#278 
 
Human User Safety in New and 
Abbreviated New Animal Drug 
Applications 
 
Guidance for Industry 
 
Draft Guidance 
 
This guidance document is being distributed for comment purposes only. 
 
Submit comments on this draft guidance by the dated provided in the Federal Register notice 
announcing the availability of the draft guidance.  Submit electronic comments to 
https://www.regulations.gov.  Submit written comments to the Dockets Management Staff 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD  
20852.  All comments should be identified with docket number FDA-2023-D-0592. 
 
For further information regarding this document, contact Dr. Karen Sussman, Center for 
Veterinary Medicine (HFV-114), Food and Drug Administration, 7500 Standish Place, Rockville 
MD 20855, 240-402-0876, karen.sussman@fda.hhs.gov. 
 
Additional copies of this draft guidance document may be requested from the Policy and 
Regulations Staff (HFV-6), Center for Veterinary Medicine, Food and Drug Administration, 
7500 Standish Place, Rockville MD 20855, and may be viewed on the Internet at 
https://www.fda.gov/animal-veterinary, https://www.fda.gov/regulatory-information/search-fda-
guidance-documents, or http://www.regulations.gov. 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine (CVM) 
April 2023
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
Table of Contents 
 
I.  Introduction ....................................................................................................................... 1 
II.  Abbreviations .................................................................................................................... 1 
III.  Background and Scope ..................................................................................................... 2 
IV.  Terminology....................................................................................................................... 4 
V.  Principles of HUS Assessment ......................................................................................... 5 
A.  Human User Safety Assessment ................................................................................ 5 
1.  Hazard .................................................................................................................... 6 
2.  Exposure ................................................................................................................ 7 
3.  Risk Characterization ........................................................................................... 9 
B.  Other Considerations................................................................................................ 10 
1.  Animal Drugs Used In or On Animal Feed ...................................................... 10 
2.  Oncology Drugs for Use in Animals .................................................................. 11 
3.  Controlled Substances ........................................................................................ 11 
4.  Emerging Technology Products......................................................................... 12 
5.  Protein-based drug products ............................................................................. 12 
VI.  Sources of Information ................................................................................................... 13 
A.  Sponsor Generated Studies ...................................................................................... 13 
1.  Toxicity Studies ................................................................................................... 13 
2.  Target Animal Studies ........................................................................................ 13 
3.  Post-Administration Studies: ............................................................................. 14 
4.  Human Factor Studies ........................................................................................ 14 
B.  Previously Approved Drug Information ................................................................. 14 
C.  Literature ................................................................................................................... 15 
D.  Safety Data Sheets (SDS) .......................................................................................... 15 
E.  Reports ....................................................................................................................... 15 
VII.  HUS Recommendations .................................................................................................. 16 
A.  Non-Labeling Based Strategies ................................................................................ 16 
1.  Marketing (Dispensing) Status (Rx, OTC or VFD): ........................................ 16 
2.  Selection of Packaging: ....................................................................................... 16 
3.  Administration Method ...................................................................................... 16 
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4.  Use of PPE: .......................................................................................................... 17 
B.  Labeling Strategies: .................................................................................................. 17 
VIII.   How HUS Information Should Be Submitted to CVM ............................................... 20 
IX.  Special Considerations for Generic New Animal Drugs (ANADA) ........................... 21 
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Human User Safety in New and Abbreviated New Animal Drug 
Applications 
 
Draft Guidance for Industry 
 
This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
Administration (FDA or Agency) on this topic.  It does not establish any rights for any person 
and is not binding on FDA or the public.  You can use an alternative approach if it satisfies the 
requirements of the applicable statutes and regulations.  To discuss an alternative approach, 
contact the FDA staff responsible for this guidance as listed on the title page. 
 
I.  Introduction 
Human User Safety (HUS) is an integral component of the overall safety evaluation of proposed 
new animal drugs.1  The FD&C Act does not provide specific guidance on data requirements or 
assessment methods to identify the risks or the risk mitigation measures for human users of new 
animal drugs.  FDA is issuing this draft Guidance for Industry (GFI) to clarify the current 
approaches and recommendations of the Food and Drug Administrations (FDAs) Center for 
Veterinary Medicine (CVM) for HUS assessment and submission of HUS information to support 
the overall safety of proposed new animal drugs prior to approval.2  
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required. 
 
II.  Abbreviations 
Abbreviation  What It Means 
ACTP  Animal Cells, Tissues, and Cell- and Tissue-Based Products 
ANADA  Abbreviated New Animal Drug Application 
 
1 As noted in section 572(c)(1)(F) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), when we evaluate the 
safety of a proposed new animal drug under section 512(d) of the FD&C Act (the provision that outlines the 
approval criteria for new animal drug applications as well as the safety standards for applications for conditional 
approval (see section 571(a)(1)(D) of the FD&C Act), we consider information that supports the conclusion that the 
proposed use of the new animal drug is safe with respect to individuals exposed to the new animal drug through its 
manufacture or use. 
2 This guidance addresses HUS considerations for dosage form new animal drugs and animal drugs for use in animal 
feed.  This guidance does not address HUS of food additives or animal food, or processes for post-approval 
reporting or monitoring of human user safety related adverse events.  For additional information about adverse drug 
experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or online at https://www.fda.gov/animal-
veterinary/report-problem/how-report-animal-drug-and-device-side-effects-and-product-problems. 
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Abbreviation  What It Means 
API  Active Pharmaceutical Ingredient 
CDER  Center for Drug Evaluation and Research 
CVM  Center for Veterinary Medicine 
FAO  Food and Agricultural Organization of the United Nations 
FDA  US Food and Drug Administration 
GFI  Guidance for Industry 
HUS  Human User Safety 
IGA  Intentional Genomic Alteration 
INAD  Investigational New Animal Drug 
JECFA  Joint FAO/WHO Expert Committee on Food Additives 
JINAD  Generic Investigational New Animal Drug 
NADA  New Animal Drug Application 
NOAEL  No-Observed-Adverse-Effect Level 
OTC  Over the Counter 
ONADE  Office of New Animal Drug Evaluation 
PPE  Personal Protective Equipment 
PM  Project Manager 
RLNAD  Reference Listed New Animal Drug 
Rx  Prescription 
SDS  Safety Data Sheet 
TAS  Target Animal Safety 
VFD  Veterinary Feed Directive 
WHO  World Health Organization 
 
III.  Background and Scope 
This draft guidance is intended for sponsors interested in pursuing the approval, or conditional 
approval, of new animal drugs (including new generic animal drugs).  This guidance is also 
intended for FDA staff, veterinary health professionals, and the general public interested in 
understanding the general principles of HUS assessment for new animal drugs.  This guidance 
addresses general principles of HUS assessment for new animal drugs, sources of data, 
mitigation strategies for proposed new animal drugs, potential recommendations to address HUS 
concerns, and how HUS information should be submitted to CVM.3  This guidance provides 
transparency to our stakeholders and is part of CVMs ongoing practice of providing relevant 
guidance on the new animal drug application process for sponsors.  
 
