Minor Use Animal Drug Program/NRSP-7 Minutes Fall 2010 1 MINUTES MINOR USE ANIMAL DRUG PROGRAM/NRSP-7 FALL MEETING 2010 OCTOBER 4TH AND 5TH, 2010 The USDA's Minor Species Animal Drug Program, National Research Support Project #7 (NRSP-7) held its semi-annual meeting of the technical committee and administrative advisors on October 4h and 5th, visiting MacFarlane Pheasants, Inc, Janesville, WI and Pfizer Animal Health, Kalamazoo, MI. MONDAY OCTOBER 4TH, 2010 LOCATION: MacFarlane Pheasants, Inc. 2821 South U.S. Hwy 51, Janesville, WI USA 53546 ATTENDANCE AT FARM MEETING NAME AFFILIATION EMAIL ADDRESS Dorothy Bailey FDA/CVM dorothy.bailey@fda.hhs.gov. John C. Baker AA/MI AES Baker@anr.msu.edu John G. Babish NRSP-7 jgb7@cornell.edu Bill MacFarlane MacFarlane Pheasants bill@pheasant.com Lisa Tell NRSP-7/UC Davis latell@ucdavis.edu Meg Oeller FDA/CVM moeller@cvm.fda.gov Ron Griffith NRSP-7/Iowa State rgriffit@iastate.edu Bret W. Hess University of Wyoming BretHess@uwyo.edu Thomas Vickroy NRSP-7/U FL vickroy@vetmed.ufl.edu 8:30 – 11:30 TOUR OF MACFARLANE PHEASANTS, INC. A Tour of MacFarlane Pheasants, Inc was conducted by President Bill MacFarlane. During the tour of the facilities, the group discussed current husbandry practices and drug needs of the pheasant and game bird industry. Following lunch with Bill MacFarlane, the group traveled to Kellogg Biological Station at Michigan State University. 7:00 to 9:30 MUADP/NRSP-7 WORKING SESSION LOCATION: Carriage House (meeting room), Kellogg Biological Station, 3700 East Gull Lake Drive Hickory Corners, MI 49060 ATTENDEES: NAME AFFILIATION EMAIL ADDRESS Dorothy Bailey FDA/CVM dorothy.bailey@fda.hhs.gov. John C. Baker AA/MI AES Baker@anr.msu.edu John G. Babish NRSP-7 jgb7@cornell.edu Lisa Tell NRSP-7/UC Davis latell@ucdavis.edu Meg Oeller FDA/CVM moeller@cvm.fda.gov Ron Griffith NRSP-7/Iowa State rgriffit@iastate.edu Bret W. Hess University of Wyoming BretHess@uwyo.edu Thomas Vickroy NRSP-7/U FL vickroy@ufl.edu Dr. John G. Babish called the meeting to order and introduced Dr. Bret W. Hess as the newly appointed Administrative Advisor for the Western Region. ADMINISTRATIVE REPORTS REPORT FROM THE ADMINISTRATIVE ADVISORS - Dr. John Baker (Chair) Minor Use Animal Drug Program/NRSP-7 Minutes Fall 2010 2 In his report, Dr. Baker described the historical background of the Kellogg Biological Station. Dr Baker then led a short discussion on the lobbying efforts at MSU and other universities. REPORTS FROM LIAISONS NIFA/USDA – Dr. Gary Sherman In his absence, Dr. Sherman provided the following written statements read by Dr. Babish: 1) The Federal Government is operating under Continuing Resolution to continue programs. This allows government operations to continue under the assumption that programs will receive the same funding as the previous fiscal year. 2) Discussions are underway at NIFA, through me, about MUADP becoming competitive using a model similar to that used by IR4. Our Policy staff point out that until a Federal budget is signed into law, and legislative language potentially associated with MUADP White House, House and Senate markup, Conference and Appropriations phases is available for review, they will not/cannot make a recommendation/determination about MUADP. For example, if Congress were to explicitly earmark MUADP to the four current universities, this would preclude NIFA from pursuing implementation of a competitive model. On the other hand, if Congress is silent on this matter, there is more flexibility. Essentially, NIFA Policy staff is not willing to assume that Congress will state no such explicit comments or preferences regarding state-specific involvement. That said, our research has shown that Congress has, in the past, not offered proscriptive language about MUADP recipient institutions. As soon as a budget bill is enacted we’ll be able to push forward. 3) Level funding for MUADP is still expected but no promises until Federal budget bill is finally passed Report from CVM – Dr. Meg Oeller Dr. Oeller began her presentation with a handout of a review of all ADR and their current status (See Appendix I to this report). She requested that each regional coordinator review the modified listing and comment on the appropriateness of those projects listed as TERMINATED. REGIONAL REPORTS SUBMITTED ELECTRONICALLY Western – Dr. Lisa Tell Progress of Work and Principal Accomplishments: Active Regional Projects: ADR#325 – Florfenicol (Nuflor® Injectable Solution) for sheep for respiratory disease The human food safety (HFS) and efficacy studies required by FDA/CVM for the old formulation of florfenicol (Nuflor Injectable Solution) have been completed. All of the data from this project have been published. The data from the HFS study has been organized and a technical report written. The final technical report for the human food safety study was reviewed for Quality Assurance in March, 2010. This report was submitted to FDA/CVM in July, 2010 and is currently undergoing review. ADR#350 – Florfenicol (Nuflor Gold®) for sheep for respiratory disease A pilot study evaluating administration route (IM vs. SC) and doses of 20 (IM) or 40 (SC) mg/kg was performed in September and October of 2009. All of the samples (n=672; 28 samples for 24 animals) have been analyzed. A product development meeting was held on November 18th, 2009 with CVM, the sponsor and the Minor Use Minor Use Animal Drug Program/NRSP-7 Minutes Fall 2010 3 Animal Drug Program. Another dose range finding study using the SC route of administration is to be performed. Once the proposed label dose is determined, the Target Animal Safety Study will be performed. Since the last meeting a subset of samples have been analyzed evaluating differences between serum and plasma samples. ADR#299 - Pirlimycin for Dairy Goats Project on hold until funding is identified and CIDR goat studies are completed. ADR#295 - Strontium Chloride for Salmonids. Steve Schroeder There is nothing to report. All information relative to this project was sent to Dr. Bowser (Northeastern NRSP-7 Region) in June 2010. CVM is going to help coordinate his oversight of this project. ADR#338 – Spectramast™ LC Sterile Suspension for Mastitis in Dairy Goats Project on hold until funding is identified and CIDR goat studies are completed. ADR#135 – Erythromycin in Salmonids The environmental assessment was sent to FDA/CVM for review and they requested a revision of certain sections and that a chronic toxicity study with Daphnia magna is performed. This chronic toxicity study has been performed and will address CVM concerns regarding chronic toxicity to aquatic insects. In addition, a study describing the physiochemical properties of erythromycin has been performed. Because of the physical characteristics of ERTT, an empirical pKa could not be established. The final environmental assessment report for erythromycin in salmonids was completed in May, 2010 and submitted to FDA/CVM for review. The results of this environmental assessment report supports the safe use of erythromycin thiocyanate in all freshwaterreared salmonids at a dose regimen of 100 mg/kg bodyweight/day for 21 to 28 days. Christine Moffitt, (author) has submitted the White Paper for erythromycin. This is currently under revision. ADR# 311 – Lincomycin soluble powder for foulbrood disease in Honeybees The human food safety technical section is complete. The effectiveness technical section is complete. Collaborative Projects: ADR# 258 - CIDRg (Controlled Internal Drug Release Devices) in Sheep FDA/CVM has accepted all of the data for this study and the information has been summarized by FDA/CVM in a Public Master File. Completed sections are effectiveness, target animal safety, human food safety, and environmental safety. This project was announced in the Federal Register, Vol 74(220), pg 59073, November 17, 2009. ADR#272 - Romet for Game birds No Western region activity on this project. Need to check what region this project was originally assigned to. ADR#280 - Fenbendazole in Game Birds (Pheasants, bobwhite quail, partridge) A conference call with Merck/Intervet/SP was held on Thursday, February 25th. See Southern Region Report. A product development meeting was held with CVM on September 9th, 2010. Plans are in place to conduct HFS and TAS summer of 2011. Western region to perform the analytical testing of samples. Minor Use Animal Drug Program/NRSP-7 Minutes Fall 2010 4 ADR#324 - Progesterone CIDRs for Goats (TAS, Milk Residue Study, and Efficacy) The target animal safety study technical report has been accepted by FDA/CVM (February 2008). The milk residue study has been completed and the quality assurance inspection has been completed. The final technical report was sent to FDA/CVM in December 2008 and accepted October 2009. FDA/CVM has provided comments regarding the efficacy protocol. The protocol has been accepted for concurrence. The efficacy study was started at UC Davis and Iowa State University during the Fall of 2009. A quality assurance inspection was performed for the stability of progesterone in goat tissue during frozen storage in September 2009. A quality assurance inspection was performed in October 2009 for CIDR-G insertion and removal. All of the raw data from UC Davis portion of this project was submitted to the Study Sponsor, Dr. Ron Griffith in August, 2010. ADR#340 - Tulathromycin in Goats (Collaborative project with the North Central region) The quality assurance was performed for the target animal safety study in February and March 2008. A tissue liquid chromatography/mass spectrometry method for analysis of the samples has been validated using 664 spiked samples to validate 4 tissues. Validation of analytical methods for liver, muscle, kidney and fat samples is complete. Plasma (444) and tissue (180) samples from the target animal safety have been analyzed. The quality assurance for the target animal safety report was completed November 2009. Plasma samples from the Human Food Safety Study have been analyzed and the PK data has been generated. Tissue samples from the Human Food Safety Study (205) have been analyzed. The method validation report has been submitted to the Central Region for quality assurance review. Other Projects/Activities: Excede in Goats: Study has been completed in non-lactating and lactating goats. The serum and milk samples have been analyzed and the pharmacokinetic data modeled. The manuscript has been written and submitted to the Journal of Veterinary Pharmacology and Therapeutics for publication. New Projects: Ceftiofur for Treating Arcanobacterium pyogenes Respiratory Infections in Deer: 27 isolates from deer have been collected. Due to the sensitivities, and pathology associated with this organism, this project is not currently being pursued for a label claim for either tulathromycin or ceftiofur. Sensitivity results are currently being compiled for publication. CIDRs for Deer: Historical conference calls with Dr. Albert Ramudo. At this time Pfizer has indicated that they are not interested in pursuing a label claim for deer. Need to follow up at a later date. Laboratory Report: Most of the activity continues as sample analysis in the laboratory. Results and plans are reported under separate projects above. Usefulness of the Findings: The findings from all of the studies above will be utilized to fulfill the data requirements for the FDA/CVM approval of these drugs for use in minor species. Work Planned for Remainder of the Year: Over the next year our primary goals are to work on helping to get the fenbendazole game bird project up and going. We will work on getting the analytical method up and Minor Use Animal Drug Program/NRSP-7 Minutes Fall 2010 5 running and analyzing the samples. In addition, we will work on publishing the MIC data from the deer work and the PK data from the florfenicol in sheep work. Manuscripts Submitted, Accepted or Published Since the Last Meeting: Clothier, K, Leavens, T, Griffith, R, Wetzlich, S, Baynes, R, Riviere, JE, Tell, L. Pharmacokinetics of tulathromycin after single and multiple subcutaneous injections in domestic goats (Capra aegagrus hircus). Submitted: Journal of Veterinary Pharmacology and Therapeutics. Clothier, K, Leavens, T, Griffith, R, Wetzlich, S, Baynes, R, Riviere, JE, Tell, L. Tulathromycin assay validation and tissue residues after single and multiple subcutaneous injections in domestic goats (Capra aegagrus hircus). Submitted: Journal of Veterinary Pharmacology and Therapeutics. Leavens, T, Tell, L, Clothier, K, Griffith, R, Baynes, R, Riviere JE. Development of PBPK model to predict tulathromycin distribution in goats. Submitted: Journal of Veterinary Pharmacology and Therapeutics. Rowe, J, Tell, L, Griffith, R, Lee, K, Hallford, D. Progesterone Milk Residues in Goats Treated with CIDR-G® Inserts. In Press: Journal of Veterinary Pharmacology and Therapeutics. Dore, E, Angelos, J, Rowe, J, Wetzlich, S, and Tell, L. Pharmacokinetics of ceftiofur crystalline free acid and metabolites after single subcutaneous administration in lactating and non-lactating domestic goats (Capra aegagrus hircus). In Press: Journal of Veterinary Pharmacology and Therapeutics. Critical Review: 1. Work accomplished under the original project The original objectives of the project were to conduct a national program to obtain minor and specialty animal drug clearances (tolerances, exemptions and registrations) in cooperation with state, federal and industry personnel to include: a. Determination and prioritization of minor-use needs and data requirements. b. Review, analysis and evaluation of minor-use research proposals. c. Development and assembly of data for minor-use registrations. d. Preparation and submission of petitions for drug registrations. Considering these objectives, considerable progress has been made towards achieving them for each of the active projects listed above, particularly in the development of the data (the actual research), its analysis, assembly and interpretation, and submission to the FDA/CVM for review. 