[Federal Register: July 26, 2007 (Volume 72, Number 143)]
[Rules and Regulations]
[Page 41010-41022]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr26jy07-3]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 20, 510, 514, and 516
[Docket No. 2005N-0329]
RIN 0910-AF60
Designation of New Animal Drugs for Minor Uses or Minor Species
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Minor Use and Minor Species Animal Health Act of 2004
(MUMS act) amended the Federal Food, Drug, and Cosmetic Act (the act)
to establish new regulatory procedures that provide incentives intended
to make more drugs legally available to veterinarians and animal owners
for the treatment of minor animal species and uncommon diseases in
major animal species. At this time, FDA is issuing final regulations to
implement the act. These regulations describe the procedures for
designating a new animal drug as a minor use or minor species drug.
Such designation establishes eligibility for the incentives provided by
the MUMS act.
DATES: This rule is effective October 9, 2007.
FOR FURTHER INFORMATION CONTACT: Bernadette Dunham, Center for
Veterinary Medicine (HFV-50), Food and Drug Administration, 7519
Standish Pl., Rockville, MD 20855, 240-276-9090, e-mail:
Bernadette.Dunham@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
I. Background
In enacting the MUMS act (Public Law 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 uses).
Congress recognized that the markets for drugs intended to treat these
species, diseases, or conditions are often so small that there are
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 these animal drugs. As a result
of these limitations, sponsors have generally not been willing or able
to collect data to
[[Page 41011]]
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 (the act) to provide
incentives to develop new animal drugs for minor species and minor
uses, while still ensuring appropriate safeguards for animal and human
health.
In the Federal Register of September 27, 2005 (70 FR 56394), FDA
issued proposed regulations to implement section 573 of the act (21
U.S.C. 360ccc-2). These regulations proposed procedures for designating
a new animal drug as a minor use or minor species drug. Such
designation provides eligibility for certain incentives established by
the MUMS act, including exclusive marketing rights associated with the
conditional approval or approval of designated new animal drugs and for
grants to support designated new animal drug development. The proposed
rule initially provided for a 75-day public comment period during which
the agency received several comments asserting that 75 days was not an
adequate amount of time to prepare and submit meaningful comments. In
response to this, in the Federal Register of December 28, 2005 (70 FR
76732), FDA reopened the comment period allowing an additional 30 days
of public comment.
II. Changes to the Proposed Rule
In response to public comment, or in two places to provide added
clarity, FDA has made the following changes to the proposed rule:
Sec. 516.3 Definitions. The definition of ``Infrequently'' was
changed by adding the words ``on an annualized basis'' to the end of
the proposed definition. The definition now reads: ``Infrequently, as
used in the minor use definition, means a disease or condition that is
uncommon or that occurs only sporadically on an annualized basis.''
Sec. 516.21 Documentation of minor use status. The language in
Sec. 516.21(b) was revised for clarity.
Sec. 516.28 Publication of MUMS-drug designations. In Sec.
516.28(b), the term ``generic name'' was changed to ``established
name'' to avoid confusion with abbreviated applications approved under
section 512(b)(2) of the act.
Sec. 516.31 Scope of MUMS-drug exclusive marketing rights. In
Sec. 516.31(a)(2), the words ``or proposes to withdraw'' were removed.
III. Comments
The agency received comments from 9 organizations or individuals on
the September 27, 2005, proposal. Comments were received from a trade
organization representing new animal drug manufacturers, a trade
organization representing pet product manufacturers, an animal feed
manufacturer, a professional association representing veterinarians, an
association representing zoos and aquariums, a consumer advocacy
organization, and 3 consumers.
A. Comments on the Proposed Rule
(Comment 1) In Sec. 516.3(b) one comment stated that for added
clarity and consistency we should add the words ``on an annualized
basis'' to the end of the definition for infrequently.
(Response) We agree. We explained in the preamble to the proposed
rule why we thought that it was appropriate to annualize the data on
the number of animals in which the indication occurs (see 70 FR at
56395 to 56396). Therefore, we have revised the codified section
accordingly.
(Comment 2) Two comments stated that the requirement for a specific
product development plan as part of a request for MUMS-drug designation
in Sec. 516.20(b)(6) is unnecessarily arduous and premature in the
designation process. Commentors also stated that frivolous requests for
designation should not be burdensome to the agency; and, therefore,
that the requirement for a specific product development plan is
unnecessary.
(Response) We do not agree that the requirement for submission of a
description of the product development plan is arduous or premature.
Also, the basis for this requirement is not primarily to reduce burden
on the agency due to frivolous requests for designation. The primary
reasons for requiring a specific product development plan as part of a
request for MUMS-drug designation are as follows. As we explained in
the preamble to the proposed rule (70 FR 56394 at 56399), for new
animal drugs, unlike for human orphan drugs, each designation must be
unique with respect to drug, dosage form, and intended use. In this
way, the MUMS act, which was enacted to address the critical shortage
of approved animal drugs for minor species/minor uses, facilitates the
development of a broad range of animal drugs in part by discouraging
multiple sponsors from pursuing identical uses. Because each MUMS
designation is unique, it is important to the effective implementation
of section 573 of the act that initial designation of a drug be based
on evidence that requesting sponsors clearly understand their
responsibilities in terms of drug research and development and are
prepared to accept those responsibilities.
Submission of a description of the product development plan helps
to ensure that timely development of the drug, consistent with the
requirement of section 573(a)(2)(B) to actively pursue approval with
due diligence, is feasible. Designation of a drug that could not
feasibly be approved under the sponsor's current drug development plan
would inappropriately delay development and marketing of a needed drug
by the same or a different sponsor and undermine the goals of the MUMS
act. Submitting the description of the product development plan also
facilitates meaningful communication between the sponsor and the agency
to help ensure that safety and effectiveness testing, which for
designated drugs may be supported by grants or contracts under section
573(b) of the act, is efficiently designed and conducted. Efficient and
effective use of sponsor and agency resources, which is enabled by this
and other requirements of final Sec. 516.20, is critically important
to alleviating the shortage of new animal drugs addressed by the MUMS
act.
(Comment 3) Two comments stated that the documentation requirements
for minor use status in Sec. 516.21 are too burdensome. They believe
there is a lack of balance between the documentation required for a
minor use designation versus a minor species designation. More
specifically, both commentors believe that Sec. 516.21(b) is asking
sponsors to prove a negative concerning the lack of medical
justification and one of these commentors stated that the financial
information requested in Sec. 516.21(c) is, for the most part,
confidential. As an alternative approach, these two commentors
submitted similar two-part working definitions for minor use that could
be used in place of the proposed provisions for Sec. 516.21 as
follows:
Either:
1. The drug is not currently approved, it is unlikely the ``minor
use'' designation for the drug will be applicable to a majority of the
major species population, and the need for the drug for a specific
disease or condition has been clearly identified by animal health
professionals or an animal industry. One commentor also added a fourth
provision that if the drug has the same active ingredient as other
approved drugs, the environmental safety assessment of the combined
active ingredient of all such drugs is shown to be adequate.
Or;
[[Page 41012]]
2. The annualized commercial return on investment for the product
is not reasonably expected to exceed the development and maintenance
costs of the product.
(Response) We do not agree that the requirements for documentation
of minor use status in Sec. 516.21 are too burdensome. FDA agrees that
these implementing regulations should not be overly burdensome to drug
sponsors in order to achieve the objectives set forth in the MUMS Act.
However, it is unavoidable that a certain amount of additional
information will be required in a request for minor use designation
that will not be required in a request for minor species designation.
Section 516.21 describes this additional information and comprises
three paragraphs.
Section 516.21(a) asks for an estimate of the total number of
animals to which a drug could potentially be administered on an annual
basis. Whether compared to a predetermined small number of animals or
as part of a case-by-case determination, this number will be essential
to any request for minor use designation. Simply put, this estimated
number of animals serves as documentation that the intended use of a
proposed MUMS drug is limited to a ``small number of animals'', as
required by the MUMS Act.
