[Federal Register Volume 70, Number 186 (Tuesday, September 27, 2005)]
[Proposed Rules]
[Pages 56394-56409]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-19196]
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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: Proposed 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 proposed regulations
to implement the act. These regulations propose 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: Submit written or electronic comments on this document by
December 12, 2005. Submit comments on the information collection
provisions by October 27, 2005.
ADDRESSES: You may submit comments, identified by Docket No. 2005N-0329
and/or RIN number 0910-AF60, 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 timely processing of electronic 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 and agency Web site, as described in the
Electronic Submissions portion of this paragraph.
Instructions: All submissions received must include the agency name
and docket number or regulatory information number 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 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.
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 (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 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 these animal drugs. 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 (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.
At this time, FDA is issuing proposed regulations to implement
section 573 of the act (21 U.S.C. 360ccc-2). These regulations propose
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. In accordance with section 573 of the act,
these proposed regulations provide for designation of a new animal drug
to be granted only when the drug is intended for a minor use or use in
a minor species and only when the same new animal drug, in the same
dosage form, for the same intended use is not already approved under
section 512 of the act (21 U.S.C. 360b), conditionally approved under
section 571 of the act (21 U.S.C. 360ccc), or designated under section
573 of the act at the time that a sponsor requests designation.
The incentives in the MUMS act and these proposed regulations are
modeled on those provided by the human orphan drug program. These
incentives include the following: (1) 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 and (2) a 7-year period of exclusive
marketing rights to enable sponsors to recover costs of drug
development without competition. Marketing exclusivity for
nondesignated drugs is limited to 3 or 5 years of protection from
generic copying (section 512(c)(2)(F) of the act). The exclusive
marketing rights for designated drugs provide protection from generic
copying and from approval of another pioneer application for the same
drug, in the same dosage form, for the same intended use.
Other major incentives of the MUMS act include the following: (1)
Conditional approval, which is
[[Page 56395]]
established by section 571 of the act and 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 (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) and (2) indexing, which is established
by section 572 of the act (21 U.S.C. 360ccc-1) and provides for legal
marketing of unapproved new animal drugs through an integrated process
of agency and expert panel review of drugs intended only for use in
minor species. Regulations to implement these provisions of the MUMS
act will be proposed in the future.
II. Proposed Regulations
A. Definitions (Proposed Sec. Sec. 516.3 and 516.13)
Under the MUMS act, there are two key factors in determining the
eligibility of a new animal drug for designation: (1) The new animal
drug must be intended for minor use or use in a minor species and (2)
the new animal drug must not be the same drug, in the same dosage form,
and for the same intended use as an animal drug already designated,
conditionally approved, or approved. The agency is proposing
definitions for terms or phrases relevant to the proposed regulations.
Discussion regarding key definitions follows.
1. Minor Species
The MUMS act defines minor species as animals other than humans
that are not major species. The MUMS act defines major species as
cattle, horses, swine, chickens, turkeys, dogs, and cats, along with
any species the Secretary of Health and Human Services adds to this
definition by regulation (see section 201(nn) and (oo) of the act (21
U.S.C. 321 (nn) and (oo)).) The proposed rule includes these
definitions for ``major species'' and ``minor species'' in proposed
Sec. 516.3(b)(5) and (b)(6).
2. Minor Use
The MUMS act defines ``minor use'' to mean ``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'' (section 201(pp) of the
act).
With respect to the definition of minor use, the Senate report (S.
Rept. 108-226) concerning the bill before the Senate (S. 741), which
included proposed definitions and a section on the designation of new
animal drugs that were identical to those contained in the MUMS
legislation enacted by Congress, stated the following:
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.)
As is clear from the quoted discussion in the Senate report,
Congress incorporated part of FDA's existing definition of ``minor
use'' in Sec. 514.1 (21 CFR 514.1) into the MUMS act definition of
``minor use.'' In 1983 FDA issued a definition of ``minor use'' as part
of regulations to provide for the agency's interpretation as to what
data for minor use drugs would be sufficient to meet the current
statutory standards (see 48 FR 1922, January 14, 1983). FDA's
definition of ``minor use'' included use of drugs ``in any animal
species for the control of a disease that (1) occurs infrequently or
(2) occurs in limited geographic areas'' (Sec. 514.1(d)(1)(i)). Thus,
minor use was previously only defined qualitatively by one of two
factors that limited the size of the population needing treatment. The
first limiting factor was that a disease occurred infrequently (i.e.,
rarely) in the total population of animals. FDA believes that the term
``infrequently'' includes both diseases or conditions that are uncommon
in that they have a low but regular rate of occurrence over time in a
given population and diseases or conditions that occur only
sporadically as irregular outbreaks in a given population with a
significantly higher rate of occurrence than normal when they occur and
may not occur at all between outbreaks. The second limiting factor was
that a disease or condition occurred in only a limited geographic area.
With the MUMS act, in respect to minor uses in major species,
Congress added a ``small number'' limitation to both prongs of FDA's
earlier definition: ``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'' (21 U.S.C. 321(pp)). The
Senate report indicates that the ``small number'' limitation added to
both prongs was to ensure that the intended uses would not be
``extended to a wider use.'' (S. Rept. 108-226 at 12). By doing this,
Congress not only required that the population of animals be limited by
one of the two qualitative factors, but also required that, in either
case, the population of animals affected must also meet the ``small
number'' quantitative criteria. As a result, while some indications may
be infrequent (because they are uncommon or occur only sporadically),
they must also meet the requirement that they occur in only a small
number of animals. Similarly, an indication may occur in a limited
geographical area, but it must also occur in only a small number of
animals annually. Congress defined ``minor use'' populations as limited
to a ``small number,'' but did not specify the small number(s), leaving
it to the agency to further clarify the definition in this regard by
regulation.
