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 food-
producing  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 
 
 
 
 
 
G  
UIDANCE 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 Administrations (FDAs) 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 antimicrobial-
resistant 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. 
 
FDAs guidance documents, including this guidance, 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. 
 
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 
manufacturers 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 food-
borne 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 
 
 
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. 
 
 
Page 10 of 10