Section 516.21(b) describes how to define a minor use population if
the proposed MUMS drug is under development for only a subset of the
estimated total number of animals to which the drug could potentially
be administered on an annual basis. In this situation, a sponsor may
utilize the provisions of this paragraph to argue that administration
of a proposed MUMS drug is only justified for a small subset of a
larger major species population potentially affected by a particular
disease or condition and that administration to the remaining larger
affected population is medically inappropriate. If the number of
animals in this medically justified subset is a small number of
animals, then such a use is a minor use.
The provisions in this paragraph were apparently misinterpreted by
two of the commentors. Its purpose is not to require medical
justification to the effect that a drug approved for disease A could
not be used for disease B or C or D. Its purpose is to allow drug
sponsors to restrict the intended use of a drug to a subset of the
animals affected by disease A, thereby reducing their estimate of the
total number of animals eligible to be treated as required in Sec.
516.21(a), by providing medical justification that only a subset of
animals afflicted with disease A are amenable to treatment. For
improved clarity, we have revised the language of Sec. 516.21(b).
Section 516.21(c) requires drug sponsors to provide economic
information relevant to why their MUMS drug should be considered a
minor use drug. In the preamble to the proposed MUMS designation rule
(70 FR 56394) we cited the Senate report (S. Rept. 108-226) concerning
the bill before the Senate (S. 741), which discusses the minor use
definition and how minor use should be determined: ``This definition
incorporates the existing definition in the Code of Federal Regulations
(21 CFR 514.1(d)(1)) with a further limitation to ``small numbers'' to
assure that such intended uses will not be extended to a wider use. The
Secretary is expected to further clarify this definition in regulations
implementing this section. FDA is given broad latitude in determining
what constitutes a minor use in a major species. The Congress intends
for FDA to make the determination of minor use by evaluating, in the
context of the drug development process, whether the incidence of the
disease or condition occurs so infrequently that the sponsor of a drug
intended for such use has no reasonable expectation of its sales
generating sufficient revenues to offset the costs of development. The
Congress does not intend for FDA to establish a test of commercial
value, but rather directs FDA to determine whether the expected low use
of a drug would discourage its development.'' (S. Rept. 108-226 at 12-
13.)
In evaluating whether the incidence of the disease or condition is
so infrequent that the sales are not reasonably expected to offset
development costs, we might take two different approaches. First, we
could consider each request on a case-by-case basis utilizing the
information provided in Sec. 516.21(c). Alternatively, we could
establish, by regulation based on industry-wide economic data, a
specific small number of animals for each of the seven major species to
be used as a yardstick against which we would measure the estimated
total number of animals to which a drug could potentially be
administered on an annual basis, as documented under Sec. 516.21(a).
If such ``small number'' for each major species is established by
regulation at some point in the future, there would no longer be a need
for requiring the information requested in Sec. 516.21(c).
(Comment 4) With respect to Sec. 516.24, two comments stated that
FDA should respond to requests for designation within 60 days from the
time the request was submitted.
(Response) FDA agrees that timely processing of requests for
designation is important. However, because of limitations on agency
resources, the agency does not believe that it is feasible to commit to
responding to all requests for designation within 60 days. We intend to
issue guidance in the future to describe target timelines for the
designation process consistent with current resources.
(Comment 5) Two comments stated that FDA should update the publicly
available list of MUMS-designated drugs within 60 days of granting a
new MUMS designation.
(Response) We agree that timely updating of the list of MUMS-
designated drugs is appropriate. However, the agency does not believe
it is feasible to commit to definite timelines in these regulations
because of uncertain resource limitations. As discussed above, we
intend to describe target timelines for our actions related to the
designation process in future guidance.
(Comment 6) Two comments stated that a 1-year advance notification
for discontinuing the manufacture of a drug, as specified in Sec.
516.29(b), is excessive and a 30-60 day timeframe would be more
appropriate.
(Response) A 1-year advance notification for discontinuing the
manufacture of a MUMS-designated drug is required by section
573(a)(2)(C) of the act and, therefore, is not subject to alteration by
regulation.
(Comment 7) One commentor requested clarification on the
hypothetical situation in which FDA has withdrawn designation status
after notification by a sponsor (sponsor A) of its intent to
discontinue production, but the drug is still being sold, as permitted
in accordance with the lengthy pre-notification required by the
statute. The commentor asked if another sponsor (sponsor B) could
potentially achieve designation and conditional approval, and thus
block any further sale by sponsor A, even if sponsor A still has time
left on their notification and still has drug to be sold.
(Response) In this situation, FDA has only withdrawn sponsor A's
designation and, therefore, its exclusivity. The approval or
conditional approval remains intact. Therefore, while approval or
conditional approval may be possible for sponsor B, designation cannot
be granted for sponsor B because the MUMS Act only allows designation
when a specific drug, dosage form, and intended use is not already
approved or conditionally approved.
[[Page 41013]]
(Comment 8) In Sec. 516.31(a)(2) one comment stated that the words
Sec. or proposes to withdraw'' should be removed because this appears
to negate the right of the sponsor to due process.
(Response) We agree that the exclusivity of an approved or
conditionally approved MUMS-designated drug should not be abrogated by
a proposal to withdraw the approval or conditional approval. We have
revised the codified section accordingly.
(Comment 9) One comment stated that oral dosage form new animal
drugs and new animal drugs for use in animal feeds should not be
considered two different dosage forms for the purpose of MUMS
designation. It argues, for example, that if an oral dosage form new
animal drug is designated and approved subsequent to the designation
and approval of a medicated feed containing the same drug and for the
same intended use, it will negatively impact the business case and
success of the medicated feed.
(Response) The agency believes that this same argument could apply
to any drug that is available in more than one dosage form. For
example, an approved injectable product could be negatively impacted by
approval of an oral form of the drug.
As stated in the preamble to the proposed rule (70 FR 56394 at
56398), current federal regulations recognize the following dosage
forms: Oral dosage forms (21 CFR part 520), implantation or injectable
dosage forms (21 CFR part 522), ophthalmic and topical dosage forms (21
CFR part 524), intramammary dosage forms (21 CFR part 526),
miscellaneous dosage forms (21 CFR part 529), and drugs in animal feeds
(21 CFR part 558). The preamble also notes that medicated feeds are
subject to different limitations from those for other oral dosage forms
(70 FR 56394 at 56398), which also supports treating medicated feeds as
a different dosage form for the purpose of MUMS designation.
In addition, the markets for medicated feeds and other oral dosage
forms may be different. An oral dosage in the form of a drench or a
water treatment may be appropriate in different settings than those
requiring treatment through the use of medicated feeds. For example,
pheasants in a hatchery setting can be treated with medicated water
while those in large outdoor pens are more efficiently treated with
medicated feeds. Because the populations served by medicated feeds and
by other oral dosage forms can be different enough to represent
separate markets and because, as already noted, the same potential
overlap can occur between any two dosage forms, we believe it is
appropriate to treat medicated feeds and other oral dosage forms as
different for MUMS designation purposes.
(Comment 10) In the definition section under Sec. 516.13, under
Intended Use, one comment asked if treatment, control, and prevention
are the same thing (i.e., one designation) or are they three different
things (i.e., three possible designations).
(Response) Given that requirements for approval may differ
significantly for these three categories, they are considered to be
different for purposes of designation.
(Comment 11) One comment disagreed with the third principle of
sameness discussed in the preamble to the proposed rule, under which an
intended use for a disease or condition caused by one organism is
considered different from an intended use for the same disease or
condition caused by a different organism. The comment perceived this
approach to determining sameness to be a disincentive to seeking MUMS
designation.
(Response) This comment raises the general issue of how different
intended uses must be to be considered separate intended uses. If the
uses are clearly separable and have different data requirements for
approval, we believe it is appropriate to permit separate MUMS-drug
designations. Intended uses for diseases or conditions caused by
different organisms are clearly separable and would need to be
supported by different data for approval; therefore, we believe that
allowing separate MUMS-drug designations for drugs for such uses would
be appropriate.