With respect to the term ``infrequently,'' the Senate report states
that FDA should determine whether the ``incidence'' of the disease
``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'' (S. Rept. 108-226 at 12-
13). With respect to both prongs of the ``minor use'' definition,
Congress did not intend FDA to establish a test of commercial value,
but rather to determine ``whether the expected low use of a drug would
discourage its development'' (S. Rept. 108-226 at 13). Consequently,
FDA in these regulations has not established a dollar value or profit
margin criterion in relation to ``minor use.''
The term ``annually'' only appears in the second prong of the
statutory definition of ``minor use'' in connection with the small
number of animals with the disease ``in limited geographical areas.''
Thus, a minor use indication that occurs in a limited geographical area
must also occur in a small number of animals annually. While
``annually'' does not apply to the first prong of the definition of
minor use, ``infrequently and in only a small number of animals'', FDA
believes that for ``a small numbers of animals'' to have meaning, data
on the number of animals in which the indication occurs must be
considered
[[Page 56396]]
over a period of time. FDA believes that to give effect to the
statutory language, it is appropriate to annualize the data. For
example, if a particular disease appears only once every 5 years, the
number of animals may be relatively large, but when annualized, the
disease may occur in only a ``small number of animals.'' Looking at
annualized numbers of affected animals is a reasonable approach under
the ``minor use'' definition to considering whether there are
sufficient drug development incentives in the absence of the MUMS
incentives.
The term ``limited geographical areas'' is defined in proposed
section 516.3(b)(4) as follows: ``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.'' If, for example, an area's mineral profile or moisture
availability (chemical factors) can cause a medical condition directly
(nutrient deficiency) or indirectly (suitable environment for specific
parasites or bacteria), the case may be argued that the condition will
only affect animals in that particular region. Chemical factors might
also include possible environmental exposure to pesticides or other
toxins used in a limited area. Physical factors such as altitude,
proximity to salt or fresh water, or temperature can also influence the
presence of parasites, vectors for parasites, as well as other
microbes. These factors can also influence an animal's susceptibility
to disease directly (high altitude disease) or indirectly if conditions
cause stresses that weaken the immune system. Biological factors
include the presence of vectors for disease, presence of toxic plants,
and inherent limitations of a species to live in a particular
environment (e.g., saltwater versus freshwater fish).
As is clear from the minor use definition, geographic limitations
alone will not be sufficient to make a particular intended use a minor
use in a major species. The number of animals that live in a particular
limited geographic area can still be very large. It was clearly the
intent of Congress to limit the definition of minor use to a small
number of animals and that is the intent of the definitions included in
this proposed rule.
Small Number of Animals
The agency intends at some time in the future to propose that
``small number of animals'' be defined in regulations as a specific
number for each of the seven major species. However, the number of
animals that will provide the upper limit for the definition of ``small
number of animals'' for each major species is, at this time, difficult
to identify. Many factors need to be considered in establishing these
numbers.
With respect to defining minor use, and by implication ``small
number of animals,'' Congress further noted in the Senate report (S.
Rept. 108-226) accompanying the MUMS act that:
FDA may initially make such determinations on a case-by-case
basis. These initial determinations may form the basis for
establishing or revising regulations which clarify the grounds or
the process for determining whether a new animal drug is intended
for a ``minor use''.
(S. Rept. 108-226 at 13).
Therefore, at this time, the agency is proposing only to clarify
various other aspects of the current statutory definition of minor use,
to gather further information to support the establishment of a ``small
number of animals'' for each major species, and to use the information
currently available to make minor use determinations on a case-by-case
basis. The agency particularly requests comment on the criteria it
should use to determine the number that constitutes a ``small number of
animals'' for each major species. Comments should clearly explain the
rationale for any criteria suggested including economic, scientific, or
other relevant factors. In an effort to stimulate comment and to
increase the specificity of comments, the agency has summarized in the
following paragraphs certain information it has considered to date
regarding defining ``small number of animals.''
a. Human orphan drugs as a model. For human orphan drugs, the act
provides that a disease or condition that affects less than 200,000
cases in the United States qualifies as a ``rare disease or condition''
(21 U.S.C. 360bb(a)(2)). As one approach to defining ``small number of
animals'' for the purpose of implementing the MUMS act, the agency
determined what percentage of the U.S. population of humans the number
200,000 represented when Congress enacted this meaning of ``rare
disease or condition.'' This calculation provided a figure of roughly
0.1 percent of the population. This percentage was then applied to
populations of major species in the United States. Initial analysis
indicated that using the 0.1 percent figure might be helpful with
respect to dogs, cats, and horses. However, using this figure did not
seem helpful for 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. Further analysis made clear that these factors
were not sufficiently comparable for this approach to be viable, even
for dogs, cats, and horses, and the approach was rejected.
While FDA recognizes classes of animals within species in the
animal drug development process (examples include beef versus dairy
cattle and broiler versus laying chickens), the diversity of these
classes and the difficulty in determining whether a disease or
condition might be unique to a class would make using these
subpopulations of a species problematic in determining a maximum number
of animals for a minor disease or condition. Therefore, using one
maximum number would appear to be appropriate for animal species as
well as humans, because for each major animal species the small number
is intended to be a reflection of the market potential for a drug. It
is immaterial whether that market potential exists because the disease
or condition is relatively evenly distributed throughout the population
or is largely confined to a particular age, gender, breed, or
production class within that population. If the same number of animals
is involved in each case, the market potential is essentially the same
in each case. Therefore, one number appears to be appropriate as a
means of determining the ``small number'' for a ``minor use'' for each
of the seven species, regardless of subpopulations.
b. Characterizing the population of animals affected by a disease
or condition. The human orphan drug maximum number for ``rare disease
or condition'' is based on the prevalence of a disease or condition.
