Guideline

Guidance For Industry: FDA Approval of New Animal Drugs for Minor Uses and for Minor Species

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR VETERINARY MEDICINE

Guidance for Industry

FDA Approval of New Animal Drugs

for Minor Uses and

for Minor Species

This document is intended to provide specific guidance on the means for generating effectiveness and safety data to support the approval of new animal drugs for minor uses and minor species. It represents the agency’s current thinking on drug approval for minor uses and minor species. It does not create or confer any rights for or on any person and does not operate to bind the FDA or public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations or both.

This Guidance Document supersedes GUIDELINE 26, “Guidelines for the Preparation of Data to Satisfy the Requirements of Section 512 of the Act Regarding Minor Use of Animal Drugs.”

FDA may amend this guidance document based upon comments submitted by interested persons. Submit written comments on the guidance document to the Policy & Regulations Team, Center for Veterinary Medicine (HFV-6), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855.

For questions regarding this document, contact Meg Oeller, Center for Veterinary Medicine (HFV-130), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-827-7581 (email: moeller@bangate.fda.gov).

Additional or updated copies of this guidance document may be requested from the Communications Staff (HFV-12), Center for Veterinary Medicine, 7500 Standish Place, Rockville, MD 20855 and may be viewed on the internet at http://www.fda.gov/cvm.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Veterinary Medicine
January 1999
(Minor revisions 4/15/99)

FDA Approval of New Animal Drugs

for Minor Uses and for Minor Species

Part 1: Introduction

I. PURPOSE OF THIS DOCUMENT

The major purpose of this document is to suggest means of generating effectiveness and safety data to support the approval of minor use animal drugs. A minor animal drug use is defined as use in a minor species OR use in any animal species for a condition that is rare or that occurs in limited geographic areas. Minor species are defined by exclusion, as any species other than major species. Major species are defined as cattle, swine, chickens, turkeys, horses, dogs, and cats. According to current regulations, sheep are a minor species except with respect to human food safety data collection requirements, for which sheep are considered major species. CVM intends to issue a proposed regulation in which sheep would be defined as a minor species for all requirements of the drug approval process. Other guidance addresses issues relating to exotic and wildlife species.

CVM currently considers veal calves separately from cattle for the drug approval process. Thus, portions of this guidance document relating to ‘Domestic and Semi-Domestic Minor Ruminants’ may prove useful with respect to supporting indications for use in veal calves.

The guidance document, as applied to minor use animal drugs, does not lessen the legal requirements for demonstrating the safety and effectiveness of a new animal drug. Instead, the guidance document suggests possible means of generating safety and effectiveness data to satisfy these requirements.

This document is intended to reflect the current way that animal drugs are approved for minor species and minor uses. The Animal Drug Availability Act of 1996 required CVM to examine the way that these products are approved and to propose means to facilitate such approvals. In the FEDERAL REGISTER, Vol. 63, No. 209, October 29, 1998, CVM published a notice of the availability of its report proposing several options to encourage animal drug approvals for minor species and for minor uses. It is very likely that additional policies and programs will be implemented over the next few years to accomplish this goal. Because policies and programs may change, sponsors are encouraged to contact CVM early in project development to determine the most efficient path to approval of their products.

A person may follow the guidance in this document, or may choose to follow alternate procedures or practices. If a person chooses to use alternate procedures or practices, that person may wish to discuss the matter further with the agency to prevent an expenditure of money and effort on activities that may later be determined to be unacceptable to FDA.

This guidance document does not bind the agency or the public, and does not create or confer any rights, privileges, or benefits for or on any person. The document represents FDA's current thinking on means to provide data supporting drug approvals for minor species and minor uses. When a guidance document states a requirement imposed by statute or regulation, the requirement is law and the force and effect of this requirement are not changed in any way by inclusion in the guidance.

II. ORGANIZATION OF THIS DOCUMENT

Part 1 of this document includes general information applicable to all types of minor uses. Part 2 presents specific plans to provide data for various categories of minor uses. These categories include minor uses in major species, minor avian species (gamebirds, semidomestic waterfowl, and ratites), minor ruminants, rabbits, and aquatic species (finfish, aquatic invertebrates, alligators, etc.).

To use this document effectively, the user need only read this introduction and the section pertinent to the animal of interest. Each section contains information on effectiveness, target animal safety, human food safety, and environmental issues. This organization reflects the major data components of the animal drug approval process exclusive of manufacturing data.

III. APPROVAL PROCESS OVERVIEW

Users of this document may range from those well acquainted with the new animal drug approval process to those who have no experience with this process at all. A brief overview of the technical sections involved in the new animal drug approval process follows. Those already familiar with these components may wish to skip to the next
section.

New animal drugs are approved for specific intended uses (indications). To get a drug approved for a new indication, a sponsor submits a new animal drug application (NADA). The application may be original or a supplement to an existing NADA. The following list outlines the types of information submitted to support an NADA.