(Comment 12) One comment was concerned that many zoo animals may be
included in the broad major species categories. It stated that FDA
should specifically identify the species and subspecies that are
considered ``major species'' with the recognition that some species/
subspecies may be appropriate only for public display or exhibition,
and that these non-domestic animals should be identified separately for
appropriate drug approval under MUMS regulations.
(Response) Zoo species will not be lumped with major species for
the purposes of drug approval. The major species are the domesticated
species only, not including hybrids or closely-related wild species.
Whether an animal belongs to a major or minor species is not affected
by its location or use; it is strictly a matter of the species.
Currently, FDA considers the major species to be:
Cattle--Bos taurus taurus / Bos taurus indicus
Horses--Equus caballus
Swine--Sus domesticus
Dogs--Canis familiaris (also called Canis lupus familiaris)
Cats--Felis domesticus (also called Felis catus or Felis silvestris
catus)
Chickens--Gallus gallus
Turkeys--Meleagris gallopavo gallopavo
All other species are considered to be minor. Therefore, there
should be no cause for concern regarding the status of zoo animals in
terms of new animal drug approval. The agency intends to clarify this
issue in guidance to be published in the future.
(Comment 13) One comment stated that a manufacturer of a drug that
is already approved in countries with substantially the same approval
requirements as the United States does not need incentives to develop
data and should not be given a MUMS designation.
(Response) The MUMS incentives exist to encourage pharmaceutical
companies to pursue approval of new animal drugs for minor uses and
minor species. Even in cases where foreign approvals exist, sponsors
generally need to provide considerable new data to meet the
requirements for FDA approval. Therefore, the MUMS incentives remain
appropriate when a drug has been approved in a foreign country.
(Comment 14) One comment stated that in order to monitor whether
the MUMS rule is fulfilling its intended goal to increase the
availability of drugs for minor uses, FDA should require annual reports
on quantities sold of each designated and conditionally approved drug.
(Response) The agency agrees that knowledge of the quantity of
designated drugs distributed on an annual basis would be useful
information in terms of assessing the success of the MUMS act. The MUMS
act itself requires the annual submission of information regarding
quantities of conditionally approved products distributed (see 21
U.S.C. 360ccc(d)(2)(B)(ii)). All fully approved new animal drugs are
required by regulation (21 CFR 514.80 (b)(4)(i)) to report the quantity
of product distributed. The Office of Minor Use and Minor Species
Animal Drug Development will have direct access to this information.
B. Comments on ``Small Number of Animals'' and Minor Use
(Comment 15) Three comments stated that companion animal ``small
numbers'' should be considered separately from food animal ``small
[[Page 41014]]
numbers.'' Two comments asked FDA to consider the numbers of animals
eligible to be designated under a minor species provision (e.g., sheep)
as a benchmark against which to compare numbers of animals to benefit
from minor use provisions.
(Response) The agency agrees that the ``small numbers'' for
companion animals need to be considered separately from the ``small
numbers'' for food animals. FDA also agrees that it is appropriate to
consider the relationship between the number of animals of a minor
species permitted to be designated under the MUMS act and the number of
animals of a major species permitted to be designated in establishing
``small numbers'' of animals under the definition of minor use in the
statute. However, the agency views the primary basis for establishing
``small numbers'' to be Congress' expression of intent in the report
language accompanying the act that the agency further define minor use
in a major species ``by evaluating, in the context of the drug
development process, whether the incidence of the disease or condition
occurs so infrequently that the sponsor of a drug intended for such use
has no reasonable expectation of its sales generating sufficient
revenues to offset the cost of development'' (S. Rept. 108-226 at 12-
13).
Since Congress provided incentives in the MUMS act to stimulate
drug development, the agency interprets the previous statement to mean
that FDA should determine for each major species what the ``small
number of animals'' eligible to be treated on an annual basis would
need to be in order to represent a drug market value that (relative to
drug development costs) would be considerably less likely to be pursued
in the absence of the MUMS incentives, than in their presence.
(Comment 16) Two comments stated that ``small numbers'' should be
based on epidemiological data and not on a percentage of the total
major species population. Commentors stated that since such
epidemiological data are not yet available, FDA should make minor use
designations on a case-by-case basis rather than setting hard numbers.
(Response) In the preamble to the proposed rule for MUMS
designation (70 FR 56394), the agency already rejected the idea of
establishing ``small numbers'' based on a percentage of the major
species population as overly simplistic. There the agency explained
that using the human orphan drug prevalence limit of 200,000 cases
(0.1% of the U.S. population in 1983) did not seem helpful for
calculating ``small numbers'' in cattle, swine, chickens, and turkeys
because the populations involved, the manner of drug use in those
populations, and the drug development processes for those species are
too dissimilar to the human drug scenario (70 FR 56394 at 56396).
Further analysis made clear that these factors were not sufficiently
comparable for this approach to be viable, even for dogs, cats, and
horses (70 FR 56394 at 56396). On the other hand, as already noted,
Congress directed the agency to define ``minor use'' and, by extension,
``small numbers,'' on the basis of determining whether a population of
animals of a major species needing drug treatment would provide
sufficient drug market value to offset the cost of drug development
given the incentives provided by the MUMS act.
The use of epidemiological data comes into play at the point that
the sponsor and the agency are trying to establish the population of
animals eligible to be treated with a particular drug for a particular
intended use. Such data need to be shared with the agency whether the
determination of minor use is being made on a case-by-case basis or
with respect to an established small number of animals.
(Comment 17) One comment stated that FDA should consider the
potential of a drug to be used extralabel when making a minor use
designation.
(Response) The agency understands the expressed concern regarding
extra-label drug use, but extra-label drug use is an issue that clearly
transcends the designation process. Extra-label use of approved new
animal drugs is statutorily permissible under specified circumstances.
(Extra-label use is not permitted for either conditionally approved or
indexed drugs because such drugs have not met the full approval
requirements of the statute.) There is no general prohibition regarding
the extra-label use in minor species of products approved for use in
major species or vice versa.
Therefore, under designation, a product designated and approved for
a minor species can be legally used in an extra-label manner in a major
species (subject to established statutory and regulatory conditions).
The same is true for a product designated for a minor use in a major
species. It is difficult enough to determine whether the population of
animals associated with the disease or condition for which a drug is
labeled for use fails to provide sufficient market value to offset the
cost of drug development (or falls above or below an established small
number of animals). It would be impossible to determine the population
of all animals subject to all potential extra-label uses of a drug. In
fact, it must be assumed that this population (which may include all
potential uses of a drug in all animal species) would very often exceed
a small number of animals. Therefore, consideration of potential extra-
label use in the designation process would have the effect of
essentially negating the designation provision of the statute and this
would clearly be contrary to the intent of the legislation.
(Comment 18) One comment stated that long term use of a drug, even
in a small number of animals, would constitute a much larger market
than for shorter term use and that FDA should not consider animal
numbers as ``small'' if food animals are to receive drugs for a long
duration, perhaps for a period longer than 21 days, consistent with
FDA's Guidance for Industry (GFI) 152.
(Response) As noted previously, the agency acknowledges the concern
regarding the use of drugs in food animals and accepts that the concept
of ``small numbers'' of animals included in the statutory definition of
minor use is based, in part, on this concern. The agency will address
the issue of establishing ``small numbers'' of animals for each major
species in future rulemaking. However, a full assessment of the
relative risks of individual drugs or drug uses is a matter that must
be left to the comprehensive analysis associated with the review of
individual new animal drug applications consistent with GFI
152 and other applicable policies and regulatory requirements.
IV. Legal Authority
FDA's authority for issuing this final rule is provided by the MUMS
act (21 U.S.C. 360ccc et seq.). When Congress passed the MUMS act, it
directed FDA to publish implementing regulations (see 21 U.S.C. 360ccc
note). In the context of the MUMS act, the statutory requirements of
section 573 of the act, along with section 701(a) of the act (21 U.S.C.
