144 

Guidance for Industry 

Pre-Approval Information for Registration of New 

Veterinary Medicinal Products for Food-Producing 

Animals with Respect to Antimicrobial Resistance 

VICH GL27 

FINAL GUIDANCE 

This guidance document is an initial step in developing harmonized technical guidance for 

approval of therapeutic antimicrobial veterinary medicinal products intended for use in foodproducing animals with regard to characterization of antimicrobial resistance selection in 

bacteria of human health concern in the European Union, Japan, and the United States. 

Comments and suggestions regarding this document should be submitted to the Division of 

Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, 

Rockville, MD 20852. Submit electronic comments to http://www.regulations.gov/. All comments 

should be identified with the Docket Number 2003D-0051. 

For questions regarding this document, contact Jeffrey M. Gilbert, Center for Veterinary 

Medicine, (HFV-157), Food and Drug Administration, 7500 Standish Place, Rockville, MD 

20855, 240-276-8174, e-mail: Jeffrey.gilbert@fda.hhs.gov. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Veterinary Medicine 

April 27, 2004 
Contains Non-Binding Recommendations

VICH GL27 (ANTIMICROBIAL RESISTANCE: PRE-APPROVAL) 

December 2003 

For implementation at Step 7 - Final 

GUIDANCE ON PRE-APPROVAL INFORMATION FOR REGISTRATION OF NEW VETERINARY MEDICINAL PRODUCTS FOR FOOD PRODUCING ANIMALS WITH RESPECT TO ANTIMICROBIAL RESISTANCE 

Recommended for Implementation 

at Step 7 of the VICH Process 

on 15 December 2004 

by the VICH Steering Committee

THIS GUIDANCE HAS BEEN DEVELOPED BY THE APPROPRIATE VICH EXPERT WORKING GROUP AND IS 

SUBJECT TO CONSULTATION BY THE PARTIES, IN ACCORDANCE WITH THE VICH PROCESS. AT STEP 7

OF THE PROCESS THE FINAL DRAFT WILL BE RECOMMENDED FOR ADOPTION TO THE REGULATORY 

BODIES OF THE EUROPEAN UNION, JAPAN AND USA. 

Page 2 of 10 
Contains Non-Binding Recommendations

Pre-Approval Information for Registration of New Veterinary 

Medicinal Products for Food-producing Animals with Respect to 

Antimicrobial Resistance 

This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this 

topic. It does not create or confer any rights for or on any person and does not operate to 

bind FDA or the public. You can use an alternative approach if the approach satisfies the 

requirements of the applicable statute(s) and/or regulation(s). If you want to discuss an 

alternative approach, contact the FDA staff responsible for implementing this guidance. If you 

cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of 

this guidance. 

Introduction 

The use of antimicrobial agents is likely to lead to selection of resistance whether administered to 

humans, animals or plants. Zoonotic organisms such as non-typhoid Salmonellae, 

Campylobacter spp. and enterohaemorrhagic E. coli (e.g. O157) can, by definition, be transferred 

to humans from animals. Therefore, it stands to reason that resistant zoonotic organisms can 

also be transferred to humans. The transfer of antimicrobial-resistant non-zoonotic bacteria or 

their genetic material from animals to humans via the food chain is also possible. However, data 

demonstrating the magnitude and importance of such transfer and whether such transfer occurs 

via consumption of contaminated meat or via contamination of water or vegetables by animal 

excreta are limited.1,2,3 Humans are also a potential reservoir of antimicrobial-resistant 

microorganisms. 4,5 

The extent to which food-producing animals contribute to human exposure to antimicrobialresistant microorganisms is difficult to quantify. However, when evaluating the safety of 

antimicrobial products for use in food-producing animals, regulatory authorities should consider 

the potential for such products to select for resistant bacteria. Therefore, guidance is needed for 

drug sponsors on the type of information that should be provided to the regulatory authorities. 

This information should help to characterize the potential for the use of the product to select for 

antimicrobial-resistant bacteria of human health concern. The information provided should be 

used as part of an overall assessment of the potential impact of the product on human health. 

FDA’s guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the Agency’s 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. 

Page 3 of 10 
Contains Non-Binding Recommendations

Objectives 

The objective of this document is to provide harmonized technical guidance in the E.U., Japan 

and the U.S. for registration of antimicrobial veterinary medicinal products intended for use in 

food-producing animals with regard to characterization of the potential for a given antimicrobial 

agent to select for resistant bacteria of human health concern. 

For clarification, this guidance outlines the types of studies and data which are recommended to 

characterize the potential resistance development as it might occur in the food-producing animal 

under the proposed conditions of use of the product. This includes information which describes 

attributes of the drug substance, the drug product, the nature of the resistance, and the potential 

exposure of the gut flora in the target animal species. It does not account for post-slaughter 

factors such as processing of food products or kitchen hygiene that affect the potential human 

health impact. 

