[Federal Register Volume 71, Number 162 (Tuesday, August 22, 2006)]
[Proposed Rules]
[Pages 48840-48864]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 06-7070]
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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: Proposed rule.
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[[Page 48841]]
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 proposed regulations
to implement section 572 of the act entitled ``Index of Legally
Marketed Unapproved New Animal Drugs for Minor Species.'' These
regulations propose 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: Submit written or electronic comments on this document by
November 20, 2006. Interested persons are requested to submit comments
on the information collection provisions by September 21, 2006.
ADDRESSES: You may submit comments, identified by [Docket No. 2006N-
0067 and/RIN number 0910-AF67], by any of the following methods:
Electronic Submissions
Submit electronic comments in the following ways:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.
Agency Web site: http://www.fda.gov/dockets/ecomments.
Follow the instructions for submitting comments on the agency Web site.
Written Submissions
Submit written submissions in the following ways:
FAX: 301-827-6870.
Mail/Hand delivery/Courier [For paper, disk, or CD-ROM
submissions]: Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
To ensure more timely processing of comments, FDA is no longer
accepting comments submitted to the agency by e-mail. FDA encourages
you to continue to submit electronic comments by using the Federal
eRulemaking Portal or the agency Web site, as described in the
Electronic Submissions portion of this paragraph.
Instructions: All submissions received must include the agency name
and Docket No(s). and Regulatory Information Number (RIN) for this
rulemaking. All comments received may be posted without change to
http://www.fda.gov/ohrms/dockets/default.htm, including any personal
information provided. For detailed instructions on submitting comments
and additional information on the rulemaking process, see the
``Comments'' heading of the SUPPLEMENTARY INFORMATION section of this
document.
Docket: For access to the docket to read background documents or
comments received, go to http://www.fda.gov/ohrms/dockets/default.htm
and insert the docket number(s), found in brackets in the heading of
this document, into the ``Search'' box and follow the prompts and/or go
to the Division of Dockets Management, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852.
To ensure that comments on the information collection are received,
OMB recommends that written comments be faxed to the Office of
Information and Regulatory Affairs, OMB, Attn: FDA Desk Officer, FAX:
202-395-6974.
FOR FURTHER INFORMATION CONTACT: Andrew Beaulieu, 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 proposed regulations
to implement the designation provision of the act on September 27, 2005
(70 FR 56394) (the designation proposed 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 proposed regulations to implement the
indexing provisions of the MUMS act. These regulations propose
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.
II. Proposed Regulations
A. Definitions (proposed Sec. 516.115).
Most of the proposed definitions are straightforward. The proposed
definition of ``qualified expert panel'' is drawn from the statutory
definition, given in section 572(d)(3) of the act. The proposed
definition of ``transgenic animal'' comes from the statutory
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definition, given in section 571(j) of the act (21 U.S.C. 360ccc). The
proposed definition of ``intended use'' is identical to one proposed
with respect to the designation proposed rule of September 27, 2005 (70
FR 56394). The designation proposed rule also included definitions for
the phrases ``same intended use,'' ``same drug,'' and ``same dosage
form'' that would be applicable to all subparts of part 516, including
the indexing regulations.
B. Permanent-resident U.S. agent for a foreign requestor (proposed
Sec. 516.119).
The proposed rule would require a foreign requestor or holder to
name a permanent-resident U.S. agent so that the agency may ensure that
notifications of decisions regarding indexing and all other
communications with the requestor or holder are legally and effectively
made.
C. Meetings (proposed Sec. 516.121)
The act provides that any person intending to file a request for
eligibility or a request for addition to the index may have an
opportunity to meet with the agency to discuss the requirements for
indexing a new animal drug.
D. Informal conferences regarding agency administrative actions
(proposed Sec. 516.123)
The act also provides that a requestor or holder be offered an
informal conference in association with an agency decision to deny a
request for a determination of eligibility to index, to deny a request
for index listing or to remove an index listing. Proposed Sec. 516.123
establishes the nature of and the procedures for requesting and
conducting such conferences. FDA would give notice of the grounds for
the initial decision and provide an opportunity to respond to that
decision. As proposed, the conference's presiding officer would not
have significantly participated in the initial decision, would prepare
a written summary of the informal conference to share with the
participants, and would issue a written report describing the basis for
his or her findings. The proposed regulation also provides for an
informal conference associated with a decision to terminate an
investigational exemption for a new animal drug proposed for indexing
or a decision not to affirm an expert panel because it does not meet
the selection criteria of Sec. 516.141. In the case of conferences
associated with adverse agency decisions, the proposed regulation
establishes that decisions to deny, remove, terminate, or not affirm
will be made by the Director, Office of Minor Use and Minor Species
Animal Drug Development (OMUMS) and a subsequent conference, if
requested, will be conducted by the Director, Center for Veterinary
Medicine or his designee, other than the Director, OMUMS. These
procedures were adapted from the process for holding regulatory
hearings before the agency under 21 CFR part 16.
E. Investigational use of new animal drugs to support indexing
(proposed Sec. 516.125).
As required by section 512(a)(1) of the act, a new animal drug may
not be legally marketed unless it is the subject of an approved New
Animal Drug Application (NADA), the subject of a conditionally approved
NADA, or on FDA's list of legally marketed unapproved new animal drugs.
The act contains two exemptions for drugs intended solely for
investigational use by experts qualified by scientific training and
experience to investigate the safety and effectiveness of drugs. The
first, in section 512(j) of the act, applies to new animal drugs
generally, including animal feeds bearing or containing new animal
drugs. FDA's regulations implementing this investigational use
exemption are at part 511 (21 CFR part 511). The second, in section
572(g) of the act, is parallel to the first exemption but is for the
purposes of indexing and applies only to minor species new animal
drugs, including animal feeds bearing or containing such new animal
drugs. Note that the coverage of these exemptions overlaps and,
therefore, in some circumstances an investigational use might qualify
for an exemption under either section 512(j) of the act or section
572(g) of the act.