3 There may be other Federal occupational health and safety regulations as well as other relevant State or local laws 
that may apply to the manufacture or use of veterinary drugs. 
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CVM evaluates HUS under the regulatory framework of the Target Animal Safety (TAS) 
technical section for new animal drugs.  HUS covers human exposures to a new animal drug or 
its metabolites resulting from expected or anticipated conditions of use or from foreseeable 
accidents associated with the use of the new animal drug.  CVM does not routinely expect HUS 
assessment for new animal drugs to address conditions of exposure that may result from 
deliberate extralabel use, misuse, or abuse of a drug.  However, for new animal drugs that 
contain active substances categorized as controlled substances,4 or that may otherwise be 
deliberately misused, it may be warranted for drug sponsors to include additional considerations 
or mitigation strategies (e.g., special packaging conditions) to limit or prevent access or 
intentional misuse of the drug. Because each proposed new animal drug and the intended use of 
the proposed drug may pose unique HUS-related considerations or challenges, CVMs 
recommendations for the type of information necessary to evaluate HUS are specific to each new 
animal drug and its proposed use.  Therefore, recommendations and information in this guidance 
are not all inclusive, but rather are intended to provide general guidance to address HUS prior to 
approval for new animal drugs. 
Drug sponsors evaluation of HUS should be an ongoing process that continues throughout the 
development and lifecycle of a new animal drug as new information becomes available.  Prior to 
approval of a new animal drug, drug sponsors should submit information to allow CVM to 
understand the drugs HUS profile and associated risks.  CVM recommends drug sponsors 
consider and discuss the components and methodology of HUS assessment described in this 
guidance early during the development of their drug.  CVM recommends that sponsors have 
additional discussions as new information pertaining to HUS becomes available during product 
development.  Discussions may be especially important when considering HUS for novel classes 
or dosage forms of new animal drugs, previously unapproved uses or use conditions of an 
approved animal drug (e.g., novel routes of administration or target animal species), the impact 
of formulation or dosage form changes for generic new animal drugs, and during development of 
applicable drug labeling.  In all cases, sponsors are encouraged to contact CVM to discuss the 
types of information that are recommended to support the HUS assessment of an animal drug or 
to discuss other questions related to this assessment.  
Agreement on the acceptability of HUS information and the proposed mitigations (i.e., labeling, 
packaging, marketing status, etc.) is most often determined under the TAS technical section.  
However, the final decision on the HUS of a new animal drug is based on all the information in 
the (Generic) Investigational New Animal Drug file ((J)INAD)/(Abbreviated) New Animal Drug 
application ((A)NADA) as a whole.  
 
4 Such drugs are required to be scheduled by the United States Drug Enforcement Administration. See 21 U.S.C.  
811 and 812. 
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Typically, generic new animal drugs do not present novel HUS considerations.5, 6  Sponsors of 
generic new animal drugs are encouraged to use the suitability petition review process to 
determine if changes from the pioneer Reference Listed New Animal Drug (RLNAD) would 
result in significant changes to the HUS assessment for their generic new animal drug.  Special 
considerations for generic new animal drugs are discussed in section IX. Special Considerations 
for Generic New Animal Drugs (ANADA). 
IV.  Terminology 
Controlled Substance:  Active substances that are regulated by the United States Drug 
Enforcement Administration for availability and access in the United States under the Controlled 
Substances Act.7 
Drug product:  A finished dosage form, for example, tablet, capsule, or solution, etc., that 
contains an active ingredient generally, but not necessarily, in association with inactive 
ingredients.8 
Formulation:  The formulation is considered to be the components and composition of the drug 
product as described in 21 CFR 514.1(b)(4).  A component is any ingredient and its grade used 
in the manufacture of a drug product, including those ingredients that may not appear in the drug 
product (e.g., those components that are removed or react during the manufacturing process).  
The composition is the per unit dose quantities (amounts and/or percentages) of all components. 
Foreseeable accidents:  The exposure of a human user to new animal drugs outside the scope of 
labeled instructions for use (e.g., spills, accidental ingestion or self-injection, etc.) or without the 
use of some or all common and specific technical, operational, and personal protective measures 
(e.g., inadequate dilution of a veterinary medicinal product, use without adequate personal 
protective equipment, etc.).  
Human User:  For the purposes of this guidance and the assessment of HUS, human user is any 
person who may come into contact with the new animal drug or components of the manufactured 
product before, during, or after its application or administration to the animal.  Human user may 
also be referred to as user and/or end-user. 
 
5 The suitability petition process under section 512(n)(3) of the FD&C Act allows a generic drug sponsor to seek 
approval for a generic new animal drug that differs from the pioneer reference listed new animal drug (RLNAD) in 
certain permissible ways (e.g., change in route of administration or dosage form).  However, such a petition cannot 
be approved if the proposed change requires additional safety or effectiveness information.  If such a change raises a 
novel HUS concern that requires additional safety information, CVM cannot approve the suitability petition.    
6 Section 512(c)(2)(A)(viii) of the FD&C Act requires that generic sponsors ensure the safety of the inactive 
ingredients in their proposed formulations.  
7 See 21 U.S.C.  811 and 812 
8 See 21 CFR  210.3(b)(4) 
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Label:  For the purposes of this guidance, the label refers to the component of labeling that is 
associated with the immediate container.9   
Labeling:  For the purposes of this guidance, labeling refers to all packaging and instructional 
components accompanying the new animal drug, including the label.10  
Labeling Language:  For the purposes of this guidance, labeling language refers to the specific 
wording used in labeling to convey information relevant to the safe and effective use of the drug.  
New Animal Drug:  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.11  
Personal Protective Equipment:  Equipment that is designed and used to protect the wearer 
from exposure to a new animal drug.  Personal protective equipment may include, but is not 
limited to, head, eye, respiratory, body, hand, and/or foot protection.  Personal protective 
equipment may also be referred to as individual protective equipment. 
V.  Principles of HUS Assessment 
Understanding the underlying risk of use of an animal drug is a critical component of HUS. 
During the new animal drug approval process, sponsors should present an assessment of the risk 
to those human users involved in handling and administering the new animal drug.  This should 
also include risks from exposure to metabolites, as well as treated animals and bodily 
fluids/excreta such as urine, feces, vomit, and saliva.  This HUS assessment may vary depending 
on multiple factors, including, but not limited to: 
  The toxicity profile of the new animal drug (Active Pharmaceutical Ingredient (API) and 
inactive ingredients) 
  The dosage form of the new animal drug (tablet, suspension, gel, injectable solution, etc.) 
  The route of administration (including any delivery device) of the new animal drug 
  The characteristics of the expected human users of the new animal drug (e.g., residential 
or home user vs. occupational or professional user) 
  The overall risk to the human user posed by the use of the new animal drug  
A.  Human User Safety Assessment  
There are three basic overarching components of a HUS assessment.  The first is hazard, 
which encompasses information based on the potential adverse effects that a new animal 
 
