Source: https://www.federalregister.gov/documents/2007/07/26/E7-14444/designation-of-new-animal-drugs-for-minor-uses-or-minor-species
Timestamp: 2018-09-25 20:51:53
Document Index: 343452503

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Federal Register :: Designation of New Animal Drugs for Minor Uses or Minor Species
A Rule by the Food and Drug Administration on 07/26/2007
72 FR 41010
41010-41022 (13 pages)
Docket No. 2005N-0329
0910-AF60
E7-14444
II. Changes to the Proposed Rule
B. Comments on “Small Number of Animals” and Minor Use
21 CFR Parts 514 and 516
https://www.federalregister.gov/d/E7-14444 https://www.federalregister.gov/d/E7-14444
In enacting the MUMS act (Public Law 108-282), Congress sought to encourage the development of animal drugs that are currently unavailable to minor species (species other than cattle, horses, swine, chickens, turkeys, dogs, and cats) in the United States or to major species afflicted with uncommon diseases or conditions (minor uses). Congress recognized that the markets for drugs intended to treat these species, diseases, or conditions are often so small that there are insufficient economic incentives to motivate sponsors to develop data to support approvals. Further, Congress recognized that some minor species populations are too small or their management systems too diverse to make it practical to conduct traditional studies to demonstrate safety and effectiveness of these animal drugs. As a result of these limitations, sponsors have generally not been willing or able to collect data to Start Printed Page 41011support legal marketing of drugs for these species, diseases, or conditions. Consequently, Congress enacted the MUMS act, which amended the Federal Food, Drug, and Cosmetic Act (the act) to provide incentives to develop new animal drugs for minor species and minor uses, while still ensuring appropriate safeguards for animal and human health.
In the Federal Register of September 27, 2005 (70 FR 56394), FDA issued proposed regulations to implement section 573 of the act (21 U.S.C. 360ccc-2). These regulations proposed procedures for designating a new animal drug as a minor use or minor species drug. Such designation provides eligibility for certain incentives established by the MUMS act, including exclusive marketing rights associated with the conditional approval or approval of designated new animal drugs and for grants to support designated new animal drug development. The proposed rule initially provided for a 75-day public comment period during which the agency received several comments asserting that 75 days was not an adequate amount of time to prepare and submit meaningful comments. In response to this, in the Federal Register of December 28, 2005 (70 FR 76732), FDA reopened the comment period allowing an additional 30 days of public comment.
In response to public comment, or in two places to provide added clarity, FDA has made the following changes to the proposed rule:
§ 516.3 Definitions. The definition of “Infrequently” was changed by adding the words “on an annualized basis” to the end of the proposed definition. The definition now reads: “Infrequently, as used in the minor use definition, means a disease or condition that is uncommon or that occurs only sporadically on an annualized basis.”
§ 516.21 Documentation of minor use status. The language in § 516.21(b) was revised for clarity.
§ 516.28 Publication of MUMS-drug designations. In § 516.28(b), the term “generic name” was changed to “established name” to avoid confusion with abbreviated applications approved under section 512(b)(2) of the act.
§ 516.31 Scope of MUMS-drug exclusive marketing rights. In § 516.31(a)(2), the words “or proposes to withdraw” were removed.
The agency received comments from 9 organizations or individuals on the September 27, 2005, proposal. Comments were received from a trade organization representing new animal drug manufacturers, a trade organization representing pet product manufacturers, an animal feed manufacturer, a professional association representing veterinarians, an association representing zoos and aquariums, a consumer advocacy organization, and 3 consumers.
(Comment 1) In § 516.3(b) one comment stated that for added clarity and consistency we should add the words “on an annualized basis” to the end of the definition for infrequently.
(Response) We agree. We explained in the preamble to the proposed rule why we thought that it was appropriate to annualize the data on the number of animals in which the indication occurs (see 70 FR at 56395 to 56396). Therefore, we have revised the codified section accordingly.
(Comment 2) Two comments stated that the requirement for a specific product development plan as part of a request for MUMS-drug designation in § 516.20(b)(6) is unnecessarily arduous and premature in the designation process. Commentors also stated that frivolous requests for designation should not be burdensome to the agency; and, therefore, that the requirement for a specific product development plan is unnecessary.