2. The degree to which objectives have been met The degree to which these objectives have been met varies from project to project, however, in most all cases there has been progress. Those projects on which there has been no movement are reevaluated during each meeting of the NRSP-7 Technical Committee and decisions made on whether to continue to pursue them or move them into the inactive project list. 3. Incomplete work or areas needing further investigation All of the projects listed above have some work that needs to be completed before they are approved by the FDA/CVM. In some cases this is just the FDA/CVM review, while in others there is work needed by the NRSP-7 project. The NRSP-7 work, which is undertaken each year within the Western Region is based on the availability of qualified and interested investigators, the capacity of the regional laboratory to validate Minor Use Animal Drug Program/NRSP-7 Minutes Fall 2010 6 methods and analyze samples, and cooperation of the pharmaceutical manufacturers whose products are investigated. SUPPLEMENT TO WESTERN REGION FALL 2010 REPORT QUALITY ASSURANCE ACTIVITIES MARCH 2010-OCTOBER 2010 Quality Assurance Review Final Technical Report: Tissue Residue Depletion After Multiple Subcutaneous Administration of Nuflor® (Florfenicol) Injectable Solution at a Dose of 40 mg/kg to Sheep Human Food Safety study University of California Davis March 2010. Review completed and submitted to Study Director, Dr. Mike Lane. May 2010. Responses submitted and reviewed by QA. Quality Assurance Review Final Technical Report: Target Animal Safety of Tulathromycin (Draxxin®) Injectable Solution in Goats Iowa State University November 2009. Completed QA report and submitted to Study Director, Dr. Ron Griffith. February 2010. Responses submitted and reviewed by QA. Quality Assurance Inspection CIDR-G® in Goats Efficacy Study University of California, Davis October 8 and 26, 2009. CIDR Insertion; CIDR Removal. Completed QA reports and submitted to Study Director, Dr. Joan Rowe. August 2010. Responses submitted and reviewed by QA. Quality Assurance Inspection Stability of Progesterone in Goat Adipose and Skeletal Muscle Tissue During Frozen Storage Human Food Safety Study New Mexico State University September 17-18, 2009. Animal slaughter; necropsy; tissue processing (liver, muscle, reprotract, fat); extraction of progesterone; RIA analyses in fat. Completed QA report and submitted to Study Director, Dr. Dennis Hallford. October 2009. Responses submitted and reviewed by QA. Quality Assurance Inspection Lasalocid in Ring-Necked Pheasants Target Animal Safety Study Iowa State University July 27-28, 2009. Dosing/feeding; bleeding; euthanasia; necropsy. Completed in life report and submitted to Study Director, Dr. Ron Griffith. Quality Assurance Review Final Technical Report: Efficacy of Lasalocid in Ring-necked Pheasants Iowa State University March 2009. Completed QA report and submitted to Study Director, Dr. Ron Griffith. Minor Use Animal Drug Program/NRSP-7 Minutes Fall 2010 7 Quality Assurance Review Final Technical Report: Progesterone Milk Residues in Goats Treated with CIDRG ® Inserts University of California, Davis October 2008. Completed QA report and submitted to Study Director, Dr. Joan Rowe. Projected Reports for QA Lasalocid in Game Birds: TAS Technical Report to be submitted by the North Central Region. Ivermectin in Rabbits for Treating Ear Mites: Human Food Safety technical report to be submitted from the Southern region. Northeast Region: Dr. Paul Bowser Progress of the Work and Principal Accomplishments Species Grouping Project: INAD 10-320 Oxytetracycline in Fish INAD 10-823 Romet-30 in Fish INAD 11-145 Florfenicol in Fish Efforts on this project consisted of providing administrative support and oversight to the New York State Department of Environmental Conservation in their conduct of field trials under our INAD 10-320 for the use of Oxytetracycline in fish. Ovadine (Western Chemical) Disinfection of Fish Eggs: We have been an evaluation of the efficacy of Ovadine (Provodine Iodine, Western Chemical) as an egg disinfection compound for fish eggs with a particular emphasis on the reduction of Viral Hemorrhagic Septicemia Genotype IVb from walleye eggs. Our trial will build on preliminary efforts, funded by New York Sea Grant Program, in which we found that the consensus treatment protocol of the Great Lakes Fishery Commission (50 mg/L iodine for 30 minutes) was not completely effective in the elimination of VHSV IVb. A disinfection trial was conducted during the 2010 walleye spawning season with the collaboration of the New York State Department of Environmental Conservation. Treatments included iodine doses of 0, 50 and 100 mg/L for 30 minutes. One publication on this work has been accepted for publication and a second publication is in development. Usefulness of the findings: In all cases, the findings to date over the course of these projects serve as the foundation for continued work on these compounds. The Human Food Safety Studies completed to date in fish to date within the Species Grouping effort are consistent with what was expected; namely that the elimination of therapeutic compounds from the edible portion of the fish tested are within the withdrawal times currently specified for labels, or available in the literature for oxytetracycline, Romet-30 and Aquaflor (Florfenicol). The unexpected finding that tannic acid can inactivate iodophores has found immediate use in the aquaculture community. Tannic acid is commonly used to remove the adherent quality of eggs, preventing them from aggregating when they are handled in a fish hatchery. Our work highlighted the need to perform copious washes of the eggs to remove residual tannic acid before an iodophore (Ovadine) is used to reduce pathogens that may contaminate the external surface of the eggs. Minor Use Animal Drug Program/NRSP-7 Minutes Fall 2010 8 Work planned for next year: Species Grouping Project: INAD 10-320 Oxytetracycline in Fish INAD 10-823 Romet-30 in Fish INAD 11-145 Aquaflor (Florfenicol) in Fish We anticipate our efforts on this project to center around the continued provision of administrative support and oversight of Efficacy Studies of oxytetracycline in a collaborative effort with the New York State Department of Environmental Conservation. The particular focus of the efficacy trials will be for the treatment of bacterial diseases not currently on the label for treatment of bacterial diseases of cool water species such as walleyes, muskellunge and tiger muskellunge (hybrid muskellunge X northern pike). These studies will be initiated when diagnosed field cases can be identified that will lend themselves to the implementation of controlled field studies. Ovadine (Western Chemical) Disinfection of Fish Eggs: Data from the Ovadine work is being summarized for publication. We are also investigating the potential of indexing Ovadine. Publications issued or manuscripts approved during the year: (see “Principal Publications” at end of report) CRITICAL REVIEW (Northeast Region) 1) Work accomplished under the original project: The original objectives of the project were to conduct a national program to obtain minor and specialty animal-drug clearances (tolerances, exemptions and registrations) in cooperation with state, federal and industry personnel. The mission of NRSP-7 is: 1. To identify animal drug needs for minor species and minor uses in major species. 2. To generate and disseminate data for safe and effective therapeutic applications, and 3. To facilitate FDA/CVM approvals for drugs identified as a priority for a minor species or minor use. Under the framework of this mission, progress has been made in the following areas: 1. Use of hydrogen peroxide for the control of bacterial gill disease in fish. 2. Species Grouping in Fish, using the compounds Oxytetracycline, Romet- 30/Romet-TC and Aquaflor as test articles. 3. Use of Ovadine for the reduction of Viral Hemorrhagic Septicemia Virus on fish eggs. 2) The degree to which the objectives have been met: Work has focused on a number of important therapeutic compounds in aquatic animals. The work is being conducted in a deliberate manner with the goal of developing appropriate data that will be submitted in support of a label for these compounds. An initial step in this process is the publication of the data in the peer reviewed scientific literature. While we consider it extremely important to have such peer-reviewed information available for the veterinary community, should they consider an extra-label use, the ultimate goal is to secure a label for the product. As an additional goal, the work is being done in a manner that could justify a species grouping concept for finfish cultured in the United States. 3) Incomplete work or areas needing further investigation: The development of a crop (species) grouping concept is seen as imperative for supporting efforts to gain labels for therapeutic compounds for fish. Our work on Oxytetracycline, Romet-30/Romet-TC and Aquaflor (Florfenicol) in fish is proposed to be Minor Use Animal Drug Program/NRSP-7 Minutes Fall 2010 9 part of an effort to utilize those compounds as models in this effort. We expect that our efforts in developing a species grouping concept for fish will be a major undertaking in the upcoming years. Principal Publications (during the past year): Emily R. Cornwell, Geoffrey H. Groocock, Rodman G., Getchell, and Paul R. Bowser. 2010. Residual tannic acid destroys virucidal properties of iodine. North American Journal of Aquaculture (In Press) North Central – Dr. Ronald W. Griffith Progress of the Work and Principal Accomplishments Goat CIDR-G Tissue Residue Study report has been submitted. Mean tissue levels of progesterone 12 hours after CIDR removal were significantly lower than tissue levels in control does without CIDRs. Goat CIDR-G Effectiveness This study is in full swing. We have received excellent cooperation from producers in a number of states. We currently have over 600 dairy goats enrolled in the study in Iowa, California, Missouri, Minnesota and Wisconsin. On the meat goat side, we are trying to find more meat goats in the Southern U.S. to hopefully complete the studies in 2010-2011. We currently have 309 does enrolled in Iowa and Texas, which is approximately 90 short of our goal. If we do not find sufficient meat goats, we may submit the dairy goat study report separately. Lasalocid in Pheasants Efficacy The study was completed in 2007 and the study report submitted this summer. Keeping fingers crossed. Lasalocid in Pheasants TAS A second high-dose group study was completed in July. The study report is currently being prepared. Draxxin Target Animal Safety in Goats The study report has been submitted to the FDA/CVM. Dr. Kris Clothier has a manuscript accepted by the Journal of Pharmacology and Therapeutics. Draxxin Tissue Residue in Goats Study report in final stages of preparation Draxxin Efficacy in Goats PK/PD studies and MIC and killing kinetics data have been obtained. A partial study report on efficacy is being prepared. A manuscript is being prepared. Bioclip in Sheep No report. Too many projects at the moment to devote any time to this. Southern – Dr. Thomas Vickroy Progress of the Work and Principal Accomplishments 1. Fenbendazole in Game Birds (pheasants, bobwhite quail, partridge). A Product Development meeting was held via teleconference on 9 September 2010 with representatives from CVM ONADE, CVM OMUMS, industry (Brent Herrig, Intervet SP) and coordinators from the Southern, North-Central and Western regions of NRSP-7. Southern region is in process of preparing and submitting protocols for studies on human food safety (HFS) and target animal safety (TAS). Plans are in place to conduct Minor Use Animal Drug Program/NRSP-7 Minutes Fall 2010 10 both the HFS and TAS studies in Summer of 2011 with the Western region to perform the analytical testing of samples. 2. Lasalocid in Game Birds (pheasants). This project is being carried out once again in light of problems with the initial study. The Southern Region is tasked with development and validation of an analytical method for testing of samples. This work is currently underway, although there has been a slow down as the former Chemist retired and a new one is brought on board. 