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U.S. Department of Health and Human Services

Animal & Veterinary

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by Aleta Sindelar, Senior Science Policy Analyst
FDA Veterinarian Newsletter November/December 1999 Volume XIV, No VI

CVM convened the first public meeting in a series of three to discuss important issues related to antimicrobial resistance (AR) in food-producing animals. The General Public Meeting held on October 4,1999, was convened to provide an opportunity for stakeholders to give input to CVM on the appropriate issues, experts, format and agenda items to be included in two subsequent scientific workshops related to AR. The first scientific workshop scheduled for December 9 and 10, 1999 will focus on issues related to risk assessment and the establishment of resistance thresholds in food-producing animals. The second scientific workshop scheduled for February 22 and 23, 2000, will discuss the design of pre-approval studies in food-producing animals to model the rate and extent of resistance development.

Dr. Stephen Sundlof, CVM's Director, welcomed over 65 participants to the meeting and provided a brief overview of the concerns and issues currently facing the Center with respect to AR. Dr. Sharon Thompson, Associate Director for Veterinary Medical and International Affairs, described new AR challenges facing the Agency and solicited comments from the participants with respect to the forthcoming workshops.

Dr. Thompson discussed CVM’s risk assessment (RA) model on resistant campylobacteriosis in poultry as a prototype by which resistance and monitoring thresholds might be established. The risk assessment models the risk of increased duration of human illness due to resistant Campylobacter infections related to the use of fluoroquinolones (FQ) in chickens. Further, it relates the prevalence of resistant Campylobacter infections in humans due to the consumption of chickens to the prevalence of resistant Campylobacter in chickens. The Agency chose this particular antimicrobial/pathogen/species combination to model because Campylobacter is a leading cause of domestic foodborne illness and FQ are important drugs for treating human foodborne infections. This model can be extrapolated to other antimicrobial and foodborne pathogen combinations with additional data. A second RA is planned to assess the transfer of resistance determinants to human pathogens from enterococci in animals. Additional information about the RA will be made available on the CVM AR website prior to the December meeting. Potential workshop issues about the model that were discussed at this meeting included: What do you see are the limitations of the model? Do you think there are significant data gaps? What are the positive aspects of the model? What aspects would you consider changing? How can this model be used to help industry reduce the level of risk? What are the issues with the mathematics of the model? Can this model be a prototype for other antimicrobial foodborne pathogen combinations? Potential workshop issues about establishing thresholds and mitigation actions that were discussed included: What relation is there to the reasonable certainty of no harm standard? How should we view the population of concern (i.e., domestic population, those with Campylobacter or those seeking care and requiring treatment)? How can industry assist in obtaining data to reduce uncertainty in the model? And, what are the appropriate mitigation actions when a monitoring threshold is reached?

The second part of Dr. Thompson’s discussion targeted the Center’s current thinking on the appropriate design of pre-approval studies in food-producing animals to model the rate and extent of resistance development of foodborne pathogens. The three primary areas of concern highlighted were: the transfer of resistant foodborne pathogens; the transfer of resistant determinants from a foodborne bacteria to a pathogen within the human gastrointestinal tract; and, the increase in pathogen load in the target animal as a result of treatment with a new animal drug. The Center is interested in the development of pre-approval studies that will predict the time it will take under approved use conditions to see changes in susceptibility to the drug; to predict the magnitude of the changes in susceptibility to the drug; and, to determine the potential of the drug to increase pathogen load in the target animal. The Center asked for input as to whether the issue of pathogen load should be included as part of the February workshop or should be discussed in a subsequent meeting.

Mr. James Heslin, FDA, facilitated the public comment period. Nearly a dozen comments were provided to the Agency by industry, academia, consumer organizations and individuals. Dr. Sundlof summarized the stakeholder comments at the conclusion of the meeting. Those that were directed at both workshops included the following: 1) The workshops should include a clear statement of purpose, briefings on critical issues, breakout sessions to examine simultaneously multiple topics by appropriate experts, and a closing plenary session bringing together the various elements. Each workshop should begin with what is envisioned as the end product of the workshop. Next steps should be defined. 2) The identification of experts to provide information should include government, industry, and international resources. Genetic experts should be included. 3) A cost–benefit analysis should be made. 3) As a measure of public accountability, deadlines should be set and leaders identified to resolve outstanding questions to hasten the implementation of the Framework Document. Consumers want to be involved in the Agency decision-making process. And, 4) All comments, debate and discussion should be made part of the public record.

Comments made about the December workshop requested the following discussions: 1) The application of and differences between risk assessment and risk as part of the plenary session. 2) Microbiological breakpoints, how they are determined and used by the medical community as part of the plenary session. 3) An analysis of the components of the RA model and how probability estimates have been applied. 4) The use of in vitro sensitivity data, susceptibility data, and breakpoints as reliable indicators for predicting human health impact. 5) Defining both a monitoring and a resistance threshold and how they would be evaluated and enforced. 5) The mitigation steps if a threshold is reached. 6) How ongoing changes could be evaluated and incorporated into the risk assessment model, including how the model might be applied to existing products. And, 7) A review including both policy and legal issues of the application of the standard "Reasonable certainty of no harm."

Comments made about the February workshop requested the following discussions: 1) An overview of the animal drug development process with an explanation of how pre-approval studies will be used in evaluating the New Animal Drug Applications. 2) Continuous feed additive product studies presented by those who conducted the studies. And, 3) Pathogen load.

CVM will consider the submission of written comments at any time, but no later than 30 days following the publication of the Federal Register Notice (October 27, 1999) to ensure time for full consideration in planning the December meeting. Written comments should be identified with Docket No. 98D-0969 and submitted to the Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. For additional information on the two workshops, please refer to the FDA CVM website. For general information regarding the meetings, please contact Lynda W. Cowatch, FDA/Center for Veterinary Medicine (HFV-150), 7500 Standish Place, Rockville, MD 20855, 301-827-5281. For technical inquiries, please contact Dr. Sharon Thompson or Aleta Sindelar at 301-594-1798 or fax 301-594-1830.