That is the total number of people affected by the disease or condition
at a given time. This differs from the incidence of a disease or
condition, which is the number of new cases diagnosed over a period of
time, e.g., the number of cases diagnosed per year. For several
reasons, using prevalence of disease or condition is problematic for
determining the number of animals for MUMS designation purposes.
In the case of cattle, swine, chickens, and turkeys, the number of
animals affected with a given disease or condition at a given time does
not take into account the fact that for animals like broiler chickens,
the lifespan is so short that several flocks will go through the same
facility in a year. Therefore, the number of birds potentially ill and/
or treated over a year is much greater than the population that is ill
on any
[[Page 56397]]
given day. This suggests that the use of an incidence rate would be
more appropriate in such cases.
However, incidence rates alone are also an imperfect descriptor
even in the case of cattle, swine, chickens, and turkeys. The number of
animals diagnosed with a disease or condition does not accurately
reflect the number that will be administered a drug. For example, in
the case of chickens, treatment of individual birds is impractical.
When there is an outbreak of disease the entire flock is treated,
including individuals with no signs of illness. In an attempt to limit
minor use to a small number of animals, the way that drugs are actually
administered should be taken into account. The number should refer to
all birds administered a drug, not just to those clinically ill. This
is significant for the determination of small number of animals because
the actual size of the market is larger than the number of sick birds.
A similar situation exists with respect to drugs intended for diagnosis
or prevention of a disease or condition in major species. Such drugs
will be subject to the same small number as those intended for
treatment of a disease or condition.
Prevalence rates can be more appropriately used for horses, dogs,
and cats because these animals' life spans typically exceed 1 year.
Such animals are likely to be treated for chronic diseases over several
years. These are added to newly diagnosed cases to provide the
prevalence of the disease.
The number of humans diagnosed with a disease or condition (i.e.,
the prevalence of a disease in humans) is a close approximation of the
number that will be treated for that disease or condition, if a
treatment exists. For animals, there may be a very significant
difference in the numbers of animals afflicted with a disease or
condition and the number that will actually be diagnosed and treated.
Many animals do not get regular veterinary care and, therefore, the
probability of diagnosis is lower for animals than for humans.
Furthermore, depending on the diagnosis, prognosis, and cost, a much
higher percentage of animals will not be treated even after diagnosis.
Economic issues figure prominently in the calculation of the number
of animals that will be treated for a disease or condition. In contrast
to human medicine, there is essentially no third-party payment for
animal drugs. Thus, cost for the treatment of animals is a major
consideration. Because euthanasia is an option for animals, expensive
or difficult treatment may be rejected by animal owners. On the other
hand, because dogs, cats, and horses may be highly valued as ``family
members,'' the amount of money expended on individual animals of these
species may far exceed that generally spent on individuals of the other
major species of animals.
In the case of animals of agricultural importance, the decision to
treat is based almost entirely on economic factors. In the case of
chickens, where the profit margin is pennies per bird, it is often not
worthwhile to treat.
It appears that for dogs, cats, and horses, the market potential
for a drug at the time of its designation is reasonably represented by
the total number of cases of the disease or condition estimated to
exist over the course of a year at the time of a request for
designation, taking into consideration that only a portion of the total
affected population will actually be treated.
In the case of cattle, swine, chickens, and turkeys, the market
potential for a drug at the time of its designation is reasonably
represented by an estimation of the number of cases of a disease or
condition that will occur in the total population of animals that will
be alive over the course of a year at the time of a request for
designation, taking into consideration that herd[sol]flock treatment
increases the number of animals administered a drug, and also taking
into consideration that only a portion of the total affected population
(and associated herd/flock mates) will actually be treated.
c. Other information to be considered. The agency is seeking
information to help clarify three general issues with respect to each
major animal species:
The cost of drug development for a new chemical entity,
adding an intended use for a new major species to a drug already
approved for an intended use in another major species, and adding a new
intended use to an existing approved drug for the same major species;
The annual return on investment over a 7-year period
necessary to stimulate the development of each of the previously
mentioned costs; and
The number of animals eligible to be administered the drug
on an annual basis necessary to produce these returns on investment.
The information made available to FDA from all sources will be
analyzed and used to establish the ``small numbers of animals'' for
each major species needed to complete the clarification of the
definition of minor use in major species. The agency reiterates its
request for comment and solicits as much additional information as
those commenting are willing to share regarding this issue. The FDA
emphasizes that it is not now proposing a specific small number of
animals for each major species, but is only proposing to establish such
numbers in the future after it has collected additional information. In
the meantime, it is proposing to make such decisions on a case-by-case
basis using the best information available at the time a decision is
required.
3. Same Drug/Same Dosage Form/Same Intended Use
For a new animal drug to be eligible for designation under section
573 of the act, it must be intended for minor use or use in a minor
species and must not be the same drug, in the same dosage form, for the
same intended use as an animal drug already designated, conditionally
approved, or approved. Therefore, the agency is also proposing to
define ``same drug,'' ``same dosage form,'' and ``same intended use''
in proposed section 516.3.
a. Same drug. The first test of sameness to determine eligibility
of an animal drug for designation is ``same drug.'' The legislative
history of the MUMS act in Senate Committee Report 108-226 states:
The Secretary has discretion to define the term ``same drug'' as
used in this section. In defining ``same drug'' the Secretary should
take into account the purpose of this legislation to promote the
development of minor use and minor species new animal drugs. A
sponsor should be able to reap the benefits of designation only for
products that are materially different from products that have
already been approved, conditionally approved, or designated. So,
for example, where two products differ only with respect to one or
more inactive ingredients, they are the ``same drug'' for purposes
of this section.
