Whitepaper a Modern Approach to EPA and FDA Product Oversight February 17 2023


Public Review Document

WHITEPAPER: A Modern Approach to EPA and FDA Product Oversight

February 17, 2023

U.S. Environmental Protection Agency

Office of Chemical Safety and Pollution Prevention

Jointly developed by:

U.S. Environmental Protection Agency's Office of Pesticide Programs
U.S. Food and Drug Administration's Center of Veterinary Medicine.

Disclaimer:

This document is not disseminated for purposes of EPA's Information Quality Guidelines
and does not represent an Agency determination or policy.

Public Comments:

EPA Docket ID No.: EPA-HQ-OPP-2023-0103 at https://www.regulations.gov.

For further information about the docket and instructions for commenting, please
consult the ADDRESSES section in the front of the Federal Register document identified
under FRL-10689-01-OCSPP.

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WHITEPAPER: A Modern Approach to EPA and FDA Product Oversight

NOTE: The following document was jointly developed by the U.S. Environmental Protection Agency and
the U.S. Food and Drug Administration. This document does not represent a final agency position or
policy but is instead intended to explain the need for a modernized approach to product oversight.

Executive Summary

EPA and FDA are considering how best to update their respective oversight responsibilities for specific
products in an efficient and transparent manner and in alignment with each agency's expertise. We are
considering this, in part, due to changes to the definition of "pesticide" in the Federal Insecticide,
Fungicide, and Rodenticide Act (FIFRA) in the mid-1970s, which excluded new animal drugs from
regulation as pesticides under FIFRA. Since that time, pesticide and animal drug technologies—and both
agencies' understanding of these technologies—have evolved. The agencies' current approach to
determining whether EPA or FDA is the appropriate regulator of products incorporating these
technologies does not effectively accommodate scientific advancement. Further, scientific
advancements and improved scientific understanding have highlighted the importance of increased
clarity for regulated entities, robust animal safety evaluations of certain products, and applying
consistent regulatory standards to similar types of products. An updated approach clarifying oversight
over new and existing products would promote the efficient use of each agency's expertise, improve
regulatory clarity, and better protect human, animal, and environmental health.

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Background on current EPA/FDA jurisdictional approach

Beginning when EPA was formed in 1970, EPA and FDA (in particular, FDA's Center for Veterinary
Medicine but, for ease of reference, "FDA" herein) sought to develop an efficient approach for
clarifying areas of potential dual jurisdiction. In 1971, both agencies entered a memorandum of
understanding (MOU) that specified which agency would be the primary regulator for products that, at
the time, met the definition of both a "pesticide" under the Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA) and a "new animal drug" under the Federal Food, Drug, and Cosmetic Act (FD&C
Act). Because manufacturers continued to have concerns about duplicative regulation despite the MOU,
FIFRA was amended in 1975 to exclude new animal drugs from the definition of "pesticide" in 7 U.S.C. §
136(u).

Since the mid-1970s, pesticide and drug technologies—and both agencies' understanding of these
technologies—have evolved. Nonetheless, in determining whether EPA or FDA is the appropriate
regulator of products incorporating these technologies, the agencies continue to rely on the rationale
described in an MOU that was written fifty years ago. An updated approach clarifying oversight over
new and existing products would promote the efficient use of each agency's expertise and provide
clarity to the regulated industry and other stakeholders.

II. Challenges with the current approach

The current approach does not accommodate scientific advancement in a way that facilitates efficient
and transparent alignment of product oversight according to each agency's mission and expertise.

Since the 1970s, new technologies have emerged, and our scientific understanding has improved. For
example, genetically engineered ("GE") pest animals, which are gaining interest as a pest control tool,
were not envisioned fifty years ago when the original regulatory approach was developed. Further, as
scientific understanding has improved, it has become clear that in some cases the current approach has
resulted in misalignment between product regulation and the agency best equipped to regulate the
product.

Scientific advances in products administered topically to animals have highlighted the need for robust
animal safety evaluation and consistent regulatory standards for these products. For example, the
agencies have historically determined oversight for products topically administered to animals to treat
fleas and ticks based on whether the chemical is systemically absorbed into the bloodstream (FDA
oversight) or remains on the skin (EPA oversight). Both EPA and FDA have developed different levels of
expertise and infrastructure to regulate similar products administered topically to animals, including to
evaluate animal safety. This is an inefficient use of government resources. FDA maintains robust animal
safety expertise to regulate products administered to animals. Additionally, the agencies operate under
different standards for product approval and adverse incident reporting, which may result in the
inconsistent regulation and post-market monitoring of similar products.