(Response) We do not agree that the requirement for submission of a description of the product development plan is arduous or premature. Also, the basis for this requirement is not primarily to reduce burden on the agency due to frivolous requests for designation. The primary reasons for requiring a specific product development plan as part of a request for MUMS-drug designation are as follows. As we explained in the preamble to the proposed rule (70 FR 56394 at 56399), for new animal drugs, unlike for human orphan drugs, each designation must be unique with respect to drug, dosage form, and intended use. In this way, the MUMS act, which was enacted to address the critical shortage of approved animal drugs for minor species/minor uses, facilitates the development of a broad range of animal drugs in part by discouraging multiple sponsors from pursuing identical uses. Because each MUMS designation is unique, it is important to the effective implementation of section 573 of the act that initial designation of a drug be based on evidence that requesting sponsors clearly understand their responsibilities in terms of drug research and development and are prepared to accept those responsibilities.
Submission of a description of the product development plan helps to ensure that timely development of the drug, consistent with the requirement of section 573(a)(2)(B) to actively pursue approval with due diligence, is feasible. Designation of a drug that could not feasibly be approved under the sponsor's current drug development plan would inappropriately delay development and marketing of a needed drug by the same or a different sponsor and undermine the goals of the MUMS act. Submitting the description of the product development plan also facilitates meaningful communication between the sponsor and the agency to help ensure that safety and effectiveness testing, which for designated drugs may be supported by grants or contracts under section 573(b) of the act, is efficiently designed and conducted. Efficient and effective use of sponsor and agency resources, which is enabled by this and other requirements of final § 516.20, is critically important to alleviating the shortage of new animal drugs addressed by the MUMS act.
(Comment 3) Two comments stated that the documentation requirements for minor use status in § 516.21 are too burdensome. They believe there is a lack of balance between the documentation required for a minor use designation versus a minor species designation. More specifically, both commentors believe that § 516.21(b) is asking sponsors to prove a negative concerning the lack of medical justification and one of these commentors stated that the financial information requested in § 516.21(c) is, for the most part, confidential. As an alternative approach, these two commentors submitted similar two-part working definitions for minor use that could be used in place of the proposed provisions for § 516.21 as follows:
1. The drug is not currently approved, it is unlikely the “minor use” designation for the drug will be applicable to a majority of the major species population, and the need for the drug for a specific disease or condition has been clearly identified by animal health professionals or an animal industry. One commentor also added a fourth provision that if the drug has the same active ingredient as other approved drugs, the environmental safety assessment of the combined active ingredient of all such drugs is shown to be adequate.
Or;Start Printed Page 41012
2. The annualized commercial return on investment for the product is not reasonably expected to exceed the development and maintenance costs of the product.
(Response) We do not agree that the requirements for documentation of minor use status in § 516.21 are too burdensome. FDA agrees that these implementing regulations should not be overly burdensome to drug sponsors in order to achieve the objectives set forth in the MUMS Act. However, it is unavoidable that a certain amount of additional information will be required in a request for minor use designation that will not be required in a request for minor species designation. Section 516.21 describes this additional information and comprises three paragraphs.
Section 516.21(a) asks for an estimate of the total number of animals to which a drug could potentially be administered on an annual basis. Whether compared to a predetermined small number of animals or as part of a case-by-case determination, this number will be essential to any request for minor use designation. Simply put, this estimated number of animals serves as documentation that the intended use of a proposed MUMS drug is limited to a “small number of animals”, as required by the MUMS Act.
Section 516.21(b) describes how to define a minor use population if the proposed MUMS drug is under development for only a subset of the estimated total number of animals to which the drug could potentially be administered on an annual basis. In this situation, a sponsor may utilize the provisions of this paragraph to argue that administration of a proposed MUMS drug is only justified for a small subset of a larger major species population potentially affected by a particular disease or condition and that administration to the remaining larger affected population is medically inappropriate. If the number of animals in this medically justified subset is a small number of animals, then such a use is a minor use.
The provisions in this paragraph were apparently misinterpreted by two of the commentors. Its purpose is not to require medical justification to the effect that a drug approved for disease A could not be used for disease B or C or D. Its purpose is to allow drug sponsors to restrict the intended use of a drug to a subset of the animals affected by disease A, thereby reducing their estimate of the total number of animals eligible to be treated as required in § 516.21(a), by providing medical justification that only a subset of animals afflicted with disease A are amenable to treatment. For improved clarity, we have revised the language of § 516.21(b).