Proposed Sec. 516.125 would implement section 572(g) of the act.
It states that certain investigational uses, although they involve a
minor species new animal drug, are nonetheless subject to part 511.
Such uses include investigations to demonstrate 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, to conduct an environmental
assessment under section 572(c)(1)(E) of the act, or to obtain approval
of a new animal drug application or abbreviated new animal drug
application under section 512(b) of the act. These investigational uses
would be required to be conducted under part 511 because, whether these
types of studies are conducted to support indexing or approval, the
agency would evaluate the study results using the same standards. Thus,
the agency believes it should apply the same substantive and procedural
requirements for these investigational uses for minor species new
animal drugs as it does for new animal drugs generally.
For other types of investigational uses, proposed Sec. 516.125
establishes separate exemption regulations, although they are very
similar to part 511. The agency believes the regulations should be
similar because of the similarity of the purpose and the language of
the two investigational use exemptions in the act. Proposed Sec.
516.125 states that, with certain modifications, part 511 applies to
minor species new animal drugs or animal feeds bearing or containing
such new animal drugs intended for investigational use for all other
purposes in support of a drug index listing (such as to demonstrate
target animal safety and effectiveness). Among the proposed
modifications is the need to specifically identify that the
investigational use is in support of index listing, which would be done
when labeling the drugs involved and when notifying the agency of the
claimed investigational exemption. Another modification is that FDA
would provide notice and an opportunity for an informal conference
before terminating an investigational use exemption. While part 511
provides for notice and an opportunity for a hearing under 21 CFR part
16 concerning whether the exemption should be terminated, the
administrative process in the proposed regulations reflects the fact
that section 572 of the act provides for an informal conference with
respect to other agency decisions regarding indexing, such as removal
of a new animal drug from the index. FDA does not believe it should
have an administrative process for terminating an investigational use
exemption relating to indexing that is different from the informal
conference process for other decisions relating to indexing.
F. Content and format of a request for determination of eligibility for
indexing (proposed Sec. 516.129).
To be added to the index, a new animal drug must meet certain
criteria. The act establishes what can be described as a two-part
regulatory decision-making process for determining whether these
criteria have been met. The first part in this regulatory process is
FDA's determination of whether the new animal drug is eligible for
indexing. This involves an evaluation of most of the indexing criteria,
with the major exceptions being target animal safety and effectiveness.
The second part
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includes the agency's determination of the suitability of the qualified
expert panel and a review of whether the new animal drug meets the
statutory criteria regarding target animal safety and effectiveness.
The determination of eligibility for indexing is initiated by a
request to the agency that must be accompanied by sufficient
information to permit the agency to make an informed decision regarding
the request. The information proposed by the agency to determine
eligibility for indexing, described in proposed Sec. 516.129(c), is
based on the requirements of 572(c)(1) of the act. The categories of
information are described below:
1. Food safety
The act allows the indexing of new animal drugs that are intended
for use in food-producing animals only in limited circumstances. The
new animal drug must be for use in an early, non-food life stage of a
minor species; it must be intended for use only in a hatchery, tank,
pond, or other similar contained man-made structure; and there must be
sufficient information to demonstrate food safety in accordance with
the standards of section 512(d) of the act (including, for an
antimicrobial new animal drug, with respect to antimicrobial
resistance).
When a new animal drug proposed for indexing is not intended for
use in an early life stage of a food-producing minor species animal,
the requestor must demonstrate that there is a reasonable certainty
that the minor species or edible products from the minor species will
not be consumed by humans or food-producing animals. For many minor
species, this should be as straightforward as an affirmation that the
species has never been traditionally consumed by humans and is not
subject to being used in the feed of food-producing animals. A new
animal drug intended for use in a wildlife species might be eligible
for indexing if it could be demonstrated that there is a reasonable
certainty that treated animals would not be subsequently harvested and
consumed by humans or food-producing animals.
Under the proposed rule, FDA would rely on its existing regulations
regarding the food safety standards of section 512(d) of the act, which
are in part 514 (21 CFR part 514) at Sec. 514.111, and be guided by
relevant policies and guidance such as FDA's Guidance for Industry
(GFI) 152.
2. Environmental assessments
Under the proposal, a request for eligibility would be required to
contain either an environmental assessment or sufficient information to
support a categorical exclusion from the requirement to prepare an
environmental assessment. The proposal would rely on the process and
the standards for environmental assessments that are already defined in
part 25 (21 CFR part 25). It would also amend part 25 to have
categorical exclusions relating to indexing that parallel those
relating to new animal drug approvals.
3. Occupational and user safety
As with new animal drug approvals, indexing includes a provision
for a demonstration of safety to individuals exposed to the new animal
drug during the drug's manufacture and use. FDA intends to rely on the
same user safety standards for both drug approval and drug indexing.
4. Chemistry, manufacturing, and control information
The required chemistry, manufacturing, and control information, and
the agency's review of that information, are much different for
indexing than they are for approval.
A request for a determination of eligibility for a new animal drug
for indexing must include ``information regarding'' the components and
composition of the involved drug (section 572(c)(1)(C) of the act) and
must also include ``a description'' of the methods used in, and the
facilities and controls used for, the manufacture, processing, and
packing of the new animal drug (section 572(c)(1)(D) of the act) for
the purpose of determining whether the requestor has an understanding
of current Good Manufacturing Practices (cGMPs) and has established
appropriate specifications for the manufacture and control of the new
animal drug (section 572(c)(2)(C) of the act). In addition, before a
new animal drug can be added to the index, the requestor must make a
commitment that the indexed drug will be manufactured in compliance
with cGMPs (section 572(d)(1)(F) of the act).
