CVM GFI #152 Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to Their Microbiological Effects on Bacteria of Human Health Concern

Description

Prior to approving an antimicrobial new animal drug application, FDA must determine that the drug is safe and effective for its intended use in the animal. The Agency must also determine that the antimicrobial new animal drug intended for use in food-producing animals is safe with regard to human health (21 CFR 514.1(b)(8)). FDA 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. This document provides guidance for industry to evaluate potential microbiological effects of antimicrobial new animal drugs on bacteria of human health concern as part of the new animal drug application process.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

5

Antimicrobial New Animal Drugs

Evaluating the safety of antimicrobial new animal drugs with regard to microbiological effects; Subject of the safety evaluation; Drugs intended for use in food-producing animals monitored through post-approval processes.

Medically Important Antimicrobial Drugs

Antimicrobial drugs important to human medicine used in food-producing animals; Drugs administered in the feed of food-producing animals with undefined durations of use.; Establishing appropriately defined durations of use for all medically important antimicrobials.; Antimicrobial drugs important to human medicine administered in feed

Raw Chicken

Food commodity analyzed for Campylobacter prevalence

Raw Turkey

Food commodity analyzed for Campylobacter prevalence

Antimicrobial New Animal Drug

Subject of the safety evaluation for microbiological effects

Stakeholders

4

Sponsor

Entity responsible for submitting applications under section 524B

Companion Animals

Category for veterinary drug approval including dogs, cats, and horses.

Licensed veterinarian

Professional authorized to issue a VFD order; Federal law restricts medicated feed containing this VFD drug to use by or on the order of a licensed veterinarian.

Food-Producing Animals

Animals intended for human consumption; Animals within a building, house, or feedlot intended for human consumption.; Category for veterinary drug approval including cattle, swine, and chickens.

Regulatory Context

Regulatory Activities

4

New Animal Drug Application

Application type identifier N; three-day NADA field alert reports

Abbreviated New Animal Drug Application

Application type identifier A; three-day ANADA field alert reports

Investigational New Animal Drug

Assessment may be submitted to an INAD file

NADA

New animal drug applications; New Animal Drug Application

Document Types

2

Human Food Safety Technical Section

Component of the NADA or INAD file

Hazard Characterization

Recommended to be submitted as a stand-alone document

Attributes

10

Withdrawal Time

Unless a sponsor demonstrates the absence of any visible lesions... a trim loss statement may be included on the labeling.

Important

Antimicrobial drugs that meet criterion 3.; Ranking (I): Antimicrobial drugs that meet Criterion 3.

Highly Important

Antimicrobial drugs that meet criterion 2.; Ranking (H): Antimicrobial drugs that meet Criterion 2.

Critically Important

Antimicrobial drugs that meet criterion 1.; Ranking (C): Antimicrobial drugs that meet Criterion 1.

Risk estimation

The overall estimate of risk (low, medium, or high) following integration of assessments.

Extent of use

Factor considering administration and duration of use in animals

Medical Importance

Antimicrobial drug designation based on importance to human medicine; Importance rankings would be defined as Critically important, Highly important, and Important.

Pharmacokinetics

PK data used to evaluate drug pharmacology.

Pharmacodynamics

PD data used to evaluate drug pharmacology.

Spectrum of Activity

Parameter in the release assessment summary

Technical Details

Substances

10

Macrolide

Example of a class of antimicrobial drug

Orthosomycins

Classified as NOT MEDICALLY IMPORTANT.

Ionophores

Classified as NOT MEDICALLY IMPORTANT.

Sulfonamides

Used to treat non-serious infections; ranked as Important (I) or Critically Important (C) in combinations.

Tetracyclines

Includes critically important drugs like doxycycline and highly important ones like chlortetracycline.

Streptogramins

Ranked as Highly Important (H) for S. aureus or Streptococcus pyogenes.

Rifamycins

Ranked as Critically Important (C) for infections like M. tuberculosis.

Polymyxins

Ranked as Critically Important (C) due to limited therapies for serious infections.

Vancomycin-resistant enterococci

Referred to as VRE.

Macrolides

One of limited available therapies for serious infections due to C. difficile and Campylobacter jejuni.