Section 516.21(c) requires drug sponsors to provide economic information relevant to why their MUMS drug should be considered a minor use drug. In the preamble to the proposed MUMS designation rule (70 FR 56394) we cited the Senate report (S. Rept. 108-226) concerning the bill before the Senate (S. 741), which discusses the minor use definition and how minor use should be determined: “This definition incorporates the existing definition in the Code of Federal Regulations (21 CFR 514.1(d)(1)) with a further limitation to “small numbers” to assure that such intended uses will not be extended to a wider use. The Secretary is expected to further clarify this definition in regulations implementing this section. FDA is given broad latitude in determining what constitutes a minor use in a major species. The Congress intends for FDA to make the determination of minor use by evaluating, in the context of the drug development process, whether the incidence of the disease or condition occurs so infrequently that the sponsor of a drug intended for such use has no reasonable expectation of its sales generating sufficient revenues to offset the costs of development. The Congress does not intend for FDA to establish a test of commercial value, but rather directs FDA to determine whether the expected low use of a drug would discourage its development.” (S. Rept. 108-226 at 12-13.)
In evaluating whether the incidence of the disease or condition is so infrequent that the sales are not reasonably expected to offset development costs, we might take two different approaches. First, we could consider each request on a case-by-case basis utilizing the information provided in § 516.21(c). Alternatively, we could establish, by regulation based on industry-wide economic data, a specific small number of animals for each of the seven major species to be used as a yardstick against which we would measure the estimated total number of animals to which a drug could potentially be administered on an annual basis, as documented under § 516.21(a). If such “small number” for each major species is established by regulation at some point in the future, there would no longer be a need for requiring the information requested in § 516.21(c).
(Comment 4) With respect to § 516.24, two comments stated that FDA should respond to requests for designation within 60 days from the time the request was submitted.
(Response) FDA agrees that timely processing of requests for designation is important. However, because of limitations on agency resources, the agency does not believe that it is feasible to commit to responding to all requests for designation within 60 days. We intend to issue guidance in the future to describe target timelines for the designation process consistent with current resources.
(Comment 5) Two comments stated that FDA should update the publicly available list of MUMS-designated drugs within 60 days of granting a new MUMS designation.
(Response) We agree that timely updating of the list of MUMS-designated drugs is appropriate. However, the agency does not believe it is feasible to commit to definite timelines in these regulations because of uncertain resource limitations. As discussed above, we intend to describe target timelines for our actions related to the designation process in future guidance.
(Comment 6) Two comments stated that a 1-year advance notification for discontinuing the manufacture of a drug, as specified in § 516.29(b), is excessive and a 30-60 day timeframe would be more appropriate.
(Response) A 1-year advance notification for discontinuing the manufacture of a MUMS-designated drug is required by section 573(a)(2)(C) of the act and, therefore, is not subject to alteration by regulation.
(Comment 7) One commentor requested clarification on the hypothetical situation in which FDA has withdrawn designation status after notification by a sponsor (sponsor A) of its intent to discontinue production, but the drug is still being sold, as permitted in accordance with the lengthy pre-notification required by the statute. The commentor asked if another sponsor (sponsor B) could potentially achieve designation and conditional approval, and thus block any further sale by sponsor A, even if sponsor A still has time left on their notification and still has drug to be sold.
(Response) In this situation, FDA has only withdrawn sponsor A's designation and, therefore, its exclusivity. The approval or conditional approval remains intact. Therefore, while approval or conditional approval may be possible for sponsor B, designation cannot be granted for sponsor B because the MUMS Act only allows designation when a specific drug, dosage form, and intended use is not already approved or conditionally approved.Start Printed Page 41013
(Comment 8) In § 516.31(a)(2) one comment stated that the words § or proposes to withdraw” should be removed because this appears to negate the right of the sponsor to due process.
(Response) We agree that the exclusivity of an approved or conditionally approved MUMS-designated drug should not be abrogated by a proposal to withdraw the approval or conditional approval. We have revised the codified section accordingly.
(Comment 9) One comment stated that oral dosage form new animal drugs and new animal drugs for use in animal feeds should not be considered two different dosage forms for the purpose of MUMS designation. It argues, for example, that if an oral dosage form new animal drug is designated and approved subsequent to the designation and approval of a medicated feed containing the same drug and for the same intended use, it will negatively impact the business case and success of the medicated feed.
(Response) The agency believes that this same argument could apply to any drug that is available in more than one dosage form. For example, an approved injectable product could be negatively impacted by approval of an oral form of the drug.
As stated in the preamble to the proposed rule (70 FR 56394 at 56398), current federal regulations recognize the following dosage forms: Oral dosage forms (21 CFR part 520), implantation or injectable dosage forms (21 CFR part 522), ophthalmic and topical dosage forms (21 CFR part 524), intramammary dosage forms (21 CFR part 526), miscellaneous dosage forms (21 CFR part 529), and drugs in animal feeds (21 CFR part 558). The preamble also notes that medicated feeds are subject to different limitations from those for other oral dosage forms (70 FR 56394 at 56398), which also supports treating medicated feeds as a different dosage form for the purpose of MUMS designation.