In contrast, an NADA must include a ``full list'' of the articles
used as components of the drug and ``a full statement'' of the
composition of the drug (section 512(b)(1)(B), (C) of the act) as well
as ``a full description'' of the methods used in, and the facilities
and controls used for, the manufacture, processing, and packing of the
new animal drug (section 512(b)(1)(D) of the act). These statutory
requirements, as implemented by regulation (21 CFR 514.1(b)(4), (5)),
result in a highly detailed NADA submission which must contain
sufficient information to permit FDA to determine the adequacy of the
``full description'' with respect to preserving the identity, strength,
quality, and purity of the subject new animal drug (see section
512(d)(1)(C) of the act).
As previously stated, FDA believes that the submission of
chemistry, manufacturing, and control information for a new animal drug
proposed for indexing that would meet the relevant statutory standard
would consist of a comprehensive summary of the manufacturing process
that is sufficient to permit a determination that the requestor
understands cGMPs and has established appropriate specifications in
accordance with that understanding. FDA believes that the ``full
description'' and underlying confirmatory information that are required
in an NADA would not be necessary in a request for determination of
eligibility for indexing.
5. Other Information
Proposed 21 CFR 516.129 also requires that a request for
determination of eligibility contain the following: (1) Identification
of the minor species or groups of minor species for which indexing is
sought; (2) a statement of the intended use(s) in those species; (3) a
statement of the conditions of use, such as dosage, route of
administration, warnings, contraindications or other significant
limitations associated with the intended use(s); (4) a brief discussion
of the need for the drug for the intended use(s); and (5) an estimate
of the anticipated annual distribution after indexing.
Additionally, the regulation provides that a single request for
eligibility may involve only one drug (or combination of drugs) in one
dosage form, may involve multiple intended uses or multiple minor
species, may not involve a new animal drug that is contained in or a
product of a transgenic animal, and may not involve the same drug in
the same dosage form for the same intended use as a new animal drug
that is already approved or conditionally approved.
G. Granting and denying requests for a determination of eligibility and
notification thereof (proposed Sec. 516.133, Sec. 516.135, and Sec.
516.137).
FDA will deny a request for determination of eligibility if a
requestor fails to submit information required by section 572(c)(1) of
the act, or the submitted information, evaluated together with other
information available to the agency, is insufficient to support a
decision to grant a request in
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accordance with section 572(c)(2) of the act.
The new animal drug that is the subject of the request must be
sufficiently characterized to enable the agency to determine whether
the same drug in the same dosage form for the same intended use is
already approved or conditionally approved. The proposed designation
rule contains a definition of sameness regarding these three elements
that would also apply to indexing (see proposed Sec. 516.3 published
in the Federal Register of September 27, 2005 (70 FR 56394)).
FDA believes that the estimate of the quantity of the indexed drug
likely to be distributed on an annual basis following indexing is
primarily required because of concern over extralabel use of indexed
drugs, which is statutorily prohibited. The anticipated quantity to be
distributed for the intended purpose(s) can serve as a baseline against
which actual distribution can be measured. Significant differences
between expected and actual distribution may indicate that an indexed
drug is being used for other than its intended purposes. An estimation
of the quantity of drug likely to be distributed may also inform
decisions associated with the extent of environmental or user exposure
following indexing.
As previously noted, a new animal drug which is contained in or is
the product of a transgenic animal may not be indexed. A transgenic
animal is defined, in section 571(j) of the act, as 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.
Under the proposal, FDA cannot determine a drug to be eligible for
indexing if the information submitted in support of the request
evaluated together with other information available to the agency is
insufficient to do the following: (1) Demonstrate food safety in an
early, non-food life stage of a food-producing minor species animal or
demonstrate that there is a reasonable certainty that treated animals
will not be consumed by humans or food-producing animals, (2) determine
that the requestor has established appropriate specifications for the
manufacture and control of the new animal drug, (3) demonstrate that
the requestor has an understanding of current good manufacturing
practices, or (4) determine that the new animal drug is safe with
respect to individuals exposed to the new animal drug during
manufacture or use; or the request fails to include an adequate
environmental assessment or sufficient information to support a
categorical exclusion from the requirement to prepare an environmental
assessment.
In addition, under the proposal a request for a determination of
eligibility for indexing may be denied if it contains any untrue
statement of a material fact or omits material information.
Within 90 days after the submission of a request for a
determination of eligibility for a non food-producing animal, or 180
days for a request for an early, non-food life stage of a food-
producing animal, FDA must grant or deny the request and notify the
requestor of its decision in writing. If FDA denies the request, the
agency will provide due notice and an opportunity for an informal
conference regarding its decision. A decision of FDA to deny a request
for determination of eligibility for indexing following an informal
conference would constitute the final agency action subject to judicial
review.
H. Qualified expert panels (proposed Sec. 516.141).
Once a requestor has received a letter granting eligibility for
indexing, as the first step in the process of requesting an index
listing, it can propose a qualified expert panel. The panel, which
operates external to FDA, plays a central role in the indexing
process--evaluating target animal safety and effectiveness information
and making a recommendation to FDA based on its evaluation. Section
572(d) of the act requires the agency to ``define the criteria for
selection of a qualified expert panel and the procedures for the
operation of the panel.'' The same section states that the panel is not
subject to the Federal Advisory Committee Act, also known as FACA.
