of 
section 572 of the act, along with section 701(a) of the act (21 U.S.C. 
371(a)) provide authority for this final rule. Section 701(a) 
authorizes the agency to issue regulations for the efficient 
enforcement of the act.

VI. Analysis of Economic Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act (Public Law 104-4). 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; and distributive impacts and equity. The Regulatory 
Flexibility Act (5 U.S.C. 601-612) requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities.
    FDA finds that the final rule does not constitute an economically 
significant regulatory action as defined in 3(f)(1) of Executive Order 
12866. We base this on the following analysis that estimates annual 
costs ranging from about $476,000 in the first year to about $869,000 
in the 10th year. Similarly, the administrative costs are unlikely to 
have a significant economic impact on a substantial number of small 
entities.
    Section 202(a) of the Unfunded Mandates Reform Act requires that 
agencies prepare a written statement, which includes an assessment of 
anticipated costs and benefits, before establishing ``any rule that may 
result in an annual expenditure by State, local and tribal governments, 
in the aggregate, or by the private sector, of $100 million (adjusted 
annually for inflation) in any one year.'' The current threshold after 
adjustment for inflation is $127 million, using the most current (2006) 
implicit price deflator for the gross domestic product. FDA does not 
expect this final rule to result in any 1-year expenditure that would 
meet or exceed this amount. As such, no further analysis of anticipated 
costs and benefits is required by the Unfunded Mandates Reform Act.

A. Summary

    The final rule is expected to result in about 30 requests for a 
determination of eligibility for indexing for 60 products annually, or 
2 per requestor. We estimate that requestors for 20 of these products 
will create and convene expert panels to review the safety and efficacy 
data. Further, the recommendations of these panels are expected to lead 
to the addition of 20 animal drug index listings each year.

B. Comments on Proposed Rule

    FDA received six comments to the proposed rule, none of which 
contained substantive comments on the methodology used in the analysis 
of impacts of the proposed rule. As such, we have retained the 
methodology for the analysis of the final rule. Our requests in the 
analysis of impacts section of the proposed rule for additional cost 
data did not elicit any data that conflicted with our estimates. We 
did, however, receive one comment that suggested the paperwork 
reporting burden may be too low. We revised the economic impacts 
associated with the paperwork reporting burden, as well as made other 
small changes to the final rule due to other public comments. We 
address comments on individual components and any changes made to the 
final rule in the administrative cost section.

C. Benefit

    This rule intends to create administrative practices and procedures 
for index listing a new animal drug for use in a minor species, thereby 
providing the benefit of a legal basis for marketing an unapproved new 
animal drug intended for use in a minor species. The need for the rule 
arises from the existence of some minor species populations that are 
too small to support traditional drug approval studies. The 
countervailing risk of this rule is that animal drugs that are 
marginally economically viable could use this system to avoid the 
traditional animal drug approval process. Under this final rule, 
however, the voluntary indexing of a new animal drug for use in a minor 
species would only be allowed when the same drug in the same dosage 
form for the same intended use is not already approved or conditionally 
approved, thereby reducing this risk.

D. Administrative Costs

    This section will describe and estimate the annual administrative 
costs by provision for both producers of currently unapproved drugs 
that would request an index listing and FDA. First, we address the 
efforts required by requestors concerned with index listing. The 
estimates of the number of requestors, frequencies of responses, and 
hours per procedure for each of the provisions of the final rule were 
determined by Center for Veterinary Medicine (CVM) personnel for the 
proposed rule. Labor hour estimates for some procedure have been 
amended in this final rule due to public comments.
    We estimate that, on average, two foreign requestors of drug 
indexing would need to hire a permanent resident agent to represent 
them. We expect this to require about 1 hour of

[[Page 69115]]

administrative time for a requestor's management employee in regulatory 
affairs. We estimate the loaded wage estimate at $42.29 per hour 
(including a 30 percent increase for benefits) for regulatory affairs 
personnel.\1\ This provision would cost the two requestors a total of 
about $85. We expect that a resident agent would expend only about 6 
hours of administrative effort per year per indexed drug. We estimate 
the wage rate of the resident agent at $100 to $150 per hour, and use 
the midpoint, $125, for our calculations. Total annual costs for 
resident agents are estimated at $1,500 (two agent times 6 hours times 
$125 per hour) in the first year. In the 10th year this is expected to 
rise to about $15,000 as two more resident agents each provide 6 more 
hours of administrative effort each additional year.
---------------------------------------------------------------------------

    \1\ 2004 National Industry-Specific Occupational Employment and 
Wage Estimates, U.S. Department of Labor, Bureau of Labor Statistics 
(www.bls.gov/oes/current/naics4_325400.htm); compliance officer 
wage rate for pharmaceutical and medicine manufacturing (NAICS 
325400).
---------------------------------------------------------------------------

    Section 516.121 of the final rule provides for one or more meetings 
between requestors and FDA to discuss the requirements for indexing a 
new animal drug. We estimate that 30 requestors will each request, on 
average, 2 meetings annually, for a total of 60 meetings. Preparation 
and participation in these meetings is estimated at 4 hours each, for 
an annual total of 240 hours.
    Section 516.123 concerns informal conferences regarding agency 
administrative actions. These would include conferences to discuss a 
request for determination of eligibility that has been denied, the 
removal of an expert panel member, a request for indexing that was 
denied or an indexed drug that was removed from the list. In response 
to public comments, we have provided for a 60-day time period for 
industry to respond with a written request for a conference, rather 
than the proposed 30-day time period. Additionally, we have amended the 
final rule to require that an informal conference be scheduled and held 
within a 45-day period from our receipt of a request for an informal 
conference. The proposed rule would have required that we only attempt 
to schedule and hold the conference within 30 days. We do not expect 
these two changes to have an impact on the cost estimates of this 
provision. We estimate that about three requestors would request one 
conference with us annually for any of these reasons. We expect that 
each requestor would expend about 8 hours (24 hours total) to prepare 
for and attend each of these conferences. The combined efforts for 
preparation and participation in all conferences (Sec.  516.123) are 
estimated at 264 hours (240 plus 24). At the same loaded wage estimate 
of $42.29 per hour, this provision is expected to cost about $11,200 
annually.
    For section 516.125, we estimate that two requestors would each 
annually submit three notices of claimed investigational exemptions for 
new animal drugs for index listing. We estimate that each submission 
would require about 20 hours for regulatory affairs personnel to 
prepare. At the loaded wage estimate of $42.29 per hour, the total of 
120 hours would cost about $5,100.
    We estimate that about 30 requestors would each average about 2 
requests for determination of eligibility for indexing of individual 
animal drugs annually, totaling to 60 requests annually for proposed 
Sec.  516.129. Based on a public comment that the paperwork burden was 
underestimated in the proposed rule, we have increased the number of 
labor hours for preparing each request from 12 to 20. At the loaded 
wage estimate of $42.29 per hour, this provision would require about 
1,200 hours equal to about $50,700. Included in this estimate of 60 
requests are any resubmitted requests that were previously denied.
    Section 516.141 requires the creation of a qualified expert panel 
to review all information, provided by any source, relevant to a 
determination of the target animal safety and effectiveness of the new 
animal drug. We are required to approve the panel members before the 
panel formally convened. We estimate that requestors of 20 animal 
drugs, or about one-third of the 60 animal drugs that annually are 
determined to be eligible for indexing, would create qualified expert 
panels to further study the safety and efficacy data. The creation of 
each panel by a requestor is estimated to take about 16 hours of effort 
by regulatory affairs personnel. This figure has been increased from 
the 8 hours estimated in the proposed rule based on a public comment. 
At the same loaded wage estimate, these 320 hours are estimated at 
about $13,500 annually. An additional 0.5 hours is estimated for 
recordkeeping for the creation of the qualified panels described in 
Sec.  516.141. This would result in an additional $400 in annual costs.
    Section 516.143 describes how the expert panel will prepare a 
written report for FDA with its findings concerning the new animal drug 
under consideration for index listing. The review of the relevant 
information and preparation of the report by each panel would take an 
estimated 120 hours, an increase from the 80 hours estimated for the 
proposed rule. This equates to 2,400 hours for 20 panels. The rule 
allows for fees to be paid to panel members for their time. We estimate 
the average wage rate for panel members at $100 to $150/hr, and use the 
midpoint ($125) in our calculations. At this wage, we estimate these 
activities to cost up to $300,000 annually for the total industry, or 
$15,000 per requestor for each animal drug under consideration.
    We estimate that the formal request for addition to the index, 
provided for in Sec.  516.145, will require about 20 hours to prepare, 
an increase from the 12 hours estimated in the proposed rule. This will 
result in another 400 hours of effort (20 requests times 20 hours) for 
regulatory affairs personnel. We project the compliance cost of this 
effort at $16,900 annually.
    We only expect to receive one request each for a modification to an 
indexed listed drug and a change in ownership of an index file annually 
(provided for in proposed Sec. Sec.  516.161 and 516.163), and estimate 
the preparation of each to require 4 and 2 hours, respectively. In 
total, these compliance efforts will cost about $250 in the first year. 
Total modification requests and ownership change notifications are 
expected to increase by one each year so that 10 of each would be 
expected to be submitted in year 10. The cost of these provisions in 
year 10 is estimated at about $2,500. This final rule will require, in 
Sec.  516.165, that records and reports be created, submitted and 
retained by the holder of the indexed drug. These records include a 3-
day indexed drug field alert report, a 15-day indexed drug field alert 
report and an annual indexed drug experience report. We expect that the 
vast majority of compliance efforts will be associated with the annual 
indexed drug experience report. Because the number of expected requests 
that are granted for addition to the index is 20 per year (on average, 
20 requestors with 1 request granted each), the number of reports to be 
created, submitted and stored is also estimated at 20 per year. We 
estimate the reports for each index listing will require 8 hours 
annually, totally about 160 hours for all 20 listings. At the loaded 
wage estimate of $42.29 per hour, we estimate the first-year reporting 
costs at about $6,800. These annual costs will increase by an 
additional $6,800 each year as an additional 20 indexed drugs are added 
to the list. In year 10 we estimate the cost of this provision at about 
$67,700. Further, we expect that the maintenance of these records 
(recordkeeping) will require an additional hour of administrative time 
for each indexed

[[Page 69116]]

drug listing. These additional 20 hours will cost about $850 at the 
same loaded wage estimate in the first year, and would also increase in 
succeeding years by an additional $850 as additional indexed drugs are 
added to the list. We estimate the cost of this provision in year 10 at 
about $8,500.
    For those choosing to seek a MUMS index listing of an unapproved 
animal drug, total requestor compliance costs are expected to sum to 
about $407,000 in the first year. This represents an increase of 
$134,000 from the $273,000 estimated cost of the proposed rule. These 
costs will be borne by 30 firms that make a request for determination 
of eligibility for indexing at an average cost per requestor of about 
$13,600 per submission. Including only those estimated 20 firms that 
followup with a request for addition to the index, we project average 
costs at about $19,000. Costs in succeeding years would be expected to 
increase slightly due to the annual reporting requirements for all 
indexed drugs, resulting in year-10 total costs for the industry at 
about $492,000.

E. Costs to Government

    The Government would also incur costs for this final rule. We 
expect that about 60 percent of a full-time equivalent employee at a 
GS-14 salary would be needed to handle the administrative work of the 
indexing of MUMS drugs in the first year. This would include all 
administrative efforts from responding to requests for presubmission 
meetings to making changes to approved indexed drugs. We estimate 
Government costs (including a 30 percent adjustment for benefits) of 
this provision at about $69,000 in the first year. In year 10 we 
estimate that up to four full time equivalent employees (one GS-14 
position, two GS-13 positions and one GS-11 position) would be needed 
to administer the program. Including a 30 percent adjustment for 
benefits, we estimate that the cost to Government in year 10 could 
increase to about $378,000.
    Total costs for this final rule would be the sum of private 
administrative and Government costs. Total costs are estimated to 
increase from $476,000 in the first year up to $869,000 in the 10th 
year.