1) Effectiveness

2) Safety to the target species

3) Human food safety (food-producing animal species)

4) Labeling

5) Chemistry, manufacturing, and controls

6) Environmental Assessment

7) Freedom of Information (FOI) Summary

The effectiveness section of an application may include data from dose titration or other dose determination, dose confirmation, and field studies. The target animal safety section may include studies which identify the toxic syndrome(s) associated with the drug and the margin of safety of use of the product in the treated animal. The human food safety section may include short and long term toxicology studies, total residue and metabolism studies, analytical method validation studies, and tissue residue depletion studies. The chemistry, manufacturing, and controls section includes information which must be supplied by the manufacturer regarding the manufacture of the product. Labeling must be provided by the NADA sponsor. These types of data are supplied to meet requirements set forth in the Federal Food, Drug, and Cosmetic Act (FFD&CA).

Environmental information is submitted to support FDA’s need to comply with the National Environmental Policy Act (NEPA). Before approving a new animal drug, the agency must consider potential effects on the environment. In many cases, for a minor use, a categorical exclusion from the need to provide an environmental assessment (EA) will be granted. In other cases, some type of EA will be necessary to support a “finding of no significant impact” (FONSI). The environmental assessment (EA) may include information on the introduction of the drug into the environment through manufacture, use, and disposal, the fate of the drug in the environment, and the effects of the drug in the environment.

The Freedom of Information summary describes the studies which serve as the basis for the drug approval. This summary, along with the EA, must be made available to the public upon approval of the drug. The FOI Summary is the means whereby the agency complies with the Freedom of Information Act (FOIA).

Data needed to support an NADA are collected during an investigational stage, before a new animal drug application is submitted. Studies are conducted at this stage under an investigational new animal drug (INAD) exemption. All correspondence with the FDA’s Center for Veterinary Medicine (CVM) regarding the drug is maintained in an INAD file. Although not required, sponsors usually submit study protocols for review before
beginning studies to make sure that CVM agrees that study designs are appropriate to obtain the required information.

We strongly recommended that sponsors contact CVM early in the process to plan the development of their NADA. Decisions on the type and number of studies to be conducted and on the designs of those studies can be made in cooperation, and should greatly facilitate the entire process. Such product development planning also puts the sponsor in direct contact with the people at CVM responsible for reviewing each of the technical
sections.

IV. MINOR USE APPROVAL PROCESS PROVISIONS--DATA EXTRAPOLATION

In recognition of the scarcity of approved drugs for minor uses and the lack of resources available for minor use drug research, CVM has included special provisions in this guidance document to encourage and facilitate minor use animal drug approvals. These include increased flexibility and interspecies data extrapolation, which can drastically minimize the amount of new research, expense, and difficulty involved in achieving approval of a minor use
new animal drug. The attached species-specific sections of this guidance document suggest ways to fulfill data requirements through use of data extrapolation.

CVM allows interspecies data extrapolation to support minor use applications whenever scientifically justifiable. Minor use applications often derive the greatest benefit from interspecies extrapolation when the drug is already approved for use in a major species and such data already exist in the approved major species application(s). This is especially true for food-producing species; if the drug is approved for use in a related food species, data extrapolation may be utilized in place of some expensive human food safety studies.

It is important to note, however, that minor use applicants who do not have access to proprietary data for a major species must first obtain written permission from the owner of that data to allow CVM to refer to the data on behalf of the minor use applicant.

V. RELATION BETWEEN NADAS AND OTHER FILES

The lack of financial incentive for a pharmaceutical firm to conduct studies needed for a minor use drug approval may lead to the funding, conduct, and submission of effectiveness and safety studies by parties other than a potential NADA sponsor. These studies may be submitted to public master files (PMFs), or, occasionally, to investigational new animal drug (INAD) files or veterinary master files (VMFs).

Once these studies are accepted by CVM as adequate to support an approval, an NADA sponsor may utilize these data by reference to support a minor use NADA (or
supplemental NADA) if one of the following conditions has been met:

1) the availability of the data in a PMF has been published in the Federal Register, or

2) the sponsor of a veterinary master file or INAD has provided authorization for CVM to refer to the data on behalf of the NADA sponsor.

VI. WORKING WITH CVM

CVM recognizes that potential participants in the minor use approval process may not have regulatory experience and many need additional guidance. CVM recommends that interested parties initiate contact with CVM early in the process. A meeting or phone conference with CVM to discuss a research plan for the drug is often useful. If needed, CVM can also explain regulatory requirements applicable to investigational use of the drug. Once a plan is developed, CVM strongly suggests that the petitioner submit protocols for CVM's review before initiating the studies. CVM may also provide the petitioner with guidance on compilation of data into an appropriate format for submission.

VII. ASSISTANCE

If a specific animal or drug indication is not addressed in this document, or if you need additional information, please contact one of the individuals listed below. General questions: FDA Liaison to the NRSP-7 Minor Use Animal Drug Program, 301-827-7581

Food/semi-domestic species: Director, Division of Therapeutic Drugs For Food Animals, 301-827-7580

Non-food species and Wildlife/Exotic Species: Director, Division of Therapeutic Drugs for Non-Food Animals, 301-827-7543

Production Drugs: Director, Division of Production Drugs For Food Animals, 301-827-0219

VIII. POLICY ON ANIMAL TESTING

It is the position of the Center for Veterinary Medicine that animal testing should derive the maximum amount of useful scientific information using the minimum number of animals necessary. Consideration should be given to the use of accepted alternative methods to whole animal testing.