Section 516.141 of the proposed implementing regulations describes the
process for selecting the qualified expert panel and describes how the
panel operates. It does this by stating the responsibilities of each of
the parties involved--the requestor, FDA, the panel members, and the
panel leader.
Because of the diverse nature of the products that are subject to
indexing and anticipated differences in the availability and
accessibility of experts qualified to review different product classes,
the proposed rule does not specify the day-to-day operations of a
qualified expert panel other than to require that the activities of the
panel be conducted in accordance with generally accepted professional
and ethical business practices and that one member of the panel be
identified to serve as the ``leader'' of the review process. The leader
would serve as the principal spokesperson for the panel and be
responsible for submitting the panel's final written report to the
requestor and maintaining records of the final report. In addition, the
agency plans to issue guidance documents regarding other aspects of the
operation of expert panels and the preparation of written reports.
In developing the selection criteria for the qualified expert
panel, FDA adapted some aspects of the agency's implementation of
section 523 of the act (21 U.S.C. 360m). That provision deals with FDA
accreditation of persons in the private sector to conduct the initial
pre-market review for certain medical devices. FDA also considered its
use of advisory committees that review information and make
recommendations to FDA on various technical and scientific issues
relating to product approval. In addition, FDA tried to minimize the
burden on the potential members to help ensure that qualified
individuals will be willing to participate while still establishing
adequate controls to help ensure that FDA obtains objective, high
quality evaluations and recommendations.
To maintain the integrity of the review process, one proposed
selection criterion is that a qualified expert panel member must not
have a conflict of interest or the appearance of a conflict of
interest, unless FDA makes a determination to allow participation
notwithstanding an otherwise disqualifying financial interest. The
proposed rule describes the factors that are, and are not, relevant to
determining whether there is a conflict of interest or the appearance
of a conflict of interest and identifies the information needed from
potential panel members to support this determination by the agency.
Proposed Sec. 516.141(e)(7) requires qualified expert panel members to
immediately notify the requestor and FDA of any change in conflict of
interest status. For purposes of this regulation, the agency believes
that this generally requires a panelist to report changes in his
conflict of interest status within 30 days.
In selecting members for the qualified expert panel, the person
requesting the index listing would be required to ensure that the
members have the requisite scientific training and experience to
evaluate the target animal safety and effectiveness of the new animal
drug at issue for the proposed intended use. The group of identified
experts would also be required to
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represent an adequate range of expertise to fully evaluate the product.
After identifying potential panel members, the requestor would be
required to provide their names and addresses to FDA, along with
sufficient information about each proposed member for FDA to determine
whether the panel meets the selection criteria other than with respect
to potential conflicts of interest. Each proposed panel member would
provide information regarding potential conflicts of interest directly
to the agency. If the agency determines that the qualified expert panel
does not meet the selection criteria, it will provide information to
the requestor so that a suitable panel can be proposed. For example,
FDA may decline some candidates and request replacements or request
that the panel include additional members to provide needed expertise.
If the requestor disagrees with FDA's determination regarding the
panel, under the proposal it may request review through an informal
conference.
The work of the expert panel centers around its primary task, which
is to prepare a written report that describes the panel's evaluation of
all available target animal safety and effectiveness information
relevant to the proposed use of the new animal drug and the panel's
conclusions based on its evaluation. In preparing the written report,
panel members would be required to review all relevant information
provided by the requestor and should also consider any other relevant
information otherwise known by panel members, including anecdotal
information. Panel members would be required to participate in the
preparation of the written report. Members could be paid a reasonable
fee to serve on expert panels by the requestor.
I. Written report (proposed Sec. 516.143).
The qualified expert panel's written report must meet the
requirements of section 572(d)(2) of the act. Under proposed Sec.
516.143, which would implement this provision, the report must describe
the panel's evaluation of all available target animal safety and
effectiveness information relevant to the proposed use of the new
animal drug; provide citations of all literature reviewed and summaries
of unpublished information considered; and 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. The purpose of these requirements is to provide
sufficient information to permit the agency to assess the quality and
quantity of the information relating to target animal safety and
effectiveness of the new animal drug assessed by the panel. Therefore,
the panel's evaluation should be such that FDA can understand the basis
for the panel's conclusion regarding the drug's benefits and risks. If
the expert panel concludes that the benefits of using the drug outweigh
its risks, it would also be required to provide as part of the report
either draft labeling, which includes all conditions of use deemed
necessary by the expert panel to assure that the benefits of the drug
will outweigh its risks, or narrative information on the basis of which
such labeling can be drafted by the requestor. All panel members would
be required to sign the report or otherwise approve it in writing.
J. Content and format of a request for addition to the index (proposed
Sec. 516.145).
As noted previously, the second part of the indexing regulatory
process involves FDA's review of whether the new animal drug meets the
statutory criteria regarding target animal safety and effectiveness
information. FDA's review is based on the qualified expert panel's
written report and recommendation. The agency's review begins with the
requestor's submission asking for addition of the new animal drug to
the index. This submission must contain the information required by
section 572(d)(1) of the act. FDA's decision to grant or deny the
request for indexing is governed by section 572(d)(4) of the act.
Therefore, the request for addition to the index needs to contain
sufficient information to permit FDA to grant the request. The sections
of the proposed rule that implement these statutory provisions are
sections 516.145 and 516.149, respectively.
K. Refusal to file and review a request for addition to the index
(proposed Sec. 516.147).
The agency proposes that if a request for indexing fails to contain
information required by Sec. 516.145, FDA will not file or review it
and will so notify the requestor within 30 days of receiving the
request.
L. Granting or denying a request for addition to the index and
notification thereof (proposed Sec. 516.149, Sec. 516.151, and Sec.