F. Regulatory Flexibility Analysis

1. Small Business Impacts
    The Regulatory Flexibility Act requires agencies to prepare a 
regulatory flexibility analysis if a rule is expected to have a 
significant economic impact on a substantial number of small entities. 
Although we believe it is unlikely that significant economic impacts 
would occur, the following constitutes the final regulatory flexibility 
analysis.
    One requirement of the Regulatory Flexibility Act is a succinct 
statement of any objectives of the rule. As stated previously in this 
analysis, with this rule the agency intends to create an administrative 
system, provided for by statute, that would allow for the legal 
marketing of unapproved animal drugs for use in minor species in the 
U.S. that would otherwise not be economically viable under current 
market conditions.
    The Regulatory Flexibility Act also requires a description of the 
small entities that would be affected by the rule, and an estimate of 
the number of small entities to which the rule would apply. The Small 
Business Administration (SBA) defines the criteria for small businesses 
using the North American Industrial Classification System (NAICS). For 
pharmaceutical preparation manufacturers (NAICS number 325412), SBA 
defines small businesses as those with fewer than 750 employees. Census 
data shows that 723 companies with 901 establishments represent this 
category.\2\ While about two-thirds of the establishments would be 
considered small using the SBA criteria, the agency acknowledges that 
many requests for MUMS index listing would likely be received from 
multi-establishment companies that exceed the 750-employee limit on 
small businesses. Nonetheless, the average cost for a requestor that 
has two meetings with us, requests a determination of eligibility for 
indexing, creates and convenes a qualified panel of experts resulting 
in a written report, requests an addition to the index and keeps all 
necessary records, would be about $19,000. This cost per request 
represents about 2.1 percent of the revenues of the smallest set of 
establishments (those establishments with 1 to 4 employees), and 0.5 
percent or less of revenues of all larger establishments.\3\ These 
costs would not represent a significant economic impact on the firms 
expected to request an index listing, especially in light of the fact 
that they incur these expenses in order to realize increased sales 
revenue from the indexing. The firms submitting requests for index 
listing are expected to already have the necessary administrative 
personnel with the skills required to prepare the requests and fulfill 
reporting requirements as identified above.
---------------------------------------------------------------------------

    \2\ 2002 Economic Census, U.S. Census Bureau, Manufacturing 
Industry Series, Pharmaceutical Preparation Manufacturing, tables 3 
and 4.
    \3\ U.S. Department of Labor, Bureau of Labor Statistics. 2002 
revenues inflated to 2007 dollars using the CPI-U.
---------------------------------------------------------------------------

2. Analysis of Alternatives
    The Regulatory Flexibility Act requires that the agency consider 
any alternatives to the final rule that would accomplish the objective 
while minimizing significant impacts of the rule. As stated previously, 
the agency believes that the final rule, due to the relatively small 
size of the costs, would not be likely to impose significant economic 
impacts on a substantial number of small entities.
    The statute that creates this system, Public Law 108-282, does not 
provide the agency a great deal of flexibility in the implementing 
regulations, such as in determining whether or not to use independent 
qualified expert panels to review the safety and efficacy data. We 
conclude that the final rule achieves the objective of increasing the 
number of drugs that can be legally marketed for minor species with 
minimal costs to industry while staying within the limits set by Public 
Law 108-282.

VII. 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 Reduction Act of 1995 (44 U.S.C. 3501-3520). A 
description of these provisions is given below with an estimate of the 
annual reporting burden. Included in the estimate is the time for 
reviewing instructions, searching existing data sources, gathering and 
maintaining the data needed, and completing and reviewing each 
collection of information.
    Title: Index of Legally Marketed Unapproved New Animal Drugs for 
Minor Species 21 CFR part 516.
    Description: The Minor Use and Minor Species Animal Health Act of 
2004 (MUMS act) amended the Federal Food, Drug, and Cosmetic Act (the 
act) to authorize FDA to establish new regulatory procedures intended 
to make more medications legally available to veterinarians and animal 
owners for the treatment of minor animal species (species other than 
cattle, horses, swine, chickens, turkeys, dogs, and cats), as well as 
uncommon diseases in major animal species.
    The MUMS act created three new sections to the act (section 571, 
572, and 573), and this final rule implements section 572 of the act, 
which provides for an index of legally marketed unapproved new animal 
drugs for minor species. Participation in any part of the MUMS program 
is optional so the associated paperwork only applies to

[[Page 69117]]

those who choose to participate. The final rule specifies, among other 
things, the criteria and procedures for requesting eligibility for 
indexing and for requesting addition to the index as well as the annual 
reporting requirements for index holders.
    Under the new subpart C of part 516 (21 CFR part 516), Sec.  
516.119 provides requirements for naming a permanent-resident U.S. 
agent by foreign drug companies, and Sec.  516.121 provides for 
informational meetings with FDA. Section 516.123 provides requirements 
for requesting informal conferences regarding agency administrative 
actions and Sec.  516.125 provides for investigational use of new 
animal drugs intended for indexing. Provisions for requesting a 
determination of eligibility for indexing can be found under Sec.  
516.129 and provisions for subsequent requests for addition to the 
index can be found under Sec.  516.145. A description of the written 
report required in Sec.  516.145 can be found under Sec.  516.143. 
Under Sec.  516.141 are provisions for drug companies to nominate a 
qualified expert panel as well as the panel's recordkeeping 
requirements. This section also calls for the submission of a written 
conflict of interest statement to FDA by each proposed panel member. 
Index holders are able to modify their index listing under Sec.  
516.161 or change drug ownership under Sec.  516.163. Requirements for 
records and reports are under Sec.  516.165.
    Description of Respondents: Pharmaceutical companies that sponsor 
new animal drugs.
    FDA estimates the burden for this collection of information as 
follows:

                                                     Table 1.--Estimated Annual Reporting Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                              No. of         Annual frequency       Total annual        Hours per
                    21 CFR Section                         respondents         per response          responses           response         Total hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
516.119                                                                 2                     1                  2                  1                  2
--------------------------------------------------------------------------------------------------------------------------------------------------------
516.121                                                                30                     2                 60                  4                240
--------------------------------------------------------------------------------------------------------------------------------------------------------
516.123                                                                 3                     1                  3                  8                 24
--------------------------------------------------------------------------------------------------------------------------------------------------------
516.125                                                                 2                     3                  6                 20                120
--------------------------------------------------------------------------------------------------------------------------------------------------------
516.129                                                                30                     2                 60                 20              1,200
--------------------------------------------------------------------------------------------------------------------------------------------------------
516.141                                                                20                     1                 20                 16                320
--------------------------------------------------------------------------------------------------------------------------------------------------------
516.143                                                                20                     1                 20                120              2,400
--------------------------------------------------------------------------------------------------------------------------------------------------------
516.145                                                                20                     1                 20                 20                400
--------------------------------------------------------------------------------------------------------------------------------------------------------
516.161                                                                 1                     1                  1                  4                  4
--------------------------------------------------------------------------------------------------------------------------------------------------------
516.163                                                                 1                     1                  1                  2                  2
--------------------------------------------------------------------------------------------------------------------------------------------------------
516.165                                                                10                     2                 20                  8                160
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                                                                                                                              4,872
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\There is no capital or operating and maintenance cost associated with this collection of information.


                                                   Table 2.--Estimated Annual Recordkeeping Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                             No. of         Annual frequency       Total annual         Hours per
                    21 CFR Section                        respondents         per response          responses           response          Total hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
516.141                                                               30                     2                 60                0.5                  30
--------------------------------------------------------------------------------------------------------------------------------------------------------
516.165                                                               10                     2                 20                1                    20
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                                                                                                                                 50
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\There is no capital or operating and maintenance cost associated with this collection of information.

    FDA announced that the proposed rule contained information 
collection provisions that were subject to review by OMB under the 
Paperwork Reduction Act of 1995 and invited public comment in the 
Federal Register of August 22, 2006 (71 FR 48840). In response to that 
notice FDA received two comments concerning the estimated paperwork 
reporting burden. One comment said that the estimates appear to be 
reasonable and accurate while the other comment said that some were 
potentially underestimated. Specifically, the second comment felt that 
the agency's estimates for the hours per response were too low for the 
time required for creation of an expert panel by regulatory 
professionals in Sec.  516.141 and for the time required to prepare the 
written report in Sec.  516.143. Although the comment did not offer new 
estimates for these sections, FDA agrees that these estimates may be 
too low. Therefore, FDA believes that 16 hours is a more reasonable 
response time required for creation of an expert panel. In view of 
increased reporting requirements under Sec.  516.141, CVM has increased 
the ``Hours per Response'' under this citation in ``Table 1. Estimated 
Annual Reporting Burden,'' from 8 to 16 hours thereby increasing the 
total burden hours to 320. FDA also believes that 120 hours is a more 
reasonable response time required to prepare the written report. In 
view of increased reporting requirements under Sec.  516.143, CVM has 
increased the

[[Page 69118]]

``Hours per Response'' under this citation in ``Table 1. Estimated 
Annual Reporting Burden,'' from 80 to 120 hours thereby increasing the 
total burden hours to 2400.
    The second comment also proposed 20 to 80 hours of response time 
for preparation of a request for determination of eligibility and 20 to 
80 hours of response time for preparation of a request for addition to 
the index. FDA agrees, in light of both comments, that 20 hours is a 
more reasonable response time required to prepare each of these two 
submissions. In view of increased reporting requirements under Sec.  
516.129, CVM has increased the ``Hours per Response'' under this 
citation in ``Table 1. Estimated Annual Reporting Burden,'' from 12 to 
20 hours thereby increasing the total burden hours to 1,200. For Sec.  
516.145, CVM has also increased the ``Hours per Response'' in ``Table 
1. Estimated Annual Reporting Burden,'' from 12 to 20 hours thereby 
increasing the total burden hours for this section to 400.
    The second comment also requested clarification on the time 
allotted for the notice of claimed investigational exemption in Sec.  
516.125. This reporting burden accounts for the time required to 
prepare information pertinent to the safety or effectiveness of a drug 
derived from investigational studies for review by the expert panel.
    Finally, it should be noted that FDA received no comment on the 
proposed conforming changes to 21 CFR 515.10(b) which describes what 
information must be contained in a medicated feed mill license 
application. Accordingly, the agency is revising Form FDA 3448 
Medicated Feed Mill License Application (OMB No. 0910-0337) to reflect 
these minor conforming changes. This revision will not change the 
information reporting burden already approved for this form. It merely 
revises one of the certifications to reflect the fact that new animal 
drugs now include index listed drugs.
    The information collection provisions of this final rule have been 
submitted to OMB for review. Prior to the effective date of this final 
rule, FDA will publish a notice in the Federal Register announcing 
OMB's decision to approve, modify, or disapprove the information 
collection provisions in this final rule. 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.

VIII. Environmental Impact

    We have carefully considered the potential environmental impacts of 
this final rule and determined under 21 CFR 25.30(h) 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.

IX. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the rule 
does not contain policies that have substantial direct effects on the 
States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, the agency has concluded 
that the rule does not contain policies that have federalism 
implications as defined in the Executive order and, consequently, a 
federalism summary impact statement is not required.

List of Subjects

21 CFR Part 20

    Confidential business information, Courts, Freedom of information, 
Government employees.

21 CFR Part 25

    Environmental impact statements, Foreign relations, Reporting and 
recordkeeping requirements.

21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 202

    Advertising, Prescription drugs.

21 CFR Part 207

    Drugs, Reporting and recordkeeping requirements.

21 CFR Part 225

    Animal drugs, Animal feeds, Labeling, Packaging and containers, 
Reporting and recordkeeping requirements.

21 CFR Part 226

    Animal drugs, Animal feeds, Labeling, Packaging and containers, 
Reporting and recordkeeping requirements.

21 CFR Part 500

    Animal drugs, Animal feeds, Cancer, Labeling, Packaging and 
containers, Polychlorinated biphenyls (PCBs).

21 CFR Part 510

    Administrative practice and procedure, Animal drugs, Labeling, 
Reporting and recordkeeping requirements.

21 CFR Part 511

    Animal drugs, Medical research, Reporting and recordkeeping 
requirements.

21 CFR Part 515

    Administrative practice and procedure, Animal drugs, Confidential 
business information, Reporting and recordkeeping requirements.

21 CFR Part 516

    Administrative practice and procedure, Animal drugs, Confidential 
business information, Reporting and recordkeeping requirements.

21 CFR Part 558

    Animal drugs, Animal feeds.

21 CFR Part 589

    Animal feeds, Animal foods, Food additives.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR 
Chapter I is amended as follows:

PART 20--PUBLIC INFORMATION

0
1. The authority citation for 21 CFR part 20 continues to read as 
follows:

    Authority: 5 U.S.C. 552; 18 U.S.C. 1905; 19 U.S.C. 2531-2582; 21 
U.S.C. 321-393, 1401-1403; 42 U.S.C. 241, 242, 242a, 242l, 242n, 
243, 262, 263, 263b-263n, 264, 265, 300u-300u-5, 300aa-1.