371(a)) provide authority for this final rule. Section 701(a)
authorizes the agency to issue regulations for the efficient
enforcement of the act.
V. Analysis of Economic Impacts
FDA has examined the impacts of the final rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and
the Unfunded Mandates Reform Act of 1995 (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,
[[Page 41015]]
environmental, public health and safety, and other advantages;
distributive impacts; and equity). The agency believes that this final
rule is not a significant regulatory action under the Executive order.
FDA finds that the final rule does not constitute an economically
significant regulatory action as defined in section 3(f)(1) of
Executive Order 12866. We believe that the annual impacts will not
exceed $100 million since by its very nature the rule applies to animal
drugs that have a very small market. 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 of 1995 requires
that agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $122 million, using the most current (2005) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
final rule to result in any 1-year expenditure that would meet or
exceed this amount.
FDA received nine comments to the proposed rule. Only two of these
comments contained any remarks that addressed the impacts analysis of
the proposed rule. Both stated that the requirement for a specific
development plan before a designation is granted would be too
burdensome. Neither of the comments provided any estimates on the size
of the burden that would be imposed. FDA responded previously in this
preamble to the burden issue in these comments. Further, FDA believes
that the development of the plan would not be overly burdensome
because, in most cases, it would be the same plan that a sponsor would
establish with FDA under the regular animal drug review process, and
because its cost, estimated at less than one thousand dollars each,
would represent less than 0.1% of revenues of even the smallest
establishments. Additionally, the MUMS act requires that FDA measure
the diligence with which sponsors work towards final approval of a
MUMS-designated drug, and a drug development plan is necessary for FDA
to measure a sponsor's progress towards this goal. FDA has therefore
not changed this provision in the final rule.
None of the changes made to the final rule would affect the
expected impacts of the rule on the animal drug producers. Accordingly,
lacking any other comments to its analysis of the proposed rule, FDA
has reviewed its impacts analysis published in the proposed rule and
retains it here for the final rule.
The intention of this rule, and therefore its benefit, is the
creation of a system that would stimulate the development and marketing
of animal drugs for rare diseases in major species and diseases found
in minor species in the United States, which would otherwise not be
economically viable under current market conditions. The countervailing
cost, or risk of this final rule, would be the possibility of limited
competition for approved drugs for a minor use drug indication or in a
minor species drug due to the granting of the 7-year exclusive
marketing right. In addition to the benefit-risk tradeoff mentioned
previously, there would be additional administrative costs for those
companies seeking the MUMS designation for a new animal drug
application (NADA). We estimate that the designation request would
require about 16 hours of preparation by a regulatory affairs official.
At a benefit adjusted wage rate of almost $48 per hour for these
employees, each request would have administrative costs of about
$760.\1\ We estimate that about 15 separate sponsors would each
annually submit, on average, 5 MUMS designation requests.
Administrative costs for these actions would total to about $57,300.
---------------------------------------------------------------------------
\1\ 2000 National Industry-Specific Occupational Employment and
Wage Estimates, U.S. Department of Labor, Bureau of Labor Statistics
(http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.bls.gov/oes/2000/oesi3_283.htm); Compliance officer wage rate
adjusted to 2005 by 2000-20004 average annual wage inflator at BLS
(http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://data.bls.gov/cgi-bin/surveymost).
---------------------------------------------------------------------------
The agency is also requiring in Sec. 516.22 that foreign sponsors
requesting designation do so through a permanent resident U.S. agent.
This is consistent with the current requirements of 21 CFR 514.1(a)
since requests for MUMS designation will ultimately be submitted to an
NADA file. The agency does not expect to receive many requests for
designation from foreign sponsors, and estimates that number at less
than one per year. As such, the agency has not quantified the cost of
this provision but believes it would be negligible.
Amendments made to existing designations are expected to occur
infrequently. We estimate that three amendments will be filed annually,
requiring about two hours of preparation. At the same wage rate, this
would cost an additional $300. Sponsors may also transfer sponsorship
of MUMS-designated drug or terminate the designation. We estimate that
these activities would result in only 3 additional hours of
administrative costs annually, totaling to $150. The preparation of the
annual report that would be required for each MUMS-designated drug is
estimated to take about 2 hours. In the first year, this would result
in another 150 hours of administrative costs, or about $7,200 in total.
FDA notifications to sponsors concerning insufficient quantities of
approved MUMS-designated drugs are expected to be rare, about once each
year. Sponsor responses are estimated to take 3 hours, at a cost of
$150.
Assuming a sponsor chooses to seek the MUMS designation for its
NADA, total administrative costs for this rule across all sponsors are
estimated at about $65,000 in the first year, and to increase each year
thereafter due to the annual reporting requirements.
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 along with other sections of this preamble
constitute the 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 a system,
provided for by statute, that would stimulate the development and
marketing of animal drugs for rare diseases in major species and
diseases found in minor species in the United States, which 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
[[Page 41016]]
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 designation would
likely be received from multi-establishment companies that exceed the
750-employee limit on small businesses. Nonetheless, the cost of
submitting a single request represents only about 0.1% of the revenues
of the smallest set of establishments (those with 1-4 employees), and
much smaller revenue percentages of all larger establishments. The
agency believes that these costs would not represent a significant
economic impact on these firms.
---------------------------------------------------------------------------
\2\ 2002 Economic Census, US Census Bureau, Manufacturing
Industry Series, Pharmaceutical Preparation Manufacturing, Table 4.
---------------------------------------------------------------------------
All of the costs described previously would be incurred by any
small business that applies for MUMS designation. These include costs
for request preparation, amendments to designations, preparing annual
reports and responding to FDA notifications of insufficient quantities.
The firms submitting requests for MUMS designation are expected to
already have the necessary administrative personnel with the skills
required to prepare the requests and fulfill reporting requirements as
identified previously.
2. Analysis of Alternatives
The Regulatory Flexibility Act requires that the agency consider
any alternatives to a rule that would accomplish the objective while
minimizing significant impacts of the rule. As stated previously, the
agency believes that the final rule, due to the relatively small costs,
would not be likely to impose significant economic impacts on small
businesses. As such, the agency believes the final rule achieves the
objective with minimal costs to industry.
The statute that creates this system, Public Law 108-282, does not
provide the agency a great deal of flexibility in the implementing
regulations, such as in determining the length of the exclusivity
period or granting an exclusivity to more than one animal drug without
regard to sameness of drug, dosage form and intended use. The agency
did consider, however, applying an explicit threshold number of animals
of each major species as the upper bound of disease incidence in the
definition of ``minor use'' of animal drugs. The agency determined that
the data needed to develop these estimates would not be available in
time for the publication date of the final rule as mandated by statute.
The agency intends in the future to propose a separate rule defining
the threshold numbers of animals of each major species. The agency will
continue to consider the acceptability of each request for designation
as a minor use animal drug on a case-by-case basis as provided for in
the Senate report concerning the legislation, until it issues any final
rule based on such a proposal.
VI. Paperwork Reduction Act of 1995
In the Federal Register of September 27, 2005, FDA published a
proposed rule and invited comments on the proposed collection of
information. Also in a Federal Register of December 28, 2005, FDA
published a notice reopening the comment period for the proposed rule
to allow interested persons additional time to comment. Concurrently,
FDA submitted the information collection request to the Office of
Management and Budget (OMB) for review and approval. OMB did not
approve this collection of information, but as terms for clearance,
filed comment. In filing comment on this collection of information, OMB
requested that FDA examine public comment in response to the notice of
proposed rulemaking and describe in the preamble of the final rule how
the agency has maximized the practical utility of the collection and
minimized the burden. Further, OMB requested for any future submissions
of this information collection, FDA indicate the submission as ``new''
and reference OMB control number 0910-0590.
In response to these Federal Register notices, FDA did not receive
any comments regarding the information collection requirements
contained in the final rule. In response to OMB's request that the
agency describe how it has maximized the practical utility of this
collection and minimized the burden, an explanation has been provided
elsewhere in the preamble of this final rule.