9 See section 201(k) of the FD&C Act 
10 See section 201(m) of the FD&C Act 
11 See section 201(v) of the FD&C Act. 
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drug may have on a human user.  The second is exposure, which encompasses information 
on how much (volume or amount), by what route, and with what frequency a human user 
may come into contact with the animal drug.  The third component of HUS assessment is risk 
characterization.  CVM uses hazard and exposure to help estimate the risk to the human user 
from a given new animal drug. Risk is the likelihood of an adverse event to the human user 
following exposure to a new animal drug (API and/or inactive ingredients).  Hazard and 
exposure may be pre-defined by the characteristics of the new animal drug, dosage form, or 
the route of administration.  Therefore, mitigation strategies (see section VII. Potential HUS 
Recommendations) may represent valuable methods to address concerns from the risk to the 
human user associated with the potential exposure to the new animal drug. 
 
1.  Hazard  
Hazard represents the intrinsic potential for adverse health events that is posed by a given 
new animal drug. Hazard, as part of a HUS assessment, is made up of two 
subcomponents: hazard identification and hazard characterization. 
 
a.  Hazard Identification 
Hazard identification focuses on determining the specific component(s) of the new 
animal drug that may elicit a toxicological response.  The factors that go into 
identifying the hazard include, but are not limited to: 
  New animal drug components (API and inactive ingredients) 
  Chemical properties of the components of the new animal drug 
  Chemical class of the new animal drug (including structurally related 
compounds) and/or known mechanism of action  
  Drug delivery device or method  
 
b.  Hazard Characterization 
Hazard characterization is defined by the understanding of the relationship between 
the dose of the hazardous material a person is exposed to and the probability of an 
adverse health event occurring at that dose.  This is sometimes known as the dose-
response relationship.  It is not always necessary or reasonable to determine a dose-
response relationship, for example when chemicals behave in idiosyncratic fashions 
where dose is not related to response.  It may also not be necessary or reasonable to 
determine a dose-response relationship when available data or information is 
insufficient to establish such a relationship and/or CVM determines that such 
information is not materially relevant to address potential HUS concerns.  Please refer 
to the section on risk characterization below (section V.A.3. Risk Characterization).  
 
Hazard characterization may be determined by reviewing toxicological data and 
literature for the identified hazards.  This review of available information should 
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focus on the potential adverse human health effects and their severity.  Potential 
sources of toxicity data are found in section VI. Sources of Information of this GFI. 
 
Sponsors may also consider the mode of action (the key events at the molecular level 
that propagate into organ level effects) and/or toxicokinetics (how the human and/or 
animal body is expected to absorb, distribute, metabolize, and eliminate a chemical) 
when evaluating the potential hazards. 
2.  Exposure  
Exposure assessment in many cases is the component of the HUS assessment that drives 
what mitigation measures may be needed to ensure safe use of a new animal drug for 
human users.  When conducting an exposure assessment, the sponsor should describe the 
exposure scenarios and define the likelihood of these exposure scenarios.  
 
The supporting information for the exposure scenarios should describe the following:  
c.  The Characteristics of the Human User Population Likely to be Exposed 
The exposure assessment should define who is the primary human user for a given 
new animal drug.  Human users may include, but are not limited to, veterinarians 
and/or their assistants, occupational workers, or pet-owners and/or household 
members.  Subpopulations that are at special risk may include children, pregnant and 
nursing women, women of child-bearing age, and women who may be pregnant or 
are attempting to become pregnant.  
 
For products intended for use in companion animals,12 CVM recommends that the 
exposure assessment specifically consider potential exposures of household members.  
Household members may include young children and persons who may be exposed to 
the new animal drug via a secondary route such as handling the animal or the 
animals bodily fluids/excreta after drug administration.  In some instances, other 
exposure scenarios may be considered, such as accidental exposure following 
improper storage or disposal of unused product.  
 
Sponsors are encouraged to include data or information on the probability of exposure 
in human users.  CVM encourages sponsors to consider known adverse events or 
existing pharmacovigilance data when assessing possible exposure probabilities. 
d.  How the Human User May be Exposed to the New Animal Drug 
Exposure may occur during any or all of the following three phases: pre-
administration, administration, and post-administration.  The pre-administration phase 
includes activities related to storage, opening, preparing, or mixing the new animal 
drug.  The pre-administration phase may include, but is not limited to, activities such 
as: assembling dosing equipment, setting/locking pre-filled oral syringes, or loading 
 
12 CVM considers companion animals to include dogs, cats, and horses. 
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an administration or drug delivery device such as a balling gun or syringe.  Exposure 
scenarios may also include accidental exposures to pre-drawn doses of an animal 
drug.  The administration phase is when the animal drug is actually administered to 
the animal.  Exposure during the administration phase may encompass many 
scenarios including, but not limited to, accidental exposure while restraining an 
animal during dosing, leakage of drug from the animals oral cavity or dosing device, 
or touching topically applied drugs.  The post-administration phase includes 
disassembly and/or cleaning of dosing equipment, disposal, handling the animal or its 
waste or bodily fluids after drug administration, or cleaning the treatment stall or area 
that was used for drug administration.  
 
In general, the most common exposure routes for human users include oral, dermal, 
inhalation, ocular, and injection.  The route of exposure for the human user may be 
influenced by the dosage form of the new animal drug and the drug delivery device 
(if one is used).  New animal drugs may be dispensed in a variety of dosage forms 
such as a powder, tablet, solution, spray, impregnated collar, etc.  The use of an 
animal drug may be associated with multiple routes of human user exposure.  Human 
exposure routes may differ from the intended route of drug administration in the 
animal. 
 
The exposure analysis should consider both the frequency of administration and the 
duration of exposure.  Different dosage forms may be associated with different 
durations and frequencies of exposure.  
 