0
2. Amend Sec.  20.100 by adding paragraph (c)(44) to read as follows:


Sec.  20.100  Applicability; cross-reference to other regulations.

* * * * *
    (c) * * *
    (44) Minor-species drug index listings, in Sec.  516.171 of this 
chapter.

PART 25--ENVIRONMENTAL IMPACT CONSIDERATIONS

0
3. The authority citation for 21 CFR part 25 continues to read as 
follows:

    Authority: 21 U.S.C. 321-393; 42 U.S.C. 262, 263b-264; 42 U.S.C. 
4321, 4332; 40 CFR parts 1500-1508; E.O. 11514, 35 FR 4247, 3 CFR, 
1971 Comp., p. 531-533 as amended by E.O. 11991, 42 FR 26967, 3 CFR, 
1978 Comp., p. 123-124 and E.O. 12114, 44 FR 1957, 3 CFR, 1980 
Comp., p. 356-360.

0
4. Amend Sec.  25.20 by revising paragraph (m) to read as follows:


Sec.  25.20  Actions requiring preparation of an environmental 
assessment.

* * * * *
    (m) Approval of NADA's, abbreviated applications, supplements, 
actions on

[[Page 69119]]

INAD's, and granting of requests for determination of eligibility for 
indexing, unless categorically excluded under Sec.  25.33 (a), (c), 
(d), or (e).
* * * * *

0
5. Amend Sec.  25.33 by revising paragraphs (a) introductory text, (c), 
(d) introductory text, and (g) to read as follows:


Sec.  25.33  Animal drugs.

* * * * *
    (a) Action on an NADA, abbreviated application, request for 
determination of eligibility for indexing, a supplement to such 
applications, or a modification of an index listing, if the action does 
not increase the use of the drug. Actions to which this categorical 
exclusion applies may include:
* * * * *
    (c) Action on an NADA, abbreviated application, request for 
determination of eligibility for indexing, a supplement to such 
applications, or a modification of an index listing, for substances 
that occur naturally in the environment when the action does not alter 
significantly the concentration or distribution of the substance, its 
metabolites, or degradation products in the environment.
    (d) Action on an NADA, abbreviated application, request for 
determination of eligibility for indexing, a supplement to such 
applications, or a modification of an index listing, for:
* * * * *
    (g) Withdrawal of approval of an NADA or an abbreviated NADA or 
removal of a new animal drug from the index.
* * * * *

PART 201--LABELING

0
6. The authority citation for 21 CFR part 201 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360, 
360b, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.

0
7. Amend Sec.  201.105 by revising paragraphs (c)(2) and (d)(1) to read 
as follows:


Sec.  201.105  Veterinary drugs.

* * * * *
    (c) * * *
    (2) If the article is subject to section 512 or 572 of the act, the 
labeling bearing such information is the labeling authorized by the 
approved new animal drug application or contained in the index listing: 
Provided, however, That the information required by paragraph (c)(1) of 
this section may be omitted from the dispensing package if, but only 
if, the article is a drug for which directions, hazards, warnings, and 
use information are commonly known to veterinarians licensed by law to 
administer the drug. Upon written request, stating reasonable grounds 
therefore, the Commissioner will offer an opinion on a proposal to omit 
such information from the dispensing package under this proviso.
    (d) * * *
    (1) Adequate information for such use, including indications, 
effects, dosages, routes, methods, and frequency and duration of 
administration, and any relevant warnings, hazards, contraindications, 
side effects, and precautions, and including information relevant to 
compliance with the new animal drug provisions of the act, under which 
veterinarians licensed by law to administer the drug can use the drug 
safely and for the purposes for which it is intended, including all 
conditions for which it is advertised or represented; and if the 
article is subject to section 512 or 572 of the act, the parts of the 
labeling providing such information are the same in language and 
emphasis as labeling approved, permitted, or indexed under the 
provisions of section 512 or 572, and any other parts of the labeling 
are consistent with and not contrary to such approved, permitted, or 
indexed labeling; and
* * * * *

0
8. Amend Sec.  201.115 by revising paragraphs (a) and (b) to read as 
follows:


Sec.  201.115  New drugs or new animal drugs.

* * * * *
    (a) To the extent to which such exemption is claimed in an approved 
application with respect to such drug under section 505 or 512 of the 
act or an index listing with respect to such drug under section 572 of 
the act; or
    (b) If no application under section 505 or 512 of the act is 
approved and no request for addition to the index is granted under 
section 572 with respect to such drug but it complies with section 
505(i), 512(j), or 572(g) of the act and regulations thereunder.
* * * * *

0
9. Amend Sec.  201.122 by revising paragraphs (a), (b), and (c) to read 
as follows:


Sec.  201.122  Drugs for processing, repacking, or manufacturing.

* * * * *
    (a) An approved new drug application or new animal drug application 
or a new animal drug index listing covers the production and delivery 
of the drug substance to the application or index listing holder by 
persons named in the application or in the request for determination of 
eligibility for indexing, and, for a new drug substance, the export of 
it by such persons under Sec.  314.410 of this chapter; or
    (b) If no application is approved with respect to such new drug or 
new animal drug, and it is not listed in the index, the label statement 
``Caution: For manufacturing, processing, or repacking'' is immediately 
supplemented by the words ``in the preparation of a new drug or new 
animal drug limited by Federal law to investigational use'', and the 
delivery is made for use only in the manufacture of such new drug or 
new animal drug limited to investigational use as provided in part 312 
or Sec.  511.1 or Sec.  516.125 of this chapter; or
    (c) A new drug application or new animal drug application or a 
request for addition to the index covering the use of the drug 
substance in the production and marketing of a finished drug product 
has been submitted but not yet approved, disapproved, granted, or 
denied, the bulk drug is not exported, and the finished drug product is 
not further distributed after it is manufactured until after the new 
drug application or new animal drug application is approved or the 
request for addition to the index is granted.

PART 202--PRESCRIPTION DRUG ADVERTISING

0
10. The authority citation for 21 CFR part 202 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 352, 355, 360b, 371.

0
11. Amend Sec.  202.1 by revising paragraph (e)(4)(i)(a) to read as 
follows:


Sec.  202.1  Prescription-drug advertisements.

* * * * *
    (e) * * *
    (4) Substance of information to be included in brief summary. 
(i)(a) An advertisement for a prescription drug covered by a new-drug 
application approved pursuant to section 505 of the act after October 
10, 1962, or a prescription drug covered by a new animal drug 
application approved pursuant to section 512 of the act after August 1, 
1969, or any approved supplement thereto, or for a prescription drug 
listed in the index pursuant to section 572 of the act, or any granted 
modification thereto, shall not recommend or suggest any use that is 
not in the labeling accepted in such approved new-drug application or 
supplement, new animal drug application or supplement, or new animal 
drug index listing or modification. The advertisement shall present 
information from labeling

[[Page 69120]]

required, approved, permitted, or granted in a new-drug or new animal 
drug application or new animal drug index listing relating to each 
specific side effect and contraindication in such labeling that relates 
to the uses of the advertised drug dosage form(s) or shall otherwise 
conform to the provisions of paragraph (e)(3)(iii) of this section.
* * * * *

PART 207--REGISTRATION OF PRODUCERS OF DRUGS AND LISTING OF DRUGS 
IN COMMERCIAL DISTRIBUTION

0
12. The authority citation for 21 CFR part 207 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 360b, 371, 
374, 381, 393; 42 U.S.C. 262, 264, 271.

0
13. Amend Sec.  207.20 by revising paragraph (c) to read as follows:


Sec.  207.20  Who must register and submit a drug list.

* * * * *
    (c) Before beginning manufacture or processing of a drug subject to 
one of the following applications, an owner or operator of an 
establishment is required to register before the agency approves or 
grants it: A new drug application, an abbreviated new drug application, 
a new animal drug application, an abbreviated new animal drug 
application, a medicated feed mill license application, a biologics 
license application, or a request for addition to the index.
* * * * *

0
14. Amend Sec.  207.21 by revising the second sentence in paragraph (a) 
to read as follows:


Sec.  207.21  Times for registration and drug listing.

    (a) * * * If the owner or operator of the establishment has not 
previously entered into such an operation, the owner or operator shall 
register within 5 days after submitting a new drug application, 
abbreviated new drug application, new animal drug application, 
abbreviated new animal drug application, request for addition to the 
index, medicated feed mill license application, or a biologics license 
application. * * *
* * * * *

0
15. Amend Sec.  207.35 by revising paragraph (b)(3)(v) to read as 
follows:


Sec.  207.35  Notification of registrant; drug establishment 
registration number and drug listing number.

* * * * *
    (b) * * *
    (3) * * *
    (v) The placing of the assigned NDC number on a label or in other 
labeling does not require the submission of a supplemental new drug 
application, supplemental new animal drug application, or a 
modification to an index listing.
* * * * *

PART 225--CURRENT GOOD MANUFACTURING PRACTICE FOR MEDICATED FEEDS

0
16. The authority citation for 21 CFR part 225 continues to read as 
follows:

    Authority: 21 U.S.C. 351, 352, 360b, 371, 374.

0
17. Amend Sec.  225.1 by revising paragraph (c) to read as follows:


Sec.  225.1  Current good manufacturing practice.

* * * * *
    (c) In addition to the recordkeeping requirements in this part, 
Type B and Type C medicated feeds made from Type A articles or Type B 
feeds under approved NADAs or indexed listings and a medicated feed 
mill license are subject to the requirements of Sec.  510.301 of this 
chapter.

0
18. Amend Sec.  225.35 by revising paragraph (b) to read as follows:


Sec.  225.35  Use of work areas, equipment, and storage areas for other 
manufacturing and storage purpose.

* * * * *
    (b) Work areas and equipment used for the manufacture or storage of 
medicated feeds or components thereof shall not be used for, and shall 
be physically separated from, work areas and equipment used for the 
manufacture of fertilizers, herbicides, insecticides, fungicides, 
rodenticides, and other pesticides unless such articles are approved 
drugs, indexed drugs, or approved food additives intended for use in 
the manufacture of medicated feed.

0
19. Revise Sec.  225.135 to read as follows:


Sec.  225.135  Work and storage areas.

    Work areas and equipment used for the production or storage of 
medicated feeds or components thereof shall not be used for, and shall 
be physically separated from, work areas and equipment used for the 
manufacture and storage of fertilizers, herbicides, insecticides, 
fungicides, rodenticides, and other pesticides unless such articles are 
approved or index listed for use in the manufacture of animal feed.

PART 226--CURRENT GOOD MANUFACTURING PRACTICE FOR TYPE A MEDICATED 
ARTICLES

0
20. The authority citation for 21 CFR part 226 continues to read as 
follows:

    Authority: 21 U.S.C. 351, 352, 360b, 371, 374.

0
21. Amend Sec.  226.1 by adding a second sentence to paragraph (b) to 
read as follows:


Sec.  226.1  Current good manufacturing practice.

* * * * *
    (b) * * * Similarly, Type A medicated articles listed in the index 
are subject to the requirements of Sec.  516.165 of this chapter.

PART 500--GENERAL

0
22. The authority citation for 21 CFR part 500 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 342, 343, 348, 351, 352, 353, 
360b, 371.

0
23. Amend Sec.  500.25 by revising paragraph (c) to read as follows:


Sec.  500.25  Anthelmintic drugs for use in animals.

* * * * *
    (c) For drugs covered by approved new animal drug applications, the 
labeling revisions required for compliance with this section may be 
placed into effect without prior approval, as provided for in Sec.  
514.8(c)(3) of this chapter. For drugs listed in the index, the 
labeling revisions required for compliance with this section may be 
placed into effect without prior granting of a request for a 
modification, as provided for in Sec.  516.161(b)(1) of this chapter.
* * * * *

0
24. Amend Sec.  500.26 by revising paragraph (b) and the second 
sentence in paragraph (c) to read as follows:


Sec.  500.26  Timed-release dosage form drugs.

* * * * *
    (b) Timed-release dosage form animal drugs that are introduced into 
interstate commerce are deemed to be adulterated within the meaning of 
section 501(a)(5) of the act and subject to regulatory action, unless 
such animal drug is the subject of an approved new animal drug 
application, or listed in the index, as required by paragraph (a) of 
this section.
    (c) * * * A new animal drug application or index listing is 
required in any such case.
* * * * *

[[Page 69121]]

PART 510--NEW ANIMAL DRUGS

0
25. The authority citation for 21 CFR part 510 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 360b, 371, 379e.