Attempts should be made to eliminate or minimize the degree and duration of suffering in the animals that are used. Pain-relieving medication, including anesthetics, should be considered and employed when such drugs will not interfere with the nature and purpose of the testing. Euthanasia of moribund animals should be considered and employed when the procedure will not interfere with the nature and purpose of the testing.

The euthanasia procedure employed should comply with the recommendations of the 1993 Report of the American Veterinary Medical Association (AVMA) Panel on Euthanasia (Journal of the American Veterinary Medical Association, 1993, Vol. 202, No. 2, pp. 229-249).

IX. WILDLIFE AND EXOTIC SPECIES

FDA differentiates wildlife and exotic animals from minor species. “Wildlife” species are those which live in an unconfined free-range environment, are usually under the jurisdiction of a local, state, or federal government, and usually are limited in number. These species may be covered by hunting statutes but they are not routinely farm- or ranch-raised for slaughter for human food.

“Exotic” species are those mammalian or avian species which are rare, not indigenous to the United States, and/or which are confined for educational, reproductive, or aesthetic purposes. Such species include those maintained in zoological parks and private collections.

Contact the Division of Drugs for Non-food Animals (301) 827-7543 for guidance regarding approval of drugs for use in wildlife and exotic animals.

X. DEFINITIONS

The following terms are used throughout this document. While more than one definition may be possible for some terms, the definitions provided are those used by the Center.

ADI - Acceptable Daily Intake; a value calculated for a new animal drug based on the noobservable effect level (NOEL) obtained in the human food safety toxicology studies in combination with an appropriate safety factor

Categorical Exclusion - Exclusion from the requirement to prepare an environmentalassessment

CFR - Code of Federal Regulations

Dose Confirmation Study - In vivo study to confirm the effectiveness of a selected drug dose; may be conducted in the laboratory or in the field

Dose Determination Study - Study used to select an appropriate dose or dose range

Environmental Assessment - Public document that describes evidence and analysis that a federal agency used to determine whether a finding of no significant impact is appropriate or if an environmental impact statement is required

FDA/CVM - U.S. Food and Drug Administration, Center for Veterinary Medicine

Federal Register - Official federal publication containing information such as proposed regulations, notices of public meetings, etc.

Field Trial - in vivo, non-laboratory study to determine effectiveness and safety of a product under actual use conditions

GLPs - Good Laboratory Practice Regulations (described in 21 CFR 58), regulations which outline requirements for documentation, quality assurance, and data integrity for safety studies

INAD - Investigational New Animal Drug

INAD Exemption - Exemption which permits the otherwise illegal shipment in interstate commerce of an unapproved animal drug for investigational studies; contact CVM regarding information on how to establish an INAD exemption

INAD File - File which holds data under direct review and correspondence between CVM and sponsors of new animal drugs regarding investigational drug use, including study protocol design and studies submitted for review

Marker Residue - The residue(s) serving as the analyte for the regulatory method; the ratio of marker residues to total residues is established so that the marker residue serves as an index of the total residues in that tissue

Major Species - Cattle, horses, swine, chickens, turkeys, dogs, and cats

Minor Species - Other than a major species, and distinguished from wildlife/exotic species

Minor Use - Any new animal drug use in a minor species OR a new animal drug use in any animal species for control of an infrequently occurring or geographically limited disease

NADA - New Animal Drug Application; application for approval of a specific drug product, so that the drug may be legally marketed; must be supported by, among other things, effectiveness, animal safety, human safety, and drug manufacturing data

NADA Sponsor - Entity that owns and is responsible for the contents of an NADA and is responsible for compliance with all post-approval requirements such as distribution, advertising, and reporting to FDA

NEPA - National Environmental Policy Act; national charter for protection of the environment. Requires FDA to perform an environmental assessment of an action such as approving an NADA

NRSP-7 - NRSP-7 is the National Research Support Project Number 7; a USDA program promoting minor species drug studies

PMF - Public Master File; file which holds publicly generated or otherwise publicly available data (generally effectiveness, animal safety, residue chemistry, and environmental assessment) that may be referenced by an NADA sponsor to support an original or supplemental NADA approval

Regulatory Method - A method of analysis to monitor drug residues and to establish a withdrawal time in an edible tissue

Safe Concentration - The total residues of the drug (parent drug and all metabolites) that are permitted in edible products

Salt Water Species - For purposes of our discussions, those non-mammalian and nonavian species found in pure seawater or water of intermediate salinity (brackish water)

Semi-Domestic Species (ruminants and waterfowl) - Animals that are otherwise considered wild species that are also reared specifically for slaughter for human consumption

Supplemental NADA - Application for modification of an existing drug approval; this could include the addition of a label indication for a minor species, approval of use in another animal species, changes in conditions of use, or other changes to the original approval

Target Animal Safety Study - In vivo study of the safety of a drug in the animal species for which drug approval is being sought

Target Tissue - May refer to that tissue where a drug is intended to have its effect, or to that edible tissue in which the regulatory method measures the concentration of the marker residue and in which the regulatory tolerance is established

Tolerance - The concentration of the marker residue, as measured by the regulatory method in the target tissue, which corresponds to the safe concentration for total residues of the drug in that tissue

Veal calves - Including , but not limited to, calves fewer than 150 pounds in weight or fewer than 3 weeks of age (bob veal) and calves fed exclusively a formula or all milk diet (formula fed or fancy veal calves)

Withdrawal Period for a drug - The interval between the time of last administration of the drug and the time when the animal can be safely slaughtered for food purposes. This is based on depletion of the marker residue in the target tissue to the tolerance.