The information collection provisions of this final rule have been
submitted to OMB for review. Prior to the effective date of this final
rule, FDA will publish notice in the Federal Register, announcing OMB's
decision to approve, modify, or disapprove the information collection
provisions in this final rule. An agency may not conduct or sponsor,
and a person is not required to respond to a collection of information,
unless it displays a currently valid OMB control number.
Title: Designated New Animal Drugs for Minor Use and Minor
Species--21 CFR Part 516, OMB Control No. 0910-0590.
Description: The MUMS act amended (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 as well as uncommon diseases in major animal
species. This legislation provides incentives designed to help
pharmaceutical companies overcome the financial burdens they face in
providing limited-demand animal drugs. These incentives are only
available to sponsors whose drugs are ``MUMS-designated'' by FDA. Minor
use drugs are drugs for use in major species (cattle, horses, swine,
chickens, turkeys, dogs, and cats) that are needed for diseases that
occur in only a small number of animals either because they occur
infrequently or in limited geographic areas. Minor species are all
animals other than the major species, for example, zoo animals,
ornamental fish, parrots, ferrets, and guinea pigs. Some animals of
agricultural importance are also minor species. These include animals
such as sheep, goats, catfish, and honeybees. Participation in the MUMS
program is completely optional for drug sponsors so the associated
paperwork only applies to those sponsors who request and are
subsequently granted ``MUMS designation.'' The proposed rule will
specify the criteria and procedures for requesting MUMS designation as
well as the annual reporting requirements for MUMS designees.
Under the new part 516, Sec. 516.20 provides requirements on the
content and format of a request for MUMS-drug designation, Sec. 516.26
provides requirements for amending MUMS-drug designation, provisions
for change in sponsorship of MUMS-drug designation can be found under
Sec. 516.27, under Sec. 516.29 are provisions for termination of
MUMS-drug designation, under Sec. 516.30 are requirements for annual
reports from sponsor(s) of MUMS designated drugs, and under Sec.
516.36 are provisions for insufficient quantities of MUMS-designated
drugs.
Description of Respondents: Pharmaceutical companies that sponsor
new animal drugs.
FDA estimates the burden for this collection of information as
follows:
[[Page 41017]]
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
----------------------------------------------------------------------------------------------------------------
516.20 15 5 75 16 1,200
----------------------------------------------------------------------------------------------------------------
516.26 3 1 3 2 6
----------------------------------------------------------------------------------------------------------------
516.27 1 1 1 1 1
----------------------------------------------------------------------------------------------------------------
516.29 2 1 2 1 2
----------------------------------------------------------------------------------------------------------------
516.30 15 5 75 2 150
----------------------------------------------------------------------------------------------------------------
516.36 1 1 1 3 3
----------------------------------------------------------------------------------------------------------------
Total 1,362
----------------------------------------------------------------------------------------------------------------
\1\ There is no capital or operating and maintenance cost associated with this collection of information.
VII. Environmental Impact
We have carefully considered the potential environmental impacts of
this final rule and determined under 21 CFR 25.30(h) that this action
is of a type that does not individually or cumulatively have a
significant effect on the human environment. Therefore, neither an
environmental assessment, nor an environmental impact statement is
required.
VIII. Federalism
FDA has analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. FDA has determined that the rule
does not contain policies that have substantial direct effects on the
States, on the relationship between the National Government and the
States, or on the distribution of power and responsibilities among the
various levels of government. Accordingly, the agency has concluded
that the rule does not contain policies that have federalism
implications as defined in the Executive order and, consequently, a
federalism summary impact statement is not required.
List of Subjects
21 CFR Part 20
Confidential business information, Courts, Freedom of information,
Government employees.
21 CFR Part 510
Administrative practice and procedure, Animal drugs, Labeling,
Reporting and recordkeeping requirements.
21 CFR Parts 514 and 516
Administrative practice and procedure, Animal drugs, Confidential
business information, Reporting and recordkeeping requirements.
0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR
chapter I is amended as follows:
PART 20--PUBLIC INFORMATION
0
1. The authority citation for 21 CFR part 20 continues to read as
follows:
Authority: 5 U.S.C. 552; 18 U.S.C. 1905; 19 U.S.C. 2531-2582;
21 U.S.C. 321-393, 1401-1403; 42 U.S.C. 241, 242, 242a, 242l, 242n,
243, 262, 263, 263b-263n, 264, 265, 300u-300u-5, 300aa-1.
0
2. Amend Sec. 20.100 by adding paragraph (c)(43) to read as follows:
Sec. 20.100 Applicability; cross-reference to other regulations.
* * * * *
(c) * * *
(43) Minor-use or minor-species (MUMS) drug designations, in Sec.
516.52 of this chapter.
PART 510--NEW ANIMAL DRUGS
0
3. The authority citation for 21 CFR part 510 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 360b, 371, 379e.
0
4. Amend Sec. 510.3 by revising paragraph (k) to read as follows:
Sec. 510.3 Definitions and interpretations.
* * * * *
(k) Sponsor means the person requesting designation for a minor-use
or minor-species drug as defined in part 516 of this chapter, who must
be the real party in interest of the development and the intended or
actual production and sales of such drug (in this context, the sponsor
may be an individual, partnership, organization, or association).
Sponsor also means the person responsible for an investigation of a new
animal drug. In this context, the sponsor may be an individual,
partnership, corporation, or Government agency or may be a
manufacturer, scientific institution, or an investigator regularly and
lawfully engaged in the investigation of new animal drugs. Sponsor also
means the person submitting or receiving approval for a new animal drug
application (in this context, the sponsor may be an individual,
partnership, organization, or association). In all contexts, the
sponsor is responsible for compliance with applicable provisions of the
act and regulations.
PART 514--NEW ANIMAL DRUG APPLICATIONS
0
5. The authority citation for 21 CFR part 514 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 360b, 371, 379e,
381.
Sec. 514.1 [Amended]
0
6. Amend Sec. 514.1 by removing paragraph (d).
0
7. Add part 516 to read as follows:
PART 516--NEW ANIMAL DRUGS FOR MINOR USE AND MINOR SPECIES
Subpart A--General Provisions
Sec.
516.1 Scope.
516.2 Purpose.
516.3 Definitions.
Subpart B--Designation of a Minor Use or Minor Species New Animal Drug
516.11 Scope of this subpart.
516.12 Purpose.
516.13 Definitions.
516.14 Submission of requests for designation.
516.16 Eligibility to request designation.
516.20 Content and format of a request for MUMS-drug designation.
516.21 Documentation of minor use status.
516.22 Permanent-resident U.S. agent for foreign sponsor.
516.23 Timing of requests for MUMS-drug designation.
[[Page 41018]]
516.24 Granting MUMS-drug designation.
516.25 Refusal to grant MUMS-drug designation.
516.26 Amendment to MUMS-drug designation.
516.27 Change in sponsorship.
516.28 Publication of MUMS-drug designations.
516.29 Termination of MUMS-drug designation.
516.30 Annual reports for a MUMS-designated drug.
516.31 Scope of MUMS-drug exclusive marketing rights.
516.34 FDA recognition of exclusive marketing rights.
516.36 Insufficient quantities of MUMS-designated drugs.
516.52 Availability for public disclosure of data and information in
requests.
Subpart C--[Reserved]
Subpart D--[Reserved]
Authority: 21 U.S.C. 360ccc-2, 371.
Subpart A--General Provisions
Sec. 516.1 Scope.
(a) This part implements section 573 of the Federal Food, Drug, and
Cosmetic Act (the act) (21 U.S.C. 360ccc-2) and contains the following
subparts:
(1) Subpart A--General Provisions.
(2) Subpart B--Designation of a Minor Use or Minor Species New
Animal Drug.
(3) Subpart C--[Reserved]
(4) Subpart D--[Reserved]
(b) References in this part to regulatory sections of the Code of
Federal Regulations are to Chapter I of Title 21, unless otherwise
noted.
Sec. 516.2 Purpose.