0
26. Amend Sec.  510.301 by revising the introductory text, paragraph 
(a)(2), and the second sentence in paragraph (b)(1) to read as follows:


Sec.  510.301  Records and reports concerning experience with animal 
feeds bearing or containing new animal drugs for which an approved 
medicated feed mill license application is in effect.

    Records and reports of clinical and other experience with the new 
animal drug will be maintained and reported, appropriately identified 
with the new animal drug application(s) or index listing(s) to which 
they relate, to the Center for Veterinary Medicine in duplicate in 
accordance with the following:
    (a) * * *
    (2) Information concerning any bacteriological or any significant 
chemical, physical, or other change or deterioration in the drug, or 
any failure of one or more distributed batches of the drug to meet the 
specifications established for it in the new animal drug application or 
request for determination of eligibility for indexing.
    (b) * * *
    (1) * * * Unexpected as used in this paragraph refers to conditions 
or developments not previously submitted as part of the new animal drug 
application or in support of the index listing or not encountered 
during clinical trials of the drug, or conditions or developments 
occurring at a rate higher than shown by information previously 
submitted as part of the new animal drug application or in support of 
the index listing or at a rate higher than encountered during such 
clinical trials.
* * * * *

0
27. Amend Sec.  510.305 by revising paragraph (b) to read as follows:


Sec.  510.305  Maintenance of copies of approved medicated feed mill 
licenses to manufacture animal feed bearing or containing new animal 
drugs.

* * * * *
    (b) Approved or index listed labeling for each Type B and/or Type C 
feed being manufactured on the premises of the manufacturing 
establishment or the facility where the feed labels are generated.

0
28. Amend Sec.  510.455 by revising paragraphs (b) and (c) to read as 
follows:


Sec.  510.455  Requirements for free-choice medicated feeds.

* * * * *
    (b) What is required for new animal drugs intended for use in free-
choice feed? Any new animal drug intended for use in free-choice feed 
must be approved for such use under section 512 of the Federal Food, 
Drug, and Cosmetic Act (the act) (21 U.S.C. 360(b)) or listed in the 
index under section 572 of the act (21 U.S.C. 360ccc-1). Such approvals 
under section 512 of the act must be:
    (1) An original new animal drug application (NADA),
    (2) A supplemental NADA, or
    (3) An abbreviated NADA.
    (c) What are the approval requirements under section 512 of the act 
for new animal drugs intended for use in free-choice feed? An approval 
under section 512 of the act for a Type A medicated article intended 
for use in free-choice feed must contain the following information:
    (1) Data, or reference to data in a master file (MF), showing that 
the target animal consumes the new animal drug in the Type C free-
choice feed in an amount that is safe and effective (consumption/
effectiveness data); and
    (2) Data, or reference to data in an MF, showing the relevant 
ranges of conditions under which the drug will be chemically and 
physically stable in the Type C free-choice feed under field 
conditions.
* * * * *

PART 511--NEW ANIMAL DRUGS FOR INVESTIGATIONAL USE

0
29. The authority citation for 21 CFR part 511 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 360b, 371.

0
30. Amend Sec.  511.1 by adding paragraph (g) to read as follows:


Sec.  511.1  New animal drugs for investigational use exempt from 
section 512(a) of the act.

* * * * *
    (g) Index of legally marketed unapproved new animal drugs for minor 
species. All provisions of part 511 apply to new animal drugs for 
investigational use in support of indexing, as described in section 572 
of the act, subject to the provisions of Sec.  516.125 of this chapter.

PART 515--MEDICATED FEED MILL LICENSE

0
31. The authority citation for 21 CFR part 515 continues to read as 
follows:

    Authority: 21 U.S.C. 360b, 371.

0
32. Amend Sec.  515.10 by revising paragraphs (b)(4) and (b)(7) to read 
as follows:


Sec.  515.10  Medicated feed mill license applications.

* * * * *
    (b) * * *
    (4) A certification that the animal feeds bearing or containing new 
animal drugs are manufactured and labeled in accordance with the 
applicable regulations published under section 512(i) of the act or in 
accordance with the index listing published under section 572(e)(2) of 
the act.
* * * * *
    (7) A commitment that current approved or index listed Type B and/
or Type C medicated feed labeling for each Type B and/or Type C 
medicated feed to be manufactured will be in the possession of the feed 
manufacturing facility prior to receiving the Type A medicated article 
containing such drug.
* * * * *

0
33. Amend Sec.  515.21 by revising paragraph (a)(3) to read as follows:


Sec.  515.21  Refusal to approve a medicated feed mill license 
application.

    (a) * * *
    (3) The facility manufactures animal feeds bearing or containing 
new animal drugs in a manner that does not accord with the 
specifications for manufacture or labels animal feeds bearing or 
containing new animal drugs in a manner that does not accord with the 
conditions or indications of use that are published under section 
512(i) or 572(e)(2) of the act.
* * * * *

PART 516--NEW ANIMAL DRUGS FOR MINOR USE AND MINOR SPECIES

0
34. The authority citation for part 516 is revised to read as follows:

    Authority: 21 U.S.C. 360ccc-1, 360ccc-2, 371.

0
35. Part 516 is amended by adding subpart C, consisting of Sec. Sec.  
516.111 to 516.171, to read as follows:
Subpart C--Index of Legally Marketed Unapproved New Animal Drugs for 
Minor Species
Sec.
516.111 Scope of this subpart.
516.115 Definitions.
516.117 Submission of correspondence under this subpart.
516.119 Permanent-resident U.S. agent for foreign requestors and 
holders.
516.121 Meetings.
516.123 Informal conferences regarding agency administrative 
actions.
516.125 Investigational use of minor species new animal drugs to 
support indexing.
516.129 Content and format of a request for determination of 
eligibility for indexing.
516.131 Refuse to file a request for determination of eligibility 
for indexing.

[[Page 69122]]

516.133 Denying a request for determination of eligibility for 
indexing.
516.135 Granting a request for determination of eligibility for 
indexing.
516.137 Notification of decision regarding eligibility for indexing.
516.141 Qualified expert panels.
516.143 Written report.
516.145 Content and format of a request for addition to the index.
516.147 Refuse to file a request for addition to the index.
516.149 Denying a request for addition to the index.
516.151 Granting a request for addition to the index.
516.153 Notification of decision regarding index listing.
516.155 Labeling of indexed drugs.
516.157 Publication of the index and content of an index listing.
516.161 Modifications to indexed drugs.
516.163 Change in ownership of an index file.
516.165 Records and reports.
516.167 Removal from the index.
516.171 Confidentiality of data and information in an index file.

Subpart C--Index of Legally Marketed Unapproved New Animal Drugs 
for Minor Species


Sec.  516.111  Scope of this subpart.

    This subpart implements section 572 of the act and provides 
standards and procedures to establish an index of legally marketed 
unapproved new animal drugs. This subpart applies only to minor species 
and not to minor use in major species. This index is only available for 
new animal drugs intended for use in a minor species for which there is 
a reasonable certainty that the animal or edible products from the 
animal will not be consumed by humans or food-producing animals and for 
new animal drugs intended for use only in a hatchery, tank, pond, or 
other similar contained man-made structure in an early, nonfood life 
stage of a food-producing minor species, where safety for humans is 
demonstrated in accordance with the standard of section 512(d) of the 
act (including, for an antimicrobial new animal drug, with respect to 
antimicrobial resistance). The index shall not include a new animal 
drug that is contained in, or a product of, a transgenic animal. Among 
its topics, this subpart sets forth the standards and procedures for:
    (a) Investigational exemptions for indexing purposes;
    (b) Submissions to FDA of requests for determination of eligibility 
of a new animal drug for indexing;
    (c) Establishment and operation of expert panels;
    (d) Submissions to FDA of requests for addition of a new animal 
drug to the index;
    (e) Modifications to index listings;
    (f) Publication of the index; and
    (g) Records and reports.


Sec.  516.115  Definitions.

    (a) The following definitions of terms apply only in the context of 
subpart C of this part:
    Director OMUMS means the Director of the Office of Minor Use and 
Minor Species Animal Drug Development of the FDA Center for Veterinary 
Medicine.
    Holder means the requestor of an index listing after the request is 
granted and the new animal drug is added to the index.
    Index means FDA's list of legally marketed unapproved new animal 
drugs for minor species.
    Intended use has the same meaning as that given in Sec.  516.13 of 
this chapter.
    Qualified expert panel means a panel that is composed of experts 
qualified by scientific training and experience to evaluate the target 
animal safety and effectiveness of a new animal drug under 
consideration for indexing.
    Requestor means the person making a request for determination of 
eligibility for indexing or a request for addition to the index.
    Transgenic animal means an animal whose genome contains a 
nucleotide sequence that has been intentionally modified in vitro, and 
the progeny of such an animal, provided that the term `transgenic 
animal' does not include an animal of which the nucleotide sequence of 
the genome has been modified solely by selective breeding.
    (b) The definitions of the following terms are given in Sec.  514.3 
of this chapter:
    Adverse drug experience.
    Product defect/manufacturing defect.
    Serious adverse drug experience.
    Unexpected adverse drug experience.
    (c) The definitions of the following terms are given in Sec.  516.3 
of this chapter:
    Same dosage form.
    Same drug.
    Same intended use.


Sec.  516.117  Submission of correspondence under this subpart.

    Unless directed otherwise by FDA, all correspondence relating to 
any aspect of the new animal drug indexing process described in this 
subpart must be addressed to the Director, OMUMS. The initial 
correspondence for a particular index listing should include the name 
and address of the authorized contact person. Notifications of changes 
in such person or changes of address of such person should be provided 
in a timely manner.


Sec.  516.119  Permanent-resident U.S. agent for foreign requestors and 
holders.

    Every foreign requestor and holder shall name a permanent resident 
of the United States as their agent upon whom service of all processes, 
notices, orders, decisions, requirements, and other communications may 
be made on behalf of the requestor or holder. Notifications of changes 
in such agents or changes of address of agents should preferably be 
provided in advance, but not later than 60 days after the effective 
date of such changes. The permanent resident U.S. agent may be an 
individual, firm, or domestic corporation and may represent any number 
of requestors or holders. The name and address of the permanent-
resident U.S. agent shall be submitted to the Director, OMUMS, and 
included in the index file.


Sec.  516.121  Meetings.

    (a) A requestor or potential requestor is entitled to one or more 
meetings to discuss the requirements for indexing a new animal drug.
    (b) Requests for such meetings should be in writing, be addressed 
to the Director, OMUMS, specify the participants attending on behalf of 
the requestor or potential requestor, and contain a proposed agenda for 
the meeting.
    (c) Within 30 days of receiving a request for a meeting, FDA will 
attempt to schedule the meeting at a time agreeable to both FDA and the 
person making the request.


Sec.  516.123  Informal conferences regarding agency administrative 
actions.

    (a) Should FDA make an initial decision denying a request for 
determination of eligibility for indexing, terminating an 
investigational exemption, determining that a qualified expert panel 
does not meet the selection criteria, denying a request for addition to 
the index, or removing a new animal drug from the index, FDA will give 
written notice that specifies the grounds for the initial decision and 
provides an opportunity for an informal conference for review of the 
decision.
    (b) The written notice will include information for scheduling the 
informal conference and state that a written request for a conference 
must be made within 60 days of the date FDA sends its notice.
    (c) Within 45 days of receiving a request for an informal 
conference, FDA will schedule and hold the informal conference at a 
time agreeable to both FDA and the person making the request.
    (d) Such an informal conference will be conducted by a presiding 
officer who will be the Director of the Center for

[[Page 69123]]

Veterinary Medicine or his or her designee, excluding the Director of 
the Office of Minor Use and Minor Species Animal Drug Development and 
other persons significantly involved in the initial decision.
    (e) The person requesting an informal conference must provide a 
written response to FDA's initial decision at least 2 weeks prior to 
the date of the scheduled meeting. Generally, this written response 
would be attached to the request for an informal conference. At the 
option of the person requesting an informal conference, such written 
response to FDA's initial decision may act in lieu of a face-to-face 
meeting. In this case, the informal conference will consist of a review 
by the presiding officer of the submitted written response.
    (f) The purpose of an informal conference is to discuss scientific 
and factual issues. It will involve a discussion of FDA's initial 
decision and any written response to that decision.
    (g) Internal agency review of a decision must be based on the 
information in the administrative file. If the person requesting an 
informal conference presents new information not in the file, the 
matter will be returned to the appropriate lower level in the agency 
for reevaluation based on the new information.
    (h) Informal conferences under this part are not subject to the 
separation of functions rules in Sec.  10.55 of this chapter.
    (i) The rules of evidence do not apply to informal conferences. No 
motions or objections relating to the admissibility of information and 
views will be made or considered, but any party to the conference may 
comment upon or rebut all such data, information and views.
    (j) [Reserved]
    (k) The presiding officer will prepare a written report regarding 
the subject of the informal conference that states and describes the 
basis for his or her findings. Whenever time permits, the parties to 
the informal conference will have 30 days to review and comment on the 
report.
    (l) The administrative record of the informal conference will 
consist of:
    (1) The notice providing an opportunity for an informal conference 
and the written response to the notice.
    (2) All written information and views submitted to the presiding 
officer at the conference or, at the discretion of the presiding 
officer, thereafter.
    (3) The presiding officer's written report.
    (4) All correspondence and memoranda of any and all meetings 
between the participants and the presiding officer.
    (m) The administrative record of the informal conference is closed 
to the submission of information at the close of the conference, unless 
the presiding officer specifically permits additional time for further 
submission.
    (n) The administrative record of the informal conference specified 
herein constitutes the exclusive record for decision.