XI. OTHER GUIDES

The following guides may be useful to use in conjunction with this document. They are available from CVM by writing to: Food and Drug Administration, Center for Veterinary Medicine, Communications Staff, 7500 Standish Place, HFV-12, Rockville, MD 20855 or by calling them at (301) 594-1755. These documents are also available on the internet at http://www.fda.gov/cvm in the on-line library under CVM Guidance and Guidelines.

#2 Anthelmintics

#3 General Principles for Evaluating the Safety of Compounds Used in Food-Producing Animals (July 1994)

#14 Guideline and Format for Reporting the Details of Clinical Trials Using An Investigational New Animal Drug in Food Producing Animals

#19 Antimicrobial Drugs in Animal Feeds: Animal Health Safety Criteria

#20 Antimicrobial Drugs in Animal Feeds: Effectiveness Criteria

#31 Guidelines for the Evaluation of Bovine Anthelmintics (July 1981)

#33 Target Animal Safety Guidelines For New Animal Drugs (June 1989)

#40 Anticoccidial Guideline

#49 Guideline for Target Animal Safety and Drug Effectiveness Studies for Anti-microbial Bovine Mastitis Products (Lactating and Non-lactating Products) (April 1996)

#56 Protocol Development Guideline for Clinical Effectiveness and Target Animal Safety Trials (November 1994)

#66 Guidance for Industry: Professional Flexible Labeling of Antimicrobial Drugs(August 1998)

The following document is available from NRSP-7. To get a copy, contact the NRSP-7 Liaison at FDA/CVM/HFV-130, 7500 Standish Place, Rockville, MD 20855.
NRSP-7: Recommendations for Evaluating Analytical Methods (January 10, 1994)

FDA Approval of New Animal Drugs

for Minor Uses and for Minor Species

Part 2A: Minor Use in a Major Species

A minor animal drug use is a drug use in a minor species, or a drug use in any animal species for control of an infrequently occurring or geographically limited disease. “Minor species” means animals other than cattle, horses, swine, chickens, turkeys, dogs, and cats. Wildlife and exotic species not raised for food or fiber use are considered separately by CVM.

I. EFFECTIVENESS

Means for demonstrating effectiveness will be determined on a case-by-case basis. The petitioner is advised to discuss the plan with CVM early in the development process. In most cases, at least one dose determination study and some clinical field data will be needed. However, CVM will take into consideration the practical limitations of data collection for an infrequently occurring disease. Literature may be utilized to demonstrate part or all of the effectiveness claim.

II. TARGET ANIMAL SAFETY

A controlled study demonstrating the safety of the drug in the target species will be needed in most cases. The sponsor may choose to conduct a study with an untreated control group and a 10X group for 3X the maximum proposed duration of treatment. If no toxic effects are observed at this dose level, this single study will be sufficient to demonstrate the safety of the drug in the target animal, unless adverse effects are identified in the effectiveness studies.

Assuming the toxic syndrome has been defined, the need for a study conducted at 10X the maximum proposed label dose may be obviated. Standard study design incorporates an untreated control group and a group or groups receiving higher than the maximum proposed label dose for three times the maximum proposed duration. This is generally accomplished by the use of 1X, 3X, and 5X the highest proposed dose. However, alternative study designs may be considered where appropriate.

III. HUMAN FOOD SAFETY

Before approving a new animal drug for minor use in a major species, the FDA must determine that people will not be exposed to unsafe residues in their food as a result of the approved use. The health risk associated with an animal drug residue equals the hazard (or inherent toxicity of the compound) times exposure. FDA regulates the public health risks associated with animal drug residues by assessing hazard and controlling exposure through the setting of tolerances and withdrawal periods. The risk standard that FDA applies, “reasonable certainty of no harm”, ensures that drug residues in edible tissues from treated animals can be consumed daily in the human diet for a lifetime with no adverse effects. CVM allows alternative ways to assess the human health risk for minor use applicants. Please contact the Center to discuss the specific drug, indications, and conditions for minor use.

IV. ENVIRONMENTAL CONSIDERATIONS

The FDA is required under the National Environmental Policy Act of 1969 (NEPA) to consider the environmental impact of investigating and approving new animal drugs as an integral part of its regulatory process. Exemptions and applications to FDA for the investigation and approval of animal drugs must include sufficient environmental information to allow the Agency to assess whether environmental impacts may occur from the manufacture, use and disposal of the drugs.