(S. Rept. 108-226 at 19).
The definition of ``same drug'' contained in this proposed rule is
intended to give protection to the first conditionally-approved or
approved MUMS-designated drug against a second sponsor's attempts to
defeat exclusive marketing rights by introducing minor molecular
changes. Because one goal of the MUMS act is to increase the
availability of new animal drugs for minor species and minor uses, a
subsequent drug with minor chemical differences will be considered
different only if the subsequent drug can be shown to be functionally
superior to the first. The burden of proof is on the sponsor of the
subsequent drug to demonstrate that its drug is safer or more effective
in some way.
FDA is proposing this approach because it provides the best
available mechanism to protect the integrity of
[[Page 56398]]
marketing exclusivity, the chief incentive for MUMS drug development
established by Congress, while allowing functionally superior drugs
with similar chemical structure to be approved in a timely manner. This
proposal is consistent with the human orphan drug regulations as
codified in 21 CFR part 316 (see 21 CFR 316.3(b)(13)).
Functional superiority of a subsequent drug cannot be determined
until the first drug is conditionally approved or approved because an
unapproved drug has no labeled dosage and corresponding safety and
effectiveness profile to which the challenger can be compared.
Therefore, a sponsor of a subsequent drug with minor chemical
differences from a MUMS-designated drug may not seek designation of the
subsequent drug based on functional superiority until after the
designated drug is conditionally approved or approved. If a drug is
found to be functionally superior to a designated new animal drug after
the designated drug is approved or conditionally approved, it will be
considered a different drug and may be granted MUMS designation. After
conditional approval or approval, it will enjoy its own 7-year period
of exclusive marketing rights and the first drug's designation,
conditional approval or approval, and period of exclusive marketing
will remain in effect.
b. Same dosage form. The second test of sameness which the statute
establishes to determine eligibility of an animal drug for designation
is ``same dosage form.'' The agency proposes to use the long-
established dosage form categories listed in Title 21 of the Code of
Federal Regulations to implement this statutory requirement.
The categories follow: Oral dosage forms (21 CFR 520), implantation
or injectable dosage forms (21 CFR 522), ophthalmic and topical dosage
forms (21 CFR 524), intramammary dosage forms (21 CFR 526),
miscellaneous dosage forms (21 CFR 529), and drugs in animal feeds (21
CFR 558).
Dosage forms that do not clearly fit within a specific category
would fall within the miscellaneous category and the sameness of dosage
form would be determined on a case-by-case basis. Drugs currently in
the miscellaneous category include, for example, products administered
by inhalation to terrestrial animals and products formulated for use by
immersion of aquatic species. Although medicated animal feeds (i.e.,
drugs in animal feeds) have much in common with certain oral dosage
forms, they are treated as a separate category because they are
regulated quite differently. For example, drugs for use in animal feeds
are subject to different manufacturing practices than other drugs and
may not be used in an extralabel manner (21 CFR 530.11(b)). Thus, they
are treated as separate dosage forms for purposes of implementing the
MUMS act.
c. Same intended use. The third test of sameness which the statute
establishes to determine the eligibility of an animal drug for
designation is ``same intended use.'' ``Intended use'' is defined in
proposed 516.3(b)(11) for the purposes of subpart B of part 516 as
``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.'' Although this definition is
generally consistent with the manner in which the phrase has been used
in the context of new animal drug approval, the definition proposed
here is to be applied solely to the phrase ``intended use'' as it is
used in these proposed regulations to determine whether two intended
uses are the ``same intended use'' for purposes of qualifying for
designation. It is not meant to define ``intended use'' in any other
context. This interpretation of ``intended use'' for the purpose of
designation is meant to protect the value of the exclusivity incentive
provided by the statute. Because there can only be one designation for
the ``same drug,'' ``same dosage form,'' and ``same intended use,'' it
is important that a minor difference in the intended use not permit a
second sponsor to be granted designation for virtually the same
product. For the purpose of new animal drug approval, it is important
that every intended use to be included on the label be supported by
data. Thus, the definition of ``intended use'' for purposes of
designation reflects the need to protect product exclusivity.
Accordingly, the agency identified four basic principles for
evaluating whether two intended uses represent the ``same intended
use.'' The first principle of ``same intended use'' establishes that
whether two intended uses are considered the same, will not depend on
whether exactly the same words are used to describe that intent on the
labels of the products. Despite attempts over the years by FDA to
increase the consistency of labeled intended uses (often also referred
to as indications or claims), there remain many different ways to state
the same intended use on a label. Differences in language alone do not
necessarily result in different intended uses in the context of drug
designation. For example, a disease or a causative organism may be
known by several different names. The fact that two intended uses
involve different names for the same disease or causative organism does
not cause the intended uses to be different.
The second principle of same intended use establishes that if one
of the intended uses falls completely within the scope of the other,
they are considered the same intended use for the purposes of
designation. For example, an intended use for a particular disease or
condition in all aquarium fish would include use for that disease or
condition in black mollies (a type of aquarium fish) and, therefore,
would be considered the same intended use for the same disease or
condition in black mollies. Similarly, designation for black mollies
would preclude a designation for all aquarium fish (but not a
designation for all aquarium fish except black mollies).
This interpretation is driven by the marketing exclusivity
provisions of the designation provision of the statute because
marketing exclusivity for all aquarium fish includes exclusivity with
respect to that intended use in all species within that designation.