In addition, the markets for medicated feeds and other oral dosage forms may be different. An oral dosage in the form of a drench or a water treatment may be appropriate in different settings than those requiring treatment through the use of medicated feeds. For example, pheasants in a hatchery setting can be treated with medicated water while those in large outdoor pens are more efficiently treated with medicated feeds. Because the populations served by medicated feeds and by other oral dosage forms can be different enough to represent separate markets and because, as already noted, the same potential overlap can occur between any two dosage forms, we believe it is appropriate to treat medicated feeds and other oral dosage forms as different for MUMS designation purposes.
(Comment 10) In the definition section under § 516.13, under Intended Use, one comment asked if treatment, control, and prevention are the same thing (i.e., one designation) or are they three different things (i.e., three possible designations).
(Response) Given that requirements for approval may differ significantly for these three categories, they are considered to be different for purposes of designation.
(Comment 11) One comment disagreed with the third principle of sameness discussed in the preamble to the proposed rule, under which an intended use for a disease or condition caused by one organism is considered different from an intended use for the same disease or condition caused by a different organism. The comment perceived this approach to determining sameness to be a disincentive to seeking MUMS designation.
(Response) This comment raises the general issue of how different intended uses must be to be considered separate intended uses. If the uses are clearly separable and have different data requirements for approval, we believe it is appropriate to permit separate MUMS-drug designations. Intended uses for diseases or conditions caused by different organisms are clearly separable and would need to be supported by different data for approval; therefore, we believe that allowing separate MUMS-drug designations for drugs for such uses would be appropriate.
(Comment 12) One comment was concerned that many zoo animals may be included in the broad major species categories. It stated that FDA should specifically identify the species and subspecies that are considered “major species” with the recognition that some species/subspecies may be appropriate only for public display or exhibition, and that these non-domestic animals should be identified separately for appropriate drug approval under MUMS regulations.
(Response) Zoo species will not be lumped with major species for the purposes of drug approval. The major species are the domesticated species only, not including hybrids or closely-related wild species. Whether an animal belongs to a major or minor species is not affected by its location or use; it is strictly a matter of the species.
Currently, FDA considers the major species to be:
Cattle—Bos taurus taurus / Bos taurus indicus
Horses—Equus caballus
Swine—Sus domesticus
Dogs—Canis familiaris (also called Canis lupus familiaris)
Cats—Felis domesticus (also called Felis catus or Felis silvestris catus)
Chickens—Gallus gallus
Turkeys—Meleagris gallopavo gallopavo
All other species are considered to be minor. Therefore, there should be no cause for concern regarding the status of zoo animals in terms of new animal drug approval. The agency intends to clarify this issue in guidance to be published in the future.
(Comment 13) One comment stated that a manufacturer of a drug that is already approved in countries with substantially the same approval requirements as the United States does not need incentives to develop data and should not be given a MUMS designation.
(Response) The MUMS incentives exist to encourage pharmaceutical companies to pursue approval of new animal drugs for minor uses and minor species. Even in cases where foreign approvals exist, sponsors generally need to provide considerable new data to meet the requirements for FDA approval. Therefore, the MUMS incentives remain appropriate when a drug has been approved in a foreign country.
(Comment 14) One comment stated that in order to monitor whether the MUMS rule is fulfilling its intended goal to increase the availability of drugs for minor uses, FDA should require annual reports on quantities sold of each designated and conditionally approved drug.
(Response) The agency agrees that knowledge of the quantity of designated drugs distributed on an annual basis would be useful information in terms of assessing the success of the MUMS act. The MUMS act itself requires the annual submission of information regarding quantities of conditionally approved products distributed (see 21 U.S.C. 360ccc(d)(2)(B)(ii)). All fully approved new animal drugs are required by regulation (21 CFR 514.80 (b)(4)(i)) to report the quantity of product distributed. The Office of Minor Use and Minor Species Animal Drug Development will have direct access to this information.
(Comment 15) Three comments stated that companion animal “small numbers” should be considered separately from food animal “small Start Printed Page 41014numbers.” Two comments asked FDA to consider the numbers of animals eligible to be designated under a minor species provision (e.g., sheep) as a benchmark against which to compare numbers of animals to benefit from minor use provisions.