Pathogen load studies, ecotoxicity studies, the process of risk assessment, the establishment of 

Acceptable Daily Intakes (ADIs), and consideration of residues of antimicrobial agents are not 

included in this guidance. 

Special considerations may be appropriate for aquaculture products, because of fundamental 

differences in production systems, bacterial populations present, and potential zoonotic public 

health threats. 

Data recommendations 

Information in the subsequent sections has been designated as ‘basic’ or ‘additional’ data. 

Where information is designated as ‘basic’, it is recommended that sponsors provide such 

information. 

Where information is designated as ‘additional’, sponsors may choose to include some or all of 

those data. The proposed use conditions of the product, the potential exposure of animal gut flora 

to the antimicrobial agent, the potential exposure of humans to resistant bacteria or their 

resistance genes, and the perceived importance of the drug (or related drugs) to human medicine 

may be factors on which the sponsor provides ‘additional’ data. 

Page 4 of 10 
Contains Non-Binding Recommendations

1. Basic information 

1.1 Antimicrobial class 

This information can be based on the drug substance's chemical structure, patent information, 

and information that is contained in subsequent sections. For example, the common name, 

chemical name, CAS (Chemical Abstract Services) registry number, chemical structure, and 

manufacturer’s code number and/or synonyms are recommended. 

1.2 Mechanism and type of antimicrobial action 

This information may be inferred from literature studies, patent information, or specific 

mechanism of action studies undertaken by the sponsor. Characterization as to bacteriostatic vs. 

bactericidal action should be included in this section. 

1.3 Antimicrobial spectrum of activity 

1.3.1 General data 

Information on the antimicrobial agent should be provided by the sponsor including data from MIC 

(minimum inhibitory concentration) tests against a wide variety of microorganisms or from 

literature studies, in order to determine the overall spectrum of activity. Where MICs are 

determined by the sponsor, the source of the isolates may be from culture collections, diagnostic 

laboratories, or other repositories. 

Where possible, MIC values should be determined with a validated and controlled method, such 

as those described in National Committee on Clinical Laboratory Standards (NCCLS) documents 

(e.g., M31-A2, Performance Standards for Antimicrobial Disk and Dilution Susceptibility Tests for 

Bacteria isolated from Animals; Approved Standard). 

1.3.2 MICs of target animal pathogens (as per product label claim) 

These data are considered supportive for the purposes of this guidance. Information on target 

animal pathogen MICs may be obtained from data within the Efficacy section of the dossier. 

1.3.3 MICs of food-borne pathogens and commensal organisms 

Data should be presented to show MICs of food-borne pathogens and commensal organisms. 

This information may be based on published data or on studies done by the sponsor. Depending 

on the spectrum of activity, appropriate organisms may include: 

Page 5 of 10 
Contains Non-Binding Recommendations

Food-borne pathogens: 

• Salmonella enterica 

• Campylobacter spp. 

Food-borne commensal organisms such as: 

• Escherichia coli 

• Enterococcus spp. 

When possible, the strains included should be selected according to the following 

recommendations: 

• Strains of relevant bacterial species/serotypes should be isolated from the proposed target 

animal species. When the product is intended for a broad range of animal species, the 

strains should be from the main food-producing species (e.g. cattle, pigs, and poultry). 

• Preferably, the strain collection should include recent isolates. 

Information on the tested strains should include: 

• Identification at least to the species level. 

• Origin, source and date of isolation.

1.4 Antimicrobial resistance mechanisms and genetics 

Where possible, information on the resistance mechanism(s) and information on the molecular 

genetic basis of resistance to the antimicrobial agent should be provided. This information may 

come from literature or from studies done by the sponsor. Information from analogues may be 

provided in the absence of data on the drug substance. 

1.5 Occurrence and rate of transfer of antimicrobial resistance genes 

Information on the occurrence, or absence, of transfer and rate of transfer of resistance genes 

should be provided. This information may come from literature or from studies done by the 

sponsor. Specific studies to evaluate the occurrence of genetic transfer may follow a protocol 

such as found in Antibiotics in Laboratory Medicine, 4th ed., V. Lorian, ed. 1996. Williams and 

Wilkins, Baltimore, Maryland. 

The sponsor may consider including data on target animal pathogens, relevant food-borne 

pathogens, and relevant commensal organisms. Information from analogues may be provided in 

the absence of data on the antimicrobial agent. 

Page 6 of 10 
Contains Non-Binding Recommendations

1.6 Occurrence of cross-resistance 

Information on cross-resistance to the antimicrobial agent should be provided. This information 

may come from literature or studies done by the sponsor. This should include a phenotypic 

description and, if available, a genotypic description. 