Sec.  516.125  Investigational use of minor species new animal drugs to 
support indexing.

    (a) The investigational use of a new animal drug or animal feed 
bearing or containing a new animal drug intended solely for 
investigational use in minor species shall meet the requirements of 
part 511 of this chapter if the investigational use is for the purpose 
of:
    (1) Demonstrating human food safety under section 572(a)(1)(B) of 
the act;
    (2) Demonstrating safety with respect to individuals exposed to the 
new animal drug through its manufacture and use under section 
572(c)(1)(F) of the act;
    (3) Conducting an environmental assessment under section 
572(c)(1)(E) of the act; or
    (4) Obtaining approval of a new animal drug application or 
abbreviated new animal drug application under section 512(b) of the 
act.
    (b) Correspondence and information associated with investigations 
described in paragraph (a) of this section shall not be sent to the 
Director, OMUMS, but shall be submitted to FDA in accordance with the 
provisions of part 511 of this chapter.
    (c) The investigational use of a new animal drug or animal feed 
bearing or containing a new animal drug intended solely for 
investigational use in minor species, other than for an investigational 
use described in paragraph (a) of this section, shall meet the 
requirements of this section. For such investigations, all provisions 
of part 511 of this chapter apply with the following modifications:
    (1) Under Sec.  511.1(a)(1) of this chapter, the label statement is 
as follows:
    ``Caution. Contains a new animal drug for investigational use only 
in laboratory animals or for tests in vitro in support of index 
listing. Not for use in humans.''
    (2) Under Sec.  511.1(b)(1) of this chapter, the label statement is 
as follows:
    ``Caution. Contains a new animal drug for use only in 
investigational animals in clinical trials in support of index listing. 
Not for use in humans. Edible products of investigational animals are 
not to be used for food for humans or other animals unless 
authorization has been granted by the U.S. Food and Drug Administration 
or by the U.S. Department of Agriculture.''
    (3) Under Sec.  511.1(b)(4) of this chapter, the notice is titled 
``Notice of Claimed Investigational Exemption for a New Animal Drug for 
Index Listing'' and is submitted in duplicate to the Director, OMUMS.
    (4) Under Sec.  511.1(c)(3) of this chapter, if an investigator is 
determined to be ineligible to receive new animal drugs, each ``Notice 
of Claimed Investigational Exemption for a New Animal Drug for Index 
Listing'' and each request for indexing shall be examined with respect 
to the reliability of information submitted by the investigator.
    (5) Under Sec.  511.1(c)(4) and (d)(2) of this chapter, with 
respect to termination of exemptions, the sponsor of an investigation 
shall not be granted an opportunity for a regulatory hearing before FDA 
pursuant to part 16 of this chapter. Instead, the sponsor shall have an 
opportunity for an informal conference as described in Sec.  516.123.
    (6) Under Sec.  511.1(c)(5) of this chapter, if the Commissioner of 
Food and Drugs determines, after the unreliable data submitted by the 
investigator are eliminated from consideration, that the data remaining 
are such that a request for addition to the index would have been 
denied, FDA will remove the new animal drug from the index in 
accordance with Sec.  516.167.
    (d) The investigational use of a new animal drug or animal feed 
bearing or containing a new animal drug subject to paragraph (c) of 
this section shall not be subject to the good laboratory practice 
requirements in part 58 of this chapter.
    (e) Correspondence and information associated with investigations 
described in paragraph (c) of this section shall be sent to the 
Director, OMUMS, in accordance with the provisions of this section.


Sec.  516.129  Content and format of a request for determination of 
eligibility for indexing.

    (a) Each request for determination of eligibility:
    (1) May involve only one drug (or one combination of drugs) in one 
dosage form;
    (2) May not involve a new animal drug that is contained in or a 
product of a transgenic animal;
    (3) May not involve the same drug in the same dosage form for the 
same intended use as a drug that is already approved or conditionally 
approved; and
    (4) Must be submitted separately.
    (b) A request for determination of eligibility for indexing may 
involve multiple intended uses and/or multiple

[[Page 69124]]

minor species. However, if a request for determination of eligibility 
for indexing that contains multiple intended uses and/or multiple minor 
species cannot be granted in any part, the entire request will be 
denied.
    (c) A requestor must submit two copies of a dated request signed by 
the authorized contact person for determination of eligibility for 
indexing that contains the following:
    (1) Identification of the minor species or groups of minor species 
for which the new animal drug is intended;
    (2) Information regarding drug components and composition;
    (3) A statement of the intended use(s) of the new animal drug in 
the identified minor species or groups of minor species;
    (4) A statement of the proposed conditions of use associated with 
the stated intended use(s) of the new animal drug, including the 
proposed dosage, route of administration, contraindications, warnings, 
and any other significant limitations associated with the intended 
use(s) of the new animal drug;
    (5) A brief discussion of the need for the new animal drug for the 
intended use(s);
    (6) An estimate of the anticipated annual distribution of the new 
animal drug, in terms of the total quantity of active ingredient, after 
indexing;
    (7) Information to establish that the new animal drug is intended 
for use:
    (i) In a minor species for which there is a reasonable certainty 
that the animal or edible products from the animal will not be consumed 
by humans or food-producing animals; or
    (ii) In a hatchery, tank, pond, or other similar contained man-made 
structure in (which includes on) an early, non-food life stage of a 
food-producing minor species, and information to demonstrate food 
safety in accordance with the standards of section 512(d) of the act 
and Sec.  514.111 of this chapter (including, for an antimicrobial new 
animal drug, with respect to antimicrobial resistance);
    (8) A description of the methods used in, and the facilities and 
controls used for, the manufacture, processing and packing of the new 
animal drug sufficient to demonstrate that the requestor has 
established appropriate specifications for the manufacture and control 
of the new animal drug and that the requestor has an understanding of 
current good manufacturing practices;
    (9) Either a claim for categorical exclusion under Sec.  25.30 or 
Sec.  25.33 of this chapter or an environmental assessment under Sec.  
25.40 of this chapter;
    (10) Information sufficient to support the conclusion that the new 
animal drug is safe under section 512(d) of the act with respect to 
individuals exposed to the new animal drug through its manufacture and 
use; and
    (11) The name and address of the contact person or permanent-
resident U.S. agent.


Sec.  516.131  Refuse to file a request for determination of 
eligibility for indexing.

    (a) If a request for determination of eligibility for indexing 
contains all of the information required by Sec.  516.129, FDA shall 
file it, and the filing date shall be the date FDA receives the 
request.
    (b) If a request for a determination of eligibility lacks any of 
the information required by Sec.  516.129, FDA will not file it, but 
will inform the requestor in writing within 30 days of receiving the 
request as to what information is lacking.


Sec.  516.133  Denying a request for determination of eligibility for 
indexing.

    (a) FDA will deny a request for determination of eligibility for 
indexing if it determines upon the basis of the request evaluated 
together with any other information before it with respect to the new 
animal drug that:
    (1) The same drug in the same dosage form for the same intended use 
is already approved or conditionally approved;
    (2) There is insufficient information to demonstrate that the new 
animal drug is intended for use:
    (i) In a minor species for which there is a reasonable certainty 
that the animal or edible products from the animal will not be consumed 
by humans or food-producing animals, or
    (ii) In a hatchery, tank, pond, or other similar contained man-made 
structure in (which includes on) an early, non-food life stage of a 
food-producing minor species, and there is insufficient evidence to 
demonstrate safety for humans in accordance with the standard of 
section 512(d) of the act and Sec.  514.111 of this chapter (including, 
for an antimicrobial new animal drug, with respect to antimicrobial 
resistance);
    (3) The new animal drug is contained in or is a product of a 
transgenic animal;
    (4) There is insufficient information to demonstrate that the 
requestor has established appropriate specifications for the 
manufacture and control of the new animal drug and that the requestor 
has an understanding of current good manufacturing practices;
    (5) The requester fails to submit an adequate environmental 
assessment under Sec.  25.40 of this chapter or fails to provide 
sufficient information to establish that the requested action is 
subject to categorical exclusion under Sec.  25.30 or Sec.  25.33 of 
this chapter;
    (6) There is insufficient information to determine that the new 
animal drug is safe with respect to individuals exposed to the new 
animal drug through its manufacture or use; or
    (7) The request for determination of eligibility for indexing fails 
to contain any other information required under the provisions of Sec.  
516.129.
    (b) FDA may deny a request for determination of eligibility for 
indexing if it contains any untrue statement of a material fact or 
omits material information.
    (c) When a request for determination of eligibility for indexing is 
denied, FDA will notify the requestor in accordance with Sec.  516.137.


Sec.  516.135  Granting a request for determination of eligibility for 
indexing.

    (a) FDA will grant the request for determination of eligibility for 
indexing if none of the reasons described in Sec.  516.133 for denying 
such a request applies.
    (b) When a request for determination of eligibility for indexing is 
granted, FDA will notify the requestor in accordance with Sec.  
516.137.


Sec.  516.137  Notification of decision regarding eligibility for 
indexing.

    (a) Within 90 days after the filing of a request for a 
determination of eligibility for indexing based on Sec.  
516.129(c)(7)(i), or 180 days for a request based on Sec.  
516.129(c)(7)(ii), FDA shall grant or deny the request, and notify the 
requestor of FDA's decision in writing.
    (b) If FDA denies the request, FDA shall provide due notice and an 
opportunity for an informal conference as described in Sec.  516.123 
regarding its decision. A decision of FDA to deny a request for 
determination of eligibility for indexing following an informal 
conference shall constitute final agency action subject to judicial 
review.


Sec.  516.141  Qualified expert panels.