516.153).
FDA must deny a request for indexing if the same drug in the same
dosage form for the same intended use is approved or conditionally
approved. While this is also a basis for denying eligibility for
indexing, it is possible that a new animal drug may be approved or
conditionally approved between the time that a determination for
eligibility is made and the request for indexing is submitted, thus
preventing the indexing of a new animal drug previously determined to
be eligible.
It is also possible that new scientific information may arise
between the time of a determination of eligibility and submission of a
request for indexing. Section 572(d)(4) of the act (by reference to
section 572(a) of the act) and proposed Sec. 516.151 require the
agency in reviewing a request for index listing to evaluate any new
information together with the information available at the time of a
determination of eligibility to determine whether the new animal drug
is still eligible for indexing.
If a request for indexing fails to contain, or appropriately
reference, information required by the statute, as implemented by
proposed Sec. 516.145, the agency would be required to deny the
request.
In general, FDA intends to rely heavily on the recommendations of
the qualified expert panel regarding target animal safety and
effectiveness, including the necessary conditions of use. However, the
written report of a qualified expert panel may not be sufficiently
clear or complete with respect to the basis for a panel recommendation
to index a new animal drug to permit FDA to make an informed decision
regarding whether it agrees with the recommendation. In this case, FDA
would either deny the request for indexing or, under proposed Sec.
516.145(c), require that the requestor submit the information provided
to the panel. It is also possible that, in some cases, the written
report of an expert panel may be sufficiently clear and complete for
the agency to make a decision regarding the panel recommendations, but
the agency may disagree in whole or in part with the recommendations.
Such disagreement may be based on the written report itself or the
report along with additional information available to the agency. In
such a case, FDA would deny the request. If FDA denies a request for
addition to the index, the requestor
[[Page 48846]]
could submit another request, which contains information to overcome
the agency's grounds for denial.
One of the grounds for denying a request for addition to the index
is that the qualified expert panel failed to meet one or more of the
selection criteria. Proposed Sec. 516.141 would require panel members
to submit any new information regarding conflicts of interest to the
agency so that FDA can determine whether a disqualifying conflict has
arisen since the agency's initial review.
Under the proposal, and consistent with FDA's regulations governing
new animal drug applications, FDA may also deny a request for addition
to the index if it contains any untrue statement of a material fact or
omits material information.
Within 180 days after the filing of a request for addition of a new
animal drug to the index, FDA will grant or deny the request, and
notify the person requesting indexing of FDA's decision in writing. If
FDA denies the request for indexing of a new animal drug, the agency
will provide due notice and an opportunity for an informal conference.
A decision by FDA to deny a request to index a new animal drug
following an informal conference will constitute final agency action
subject to judicial review.
M. Publication of the index and content of an index listing (proposed
Sec. 516.157).
FDA proposes to meet the requirement of section 572(e)(2) of the
act by maintaining and updating, at least annually, a publicly
available list of indexed drugs. Each index listing would contain the
following: (1) The name and address of the person who holds the index
listing, (2) the name of the new animal drug and the intended use and
conditions of use for which it is indexed, (3) product labeling, and
(4) conditions and any limitations that the agency deems necessary
regarding the use of the new animal drug.
N. Modifications to indexed drugs (proposed Sec. 516.161).
As with approved new animal drugs, and as provided for by section
572(e)(3) of the act, there will almost certainly be a need to change
the conditions under which a new animal drug is indexed or other
aspects of an indexed drug at some point after indexing. The proposed
regulations for making such changes are based on those governing new
animal drug applications, although the proposed regulations are
generally less burdensome than the regulatory requirements of the
corresponding section of 21 CFR part 514.
Proposed Sec. 516.161 provides for three classes of changes to
indexed drugs.
The first class of changes involves the following: (1) The addition
to labeling or prescription drug advertising of additional warning,
contraindication, side effect, or cautionary information, (2) the
deletion from labeling or prescription drug advertising of false,
misleading, or unsupported indications for use or claims of
effectiveness, or (3) changes in manufacturing methods or controls
required to correct product or manufacturing defects that may result in
serious adverse drug events. Changes of this nature should be made as
soon as possible and a request for modification of an index listing
containing information describing the need for the change should be
concurrently submitted to the agency.
The second class of changes involves the following: (1) Addition of
an intended use, (2) addition of a species, (3) addition or alteration
of an active ingredient, (4) alteration of the concentration of an
active ingredient, (5) alteration of the dose or dosage regimen, or (6)
alteration of prescription or over-the-counter status. Changes of this
nature can be made only after a request to make such a change has been
granted by FDA. Each such change must go through the same review
process as the original index listing. Therefore, the initial
submission to FDA relating to such a change should be a request for a
determination of eligibility for indexing that relates specifically to
the proposed change. However, while the process for modifications to
index listings of this kind follows the same process as a new index
listing, much of the work to support the initial listing might also
support the change to the listing and so would not have to be
duplicated. Likewise, the panel that reviewed the original request for
listing would likely be acceptable to review the proposed change as
well. The agency notes, however, that the nature of the change or new
information about, for example, the product's safety or effectiveness,
may mean that previous work would no longer be adequate to support the
change.
The third class of changes involves any change to the conditions
established in labeling or otherwise described in the request for
determination of eligibility or request for indexing at the time a new
animal drug was indexed other than those noted above. Information
describing such changes would be required to be submitted as part of
the annual indexed drug experience report. These changes include
changes to the formulation of the product or to the manufacturing
methods or controls other than those to correct defects that may cause
serious adverse drug events. Changes to the formulation or
manufacturing process would be required to be reported at the same
level of detail as the level of detail at which the formulation or
manufacturing process were initially described in the request for
determination of eligibility for indexing.