This part establishes standards and procedures for implementing
section 573 of the act, including designation of minor use or minor
species new animal drugs and associated exclusive marketing rights.
Sec. 516.3 Definitions.
(a) The definitions and interpretations contained in section 201 of
the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 321)
apply to those terms when used in this part.
(b) The following definitions of terms apply to all subparts of
part 516:
Active moiety means the molecule or ion, excluding those appended
portions of the molecule that cause the drug to be an ester, salt
(including a salt with hydrogen or coordination bonds), or other
noncovalent derivative (such as a complex, chelate, or clathrate) of
the molecule, responsible for the pharmacological action of the drug
substance.
Functionally superior means that a drug has been shown to provide a
significant therapeutic or physiologic advantage over that provided by
a conditionally-approved or approved MUMS drug, that is otherwise the
same drug, in one or more of the following ways:
(i) The drug has been shown to be more effective, as assessed by
effect on a clinically meaningful endpoint in adequate and well-
controlled clinical trials, than a conditionally approved or approved
MUMS drug, that is otherwise the same drug. Generally, this would
represent the same kind of evidence needed to support a comparative
effectiveness claim for two different drugs; in most cases, direct
comparative clinical trials will be necessary; or
(ii) The drug has been shown to be safer than a conditionally-
approved or approved MUMS drug, that is otherwise the same drug, in a
substantial portion of the target population, for example, by the
elimination of an ingredient or contaminant that is associated with
relatively frequent adverse effects. In some cases, direct comparative
clinical trials will be necessary.
Infrequently, as used in the minor use definition, means a disease
or condition that is uncommon or that occurs only sporadically on an
annualized basis.
Limited geographical areas, as used in the minor use definition,
means regions of the United States distinguished by physical, chemical,
or biological factors that limit the distribution of a disease or
condition.
Major species means cattle, horses, swine, chickens, turkeys, dogs,
and cats.
Minor species means animals, other than humans, that are not major
species.
Minor use means the intended use of a drug in a major species for
an indication that occurs infrequently and in only a small number of
animals or in limited geographical areas and in only a small number of
animals annually.
MUMS drug means a new animal drug, as defined in section 201 of the
act, intended for a minor use or for use in a minor species.
Same dosage form means the same as one of the dosage forms
specified in the following parts of this chapter:
(i) Part 520: Oral dosage form new animal drugs (excluding use in
animal feeds as specified in part 558 of this chapter).
(ii) Part 522: Implantation or injectable dosage form new animal
drugs.
(iii) Part 524: Ophthalmic and topical dosage form new animal
drugs.
(iv) Part 526: Intramammary dosage forms.
(v) Part 529: Certain other dosage form new animal drugs.
(vi) Part 558: New animal drugs for use in animal feeds.
Same drug means a MUMS drug for which designation, indexing, or
conditional approval is sought that meets the following criteria:
(i) If it is a MUMS drug composed of small molecules and contains
the same active moiety as a prior designated, conditionally-approved,
or approved MUMS drug, even if the particular ester or salt (including
a salt with hydrogen or coordination bonds) or other noncovalent
derivative such as a complex, chelate or clathrate is not the same, it
is considered the same drug; except that, if the prior MUMS drug is
conditionally approved or approved and the second MUMS drug is shown to
be functionally superior to the conditionally approved or approved MUMS
drug for the same intended use, it is not considered the same drug.
(ii) If it is a MUMS drug composed of large molecules
(macromolecules) and contains the same principal molecular structural
features (but not necessarily all of the same structural features) as a
prior designated, conditionally approved, or approved MUMS drug, it is
considered the same drug; except that, if the prior MUMS drug is
conditionally approved or approved and the second MUMS drug is shown to
be functionally superior to the conditionally approved or approved MUMS
drug for the same intended use, it is not considered the same drug.
This criterion will be applied as follows to different kinds of
macromolecules:
(A) Two protein drugs would be considered the same if the only
differences in structure between them were due to post-translational
events or infidelity of translation or transcription or were minor
differences in amino acid sequence; other potentially important
differences, such as different glycosylation patterns or different
tertiary structures, would not cause the drugs to be considered
different unless the subsequent drug is shown to be functionally
superior.
(B) Two polysaccharide drugs would be considered the same if they
had identical saccharide repeating units, even if the number of units
were to vary and even if there were postpolymerization modifications,
unless the subsequent drug is shown to be functionally superior.
(C) Two polynucleotide drugs consisting of two or more distinct
nucleotides would be considered the same if they had an identical
sequence of purine and pyrimidine bases (or their derivatives) bound to
an identical sugar backbone (ribose, deoxyribose, or modifications of
these sugars), unless
[[Page 41019]]
the subsequent drug is shown to be functionally superior.
(D) Closely related, complex partly definable drugs with similar
pharmacologic intent would be considered the same unless the subsequent
drug is shown to be functionally superior.
Same intended use means an intended use of a MUMS drug, for which
designation, indexing, or conditional approval is sought, that is
determined to be the same as (or not different from) a previously
designated, conditionally approved, or approved intended use of a MUMS
drug. Same intended use is established by comparing two intended uses
and not by simply comparing the specific language by means of which the
intent is established in labeling in accordance with the following
criteria:
(i) Two intended uses are considered the same if one of the
intended uses falls completely within the scope of the other.
(ii) For intended uses associated with diseases or conditions with
multiple causative organisms, two intended uses are not considered the
same when they involve different causative organisms or different
subsets of causative organisms of that disease or condition when the
causative organisms involved can reliably be shown to be clinically
significant causes of the disease or condition.
(iii) Two intended uses of a drug are not considered the same if
they involve different intended species or different definable
subpopulations (including ``production classes'') of a species.
Sponsor means the person requesting designation for a MUMS drug who
must be the real party in interest of the development and the intended
or actual production and sales of such drug (in this context, the
sponsor may be an individual, partnership, organization, or
association). Sponsor also means the person responsible for an
investigation of a new animal drug (in this context, the sponsor may be
an individual, partnership, corporation, or Government agency or may be
a manufacturer, scientific institution, or an investigator regularly
and lawfully engaged in the investigation of new animal drugs). Sponsor
also means the person submitting or receiving approval for a new animal
drug application (in this context, the sponsor may be an individual,
partnership, organization, or association). In all contexts, the
sponsor is responsible for compliance with applicable provisions of the
act and regulations.
Subpart B--Designation of a Minor Use or Minor Species New Animal
Drug
Sec. 516.11 Scope of this subpart.
This subpart implements section 573 of the act. Specifically, this
subpart sets forth the procedures and requirements for submissions to
FDA of requests for designation of a new animal drug for a minor use or
a minor species.
Sec. 516.12 Purpose.
This subpart establishes standards and procedures for determining
eligibility for designation and the associated incentives and benefits
described in section 573 of the act, including a 7-year period of
exclusive marketing rights.
Sec. 516.13 Definitions.
The following definitions of terms apply only in the context of
subpart B 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.
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.
MUMS-designated drug means a new animal drug, as defined in section
201 of the act, intended for a minor use or for use in a minor species
that has been designated under section 573 of the act.
MUMS-drug exclusive marketing rights or exclusive marketing rights
means that, effective on the date of FDA conditional approval or
approval as stated in the approval letter of an application for a MUMS-
designated drug, no conditional approval or approval will be given to a
subsequent application for the same drug, in the same dosage form, for
the same intended use for 7 years, except as otherwise provided by law
or in this subpart.
Sec. 516.14 Submission of requests for designation.
All correspondence relating to a request for designation of a MUMS
drug must be addressed to the Director of the Office of Minor Use and
Minor Species Animal Drug Development. Submissions not including all
elements specified in Sec. 516.20 will be returned to the sponsor
without review.
Sec. 516.16 Eligibility to request designation.
The person requesting designation must be the sponsor and the real
party in interest of the development and the intended or actual
production and sales of the drug or the permanent-resident U.S. agent
for such a sponsor.
Sec. 516.20 Content and format of a request for MUMS-drug
designation.