The third principle of same intended use establishes that an
intended use for a disease or condition caused by one (or a subset) of
causative organisms is considered different from an intended use for
the same disease or condition caused by a different causative organism
(or subset of organisms) when the causative organisms involved can
reliably be shown to be clinically significant causes of the disease or
condition. For example, intended use for the treatment of pneumonia in
cattle caused by Pasteurella multocida is not the same as intended use
for the treatment of pneumonia in cattle caused by Histophilus somni
(Haemophilus somnus).
The fourth principle of same intended use establishes that two
intended uses that involve the same disease or condition but in
different species, or in different generally recognized subsets of the
same species (such as production classes of food species), are not the
same intended use. For example, an intended use for a particular
disease or condition in growing turkeys is not the same as an intended
use for the same disease or condition in laying turkeys.
B. Submission of Requests for Designation (Proposed Sec. 516.14)
The agency proposes that all correspondence relating to a request
for designation of a MUMS drug must be addressed to the Director,
Office of
[[Page 56399]]
Minor Use and Minor Species Animal Drug Development.
C. Eligibility to Request Designation (Proposed Sec. Sec. 516.16 and
516.22)
The agency proposes that the person requesting designation must be
the real party in interest of the development and the intended or
actual production and sales of the drug because only this party can
assure active pursuit of approval under section 512 or 571 of this act
with due diligence required by section 573(a)(3)(B) of the act. In
proposed Sec. 516.22, the agency is proposing that foreign sponsors
must have a permanent-resident U.S. agent to submit the request for
designation so that the agency may assure that certain notifications
(such as under section 573(c)(2)(A) of the act) and other
communications with the sponsor are legally and effectively made.
D. Content and Format of a Request for MUMS-Drug Designation (Proposed
Sec. 516.20)
Proposed Sec. 516.20 describes the content and format for a
request for MUMS designation. Under proposed Sec. 516.20, the request
must be specific and must include certain information about the
sponsor; a description of the proposed intended use for the drug; a
description of the drug and dosage form; a discussion of the scientific
rationale for the intended use of the drug with reference to data; a
specific description of the product development plan for the drug, its
dosage form, and the intended use; if MUMS designation is based on a
minor use, documentation that the proposed intended use is a minor use;
a statement that the requestor is the real party in interest of the
development and the intended or actual production and sales of the
product; and a statement that the sponsor acknowledges that FDA will
make certain information regarding the designation public. The
information required to be included in a request for designation
parallels that required for human orphan drug designation, but with
some differences due to differences in the governing statutes and to
differences between the health care practices for animals and humans in
the United States.
For new animal drugs, each designation must be unique. That is,
each designation is unique with respect to the drug and dosage form for
use in the species or group of species for the treatment, control, or
prevention of the disease or condition; or to affect the structure or
function. This differs from the provisions of the human orphan drug
legislation, which permits designation of multiple identical drugs
prior to approval of any one of the drugs. The MUMS act 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 in this way, it is
important for the effective implementation of section 573(a)(2)(B) of
the act that the 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. The most effective means of ensuring this is for the
sponsor to work closely with the personnel in the agency who will be
responsible for reviewing the information submitted in support of the
drug's conditional approval or approval. The parties should mutually
agree that the scientific rationale for the drug is credible and that
timely development of the drug in accordance with a drug development
plan is possible. While not required, this is most effectively
accomplished to the benefit of both the sponsor and the agency through
the presubmission conference provisions of the investigational new
animal drug (INAD) review process of the Center for Veterinary Medicine
(CVM). Such presubmission conferences are held with members of CVM's
Office of New Animal Drug Evaluation under the provisions of Sec.
514.5 and may be held in person or via teleconference. The memorandum
of conference that is created under the provisions of Sec. 514.5(f)
would suffice to document that the requirements of proposed Sec.
516.20(b)(5) and (b)(6) have been met. Because a clear understanding by
sponsors of agency approval requirements and the mutual development of
a drug development plan to meet those requirements is so obviously
beneficial to the effective utilization of resources by both parties,
most new animal drug sponsors routinely follow this process and,
therefore, for these sponsors, many of the requirements for submission
of information under proposed Sec. 516.20 to support designation would
be met by reference to information routinely present in an INAD file.
Given the relatively limited return on investment associated with
new animal drugs intended for minor uses or minor species, it is
particularly critical, in keeping with the intent of the MUMS
legislation, to enhance the availability of such drugs, that both
sponsor and agency resources associated with MUMS drug development be
used effectively and efficiently. The information proposed under Sec.
516.20(b)(5) and (b)(6) as a condition of granting a designation is
essential for evaluation of a request for designation. Furthermore, as
noted previously, the person requesting the designation must be the
real party in interest of the development, production, and sale of the
subject drug as proposed under Sec. 516.20(b)(8). The information
described in Sec. 516.20(b)(1) through (b)(4) of the proposed rule is
required to make the statutorily required determination under section
573(a)(2)(B) of the act that the drug requested for designation is not
the same drug, in the same dosage form, for the same intended use as a
drug already approved or conditionally approved. Proposed Sec.
516.20(b)(7) and (b)(9) is similarly a reflection of specific
requirements of the MUMS legislation.
E. Documentation of Minor Use Status (Proposed Sec. 516.21)
Under proposed Sec. 516.21, if the sponsor seeks MUMS-drug
designation for a drug intended to be used as a minor use in a major
species, the sponsor must include documentation that the use is limited
to a small number of animals. Proposed Sec. 516.21 details the
documentation that is required.