FDA’s regulations for implementing NEPA are contained in Title 21 of the Code of Federal Regulations (CFR), Part 25. These regulations were recently revised and published in the FEDERAL REGISTER on July 29, 1997 (62 FR 40569) and became effective on August 28, 1997. Under these regulations, sponsors filing investigational exemptions or new animal drug applications must submit an environmental assessment (EA) unless the exemption or application qualifies for a categorical exclusion from the requirement to prepare an EA.

An EA is not required for most minor use applications. In most cases, a minor use application will be granted a categorical exclusion from the requirement to provide an EA. The regulations under which a categorical exclusion for a minor use can be granted are included in 21 CFR 25.33(d)(4), 25.33(c) and 25.33(d)(5). Section 25.33(d)(4) provides a categorical exclusion for drugs intended for minor species, when the drug has been previously approved for use in another or the same species where similar animal management practices are used. FDA believes similar animal management practices generally include dosage, duration of use and concentration of the medication, as well as management style, such as feedlot, pasture or open pens. Although 25.33(d)(4) does not specifically include minor use, for environmental review, FDA will consider this to be equivalent to a minor species. In both cases, minor use and minor species, if the animal drug is already being used under similar animal management practices, then no significant differences from the major use approval are anticipated in the environmental introduction, fate and effects of the drug.

If for some reason an application cannot be excluded under 21 CFR 25.33(d)(4), then it may still be possible to obtain a categorical exclusion under 21 CFR 25.33(c) or
25.33(d)(5). Section 25.33(c) provides for a categorical exclusion for animal drug substances that occur naturally in the environment when the use does not alter significantly the concentration or distribution of the drug, its metabolites or degradation product(s) in the environment.

Section 25.33(d)(5) provides a categorical exclusion for drugs intended for use under prescription or veterinarian’s order for therapeutic use in terrestrial species. Although not specifically covered under this regulation, feed additives issued under a veterinary feed directive (VFD) would be considered equivalent to a prescription use. Because VFDs are issued under a veterinarian’s order, they may also be categorically excluded.

For a categorical exclusion from the reqirement to prepare an EA to be claimed, the sponsor submitting an exemption or application must state in the submission that the use qualifies for a categorical exclusion, cite the particular categorical exclusion that is claimed, and state that to the applicant’s knowledge, no extraordinary circumstances exist. Section 21 CFR 25.15(d) can be consulted regarding this requirement. FDA will review the claim and determine whether the categorical exclusion is applicable and whether any extraordinary circumstances exist that indicate that the proposed use may significantly affect the quality of the human environment.

Extraordinary circumstances are described in 21 CFR 25.21 and may include any use where the available data establish that there is potential for serious harm to the environment. This includes uses that adversely affect a species (flora or fauna), or the critical habitat of a species that is entitled to special protection under Federal law, such as the Endangered Species Act or the Convention on International Trade in Endangered Species of Wild Flora and Fauna. Additional extraordinary circumstances are described in the regulations for implementing the provisions of NEPA contained in 40 CFR 1508.27. These may include uses that are controversial, that result in high uncertainty or unknown risks, that are precedent setting in nature, and uses that threaten a violation of Federal, state or local law or requirements imposed for the protection of the environment.

In some cases, an EA may be necessary. There are no specific guidelines available for the preparation and submission of an EA under the new regulations. Some information on the purpose and scope of an EA is contained in 21 CFR 25.40. In general, the content and format of an EA for veterinary drugs should consist of 11 parts. These are:

1. date, name, and address of the applicant

2. description of the proposed use (including descriptions of what the use is and any anticipated disposal)

3. identification of the substances that are subject of the use

4. description of the ecosystem at the site of introduction (including a conceptual model with assessment endpoints of the potential impacts at exposed sites in the environment)

5. an analysis section (including analysis of the fate and effects of the substances)

6. a risk characterization based upon the exposures and the hazards (derived from the conceptual model and analysis of the fate and effects information)

7. description of any alternatives to the proposed use (including mitigations)

8. preparer’s names

9. signature block of responsible individual

10. references

11. appendices

The critical portions of the EA are the formulation of the conceptual model and the risk analysis that are conducted in sections 4, 5, 6, and 7. Data included in these sections may be obtained from the literature and from laboratory studies. The data should follow good laboratory practices or, in the case of literature, be of similar quality and well documented.

Guidance for performing an environmental risk analysis includes the following:

1. Baker, J.L., et al., editiors. 1994. Aquatic Dialogue Group: Pesticide Risk Assessment and Mitigation. SETAC Press, Pensacola, FL.

2. Cockerham, Lorris and Shane, Barbara, editors. 1994. Basic Environmental Toxicology. CRC, Boca Raton, FL.

3. Environmental Protection Agency. Proposed Guidelines for Ecological Risk Assessment. the FEDERAL REGISTER of September 9, 1996 (61 FR 47552).

4. Suter, G.W. 1993. Ecological Risk Assessment. Lewis Publishers, Boca Raton, FL.

FDA will evaluate the information contained in the EA to determine whether it is accurate and objective and whether the proposed action may significantly affect the quality of the human environment. If significant effects requiring the preparation of an Environmental Impact Statement (EIS) are identified, FDA will prepare an EIS. If such effects are not identified, FDA will prepare a finding of no significant impact (FONSI).