(Response) The agency agrees that the “small numbers” for companion animals need to be considered separately from the “small numbers” for food animals. FDA also agrees that it is appropriate to consider the relationship between the number of animals of a minor species permitted to be designated under the MUMS act and the number of animals of a major species permitted to be designated in establishing “small numbers” of animals under the definition of minor use in the statute. However, the agency views the primary basis for establishing “small numbers” to be Congress' expression of intent in the report language accompanying the act that the agency further define minor use in a major species “by evaluating, in the context of the drug development process, whether the incidence of the disease or condition occurs so infrequently that the sponsor of a drug intended for such use has no reasonable expectation of its sales generating sufficient revenues to offset the cost of development” (S. Rept. 108-226 at 12-13).
Since Congress provided incentives in the MUMS act to stimulate drug development, the agency interprets the previous statement to mean that FDA should determine for each major species what the “small number of animals” eligible to be treated on an annual basis would need to be in order to represent a drug market value that (relative to drug development costs) would be considerably less likely to be pursued in the absence of the MUMS incentives, than in their presence.
(Comment 16) Two comments stated that “small numbers” should be based on epidemiological data and not on a percentage of the total major species population. Commentors stated that since such epidemiological data are not yet available, FDA should make minor use designations on a case-by-case basis rather than setting hard numbers.
(Response) In the preamble to the proposed rule for MUMS designation (70 FR 56394), the agency already rejected the idea of establishing “small numbers” based on a percentage of the major species population as overly simplistic. There the agency explained that using the human orphan drug prevalence limit of 200,000 cases (0.1% of the U.S. population in 1983) did not seem helpful for calculating “small numbers” in cattle, swine, chickens, and turkeys because the populations involved, the manner of drug use in those populations, and the drug development processes for those species are too dissimilar to the human drug scenario (70 FR 56394 at 56396). Further analysis made clear that these factors were not sufficiently comparable for this approach to be viable, even for dogs, cats, and horses (70 FR 56394 at 56396). On the other hand, as already noted, Congress directed the agency to define “minor use” and, by extension, “small numbers,” on the basis of determining whether a population of animals of a major species needing drug treatment would provide sufficient drug market value to offset the cost of drug development given the incentives provided by the MUMS act.
The use of epidemiological data comes into play at the point that the sponsor and the agency are trying to establish the population of animals eligible to be treated with a particular drug for a particular intended use. Such data need to be shared with the agency whether the determination of minor use is being made on a case-by-case basis or with respect to an established small number of animals.
(Comment 17) One comment stated that FDA should consider the potential of a drug to be used extralabel when making a minor use designation.
(Response) The agency understands the expressed concern regarding extra-label drug use, but extra-label drug use is an issue that clearly transcends the designation process. Extra-label use of approved new animal drugs is statutorily permissible under specified circumstances. (Extra-label use is not permitted for either conditionally approved or indexed drugs because such drugs have not met the full approval requirements of the statute.) There is no general prohibition regarding the extra-label use in minor species of products approved for use in major species or vice versa.
Therefore, under designation, a product designated and approved for a minor species can be legally used in an extra-label manner in a major species (subject to established statutory and regulatory conditions). The same is true for a product designated for a minor use in a major species. It is difficult enough to determine whether the population of animals associated with the disease or condition for which a drug is labeled for use fails to provide sufficient market value to offset the cost of drug development (or falls above or below an established small number of animals). It would be impossible to determine the population of all animals subject to all potential extra-label uses of a drug. In fact, it must be assumed that this population (which may include all potential uses of a drug in all animal species) would very often exceed a small number of animals. Therefore, consideration of potential extra-label use in the designation process would have the effect of essentially negating the designation provision of the statute and this would clearly be contrary to the intent of the legislation.
(Comment 18) One comment stated that long term use of a drug, even in a small number of animals, would constitute a much larger market than for shorter term use and that FDA should not consider animal numbers as “small” if food animals are to receive drugs for a long duration, perhaps for a period longer than 21 days, consistent with FDA's Guidance for Industry (GFI) #152.
(Response) As noted previously, the agency acknowledges the concern regarding the use of drugs in food animals and accepts that the concept of “small numbers” of animals included in the statutory definition of minor use is based, in part, on this concern. The agency will address the issue of establishing “small numbers” of animals for each major species in future rulemaking. However, a full assessment of the relative risks of individual drugs or drug uses is a matter that must be left to the comprehensive analysis associated with the review of individual new animal drug applications consistent with GFI #152 and other applicable policies and regulatory requirements.
FDA's authority for issuing this final rule is provided by the MUMS act (21 U.S.C. 360ccc et seq.). When Congress passed the MUMS act, it directed FDA to publish implementing regulations (see 21 U.S.C. 360ccc note). In the context of the MUMS act, the statutory requirements of section 573 of the act, along with section 701(a) of the act (21 U.S.C. 371(a)) provide authority for this final rule. Section 701(a) authorizes the agency to issue regulations for the efficient enforcement of the act.