(a) A sponsor that submits a request for designation of a new
animal drug intended for a minor use or minor species must submit each
request in the form and containing the information required in
paragraph (b) of this section. While a request for designation may
involve multiple intended uses, each request for designation must
constitute a separate submission. A sponsor may request MUMS-drug
designation of a previously unapproved drug, or a new intended use or
dosage form for an already conditionally approved or approved drug.
Only one sponsor may receive MUMS-drug designation of the same drug, in
the same dosage form, for the same intended use.
(b) A sponsor must submit two copies of a completed, dated, and
signed request for designation that contains the following information:
(1) A request for designation of a new animal drug for a minor use
or use in a minor species, which must be specific.
(2) The name and address of the sponsor; the name of the sponsor's
primary contact person and/or permanent-resident U.S. agent including
title, address, and telephone number; the generic and trade name, if
any, of the drug; and the name and address of the source of the drug.
(3) A description of the proposed intended use for which the drug
is being or will be investigated.
(4) A description of the drug and dosage form.
(5) A discussion of the scientific rationale for the intended use
of the drug; specific reference, including date(s) of submission, to
all data from nonclinical laboratory studies, clinical investigations,
copies of pertinent unpublished and published papers, and other
relevant data that are available to the sponsor, whether positive,
negative, or inconclusive.
(6) A specific description of the product development plan for the
drug, its dosage form, and its intended use.
(7) If the drug is intended for a minor use in a major species,
documentation in accordance with Sec. 516.21, with appended
authoritative references, to demonstrate that such use is a minor use.
(8) A statement that the sponsor submitting the request is the real
party in interest of the development and the intended or actual
production and sales of the product.
(9) A statement that the sponsor acknowledges that, upon granting a
[[Page 41020]]
request for MUMS designation, FDA will make information regarding the
designation publicly available as specified in Sec. 516.28.
Sec. 516.21 Documentation of minor use status.
So that FDA can determine whether a drug qualifies for MUMS-drug
designation as a minor use in a major species under section 573 of the
act, the sponsor shall include in its request to FDA for MUMS-drug
designation under Sec. 516.20 documentation demonstrating that the use
is limited to a small number of animals (annualized). This
documentation must include the following information:
(a) The estimated total number of animals to which the drug could
potentially be administered on an annual basis for the treatment,
control, or prevention of the disease or condition for which the drug
is being developed, including animals administered the drug as part of
herd or flock treatment, together with a list of the sources (including
dates of information provided and literature citations) for the
estimate.
(b) The estimated total number of animals referred to in paragraph
(a) of this section may be further reduced to only a subset of the
estimated total number of animals if administration of the drug is only
medically justified for this subset. To establish this, requestors must
demonstrate that administration of the drug to animals subject to the
disease or condition for which the drug is being developed other than
the subset is not medically justified. The sponsor must also include a
list of the sources (including dates of information provided and
literature citations) for the justification that administration of the
drug to animals other than the targeted subset is medically
inappropriate.
(c) An estimate of the potential market associated with the total
number of animals established in paragraph (a) of this section compared
to an estimate of the development costs of the proposed drug, in the
proposed dosage form, for the proposed intended use.
Sec. 516.22 Permanent-resident U.S. agent for foreign sponsor.
Every foreign sponsor that seeks MUMS-drug designation shall name a
permanent resident of the United States as the sponsor's agent upon
whom service of all processes, notices, orders, decisions,
requirements, and other communications may be made on behalf of the
sponsor. 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 sponsors. The name and address of the
permanent-resident U.S. agent shall be provided to the Director of the
Office of Minor Use and Minor Species Animal Drug Development.
Sec. 516.23 Timing of requests for MUMS-drug designation.
A sponsor may request MUMS-drug designation at any time in the drug
development process prior to the submission of an application for
either conditional approval or approval of the MUMS drug for which
designation is being requested.
Sec. 516.24 Granting MUMS-drug designation.
(a) FDA may grant the request for MUMS-drug designation if none of
the reasons described in Sec. 516.25 for refusal to grant such a
request apply.
(b) When a request for MUMS-drug designation is granted, FDA will
notify the sponsor in writing and will give public notice of the MUMS-
drug designation in accordance with Sec. 516.28.
Sec. 516.25 Refusal to grant MUMS-drug designation.
(a) FDA will refuse to grant a request for MUMS-drug designation if
any of the following reasons apply:
(1) The drug is not intended for use in a minor species or FDA
determines that there is insufficient evidence to demonstrate that the
drug is intended for a minor use in a major species.
(2) The drug is the same drug in the same dosage form for the same
intended use as one that already has a MUMS-drug designation but has
not yet been conditionally approved or approved.
(3) The drug is the same drug in the same dosage form for the same
intended use as one that is already conditionally approved or approved.
A drug that FDA has found to be functionally superior is not considered
the same drug as an already conditionally approved or approved drug
even if it is otherwise the same drug in the same dosage form for the
same intended use.
(4) The sponsor has failed to provide:
(i) A credible scientific rationale in support of the intended use,
(ii) Sufficient information about the product development plan for
the drug, its dosage form, and its intended use to establish that
adherence to the plan can lead to successful drug development in a
timely manner, and
(iii) Any other information required under Sec. 516.20.
(b) FDA may refuse to grant a request for MUMS-drug designation if
the request for designation contains an untrue statement of material
fact or omits material information.
Sec. 516.26 Amendment to MUMS-drug designation.
(a) At any time prior to conditional approval or approval of an
application for a MUMS-designated drug, the sponsor may apply for an
amendment to the designated intended use if the proposed change is due
to new and unexpected findings in research on the drug, information
arising from FDA recommendations, or other unforeseen developments.
(b) FDA will grant the amendment if it finds:
(1) That the initial designation request was made in good faith;
(2) That the amendment is intended to make the MUMS-drug designated
intended use conform to the results of new and unexpected findings in
research on the drug, information arising from FDA recommendations, or
other unforeseen developments; and
(3) In the case of a minor use, that as of the date of the
submission of the amendment request, the amendment would not result in
the intended use of the drug no longer being considered a minor use.
Sec. 516.27 Change in sponsorship.
(a) A sponsor may transfer sponsorship of a MUMS-designated drug to
another person. A change of sponsorship will also transfer the
designation status of the drug which will remain in effect for the new
sponsor subject to the same conditions applicable to the former sponsor
provided that at the time of a potential transfer, the new and former
sponsors submit the following information in writing and obtain
permission from FDA:
(1) The former sponsor shall submit a letter to FDA that documents
the transfer of sponsorship of the MUMS-designated drug. This letter
shall specify the date of the transfer. The former sponsor shall also
certify in writing to FDA that a complete copy of the request for MUMS-
drug designation, including any amendments to the request, and
correspondence relevant to the MUMS-drug designation, has been provided
to the new sponsor.
(2) The new sponsor shall submit a letter or other document
containing the following information:
(i) A statement accepting the MUMS-drug designated file or
application;
(ii) The date that the change in sponsorship is intended to be
effective;
(iii) A statement that the new sponsor has a complete copy of the
request for
[[Page 41021]]
MUMS-drug designation, including any amendments to the request and any
correspondence relevant to the MUMS-drug designation;
(iv) A statement that the new sponsor understands and accepts the
responsibilities of a sponsor of a MUMS-designated drug established
elsewhere in this subpart;
(v) The name and address of a new primary contact person or
permanent resident U.S. agent; and
(vi) Evidence that the new sponsor is capable of actively pursuing
approval with due diligence.
(b) No sponsor may relieve itself of responsibilities under the act
or under this subpart by assigning rights to another person without:
(1) Assuring that the new sponsor will carry out such
responsibilities; and
(2) Obtaining prior permission from FDA.
Sec. 516.28 Publication of MUMS-drug designations.