FDA Approval of New Animal Drugs

for Minor Uses and for Minor Species

Part 2B: Minor Avian Species

(Gamebirds, Semi-Domestic Waterfowl, and Ratites)

I. EFFECTIVENESS

A. COCCIDIOSTATS

1. Introduction

Suggested below are some possible approaches, which may be used alone or in combination, to demonstrate the effectiveness of a minor avian coccidiostat.

The petitioner is advised to discuss the plan with CVM early in the development process. It is also advisable to come to protocol agreement with CVM prior to the initiation of any studies.

Studies should be conducted using the target animal for which the drug is intended. Each coccidial species for which a claim is being made should be confirmed by experimentation with that species. We recommend that a claim include the most pathogenic species occurring in the host minor species. Mixed infections are acceptable, but the predominant species should be documented.

a. Literature

We suggest that the petitioner begin with a literature review. The petitioner should search particularly for carefully controlled experiments using the candidate compound for the intended label claim. Should adequate documentation not exist in the literature, the effectiveness of the compound should be evaluated in a sequence of trials that includes dose confirmation.

b. Method of Infection

Natural infection is ideal; however, induced infection is acceptable for dose determination studies. The history and drug exposure of the isolate used for induced infection should be indicated, if known. Titration studies conducted to determine the number oocysts to be used in the induced infection should be included. Single cell isolation is not required. Virulence studies should be conducted to determine the appropriate number of oocysts to produce an acceptable infection that will allow the therapeutic effects of the compound to be clearly measured. The virulence of the parasite may be characterized by depression in rate of weight gain, total number of excreted fecal oocysts, and increased mortality.

c. Measures of Effectiveness

Parameters for evaluation of the drug effectiveness will depend on the coccidial species and disease being evaluated, as well as what is practicable as an objective measurement in a given species. Potential parameters include mortality due to the coccidial infection, number of excreted fecal oocysts, weight gain, lesion scores (a key should be provided), and/or dropping scores (a key should be provided). If total fecal oocyst numbers are used as one of the parameters to evaluate effectiveness, CVM prefers the measurement of total oocyst counts over a collection period of several days.

All mortality and morbidity, whether resulting from coccidiosis or other pathogens should be diagnosed. For coccidiosis, wet mount examinations should be made and coccidia identified.

d. Product Assays

Feed and/or water must be assayed for drug content. The results of assays should be provided with the final study report. e. Medication & Induced Infection. The administration of medicated feed and oocysts may be initiated concurrently. However, if the drug exerts its activity during initial stages of the parasite life cycle, the drug may be administered no more than two days prior to the induced infection.

2. Dose Determination

CVM will not require dose determination studies for anticoccidial products. The sponsor may determine the dose without concurrence from CVM. The Center will not review protocols for dose determination studies. The trials conducted or supporting data for the chosen dose or dose range should be submitted as nonpivotal studies only, in accordance with the legal requirements for the sponsor to submit all data relevant to an NADA approval. 21 CFR 514.1(b)(8)(iv).

The non-pivotal studies may provide the rationale for the dose selection, although CVM will not comment on the adequacy of the studies. The sponsor should summarize the rationale for dose selection for inclusion in the FOI Summary.

3. Dose Confirmation

A minimum of two dose confirmation studies should be conducted including the most relevant parasites for the target bird. Dose confirmation trials should be conducted using induced infection. The sponsor should ensure that an adequate coccidiosis model is designed in the protocol which will allow a clear evaluation of the data to support effectiveness of the compound.

B. ANTIMICROBIALS

1. Introduction

Suggested below are some possible approaches, which may be used alone or in combination, to demonstrate the effectiveness of a minor avian antimicrobial. These approaches have been divided into two categories, based on the proposed claim for the minor avian species:

antimicrobials which have not been approved in another avian species for a similar indication.

antimicrobials which have been approved in another avian species for a similar indication

The petitioner is advised to discuss the plan with CVM early in the development process. It is also advisable to come to protocol agreement with CVM prior to the initiation of any studies.

a. Literature

No matter which of these categories applies, CVM suggests that the petitioner begin with a literature search and review for studies relevant to the proposed claim. Reports of controlled experiments are most useful. CVM suggests that the petitioner discuss, early in the development process, the use of literature to meet some or all of the effectiveness requirements.

b. Other Considerations

Some factors that will influence the approach selected include the nature of the disease condition, the drug, the nature and availability of the animals, and other practical considerations.

2. Drug Which Has NOT Already Been Approved in Another Avian Species for the Same Claim

The following are possible options:

a. Literature

As noted in Section 1a above, literature may be used to meet some or all of the effectiveness requirements.

b. Dose Determination Via PK/MIC

Dose may be determined by using pharmacokinetic and MIC data in association with a clinical confirmation study in naturally-infected animals.

c. Dose Determination in Animals With Induced Infections

Dose may be determined via a dose determination study in animals with induced infections (generally using 3 non-zero doses and a zero dose control group) with a clinical confirmation study in naturally-infected animals.

d. Dose Determination With Naturally-Infected Animals

Dose may be determined via field dose determination in naturally-infected animals using several doses including a negative control with a clinical confirmation study in naturally-infected animals. If the field dose determination study is large enough, a second confirmation study should not be necessary.