FDA has examined the impacts of the final rule under Executive Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive Order 12866 directs agencies to assess all costs and benefits of available regulatory alternatives and, when regulation is necessary, to select regulatory approaches that maximize net benefits (including potential economic, Start Printed Page 41015environmental, public health and safety, and other advantages; distributive impacts; and equity). The agency believes that this final rule is not a significant regulatory action under the Executive order.
FDA finds that the final rule does not constitute an economically significant regulatory action as defined in section 3(f)(1) of Executive Order 12866. We believe that the annual impacts will not exceed $100 million since by its very nature the rule applies to animal drugs that have a very small market. Similarly, the administrative costs are unlikely to have a significant economic impact on a substantial number of small entities.
FDA received nine comments to the proposed rule. Only two of these comments contained any remarks that addressed the impacts analysis of the proposed rule. Both stated that the requirement for a specific development plan before a designation is granted would be too burdensome. Neither of the comments provided any estimates on the size of the burden that would be imposed. FDA responded previously in this preamble to the burden issue in these comments. Further, FDA believes that the development of the plan would not be overly burdensome because, in most cases, it would be the same plan that a sponsor would establish with FDA under the regular animal drug review process, and because its cost, estimated at less than one thousand dollars each, would represent less than 0.1% of revenues of even the smallest establishments. Additionally, the MUMS act requires that FDA measure the diligence with which sponsors work towards final approval of a MUMS-designated drug, and a drug development plan is necessary for FDA to measure a sponsor's progress towards this goal. FDA has therefore not changed this provision in the final rule.
None of the changes made to the final rule would affect the expected impacts of the rule on the animal drug producers. Accordingly, lacking any other comments to its analysis of the proposed rule, FDA has reviewed its impacts analysis published in the proposed rule and retains it here for the final rule.
The intention of this rule, and therefore its benefit, is the creation of a system that would stimulate the development and marketing of animal drugs for rare diseases in major species and diseases found in minor species in the United States, which would otherwise not be economically viable under current market conditions. The countervailing cost, or risk of this final rule, would be the possibility of limited competition for approved drugs for a minor use drug indication or in a minor species drug due to the granting of the 7-year exclusive marketing right. In addition to the benefit-risk tradeoff mentioned previously, there would be additional administrative costs for those companies seeking the MUMS designation for a new animal drug application (NADA). We estimate that the designation request would require about 16 hours of preparation by a regulatory affairs official. At a benefit adjusted wage rate of almost $48 per hour for these employees, each request would have administrative costs of about $760.1 We estimate that about 15 separate sponsors would each annually submit, on average, 5 MUMS designation requests. Administrative costs for these actions would total to about $57,300.
The agency is also requiring in § 516.22 that foreign sponsors requesting designation do so through a permanent resident U.S. agent. This is consistent with the current requirements of 21 CFR 514.1(a) since requests for MUMS designation will ultimately be submitted to an NADA file. The agency does not expect to receive many requests for designation from foreign sponsors, and estimates that number at less than one per year. As such, the agency has not quantified the cost of this provision but believes it would be negligible.
Amendments made to existing designations are expected to occur infrequently. We estimate that three amendments will be filed annually, requiring about two hours of preparation. At the same wage rate, this would cost an additional $300. Sponsors may also transfer sponsorship of MUMS-designated drug or terminate the designation. We estimate that these activities would result in only 3 additional hours of administrative costs annually, totaling to $150. The preparation of the annual report that would be required for each MUMS-designated drug is estimated to take about 2 hours. In the first year, this would result in another 150 hours of administrative costs, or about $7,200 in total. FDA notifications to sponsors concerning insufficient quantities of approved MUMS-designated drugs are expected to be rare, about once each year. Sponsor responses are estimated to take 3 hours, at a cost of $150.
Assuming a sponsor chooses to seek the MUMS designation for its NADA, total administrative costs for this rule across all sponsors are estimated at about $65,000 in the first year, and to increase each year thereafter due to the annual reporting requirements.
The Regulatory Flexibility Act requires agencies to prepare a regulatory flexibility analysis if a rule is expected to have a significant economic impact on a substantial number of small entities. Although we believe it is unlikely that significant economic impacts would occur, the following along with other sections of this preamble constitute the regulatory flexibility analysis.