The proposed provisions under Sec. 516.161 would apply only to
modifications to the indexed drug. Regardless of which class of changes
is requested, these provisions would not apply to changes that would
cause an indexed drug to be a different drug (or different combination
of drugs) or a different dosage form. In the case of such a submission,
the agency would deny the request for modification and notify the
holder that a new index listing is required for the new drug or dosage
form. The designation proposed rule (September 27, 2005, 70 FR 56394)
contains proposed definitions for ``same drug'' and ``same dosage
form.'' The holder could then initiate the new listing by submitting a
request for eligibility for the new drug or dosage form.
O. Change in ownership of an index file (proposed Sec. 516.163).
The agency proposes that, in order to meet the requirement of
section 572(e)(1)(A) of the act, the owner of an index file supporting
an index listing may transfer ownership of the file provided that the
agency is appropriately notified of this. The agency would then update
the index listing accordingly.
P. Records and reports (proposed Sec. 516.165).
Section 572(i) of the act requires the maintenance of records and
the submission of reports sufficient to permit a determination of
whether an indexed drug should be removed from the index. The
information FDA believes is necessary to make this determination is
described in proposed Sec. 516.165. This information would be similar
in nature but less extensive than the information required with respect
to approved new animal drugs. Most of the information required would be
submitted annually, on, or within 60 days of, the anniversary date of
the letter granting the request for indexing.
Under the proposed regulation, product or manufacturing defects
that may result in serious adverse drug experiences must be reported to
the appropriate FDA District Office or resident post within three
working days of their discovery. Serious and unexpected adverse drug
experiences must be reported to the Director,
[[Page 48847]]
OMUMS within 15 working days of the index holder first receiving the
information.
Distribution of an indexed drug by a distributor would be
permissible provided that the holder of the index listing submits a
special report at the time of initial distribution by the distributor
containing the information required under proposed Sec. 516.165. This
includes a signed statement from the distributor that the indexed drug
will be distributed and promoted only in accordance with the index
listing.
The agency proposes that all other required information be
submitted annually. This includes the following: The quantity of the
drug distributed (domestically and for export), holder and distributor
current package labeling with a summary of any changes in labeling
since the previous annual report, a summary of changes in the
manufacturing process (at the level of detail that the manufacturing
process was described in the request for determination of eligibility)
not already reported under proposed Sec. 516.161, any pertinent safety
or effectiveness information not previously reported, and any adverse
drug experience information not previously reported.
Q. Removal from the index (proposed Sec. 516.167).
Proposed Sec. 516.167 provides for removal of a new animal drug
from the index, after due notice to the holder of the index listing and
an opportunity for an informal conference.
The proposed grounds for removal, which track those in the act,
include that the same drug in the same dosage form for the same
intended use has been approved or conditionally approved.
In accordance with section 572(f)(1) of the act, if FDA determines,
subsequent to the indexing of a new animal drug, that the qualified
expert panel failed to meet its applicable requirements, FDA would
remove the drug from the index.
In light of the purpose of the MUMS act to increase the
availability of legally marketed new animal drugs to treat minor
species, the agency proposes to only partially remove an index listing
if it believes that doing so would satisfactorily resolve a safety or
effectiveness issue otherwise warranting complete removal of the drug
from the index. For example, if an index listing provides for the use
of a new animal drug in several minor species and new information
indicates that the benefits of using the drug in one of those minor
species does not outweigh its risks to that species, the agency may
remove only the use of the new animal drug in that minor species from
the index listing.
In accordance with section 572(f)(2) of the act, the regulation
proposes that FDA may immediately suspend a new animal drug from the
index if it 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 would subsequently offer the holder of the index
listing an opportunity for an informal conference.
A decision by FDA to remove a new animal drug from the index
following an informal conference would constitute final agency action
subject to judicial review.
R. Confidentiality of data and information in an index file (proposed
Sec. 516.171).
This proposed regulation is based on Sec. 514.11, which applies to
new animal drug application files. It would apply to index files, which
would encompass all data and information submitted to or incorporated
by reference into the index file including requests for determination
of eligibility for indexing, information supporting selection of expert
panel members, requests for addition to the index, claimed
investigational exemptions under proposed Sec. 516.125, requests for
modification to indexed drugs, reports submitted under proposed Sec.
516.165, and master files.
III. Conforming Changes
FDA is proposing conforming changes to certain applicable sections
of the Code of Federal Regulations (CFR) that would add a reference to
new animal drugs that are index listed under section 572 of the act.
The affected sections in title 21 of the CFR are:
Sec. 20.100 Applicability; cross-reference to other regulations.
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.
In Sec. 201.105, FDA is also proposing to remove a reference to
certification requirements applicable to preparations of antibiotic
drugs. FDA no longer certifies or recognizes certification of
antibiotic drugs.
In addition, FDA is proposing to remove the last sentence in Sec.
500.25(c) because it cites Sec. 514.9 which no longer exists. Labeling
revisions for animal feeds bearing or containing anthelmintic drugs are
now subject to the same requirements under 21 CFR 500.25 as dosage form
drugs. Medicated animal feeds covered by approved applications are
subject to the provisions of Sec. 514.8 (d) and (e). Medicated animal
feeds covered by an index listing are subject to the provisions of 21
CFR 516.161(b)(1).
IV. Legal Authority
FDA's authority for issuing this proposed 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 proposed rule.
Section 701(a) authorizes the agency to issue regulations for the
efficient enforcement of the act.