1.7 Occurrence of co-resistance 

Information on co-resistance of the antimicrobial agent in question with other antimicrobial agents 

should be provided by literature information or studies done by the sponsor. This should include a 

phenotypic description and, if available, a genotypic description. 

1.8 Pharmacokinetic data 

Pharmacokinetic data may be obtained from other sections of the dossier in order to predict the 

antimicrobial activity in the intestinal tract. Data may include the following: 

• Serum / plasma concentrations versus time data 

• Maximum concentration (Cmax) 

• Time of maximum concentration (Tmax) 

• Volume of distribution (VD) 

• Clearance (Cl) 

• Area under the concentration-time curve (AUC) 

• Bioavailability 

• Protein binding 

2. Additional information

Sponsors may also choose to include some or all of the following: 

2.1 In vitro mutation frequency studies 

In vitro mutation frequency studies involving test organisms may follow a protocol such as found 

in Antibiotics in Laboratory Medicine, 4th ed., V. Lorian, ed. 1996. Williams and Wilkins, 

Baltimore, Maryland. 

2.2 Antimicrobial agent activity in intestinal tract 

Where available, details may be provided on the concentrations of microbiologically-active 

compound within the intestinal tract contents or the feces when the antimicrobial product is 

administered according to the proposed conditions of use. The activity in question may be due to 

the parent antimicrobial agent, or to active metabolites. 

Page 7 of 10 
Contains Non-Binding Recommendations

Where such data are not available, details may be provided by metabolism studies relevant to the 

intestinal tract. Data from metabolism studies may be obtained from other sections of the dossier. 

2.3 Other animal studies 

The sponsor may choose to include information from other animal studies conducted to help 

characterize the rate and extent of resistance development associated with the proposed use of 

the antimicrobial product. This may include data from clinical studies conducted in support of 

other sections of the dossier. 

The predictive value of the results of such studies is yet to be established with regards to 

resistance development. Therefore, the results of such studies should be interpreted in the 

context of all other pre-approval information described in this document. 

2.4 Supporting information 

When available and relevant, supporting information from literature or studies on previously 

approved uses of the drug product or related products may be provided. 

3. Discussion 

The sponsor should characterize the potential for the use of the product to select for 

antimicrobial-resistant bacteria of human health concern. To accomplish this, the sponsor should 

discuss the information provided in the previous sections in terms of the exposure of food-borne 

pathogens and commensal organisms to microbiologically active substance in the target animal 

after administration of the veterinary medicinal product under the proposed conditions of use. 

Page 8 of 10 
Contains Non-Binding Recommendations

Glossary 

Antimicrobial agent or antimicrobial(s): naturally occurring, semi-synthetic or synthetic substances 

that exhibit antimicrobial activity (kill or inhibit the growth of other micro-organisms). 

Food-producing animals: Cattle, poultry and pigs are considered as food-producing animals. 

Because of regional differences, in some countries other animal species may be considered as 

food-producing animals. 

Target animal pathogen: pathogenic bacterial species causing infection in the target animals for 

which the veterinary antimicrobial medicinal product is indicated to be used for, as claimed on the 

label. 

Food-borne pathogens: zoonotic organisms, of which animals could be carriers in the intestinal 

content, that could be transmitted to humans by the food chain and subsequently cause foodborne infections in humans. 

Food-borne commensal organisms: non-zoonotic bacterial species, living in the intestinal content 

of animals, that could be transmitted to humans by the food chain and that normally do not cause 

food-borne infections in humans. 

Page 9 of 10 
Contains Non-Binding Recommendations

Page 10 of 10 

References 

1. Ministry of Agriculture Fisheries and Food. A Review of Antimicrobial resistance in the Food 

Chain: A Technical Report for MAFF. July 1998. http://archive.food.gov.uk/maff/pdf/resist.pdf. 

2. European Commission. Opinion of the Scientific Steering Committee on Antimicrobial Resistance. 

May 1999. http://ec.europa.eu/food/fs/sc/ssc/out50_en.pdf. 

3. Commonwealth Department of Health ad Aged Care and the Commonwealth Department of 

Agriculture, Fisheries and Forestry-Australia. The use of antibiotics in food-producing animals: 

antibiotic-resistant bacteria in animals and humans. Report of the Joint Expert Advisory 

Committee on Antibiotic Resistance (JETACAR). September 1999.

http://www.health.gov.au/internet/main/publishing.nsf/content/2A8435C711929352CA256F180057

901E/$File/jetacar.pdf. 

4. H. Kinde, et.al. Sewage Effluent: Likely Source of Salmonella enteritidis, Phage Type 4 Infection in 

a Commercial Chicken Layer Flock in Southern California. Avian Diseases 40:672-679, 1996. 

5. H. Kinde, et.al. Prevalence of Salmonella in Municipal Sewage Treatment Plant Effluents in 

Southern California. Avian Diseases 41:392-398, 1997.