3. Ivermectin in Rabbits. The Method Validation Report was completed and submitted to the Western Region for QA review. However, that review was put on hold owing to two factors: 1) age of the study and 2) unwillingness of the manufacturer to seek designation. The project is currently in limbo. Overview of Other Programmatic Efforts The Southern Region is responsible for maintaining and updating the NRSP-7 website, including MUMsRx and the RUSTi system for tracking the status of regional projects. Some of these have not been updated for quite some time and are currently undergoing a substantial overhaul. In addition, the Southern Region coordinator organizes, sets the agenda and coordinates monthly teleconferences among the regional coordinators and administrators. Anticipated Use of Project Outcomes The findings from all of the studies above will be utilized to fulfill the data requirements for the FDA/CVM approval of these drugs for use in minor species. Work Planned for Remainder of the Year Over the next quarter our primary goals are to submit the HFS and TAS protocols for fenbendazole in game birds and to gain final approval of the modified analytical method for lasalocid in pheasants. The target animal safety studies for that project are slated to begin in late spring or early summer of 2011 at the North-Central region. The Southern region will be responsible for analysis of tissue samples from that study. ACTION ITEMS FOR FOLLOW-UP Fenbendazole in Pheasants Product development meeting scheduled. 1. Tom and Lisa to look at TAS data and make sure that there were not any problems with the pheasants. 2. Tom and Lisa to look at TAS protocol and see what should be asked as a exclusion for the next TAS study during product development meeting. If we need to do the TAS study (and it is not to our advantage to wait for the PD meeting, then we could try to do this part of the study this summer). We could essentially do it the same as the lasalocid TAS study. I know this is not ideal but Ron can comment on whether or not he has money he needs to spend regardless so minimizing what we do might not necessarily be necessary if it gets this part of the study done and allows us to get tissues to plan for the HFS and efficacy study the next summer. We would essentially be doing the fenbendazole study without protocol concurrence but would be modeling the study after the lasalocid TAS that had protocol concurrence. Worst case scenario is that we will have more data than less. Minor Use Animal Drug Program/NRSP-7 Minutes Fall 2010 11 3. Product Development meeting: Ask for efficacy data to be admissible; touch base about partial method validation. 4. Meg/Dorothy: Get data from current INAD to support efficacy/talk with McFarlane about efficacy 5. Davis to get assay up and running during 2010. Product development meeting ask if method validation is still acceptable. 6. Ron: Get samples during summer of 2010 for Davis to work with 7. Tom: Check with Brett Herrig (brent.herrig@sp.intervet.com) about designation?? Not sure if this is already designated?? 8. Tom: Target this summer for submission of protocols (HFS for sure; ?do we do TAS this summer without protocol concurrence) 9. Potential study to apply for MUMS’ Grant 10. Summer 2011: Do study for HFS and efficacy? Lasalocid in Game Birds 1. U of F: Generate questions relative to the fact that the columns can no longer be purchased for the “official method” 2. Meg: Request a conference call with CVM 3. Note: Lisa Tell and Scott Wetzlich would like to attend conference call also 4. Ron: TAS technical support will be submitted 5. Ron: What happened to samples for TAS (1x, 3x and 5x?) 6. Efficacy: Georgia investigators are writing technical report. Report has been written and QAed, but investigators need to respond to QA issues. This may be a good one for having a pre-submission conference call with CVM due to some QA issues. 7. HFS: Still waiting for assay to be worked out Tulathromycin in Goats: 1. TAS submitted to CVM by Kris Clothier/Ron Griffith. 2. Efficacy: Lisa to do literature search regarding plasma and lung secretions correlations 3. Efficacy: Marilyn to get information to us regarding Office of Research studies 4. Efficacy: Tom to send information about diffusion method 5. Efficacy: Lisa to do PK modeling of serum data for Kris to provide new AUC’s for data that was generated with rerun of diluted samples 6. Ron and Kris: Work on isolate information. MIC/AUC needs to be substantiated with kill kinetics (5 isolates) 7. HFS: Western region to get method validation written 8. HFS: Western region to finish tissue data analysis and gather data and send it to ISU 9. Lisa to follow up with Albert about designation 10. Doc 152: Dorothy or Meg to start working on CIDRs Goats and Deer: 1. Western region to send goat data from Fall 2009 to ISU. ISU grad student who is doing HFS (meat) report will also work on compilation of efficacy data. 2. Goat HFS: To be submitted by ISU (grad student working on it currently). NOTE TO RON: Need to submit an interpretation/summary of the method validation from Dennis. Even though he gives all of the information for meat method validation, he needs to give them a summary of what was done and what it meant. Minor Use Animal Drug Program/NRSP-7 Minutes Fall 2010 12 3. Both UC Davis and ISU to get ready for Fall 2010 efficacy work with goats 4. Lisa: Follow up on foreign data information for deer. Meg already has HFS data. Efficacy will need to be done in US. Need to see if we can get TAS data Ivermectin in Rabbits: 1. Tom to check with Merial about interest in label claim (Merial product). Tom: Please check with Brett Herrig (brent.herrig@sp.intervet.com). This has priority before we proceed with anything relative to this project. 2. If there is an interest in label claim, then decide where to go from here 3. Method validation to be arriving to Davis for QA. Will send it on to ISU for QA. Florfenicol for Sheep: 1. Western Region: QA of HFS currently underway (old formulation). Road map to be written. New Projects: Lisa to check with sponsor about interest for following products 1. flunixin meglumine 2. Zolvix: Meg please send Lisa a contact and forward email request. GRD/Program Action Items: 1. Lisa to touch base with Karl/Gina to find champions for Farm Bill 2. Gary Sherman to start process to “investigate” NRSP-7 moving into competitive grant system similar to IR-4 3. Lisa to contact Joan Bowen to see interest in leading stakeholders groups 4. Tom to look into sustainable farming/family farming groups as stakeholders 5. GROUP to brainstorm for other stakeholder groups for next teleconference 6. All regional coordinators to get Appendix E filled out for NIMS system as participants Web Site: 1. Meg to send Tom PowerPoint presentations 2. Meg to look at FAQ and give some suggestions 3. Tom is looking at overall general structure 4. Development of a protocol (non public) section 5. Development of a section where people can view current activity of a project OTHER BUSINESS Spring Meeting It was tentatively decided to hold the annual spring meeting in Rockville, MD on the condition of coordinating lobbying efforts at that time. The final decision on the timing of the meeting will be made when the budget situation becomes clearer this fall after the election. This will be followed on a month-to-month basis and discussed at our monthly teleconferences. There being no further business, the meeting was adjourned at 9:30 pm. Minor Use Animal Drug Program/NRSP-7 Minutes Fall 2010 13 Tuesday October 5th, 2010 Pfizer Animal Health The USDA's Minor Species Animal Drug Program, National Research Support Project #7 (NRSP-7) held the second day of its semi-annual fall meeting at Pfizer Animal Health, 333 Portage Street, Kalamazoo, MI 49007 MEETING ATTENDEES NAME AFFILIATION EMAIL ADDRESS Albert Ramudo Pfizer Animal Health albert.a.ramudo@pfizer.com Bret W. Hess University of Wyoming BretHess@uwyo.edu David Gottschall Pfizer Animal Health d.gottschall@pfizer.com Dawn Cleaver Pfizer Animal Health d.cleaver@pfizer.com Dorothy Bailey FDA/CVM dorothy.bailey@fda.hhs.gov. Gordon Brumbaugh Pfizer Animal Health g.brumbaugh@pfizer.com John Babish NRSP-7 jgb7@cornell.edu John C. Baker AA/MI AES/Michigan State U Baker@anr.msu.edu John Chenault Pfizer Animal Health j.chenault@pfizer.com John Hallberg Pfizer Animal Health j.hallberg@pfizer.com Lisa Tell NRSP-7/UC Davis latell@ucdavis.edu Meg Oeller FDA/CVM moeller@cvm.fda.gov Michael Sweeney Pfizer Animal Health m.sweeney@pfizer.com Pamela Boner Pfizer Animal Health p.boner@pfizer.com Raymond Zielinski Pfizer Animal Health r.zielinski@pfizer.com Robert Nutsch Pfizer Animal Health r.nutsch@pfizer.com Ron Griffith NRSP-7/Iowa State University rgriffit@iastate.edu Steve Sutherland Pfizer Animal Health s.sutherland@pfizer.com Steven Cox Pfizer Animal Health s.cox@pfizer.com Susan Kotarski Pfizer Animal Health s.kotarski@pfizer.com Thomas Schriemer Pfizer Animal Health t.schriemer@pfizer.com Thomas Vickroy NRSP-7/U FL vickroy@vetmed.ufl.edu 9:15 – 9:45 Dr. John G. Babish - MUADP/NRSP-7 Background Presentation – (See Appendix II) 9:45 – 10:00 Dr. Ron Griffith - Research Summary of Draxxin (tulathromycin) approvals in sheep and goats (See Appendix III) 10:00 – 12:00 Upon completion of the presentation by Dr Griffith, discussion sessions were held concerning Draxxin Sheep and Goat Effectiveness Discussion (45 min), Draxxin Sheep and Goats Metabolism and Safety (30 min), Dr. Susan Kotarski, Draxxin Sheep and Goats Microbial Safety Discussion (cf. Appendix IV; 60 min) and Review of Protocol Templates, and eSubmitter. There being no further business, the meeting was adjourned at 12:30 pm. RESPECTFULLY SUBMITTED: John G. Babish, Ph.D. Date: 9/2/10 Minor Use Animal Drug Program/NRSP-7 National Coordinator APPENDIX I MINOR USE ANIMAL DRUG PROGRAM (NRSP-7) ADMINISTRATIVE STATUS NRSP-7 Administrative Status September, 2010 1 ADR # INAD # PMF Drug Formulation Species Indication NADA Status 1 2792? 5055 Monensin Type A Goats Coccidiosis 095-735 Approved 2 2876 3887 Amprolium Type A Pheasants Coccidiosis 012-350 Approved 5 2875 3857 Thiabendazole Type A Pheasants Gapeworm 015-875 Approved 8 5582 Albendazole oral suspension Goats Liver flukes 110-048 Approved 11 3895 Ivermectin Injection Reindeer Warbles 128-409 Approved 14 8544 5258 Decoquinate Type A Sheep Coccidiosis 039-417 Approved 15 4254 5028 Oxytetracycline Type A Lobster Gaffkemia 038-439 Approved 30 4450 5178 Bacitracin Type A Quail Ulcerative enteritis 046-592 Approved 90 2792? 5014 Monensin Type A Quail Coccidiosis 130-736 Approved 96 5056 Sulfa/ormetoprim Type A Catfish Bacterial infections 125-933 Approved 110 5307 Ivermectin Injection Foxes Ear mites 128-409 Approved 111 8170? 5012 Decoquinate Type A Goats Coccidiosis 039-417 Approved 115 5020 Salinomycin Type A Quail Coccidiosis 128-686 Approved 122 5042 Lasalocid Type A Rabbits Coccidiosis 096-298 Approved 124 5118 Fenbendazole Oral suspension Goats GI Parasites 128-620 Approved 125 5059 Ivermectin Injection Am Bison Hypodermosis 128-409 Approved 127 5071 Fenbendazole Type A Bighorn sheep Lungworms 121-473 131-675 Approved 137 5157 Sulfa/ormetoprim Type A Partridges Coccidiosis 040-209 Approved 144 6272 5366 Morantel tartrate Type A Goats GI Parasites 092-444 Approved 165 6586 5544 Ceftiofur Injection Sheep Baterial pneumonia 140-338 Approved 169 3543 Formalin Immersion Shrimp Ext protozoal parasites 137-687 140-831 140-989 Approved 171 9266 5671 Ceftiofur Injection Goats Bacterial pneumonia 140-338 Approved 191 6865 5429 Lasalocid Type A Partridges Coccidiosis 096-298 Approved 217 10-772 5783 Tylosin WSP Honey bees American foulbrood 013-076 Approved 238 5228 Formalin Immersion Fin fish & eggs Ext protozoal parasites 140-989 Approved 245 8096 8054 8512 5667 Oxytetracycline Immersion Fin fish Skeletal marking 008-622 130-435 200-247 Approved 246 9693 5673 Tilmicosin Injection Sheep Chronic resp disease 140-929 Approved 258 10-321 5947 Progesterone CIDR Sheep Out-of-season breeding 141-302 Approved 17 3883 Ivermectin Oral suspension Goats GI parasites PMF 87 4449 5433 Amoxicillin Injection Sheep Bacterial pneumonia PMF 95 5117 Levamisole Oral suspension Goats GI parasites PMF 112 4543 5440 Clorsulon Oral suspension Goats Liver flukes PMF 107 9557 5421 Ivermectin Injection Rabbit Ear mites Active 135 6013 5165 Erythromycin Type A Salmonids Bacterial Kidney Disease Active 216 10-993 Fenbendazole Type A Fallow Deer GI parasites Active 235 9096 Lasalocid Type A Pheasants Coccidiosis Active 271 9757 Carp Pituitary Injection Fin fish Spawning aid Active NRSP-7 Administrative Status September, 2010 2 ADR # INAD # PMF Drug Formulation Species Indication NADA Status 280 10-062 5644 Fenbendazole Type A Pheasants Gapeworm & Cecal worm Active 285 10-319 10-320 Oxytetracycline Type A Fin fish Vibriosis Active 294 10-746 Lasalocid Type A Deer Coccidiosis Active 295 10-536 Strontium Chloride Immersion Fin fish Skeletal Marking Active 298 10-872 Lasalocid Type A Goats Coccidiosis Active 311 10-766 Lincomycin WSP Honey bees American foulbrood Active 313 10-823 Sulfa/ormetoprim Type A Fin fish Bacterial Infections Active 324 11-389 Progesterone CIDR Goats Estrus synchronization Active 334 11-145 Florfenicol Type A Fin fish Bacterial infections Active 335 Western Ovaprim (GnRHa +) Injection Ornament fish Spawning aid Active 336 Western Metomidate Injection Ornament fish Anesthetic Active 339 11-513 Tulathromycin Injection Sheep Respiratory infections Active 340 11-512 Tulathromycin Injection Goats Respiratory infections Active 18 4352 9093 Chloramine-T Immersion Salmonids Bacterial Gill Disease Transfer 43 6006 5316 Oxytetracycline Injection Goats Bacterial pneumonia Closed 83 6005 5321 Oxytetracycline Injection Sheep Bacterial pneumonia Closed 231 8826 Copper sulfate Immersion Catfish External protozoa Transfer 252 10-773 Tilmicosin phosphate Injection Veal calf Respiratory infection Terminated 259 9493 Hydrogen peroxide Immersion Fin fish Bacterial Gill Disease Closed 329 11-091 Florfenicol Injection Veal calf Respiratory infection Terminated 19 4320 Oxytetracycline Type A Alligators (7 subs - data) Inactive 66 6119 Penicillin Novobiocin Intramammary Goats (milk study) Inactive 