CVM Publishes Draft Guidance on Evaluating the Microbial Food Safety Risks Posed by Antimicrobial New Animal Drugs

On December 16, 2022, the United States Food and Drug Administration’s (FDA) Center for Veterinary Medicine (CVM) published Draft Guidance for Industry (GFI) No. 152, “Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to Their Microbiological Effects on Bacteria of Human Health Concern” (Draft Guidance). The Draft Guidance outlines a risk assessment approach for evaluating the microbial food safety risk posed by antimicrobial drug use in food-producing animals as part of the new animal drug application (NADA) process. If finalized, the Draft Guidance will replace the current version, which was published in October 2003.

Background

To approve an antimicrobial NADA, CVM must determine that the drug is safe and effective for its intended use in the animal. In addition, when the drug is intended for use in food-producing animals, CVM must determine that the drug is safe with regard to human health.[1] CVM considers an antimicrobial new animal drug to be “safe” if it concludes that there is reasonable certainty of no harm to human health from the proposed use of the drug in food-producing animals.

In 2003, CVM issued the original GFI #152 (2003 Guidance), which outlined a qualitative risk assessment methodology to evaluate the risk of foodborne microbial resistance related to the use of antimicrobial drugs in food-producing animals. To assist in the assessment of potential human health consequences, the 2003 Guidance also set forth a list (commonly referred to as “Appendix A”) of medically important antimicrobial drugs, ranked into three tiers according to their utility for therapeutic use in human medicine (“important,” “highly important,” and “critically important”).

The medical importance ranking contributes to the overall risk estimation for an antimicrobial new animal drug, which informs CVM’s determination as to the approvability of the drug and the steps necessary to manage the risks associated with the proposed conditions of use (e.g., marketing status and extent-of-use limitations, extralabel use prohibitions, post-approval monitoring). Generally, drugs with a “critically important” ranking are estimated to be high risk with regard to potential impact on human health; CVM determines the approvability of these drugs on a case-by-case basis and considers them to warrant more restricted use conditions. Drugs with an “important” ranking are more likely to be considered approvable under specific use restrictions. Recognizing that various factors may cause the rankings to change over time, CVM stated in the 2003 Guidance that it would be “appropriate to periodically reassess” the rankings “to align with contemporary science and current human clinical practices.”

The 2003 Guidance listed five criteria to rank the importance of antimicrobial drugs in human medicine (the medical importance criteria), and, among other things, specified that the first criterion—use to treat enteric pathogens caused by foodborne disease—was the most important.[2] As such, CVM weighted its ranking criteria on antimicrobial drugs used to treat enteric pathogens resulting from foodborne disease.

In light of the scientific advancements and the availability of new relevant information since 2003, on October 13, 2020, CVM published a Federal Register Notice announcing a public meeting and requesting comments on a concept paper describing potential revisions to the rankings in Appendix A.[3] In the 2020 concept paper, CVM proposed modifying the medical importance criteria by broadening the risk assessment to “consider other, non-foodborne exposure pathways that may impact the potential of the antimicrobial drug to select for antimicrobial resistance and adversely affect human health” as part of the overall risk assessment.[4] More specifically, CVM proposed replacing the existing five criteria with three criteria, each corresponding to a medical importance ranking, that focus on whether or not the new animal drug belongs to an antimicrobial class that is the sole or one of limited therapies to treat serious bacterial infections in humans, rather than focusing on whether the drug belonged to a class used to treat enteric pathogens.  

The 2020 concept paper proposed the following medical importance ranking criteria:

• Drugs from an antimicrobial class that are the sole or one of limited available therapies used to treat serious bacterial infections in humans are ranked as “critically important.”
• Drugs from an antimicrobial class that are not the sole or one of limited available therapies to treat serious bacterial infections in humans (meaning that, drugs from more than a few antimicrobial classes are available), or drugs from an antimicrobial class that are the sole or one of limited available therapies to treat non-serious bacterial infections in humans are ranked as “highly important.”
• Drugs from an antimicrobial class that are not the sole or one of limited available therapies to treat non-serious bacterial infections in humans (meaning that, drugs from more than a few antimicrobial classes are available) are ranked as “important.”

Antimicrobial drugs that do not meet any of the three criteria would not be considered medically important.

CVM received more than 60 comments on the concept paper across various stakeholder groups, which were considered in the issuance of the Draft Guidance.

Draft Guidance

Changes from the 2003 Guidance. Key changes from the 2003 Guidance include:

• Updates to the medical importance criteria as outlined in the 2020 concept paper;
• Recommendation that sponsors of antimicrobial drugs that are considered “not medically important” (NMI) consult with FDA to determine if a qualitative risk assessment is necessary;
• Inclusion of microbial food safety requirements for NMI drug products; and
• Updates to the exposure assessment tables containing data on food commodity consumption and contamination of various animal-derived food commodities.

Based on the revised medical importance criteria in Appendix A, eight classes of antimicrobial drugs formerly considered “highly important” would be “critically important,”[5] three classes of antimicrobial drugs formerly considered “important” would be “highly important,”[6] and one class of antimicrobial drugs formerly considered “important” would be “critically important.”[7] Accordingly, the revised criteria would shift the importance rankings for each of these classes of antimicrobial drugs into higher rankings, potentially elevating the overall risk estimations and, in turn, CVM’s determinations as to the approvability of drugs within these classes and applicable use restrictions.

Risk Assessment Process. The overall risk assessment framework outlined in the Draft Guidance remains largely the same. As in the 2003 Guidance, the risk assessment process is comprised of five steps, summarized below.

1. Hazard Characterization. CVM recommends that a hazard characterization be submitted as a standalone document to enable the sponsor and CVM to determine the information and data that should be included in the risk assessment. The hazard characterization would include information regarding the chemical, biochemical, microbiological, and physical properties of the antimicrobial new animal drug relating to the downstream effects of the drug.
2. Release Assessment. The release assessment estimates the probability that resistant bacteria will be present in the food-producing animal as a result of the proposed use of the antimicrobial new animal drug. The assessment would describe the factors of the antimicrobial new animal drug that contribute to the emergence of resistant bacteria.
3. Exposure Assessment. The exposure assessment estimates the likelihood of human exposure to foodborne bacteria of human health concern through consumption of animal-food derived products. The assessment would consider the relative quantity of food product consumed and the relative amount of relevant bacterial contamination of the food product.
4. Consequence Assessment. The consequence assessment estimates the probability that human exposure to resistant bacteria results in an adverse health consequence, taking into account the medical importance of the antimicrobial drug or antimicrobial class in question.
5. Risk Estimation. The final step of the risk assessment entails integrating the results from the release assessment, exposure assessment, and consequence assessment into an overall risk estimation of potential risk to human health associated with the proposed use of the antimicrobial new animal drug. CVM considers the overall risk estimation, in conjunction with other relevant data and information submitted in support of the NADA, to make its final determination regarding approval of the drug.

Although CVM recommends this risk assessment approach for the evaluation of applications submitted for all antimicrobial new animal drugs in food-producing animals, CVM also notes that sponsors may choose to characterize the microbial food safety of their new animal drugs through an alternative process that may be more appropriate for their products. CVM also encourages sponsors of certain NADAs to first consult with CVM on whether the risk assessment approach is suitable for their applications, as microbial food safety information may not be needed in some circumstances.

The Draft Guidance also notes that CVM may periodically assess the rankings in Appendix A to align with continuing advancements in science and human clinical practices.

What Can You Do?

Interested stakeholders can submit comments on the draft guidance at www.regulations.gov, Docket FDA-1998-D-0038. The comment deadline is March 20, 2023.

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