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Memorandum of Understanding

Between CVB and FDA

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APHIS Agreement # 04-9100-0859-MU

FDA Serial # 225-05-7000

MEMORANDUM OF UNDERSTANDING

Between the

ANIMAL AND PLANT HEALTH INSPECTION SERVICE,

UNITED STATES DEPARTMENT OF AGRICULTURE

and the

FOOD AND DRUG ADMINISTRATION,

DEPARTMENT OF HEALTH AND HUMAN SERVICES

NOTE: Amended May 26, 2021, to update the primary contact information regarding

any matters relative to the agreement. All other content of the MOU APHIS

Agreement #04-9100-0859-MU; FDA Serial #225-05-7000, executed on February 4,

2013, remains unchanged.

I. PURPOSE

This agreement reflects the understanding between the Animal and Plant Health

Inspection Service (APHIS) and the Food and Drug Administration (FDA) regarding
procedures and responsibilities for resolving jurisdictional issues/questions

concerning the regulation of certain animal products as biologicals under the VirusSerum-Toxin Act (21 U.S.C. §§ 151 et seq.), (VSTA), or as drugs under the Federal

Food, Drug, and Cosmetic Act (FFDCA § 201(g)(l), 21 U.S.C. § 321(g)(l)).

II. BACKGROUND

The 1985 Food Security Act which provided for additional enforcement authorities

under the VSTA and the regulations revising the definition of animal "biological

products" in 1997 rendered the 1982 Memorandum of Understanding (1982 MOU)

between the Animal and Plant Inspection Service, United States Department of

Agriculture (USDA) and the Food and Drug Administration, Department of Health and

Human Services (DHHS) obsolete. This Memorandum of Understanding replaces the

1982 MOU between the agencies.

Under the regulations implementing VSTA (9 CFR Part 101), animal biological

products are all viruses, serums, toxins (excluding substances that are selectively

toxic to microorganisms, e.g., antibiotics), or analogous products at any stage of

production, distribution, or sale which are intended for use in the treatment of

animals and which act primarily through the direct stimulation, supplementation,

enhancement, or modulation of the immune system or immune response. The term

"biological products" includes but is not limited to vaccines, bacterins, allergens,

antibodies, antitoxins, toxoids, imrnunostimulants, certain cytokines, antigenic or

immunizing components of live microorganisms, and diagnostic components of

natural or synthetic origin, or that are derived from synthesizing or altering various

substances or components of substances such as microorganisms, genes or genetic

sequences, carbohydrates, proteins, antigens, allergens, or antibodies.

Under the FFDCA (Section 201 [21 U.S.C. § 321] (g)(l)), drugs are defined as articles

intended for use in the diagnosis, cure, mitigation, treatment, or prevention of

disease in man or other animals and articles (other than food) intended to affect the

structure or any function of the body of man or animals. Thus, articles that are

intended to improve animal performance, such as increased production, weight gain

and enhanced feed efficiency are considered to be drugs under the FFDCA. Although

animal biological products are "drugs" within the meaning of the FFDCA, FDA

regulates such products when they are not produced and distributed in full

conformance with the VSTA and its implementing regulations (see 21 CFR § 510.4).
The phrase "biological product" does not apply to antimicrobials, corticosteroids,

steroidal and non-steroidal antiinflammatories, hormones, and products that are

intended for use to treat disease but their primary mechanism of action is not

immunological. See section IIIC of this MOU. These drug products are regulated

under section 512 of the FFDCA (21 U.S.C. § 360b).

III. SUBSTANCE OF AGREEMENT

A. Exchange of information for jurisdictional issues

For the purpose of expediting the resolution of jurisdictional issues, APHIS and FDA

agree to provide each other all information that has been submitted to their

respective agencies regarding the product or issue to be decided as long as the

release of such information has been authorized by the appropriate party. In order to

comply with restrictions that limit sharing and/or discussing confidential business

information (CBI), which includes confidential commercial information and trade

secrets, the agency that brings forth the issue/question for resolution will be

responsible for notifying the applicant of the uncertainty of jurisdictional authority,

and the agency that wishes to reveal the information will be responsible for securing

from the applicant authorization to share CBI with the other party. Alternatively,

applicants may be requested by either agency to submit materials/information

concerning products that pose jurisdictional questions to each agency. Such

information will be provided to the liaison officers of the agencies, who are named in

paragraph V of this MOU.

B. Standing Committee

APHIS and FDA agree to appoint a liaison from each agency to coordinate issues

concerning regulatory responsibility and interested persons may contact the liaison

officer of either agency regarding regulatory status. The agencies also agree to

establish and maintain a standing committee of not less than three persons from

each agency to address issues concerning regulatory responsibility for products

which raise a jurisdictional or definitional issue.

The standing committee will meet at least once every three months and at such

other times as may be necessary to address the status of such new products as well

as to consider regulatory authority over them. The decision as to whether the
product falls under the VSTA or the FFDCA will be communicated to the applicant in

writing by a representative of the agency determined to have regulatory authority.