3. Drug Which Has Already Been Approved in Another Avian Species for the Same Claim

The following are possible options:

a. Literature

As noted in Section 1a above, literature may be used to meet some or all of the effectiveness requirements.

b. Interspecies Data Extrapolation

Data may be extrapolated between a major and a minor species when a comparable host/disease relationship exists. A dose or dose range may be determined by allometric scaling or by direct extrapolation of the already approved dose in the comparable major species, with supportive serum concentration/bioavailability data and minimum inhibitory concentration (MIC) data, and without a clinical confirmation study.

A dose or dose range may also be determined by allometric scaling or by direct extrapolation of the already approved dose in the comparable major species, with a clinical confirmation study in naturally-infected animals.

Allometric scaling of dose may be done using the equation developed by Jim Riviere, D.V.M., Ph.D., at North Carolina State University:

dm = dM (BwM / Bwm) 0.25

Where: dm = Total dose in the minor species (in mg)

dM = Total dose in the major species (in mg)

Bwm = Average body weight in the minor species

BwM = Average body weight in the major species

Other equations for allometric scaling may be proposed as appropriate.

c. Dose Determination in Animals With Induced Infections

Dose may be determined via a dose determination study in animals with induced infections (generally using 3 non-zero doses and a zero dose control group) with a clinical confirmation study in naturally-infected animals.

d. Dose Determination With Naturally-Infected Animals

Dose may be determined via field dose determination in naturally-infected animals using several doses including a negative control with a clinical confirmation study in naturally-infected animals. If the field dose determination study is large enough, a second confirmation study should not be necessary.

4. Other

The development of alternative approaches to the demonstration of effectiveness should take into account the following questions to which CVM will be seeking answers.

How is effectiveness defined and what is an adequate level of effectiveness, as viewed by the veterinarian and/or producer?

Do the parameters and means of data evaluation used constitute an appropriate measure of effectiveness?

Is effectiveness related to the administered drug? Is there a dose-response relationship? Has the influence of other confounding factors on the study results been minimized?

What is an appropriate dose or dose range by the proposed route of administration, i.e., what dose or dose range achieves an adequate level of effectiveness?

What are the adverse effects of administration of the proposed dose or dose range? Adverse reactions observed in effectiveness studies should always be reported, and birds dying during effectiveness experiments should be necropsied to determine cause of death. See also the next section on target animal safety.

C. P RODUCTION DRUGS

Production drugs are those new animal drugs intended to affect the structure and/or function of an animal’s body. Effects claimed for production drugs are normally related to improved animal performance, e.g., increased rate of weight gain, increased milk production, improved feed efficiency, increased carcass leanness, and improved reproductive performance. In the past, the minor species/minor use regulations were not interpreted to apply to production uses of new animal drugs, and the requirements for production uses of new animal drugs in minor species were the same as for major species. The Center will now consider production claims for minor species.

The requirements for approval of production claims for minor species will depend upon whether or not an approval in a similar major species already exists. All requests will be handled on a case-by-case basis and an attempt will be made to make use of all available data that may relate to the request. Thus, sponsors are encouraged to work closely with the Center and to share all available information early in the approval process. Sponsors should be aware that the ability to show effectiveness depends upon the relative size of the response of a drug as well as upon the variability associated with the response.

II. TARGET ANIMAL SAFETY

The type of target animal safety studies needed in the minor avian species will be determined on a case-by-case basis. Requirements will depend upon the available information on the drug's margin of safety in other species and the available information on the safety of the drug in the minor species. This information includes literature reports, adverse reactions reports, and safety information gleaned in effectiveness studies. For example, if a drug is approved and has a wide margin of safety in several other species, including chickens or turkeys, and no adverse effects were found in an effectiveness study and several literature reports, a target animal safety study in the minor avian species may not be required. Rather, the basis for demonstrating animal safety may include interspecies extrapolation and data in the minor species at the proposed use level.

In most cases, a basic target animal safety study will be needed. The target animal safety study may be combined with an effectiveness study, if desired, to minimize the total number of animals required. Such a combination study takes careful planning.

In order to establish safety of drugs intended for use in breeding animals, reproductive data is necessary. Otherwise, a label restriction to non-breeding animals will be required.

The petitioner is advised to discuss the plan with CVM early in the development process. It is also advisable to come to protocol agreement with CVM prior to the initiation of any studies. A Target Animal Safety Guideline is available from CVM and provides additional study design information.

A. LITERATURE

CVM suggests that the petitioner search the literature for relevant reports and submit these as soon as possible. CVM will use these reports, in conjunction with its own review of adverse reactions reported to FDA, to make a preliminary determination of remaining animal safety requirements, if any. If adverse effects are discovered in the course of subsequent effectiveness studies, this determination will be reassessed in light of the additional data.