Frequency is how often an exposure event occurs.  Frequency is generally broken into 
one of three time-factors: acute, sub-chronic, and chronic.  Acute exposures are 
generally considered to be single exposures, such as accidental injection, dermal 
contact, eye contact, or oral ingestion.  Sub-chronic exposures are generally 
considered to be those where there are multiple (often daily) exposures events, and 
this series of exposures may occur over a timeframe up to 90 days in length.  Chronic 
exposures are generally considered to be those where there are multiple (often daily) 
exposures events, and this series of exposures may occur over a period of 91 days up 
to the lifetime of the human user.  
 
The duration of exposure is how long a single exposure event lasts following initial 
exposure to the drug product.  The duration of exposure to the human user may affect 
the likelihood of a toxic effect occurring.  One example is an animal drug 
administered by a topical route of administration to a companion animal.  A topical 
exposure may increase the duration of exposure per exposure event for the human 
user and other household members because it may be absorbed by the user or other 
household members if not immediately washed off. 
 
Another example is that the duration of exposure resulting from an accidental 
injection may last for multiple drug half-lives because once the drug is injected there 
are not typically methods to remove this exposure. 
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3.  Risk Characterization  
A risk characterization should communicate the overall determination of the risk or risks 
to the human user associated with use of an animal drug product.  The risk 
characterization should describe all of the assumptions used in making the risk 
determination as well as any uncertainties that may exist within the risk assessment.  The 
risk characterization may also describe what potential mitigations exist to reduce the 
overall HUS risk for an animal drug product.  There are three main types of risk 
characterization for human user safety: qualitative, semi-quantitative, and quantitative.  
CVM will evaluate the HUS risk of a new animal drug product in a qualitative, semi-
quantitative, or quantitative manner, based on the toxicity profile (hazard) of the new 
animal drug product and reasonably likely human exposure scenario(s).  A quantitative 
risk assessment may not be necessary for all new animal drugs, as not all exposure 
patterns lend themselves to this type of assessment. Sponsors are encouraged to consider 
which type of assessment is most appropriate for the new animal drug under review.  
a.  Qualitative Risk Characterization 
Qualitative risk characterization is focused on a descriptive analysis of hazard and 
exposure.  An example of an exposure scenario whereby a qualitative risk 
characterization might be appropriate is the administration of a tablet dosage form.  In 
this case, hazard is variable, the likelihood of exposure is low, and mitigation is 
reasonably likely to be adequately addressed by labeling language indicating that 
handwashing after administration is advised.  Additional language in this scenario 
might also include instructions on what to do in case of accidental ingestion.  
b.  Semi-Quantitative Risk Characterization 
A semi-quantitative risk characterization is predominantly used when sufficient 
information exists to help determine quantitatively either the hazard or exposure, but 
not both.  An example might be a dermally applied animal drug product.  If the 
hazard is well-defined, assumptions may be made about the exposure, even in the 
absence of specific exposure data.  These exposure assumptions typically incorporate 
the use of maximal potential exposure which can give some information as to the 
overall risk profile for a new animal drug product and allow a HUS assessment to be 
conducted. 
c.  Quantitative Risk Characterization 
A quantitative risk characterization may be used where sufficient information exists 
to quantitatively define both the hazard and exposure for a given animal drug product.  
This generally includes sufficient hazard information to identify the No-Observed-
Adverse-Effect Level (NOAEL) as well as information on exposure estimates.  
Exposure information may come from default values that are scientifically justifiable 
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or from exposure studies conducted with the drug product, such as dislodgeable 
residue studies13 for a topical product. 
 
A risk characterization may include a quantitative evaluation such as a calculation of 
the margin of exposure (MOE) and its relationship to the uncertainty factors for a 
drug and its exposure scenario.  The MOE is the ratio of the NOAEL to the estimated 
human exposure of a drug.  Assessing whether the MOE value calculated represents 
acceptable user risk considers the uncertainty factors for the toxicity profile of a drug 
and exposure estimates.  Uncertainty factors represent the uncertainty in the 
understanding of the data available to describe the adverse effect of a drug in an 
intended population.  This may include the uncertainty in the difference of toxicity of 
an animal drug between humans and the animals used in a toxicity study (the 
interspecies factor), in the difference in sensitivity to an animal drug between humans 
(the intraspecies factor), in the difference of effects of studies of different exposure 
length (duration factor), or in other factors that are necessary to account for 
uncertainty in the knowledge base.  The most common approach to applying 
uncertainty factors to a toxicological assessment is to consider a factor of 100X which 
represents both the intra- and inter-species uncertainty factors.  The MOE should be 
higher than the uncertainty factors for a given drug product exposure scenario to 
ensure that there is a sufficient margin of safety to account for possible unknowns in 
exposure or toxicity of the animal drug product relative to the human user.  
B.  Other Considerations 
Certain new animal drugs, such as drugs used in or on animal feeds, oncology drugs, 
controlled substances, emerging technology products, and protein-based drug products may 
have unique HUS safety concerns.  Specific information, concerns, or types of studies may 
be relevant to the HUS assessment of these types of new animal drugs.  Considerations for 
these types of new animal drugs are discussed below.  Similar to other new animal drugs, 
HUS information for drugs used in or on animal feed, oncology drugs, controlled substances, 
emerging technology products, and protein-based drug products should be of sufficient depth 
to allow an adequate risk assessment by CVM.  
1.  Animal Drugs Used In or On Animal Feed14 
The HUS risks associated with animal drugs used in or on animal feed may depend on 
factors such as the physical characteristics of the medicated article or Type B or C 
medicated feed (e.g., likelihood of dust generation during handling or the concentration 
of drug in the Type A medicated article versus that in the finished Type C medicated 
feed), or the type of feed in which the medicated article is proposed to be mixed (e.g., dry 
versus liquid, or pelleted versus mash feed, etc.).  Routes of exposure to Type A 
 
13 Dislodgeable residue studies may also be referred to as transferrable residue studies, wipe test or studies, 
petting with white gloves studies, stroking studies, or petting studies. 
14 A sponsor may seek approval for a medicated feed for use in companion animals.  In such a case, sponsors may 
also need to address factors relevant to companion animal exposure scenarios.  Sponsors are encouraged to contact 
CVM to discuss HUS for such proposed products. 
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medicated articles and drugs in Type B or C medicated feeds may include inhalation, 
ingestion, and exposure of skin and eyes. 
Relevant differences in overall exposure and mitigation strategies are drug and 
formulation dependent and evaluation of this information occurs on a case-by-case basis.  
For animal drugs used in or on animal feed, Type A medicated articles contain higher 
concentrations of the API than the medicated feed.  Hazards, routes of exposure, and 
mitigation strategies for a Type A medicated article may be different than those for a 
Type B and/or C medicated feed containing that Type A medicated article.  The HUS 
assessment for new animal drug applications for Type A medicated articles should 
address both the concerns relevant to the use and handling of the Type A medicated 
article as well as the concerns relevant to the preparation, handling, and feeding of the 
resulting medicated feed(s) when prepared at the maximum inclusion rates proposed for 
the labeling.  
 