    (a) Establishment of a qualified expert panel. Establishing a 
qualified expert panel is the first step in the process of requesting 
the addition of a new animal drug to the index. A qualified expert 
panel may not be established until FDA has determined that the new 
animal drug is eligible for indexing. The requestor must choose members 
for the qualified expert panel in accordance with selection criteria 
listed in paragraph (b) of this section and submit information about 
these proposed

[[Page 69125]]

members to FDA. FDA must determine whether the proposed qualified 
expert panel meets the selection criteria prior to the panel beginning 
its work. Qualified expert panels operate external to FDA and are not 
subject to the Federal Advisory Committee Act, as amended, 5 U.S.C. 
App.
    (b) Criteria for the selection of a qualified expert panel. (1) A 
qualified expert panel member must be an expert qualified by training 
and experience to evaluate a significant aspect of target animal safety 
or effectiveness of the new animal drug under consideration.
    (2) A qualified expert panel member must certify that he or she has 
a working knowledge of section 572 of the act (the indexing provisions 
of the statute) and this subpart, and that he or she has also read and 
understood a clear written statement provided by the requestor stating 
his or her duties and responsibilities with respect to reviewing the 
new animal drug proposed for addition to the index.
    (3) A qualified expert panel member may not be an FDA employee.
    (4) A qualified expert panel must have at least three members.
    (5) A qualified expert panel must have members with a range of 
expertise such that the panel, as a whole, is qualified by training and 
experience to evaluate the target animal safety and effectiveness of 
the new animal drug under consideration.
    (6) Unless FDA makes a determination to allow participation 
notwithstanding an otherwise disqualifying financial interest, a 
qualified expert panel member must not have a conflict of interest or 
the appearance of a conflict of interest, as described in paragraph (g) 
of this section.
    (c) Requestor responsibilities. (1) The requestor must:
    (i) Choose members for the qualified expert panel in accordance 
with selection criteria listed in paragraph (b) of this section.
    (ii) Provide each potential expert panel member a copy of section 
572 of the act (the indexing provisions of the statute) and this 
subpart and obtain certification that he or she has a working knowledge 
of the information.
    (iii) Provide each potential expert panel member a written 
statement describing the purpose and scope of his or her participation 
on the qualified expert panel and obtain certification that he or she 
has read and understood the information. The written statement should 
describe the duties and responsibilities of qualified expert panels and 
their members established by paragraphs (e) and (f) of this section, 
including the need to prepare a written report under Sec.  516.143.
    (iv) Obtain information from each potential expert panel member 
demonstrating that he or she is qualified by training and experience to 
evaluate the target animal safety and effectiveness of the new animal 
drug under consideration. This information can be obtained from a 
comprehensive curriculum vitae or similar document.
    (v) Notify each potential expert panel member that he or she must 
submit information relating to potential conflict of interest directly 
to FDA in a timely manner, as required in paragraph (e)(6) of this 
section.
    (2) The requestor must submit, in writing, the names and addresses 
of the proposed qualified expert panel members and sufficient 
information about each proposed member for FDA to determine whether the 
panel meets the selection criteria listed in paragraphs (b)(1) through 
(b)(5) of this section.
    (3) After FDA has determined that the qualified expert panel meets 
the selection criteria, the requestor must provide to the panel all 
information known by the requestor that is relevant to a determination 
of the target animal safety and the effectiveness of the new animal 
drug at issue. In addition, the requestor must notify FDA of the name 
of the qualified expert panel leader.
    (4) The requestor must immediately notify FDA if it believes a 
qualified expert panel member no longer meets the selection criteria 
listed in paragraph (b) of this section or is otherwise not in 
compliance with the requirements of this section.
    (5) If a qualified expert panel member cannot complete the review 
for which he or she was selected, the requestor must either choose a 
replacement or justify the continued work of the panel in the absence 
of the lost panelist. In either case, the requestor must submit 
sufficient information for FDA to determine whether the proposed 
revised qualified expert panel meets the selection criteria listed in 
paragraphs (b)(1) through (b)(5) of this section.
    (6) The requestor must keep copies of all information provided to, 
or received from, qualified expert panel members, including the written 
report, for 2 years after the completion of the report, or the product 
is added to the index, whichever occurs later, and make them available 
to a duly authorized employee of the agency at all reasonable times.
    (d) FDA responsibilities. (1) FDA will determine whether the 
requestor's proposed qualified expert panel meets the selection 
criteria listed in paragraph (b) of this section. FDA will 
expeditiously inform the requestor, in writing, of its determination. 
If FDA determines that the qualified expert panel does not meet the 
selection criteria, FDA will provide due notice and an opportunity for 
an informal conference as described in Sec.  516.123. A determination 
by FDA that a proposed qualified expert panel does not meet the 
selection criteria following an informal conference shall constitute 
final agency action subject to judicial review.
    (2) If FDA determines that a qualified expert panel no longer meets 
the selection criteria listed in paragraph (b) of this section or that 
the panel or its members are not in compliance with the requirements of 
this section, the agency will expeditiously inform the requestor, in 
writing, of this determination and provide due notice and an 
opportunity for an informal conference as described in Sec.  516.123. A 
determination by FDA, following an informal conference, that a 
qualified expert panel no longer meets the selection criteria listed in 
paragraph (b) of this section or that the panel or its members are not 
in compliance with the requirements of this section shall constitute 
final agency action subject to judicial review.
    (e) Responsibilities of a qualified expert panel member. A 
qualified expert panel member must do the following:
    (1) Continue to meet all selection criteria described in paragraph 
(b) of this section.
    (2) Act in accordance with generally accepted professional and 
ethical business practices.
    (3) Review all information relevant to a determination of the 
target animal safety and effectiveness of the new animal drug provided 
by the requestor. The panel should also consider all relevant 
information otherwise known by the panel members, including anecdotal 
information.
    (4) Participate in the preparation of the written report of the 
findings of the qualified expert panel, described in Sec.  516.143.
    (5) Sign, or otherwise approve in writing, the written report. Such 
signature or other written approval will serve as certification that 
the written report meets the requirements of the written report in 
Sec.  516.143.
    (6) Provide the information relating to potential conflict of 
interest described in paragraph (g) of this section to FDA for its 
consideration. Such information should be submitted directly to the 
Director, OMUMS, when notified by the requestor.
    (7) Immediately notify the requestor and FDA of any change in 
conflict of interest status.
    (8) Certify at the time of submission of the written report that 
there has been

[[Page 69126]]

no change in conflict of interest status, or identify and document to 
FDA any such change.
    (f) Additional responsibilities of a qualified expert panel leader. 
(1) The qualified expert panel leader must ensure that the activities 
of the panel are performed efficiently and in accordance with generally 
accepted professional and ethical business practices.
    (2) The qualified expert panel leader serves as the principal point 
of contact between representatives of the agency and the panel.
    (3) The qualified expert panel leader is responsible for submitting 
the written report and all notes or minutes relating to panel 
deliberations to the requestor.
    (4) The qualified expert panel leader must maintain a copy of the 
written report and all notes or minutes relating to panel deliberations 
that are submitted to the requestor for 2 years after the report is 
submitted. Such records must be made available to a duly authorized 
employee of the agency for inspection at all reasonable times.
    (g) Prevention of conflicts of interest. (1) For the purposes of 
this subpart, FDA will consider a conflict of interest to be any 
financial or other interest that could impair a person's objectivity in 
serving on the qualified expert panel or could create an unfair 
competitive advantage for a person or organization.
    (2) Factors relevant to whether there is a conflict of interest or 
the appearance of a conflict of interest include whether the qualified 
expert panel member, their spouse, their minor children, their general 
partners, or any organizations in which they serve as an officer, 
director, trustee, general partner or employee:
    (i) Is currently receiving or seeking funding from the requestor 
through a contract or research grant (either directly or indirectly 
through another entity, such as a university).
    (ii) Has any employment, contractual, or other financial 
arrangement with the requestor other than receiving a reasonable fee 
for serving as a member of the qualified expert panel.
    (iii) Has any ownership or financial interest in any drug, drug 
manufacturer, or drug distributor which will benefit from either a 
favorable or unfavorable evaluation or opinion.
    (iv) Has any ownership or financial interest in the new animal drug 
being reviewed by the qualified expert panel.
    (v) Has participated in the design, manufacture, or distribution of 
any drug that will benefit from either a favorable or unfavorable 
opinion of the qualified expert panel.
    (vi) Has provided within 1 year any consultative services regarding 
the new animal drug being reviewed by the qualified expert panel.
    (vii) Has entered into an agreement in which fees charged or 
accepted are contingent upon the panel member making a favorable 
evaluation or opinion.
    (viii) Receives payment for services related to preparing 
information the requestor presents to the qualified expert panel, other 
than for services related to the written report described in Sec.  
516.143.
    (3) To permit FDA to make a decision regarding potential conflict 
of interest, a potential qualified expert panel member must submit to 
the Director, OMUMS, the following information relating to themselves, 
their spouse, their minor children, their general partners, or any 
organizations in which they serve as an officer, director, trustee, 
general partner or employee, regarding the following issues to the 
extent that they are, in any way, relevant to the subject of the review 
of the qualified expert panel:
    (i) Investments (for example, stocks, bonds, retirement plans, 
trusts, partnerships, sector funds, etc.), including for each the 
following: Name of the firm, type of investment, owner (self, spouse, 
etc.), number of shares / current value.
    (ii) Employment (full or part time, current or under negotiation), 
including for each the following: Name of the firm, relationship (self, 
spouse, etc.), position in firm, date employment or negotiation began.
    (iii) Consultant/advisor (current or under negotiation), including 
for each the following: Name of the firm, topic/issue, amount received, 
date initiated.
    (iv) Contracts, grants, Cooperation Research and Development 
Agreement (CRADAs) (current or under negotiation), including for each 
the following: Type of agreement, product under study and indications, 
amount of remuneration (institution/self), time period, sponsor 
(government, firm, institution, individual), role of the person (site 
investigator, principal investigator, co-investigator, partner, no 
involvement, other), awardee.
    (v) Patents/royalties/trademarks, including for each the following: 
Description, name of firm involved, income received.
    (vi) Expert witness (last 12 months or under negotiation), 
including for each the following: For or against, name of firm, issue, 
amount received.
    (vii) Speaking/writing (last 12 months or under negotiation), 
including for each the following: Firm, topic/issue, amount received 
(honorarium/travel), date.
    (viii) Whether the potential qualified expert panel member, their 
spouse, their minor children, their general partners or any 
organizations in which they serve as an officer, director, trustee, 
general partner or employee, have had, at any time in the past, 
involvement of the kind noted in paragraph (g)(3)(i) through 
(g)(3)(vii) of this section with respect to the animal drug that is the 
subject of the qualified expert panel review.
    (ix) Whether there are any other involvements (other kinds of 
relationships) that would give the appearance of a conflict of interest 
which have not been described in paragraph (g)(3)(i) through 
(g)(3)(viii) of this section.
    (x) In all cases, a response of ``no,'' ``none,'' or ``not 
applicable'' is satisfactory when there is no relevant information to 
submit.
    (xi) A certification statement signed by the potential qualified 
expert panel member to the effect that all information submitted is 
true and complete to the best of their knowledge, that they have read 
and understood their obligations as an expert panel member, and that 
they will notify FDA and the requestor of any change in their conflict 
of interest status.
    (4) The fact that a qualified expert panel member receives a 
reasonable fee for services as a member of the qualified expert panel, 
provided that the fee is no more than commensurate with the value of 
the time that the member devotes to the review process, does not 
constitute a conflict of interest or the appearance of a conflict of 
interest.


Sec.  516.143  Written report.

    The written report required in Sec.  516.145(b)(3) shall:
    (a) Be written in English by a qualified expert panel meeting the 
requirements of Sec.  516.141;
    (b) Describe the panel's evaluation of all available target animal 
safety and effectiveness information relevant to the proposed use of 
the new animal drug, including anecdotal information;
    (c) For all information considered, including anecdotal 
information, include either a citation to published literature or a 
summary of the information;
    (d) State the panel's opinion regarding whether the benefits of 
using the new animal drug for the proposed use in a minor species 
outweigh its risks to the target animal, taking into account the harm 
being caused by the absence of an approved or conditionally-approved 
new animal drug for the minor species in question;
    (e) Be signed, or otherwise approved in writing, by all panel 
members, in accordance with Sec.  516.141; and

[[Page 69127]]

    (f) If the panel unanimously concludes that the benefits of using 
the new animal drug for the proposed use in a minor species outweigh 
its risks to the target animal, taking into account the harm being 
caused by the absence of an approved or conditionally-approved new 
animal drug for the minor species in question, the written report 
shall:
    (1) Provide draft labeling that includes all conditions of use and 
limitations of use of the new animal drug deemed necessary by the panel 
to assure that the benefits of use of the new animal drug outweigh the 
risks, or provide narrative information from which such labeling can be 
written by the requestor; and
    (2) Include a recommendation regarding whether the new animal drug 
should be limited to use under the professional supervision of a 
licensed veterinarian.


Sec.  516.145  Content and format of a request for addition to the 
index.

    (a) A requestor may request addition of a new animal drug to the 
index only after the new animal drug has been granted eligibility for 
indexing.
    (b) A requestor shall submit two copies of a dated request signed 
by the authorized contact for addition of a new animal drug to the 
index that contains the following:
    (1) A copy of FDA's determination of eligibility issued under Sec.  
516.137;
    (2) A copy of FDA's written determination that the proposed 
qualified expert panel meets the selection criteria provided for in 
Sec.  516.141(b);
    (3) A written report that meets the requirements of Sec.  516.143;
    (4) A proposed index entry that contains the information described 
in Sec.  516.157;
    (5) Proposed labeling, including representative labeling proposed 
to be used for Type B and Type C medicated feeds if the drug is 
intended for use in the manufacture of medicated feeds;
    (6) Anticipated annual distribution of the new animal drug, in 
terms of the total quantity of active ingredient, after indexing;
    (7) A written commitment to manufacture the new animal drug and 
animal feeds bearing or containing such new animal drug according to 
current good manufacturing practices;
    (8) A written commitment to label, distribute, and promote the new 
animal drug only in accordance with the index entry;
    (9) The name and address of the contact person or permanent-
resident U.S. agent; and
    (10) A draft Freedom of Information summary which includes the 
following information:
    (i) A general information section that contains the name and 
address of the requestor and a description of the drug, route of 
administration, indications, and recommended dosage.
    (ii) A list of the names and affiliations of the members of the 
qualified expert panel, not including their addresses or other contact 
information.
    (iii) A summary of the findings of the qualified expert panel 
concerning the target animal safety and effectiveness of the drug.
    (iv) Citations of all publicly-available literature considered by 
the qualified expert panel.
    (v) For an early life stage of a food-producing minor species 
animal, a human food safety summary.
    (c) Upon specific request by FDA, the requestor shall submit the 
information described in Sec.  516.141 that it submitted to the 
qualified expert panel. Any such information not in English should be 
accompanied by an English translation.