V. Analysis of Economic Impacts
FDA has examined the impacts of the proposed rule under Executive
Order
[[Page 48848]]
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 tentatively finds that the proposed 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 $342,000 in the first year to
about $735,000 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 proposing ``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 $115 million, using the most current (2003)
implicit price deflator for the Gross Domestic Product. FDA does not
expect this proposed 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.
Summary
The proposed rule is expected to result in about 30 requestors,
each averaging about 2 requests for a determination of eligibility for
indexing of individual animal drugs annually, submitting a total of 60
requests annually. 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.
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 sponsors of animal drugs that
are marginally economically viable could use this system to avoid the
traditional animal drug approval process. Under this proposed 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.
Administrative Costs
This section will describe and estimate the annual administrative
costs by proposed 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 proposed rule
were determined by Center for Veterinary Medicine personnel.
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 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 agents 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. Due to the uncertainty in
the costs for resident agents, we request public comment and data on
this issue.
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\1\2004 National Industry-Specific Occupational Employment and
Wage Estimates, U.S. Department of Labor, Bureau of Labor Statistics
(http://www.bls.gov/oes/current/naics4_325400.htm); compliance
officer wage rate for pharmaceutical and medicine manufacturing
(NAICS 325400).
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Proposed Sec. 516.121 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. Proposed Sec. 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. We estimate that about three requestors
would request one conference with FDA 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
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 proposed Sec. 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. At the loaded wage estimate of $42.29 per hour, and our
estimate of 12 hours of preparation for each request, this provision
would require about 720 hours equal to about $30,400. Included in this
estimate of 60 requests are any resubmitted requests that were
previously denied.
Proposed Sec. 516.141 would require 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. FDA would be 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
[[Page 48849]]
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 8
hours of effort by regulatory affairs personnel. At the same loaded
wage estimate, these 160 hours would cost about $6,800 annually.
Proposed Sec. 516.143 describes how the expert panel would 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 80 hours. This equates to 1,600 hours for 20 panels. The
proposed rule allows for fees to be paid to panel members for their
time. We estimated 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 $200,000 annually for the
total industry, or $10,000 per requestor for each animal drug under
consideration. An additional 0.5 hours is estimated for recordkeeping
of the final written report described in proposed Sec. 516.143 by the
panel leader. This would result in an additional $400 in costs
annually. We request comment and data on the range of hourly wage rates
for qualified panel members.
We estimate that the formal request for addition to the index,
provided for in proposed Sec. 516.145, would require about 12 hours to
prepare. This would result in another 240 hours of effort (20 requests
times 12 hours) for regulatory affairs personnel. We project the
compliance cost of this effort at $10,200 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 would cost about $250 in the first
year. Total modification requests and ownership change notifications
are expected to increase by 1 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 proposed rule would 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 would 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) would
require an additional hour of administrative time for each indexed drug
listing. These additional 20 hours would 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 $273,000 in the first year. These costs would be borne by 30
requestors at an average cost per requestor of about $9,100 per indexed
drug. Costs in succeeding years would be expected to increase slightly
due to the annual reporting requirements for all indexed drugs
resulting in year-10 costs of about $358,000.
Costs to Government
The Government would also incur costs for this proposed 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 proposed rule would be the sum of private
administrative and Government costs. Total costs are estimated to
increase from $342,000 in the first year up to $735,000 in the 10th
year.
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 initial 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 intended uses 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 less 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 $12,600. This cost per request
represents about 1.5 percent of the revenues of the smallest set of
establishments (those with one to four employees), and less than 0.4
[[Page 48850]]
percent of revenues of all larger establishments. These costs would not
represent a significant economic impact on these firms, 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.
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2. Analysis of Alternatives
The Regulatory Flexibility Act requires that the agency consider
any alternatives to the proposed rule that would accomplish the
objective while minimizing significant impacts of the rule. As stated
previously, the agency believes that the proposed 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
businesses.
The statute that creates this system, Pub. L. 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 proposed rule achieves the objective of increasing
drug availability for minor species with minimal costs to industry
while staying within the limits set by Pub. L. 108-282.
VI. Paperwork Reduction Act of 1995
This proposed 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 (the PRA) (44 U.S.C. 3501-
3520). A description of these provisions is given below with an
estimate of the annual reporting and recordkeeping 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.
FDA invites comments on these topics: (1) Whether the proposed
collection of information is necessary for the proper performance of
FDA`s functions, including whether the information will have practical
utility; (2) the accuracy of FDA`s estimate of the burden of the
proposed collection of information including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility and clarity of the information to be collected; (4) ways to
minimize the burden of the collection of information on respondents,
including through the use of automated collection techniques and other
forms of information technology.
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 proposed rule is intended to implement 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 those who choose to participate. The proposed 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, proposed Sec. 516.119
provides requirements for naming a permanent-resident U.S. agent by
foreign drug companies, and Sec. 516.121 would provide for
informational meetings with FDA. Section 516.123 provides proposed
requirements for requesting informal conferences regarding agency
administrative actions and proposed 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 proposed Sec. 516.129 and provisions for subsequent
requests for addition to the index can be found under proposed Sec.
516.145. A description of the written report required in Sec. 516.145
can be found under proposed Sec. 516.143. Under proposed Sec. 516.141
are provisions for drug companies to nominate a qualified expert panel
as well as the panel's recordkeeping requirements. This section would
also call for the submission of a written conflict of interest
statement to FDA by each proposed panel member. Index holders would be
able to modify their index listing under proposed Sec. 516.161 or
change drug ownership under proposed Sec. 516.163. Requirements for
records and reports are proposed under Sec. 516.165.
Description of Respondents: Pharmaceutical companies that sponsor
new animal drugs.