2.  Oncology Drugs for Use in Animals 
The narrow therapeutic margin of safety for many oncology drugs for use in animals 
presents unique HUS considerations for the person(s) administering these types of drugs 
and those exposed to the treated animal via residual drug or active metabolites on the 
animal or in bodily fluids/excreta such as urine, feces, vomit, and saliva.  The HUS 
assessment for oncology drugs may necessitate evaluations of the pharmacokinetics, 
pharmacodynamics, and excretion of the drug product and active metabolites.  These 
evaluations may be necessary to: 1) estimate the potential exposure to excreted drug or 
active metabolites, and 2) guide labeling recommendations for safe handling of the 
animal and bodily fluids/excreta after treatment.  Refer to CVM GFI #237, Oncology 
Drugs for Companion Animals,15 for specific recommendations regarding HUS for 
oncology drugs.  
 
3.  Controlled Substances 
New chemical entities with the potential for abuse, as well as drugs that are scheduled 
under the Controlled Substances Act, are candidates for an assessment of abuse potential.  
These drugs may have unique HUS concerns associated with accidental exposure or 
intentional misuse.  Sponsors may refer to the CDER GFI, Assessment of Abuse 
Potential of Drugs,16 (January 2017) for additional guidance.  Specific information on 
controlled substances may also be found in the Controlled Substances Act.17  
 
Specific HUS concerns related to controlled substances depend on factors such as the 
active ingredient, dosage form, route of administration, and whether the new animal drug 
is intended to be used on farms/within animal production facilities, dispensed for 
administration at home to a companion animal, or limited to use within veterinary 
 
15 https://www.fda.gov/media/98399/download 
16 https://www.fda.gov/media/116739/download 
17 See 21 U.S.C.  13 
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practices.  Sponsors should contact CVM early in the development process to determine 
if an assessment of abuse potential is needed and how best to address potential HUS 
concerns associated with the proposed new animal drug.  
 
4.  Emerging Technology Products 
Products that utilize an emerging technology often have novel mechanisms of action or 
other characteristics and may have unique HUS considerations.  Examples of these 
products may include animal cells, tissues, and cell- and tissue-based products (ACTPs), 
intentional genomic alterations (IGAs), and gene therapy-based animal drugs. HUS 
assessments for products that utilize an emerging technology may differ from 
assessments of traditional new animal drugs; for example, the dose-response 
relationship may not apply to the risks of some ACTPs and IGAs. 
 
  HUS considerations for ACTPs may include, but are not limited to: 
  Exposure to donor infectious disease agents  
  Exposure to toxins produced by the ACTP  
  Hypersensitivity to the ACTP or excipients  
  Handling coolants such as liquid nitrogen and solid carbon dioxide   
 
  HUS considerations for IGAs may include, but are not limited to: 
  Human exposure in the environment to any substances produced by the 
IGA in animals, such as toxins, allergens, or substances that may 
contribute to antimicrobial resistance   
  Infectious agents if the animals are modified to serve as infectious disease 
models or are intended to be resistant to zoonotic pathogens, and   
  Risks associated with handling the construct, vector, or other material used 
to create the IGA   
 
  HUS considerations for gene therapy-based products may include, but are not 
limited to: 
  Viral shedding  
  Immunogenicity 
  Handling viral vectors  
  Specific risks related to inadvertent gene expression in the human user  
 
5.  Protein-based drug products  
Protein-based drug products (e.g., proteins, modified proteins, and peptide products) for 
use in animals may pose a risk to the human user due to their potential to induce an 
adverse immune system response subsequent to accidental exposure.  Examples of 
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adverse immune system responses may be anaphylactoid reactions, immunogenicity, or 
immune system activation.  Additionally, if the animal drug protein is highly homologous 
to a human protein, it may cross-react with human protein receptors and potentially result 
in an effect in humans that is similar to the desired effect in the target animal or adversely 
affect an endogenous protein.  
 
HUS assessments for protein-based drug products may differ somewhat from 
assessments of traditional new animal drugs.  While the dose-response relationship 
may not apply to the hazard characterization of some protein-based animal drugs, there 
may be safety concerns associated with accidental exposure to these drugs that should be 
factored into the overall risk to the human user. 
 
VI.  Sources of Information 
A variety of sources of information may be used to support a HUS assessment.  Sponsors should 
consider how the quality and relevance of the information submitted for evaluation may impact 
the HUS assessment.  If foreign language documents are used to support the HUS assessment, 
complete and accurate English translations of such documents must be included in the 
submission.  Sponsors may consider including, but are not limited to providing, the following 
types of information: 
A.  Sponsor Generated Studies 
1.  Toxicity Studies 
Toxicity studies are studies conducted in vivo or in vitro to demonstrate hazards 
associated with exposure to an animal drug.  These studies may be conducted in a variety 
of non-human species or cell-based models.  Toxicity information should typically focus 
on studies using standard laboratory animal species.  Toxicity studies can be used to 
identify if the API, inactive ingredients, or drug product possesses a potential human 
health hazard. The information provided by these studies may be extrapolated to estimate 
the effects of human exposure.  These studies may include acute lethal toxicity studies 
(oral, dermal and inhalation), irritation studies (dermal and ocular), and skin sensitization 
studies, in addition to longer term subchronic, chronic, reproductive, developmental, 
carcinogenicity, and genotoxicity studies.  For new animal drugs intended for use in 
food-producing animals, the studies conducted to determine human food safety may also 
provide information that can be used when determining HUS.  
2.  Target Animal Studies 
a.  Target Animal Safety Studies 
Target animal safety studies are studies conducted in the target animal species to 
provide information on the safety of an investigational product in the intended species 
under the proposed conditions of use.  These studies are typically conducted under 
laboratory conditions and include reports of adverse findings in animals after drug 
administration which may provide information relevant to various routes of exposures 
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(i.e., oral, skin eye, etc.) consistent with accidental human exposure(s) and/or 
resultant clinical signs.  These studies may also capture data on accidental 
exposure(s) in humans administering the drug and handling the animals during the 
study and resultant clinical signs observed during the study.   
b.  Field Studies:  
Field studies are studies conducted in the target animal species to demonstrate 
effectiveness and safety of a proposed new animal drug when it is used under typical 
or expected conditions of use and according to the proposed labeling.  These studies 
also include reports of adverse events in animals and may include information on any 
accidental human exposure(s) and resultant clinical signs observed during the study.  
3.  Post-Administration Studies:  
Post-administration studies are studies conducted in the target animal species to 
determine the likely exposure of a human user to a new animal drug, or metabolized 
component of the new animal drug, after the animal drug has been administered.  Post-
administration studies may include, but are not limited to, the use of pharmacological 
modeling or evaluation of excretion data or physical evaluation of drug residues.  One 
type of post-administration study that CVM may recommend is the dislodgeable residue 
study for topical products.  Dislodgeable residue studies for topical products can provide 
information to estimate the dermal exposure levels of users after administration of the 
new animal drug.  Dislodgeable residue studies may also be used to help determine the 
seclusion time18 (time the animal should be secluded without human contact) needed 
following treatment of the animal to mitigate human exposure to the drug.  CVM 
generally recommends sponsors submit study protocols for dislodgeable residue studies 
for review prior to study conduct.  
4.  Human Factor Studies 
Human factor studies can provide information regarding risk of accidental human 
exposure during animal drug administration.  Human factor studies are conducted with 
representative users to assess the adequacy of the product-user interface design to 
eliminate or mitigate potential use-related hazards.  Human factor studies may be 
recommended when administration of the new animal drug includes a proprietary dosing 
device (e.g., syringe).  The human factor study primarily evaluates: (i) the ability of the 
user to perform critical tasks necessary for the safe and effective administration and use 
of the new animal drug, and (ii) the ability of the user to understand labeling language 
critical to the safe and effective use of the new animal drug.  Additional information or 
data may be collected during these studies as needed.  
B.  Previously Approved Drug Information 
 