117 10-872 Lasalocid Type A Goats (2 subs - meeting) Inactive 177 6481 Enrofloxacin Rabbits (4 subs - data) Inactive 178 6976 Spectinomycin inj/oral Ducks (3 subs - tissue residue) Inactive 202 8249 Ivermectin Injection Llamas (2 subs - data) Inactive 222 8798 5484 Ivermectin Pour-on Am Bison GI parasites Inactive 236 9097 Clopidol Type A Pheasant Coccidiosis (data) Inactive 272 10-804 Sulfa/ormetoprim Type A Pheasant Coccidiosis Inactive 273 10-342 Nitarsone Type A Partridge Blackhead Inactive 274 10-333 Zoamix Type A Pheasant Coccidiosis Inactive 299 11-193 Pirlimycin Intramammary Goats Mastitis Inactive 325/6 10-958 Florfenicol Injection Sheep Respiratory infections Inactive 327/8 11-836 Florfenicol Injection Goats (11 subs - data) Inactive 333 11-271 Florfenicol Type A Shrimp Necrotizing pancreatitis Inactive 14 4499 Decoquinate Type A Sheep (no data) TERMINATE 33 4406 Amoxicillin Injection Goats (no data) TERMINATE NRSP-7 Administrative Status September, 2010 3 ADR # INAD # PMF Drug Formulation Species Indication NADA Status 34 4447 Amoxicillin Injection Goats (no data) TERMINATE 35 4448 Amoxicillin Oral Goats (no data) TERMINATE 42 4405 Oxytetracycline Injection Dairy Goats (no data) TERMINATE 66 4411 Penicillin Novobiocin Intramammary Dairy goats (no data) TERMINATE 106 4785 Azaperone Injection Wild ungulates (1st submission only) TERMINATE 118 4414 Tiamulin Type A Trout (no data) TERMINATE 120 6492 Oxolinic acid Type A Salmon (no data) TERMINATE 131 4890 Benzocaine Injection Salmonids (no data) TERMINATE 145/6 6766 Fluoroquinolone Type A Salmon (no data) TERMINATE 172 6613 Bacitracin Zinc Type A Rabbits (1st submission only) TERMINATE 174 6302 Erythromycin Injection Salmon (1st submission only) TERMINATE 176 6725 Amoxicillin Injection Dairy goats (1st submission only) TERMINATE 179 6566 Fluoroquinolone Oral in water Cockatiels (2 subs - meeting) TERMINATE 182/206 8499 Albendazole feed/block Deer (no data) TERMINATE 187 6818 Avermectin Bio bullet Deer (1st submission only) TERMINATE 188 6823 Avermectin Bio bullet Sheep (1st submission only) TERMINATE 190 6862 Ceftiofur Bio bullet Bighorn Sheep (3 subs - ???) TERMINATE 197 8258 Ivermectin Pour-on Red Deer (no data) TERMINATE 199 8603 Enrofloxacin Soluble powder Shrimp (no data) TERMINATE 202 8800 Clorsulon Ivermectin Injection Llamas (1st submission only) TERMINATE 209 8500 Amoxicillin Type A Salmon (no data) TERMINATE 215 8558 Sarafloxacin Type A HSB (fish) (1st submission only) TERMINATE 251 9398 Ceftiofur Injection Deer (meeting only) TERMINATE 253 9481 Fenbendazole Type A Bison (1st submission only) TERMINATE 257 9476 Oxytetracycline Type A Lobster (meeting only) TERMINATE 275 11-898 Ceftiofur CFA Injection Deer (1st submission only) TERMINATE 284 10-146 Melengestrol acetate Oral Sheep (1st submission only) TERMINATE 297 10607 Triclabendazole Oral drench Deer Elk (1st submission only) TERMINATE APPENDIX II MINOR USE ANIMAL DRUG PROGRAM (NRSP-7) PRESENTATION Approvals and Activity by Industry ACTIVITY INDUSTRY APPROVAL S ACTIVE PROJECTS Game Bird Chukar partridges Sulfadimethoxine/Ormetoprim Lasalocid Pheasants Amprolium Thiabendazole Quail Salinomycin Bacitracin Monensin Pheasants Lasalocid Sulfadimethoxine/Ormetoprim Fenbendazole Rabbits Lasalocid Ivermectin Honey Bees Tylosin Lincomycin Cervid Bison Ivermectin Reindeer Ivermectin Deer Lasalocid Fallow Deer Fenbendazole Meat Goats Fenbendazole Monensin Decoquinate Morantel tartrate Lasalocid CIDR (progesterone) Tulathromycin Dairy Goats Fenbendazole Monensin Decoquinate Morantel tartrate Lasalocid CIDR (progesterone) Ceftiofur HCl (Intramammary) Tulathromycin Sheep Bighorn Sheep Fenbendazole Sheep Decoquinate Ceftiofur Tilmicosin phosphate CIDR (progesterone) Sheep Tulathromycin Catfish/Aquaculture† Catfish Sulfadimethoxine/Ormetoprim Finfish Formalin Oxytetracycline Hydrogen peroxide Lobster Oxytetracycline Fish Sulfadimethoxine/Ormetoprim Florfenicol Erythromycin Oxytetracycline Strontium chloride Shrimp Florfenicol †Approvals resulted in an additional 16 label claims for these aquatic species. APPENDIX III PRESENTATION OF PROJECTS OF INTEREST TO PFIZER APPENDIX IV ANTIMICROBIAL GUIDANCE DOCUMENT #152 # 152 Guidance for Industry Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to Their Microbiological Effects on Bacteria of Human Health Concern This document discusses a recommended approach for assessing the safety of antimicrobial new animal drugs with regard to their microbiological effects on bacteria of human health concern. Comments and suggestions regarding this document should be sent to the Division of Dockets Management (HFA 305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD 20852. All comments should be identified with the Docket No.98D-1146. Submit electronic comments to http://www.fda.gov/dockets/ecomments. Direct questions regarding this document to Jeffrey M. Gilbert, (HFV-157), Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-827-0233, e-mail: jgilbert@cvm.fda.gov. Additional copies of this guidance document may be requested from the Communications Staff (HFV-12), Center for Veterinary Medicine, Food and Drug Administration, 7519 Standish Place, Rockville, MD 20855 and may be viewed on the Internet at http://www.fda.gov/cvm. Paperwork Reduction Act Public Burden Statement According to the Paperwork Reduction Act of 1995, a collection of information should display a valid OMB control number. The valid OMB control number for this information collection is 0910-0522 (Expires 4/30/05). The time required to complete this information collection is estimated to average 1,084 hours per response, including the time to review instructions, search existing data resources, gather the data needed, and complete and review the information collection. U.S. Department of Health and Human Services Food and Drug Administration Center for Veterinary Medicine October 23, 2003 Guidance #152 i Table of Contents I. Introduction...............................................................................................................................2 II. Scope of Guidance .....................................................................................................................3 III. Risk Analysis Methodology.......................................................................................................5 IV. Hazard Characterization.............................................................................................................8 V. Qualitative Antimicrobial Resistance Risk Assessment ............................................................9 A. Release Assessment ...........................................................................................................10 B. Exposure Assessment .........................................................................................................14 C. Consequence Assessment ..................................................................................................20 D. Risk Estimation..................................................................................................................20 VI. Antimicrobial Resistance Risk Management Considerations .................................................22 VII. Application of Risk Management Strategies ..........................................................................24 VIII. Summary of Microbial Food Safety Assessment Process .....................................................26 Glossary ..................................................................................................................................27 Appendix A: Ranking of antimicrobial drugs according to their importance in human medicine ...............................................................................................28 References ...............................................................................................................................34 Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Introduction 2 Evaluating the Safety of Antimicrobial New Animal Drugs With Regard to Their Microbiological Effects on Bacteria of Human Health Concern1 I. INTRODUCTION 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 on a possible process for evaluating the potential effects of antimicrobial new animal drugs on non-target bacteria as part of the new animal drug application process. This guidance document outlines a risk assessment approach for evaluating the microbial food safety of antimicrobial new animal drugs. Within the context of risk assessment, many possible mechanisms to address the development of antimicrobial resistance resulting from the use of antimicrobial new animal drugs in food-producing animals are available to the sponsor. Alternative processes that may be more appropriate to a sponsor’s drug and its intended conditions of use, may be used to characterize the microbial food safety of that drug. 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 guidance, 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. 1 This guidance has been prepared by the Division of Human Food Safety, Office of New Animal Drug Evaluation, Center for Veterinary Medicine (CVM), at the Food and Drug Administration. 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 and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing the guidance. If you cannot identify the appropriate staff, call the appropriate number listed on the title page of this guidance. Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Scope of Guidance 3 II. SCOPE OF GUIDANCE DOCUMENT As part of the pre-approval safety evaluation process, FDA intends to consider the potential impact on human health of all uses of all classes of antimicrobial new animal drugs intended for use in food-producing animals. The scope of this document is an assessment of the effect of the transmission of foodborne bacteria of human health concern through the consumption of animal derived food products. Although FDA’s primary focus will be foodborne pathogens, other (enteric/gastrointestinal) bacteria may be considered when deemed necessary. Further clarification is provided regarding microbial food safety considerations that should be addressed, and the investigational new animal drugs (INADs) or new animal drug applications (NADAs) covered by the guidance described herein. This document focuses on the concern that the use of antimicrobial new animal drugs in food-producing animals will result in the emergence and selection of antimicrobial resistant food-borne bacteria which impact human health adversely. Note: Effects of drug residues on human intestinal microflora: Antimicrobial drug residues present in food from food-producing animals may cause adverse effects on the ecology of the intestinal microflora of consumers.1, 2 For further information on requirements regarding these effects, refer to FDA Guidance for Industry #52 entitled “Assessment of the Effects of Antimicrobial Drug Residues from Food of Animal Origin on the Human Intestinal Flora.” The FDA believes that human exposure through the ingestion of antimicrobial resistant bacteria from animal-derived foods represents the most significant pathway for human exposure to bacteria that have emerged or been selected as a consequence of antimicrobial drug use in animals. This risk assessment approach is recommended for all uses of all antimicrobial new animal drugs in food-producing animals; however, sponsors of applications described below are encouraged to consult with FDA to decide if the risk assessment approach is recommended for their application. 1. Certain supplemental NADAs: Microbial food safety information is not typically needed for Category I supplemental NADAs (21 CFR 514.106(b)(1)). These supplements ordinarily do not require a reevaluation of any of the safety or Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Scope of Guidance 4 effectiveness data in the parent application. However, information may be needed for certain Category II supplemental NADAs (21 CFR 514.106(b)(2)). These supplements may require a re-evaluation of certain safety or effectiveness data in the parent application. 2. NADAs for antimicrobial drug combinations: Microbial food safety information would ordinarily not be needed for antimicrobial drug combinations as defined in Section 512(d) of the Act (21 U. S. C. 360b(d)), as amended by the Animal Drug Availability Act (ADAA) of 1996. Microbial food safety would typically be addressed as part of the NADAs for the individual antimicrobial drugs that comprise the combination. However, in certain circumstances information may be requested for drug applications for antimicrobial drug combinations. 3. Abbreviated (generic) NADAs: Microbial food safety information would not be needed for abbreviated new animal drug applications (ANADAs) filed under section 512(b)(2) of the Act for generic copies of approved antimicrobial new animal drugs. Microbial food safety information would be needed for supplements to add claims to approved ANADAs. Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Risk Assessment 5 III. RISK ANALYSIS METHODOLOGY This guidance document outlines a risk analysis method, and describes its application as a process for evaluating human food safety with respect to the potential microbiological effects of antimicrobial new animal drugs on food-borne bacteria of human health concern. The sponsor of an antimicrobial new animal drug may use this guidance and the methodology described herein to conduct a qualitative risk assessment as part of the pre-approval safety evaluation of a new animal drug. It is important to note that the sponsor is free to demonstrate the safety of their proposed drug product in other ways. FDA’s current thinking on a qualitative approach for risk assessment, especially where there may be a lack of substantial data, is described in this guidance. FDA does not intend to exclude quantitative risk assessment in favor of a qualitative process. Further, FDA encourages sponsors to seek data and modeling approaches that can best refine and improve the approach and assumptions incorporated in this risk assessment process. If the sponsor elects to use this or a similar process, FDA recommends the assessment be submitted to the INAD file with supporting data as a component of the Human Food Safety technical section, or should be included in the NADA as part of the sponsor’s submission under 21 CFR 514.1(b)(8). The results of this risk assessment can help to estimate the overall risk, allowing an informed risk management decision. Evaluation of all available information submitted in support of the NADA may result in actions ranging from approval of the new animal drug to denial of the new animal drug application. The remainder of the document provides guidance on this risk analysis method. A. Background: The risk analysis process outlined in this document is based on the process described by the Office International des Epizooties (OIE) Ad Hoc Group on Antimicrobial Resistance.3 The OIE risk analysis methodology is tailored to address antimicrobial resistance in animals and includes hazard identification, risk assessment, risk management, and risk communication. Although the OIE approach differs organizationally from the risk analysis paradigm described by the National Academy of Science/National Research Council (NAS/NRC), the OIE process includes similar steps to describe the risk assessment.4 Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Risk Assessment 6 The risk assessment process described in this guidance is comprised of a hazard characterization, a release assessment, an exposure assessment, a consequence assessment, and a risk estimation (See Figure 1). The risk estimation integrates the components of the risk assessment into an overall conclusion, provid ing a qualitative indication of the potential risk to human health of the proposed use of the antimicrobial new animal drug. FDA then uses the overall risk estimation ranking, along with other relevant data and information submitted in support of the NADA, to determine whether the drug is approvable under specific risk management conditions. Figure 1: Components of a qualitative antimicrobial resistance risk assessment Hazard Characterization Qualitative Risk Assessment Release Assessment Exposure Assessment Consequence Assessment probability that resistant bacteria are present in target animal as a consequence of drug use (rank as High , Medium , or Low ) Risk Estimation Overall Risk Estimate: Integration of release, exposure and consequence assessments. (rank as High , Medium , or Low ) probability for humans to ingest bacteria in question from the relevant food commodity (rank as High, Medium, or Low ) probability that human exposure to resistant bacteria results in an adverse health consequence (rank Important, Highly Important, or Critically Important) Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Risk Assessment 7 B. Definitions: 1. Hazard: Human illness, caused by an antimicrobial-resistant bacteria, attributable to an animal-derived food commodity, and treated with the human antimicrobial drug of interest. 2. Hazardous agent: Antimicrobial-resistant food-borne bacteria of human health concern that are in or on a food-producing animal as a consequence of the proposed use of the antimicrobial new animal drug. 3. Risk: The probability that human food-borne illness is caused by an antimicrobialresistant bacteria, is attributable to an animal-derived food commodity, and is treated with the human antimicrobial drug of interest. FDA’s overriding concern is the decreased or lost effectiveness of antimicrobial drugs in humans as a consequence of human exposure to resistant bacteria through ingestion of animal derived food products. FDA is concerned about a range of deleterious effects that antimicrobial resistant bacteria may have on human health. These effects include but are not limited to increased duration of illness, treatment failure, and loss of therapeutic options. Due to the difficulties associated with measuring loss of effectiveness, the risk assessment process described in this guidance document estimates the probability of the occurrence of the hazard. C. Data sources/data quality: A variety of materials may be used to support a microbial food safety assessment. These materials should meet FDA standards for data used to support an approval. Sponsors may consider: 1) Generating necessary data through the conduct of prospective studies. FDA recommends that drug sponsors refer to 21 CFR Part 58 for requirements related to Good Laboratory Practices for conducting non-clinical laboratory studies. 2) Submission of current and relevant literature (including peer reviewed, published literature). FDA recommends that sponsors refer to Guidance for Industry #106, Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Risk Assessment 8 “The Use of Published Literature in Support of New Animal Drug Approval” for guidance regarding use of published literature. IV. HAZARD CHARACTERIZATION Note: Prior to initiating and submitting the risk assessment, FDA recommends that sponsors electing to use this process characterize the hazard, and the conditions that influence the occurrence of that hazard. CVM envisions hazard characterization as distinct and separate from the qualitative risk assessment and it is recommended that the hazard characterization be submitted to the FDA as a stand alone document. This submission will enable the sponsor and the FDA to determine the information that should be included in the risk assessment. In addition, based on the hazard characterization, it may be determined in certain cases that completion of a risk assessment is not recommended. The hazard has been defined as human illness, caused by an antimicrobial-resistant bacteria, attributable to an animal-derived food commodity, and treated with the human antimicrobial drug of interest. FDA recommends that sponsors address the hazard characterization step of the risk assessment by submitting information regarding the chemical, biochemical, microbiological, and physical properties of the antimicrobial new animal drug that bear on characterizing the downstream effects of the drug. This information may include, but should not be limited to: A. Drug-specific information: Chemical name and structure 1. Class of antimicrobial drug (e.g., macrolide) 2. Mechanism (e.g., protein synthesis inhibitor) and type of action (i.e., bactericidal vs. bacteriostatic) 3. Spectrum of activity (e.g., Gram-positive, Gram-negative, broad, or narrow spectrum, etc.) 4. Standardized antimicrobial susceptibility testing methodology and specific susceptibility data (i.e., minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) data pertinent to the appropriate bacteria of human health concern). FDA recommends that if the sponsor does not use standardized susceptibility test methods, the sponsor should include a detailed description of the antimicrobial susceptibility testing method(s) used for determining the susceptibility of the bacterial isolates of concern and the reason(s) for the needed change. The Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Risk Assessment 9 methods should include the quality control organism(s), the dilution scheme used, and the source for the interpretive criteria for human or veterinary isolates. The methods may include citations, if available, of relevant laboratory standards such as the National Committee on Clinical Laboratory Standards (NCCLS). Additional guidance on susceptibility testing may be obtained from recognized sources such as NCCLS documents. 5. Relative importance of the drug in human medicine (see Appendix A). B. Bacteria l resistance information: Taking into account the target animal species to be treated with the drug, the conditions of intended animal use of the drug in animals, and the antimicrobial properties of the drug in question, FDA recommends that the sponsor identify: 1. Bacterial species and strains for which resistance acquisition has potential human health consequence. 2. Known resistance determinants or mechanisms associated with the antimicrobial drug(s) of interest. FDA recommends that information describ ing phenotypic and genotypic similarities with resistance determinants in other food-borne bacteria of human concern be identified. C. Data gaps and emerging science: The sponsor or FDA may identify data gaps and areas of emerging science that may be relevant to the microbial food safety assessment for the proposed conditions of use. V. QUALITATIVE RISK ASSESSMENT Note: After submission and review of the hazard characterization, and prior to completing the risk assessment, the sponsor may wish to consult with FDA regarding recommendations on additional information to complete the risk assessment. The OIE method is described below in a simplified format. The risk assessment approach is comprised of a release assessment, an exposure assessment, a consequence assessment, and a risk estimation (refer to Figure 1). FDA recommends that sponsors adapt and expand their risk assessment to accommodate the unique relationships that may exist among an antimicrobial new animal drug, affected microbe(s), proposed condition(s) of use, and other parameters that potentially affect human health. The assessment process outlined below will result in an overall estimate of the level Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Risk Assessment 10 of concern (risk estimation) associated with the emergence or selection of resistant bacteria as a consequence of the proposed use of the drug in animals. This process may help guide the selection of appropriate risk management steps. Note: FDA intends to determine the appropriate use conditions or other risk management steps based on its review and consideration of the new animal drug application as a whole, including any risk assessment submitted by the sponsor as part of the application. A. Release Assessment: The release assessment estimates the probability that the proposed use of the antimicrobial new animal drug in food-producing animals will result in the emergence or selection of resistant bacteria in the animal. 1. Defining the boundaries of the release assessment: The boundaries of the release assessment span from the point the antimicrobial new animal drug is administered to the food-producing animal, to the point the animal is presented for slaughter or the animal-derived food is collected. For the purposes of this guidance, FDA is focusing on the food-producing animal as the source of human exposure to the hazardous agent. Human exposure to the hazardous agent should be addressed in the exposure assessment. 2. Factors that may be considered in release assessment: A number of relevant factors are suggested for consideration in completing the release assessment. These factors include items that are also considered as part of the hazard characterization step described earlier. Note: Following submission of the hazard characterization, the sponsor may wish to consult with FDA to determine the specific factors most relevant to the proposed conditions of use of the antimicrobial new animal drug in question. In order to address specific considerations pertinent to the drug and its proposed conditions of use, the sponsor or FDA may consider factors not listed below. The relative significance of any particular factor may vary depending on the specific antimicrobial new animal drug application under consideration. Therefore, when determining the overall release assessment ranking, certain factors may carry greater weight than other factors. FDA recommends that the factors considered in the release assessment include the following. Other factors may also be relevant. FDA recommends these be clearly defined and supported. Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Risk Assessment 11 a. Product description: · Product formulation (active and inactive ingredients) · Information regarding proposed conditions of use including: - Route of administration (i.e., injection, water, feed) - Dosing regimen - Proposed product indication - Intended target animal species - Proposed withdrawal time b. Drug substance description: · Class of antimicrobial drug (e.g., macrolide) · Chemical name, CAS number, and structure c. Mechanism and type of antimicrobial action: · Specifics regarding antimicrobial mechanisms (e.g., protein synthesis inhibitor) · Type of action (e.g., bactericidal action vs. bacteriostatic) d. Spectrum of activity: · General information (e.g., is active against Gram-positive, Gram- negative, broad, or narrow spectrum, etc.) · Specific susceptibility data (e.g., minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) data pertinent to the foodborne bacteria of human concern in question) e. The pharmacokinetics/pharmacodynamics of the drug: · absorption, distribution, metabolism, and elimination of the drug in the target animal · data on, or an estimation of, the active antimicrobial drug in colonic contents Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Risk Assessment 12 · additional effects such as first-exposure effects, post-antibiotic effects, sub- MIC effects, etc. · Pharmacodynamics, such as concentration and/or time dependent effects, etc. f. Resistance mechanisms and genetics: FDA recommends that the sponsor provide information regarding the mechanism(s) and genetic basis of resistance development that includes: · Known mechanism(s) of resistance in animal and human pathogens (e.g., antimicrobial inactivation, alteration of the drug target, reduced uptake, efflux of the antimicrobial drug, etc.) · Location of resistance determinants (e.g., plasmid-mediated vs. chromosomal; present on transposon, integron, or phage) g. Occurrence and rate of transfer of resistance determinants: FDA recommends that the sponsor provide information regarding whether resistance determinants are transferable and, if so, at what rate. Relevant questions may include, but are not limited to: · Can resistance determinants be transferred among bacteria by transformation, transduction, conjugation, or transposition? If so, at what rate? · If resistance occurs by point mutation, at what rate do the point mutations occur? h. Resistance selection pressures: FDA recommends that the sponsor provide information to help characterize the relative magnitude of selection pressure for resistance that may exist for the particular drug use in question. Pertinent information may include: · Information regarding other antimicrobials that may co-select for resistance · Information regarding cross resistance to other antimicrobial drugs approved in veterinary and human medicine · Consideration of the extent of use of the proposed product (e.g., duration of administration; individual vs. small groups vs. flocks/herds) i. Baseline prevalence of resistance: FDA recommends that the sponsor provide available epidemiological data outlining the existing prevalence of resistance to the drug and/or related drugs in target pathogens and commensal gut flora. This Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Risk Assessment 13 may be obtained from newly generated data, or existing sources of data, such as the National Antimicrobial Resistance Monitoring System (NARMS) data, current literature, or other reliable surveillance sources. If baseline data is not available for the proposed antimicrobial drug, sponsors may wish to consult with FDA regarding collection or generation of such data. j. Other information relevant to the release assessment: · Relevant information relating to the rate of resistance development and decline after treatment · Information or studies to characterize the rate of resistance development in food-borne bacteria of human health concern following use of the drug under the proposed conditions of use. · Information or studies to characterize the decline of resistance in food-borne bacteria of human health concern following cessation of therapy. Of particular interest is information relative to the interval up to the earliest time point (post-drug administration) at which animals would be presented for slaughter. 3. Summarizing the Release Assessment: FDA recommends that the sponsor qualitatively characterize all factors relevant to the release assessment based on supporting information. We recommend that this characterization include an estimate of whether each factor would have a high, medium, or low likelihood of favoring resistance emergence. For example, the spectrum of activity of the drug might be ranked high for favoring resistance emergence or selection if the new animal drug in question readily selects for mutations conferring resistance; in contrast, pharmacodynamics might be ranked low with regard to impact on resistance if the drug did not enter the target animal intestinal tract at concentrations shown to have an effect on resistance development, etc. These rankings would then be integrated into an overall release assessment ranking of high, medium, or low. FDA recommends that the sponsor provide a detailed discussion of the conclusions as well as present the conclusions in summary format (see Table 1). Note: If sufficient information regarding a factor is not available or has not been generated for the assessment, the most conservative estimate (high) of the particular factor should be assumed. Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Risk Assessment 14 Table 1: Sample table for collating and summarizing interpretation of relevant factors considered in completing the release assessment Relevant parameters Extent to which relevant factors favor emergence of resistance Release2 (H, M, L) Comments/conclusions regarding factors Mechanism of activity Spectrum of activity Pharmacokinetics Pharmacodynamics Resistance mechanism(s) Resistance transfer Selection pressure Other factors 1 1Other factors may be identified that are thought to be of importance to the evaluation. After submission of the hazard characterization, the sponsor may wish to consult with FDA regarding additional factors prior to completing the assessment. 2Potential for favoring the release of resistant bacteria. 4. Release Assessment conclusion: The outcome of the release assessment is intended to estimate the probability that resistant bacteria will emerge or be selected for as a consequence of the proposed drug use in animals. FDA recommends that the sponsor use the conclusions obtained from assessing all relevant factors to derive an overall qualitative ranking for the release assessment. This overall conclusion may be expressed in terms of a high, medium, or low probability that resistant food-borne bacteria will occur in animals as a consequence of the proposed drug use. B. Exposure Assessment: The exposure assessment describes the likelihood of human exposure to food-borne bacteria of human health concern through particular exposure pathways, in this case animal derived food products. The exposure assessment should provide a qualitative estimate of the probability of this exposure occurring. The division of the qualitative risk assessment into “release” and “exposure” components effectively produces a natural placement of animal and animal treatment Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Risk Assessment 15 factors into the “release assessment component” and food-chain and human factors within the “exposure assessment component.” FDA recognizes that there are many factors that may affect the bacteria of interest between the time animals are presented for slaughter (or the animal-derived food is collected) and the time the final food product is consumed. Note: For the purposes of this qualitative risk assessment, FDA assumes that the probability that bacteria in or on the animal at slaughter may be used as an estimate of the probability of human exposure to that bacterial species in the food commodity derived from that animal. FDA recognizes that food-borne human exposure to antimicrobial resistant bacteria is complex and often involves the contributions from other sources of exposure (e.g., direct contact between animals and humans, introduction of resistant bacteria and resistance determinants into the environment). However, FDA believes that evaluating antimicrobial new animal drug safety relative to the most significant exposure pathway (i.e., food-borne pathway) is the best way to qualitatively assess the risk of antimicrobial drug use in food-producing animals. Uncertainties regarding the contribution of other exposure pathways may be considered during the development of appropriate risk management strategies. 1. Factors to consider in the exposure assessment: The exposure assessment is independent of the use of the antimicrobial drug under review and may be estimated by considering the relative amount of relevant bacterial contamination of the food product and the relative quantity of the food product consumed by humans. While it is acknowledged that other factors such as food preparation practices can affect exposure, the two prior considerations are intended to provide a qualitative indication of the probability of human exposure to the foodborne bacteria of human health concern. Appropriate current survey data of both food commodity contamination and consumption may be submitted to support a qualitative ranking of the probability of human exposure to the given bacteria via a particular food commodity. FDA recommends that the sponsor derive the exposure assessment ranking by integrating the ranking of the probability of human exposure (through food) to the bacteria in question with the ranking of consumption of the animal derived food commodity. The qualitative probability should be expressed in terms of high, medium, or low as discussed below. Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Risk Assessment 16 2. Example process for the estimation of exposure to the hazardous agent: Note: The specific information provided in the tables in this section is for illustrative purposes only. Sponsors may reference a variety of data sources which best characterize human exposure to bacteria of human health concern via animal-derived foods. FDA recommends that sponsors reference the most reliable, current data available at the time that the assessment for their product is conducted. FDA believes that the concept of qualitatively ranking bacterial contamination in the manner described is consistent with the overall risk assessment process outlined. In addition, FDA believes that the incidence of carcass contamination is a relevant factor in estimating the probability of human exposure to foodborne bacteria. For the purposes of this risk assessment, FDA assumes that a high incidence of carcass contamination is more likely to lead to human exposure through food than a low incidence of carcass contamination. Based on this assumption, FDA believes that it is appropriate to rank contamination qualitatively as high, medium, or low. Food commodity consumption: As an example of food commodity consumption data, per capita meat consumption data are provided in Table 2. The data presented are for the year 2001 and are published by the USDA Economic Research Service. FDA recommends that the sponsor reference this type of information when completing the risk assessment for their product. The most recent available information should be used for the assessment. The qualitative rankings provided in Table 2 are illustrative, and represent relative rankings of consumption of the commodities listed for the year 2001. Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Risk Assessment 17 Table 2: Per capita consumption data for red meats, poultry, fish and shellfish for the year 2001. Commodity Per capita consumption* (pounds per capita per year) Qualitative ranking** Beef 62.9 High Chicken 53.9 High Pork 46.7 High Fish and shellfish 15.2 Medium Turkey 13.7 Medium Lamb and mutton 0.8 Low Veal 0.5 Low Total meat 193.7 *From USDA Economic Research Service5; Boneless, trimmed (edible) weight. **Qualitative ranking based on relative proportion of the total per capita consumption of meat that is attributable to each of the individual meat commodities. Food commodity contamination: FDA recommends that the sponsor reference food commodity contamination data when completing the risk assessment for their product. The most recent information should be used for the assessment. The relative qualitative ranking of the level of contamination among various food commodities, High (> 25%), Medium (5–25%), Low (< 5%), is a general ranking, proposed here for illustrative purposes only, and may be subject to modification to more appropriately reflect the most current data. For illustrative purposes, Tables 3 and 4 present Salmonella and Campylobacter contamination rates in various animal-derived food commodities. Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Risk Assessment 18 Table 3. Prevalence of Salmonella contamination of various animal-derived food commodities and qualitative contamination rankings. Commodity Baseline prevalence (%)1 Calendar Year 2001 Prevalence (%)1,2 Qualitative ranking3 Ground Turkey 49.9 26.2 High Ground Chicken 44.6 19.5 Medium Broilers 20.0 11.9 Medium Market hog 8.7 3.8 Low Ground Beef 7.5 2.8 Low Cows/bulls 2.7 2.4 Low Steer/Heifer 1.0 0.6 Low 1As reported in the USDA/FSIS “Progress Report on Salmonella Testing of Raw Meat and Poultry Products, 1998-2001”6 2Prevalence data for CY 2001 for all size slaughter establishments and establishments that produce raw ground product 3Relative qualitative ranking of the level of contamination among various food commodities, Low (< 5%), Medium (5 – 25%), High (> 25%), is a general ranking, proposed here for illustrative purposes only, and may be subject to modification to more appropriately reflect the most current data. Table 4. Prevalence of Campylobacter contamination of various animal-derived food commodities and provisional qualitative contamination rankings. Commodity Prevalence (%)1 Qualitative ranking2 Turkeys 90 High Broilers 88 High Ground Chicken 60 High Market hog 32 High Ground Turkey 25 Medium Steer/Heifer 4 Low Cows/bulls 1 Low Ground Beef 0 Low 1Data from national surveys conducted between 1992 – 1997.7-14 2Relative qualitative ranking of the level of contamination among various food commodities; Low (< 5%), Medium (5–25%), High (> 25%) is a general ranking, Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Risk Assessment 19 proposed here for illustrative purposes only, and may be subject to modification to more appropriately reflect the most current data. FDA acknowledges that the calendar year 2001 contamination data listed in Table 3 indicate that all listed food commodities are below their respective Salmonella performance standards (i.e., baseline preva lence). For the purposes of the assessment outlined here, FDA has decided to base the criterion for “high” contamination upon the highest leve l of contamination reported for Salmonella in 2001. Therefore, for the year 2001, a prevalence of contamination of greater than 25 percent is considered a “high” level of contamination. The medium and low rankings of contamination are bracketed at 5 to 25 percent and less than 5 percent, respectively. For consistency, as described in Table 4, the same ranking criteria may be applied to other bacteria such as Campylobacter. Sponsors may propose alternative criteria and rankings, if data are available to support their position. 