CVM Releases Draft Guidance for Industry on Human User Safety in New and Abbreviated New Animal Drug Applications

On April 4, 2023, the Food and Drug Administration’s (FDA) Center for Veterinary Medicine (CVM) issued a draft guidance (GFI #278: Human User Safety in New and Abbreviated New Animal Drug Applications) to clarify the preapproval submission recommendations and current approach for assessing human user safety (HUS) information in support of a new animal drug’s safety. In the draft guidance, CVM describes the components and supporting information it says are necessary for an HUS assessment, the sources of information that may support an HUS assessment, and potential labeling and non-labeling mitigation strategies to reduce the HUS risk for a proposed new animal drug.

The new animal drug provisions of section 512 of the Federal Food, Drug, and Cosmetic Act (FDCA) do not expressly address HUS. That said, FDCA section 572, which governs index listing of legally marketed, unapproved new animal drugs for minor species, provides that a request for an eligibility determination for inclusion in the index must include, among other things, “information to  support the conclusion that the proposed use of the new animal drug is safe under section 512(d) with respect to individuals exposed to the new animal drug through its manufacture or use.” 21 U.S.C. § 360ccc-1(c)(1)(F). In the draft guidance, CVM relies upon this provision in section 572 to maintain that it has the authority to consider HUS when it evaluates the safety of a proposed new animal drug more generally.  

The FDCA does not provide specific guidance on data requirements or assessment methods to identify the risks or risk mitigation measures for human users of new animal drugs. CVM states in the draft guidance that it typically evaluates HUS information under the regulatory framework of the New Animal Drug Application (NADA) Target Animal Safety (TAS) technical section. Under this framework, the HUS assessment includes 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 explains that each proposed new animal drug and its intended use may pose unique HUS-related considerations or challenges, so CVM’s recommendations on the information necessary to evaluate HUS are specific to each case. CVM notes that a drug sponsor’s HUS evaluation should continue throughout the product’s development and lifecycle as new information becomes available.   

For drugs that do pose HUS risks, CVM often determines agreement between the sponsor and CVM on the acceptability of HUS information and the proposed mitigations (i.e., labeling, packaging, etc.) in CVM’s review of the TAS technical section, but the final decision on the HUS for a new animal drug is based on all the information in the application as a whole. 

The draft guidance addresses general principles for HUS assessments, sources of data, mitigation strategies, and potential recommendations to address HUS concerns for generic animal drugs.

Components and Supporting Information of HUS Assessment

The draft guidance explains that understanding the underlying risk of use of an animal drug is a critical component of HUS, and describes three overarching components of an HUS Assessment:

1. Hazard: Information based on potential adverse effects that a new animal drug may have on a human user.
   1. Hazard Identification: Determining the specific component(s) of the new animal drug that may elicit a toxicological response.
   2. Hazard Characterization: Understanding of the relationship between the dose of the hazardous material to which a person is exposed and the probability of an adverse health event occurring at that dose. 
2. Exposure: Information on how much, by what route, and with what frequency a human user may come into contact with the animal drug.
   1. Characteristics of the Human User Population Likely to Be Exposed: Defining the primary human user for a given new animal drug.
   2. How Human User May Be Exposed to New Animal Drug: Describing exposure prior to, during, and after administration, including accidental exposures.
   1. Frequency of Exposure: How often an exposure event occurs (i.e., acute, sub-chronic, and chronic).
   2. Duration of Exposure: How long a single exposure event lasts following initial exposure to the drug product.
3. Risk Characterization: Overall determination of the risk to the human user associated with the use of an animal drug product. The risk characterization can be qualitative, semi-quantitative, or quantitative depending on the toxicity profile (hazard) of the new animal drug product and reasonably likely human exposure scenario(s).
   1. Qualitative: Providing a descriptive analysis of hazard and exposure.
   2. Semi-Quantitative: Predominantly used when sufficient information exists to help determine quantitatively either the hazard or exposure, but not both.
   3. Quantitative: Predominantly used when sufficient information exists to quantitatively determine both the hazard and exposure.

Unique HUS safety concerns may arise with 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.

Sources of Information

CVM notes that a variety of sources of information may be used to support an HUS assessment. Sponsors should consider how the quality and relevance of the information submitted may impact the assessment.

1. Sponsor Generated Studies
   1. Toxicity Studies: Conducted in vivo or in vitro to demonstrate hazards associated with exposure to an animal drug.
   2. Target Animal Studies
      1. Target Animal Safety 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.
      2. Field Studies: Conducted in the target animal species to demonstrate effectiveness and safety of a proposed new animal drug when used under typical or expected conditions of use and according to the proposed labeling.
   3. Post-Administration Studies: Conducted in the target animal species to determine the likely exposure of a human user to a new animal drug or metabolized component thereof following administration.
   4. Human-Factor Studies: Conducted with representative users to assess the adequacy of the product-user interface design to eliminate or mitigate potential use-related hazards.
2. Previously Approved Drug Information: Includes, but is not limited to, animal drug labeling, human drug labeling, Freedom of Information summaries, adverse drug event reports, and pharmacovigilance reports for previously approved drugs.
3. Literature: When used in aggregate, may provide inferential value on the HUS risks posed by a new animal drug, reducing or eliminating the need for additional animal or in vitro studies to support HUS.
4. Safety Data Sheets (SDS): Provides information on the physical properties of chemical components of an animal drug product or the active pharmaceutical ingredient (API), health and environmental hazards, protective measures, and safety precautions for handling and storing the drug product, its API, or excipients.
5. Reports: Published reports from sources such as, but not limited to, other federal regulatory authorities or international bodies describing HUS risks.

Mitigation Strategies

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. Proposed 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.

1. Non-Labeling Based Strategies
   1. Marketing (Dispensing) Status (Rx, OTC, or VFD): Consider whether adequate directions for safe lay use can be added to new animal drug.
   2. Selection of Packaging: Modifying the primary and secondary conditions to reduce risk for a new animal drug.
   3. Administration Method: Appropriate drug delivery equipment to administer the drug to limit or prevent exposures of concern with new animal drug.Use of PPE: Use of PPE to limit or prevent exposures of concern to human users.
2. Labeling Strategies: Specific labeling elements (e.g., label or labeling statements, boxed warnings, client information sheet) 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.

Special Considerations for Generic New Animal Drugs

CVM states that generic drugs typically do not present novel HUS considerations. If a sponsor seeks approval for a generic new animal drug that differs from the pioneer reference listed new animal drug (RLNAD), CVM advises the sponsor to use the suitability petition review process to determine whether the difference would result in a significant change to the HUS assessment, as it cannot approve an Abbreviated New Animal Drug Application (ANADA) that requires 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 and determine if additional labeling language is necessary. Otherwise, labeling and packaging should generally incorporate the same risk mitigation techniques as the RLNAD.

Sponsors are encouraged to contact CVM if unsure of when to submit HUS information, what information and data should be submitted, or how to make an HUS submission (including those related to devices necessary for drug administration).

CVM is accepting comments on the draft guidance until June 5, 2023 through CVM’s docket (No. FDA-2023-D-0592).

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If you have any questions concerning the material discussed in this client alert, please contact the members of our Animal Food and Drug practice.