18 Seclusion time may also be referred to as no contact time. 
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This includes, but is not limited to, animal drug labeling, human drug labeling, Freedom of 
Information summaries, adverse drug event reports (for the same or similar drugs or APIs 
used in veterinary or human medicine), and pharmacovigilance reports (e.g., periodic safety 
update reports or periodic drug experience reporting) for previously approved drugs.  
C.  Literature 
Use of scientific literature is of interest because it makes use of existing knowledge and may 
reduce or eliminate the need for additional animal studies, or in vitro studies, to support 
HUS.  While publications may describe an animal drugs safety, effectiveness, and chemical 
or pharmacological characteristics, individual publications may be insufficient to define all 
the relevant HUS risks of a given animal drug.  However, when used in aggregate, literature 
may provide significant inferential value on the HUS risks posed by a new animal drug.  
Considerations for the use of literature, including types of review methods to synthesize 
information from a single or multiple publications, as well as other information on the use of 
literature to support drug approval, may be found in CVM GFI #106, The Use of Published 
Literature in Support of New Animal Drug Approvals.19  
D.  Safety Data Sheets (SDS) 
SDS may provide information on the physical properties of chemical components of an 
animal drug product or the API, health and environmental hazards, protective measures, and 
safety precautions for handling and storing the drug product, its API, or excipients.  If SDS 
are submitted by sponsors, they should contain the information required by Occupational 
Safety and Health Administration and the United Nations Global Harmonization System. 
Sponsors should provide the source of SDS submitted to CVM.  
E.  Reports  
Use of published reports may provide relevant supporting information. These reports may 
come from sources such as, but not limited to:  
  Other Federal regulatory authorities (e.g., Environmental Protection Agency, United 
States Department of Agriculture). 
  International bodies (e.g., FAO/WHO JECFA) or regulatory authorities (e.g., 
European Medicines Agency). 
In combination with the information provided by the sponsor, CVM may also consider 
information from other sources, including, but not limited to, independent literature searches, 
opinions published or communicated by other regulatory agencies (US or foreign countries), 
other submissions to the INAD or NADA file, professional conferences and communication with 
subject matter experts, similarity to drugs approved for human use, and adverse drug experience 
reports of the same or similar drugs used in veterinary or human medicine. 
 
 
19 https://www.fda.gov/media/70056/download (April 2022). 
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VII. HUS Recommendations 
The HUS concerns identified for each new animal drug help determine which mitigation 
strategies are appropriate to address potential risks to human users.  CVM recommends that 
sponsors use all available data and information to consider how to appropriately address the HUS 
risk for a proposed new animal drug.  
 
Mitigation strategies may incorporate the use of labeling language and/or other non-labeling-
based strategies such as marketing status, packaging (including special storage conditions), or 
other physical mitigations (including dosing equipment).  Proposed risk mitigation strategies 
should reduce human user exposure to an acceptable level and should be reasonable to 
implement for a given animal drug.  Sponsors should consider that more than one strategy may 
be necessary to sufficiently minimize the HUS risk. Sponsors should be aware that risk 
mitigation strategies for a new animal drug may be different across various animal species and 
classes, as well as with different dosage forms and conditions of use.  These risk mitigation 
strategies may also differ from risk mitigation strategies implemented for human drug products.  
Sponsors are encouraged to proactively examine what risks may occur during use or exposure to 
the new animal drug and propose appropriate mitigation strategy(ies). 
A.  Non-Labeling Based Strategies 
Some non-labeling based strategies by which HUS risk may be mitigated include, but are not 
limited to, the following:  
1.  Marketing (Dispensing) Status (Rx, OTC or VFD):  
HUS is part of the determination of marketing status.  A new animal drug that has HUS 
concerns, such that adequate directions for safe lay use cannot be written, is not eligible 
for approval for OTC use. 
2.  Selection of Packaging:  
The primary (immediate) and secondary containers (packaging surrounding the 
immediate container) are instrumental in mitigating risk to the human user, as are the 
volume or amount of the new animal drug in the immediate container and how the new 
animal drug is removed or withdrawn from the container.  Modification of packaging is a 
mechanism by which risk may be reduced for a new animal drug.  Examples of risk 
mitigating packaging include, but are not limited to, child safe packaging, blister packs, 
or pre-loaded syringes.  Furthermore, a new animal drug may pose a risk only when the 
exposure reaches a certain dose.  In these cases, risk might be reduced by limiting the 
volume or amount of the drug in the primary container, vial, or syringe.  
3.  Administration Method 
Drug delivery equipment (e.g., a safety syringe or other dosing device) may be important 
to limit or prevent exposures of concern to human users.  In the new animal drug 
application, sponsors should include information on the use of appropriate drug delivery 
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equipment, if applicable.  If a specific dosing device is necessary to administer a new 
animal drug, the dosing device will be evaluated as part of the overall new animal drug 
approval.  Instructions may be necessary to direct the safe use of drug specific dosing 
devices.  If non-specific administration devices are used (e.g., non-proprietary oral 
syringes), risk mitigation might include, for example, limiting the volume or amount of 
drug to be administered at each dosing.  
4.  Use of PPE:  
The use of PPE, where appropriate, during any phase of new animal drug administration 
may be important to limit or prevent exposures of concern to human users.  PPE may 
include, but is not limited to, goggles, face shields, respirators of varying types, long 
sleeves and long pants, lab coats, gloves, and boot covers.  Another time when PPE use 
might be appropriate may be when handling animal waste from treated animals.  
Proposed PPE should be reasonable to implement for a given animal drug under expected 
conditions of use.   
B.  Labeling Strategies:  
Specific labeling elements (e.g., labeling statements, boxed warnings, client information 
sheet, etc.) may be appropriate as mitigation strategies to direct the safe use of the product 
and convey HUS concerns related to risk (hazard and/or exposure) to the human user that are 
not otherwise mitigated through non-labeling based strategies.  New animal drugs with novel 
chemical entities or routes of administration in a given species may benefit from use of 
specific labeling statements or incorporation of other labeling elements (e.g., client 
information sheets, instructional media, etc.) to adequately direct their safe use.  In addition, 
some animal drugs (e.g., oncology drugs or gene therapy-based drugs) should include 
specific HUS related language on investigational labeling or other documents (e.g., informed 
consent sheets) used during investigational studies prior to approval.  Sponsors should 
contact CVM if there are questions regarding labeling or related documents.  
HUS-related labeling language from similar animal drugs/drug classes may be applicable to a 
proposed new animal drug.  Final labeling will reflect current scientific knowledge and 
supportive data in the drug submission file(s) for the new animal drug as well as general best 
practices related to risk communication.  Therefore, HUS-related language for certain new 
animal drugs might not be identical to other similar approved products.  
For new animal drugs with approved counterparts for human use that have HUS warning, 
precaution, or contraindication language, CVM recommends that sponsors use all of the 
appropriate warning, precaution, and contraindication HUS language related to human 
exposures for these drugs.20  Such HUS labeling language of a new animal drug should be  
consistent with the language present on approved human drugs; however, labeling language 
 