One requirement of the Regulatory Flexibility Act is a succinct statement of any objectives of the rule. As stated previously in this analysis, with this rule the agency intends to create a system, provided for by statute, that would stimulate the development and marketing of animal drugs for rare diseases in major species and diseases found in minor species in the United States, which would otherwise not be economically viable under current market conditions.
The Regulatory Flexibility Act also requires a description of the small entities that would be affected by the rule, and an estimate of the number of small entities to which the rule would apply. The Small Business Administration (SBA) defines the criteria for small businesses using the North American Industrial Classification System (NAICS). For pharmaceutical preparation manufacturers (NAICS number 325412), SBA defines small businesses as those with less than 750 employees. Census data shows that 723 companies with 901 Start Printed Page 41016establishments represent this category.2 While about two-thirds of the establishments would be considered small using the SBA criteria, the agency acknowledges that many requests for MUMS designation would likely be received from multi-establishment companies that exceed the 750-employee limit on small businesses. Nonetheless, the cost of submitting a single request represents only about 0.1% of the revenues of the smallest set of establishments (those with 1-4 employees), and much smaller revenue percentages of all larger establishments. The agency believes that these costs would not represent a significant economic impact on these firms.
All of the costs described previously would be incurred by any small business that applies for MUMS designation. These include costs for request preparation, amendments to designations, preparing annual reports and responding to FDA notifications of insufficient quantities. The firms submitting requests for MUMS designation are expected to already have the necessary administrative personnel with the skills required to prepare the requests and fulfill reporting requirements as identified previously.
The Regulatory Flexibility Act requires that the agency consider any alternatives to a rule that would accomplish the objective while minimizing significant impacts of the rule. As stated previously, the agency believes that the final rule, due to the relatively small costs, would not be likely to impose significant economic impacts on small businesses. As such, the agency believes the final rule achieves the objective with minimal costs to industry.
The statute that creates this system, Public Law 108-282, does not provide the agency a great deal of flexibility in the implementing regulations, such as in determining the length of the exclusivity period or granting an exclusivity to more than one animal drug without regard to sameness of drug, dosage form and intended use. The agency did consider, however, applying an explicit threshold number of animals of each major species as the upper bound of disease incidence in the definition of “minor use” of animal drugs. The agency determined that the data needed to develop these estimates would not be available in time for the publication date of the final rule as mandated by statute. The agency intends in the future to propose a separate rule defining the threshold numbers of animals of each major species. The agency will continue to consider the acceptability of each request for designation as a minor use animal drug on a case-by-case basis as provided for in the Senate report concerning the legislation, until it issues any final rule based on such a proposal.
In the Federal Register of September 27, 2005, FDA published a proposed rule and invited comments on the proposed collection of information. Also in a Federal Register of December 28, 2005, FDA published a notice reopening the comment period for the proposed rule to allow interested persons additional time to comment. Concurrently, FDA submitted the information collection request to the Office of Management and Budget (OMB) for review and approval. OMB did not approve this collection of information, but as terms for clearance, filed comment. In filing comment on this collection of information, OMB requested that FDA examine public comment in response to the notice of proposed rulemaking and describe in the preamble of the final rule how the agency has maximized the practical utility of the collection and minimized the burden. Further, OMB requested for any future submissions of this information collection, FDA indicate the submission as “new” and reference OMB control number 0910-0590.
In response to these Federal Register notices, FDA did not receive any comments regarding the information collection requirements contained in the final rule. In response to OMB's request that the agency describe how it has maximized the practical utility of this collection and minimized the burden, an explanation has been provided elsewhere in the preamble of this final rule.
Title: Designated New Animal Drugs for Minor Use and Minor Species—21 CFR Part 516, OMB Control No. 0910-0590.
Description: The MUMS act amended (the act) to authorize FDA to establish new regulatory procedures intended to make more medications legally available to veterinarians and animal owners for the treatment of minor animal species as well as uncommon diseases in major animal species. This legislation provides incentives designed to help pharmaceutical companies overcome the financial burdens they face in providing limited-demand animal drugs. These incentives are only available to sponsors whose drugs are “MUMS-designated” by FDA. Minor use drugs are drugs for use in major species (cattle, horses, swine, chickens, turkeys, dogs, and cats) that are needed for diseases that occur in only a small number of animals either because they occur infrequently or in limited geographic areas. Minor species are all animals other than the major species, for example, zoo animals, ornamental fish, parrots, ferrets, and guinea pigs. Some animals of agricultural importance are also minor species. These include animals such as sheep, goats, catfish, and honeybees. Participation in the MUMS program is completely optional for drug sponsors so the associated paperwork only applies to those sponsors who request and are subsequently granted “MUMS designation.” The proposed rule will specify the criteria and procedures for requesting MUMS designation as well as the annual reporting requirements for MUMS designees.