The agencies now understand that many of these topically administered products regulated by EPA are
systemically absorbed into the bloodstream. This improved scientific understanding, combined with the
development of novel ingredients, longer-lasting products, and other technological advances, has
highlighted additional potential animal safety concerns (supported by new toxicological data and
reported adverse incidents). In the past several years, reports of adverse effects on animals associated

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with certain EPA-registered products to control fleas and ticks on dogs and cats have garnered public
and congressional attention and further highlighted the importance of robust animal safety evaluations.
These reports have also raised the question about whether a consistent approach to regulating these
types of products would improve animal safety and public confidence in the safety of these products for
animals.

The current approach has hampered the agencies' ability to clearly explain oversight responsibilities,
which may be stifling innovation. Firms sometimes need to contact both agencies before knowing who
will regulate their product, which results in uncertainty for both industry and the agencies and may
interfere with predictability and enforceability. Additionally, the current approach may stifle innovation
by making firms hesitant to invest in product development when they are uncertain how their product
will be regulated. As new products are developed and technology continues to evolve, the current
regulatory approach last updated in the 1970s is expected to grow more inefficient for the agencies and
stakeholders alike.

III. Benefits of a modernized approach

Clarifying product oversight based on improved scientific understanding and in alignment with each
agency's mission and expertise would help the agencies adapt their approach to better respond to
current science and technologies. Breakthrough technologies, like genome-editing, have created unique
opportunities and prompted the development of novel products. Among these products are animals
genetically altered for a pesticidal use (e.g., mosquitos genetically engineered to control the mosquito
population in the environment).

In 2016, federal agencies, including EPA and FDA, agreed in the National Strategy for Modernizing the
Regulatory System for Biotechnology to work to ensure an efficient, transparent, and predictable
process for products developed with biotechnology and to clarify regulatory responsibility over
genetically engineered insects. Since then, there have been additional efforts spanning multiple
administrations, including executive orders and interagency strategies, that call for modernized
regulatory approaches to biotechnology (e.g., Coordinated Framework and updates, Executive Orders).
Most recently, Executive Order 14081, issued September 12, 2022, directed FDA, EPA, and USDAto
improve the clarity and efficiency of the regulatory process for biotechnology products. These efforts
underline the need for coordination between the agencies to meet the needs of new and future
biotechnologies.

Improved scientific understanding about existing products, like products administered topically to
animals, also reinforces the importance of clarifying product oversight to ensure alignment with each
agency's mission and expertise. These products frequently contain novel chemicals, use novel
technologies, and may be longer-lasting, raising new animal safety questions. For example, reports of
serious adverse incidents that may be associated with flea and tick collars have further highlighted the
value of a robust program to evaluate and monitor the safety of products administered topically to
animals. Therefore, this is an opportune moment to consider how the products the agencies regulate,
old and new, align with their expertise and mission and to make changes to improve efficiency.

To better protect animal health, FDA's expertise and infrastructure could be leveraged to evaluate
and monitor the safety of products topically administered to animals. Both agencies agree that FDA's
animal safety evaluation process is best equipped to evaluate and monitor products topically

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administered to animals. While EPA considers animal safety for these products, EPA's expertise is in
evaluating the efficacy of products intended to control pests and the effects of such products, including
effects on the environment. EPA has fewer resources (e.g., staff, expertise, regulatory authorities,
adverse incident tracking systems, and funding) than FDA to evaluate animal safety and conduct ongoing
post-market monitoring of the safety of these products for animals. In contrast, FDA has more extensive
expertise in animal safety with established pre-market evaluation and post-market monitoring
infrastructure. FDA also has more robust animal safety data and adverse incident reporting
requirements. For these reasons, FDA is currently providing staff resources to help EPA review safety
information for certain flea and tick collars.

Aligning product regulation with each agency's expertise and mission ensures that they are regulated
in a manner appropriate to their risks and avoids duplicative resource expenditures by the agencies.

With respect to these products, FDA's mission is to protect human and animal health. FDA has expertise
to evaluate drug claims (i.e., disease claims and structure/function claims), animal safety, and where
relevant, food safety. EPA's mission is to protect human health and the environment and EPA has
scientific expertise to evaluate products to control pest animals in the environment, and where relevant,
food safety for pesticide residues. Maintaining redundant programs at both agencies, such as replicating
FDA's robust program to evaluate animal safety at EPA, would require significant resources and
expanded adverse incident and safety data regulations and/or guidance for EPA. Alternatively,
alignment would reduce the need for the agencies to develop and maintain duplicative expertise and
infrastructure.