3. Summarizing exposure assessment: Ranking human exposure to foodborne bacteria. Table 5 describes a possible process for estimating the probability of human exposure to the hazardous agent through consumption of animal derived food commodities. Table 5: Possible process for ranking qualitatively the probability of human exposure to a given bacteria in a given food commodity Probability of human exposure to a given bacteria Amount of food commodity being consumed Amount of food commodity contamination High Medium Low High H H M Medium H M L Low M L L 4. Exposure assessment conclusion The outcome of the exposure assessment is intended to estimate the probability that humans will be exposed to the hazardous agent through consumption of animal derived food commodities. FDA recommends that the sponsor use the outcome of the integration process described in Table 5 to reach an overall qualitative rank of a high, medium, or low probability of human exposure to the hazardous agent. Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Risk Assessment 20 C. Consequence Assessment FDA believes that the potential human health consequences of exposure to the defined hazardous agent may be qualitatively estimated by considering the human medical importance of the antimicrobial drug in question. While antimicrobial agents are important for the treatment of infectious disease in humans, certain antimicrobial agents are believed to be of greater importance to the therapy of infectious diseases in humans than are others. Therefore, it is assumed that the human health consequences associated with bacteria that are resistant to drugs of greater importance are more significant than the consequences associated with bacteria that are resistant to drugs of lesser importance. FDA recommends the sponsor refer to Appendix A of this document to assess the importance of the drug or antimicrobial class in question for human medicine. FDA recommends that the sponsor base the consequence assessment conclusion on the human medical importance ranking and be expressed as critically important, highly important or important. This ranking will be integrated along with the outcomes of the release and exposure assessments to derive an overall risk estimation as described below. D. Risk estimation: The risk estimation integrates the results from the release, exposure, and consequence assessments into an overall risk estimation associated with the proposed conditions of use of the drug. FDA recommends that the risk estimation rank drugs as high, medium, or low risk. The risk rankings represent the potential for human health to be adversely impacted by the selection or emergence of antimicrobial resistant food-borne bacteria associated with the use of the drug in food-producing animals. Table 6 provides a possible method for integrating the outcomes of the release, exposure, and consequence assessments into a single risk estimation ranking. The distribution of risk estimation rankings listed in Table 6 provides an initial indication as to the integration of rankings. Refinement of the risk estimation ranking may be appropriate for specific cases based on available information. Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Risk Assessment 21 Table 6. Possible risk estimation outcomes based on the integration of the release, exposure, and consequence assessment rankings Release Exposure Consequence Risk Estimation low low important low low medium important low medium low important low low low highly important low low high important medium high low important medium medium medium important medium medium high important medium high medium important medium high high important medium low medium highly important medium low high highly important medium medium medium highly important medium medium low highly important medium medium high highly important medium high low highly important medium high medium highly important medium low low critically important high high high highly important high low medium critically important high medium low critically important high low high critically important high high low critically important high medium medium critically important high medium high critically important high high medium critically important high high high critically important high Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Risk Management 22 VI. RISK MANAGEMENT CONSIDERATIONS Possible risk management steps range from denying the approval of a drug application (i.e., the drug is unsafe or not shown to be safe) to approving the application under various use conditions that assure the safe use of the product. A. Denying approval of a drug application: The Federal Food, Drug, and Cosmetic Act (FFDCA), Sec. 512(d), and regulations promulgated thereunder (see 21 CFR 514.111), provides possible grounds for denying the approval of a new animal drug application. The statutory grounds for denying approval include the results of tests that show the drug is unsafe or the determination that there is insufficient information as to whether the drug is safe. Consequently, denying the approval of an antimicrobial drug application is one possible outcome of an overall safety evaluation which could include the qualitative antimicrobial resistance risk assessment process described above. B. Drug approval under safe conditions of use: Approval of the use of the drug under those conditions for which safety and effectiveness has been demonstrated is another possible outcome of an overall safety evaluation that could include the qualitative antimicrobial resistance risk assessment process described above. Drugs considered to be of high concern (with regard to potential human health impact) would typically be associa ted with more restricted use conditions. Drugs considered to be of lower concern would typically be associated with less restricted use conditions in food-producing animals. C. The following represent relevant risk management steps or conditions that may be appropriate based on the outcome of the qualitative antimicrobial resistance risk assessment process. 1. Marketing status limitations: Antimicrobial drugs approved for use in animals may be marketed as prescription (Rx), over-the-counter (OTC), or veterinary feed directive (VFD) products. FDA believes that for certain antimicrobial drugs veterinary supervision is critical to assuring the judicious and safe use of the antimicrobial drug. Therefore, such drugs might be approved for limited use by, or under the supervision of, a veterinarian. For other antimicrobial drugs, the requirement for this level of veterinary supervision may not be warranted. 2. Extra-label use prohibition: As provided under 21 CFR 530.21(a)(2), FDA may prohibit the extralabel use of an approved new animal drug or class of drugs in foodproducing animals if FDA determines that “the extralabel use of the drug or class of drugs presents a risk to the public health.” If significant concerns exist regarding Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Risk Management 23 assurance of drug safety in light of potential extralabel use, extralabel use may be prohibited according to the procedures described in 21 CFR 530. 3. Extent-of- use limitations: FDA believes that “extent of use” is an important factor to consider when determining safe conditions of use for an antimicrobial new animal drug. Table 7 presents a possible process for integration of administration and duration of administration of an antimicrobial drug into a qualitative ranking for “extent of use”. Table 7: Possible process for ranking (High, Medium, Low) of extent of antimicrobial drug use in animals based on duration and method of administration. Intended administration to: Duration of use individual animals select groups or pens of animals flocks or herds of animals Short (<6 days) L1 M2 H3 Medium (6-21 days) L M H Long (>21 days) M H H 1Low, 2Medium, and 3High extent of use In general, administration to groups or pens of animals is defined as administration to a segregated group of animals within a building, house or feedlot, whereas administration to flocks or herds of animals is defined as administration to all animals within a building, house, feedlot. The sponsor may use another definition of these terms that is more reflective of relevant, current animal husbandry practices. D. The following are examples of additional risk management steps that may be associated with the approval of antimicrobial new animal drugs in food-producing animals. 1. Post-approval monitoring: Antimicrobial new animal drugs intended for use in foodproducing animals may be subject to monitoring through a post-approval process, such as the National Antimicrobial Resistance Monitoring System (NARMS). 2. Advisory committee review: When making an approval decision regarding a Category 1 or select Category 2 drugs, FDA may choose to convene an advisory committee to discuss the application. Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Risk Management 24 FDA believes that antimicrobial drugs ranked as high risk may be approvable if, after evaluating all supporting information, FDA can conclude that there is a reasonable certainty of no harm to human health when the drug is approved under specific use restrictions. Such a determination would be made on a case-by-case basis and based on a review of the entire application. FDA’s concerns associated with drugs estimated to pose high risk may be mitigated through the introduction of risk management steps that minimize resistance emergence or selection associated with any adverse impact on human health. FDA believes that antimicrobial drugs ranked as medium risk may be approvable if, after evaluating all supporting information, FDA can conclude that there is a reasonable certainty of no harm to human health when the drug is approved under specific use restrictions. Interpreting the medium risk category of drugs is more complex than the other categories, since the conclusions for the various risk assessment components are potentially more disparate (i.e., ranging from low to high). However, FDA believes it is appropriate to conclude that drugs in this category are associated with a level of risk that is intermediate between the high and low risk category drugs. Therefore, it is consistent to conclude that a finding of reasonable certainty of no harm might be reached for such drugs when use conditions are intermediately restrictive. Such a determination would be made on a case-by-case basis and based on a review of the entire application. FDA believes that antimicrobial drugs ranked as low risk may be considered approvable if, after evaluating all supporting information, FDA can conclude that there is a reasonable certainty of no harm to human health when the drug is approved under specific use restrictions. Such a determination would be made on a case-by-case basis and based on a review of the entire application. For a drug to be ranked as low risk overall, two of three major components of the risk assessment would have been ranked as low and the third component ranked moderate. FDA believes that a single medium ranking when the other two risk assessment components are ranked low should not substantially increase the overall level of risk. Therefore, combinations involving two low ranks and one medium are consistent with an overall risk estimation ranking of low. VII. Application of Risk Management Strategies: The integration process outlined above (Table 6) results in an estimation of the risk that the use of an antimicrobial new animal drug will adversely impact human health. The outcome of the risk estimation (high, medium or low) can be used to help identify steps necessary to manage the risks associated with the proposed conditions of use for an antimicrobial new animal drug. Examples of risk management steps and how these steps might be applied to manage the estimated level of risk are described below. Table 8 contains three categories (1, 2, and 3) which associate the overall drug risk estimation (i.e., high, medium, or low risk) with a set of possible Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Risk Management 25 risk management strategies. In general, Category 1 includes those drugs ranked “high” in the risk estimation, Category 2 includes those ranked “medium”, and Category 3 includes those ranked as “low.” However, certain cases may warrant alternative categorization. Table 8. Examples of potential risk management steps associated with the approval of antimicrobial new animal drugs in food-producing animals based on the level of risk (high, medium, or low). Approval