The agency is proposing to define ``intended use'' of a drug and,
more specifically, ``same intended use'' of a drug in these
regulations. The primary discussion of these definitions can be found
in section II.A.2.c of this document. It is important to reiterate here
that this definition of intended use is to determine whether two
intended uses are the ``same intended use'' for purposes of qualifying
for designation; the definition is not directly applicable to the
determination of whether a particular use in a major species is a minor
use. As previously discussed, it is clear that Congress intended the
agency's determination of whether a use is minor to depend upon the
existence of a disease or condition in a major species that occurs in
such a small number of animals that it would not warrant drug
development in the absence of special incentives. Thus, whether a use
is a minor use in a major species is determined on the basis of the
existence or occurrence of a disease or condition in the total
population of a major species, and not by any population of animals
that the sponsor may choose to define by the intended use or conditions
of use that it places on its label.
Once the use of a drug for a given disease or condition is
determined to be a minor use in a major species, a sponsor may
establish an intended use for the product that represents only a
[[Page 56400]]
subset of that minor use. That is, while a sponsor might be encouraged
by the agency to develop the product for use in the entire population
of animals comprising the minor use so that the drug would provide
maximum benefit when used in accordance with its label, a sponsor
generally may limit the intended use to only a portion of the eligible
population. Marketing exclusivity will, however, be determined by the
scope of the intended use on the label of the product.
Until the number for ``small number of animals'' for each major
species has been formally established by regulation, a request for
designation of a drug as a minor use in a major species needs to be
supported by evidence that such intended use involves only a small
number of animals of a major species as represented by the market
associated with the potential population of animals to be administered
the drug relative to the cost of drug development as discussed
previously. Thus, such a request for designation must include
information regarding the presence of the relevant disease or condition
in the relevant major species on an annual basis, as well as
information regarding the potential market represented by that number
of animals relative to the development cost for the particular intended
use being proposed.
The agency recognizes that such information is not readily
available for uncommon animal diseases or conditions. Because there are
no insurance records and national databases are lacking for diseases of
animal species, except perhaps databases for diseases reportable
because of their public health significance, it is difficult to
determine verifiable numbers of cases for animal diseases or conditions
on a National basis. Nevertheless, the agency understands that sponsors
routinely do their own marketing research to determine the economic
feasibility of pursuing any new animal drug approval.
As discussed previously, the number of concern with respect to
minor use is the total number of animals that could potentially be
administered a drug in association with the treatment, control, or
prevention of a given disease or condition (annualized) taking into
account that, for a variety of reasons, not all of those animals will
actually be administered the drug.
Therefore, a sponsor needs to demonstrate through verifiable
sources (surveys, literature, etc.) that the number of animals that
could potentially be administered a drug in association with the
treatment, control, or prevention of a given disease or condition
(annualized) represents a market potential sufficient to support drug
development with the added incentives of the MUMS act, but not without
them.
A sponsor may request that the agency determine that the total
population of animals that is affected by a particular disease or
condition for which a MUMS drug is being considered for development
should be decreased by the size of any subset of the total population
to which administration of the drug can be demonstrated to be not
medically justified. If such a demonstration can be made to the
satisfaction of the agency, the remaining population of animals
affected by that disease or condition would be used to estimate the
market potential for the drug.
A sponsor may demonstrate that administration is not medically
justified in a subset of animals by, for example, referencing a
consensus standard of practice established by an authoritative source
that recommends against the administration of either the MUMS drug
itself or drugs of the class of which the MUMS drug is a member to a
subset of the population. In the absence of a consensus standard, the
sponsor would need to provide reliable evidence that there is some
attribute of the MUMS drug that renders its administration to the
identified subset of animals not medically justified. A specific
analysis of the relative risks and benefits of administering the MUMS
drug to the subset of animals at issue, supported by all reliable
information available to the sponsor, would be needed.
F. Timing of Requests for MUMS-Drug Designation (Proposed Sec. 516.23)
In accordance with the requirement of section 573(a)(1) of the act,
the agency is proposing that requests for designation of a new animal
drug be accepted only prior to submission of a new animal drug
application (NADA) for the drug under section 512 or 571 of the act.
G. Granting and Refusal to Grant MUMS-Drug Designation (Proposed
Sec. Sec. 516.24 and 516.25)
As required by sections 573(a)(2)(A) and (a)(2)(B) of the act, FDA
proposes to refuse to grant a request for designation when the involved
new animal drug is not intended for use in a minor species or for a
minor use in a major species or the same drug in the same dosage form
for the same intended use is already designated, conditionally
approved, or approved. The agency is also proposing to refuse to grant
a request for MUMS-drug designation if the request is found to contain
any untrue statement of a material fact, or to omit material
information. As noted previously, the agency also proposes to refuse to
grant designation if the request fails to contain a credible scientific
rationale supporting the intended use, or fails to contain
documentation sufficient to support an agency determination that
successful drug development in a timely manner is possible.
H. Amendment to MUMS-Drug Designation (Proposed Sec. 516.26)
The agency is proposing to allow sponsors to apply for amendments
to MUMS-drug designation up to the time of approval of their marketing
applications. The purpose of this proposal is to allow for situations
in which testing data demonstrate that the proposed intended use is
inappropriate due to unexpected issues of safety or effectiveness. This
can occur when data demonstrate that the effectiveness of a drug in
different populations or for different diseases or conditions differs
from that for which the drug was initially designated. It can also
occur when a group of species was originally designated, such as ``all
finfish'' and it is subsequently discovered that the drug is not safe
for use in a subset of fish species. The proposed intended use may have
to be expanded or narrowed based on such unexpected findings. FDA would
grant such an amendment request only if it found that the initial
designation request was made in good faith and that the amendment is
sought only to render the MUMS-drug designation consistent with
unanticipated test results. If an amendment request for a minor use
designation was to involve a new or expanded disease or condition and
the number of animals affected would then exceed what would be
considered a small number of animals annually, the amendment could not
be granted.