A modernized approach would support clear communication with stakeholders, including consumers,
veterinarians, and industry, regarding product regulation, safety information, and reporting of
adverse incidents. Improved regulatory certainty would allow industry to plan product development
more efficiently and may encourage the introduction of novel and beneficial products into the
marketplace (such as genetic modifications in pest animals for population control). It would also help
both agencies provide consumers and veterinary health professionals with the safety information they
need, ensure adverse incidents are promptly reported to the appropriate regulatory agency, assess risks
accurately, and if necessary, take action to protect human and animal health. Applying the current
regulatory approach continues to be inefficient for the agencies and stakeholders to accomplish these
goals.

IV. Elements of a modernized approach

EPA and FDA have identified two complementary components of a modernized approach. The first
component is one that would provide the agencies with more flexibility to update and align their
regulatory oversight of relevant products consistent with each agency's mission and expertise.

The second component is one that would then provide a seamless process for the transfer of oversight
from EPA to FDA of topically administered products for external parasites of animals, which are
currently regulated as pesticides. Importantly, this component should be designed to be minimally
burdensome and not require an FDA approval for products previously regulated by EPA, except in the
limited circumstance that products raise serious safety concerns.

Together, these components would facilitate the agencies' ability to proactively communicate with
stakeholders and the public about oversight responsibilities and respond swiftly to an evolving scientific
and technological landscape.

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We recognize that FDA would need significant new resources over the first five years to transfer
approximately 600 topically administered products for external parasites on animals currently regulated
by EPA to FDA. Conversely, to build a comparable animal safety program to FDA's existing program, EPA
would likely need several times more resources than the amount needed for FDA to oversee these
products.

Additionally, EPA may need resources to expand its existing biotechnology program for products to
control populations of pest animals and clarify the program's approach to meet the needs of this
growing industry.

V. Appendix

A.	Terminology

Use of "pest" within this document refers to a nuisance animal.

Use of "animal" refers to any eukaryotic organism (multicellular), including mammals, birds,
amphibians, mollusks, insects, etc. and excluding humans.

Use of "animal safety" refers to the health of the animal being administered the product rather than
to the external parasite being killed or repelled.

Use of "topically administered products for animals" refers to topically administered products
intended to treat external parasites of animals.

B.	Acronyms

i.	CVM: Center for Veterinary Medicine

ii.	EPA: Environmental Protection Agency

iii.	FD&C Act: Federal Food, Drug, and Cosmetic Act

iv.	FDA: Food and Drug Administration

v.	FIFRA: Federal Insecticide, Fungicide, and Rodenticide Act

vi.	MOU: Memorandum of Understanding

vii.	NADA: New Animal Drug Application

viii.	OTC: Over the counter
ix.	Rx: Prescription

C.	References

•	1971 MOU (last updated 1973)

•	U.S. Coordinated Framework for the Regulation of Biotechnology joint agency webpage

•	Modernizing the Regulatory System for Biotechnology Products: Final Version of the 2017
Update to the Coordinated Framework for the Regulation of Biotechnology

•	National Strategy for Modernizing the Regulatory System for Biotechnology Products

•	Advancing Biotechnology and Biomanufacturing Innovation for a Sustainable, Safe, and
Secure American Bioeconomy

Legal Definitions

a) A drug is defined, in part, as (B) articles intended for use in the diagnosis, cure, mitigation,
treatment, or prevention of disease in man or other animals; and (C) articles (other

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than food) intended to affect the structure or any function of the body of man or other
animals (21 U.S.C. § 321(g)(1)).

b)	A new animal drug is defined, in part, as any drug intended for use in animals other than
man, including any drug intended for use in animal feed but not including the animal feed,
the composition of which is such that the drug is not generally recognized as safe and
effective for the use under the conditions prescribed, recommended, or suggested in the
labeling of the drug (21 U.S.C. § 321(v)).

c)	A pesticide is defined, in part, as (1) any substance or mixture of substances intended for
preventing, destroying, repelling, or mitigating any pest..., except that the term "pesticide"
shall not include any article that is a "new animal drug" within the meaning of section
201(w) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. § 321(w)), that has been
determined by the Secretary of Health and Human Services not to be a new animal drug by

a regulation establishing conditions of use for the article, or that is an animal feed within the
meaning of section 201(x) of such Act (21 U.S.C. § 321(x)) bearing or containing a new
animal drug. (7 U.S.C. § 136(u))

D. Additional Information about FDA/CVM and EPA regulatory processes
FDA CVM

A new animal drug application (NADA) is used to seek approval of a new animal drug. Before
FDA can approve a NADA, sponsors must demonstrate that the drug is:

1.	Safe: The drug must be safe for the animals given the drug, humans consuming food derived
from treated animals and users administering the drug.