20 See CDER/CBER GFI, Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling 
for Human Prescription Drug and Biological Products  Content and Format.  
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may be adapted to reflect applicable differences between the animal drug and human drug 
(e.g., formulation, dosage and administration, etc.).  
If HUS risks and mitigation strategies associated with a Type A medicated article apply to 
the Type B and/or C medicated feed at the proposed inclusion rates, then relevant HUS 
labeling statements may be appropriate for the medicated feed Blue Bird label for that 
product.  Conversely, there may also be risks and mitigation strategies associated with the 
Type B and/or Type C medicated feed that are not applicable to the Type A medicated 
article.  Applicable HUS statements should be included on the representative labeling21 for 
Type B and/or Type C medicated feed, including free-choice medicated feed.  
Applicable HUS product warnings and safety measures are communicated in the User Safety 
Warnings section of the package insert, as well as the FOI summary document for all 
approved new animal drugs.  This information may also be presented on other labeling 
components (e.g., the label, client information sheets, product cartons, and shipping 
containers) if needed.  Labeling language to address HUS concerns should clearly convey the 
specific risks associated with use of the product and safety measure descriptions for 
mitigation of those risks.  Applicable labeling language should be expressed using simple 
terminology where possible and should consider the end-user reading the label.  In addition 
to the warning language, the placement, size, and prominence of these warnings may also aid 
in mitigation of risk.  
Boxed warnings [21 CFR 201.57(c)(1)] might be appropriate in the case of  
serious warnings, particularly human user exposures or adverse events that may lead to death 
or serious injury of the human user.  These practices generally follow recommendations 
made in Section IV. Boxed Warning ( 201.57(c)(5)) of the CDER/CBER 2011 GFI, 
Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling for 
Human Prescriptions Drug and Biological ProductsContent and Format.22 
CVM recommends that sponsors include the following HUS related information on new 
animal drug labeling: 
1.  In the User Safety Warnings section: 
a.  Begin the User Safety Warnings section of labeling with: Not for use in 
humans. Keep out of reach of children. 
b.  Describe how to obtain a copy of the SDS for the product. 
2.  In the Contact Information section: Describe how to report suspected adverse drug 
experiences associated with product use.  We recommend the following language: 
To report suspected adverse drug experiences, contact [insert name of business] at 
[insert business telephone number].  For additional information about reporting 
 