I. Change in Sponsorship (Proposed Sec. 516.27)
The agency proposes that the sponsor of a MUMS-designated drug may
transfer sponsorship to another person. Such a transfer of sponsorship
of the MUMS-designated drug will include transfer of the designation
provided that this transfer of sponsorship is appropriately documented
by both parties to the transfer and that the sponsor accepting the
transfer certifies understanding of the responsibilities associated
with developing or maintaining a MUMS-designated drug and demonstrates
the capability of meeting those responsibilities as a
[[Page 56401]]
condition of agency approval of the transfer.
Because MUMS-drug designations are unique and because the initial
sponsor obtained designation after request and demonstration of
capability to meet the requirements of section 573 of the act with
respect to development and production of the designated drug, transfer
of sponsorship of a MUMS-designated drug must depend upon a similar
demonstration and agency approval.
J. Publication of MUMS-Drug Designations (Proposed Sec. 516.28)
As required by section 573(a)(4) of the act, the agency will make
public the designation and termination of designation of MUMS drugs.
The agency proposes to meet this requirement by periodically updating a
publicly available list of MUMS-designated drugs which would include
basic identifying information regarding each MUMS drug on the list.
K. Termination of MUMS-Drug Designation (Proposed Sec. 516.29)
The agency proposes to terminate designation of a MUMS drug on any
of the grounds specified in section 573 of the act, or because the
request is found to contain an untrue statement of material fact or to
omit material information, or because the agency withdraws approval of
the application for the drug.
For the purposes of this proposed rule, the phrase ``actively
pursuing approval or conditional approval with due diligence'' is
intended to encompass a MUMS drug developer's good faith effort to
pursue drug development and approval, or drug development, conditional
approval, and subsequent approval, in a timely manner. Under proposed
Sec. 516.29(d), at a minimum, due diligence must be demonstrated by
submission of annual progress reports in accordance with proposed Sec.
516.30 that demonstrate the sponsor is progressing in accordance with
the drug development plan submitted to the agency under proposed Sec.
516.20 and by compliance with all applicable INAD requirements.
However, FDA will consider the circumstances and may determine that
other factors demonstrate an absence of due diligence.
L. Annual Reports for a MUMS-Designated Drug (Proposed Sec. 516.30)
The agency proposes to require brief annual progress reports to the
INAD file as one effective means of ensuring sponsor compliance with
the requirement of section 573(a)(3)(B) of the act that new animal drug
approval for a MUMS-designated drug be pursued with due diligence.
M. Exclusive Marketing Rights (Proposed Sec. Sec. 516.31 and 516.34)
Under proposed Sec. 516.34, the agency will send the sponsor of a
conditionally-approved or approved MUMS-designated drug timely written
notice recognizing exclusive marketing rights and make the same
information publicly available by Federal Register publication. Under
section 573(c)(1) of the act, FDA may not conditionally approve or
approve another application for the same new animal drug, in the same
dosage form, for the same intended use within 7 years after FDA has
approved or conditionally approved a designated MUMS drug. For this
reason, no further action by FDA to bring about exclusive marketing
rights is necessary. Proposed Sec. 516.31 reflects the grounds for
termination of designation and associated exclusive marketing rights
established by section 573 of the act and discussed in association with
proposed Sec. 516.29 in section II.K of this document.
N. Insufficient Quantities of MUMS-Designated Drugs (Proposed Sec.
516.36)
Proposed Sec. 516.36 addresses situations where insufficient
quantities of MUMS-designated drugs are being produced to meet demand.
Under section 573(c)(2)(A) of the act, whenever the agency finds that a
conditionally-approved or approved MUMS-designated drug sponsor cannot
assure the availability of sufficient quantities of the drug to meet
the needs of animals for which it was designated, the act provides that
the agency may approve another application for the same drug in the
same dosage form for the same intended use. Proposed Sec. 516.36
provides a procedure whereby the agency would notify the approved MUMS-
designated drug sponsor of the possible insufficiency of supply and
would request, within a specified time, that the sponsor provide in
writing information and data regarding how the sponsor can assure the
availability of sufficient quantities of the drug, or consent to the
approval of other marketing applications.
Following evaluation of the submitted information, the agency would
issue an order with findings and conclusions, either reaffirming or
terminating the MUMS-drug designation and the associated exclusive
marketing rights. Any such order which the agency issues would
constitute final agency action. In the event the agency's decision is
to terminate the MUMS-drug designation and the associated exclusive
marketing rights, FDA may approve any number of applications for the
same drug, in the same dosage form, for the same intended use, even if
the additional sponsors cannot themselves assure the availability of
sufficient quantities of the MUMS drug in question.
Once designation and exclusive marketing rights are terminated for
failure to ensure the availability of adequate supplies, they cannot be
restored even if the sponsor losing these privileges is later able to
assure the availability of adequate supplies. It would be unreasonable
to expect a second sponsor to invest in drug development to fill a gap
if it could be shut out of the market at any time that the original
sponsor could assure adequate supplies.
O. Availability for Public Disclosure of Data and Information in
Requests and Applications (Proposed Sec. 516.52)
Proposed Sec. 516.52 provides rules for public disclosure of
information. The agency recognizes that designation requests will
contain confidential commercial information and, indeed, that the very
existence of a MUMS-drug designation request may itself be confidential
commercial information. In addition, a request for MUMS-drug
designation is, in most instances, supported by information that will
be incorporated into a sponsor's application for conditional approval
or approval.
For all these reasons, proposed Sec. 516.52(a) provides that
unless previously publicly disclosed or acknowledged, FDA will not make
public the existence of any pending MUMS-drug designation request prior
to such time as FDA takes final action on the request. Proposed Sec.