Sec.  516.147  Refuse to file a request for addition to the index.

    (a) If a request for addition to the index contains all of the 
information required by Sec.  516.145(b), FDA shall file it, and the 
filing date shall be the date FDA receives the request.
    (b) If a request for addition to the index lacks any of the 
information required by Sec.  516.145, FDA will not file it, but will 
inform the requestor in writing within 30 days of receiving the request 
as to what information is lacking.


Sec.  516.149  Denying a request for addition to the index.

    (a) FDA will deny a request for addition to the index if it finds 
the following:
    (1) The same drug in the same dosage form for the same intended use 
is already approved or conditionally approved;
    (2) On the basis of new information, the new animal drug no longer 
meets the conditions for eligibility for indexing;
    (3) The request for indexing fails to contain information required 
under the provisions of Sec.  516.145;
    (4) The qualified expert panel fails to meet any of the selection 
criteria listed in Sec.  516.141(b);
    (5) The written report of the qualified expert panel and other 
information available to FDA is insufficient to permit FDA to determine 
that the benefits of using the new animal drug for the proposed use in 
a minor species outweigh its risks to the target animal, taking into 
account the harm caused by the absence of an approved or conditionally-
approved new animal drug for the minor species in question;
    (6) On the basis of the report of the qualified expert panel and 
other information available to FDA, the benefits of using the new 
animal drug for the proposed use in a minor species do not outweigh its 
risks to the target animal, taking into account the harm caused by the 
absence of an approved or conditionally-approved new animal drug for 
the minor species in question; or
    (7) The request contains any untrue statement of a material fact or 
omits material information.
    (b) When a request for addition to the index is denied, FDA will 
notify the requestor in accordance with Sec.  516.153.


Sec.  516.151  Granting a request for addition to the index.

    (a) FDA will grant the request for addition of a new animal drug to 
the index if none of the reasons described in Sec.  516.149 for denying 
such a request applies.
    (b) When a request for addition of a new animal drug to the index 
is granted, FDA will notify the requestor in accordance with Sec.  
516.153.


Sec.  516.153  Notification of decision regarding index listing.

    (a) Within 180 days after the filing of a request for addition of a 
new animal drug to the index, FDA shall grant or deny the request and 
notify the requestor of FDA's decision in writing.
    (b) If FDA denies the request for addition of a new animal drug to 
the index, FDA shall provide due notice and an opportunity for an 
informal conference as described in Sec.  516.123. A decision of FDA to 
deny a request to index a new animal drug following an informal 
conference shall constitute final agency action subject to judicial 
review.


Sec.  516.155  Labeling of indexed drugs.

    (a) The labeling of an indexed drug that is found to be eligible 
for indexing under Sec.  516.129(c)(7)(i) shall state, prominently and 
conspicuously: ``NOT APPROVED BY FDA.--Legally marketed as an FDA 
indexed product. Extra-label use is prohibited.'' ``This product is not 
to be used in animals intended for use as food for humans or other 
animals.''
    (b) The labeling of an indexed drug that was found to be eligible 
for indexing for use in an early, non-food life stage of a food-
producing minor species animal, under Sec.  516.129(c)(7)(ii), shall 
state, prominently and

[[Page 69128]]

conspicuously: ``NOT APPROVED BY FDA.--Legally marketed as an FDA 
indexed product. Extra-label use is prohibited.''
    (c) The labeling of an indexed drug shall contain such other 
information as may be prescribed in the index listing.


Sec.  516.157  Publication of the index and content of an index 
listing.

    (a) FDA will make the list of indexed drugs available through the 
FDA Web site. A printed copy can be obtained by writing to the FDA 
Freedom of Information Staff or by visiting the FDA Freedom of 
Information Public Reading Room.
    (b) The list will contain the following information for each 
indexed drug:
    (1) The name and address of the person who holds the index listing;
    (2) The name of the drug and the intended use and conditions of use 
for which it is indexed;
    (3) Product labeling; and
    (4) Conditions and any limitations that FDA deems necessary 
regarding use of the drug.


Sec.  516.161  Modifications to indexed drugs.

    (a) After a drug is listed in the index, certain modifications to 
the index listing may be requested. Any modification of an index 
listing may not cause an indexed drug to be a different drug (or 
different combination of drugs) or a different dosage form. If such 
modification is requested, FDA will notify the holder that a new index 
listing is required for the new drug or dosage form.
    (b) Modifications to the indexed drug will fall under one of three 
categories and must be submitted as follows:
    (1) Urgent changes. (i) The following modifications to an indexed 
drug or its labeling should be made as soon as possible, and a request 
to modify the indexed drug should be concurrently submitted:
    (A) The addition to package labeling, promotional labeling, or 
prescription drug advertising of additional warning, contraindication, 
side effect, or cautionary information.
    (B) The deletion from package labeling, promotional labeling, and 
drug advertising of false, misleading, or unsupported indications for 
use or claims for effectiveness.
    (C) Changes in manufacturing methods or controls required to 
correct product or manufacturing defects that may result in serious 
adverse drug events.
    (ii) The modifications described in paragraph (b)(1)(i) of this 
section must be submitted to the Director, OMUMS, in the form of a 
request for modification of an indexed drug, and must contain 
sufficient information to permit FDA to determine the need for the 
modification and whether the modification appropriately addresses the 
need.
    (iii) FDA will take no action against an indexed drug or index 
holder solely because modifications of the kinds described in paragraph 
(b)(1)(i) of this section are placed into effect by the holder prior to 
receipt of a written notice granting the request if all the following 
conditions are met:
    (A) A request to modify the indexed drug providing a full 
explanation of the basis for the modifications has been submitted, 
plainly marked on the mailing cover and on the request as follows: 
``Special indexing request-- modifications being effected;''
    (B) The holder specifically informs FDA of the date on which such 
modifications are to be effected and submits two printed copies of any 
revised labeling to be placed in use, and
    (C) All promotional labeling and all drug advertising are promptly 
revised consistent with modifications made in the labeling on or within 
the indexed drug package.
    (2) Significant changes. (i) The following modifications to an 
indexed drug or its labeling may be made only after a request has been 
submitted to and subsequently granted by FDA:
    (A) Addition of an intended use.
    (B) Addition of a species.
    (C) Addition or alteration of an active ingredient.
    (D) Alteration of the concentration of an active ingredient.
    (E) Alteration of dose or dosage regimen.
    (F) Alteration of prescription or over-the-counter status.
    (ii) Each modification described in paragraph (b)(2)(i) of this 
section must go through the same review process as an original index 
listing and is subject to the same standards for review.
    (iii) Each submission of a request for a modification described in 
paragraph (b)(2)(i) of this section should contain only one type of 
modification unless one modification is actually necessitated by 
another, such as a modification of dose necessitated by a modification 
of the concentration of an active ingredient. Submissions relating to 
addition of an intended use for an existing species or addition of a 
species should be submitted separately, but each such submission may 
include multiple additional intended uses and/or multiple additional 
species.
    (3) Minor changes. All modifications other than those described in 
paragraphs (b)(1) and (b)(2) of this section including, but not limited 
to, formulation, labeling, and manufacturing methods and controls (at 
the same level of detail that these were described in the request for 
determination of eligibility for indexing) must be submitted as part of 
the annual indexed drug experience report or as otherwise required by 
Sec.  516.165.
    (c) When changes affect the index listing, it will be updated 
accordingly.


Sec.  516.163  Change in ownership of an index file.

    (a) A holder may transfer ownership of a drug's index file to 
another person.
    (1) The former owner shall submit in writing to FDA a statement 
that all rights in the index file have been transferred, giving the 
name and address of the new owner and the date of the transfer. The 
former owner shall also certify that a complete copy of the following, 
to the extent that they exist at the time of the transfer of ownership, 
has been provided to the new owner:
    (i) The request for determination of eligibility;
    (ii) The request for addition to the index;
    (iii) Any modifications to the index listing;
    (iv) Any records and reports under Sec.  516.165; and
    (v) All correspondence with FDA relevant to the indexed drug and 
its index listing.
    (2) The new owner shall submit the following information in writing 
to FDA:
    (i) The date that the change in ownership is effective;
    (ii) A statement that the new owner has a complete copy of all 
documents listed in paragraph (a)(1) of this section to the extent that 
they exist at the time of the transfer of ownership;
    (iii) A statement that the new owner understands and accepts the 
responsibilities of a holder of an indexed drug;
    (iv) The name and address of a new primary contact person or 
permanent-resident U.S. agent; and
    (v) A list of labeling changes associated with the change of 
ownership (e.g., a new trade name) as draft labeling, with complete 
final printed labeling to be submitted in the indexed drug annual 
report in accordance with Sec. Sec.  516.161 and 516.165.
    (b) Upon receiving the necessary information to support a change of 
ownership of a drug's index file, FDA will update its publicly-
available listing in accordance with Sec.  516.157.


Sec.  516.165  Records and reports.

    (a) Scope and purpose. (1) The recordkeeping and reporting

[[Page 69129]]

requirements of this section apply to all holders of indexed drugs, 
including indexed drugs intended for use in medicated feeds.
    (2) A holder is not required to report information under this 
section if the holder has reported the same information under Sec.  
514.80 of this chapter.
    (3) The records and reports referred to in this section are in 
addition to those required by the current good manufacturing practice 
regulations in parts 211, 225, and 226 of this chapter.
    (4) FDA will review the records and reports required in this 
section to determine, or facilitate a determination, whether there may 
be grounds for removing a drug from the index under section 572(f) of 
the act.
    (b) Recordkeeping requirements. (1) Each holder of an indexed drug 
must establish and maintain complete files containing full records of 
all information pertinent to the safety or effectiveness of the indexed 
drug. Such records must include information from foreign and domestic 
sources.
    (2) The holder must, upon request from any authorized FDA officer 
or employee, at all reasonable times, permit such officer or employee 
to have access to copy and to verify all such records.
    (c) Reporting requirements. (1) Three-day indexed drug field alert 
report. The holder must inform the appropriate FDA District Office or 
local FDA resident post of any product or manufacturing defects that 
may result in serious adverse drug events within 3 working days of 
first becoming aware that such a defect may exist. The holder may 
initially provide this information by telephone or other electronic 
communication means, with prompt written followup. The mailing cover 
must be plainly marked ``3-Day Indexed Drug Field Alert Report.''
    (2) Fifteen-day indexed drug alert report. The holder must submit a 
report on each serious, unexpected adverse drug event, regardless of 
the source of the information. The holder must submit the report within 
15 working days of first receiving the information. The mailing cover 
must be plainly marked ``15-Day Indexed Drug Alert Report.''
    (3) Annual indexed drug experience report. The holder must submit 
this report every year on the anniversary date of the letter granting 
the request for addition of the new animal drug to the index, or within 
60 days thereafter. The report must contain data and information for 
the full reporting period. Any previously submitted information 
contained in the report must be identified as such. The holder may ask 
FDA to change the date of submission and, after approval of such 
request, file such reports by the new filing date. The report must 
contain the following:
    (i) The number of distributed units of each size, strength, or 
potency (e.g., 100,000 bottles of 100 5-milligram tablets; 50,000 10-
milliliter vials of 5- percent solution) distributed during the 
reporting period. This information must be presented in two categories: 
Quantities distributed domestically and quantities exported. This 
information must include any distributor-labeled product.
    (ii) If the labeling has changed since the last report, include a 
summary of those changes and the holder's and distributor's current 
package labeling, including any package inserts. For large-size package 
labeling or large shipping cartons, submit a representative copy (e.g., 
a photocopy of pertinent areas of large feed bags). If the labeling has 
not changed since the last report, include a statement of such fact.
    (iii) A summary of any changes made during the reporting period in 
the methods used in, and facilities and controls used for, manufacture, 
processing, and packing. This information must be presented in the same 
level of detail that it was presented in the request for determination 
of eligibility for indexing. Do not include changes that have already 
been submitted under Sec.  516.161.
    (iv) Nonclinical laboratory studies and clinical data not 
previously reported under this section.
    (v) Adverse drug experiences not previously reported under this 
section.
    (vi) Any other information pertinent to safety or effectiveness of 
the indexed drug not previously reported under this section.
    (4) Distributor's statement. At the time of initial distribution of 
an indexed drug by a distributor, the holder must submit a report 
containing the following:
    (i) The distributor's current product labeling. This must be 
identical to that in the index listing except for a different and 
suitable proprietary name (if used) and the name and address of the 
distributor. The name and address of the distributor must be preceded 
by an appropriate qualifying phrase such as ``manufactured for'' or 
``distributed by.''
    (ii) A signed statement by the distributor stating:
    (A) The category of the distributor's operations (e.g., wholesale 
or retail);
    (B) That the distributor will distribute the drug only under the 
indexed drug labeling;
    (C) That the distributor will promote the indexed drug only for use 
under the conditions stated in the index listing; and
    (D) If the indexed drug is a prescription new animal drug, that the 
distributor is regularly and lawfully engaged in the distribution or 
dispensing of prescription products.
    (5) Other reporting. FDA may by order require that a holder submit 
information in addition to that required by this section or that the 
holder submit the same information but at different times or reporting 
periods.