2.	Effective: Substantial evidence of effectiveness of a new animal drug shall demonstrate that
the new animal drug is effective for each intended use and associated conditions of use for
and under which approval is sought (21 CFR 514.4).

3.	Properly manufactured: The drug must be manufactured under validated manufacturing
processes in accordance with Good Manufacturing Practice regulations (21 CFR Part 200).

4.	Properly labeled: The drug must be labeled such that it is not false or misleading (Section
502(a)) and must contain adequate directions for use (Section 502(f)(1)) to inform users how
to use and store the drug safely and effectively and adhere to residue withdrawal
procedures.

Following approval of a new animal drug, sponsors must submit to FDA reports of adverse drug
events (referred to as "adverse incidents" throughout this document), product
defects/manufacturing defects, periodic drug experience reports (annually or semi-annually in a
specific format), and other submissions and reports as applicable (21 CFR 514.80). In addition,
establishment registration and drug listing are required.

Continuous monitoring of approved NADAs and Abbreviated NADAs throughout a drug's
lifecycle ensures that FDA obtains information regarding potential problems with the safety and
effectiveness of marketed animal drugs and potential product quality issues/manufacturing
problems.

Prescription (Rx) vs. Over the Counter (OTC):

Labeling must contain adequate directions for use, defined as directions under which the
layman can use a drug safely and for the purposes for which it is intended (21 CFR 201.5).

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Veterinary drugs are exempt from adequate directions for use when such directions cannot be
written and when the veterinary drug bears the prescription legend (21 CFR 201.105).

Thus, the primary basis for distinguishing Rx and OTC animal drug products is the ability (or lack
of ability in the case of Rx products) to prepare adequate directions for use that would allow
persons other than licensed veterinarians to use the product safely and effectively. Under the
FD&C Act Section 503(f)(1) (21 U.S.C. § 352(f)(1)), an animal drug that "because of its toxicity or
other potentiality for harmful effect, or the method of its use, or the collateral measures
necessary for its use, is not safe for animal use except under the professional supervision of a
licensed veterinarian" is limited to use by or on the order of a licensed veterinarian.

EPA

Before manufacturers can sell or distribute pesticides in the United States, EPA must evaluate
the pesticides thoroughly to ensure that they meet the federal standard for registration under
FIFRA. For a pesticide to be approved for registration, EPA must determine that it will not cause
any unreasonable adverse effects on the environment, including "water, air, land, and all plants,
animals, and people living therein." (7 U.S.C. § 136(j), (bb)).

In evaluating a pesticide registration application, EPA assesses a wide variety of potential human
health and environmental effects associated with use of the product. Companies must generate
scientific data necessary to address concerns pertaining to the identity, composition, potential
adverse effects, and environmental fate of each pesticide. Data requirements for pesticides are
listed in 40 CFR Part 158. The purpose of these data requirements is to demonstrate that the
product will not cause unreasonable adverse effects to the environment (including to humans
and animals). In the case of pesticide products intended for use on food, EPA relies on these
data to determine whether there is a reasonable certainty of no harm to human health from
aggregate exposure to these products.

After a product is registered, the pesticide registrant must report any adverse incidents
associated with the product to EPA per FIFRA Section 6(a)(2). EPA defines an adverse incident as
any exposure or effect from a pesticide's use that is not expected or intended. Adverse incidents
may involve humans, wildlife, plants, or domestic animals. Adverse incident reports tell EPA if
there are problems with a pesticide and help EPA determine whether the pesticide's application
directions need to be clarified, restrictions need to be placed on the pesticide's use, and/or if
additional protective safety equipment may be needed.

General Use vs. Restricted Use Pesticides (RUPs):

General Use Pesticides are typically available for sale to and use by the general public. Restricted
Use Pesticides are not available for purchase or use by the general public, as they have the
potential to cause unreasonable adverse effects to the environment and injury to applicators or
bystanders without added restrictions. The "Restricted Use" classification restricts a product, or
its uses, to use by a certified applicator or someone under the certified applicator's direct
supervision (40 CFR 152.160-152.175). Certified applicators are trained in the safe application
and use of RUPs. Most pesticide products are not Restricted Use Pesticides, including almost all
products topically administered to animals and GE pest animals.

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