516.52(b) provides that, irrespective of whether 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.
Upon final FDA action on a request for designation, proposed Sec.
516.52(c) provides that FDA will determine the public availability of
data and information in the designation request in accordance with part
20 (21 CFR part 20) and other applicable statutes and regulations.
Under proposed Sec. 516.52(d), via reference to proposed Sec. 516.28,
FDA will make a cumulative list of all MUMS-drug designations available
to the public and update it periodically. Under proposed Sec. 516.28,
the list will contain the following information regarding each MUMS-
designated drug: The name and address
[[Page 56402]]
of the sponsor; the generic name and trade name, if any, of the drug;
the date of granting MUMS-drug designation; the dosage form; and the
species and intended use of the drug. In accordance with proposed Sec.
516.29, FDA will give public notice of the termination of all MUMS-drug
designations.
III. Conforming Changes
FDA is proposing to revise the definition of ``sponsor'' currently
appearing in Sec. 510.3 (21 CFR 510.3) to be consistent with the
definition of ``sponsor'' proposed in the MUMS regulations in proposed
Sec. 516.3. The agency has recognized for some time that the scope of
the definition in Sec. 510.3 is overly narrow. It is inconsistent with
one of the major subparts of part 510, Subpart G-Sponsors of Approved
Applications, in failing to recognize that persons submitting and
receiving approval for NADAs are also considered sponsors. The agency
is taking this opportunity to resolve this long-standing inconsistency.
FDA is also proposing conforming changes in its regulations by
removing Sec. 514.1(d). The definitions under Sec. 514.1(d)(1) were
redefined by Congress in the MUMS act and are further clarified under
proposed Sec. 516.3. The provisions of Sec. 514.1(d)(2) regarding the
availability of guidance relating to MUMS drugs are now covered under
FDA's good guidance practices in 21 CFR 10.115.
FDA also proposes to add a cross-reference to the MUMS designation
records to 21 CFR 20.100, which lists regulations on the availability
of specific categories of FDA records.
IV. Legal Authority
FDA's authority for issuing this proposed rule is provided by the
Minor Use and Minor Species Animal Health Act of 2004 (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 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 12866, 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, environmental, public health and safety, and other
advantages; and distributive impacts; and equity). The Regulatory
Flexibility Act 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 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 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 of 1995.
The intention of this proposed 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 proposed 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 an 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 about $57,300.
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\1\ 2000 National Industry-Specific Occupational Employment and
Wage Estimates, U.S. Department of Labor, Bureau of Labor Statistics
(http://www.bls.gov/oes/2000/oesi3_283.htm).
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The agency is also proposing 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 Sec. 514.1(a)
because 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 2 hours of preparation. At the same wage rate, this
would cost an additional $300. Sponsors may also transfer sponsorship
of a MUMS-designated drug or terminate the designation. We estimate
that these activities would result in only 3 additional hours of
administrative costs annually, totaling $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. 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, for a cost of
$150.
Assuming a sponsor chooses to seek the MUMS designation for its
NADA, total administrative costs for this proposed rule 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
[[Page 56403]]
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 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 proposed 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 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 percent of the revenues of the smallest set
of establishments (those with one to four 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, U.S. Census Bureau, Manufacturing
Industry Series, Pharmaceutical Preparation Manufacturing, Table 4.
---------------------------------------------------------------------------
All of the costs described previously in this document 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 in this document.
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 proposed 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 small businesses. As such, the agency
believes the proposed 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 this proposed rule as mandated by
statute. The agency has therefore decided to address this issue in a
later rulemaking, and instead 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.
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 follows with an estimate of
the annual reporting burden. Included in the estimate is the time for
reviewing instructions, searching existing data sources, gathering and
maintaining the data needed, and completing and reviewing each
collection of information.
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; and (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: Designated New Animal Drugs for Minor Use and Minor Species
21 CFR Part 516
Description: The Minor Use and Minor Species (MUMS) Animal Health
Act of 2004 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 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 proposed new part, 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
[[Page 56404]]
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:
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 are no capital or operating and maintenance costs associated with this collection of information.
The burden estimate for this reporting requirement was derived in
our Office of Minor Use and Minor Species Animal Drug Development by
extrapolating the current INAD/NADA reporting requirements for similar
actions by this same segment of the regulated industry and from
previous interactions with the minor use/minor species community.
As required by section 3504(h) of the PRA, FDA has submitted a copy
of this proposed rule to OMB for its review of these information
collection provisions. Other organizations and individuals desiring to
submit comments on the information collection requirements should send
their comments to OMB. Submit written comments on the information
collection provisions to the Office of Information and Regulatory
Affairs, Office of Management and Budget (OMB).
OMB is still experiencing significant delays in the regular mail,
including first class and express mail, and messenger deliveries are
not being accepted. 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: Fumie
Yokota, Desk Officer for FDA, FAX: 202-395-6974.
VII. Environmental Impact
We have carefully considered the potential environmental impacts of
this proposed 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 set forth 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 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.
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 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)(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
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.
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
[[Page 56405]]
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
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]
6. Amend Sec. 514.1 by removing paragraph (d).
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
Sec.
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.
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 and applications.
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.
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,
[[Page 56406]]
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 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
[[Page 56407]]
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
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) If the 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 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, a demonstration that administration of the drug to
animals 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.
[[Page 56408]]
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 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 generic 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 the 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:
[[Page 56409]]
(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 or proposes to withdraw 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-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 the 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, the 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: August 31, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-19196 Filed 9-26-05; 8:45 am]
BILLING CODE 4160-01-S