Sec.  516.167  Removal from the index.

    (a) After due notice to the holder of the index listing and an 
opportunity for an informal conference as described in Sec.  516.123, 
FDA shall remove a new animal drug from the index if FDA finds that:
    (1) The same drug in the same dosage form for the same intended use 
has been approved or conditionally approved;
    (2) The expert panel failed to meet the requirements in Sec.  
516.141;
    (3) On the basis of new information before FDA, evaluated together 
with the evidence available to FDA when the new animal drug was listed 
in the index, the benefits of using the new animal drug for the indexed 
use do not outweigh its risks to the target animal, taking into account 
the harm caused by the absence of an approved or conditionally-approved 
new animal drug for the minor species in question;
    (4) Any of the conditions in Sec.  516.133(a)(2), (5), or (6) are 
present;
    (5) The manufacture of the new animal drug is not in accordance 
with current good manufacturing practices;
    (6) The labeling, distribution, or promotion of the new animal drug 
is not in accordance with the index listing;
    (7) The conditions and limitations of use associated with the index 
listing have not been followed; or
    (8) Any information used to support the request for addition to the 
index contains any untrue statement of material fact.
    (b) The agency may partially remove an indexing listing if, in the 
opinion of the agency, such partial removal would satisfactorily 
resolve a safety or effectiveness issue otherwise warranting removal of 
the listing under section 572(f)(1)(B) of the act.
    (c) FDA may immediately suspend a new animal drug from the index if 
FDA determines that there is a reasonable probability that the use of 
the drug would present a risk to the health of humans or other animals. 
The agency will subsequently provide due notice and an opportunity for 
an informal conference as described in Sec.  516.123.
    (d) A decision of FDA to remove a new animal drug from the index

[[Page 69130]]

following an informal conference, if any, shall constitute final agency 
action subject to judicial review.


Sec.  516.171  Confidentiality of data and information in an index 
file.

    (a) For purposes of this section, the index file includes all data 
and information submitted to or incorporated by reference into the 
index file, such as data and information related to investigational use 
exemptions under Sec.  516.125, requests for determination of 
eligibility for indexing, requests for addition to the index, 
modifications to indexed drugs, changes in ownership, reports submitted 
under Sec.  516.165, and master files. The availability for public 
disclosure of any record in the index file shall be handled in 
accordance with the provisions of this section.
    (b) The existence of an index file will not be disclosed by FDA 
before an index listing has been made public by FDA, unless it has 
previously been publicly disclosed or acknowledged by the requestor.
    (c) If the existence of an index file has not been publicly 
disclosed or acknowledged, no data or information in the index file are 
available for public disclosure.
    (d) If the existence of an index file has been publicly disclosed 
or acknowledged before an index listing has been made public by FDA, no 
data or information contained in the file will be available for public 
disclosure before such index listing is made public, but the agency 
may, at its discretion, disclose a brief summary of such selected 
portions of the safety and effectiveness data as are appropriate for 
public consideration of a specific pending issue, e.g., at an open 
session of a Food and Drug Administration advisory committee or 
pursuant to an exchange of important regulatory information with a 
foreign government.
    (e) After FDA sends a written notice to the requestor granting a 
request for addition to the index, the following data and information 
in the index file are available for public disclosure unless 
extraordinary circumstances are shown:
    (1) All safety and effectiveness data and information previously 
disclosed to the public, as defined in Sec.  20.81 of this chapter.
    (2) A summary or summaries of the safety and effectiveness data and 
information submitted with or incorporated by reference in the index 
file. Such summaries do not constitute the full information described 
under section 572(c) and (d) of the act on which the safety or 
effectiveness of the drug may be determined. Such summaries will be 
based on the draft Freedom of Information summary submitted under Sec.  
516.145, which will be reviewed and, where appropriate, revised by FDA.
    (3) A protocol for a test or study, unless it is shown to fall 
within the exemption established for trade secrets and confidential 
commercial information in Sec.  20.61 of this chapter.
    (4) Adverse reaction reports, product experience reports, consumer 
complaints, and other similar data and information, after deletion of 
the following:
    (i) Names and any information that would identify the person using 
the product.
    (ii) Names and any information that would identify any third party 
involved with the report, such as a veterinarian.
    (5) A list of all active ingredients and any inactive ingredients 
previously disclosed to the public as defined in Sec.  20.81 of this 
chapter.
    (6) An assay method or other analytical method, unless it serves no 
regulatory or compliance purpose and is shown to fall within the 
exemption established in Sec.  20.61 of this chapter.
    (7) All correspondence and written summaries of oral discussions 
relating to the index file, in accordance with the provisions of part 
20 of this chapter.
    (f) The following data and information in an index file are not 
available for public disclosure unless they have been previously 
disclosed to the public as defined in Sec.  20.81 of this chapter, or 
they relate to a product or ingredient that has been abandoned and they 
no longer represent a trade secret or confidential commercial or 
financial information as defined in Sec.  20.61 of this chapter:
    (1) Manufacturing methods or processes, including quality control 
procedures.
    (2) Production, sales, distribution, and similar data and 
information, except that any compilation of such data and information 
aggregated and prepared in a way that does not reveal data or 
information which is not available for public disclosure under this 
provision is available for public disclosure.
    (3) Quantitative or semiquantitative formulas.
    (g) Subject to the disclosure provisions of this section, the 
agency shall regard the contents of an index file as confidential 
information unless specifically notified in writing by the holder of 
the right to disclose, to reference, or otherwise utilize such 
information on behalf of another named person.
    (h) For purposes of this regulation, safety and effectiveness data 
include all studies and tests of an animal drug on animals and all 
studies and tests on the animal drug for identity, stability, purity, 
potency, and bioavailability.
    (i) Safety and effectiveness data and information that have not 
been previously disclosed to the public are available for public 
disclosure at the time any of the following events occurs unless 
extraordinary circumstances are shown:
    (1) No work is being or will be undertaken to have the drug indexed 
in accordance with the request.
    (2) A final determination is made that the drug cannot be indexed 
and all legal appeals have been exhausted.
    (3) The drug has been removed from the index and all legal appeals 
have been exhausted.
    (4) A final determination has been made that the animal drug is not 
a new animal drug.

PART 558-- NEW ANIMAL DRUGS FOR USE IN ANIMAL FEEDS

0
36. The authority citation for 21 CFR part 558 continues to read as 
follows:

    Authority: 21 U.S.C. 360b, 371.

0
37. Amend Sec.  558.3 by revising the last sentence of paragraph (b)(2) 
and revising paragraphs (b)(5), (b)(6), and (b)(7) to read as follows:


Sec.  558.3  Definitions and general considerations applicable to this 
part.

* * * * *
    (b) * * *
    (2) * * * The manufacture of a Type A medicated article requires an 
application approved under Sec.  514.105 of this chapter or an index 
listing granted under Sec.  516.151 of this chapter.
* * * * *
    (5) A Type B or Type C medicated feed manufactured from a drug 
component (bulk or ``drum-run'' (dried crude fermentation product)) 
requires an application approved under Sec.  514.105 of this chapter or 
an index listing granted under Sec.  516.151 of this chapter.
    (6) A ``veterinary feed directive (VFD) drug'' is a new animal drug 
approved under section 512(b) of the Federal Food, Drug, and Cosmetic 
Act (the act) or listed in the index under section 572 of the act for 
use in or on animal feed. Use of a VFD drug must be under the 
professional supervision of a licensed veterinarian.
    (7) A ``veterinary feed directive'' is a written statement issued 
by a licensed veterinarian in the course of the veterinarian's 
professional practice that orders the use of a VFD drug in or on an 
animal feed. This written statement authorizes the client (the owner of 
the

[[Page 69131]]

animal or animals or other caretaker) to obtain and use the VFD drug in 
or on an animal feed to treat the client's animals only in accordance 
with the directions for use approved or indexed by the Food and Drug 
Administration (FDA). A veterinarian may issue a VFD only if a valid 
veterinarian-client-patient relationship exists, as defined in Sec.  
530.3(i) of this chapter.
* * * * *

0
38. Amend Sec.  558.5 by revising paragraphs (c) and (d) to read as 
follows:


Sec.  558.5  Requirements for liquid medicated feed.

* * * * *
    (c) What is required for new animal drugs intended for use in 
liquid feed? Any new animal drug intended for use in liquid feed must 
be approved for such use under section 512 of the Federal Food, Drug, 
and Cosmetic Act (the act) or index listed under section 572 of the 
act. Such approvals under section 512 of the act must be:
    (1) An original NADA,
    (2) A supplemental NADA, or
    (3) An abbreviated NADA.
    (d) What are the approval requirements under section 512 of the act 
for new animal drugs intended for use in liquid feed? An approval under 
section 512 of the act for a new animal drug intended for use in liquid 
feed must contain the following information:
    (1) Data, or a reference to data in a master file (MF), that shows 
the relevant ranges of conditions under which the drug will be 
chemically stable in liquid feed under field use conditions; and
    (2) Data, or a reference to data in an MF, that shows that the drug 
is physically stable in liquid feed under field conditions; or
    (3) Feed labeling with recirculation or agitation directions as 
follows:
    (i) For liquid feeds stored in recirculating tank systems: 
Recirculate immediately prior to use for not less than 10 minutes, 
moving not less than 1 percent of the tank contents per minute from the 
bottom of the tank to the top. Recirculate daily as described even when 
not used.
    (ii) For liquid feeds stored in mechanical, air, or other 
agitation-type tank systems: Agitate immediately prior to use for not 
less than 10 minutes, creating a turbulence at the bottom of the tank 
that is visible at the top. Agitate daily as described even when not 
used.
* * * * *

0
39. Amend Sec.  558.6 by revising paragraphs (a)(4)(iv) and (a)(6) to 
read as follows:


Sec.  558.6  Veterinary feed directive drugs.

    (a) * * *
    (4) * * *
    (iv) Approved or index listed indications for use.
* * * * *
    (6) You must issue a VFD only for the approved or indexed 
conditions and indications for use of the VFD drug.
* * * * *

PART 589--SUBSTANCES PROHIBITED FROM USE IN ANIMAL FOOD OR FEED

0
40. The authority citation for 21 CFR part 589 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 342, 343, 348, 371.

0
41. Revise Sec.  589.1000 to read as follows:


Sec.  589.1000  Gentian violet.

    The Food and Drug Administration has determined that gentian violet 
has not been shown by adequate scientific data to be safe for use in 
animal feed. Use of gentian violet in animal feed causes the feed to be 
adulterated and in violation of the Federal Food, Drug, and Cosmetic 
Act (the act), in the absence of a regulation providing for its safe 
use as a food additive under section 409 of the act, unless it is 
subject to an effective notice of claimed investigational exemption for 
a food additive under Sec.  570.17 of this chapter, or unless the 
substance is intended for use as a new animal drug and is subject to an 
approved application under section 512 of the act, or an index listing 
under section 572 of the act, or an effective notice of claimed 
investigational exemption for a new animal drug under part 511 of this 
chapter or Sec.  516.125 of this chapter.

    Dated: November 27, 2007.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E7-23580 Filed 12-5-07; 8:45 am]
BILLING CODE 4160-01-S