Under the new part 516, § 516.20 provides requirements on the content and format of a request for MUMS-drug designation, § 516.26 provides requirements for amending MUMS-drug designation, provisions for change in sponsorship of MUMS-drug designation can be found under § 516.27, under § 516.29 are provisions for termination of MUMS-drug designation, under § 516.30 are requirements for annual reports from sponsor(s) of MUMS designated drugs, and under § 516.36 are provisions for insufficient quantities of MUMS-designated drugs.
FDA estimates the burden for this collection of information as follows:Start Printed Page 41017
1 There is no capital or operating and maintenance cost associated with this collection of information.
and 516
2. Amend § 20.100 by adding paragraph (c)(43) to read as follows:
(43) Minor-use or minor-species (MUMS) drug designations, in § 516.52 of this chapter.
4. Amend § 510.3 by revising paragraph (k) to read as follows:
(k) Sponsor means the person requesting designation for a minor-use or minor-species drug as defined in part 516 of this chapter, who must be the real party in interest of the development and the intended or actual production and sales of such drug (in this context, the sponsor may be an individual, partnership, organization, or association). Sponsor also means the person responsible for an investigation of a new animal drug. In this context, the sponsor may be an individual, partnership, corporation, or Government agency or may be a manufacturer, scientific institution, or an investigator regularly and lawfully engaged in the investigation of new animal drugs. Sponsor also means the person submitting or receiving approval for a new animal drug application (in this context, the sponsor may be an individual, partnership, organization, or association). In all contexts, the sponsor is responsible for compliance with applicable provisions of the act and regulations.
6. Amend § 514.1 by removing paragraph (d).
7. Add part 516 to read as follows:
Timing of requests for MUMS-drug designation.Start Printed Page 41018
Subpart C—[Reserved] Subpart D—[Reserved]
§ 516.1
(3) Subpart C—[Reserved]
(4) Subpart D—[Reserved]
§ 516.2
Same dosage form means the same as one of the dosage forms specified in the following parts of this chapter:
(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 Start Printed Page 41019the subsequent drug is shown to be functionally superior.
§ 516.11
§ 516.12
§ 516.13
§ 516.14
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 § 516.20 will be returned to the sponsor without review.
§ 516.16
(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.
(7) If the drug is intended for a minor use in a major species, documentation in accordance with § 516.21, with appended authoritative references, to demonstrate that such use is a minor use.
(9) A statement that the sponsor acknowledges that, upon granting a Start Printed Page 41020request for MUMS designation, FDA will make information regarding the designation publicly available as specified in § 516.28.
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 § 516.20 documentation demonstrating that the use is limited to a small number of animals (annualized). This documentation must include the following information:
(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.
§ 516.22
§ 516.23
§ 516.24
(a) FDA may grant the request for MUMS-drug designation if none of the reasons described in § 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 § 516.28.
(iii) Any other information required under § 516.20.
§ 516.26
§ 516.27
(iii) A statement that the new sponsor has a complete copy of the request for Start Printed Page 41021MUMS-drug designation, including any amendments to the request and any correspondence relevant to the MUMS-drug designation;
§ 516.28
§ 516.29
(1) Submission of annual progress reports in a timely manner in accordance with § 516.30 that demonstrate that the sponsor is progressing in accordance with the drug development plan submitted to the agency under § 516.20 and
§ 516.31
(1) FDA terminates the MUMS-drug designation and associated exclusive marketing rights under § 516.29; or
(4) The sponsor fails to assure a sufficient quantity of the drug in accordance with section 573 of the act and § 516.36.
§ 516.34
(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-Start Printed Page 41022designated 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.
§ 516.36
§ 516.52
(d) In accordance with § 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 § 516.29, FDA will give public notice of the termination of all MUMS-drug designations.
This document was received at the Office of the Federal Register on July 23, 2007.
1. 2000 National Industry-Specific Occupational Employment and Wage Estimates, U.S. Department of Labor, Bureau of Labor Statistics (www.bls.gov/​oes/​2000/​oesi3_​283.htm); Compliance officer wage rate adjusted to 2005 by 2000-20004 average annual wage inflator at BLS (http://data.bls.gov/​cgi-bin/​surveymost).
2. 2002 Economic Census, US Census Bureau, Manufacturing Industry Series, Pharmaceutical Preparation Manufacturing, Table 4.
[FR Doc. E7-14444 Filed 7-25-07; 8:45 am]