FDA will periodically update a publicly available list of MUMS-
designated drugs. This list will be placed on file at the FDA Division
of Dockets Management, and will contain the following information for
each MUMS-designated drug:
(a) The name and address of the sponsor;
(b) The established name and trade name, if any, of the drug;
(c) The dosage form of the drug;
(d) The species and the proposed intended use for which MUMS-drug
designation was granted; and
(e) The date designation was granted.
Sec. 516.29 Termination of MUMS-drug designation.
(a) The sponsor of a MUMS-designated drug must notify FDA of any
decision to discontinue active pursuit of conditional approval or
approval of such MUMS drug. FDA must terminate the designation upon
such notification.
(b) A conditionally-approved or approved MUMS-designated drug
sponsor must notify FDA at least 1 year before it intends to
discontinue the manufacture of such MUMS drug. FDA must terminate
designation upon such notification.
(c) MUMS designation shall terminate upon the expiration of any
applicable period of exclusive marketing rights under this subpart.
(d) FDA may terminate designation if it independently determines
that the sponsor is not actively pursuing conditional approval or
approval with due diligence. At a minimum, due diligence must be
demonstrated by:
(1) Submission of annual progress reports in a timely manner in
accordance with Sec. 516.30 that demonstrate that the sponsor is
progressing in accordance with the drug development plan submitted to
the agency under Sec. 516.20 and
(2) Compliance with all applicable requirements of part 511 of this
chapter.
(e) Designation of a conditionally approved or approved MUMS-
designated drug and the associated exclusive marketing rights may be
terminated if the sponsor is unable to provide sufficient quantities of
the drug to meet the needs for which it is designated.
(f) FDA may also terminate MUMS-drug designation for any drug if
the agency finds that:
(1) The request for designation contained an untrue statement of
material fact; or
(2) The request for designation omitted material information
required by this subpart; or
(3) FDA subsequently finds that the drug in fact had not been
eligible for MUMS-drug designation at the time of submission of the
request;
(4) The same drug, in the same dosage form, for the same intended
use becomes conditionally approved or approved for another sponsor; or
(5) FDA withdraws the conditional approval or approval of the
application for the new animal drug.
(g) For a conditionally approved or approved drug, termination of
MUMS-drug designation also terminates the sponsor's exclusive marketing
rights for the drug but does not withdraw the conditional approval or
approval of the drug's application.
(h) Where a drug has been MUMS-designated for a minor use in a
major species, its designation will not be terminated on the grounds
that the number of animals to which the drug could potentially be
administered on an annual basis for the treatment, control, or
prevention of the disease or condition for which the drug is being
developed, including animals administered the drug as part of herd or
flock treatment, subsequently increases.
(i) When a MUMS-drug designation is terminated, FDA will notify the
sponsor in writing and will give public notice of the termination of
the MUMS-drug designation.
Sec. 516.30 Annual reports for a MUMS-designated drug.
Within 14 months after the date on which a MUMS drug is granted
designation and annually thereafter until approval, the sponsor of a
MUMS-designated drug shall submit a brief progress report on the drug
to the investigational new animal drug file addressed to the Director
of the Office of Minor Use and Minor Species Animal Drug Development
that includes the following information:
(a) A short account of the progress of drug development including a
description of studies initiated, ongoing, and completed, and a short
summary of the status or results of such studies;
(b) A description of the investigational plan for the coming year,
as well as any anticipated difficulties in development, testing, and
marketing; and
(c) A brief discussion of any changes that may affect the MUMS-
designated drug status of the product. For example, situations in which
testing data demonstrate that the proposed intended use is
inappropriate due to unexpected issues of safety or effectiveness.
Sec. 516.31 Scope of MUMS-drug exclusive marketing rights.
(a) After conditional approval or approval of an application for a
MUMS-designated drug in the dosage form and for the intended use for
which MUMS-drug designation has been granted, FDA will not
conditionally approve or approve another application or abbreviated
application for the same drug in the same dosage form for the same
intended use before the expiration of 7 years after the date of
conditional approval or approval as stated in the approval letter from
FDA, except that such an application can be conditionally approved or
approved sooner if, and at such time as, any of the following occurs:
(1) FDA terminates the MUMS-drug designation and associated
exclusive marketing rights under Sec. 516.29; or
(2) FDA withdraws the conditional approval or approval of the
application for the drug for any reason; or
(3) The sponsor with exclusive marketing rights provides written
consent to FDA to conditionally approve or approve another application
before the expiration of 7 years; or
(4) The sponsor fails to assure a sufficient quantity of the drug
in accordance with section 573 of the act and Sec. 516.36.
(b) If an application for a MUMS drug cannot be approved until the
expiration of the period of exclusive marketing of a MUMS-designated
drug, FDA will so notify the sponsor in writing.
Sec. 516.34 FDA recognition of exclusive marketing rights.
(a) FDA will send the sponsor (or the permanent-resident U.S.
agent, if applicable) timely written notice recognizing exclusive
marketing rights when an application for a MUMS-
[[Page 41022]]
designated drug has been conditionally approved or approved. The
written notice will inform the sponsor of the requirements for
maintaining MUMS-designated drug exclusive marketing rights for the
full 7-year term. This notice will generally be contained in the letter
conditionally approving or approving the application.
(b) When an application is conditionally approved or approved for a
MUMS-designated drug that qualifies for exclusive marketing rights, FDA
will publish this information in the Federal Register at the time of
the conditional approval or approval. This notice will generally be
contained in the notice of conditional approval or approval of the
application.
Sec. 516.36 Insufficient quantities of MUMS-designated drugs.
(a) Under section 573 of the act, whenever FDA has reason to
believe that sufficient quantities of a conditionally-approved or
approved, MUMS-designated drug to meet the needs for which the drug was
designated cannot be assured by the sponsor, FDA will so notify the
sponsor of this possible insufficiency and will offer the sponsor the
following options, one of which must be exercised by a time that FDA
specifies:
(1) Provide FDA information and data regarding how the sponsor can
assure the availability of sufficient quantities of the MUMS-designated
drug within a reasonable time to meet the needs for which the drug was
designated; or
(2) Provide FDA in writing the sponsor's consent for the
conditional approval or approval of other applications for the same
drug before the expiration of the 7-year period of exclusive marketing
rights.
(b) If, within the time that FDA specifies, the sponsor fails to
consent to the conditional approval or approval of other applications
and if FDA finds that the sponsor has not shown that it can assure the
availability of sufficient quantities of the MUMS-designated drug to
meet the needs for which the drug was designated, FDA will issue a
written order terminating designation of the MUMS drug and the
associated exclusive marketing rights. This order will state FDA's
findings and conclusions and will constitute final agency action. An
order terminating designation and associated exclusive marketing rights
may issue whether or not there are other sponsors that can assure the
availability of alternative sources of supply. Such an order will not
withdraw the conditional approval or approval of an application. Once
terminated under this section, neither designation, nor exclusive
marketing rights may be reinstated.
Sec. 516.52 Availability for public disclosure of data and
information in requests.
(a) FDA will not publicly disclose the existence of a request for
MUMS-drug designation under section 573 of the act prior to final FDA
action on the request unless the existence of the request has been
previously publicly disclosed or acknowledged.
(b) Whether or not the existence of a pending request for
designation has been publicly disclosed or acknowledged, no data or
information in the request are available for public disclosure prior to
final FDA action on the request.
(c) Except as provided in paragraph (d) of this section, upon final
FDA action on a request for designation, the public availability of
data and information in the request will be determined in accordance
with part 20 of this chapter and other applicable statutes and
regulations.
(d) In accordance with Sec. 516.28, FDA will make a cumulative
list of all MUMS-drug designations available to the public and update
such list periodically. In accordance with Sec. 516.29, FDA will give
public notice of the termination of all MUMS-drug designations.
Subpart C--[Reserved]
Subpart D--[Reserved]
Dated: March 12, 2007.
Jeffrey Shuren,
Assistant Commissioner for Policy.
Editorial Note: This document was received at the Office of the
Federal Register on July 23, 2007.
[FR Doc. E7-14444 Filed 7-25-07; 8:45 am]
BILLING CODE 4160-01-S