Testing Methods

1

Antimicrobial Susceptibility Testing

Methodology used to determine MIC and MBC data

Processes

4

Qualitative Risk Assessment

Methodology to evaluate microbial food safety risks

Pharmacokinetics

Dosing considerations for pregnant women in trials; Study of drug movement in the body, which may change during pregnancy.

Whole Genome Sequencing

Method to identify factors of importance to the evaluation

Metagenomics Analysis

Analytical method for evaluation

Clinical Concepts

10

Antimicrobial Resistance

Development of resistance resulting from use in food-producing animals

MRSA

Pathogen treated by Rifamycins in combination therapy.

P. aeruginosa

Pathogen treated by Polymyxins.

Cystic fibrosis

Condition in which NTM-PD occurs

Tuberculosis

Treated by Antimycobacterials.

Campylobacter jejuni

Target of Macrolide therapy.

Methicillin-resistant S. aureus

Commonly referred to as MRSA in the context of Glycopeptides and Lipopeptides.

Serious bacterial infections

Criterion 1 and 2 involve drugs used to treat serious bacterial infections in humans.; Criterion for ranking medically important antimicrobial drugs.

Bacteria of Human Health Concern

Microbiological effects being evaluated

Salmonella

Pathogen studied for survival during drying and storage

Identified Hazards

Hazards

3

Antimicrobial Resistant Foodborne Bacteria

The hazardous agent which can adversely impact human health

Bacterial foodborne illness

Defined as a hazard when clinical treatment is adversely impacted by resistance.

Antimicrobial Resistance

Public health threat resulting from loss of effectiveness of antimicrobial therapies; Efforts to mitigate the development of antimicrobial resistance.; Public health concern that labeling changes aim to mitigate.; development and spread of antimicrobial resistance encouraged by certain practices

Standards & References

External Standards

3

NARMS

National Antimicrobial Resistance Monitoring System cecal data

CLSI

Susceptibility tests should be conducted in accordance with CLSI methods.

EUCAST

European Committee on Antimicrobial Susceptibility Testing guidelines

Specifications

1

Minimum Inhibitory Concentration

MIC data pertinent to bacteria of human health concern

Related CFR Sections (5)

21CFR514.1§ 514.1 Applications.
(a) Applications to be filed under section 512(b) of the act shall be submitted in the form and contain the information described in paragraph (b) of this section, as appropriate to support the particular submission. If any part of the application is in a foreign language, an accurate and complete ERead full regulation →
21CFR312.300§ 312.300 General.
(a) Scope. This subpart contains the requirements for the use of investigational new drugs and approved drugs where availability is limited by a risk evaluation and mitigation strategy (REMS) when the primary purpose is to diagnose, monitor, or treat a patient's disease or condition. The aim of thisRead full regulation →
21CFR530.21§ 530.21 Prohibitions for food-producing animals.
(a) FDA may prohibit the extralabel use of an approved new animal or human drug or class of drugs in food-producing animals if FDA determines that:Read full regulation →
21CFR514.111§ 514.111 Refusal to approve an application.
(a) The Commissioner shall, within 180 days after the filing of the application, inform the applicant in writing of his intention to issue a notice of opportunity for a hearing on a proposal to refuse to approve the application, if the Commissioner determines upon the basis of the application, or upRead full regulation →
21CFR514.106§ 514.106 Approval of supplemental applications.
(a) Within 180 days after a supplement to an approved application is filed pursuant to § 514.8 , the Commissioner shall approve the supplemental application in accordance with procedures set forth in § 514.105(a)(1) and (2) if he/she determines that the application satisfies the requirements of applRead full regulation →

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

Failure to maintain complete and accurate treatment records

4

Adulteration of an Animal Offered for Human Consumption

3

Failure to maintain treatment records

2

Failure to implement procedures for reviewing treatment records

1

Extralabel use of EXCEDE without veterinary supervision

1

Extralabel use of enrofloxacin

1

Adulterated food due to illegal drug residues

1

Extralabel use of ceftiofur hydrochloride

1

Extralabel use of a drug not in conformance with its approved labeling

1

Extralabel use of a prohibited drug

1