B. TOXICITY TEST

A single study may be conducted using the drug at 10X the recommended dose for 3X the recommended duration. This study may be used as a first step to identify the toxic effects prior to conducting a multiple dose Target Animal Safety study. If no toxic effects are observed at this dose level, this single study will be sufficient to demonstrate the safety of the drug in the target animal unless adverse effects are identified in the effectiveness studies.

C. MULTIPLE DOSE TARGET ANIMAL SAFETY STUDIES

Safety studies should be conducted in apparently normal birds and should demonstrate the margin of safety for the use of the product in the intended species. The treatment groups used in the safety study for each species should generally include a non-medicated control, the proposed use level, an estimated toxic level, and an intermediate level. This approach is generally accomplished by the use of 1X, 3X, and 5X the highest proposed dose. The drug should be administered for 3 times the recommended maximum use duration.

III. HUMAN FOOD SAFETY

A. INTRODUCTION

Before approving a new animal drug for minor use, the FDA must determine that people will not be exposed to unsafe residues in their food as a result of the approved use. The health risk associated with an animal drug residue equals the hazard (or inherent toxicity) of the compound times the exposure. FDA regulates the public health risks associated with animal drug residues by assessing hazard and controlling exposure through the setting of tolerances and withdrawal periods. The risk standard that FDA applies, “reasonable certainty of no harm”, ensures that drug residues in edible tissues from treated animals can be consumed daily in the human diet for a lifetime with no adverse effects. In making that determination, FDA considers the safe concentration of total residues, the rate of residue depletion under the conditions of minor use, and the probability of a unique metabolite of toxicological concern occurring from the proposed minor use.

In many cases, the new animal drug proposed for minor use will already have a major use approval. The sponsor of the major use approval may authorize the FDA to access the human food safety data contained in the major use approval file on behalf of the minor use approval. Whenever scientifically and legally possible, the FDA intends to extrapolate results obtained from tests demonstrating human safety of major use drugs to support approvals of minor uses of these drugs. In general, data from the approved drug use in poultry (chickens or turkeys) will be used to extrapolate to the minor use avian species. However, it must be recognized that instances will arise when such data extrapolation is not justified. Acceptability of the data extrapolation from major to minor species will be determined on a case-by-case basis by considering a sponsored drug's currently approved use(s), proposed use(s), and all other available relevant information.

In a limited number of instances, an adequate assurance of safety can be achieved without major-use approval. The type and extent of toxicological data required to support the approval will be decided based on the particular use of the drug and the class of compounds to which the drug is related. Sources for these data may include the scientific literature, proprietary data, or original research. Examples of drug uses which may qualify for consideration of approval under this category are drugs for which sufficient toxicological data exist to establish a safe concentration but do not have a major use approval; and cases where drug administration may be limited to a very brief period at early life stages. Consideration will be given for production practices which incorporate a prolonged inherent withdrawal time for the drug. Examples include free-ranging gamebirds held for sport and egg dips for those species in which the egg is not considered edible. For the treatment of wildlife, please consult CVM for guidance.

B. FOOD SAFETY ASSESSMENT

1. Hazard Assessment (Toxicological Considerations)

The hazard associated with an animal drug product is assessed using a standard battery of toxicology tests. Each test is designed to examine a different toxicological endpoint. In determining the toxicological endpoints to be examined, the hazard assessment focuses on the effect of multiple exposures to low levels of the drug. The no effect dose from these toxicology studies is divided by a safety factor to determine an acceptable daily intake (ADI). The ADI represents the total drug residues, parent and all metabolites, that can be safely consumed daily throughout one’s lifetime. A safe concentration is then calculated for each edible tissue. See the guideline "General Principles for Evaluating the Safety of Compounds Used in Food-Producing Animals".

a. An Approved NADA Exists for the New Animal Drug.

The safe concentration established for the NADA approved for a major food animal species (or in a minor species where a complete human food safety data package was generated) will be applied, where appropriate, to the minor avian species food animal application.

b. An Approved NADA Does NOT Exist for the New Animal Drug.

If an approved NADA does not exist for the new animal drug, the petitioner will need to provide hazard assessment data appropriate to the assignment of an ADI. See the guideline "General Principles for Evaluating the Safety of Compounds Used in Food-Producing Animals".

2. Controlling Exposure (Residue Chemistry Considerations)

Once the ADI and safe concentration have been determined, the risk to consumers is minimized by controlling exposure. The first step in controlling exposure is to determine when the concentration of drug in the edible tissues of the food animal reaches the calculated safe concentration. In some cases, a tolerance (i.e., a legal limit on the amount of drug residues permitted in edible tissue) and a withdrawal period (i.e., a drug-free period prior to slaughter) are established to ensure that consumers are not exposed to harmful drug residues.

The withdrawal period is the time period prior to slaughter during which a drug is not to be used. This period enables the animal’s normal metabolism to detoxify the drug and facilitate the drug’s depletion by natural excretion. In other cases, the compound’s inherent toxicity and the residue levels are such that no tolerance or withdrawal period are necessary to ensure food safety.

The general residue chemistry data required to satisfy questions regarding the human food safety of drugs for use in minor avian species may be found in the guideline "General Principles for Evaluating the Safety of Compounds Used in Food-Producing Animals".