Designation of New Animal Drugs for Minor Uses or Minor Species, 56394-56409 [05-19196]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 70, Number 186 (Tuesday, September 27, 2005)]
[Proposed Rules]
[Pages 56394-56409]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 05-19196]


=======================================================================
-----------------------------------------------------------------------

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.

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

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: https://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web site: https://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 https://
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 https://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: Andrew.Beaulieu@fda.gov.

SUPPLEMENTARY INFORMATION:

I. Background

    In enacting the MUMS act (Public Law 108-282), Congress sought to 
encourage the development of animal drugs that are currently 
unavailable to minor species (species other than cattle, horses, swine, 
chickens, turkeys, dogs, and cats) in the United States or to major 
species afflicted with uncommon diseases or conditions (minor uses). 
Congress recognized that the markets for drugs intended to treat these 
species, diseases, or conditions are 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-yea