C. Established product jurisdictions

This list is not all encompassing; the list focuses on those products that are known to

us presently and/or are predicted to present a jurisdictional challenge in the future.

It is agreed that the list may be jointly modified as necessary (see section VI of this

MOU).

The following products, to the extent they meet the definition of "drug" in the

FFDCA, will be regulated as drugs by FDA: 1) articles intended for use in the

diagnosis, cure, mitigation, treatment, or prevention of animal disease if the primary

mechanism of action is not immunological or is undefined (unknown); and 2) articles

intended to solely affect the structure or function of the body of animals:

1. Antibiotics, including antimicrobial peptides such as alpha and beta-defensins,

chemotherapeutics

2. Anti-inflammatories (steroidal and nonsteroidal)

3. Anthelmintics/Antiprotozoals, except vaccines

4. Competitive Exclusion products

5. Genetic constructs, excluding DNA vaccines and live vaccines that stimulate a

protective immune response.

6. Stem cell therapies

7. Gene therapies and somatic cell therapies utilizing viral and non-viral vectors

8. Hormones, growth factors, growth promotants

9. Cytokines administered for systemic1 or anti-inflammatory effect

10. Cytokines intended to treat mastitis either as (a) stand alone therapies, (b) in

combination with approved antibiotics or(c) any other treatment modalities.

11. Cytokines of human origin for human use already regulated under the FFDCA or

the Public Health Service Act.

12. Cytokines that affect blood cell formation (hematopoiesis, erythropoiesis,

myelopoiesis).

13. Interferons whose primary mechanism of action does not require stimulation of

the immune system.

14. Agents or products administered to animals for the purpose ofreducing human

exposure to pathogens.
15. Whole blood, transfusion, and clotting products except serum and plasma

products for passive transfer of immunity.

The following products will be regulated as biologics under the VSTA because they

are intended for use to diagnose, cure, mitigate, treat, or prevent disease in animals

and they work primarily through an immune process:

1. Cytokines and/or interferons co-administered (a) with an approved vaccine

produced by the sponsor and intended to be an integral component of the

vaccine, (b) with an approved vaccine produced by another supplier, or (c) with

an approved vaccine produced by the sponsor but not intended to be used

exclusively with any one product.

2. Localized2, including topically administered cytokines where the intent is to

affect local immune responses and there is reasonable certainty that

administration will not result in systemic circulation of the cytokine.

3. Cytokine nucleotide sequences administered, either as an integral part of a

DNA vaccine, or administered as an adjunct to vaccine administration.

4. Bacteria, viruses, bacterial, and viral-derived products whose intended use is

the treatment or cure of cancer in animals by immune mediated mechanisms.

5. Bacterial-derived CpG oligonucleotides administered as a stand-alone

treatment. CpG oligonucleotides administered as part of a vaccine shall be

considered to be an integral part of the vaccine acting as an adjuvant and will

be regulated by the Agency with jurisdiction over the vaccine.

6. Vaccines, viruses, bacterins, bacterial extracts, allergens, antiserums,

antitoxins, toxoids, diagnostics, and immunomodulators for the prevention

and/or treatment of animal disease.

7. Immunoglobulins, serum, and plasma for passive transfer.

IV. NAME AND ADDRESS OF PARTICIPATING AGENCIES

Animal and Plant Health Inspection Service

United States Department of Agriculture

12th Street and Independence Avenue, S.W.

Washington, DC 20250

Center for Veterinary Medicine

Food and Drug Administration

7500 Standish Place
Rockville, MD 20855

V. Liaison Officers

Individuals in the following positions are designated as the liaison officers for the

purpose of this agreement and shall be the primary contacts regarding any matters

relative to the agreement.

A. For the Animal and Plant Health Inspection Service:

Center for Veterinary Biologics

1920 Dayton Avenue

Ames, Iowa 50010

CVB@usda.gov

TEL. 515-337-7838

B. For the Food and Drug Administration:

Center for Veterinary Medicine

7519 Standish Place

Rockville, MD 20855

AskCVM@fda.hhs.gov

Vl. Period of Agreement

This agreement, when accepted by both parties, will be effective indefinitely. It may

be modified by mutual written consent or terminated by either party upon written

notification to the other.

Approved for USDA/APHIS by:

Dr. Byron E. Rippke, DVM

Director, Center for Veterinary Biologics

Veterinary Services

Animal and Plant Health Inspection Service

United States Department of Agriculture

Date: May 12, 2021
Approved for DHHS/FDA by:

Dr. Steven M. Solomon, DVM

Director, Center for Veterinary Medicine

U.S. Food and Drug Administration

Department of Health and Human Services

Date: May 26, 2021

1 For the purposes of this MOU, systemic administration of a cytokine will mean any

route of administration in which the intended effect is expected to occur at a

location/site other than at the site of administration.

2 Local administration of a cytokine will mean a route of administration in which the

effect of the cytokine is expected to occur at or near the site of administration.