21 See Guidance for Industry #181, Blue Bird Medicated Feed Labels.  The guidance provides recommendations 
on the content and format of the representative Blue Bird labeling proposed to be used for Type B and Type C 
medicated feed only. 
22 https://www.fda.gov/media/71866/download 
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adverse drug experiences for animal drugs, contact FDA at [insert current FDA 
telephone number for voluntary reporting of adverse drug experiences] or 
http://www.fda.gov/reportanimalae. 
To further protect human health, additional descriptive warnings and safety measures are 
sometimes used on new animal drug labeling.  The following are examples of other HUS 
information that might appear on labeling:  
1.  Words, icons, and/or graphics to identify specific product risks or to illustrate 
mitigation procedures. 
2.  Statements addressing use and handling of the new animal drug by sensitive 
populations (e.g., women who are pregnant or may become pregnant, women who are 
breastfeeding, children, persons who are immunocompromised, or persons with 
hypersensitivity to a drug or drug class).  If handling of an animal drug may result in 
increased risk to certain populations, then labeling statements recommending extra 
caution for those administering or coming into contact with the animal drug or treated 
animals should be considered. 
3.  Labeling statement(s) to identify the types of exposure that should be avoided to 
minimize the identified risk(s) and what safety measures should be taken to avoid 
such exposures (e.g., use of PPE during product handling or administration, avoiding 
contact with the treated area of an animal after application of transdermal drug 
products). 
a.  This information typically focuses on the most likely routes of accidental or 
inadvertent exposure for a given animal drug.  
b.  If PPE is recommended for use with a new animal drug, then it should be 
available to the end-user and able to be used appropriately when handling or 
administering the new animal drug.  
4.  Recommended steps for medical attention in the event of human exposure. These 
may include, but are not limited to: 
a.  Specific first aid measures that can be undertaken to reduce potential harm 
(e.g., washing hands, flushing eyes, or inducing vomiting). 
b.  How to seek professional medical help (e.g., contact poison control or a 
human physician). 
c.  Information for physicians or poison control centers on specific treatment 
procedures that should or can be employed after potential or confirmed 
exposure, if defined care options are known.  
5.  Considerations for handling bodily fluids/excreta or animal carcasses of treated 
animals in special situations.  Examples of such special situations may include, but 
are not limited to: 
a.  Oncology drugs for animals: For oncology drugs proposed for use in animals, 
CVM recommends that sponsors refer to the CVM GFI #237, Oncology 
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Drugs for Companion Animals, for specific recommendations for the client 
information sheet and labeling.  
b.  Emerging Technologies: Waste and carcasses from animals with IGAs and 
animals treated with ACTPs or gene therapy products may necessitate special 
disposal procedures. 
When the immediate container and/or outer packaging for a new animal drug cannot fully 
accommodate HUS warnings from the package insert due to space considerations, sponsors 
should ensure that relevant information is communicated to the user on the animal drug label 
and outer packaging.  In such cases, an abbreviated User Safety Warning referring the human 
user to the package insert should be added to the immediate container label and secondary 
container (e.g., packaging that surrounds the immediate container) for the animal drug.  
Sponsors should also consider the need for User Safety Warning language on shipping 
labeling.  
CVMs Office of New Animal Drug Evaluation (ONADE) considers, on a case-by-case 
basis, requests to provide a translation of significant HUS related language into another 
language (typically Spanish) in situations where non-English speaking farm personnel are 
likely to administer the new animal drug and significant harm could come to the worker(s) if 
accidentally exposed to the new animal drug or if the new animal drug is used 
inappropriately.  Sponsors are responsible for the accuracy of the foreign-language 
translation.  
VIII.  How HUS Information Should Be Submitted to CVM 
Sponsors are encouraged to contact CVM if unsure of when to submit HUS information, what 
information and data should be submitted together, or how to make a HUS submission (including 
those related to devices necessary for drug administration).  The ONADE project managers 
(PMs) serve as a central point of contact for pioneer drug sponsors and can provide information 
about the new animal drug review process and ONADEs regulatory procedures.  If sponsors 
have questions and do not have an ONADE PM assigned to their company, sponsors can contact 
the PMs through the CVM mailbox 
CVM.ONADE.PM@fda.hhs.govmailto:AskCVM@fda.hhs.gov.  Sponsors of generic new 
animal drugs should contact the Division of Generic Animal Drugs at 
CVMDGADMGT@fda.hhs.gov. 
HUS information can be discussed with CVM at various points in the development process.  
Correspondingly, HUS information may be submitted to ONADE for review under various 
submission types.  CVM recommends considering what HUS concerns a new animal drug may 
have as early in the drug approval process as possible.  Information relevant to the HUS 
assessment for a new animal drug can be submitted with the initial submission (A-0000) to the 
INAD file or JINAD file, with a request for a presubmission conference (Z-submission), or as a 
data submission (P-submission) to the INAD file or as a part of the NADA file.  In certain 
circumstances, HUS information can also be submitted under other submission types.  If HUS 
information is submitted under a data submission it can be submitted as a stand-alone submission 
to the INAD file (under the TAS technical section) or in conjunction with TAS data.  While 
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CVM generally requests that substantive HUS information be submitted as part of a data 
submission, CVM encourages sponsors to discuss during the presubmission conference, or other 
relevant meetings, what HUS information should be submitted and when the HUS information 
should be submitted.  
CVM recommends sponsors use the initial presubmission conference process to discuss plans to 
address HUS or unique aspects of the new animal drug or conditions of use that impact HUS.  
The amount of information provided and the level of detail of the information provided should 
be commensurate with the submission type.  If substantive HUS information and/or study 
report(s) commensurate with a major technical section will be submitted, this information should 
be submitted as a data submission (P-submission; TAS technical section submission) or in a 
NADA.  Sponsors should consult with CVM prior to submitting substantial HUS information 
outside of a major technical section.  The assessment of abuse potential for veterinary products 
can be addressed as part of the HUS assessment under the Target Animal Safety technical 
section or as agreed upon with CVM.  
When submitting HUS information as part of a technical section, sponsors should include a 
cohesive justification of appropriate mitigation measures that incorporate aforementioned HUS 
components (exposure, hazard, user population, target animal population, etc.).  If HUS 
information is submitted under multiple submissions, sponsors should bring this to the attention 
of CVM.  CVM recommends sponsors submit all relevant draft labeling statements pertaining to 
HUS with the HUS information as it is submitted to CVM for review.  Any additional relevant 
HUS information that becomes apparent subsequent to the initial review of HUS information 
may be included in the next TAS technical section submission, if applicable, or in the All Other 
Information technical section.  If this situation occurs, sponsors should inform CVM of the 
presence of this new information in the cover letter for the submission.  
IX.  Special Considerations for Generic New Animal Drugs (ANADA) 
CVM cannot approve an ANADA that necessitates the conduct of novel safety studies to support 
HUS. Deviations from the RLNAD that generate questions on the comparability of HUS 
between the RLNAD and the proposed generic drug are typically not permissible.  If a generic 
new animal drug sponsor submits a suitability petition that requires review of additional HUS 
considerations, CVM will review the petition and determine if additional labeling language (e.g., 
warning language) is necessary.  It is not possible for CVM to grant a suitability petition if the 
change requested necessitates completion of additional safety studies to support the generic new 
animal drug approval.  As early in product development as possible, sponsors with a suitability 
petition granted for a change in route of administration or dosage form should consider 
discussing with CVM if there is a need to modify HUS language due to the change. 
During the generic new animal drug approval process, HUS warnings or related labeling 
language are evaluated as part of the labeling review.  In general, generic labeling must include 
all HUS labeling language and HUS warnings that are present on all RLNAD labeling.23  
However, for some generic drugs (e.g., generic versions of older drugs), CVM may recommend 
 
23 See section 512(c)(2)(A)(vii) of the FD&C Act. 
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the use of updated HUS labeling language to reflect current thinking or general labeling 
improvements that CVM is recommending for all products.  To update HUS labeling language 
for an approved generic new animal drug, sponsors should submit a supplemental application for 
review to the Division of Generic Animal Drugs. 
Packaging for generic drugs should generally incorporate the same risk mitigation techniques as 
the RLNAD.  However, generic drug sponsors may employ different risk mitigation techniques 
provided the alternative method has demonstrated the desired safety properties and achieves the 
same goal as those used for the RLNAD product.  CVM recommends that generic drug sponsors 
discuss proposed mitigation methods with CVM as early as possible in the product development. 
For further questions regarding HUS for generic new animal drugs, sponsors should contact the 
Division of Generic Animal Drugs at: CVMDGADMGT@fda.hhs.gov. 
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