Thus, 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 12 720
--------------------------------------------------------------------------------------------------------------------------------------------------------
516.141 20 1 20 8 160
--------------------------------------------------------------------------------------------------------------------------------------------------------
516.143 20 1 20 80 1,600
--------------------------------------------------------------------------------------------------------------------------------------------------------
516.145 20 1 20 12 240
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 48851]]
516.161 1 1 1 4 4
--------------------------------------------------------------------------------------------------------------------------------------------------------
516.163 1 1 1 2 2
--------------------------------------------------------------------------------------------------------------------------------------------------------
516.165 10 2 20 8 160
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total 3,272
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\There is no capital or operating and maintenance costs 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 costs associated with this collection of information.
The burden estimate for this reporting requirement was derived by
our Office of Minor Use and Minor Species Animal Drug Development by
extrapolating from relevant portions of the current Investigational New
Animal Drug (INAD) and NADA reporting requirements for similar actions
by a similar segment of the regulated industry and from previous
interactions with the minor species community.
In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C.
3507(d)), the agency has submitted the information collection
provisions of this proposed rule to OMB for review.
VII. Environmental Impact
We have carefully considered the potential environmental impacts of
this 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.
VIII. Federalism
We have analyzed this proposed rule in accordance with the
principles in Executive Order 13132. We have determined that the
proposed 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,
we have tentatively concluded that the proposed rule does not contain
policies that have federalism implications as defined in the Executive
order and, consequently, a federalism summary impact statement has not
been prepared.
IX. Comments
You may submit to the Division of Dockets Management (see
ADDRESSES) written or electronic comments regarding this document.
Please submit a single copy of electronic comments or two paper copies
of any mailed comments, except that individuals may submit one paper
copy. Identify your comments with the docket number found in brackets
in the heading of this document. You may view received comments in the
Division of Dockets Management between 9 a.m. and 4 p.m., Monday
through Friday.
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.
[[Page 48852]]
21 CFR Part 589
Animal feeds, Animal foods, Food additives.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR Chapter I be amended as follows:
PART 20--PUBLIC INFORMATION
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.
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
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.
4. 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
5. 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.
6. 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
* * * * *
7. 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 of the act is approved with
respect to such drug but it complies with section 505(i), 512, or 572
of the act and regulations thereunder.
* * * * *
8. 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
9. The authority citation for 21 CFR part 202 continues to read as
follows:
[[Page 48853]]
Authority: 21 U.S.C. 321, 331, 352, 355, 360b, 371.
10. 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 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
11. 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.
12. 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. * * *
* * * * *
13. 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
14. The authority citation for 21 CFR part 225 continues to read as
follows:
Authority: 21 U.S.C. 351, 352, 360b, 371, 374.
15. 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.
16. 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.
17. 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
18. The authority citation for 21 CFR part 226 continues to read as
follows:
Authority: 21 U.S.C. 351, 352, 360b, 371, 374.
19. 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
20. 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.
21. 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 (d) and (e) 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 approval, as provided for in Sec.
516.161(b)(1) of this chapter.
* * * * *
22. 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.
[[Page 48854]]
(c) * * * A new animal drug application or index listing is
required in any such case.
* * * * *
PART 510--NEW ANIMAL DRUGS
23. 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.
24. 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.
* * * * *
25. 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.
26. 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
27. The authority citation for 21 CFR part 511 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 360b, 371.
28. Amend Sec. 511.1 by adding a 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
29. The authority citation for 21 CFR part 515 continues to read as
follows:
Authority: 21 U.S.C. 360b, 371.
30. 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.
* * * * *
31. 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
32. 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 48855]]
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.
Authority: 21 U.S.C. 360ccc-1, 371.
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, non-food 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 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 means the intended treatment, control or prevention of
a disease or condition, or the intention to affect the structure or
function of the body of animals within an identified species,
subpopulation of a species, or collection of species.
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.
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 of the Office of Minor Use
and Minor Species Animal Drug Development. 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 of the Office of
Minor Use and Minor Species Animal Drug Development 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, 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 30 calendar days of the date FDA sends its notice.
(c) Within 30 days of receiving a request for an informal
conference, FDA will attempt to schedule the meeting at
[[Page 48856]]
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 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) The presiding officer will prepare a written summary of the
informal conference and share it with the parties to the conference.
(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.
(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 written summary of the informal conference.
(4) The presiding officer's written report.
(5) 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 and views 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.
(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 of the Office of Minor Use and Minor Species 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
[[Page 48857]]
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 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
[[Page 48858]]
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 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 the target animal safety and 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
[[Page 48859]]
should be submitted directly to the Director 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 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 of the Office of Minor Use and Minor Species 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
[[Page 48860]]
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
(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
[[Page 48861]]
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 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, Office of Minor Use and
Minor Species Animal Drug Development 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
[[Page 48862]]
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
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 follow up. 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
[[Page 48863]]
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
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
33. The authority citation for 21 CFR part 558 continues to read as
follows:
Authority: 21 U.S.C. 360b, 371.
34. 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) or listed in the index under section 572
of the Federal Food, Drug, and Cosmetic Act (the act) for use in or on
animal feed. Use of a VFD drug must be under the professional
supervision of a licensed veterinarian.
[[Page 48864]]
(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 veterinary feed
directive (VFD) drug in or on an animal feed. This written statement
authorizes the client (the owner of the 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.
* * * * *
35. 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 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.
* * * * *
36. 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
37. The authority citation for 21 CFR part 589 continues to read as
follows:
Authority: 21 U.S.C. 321, 342, 343, 348, 371.
38. 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: June 15, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 06-7070 Filed 8-21-06; 8:45 am]
BILLING CODE 4160-01-S