conditions Category 1 (High) Category 2(Medium) Category 3 (Low) Marketing Status1 Rx Rx/VFD Rx/VFD/OTC Extra-label use (ELU) ELU Restrictions Restricted in some cases3 ELU permitted Extent of use2 Low Low, medium Low, medium, high Post-approval monitoring (e.g., NARMS) Yes Yes In certain cases Advisory committee review considered Yes In certain cases3 No 1Prescription (Rx), Veterinary Feed Directive (VFD), Over-the-counter (OTC) 2See Table 7 for characterization of extent of use 3These risk management steps may be appropriate for certain Category 2 drugs that were ranked critically important for consequence assessment and ranked “high” for release or exposure assessment As illustrated in Table 8, drugs in Category 1 are associated with a high risk ranking and would typically be subject to the most restrictive use conditions. Category 3 drugs have the lowest risk ranking and would typically be subject to the least limitations. Category 2 drugs, ranked intermediate for risk to human health, would typically be subject to limitations that are intermediate between those of Categories 1 and 3. Category 2 drugs (as described in Table 8) include several approval conditions that may or may not be applied to all drugs in the category. For example, the table indicates that restrictions limiting extra-label use may be considered for certain Category 2 drugs. The conditions listed for a given drug category in Table 8 are intended to provide an example of the conditions of use or limitations that FDA might expect to be associated with a drug product in that category. However, FDA’s final determination of the approvability of antimicrobial new animal drug applications will depend on a consideration of all information available for the drug application in question. FDA may determine that a proposed drug product can be approved under alternative use conditions/limitations Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Risk Management 26 proposed by the sponsor, if the sponsor provides adequate information to support the safety of the drug under those conditions. VIII. Summary of Microbial Food Safety Assessment Process FDA recommends that sponsors choosing to use this process: · Prepare a hazard characterization (described in pages 7 through 8) and submit the characterization to the FDA for review. · After review of the hazard characterization, FDA and the sponsor may discuss whether a risk assessment needs to be completed and, if so, what information is recommended for completion of the risk assessment. · Prepare the risk assessment and submit the assessment to the FDA for review. · Following review of the safety package as a whole, including the risk assessment, FDA will determine the risk estimation and associated risk management steps applicable to the proposed conditions of use for the antimicrobial new animal drug. Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Glossary 27 Glossary Consequence assessment: The consequence assessment describes the relationship between specified exposures to a biological agent (the hazardous agent) and the consequences of those exposures. For the purposes of this risk assessment, FDA has decided that the potential human health consequences of exposure to the defined hazardous agent may be estimated qualitatively by considering the human medical importance of the antimicrobial drug in question. Exposure assessment: The exposure assessment describes the likelihood of human exposure to the hazardous agent through food-borne exposure pathways. The exposure assessment should estimate qualitatively the probability of this exposure to bacteria of human health concern through food-related pathways. Hazard: Human illness, caused by an antimicrobial-resistant bacteria, attributable to an animalderived food commodity, and treated with the human antimicrobial drug of interest. Hazardous agent: Antimicrobial-resistant food-borne bacteria of human health concern that are in or on a food-producing animal as a consequence of the proposed use of the antimicrobial new animal drug. Hazard characterization: The process by which one may identify the hazard and the conditions that influence the occurrence of that hazard. This is based upon drug-specific information, bacteria/resistance determinant information, and the methodology for the determination of “resistant” or “susceptible” bacteria. Release assessment: The release assessment should describe those factors related to the antimicrobial new animal drug and its use in animals that contribute to the emergence of resistant bacteria or resistance determinants (i.e., release of the hazardous agent) in the animal. The release assessment should also estimate qualitatively the probability that release of the hazardous agent would occur. For the purposes of this assessment process, the boundaries of the release assessment span from the point the antimicrobial new animal drug is administered to the foodproducing animal, to the point the animal is presented for slaughter or the animal-derived food is collected. Risk: The probability that human food-borne illness is caused by a specified antimicrobial resistant bacteria, is attributable to a specified animal-derived food commodity, and is treated with the human antimicrobial drug of interest. Risk estimation: The overall estimate of the risk associated with the proposed use of the drug in the target food-producing animals following the integration of the release assessment, exposure assessment and consequence assessment. The risk rankings represent the relative potential for human health to be adversely impacted by the emergence of antimicrobial resistance associated in a food-borne pathogen with the use of the drug in food-producing animals. Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Appendix A 28 Appendix A Ranking of antimicrobial drugs according to their importance in human medicine Objective: This appendix describes a process for ranking antimicrobial drugs with regard to their relative importance in human medicine. FDA recommends this ranking be considered when completing the hazard identification and the consequence assessment portions of the qualitative risk assessment outlined in this guidance document. The general criteria for determining the importance ranking are outlined and a preliminary listing of various antimicrobial drugs and assigned rankings is provided. Ranking process: Based on a consideration of the factors described below, specific antimicrobial drugs or classes of antimicrobials should be ranked as to whether they are critically important, highly important, or important to human medical therapy. The assignment of a ranking to a given antimicrobial or class of antimicrobials is dependent upon the degree to which any one or more of the factors described below is applicable to the drug in question. Table A1 provides a ranking based on a consideration of the criteria described below. The possible importance rankings are defined as follows: Critically Important: Antimicrobial drugs which meet BOTH criteria 1 and 2 below. Highly Important: Antimicrobial drugs which meet EITHER criteria 1 or 2 below. Important: Antimicrobial drugs which meet EITHER criterio n 3 and/or 4 and/or 5. Note: Table A1 does not necessarily include all antimicrobial drugs or drug classes. The development of new antimicrobials for human therapy, the emergence of diseases in humans, or changes in prescribing practices, etc., are among the factors that may cause the rankings to change over time. Therefore, it is the intent of the Agency to reassess the rankings provided in Table A1 periodically to confirm that the ranking is consistent with current circumstances. The rankings of drugs in Appendix A may be subject to change at any time when information becomes available that would impact those rankings. The sponsor may wish to consult with FDA regarding the ranking relevant to their proposed drug at the time the assessment is made. Criteria considered in ranking process: In developing criteria for ranking antimicrobial drugs with regard to their importance in human medicine, the FDA considered broad issues associated with the efficacy of drugs in human medicine and factors influencing the development of antimicrobial resistance. Specific factors include the usefulness of the drug in food-borne infections, the types of infections treated, the availability of alternative therapies, the uniqueness of the mechanism of action, and the ease with which resistance develops and is transferred between organisms. Note that multiple factors may be applicable to some products, illustrating their considerable importance to human medicine. We recommend that drug sponsors use the Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Appendix A 29 following criteria to rank the importance of drugs in human medicine. The criteria are ranked from most to least important, e.g. criterion 1 is the most important. 1. Antimicrobial drugs used to treat enteric pathogens that cause food-borne disease The Infectious Disease Society of America (IDSA) guidelines on the treatment of diarrhea and other sources such as the Sanford Guide provide the drugs typically used in the treatment of food-borne diseases. 2. Sole therapy or one of few alternatives to treat serious human disease or drug is essential component among many antimicrobials in treatment of human disease. A. Includes antimicrobials like vancomycin and linezolid for MRSA infections. Although they are not the “sole” therapy, they are one of only a few alternatives. B. This would also include a drug like polymyxin where it is one of few alternatives for multi-drug resistant Pseudomonas aeruginosa infections. C. Rifampin is not only a drug used to treat TB but also it is an essential part of the treatment regimen as the cure rate is lower without it. D. Serious diseases are defined as those with high morbidity or mortality without proper treatment regardless of the relationship of animal transmission to humans. For example, rifampin is an essential drug to treat disease caused by Mycobacterium tuberculosis (high morbidity and mortality if untreated) even though this is a human pathogen. Gonorrhea occurs only in humans and is not lethal but can result in sterility if left untreated (high morbidity). 3. Antimicrobials used to treat enteric pathogens in non-food-borne disease Enteric pathogens may cause disease other than food-borne illness. For instance, E. coli, which causes food-borne disease, is also capable of causing diseases as diverse as urinary tract infections and neonatal meningitis. 4. No cross-resistance within drug class and absence of linked resistance with other drug classes A. Absence of resistance linked to other antimicrobials makes antimicrobials more valuable. An example is quinolone resistance in pneumococci, which currently does not appear linked to penicillin resistance. On the other hand, penicillin resistance appears to be linked to macrolide, tetracycline, and trimethoprim-sulfamethoxazole resistance in pneumococci. B. Cross-resistance within antimicrobial classes and absence of linked resistance may change over time and will need to be updated periodically. C. In this context, “cross-resistance” refers to the transmission of resistant determinants between bacterial species or genera and does not refer to transmission of resistant organisms between animals and humans. This is addressed in the release assessment part of the guidance. 5. Difficulty in transmitting resistance elements within or across genera and species of organisms A. Antimicrobials to which organisms have chromosomal resistance would be more valuable compared to those antimicrobials whose resistance mechanisms are present on plasmids and transposons. B. This does not refer to “ease of transmissibility” from animals to humans of the resistant pathogen as this is addressed elsewhere in the guidance in the release assessment. Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Appendix A 30 Table A1: Potential ranking of antimicrobial drugs/drug classes based on the identified relevant factors. C- Critically important; H- Highly important; I – Important. Classification 1) Enteric pathogen responsible for foodborn disease 2) Sole/limited therapy or essential therapy for serious disease (See "Comments" for examples) 3) Used to treat enteric pathogens in nonfood- borne disease 4) No cross-resistance within class/no linked cross-resistance w ith other classes 5) Limited risk of transmission of resistance elements within/across species of organisms Comments Natural penicillins H X Neurosyphilis: Serious infection due to Group A streptococci Benzathine pen G Penicillin G Penicillin V Penase Resistant Pens H X Serious infections due to Staphylococcus aureus Cloxacillin Dicloxacillin Nafcillin Oxacillin Antipseudomonal Pens H X X Serious infections due to Pseudomonas aeruginosa Mezlocillin Pipercillin Pipercillin/tazo Ticarcillin Ticarcillin/Clav Carbenicillin Aminopenicillins H X X Infections due to Listeria monocytogenes Amoxicillin Ampicillin Ampicillin/Sulbacta 1st Gen Ceph I X Cefazolin Cafadroxil Cephalexin Cephradine 2nd Gen Ceph I X Cefaclor Cefaclor-CD Cefamandole Cefonacid Cefprozil Cefuroxime Lorcacarbef Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Appendix A 31 Classification 1) Enteric pathogen responsible for foodborn disease 2) Sole/limited therapy or essential therapy for serious disease (See "Comments" for examples) 3) Used to treat enteric pathogens in non-food-borne disease 4) No crossresistance within class/no linked cross-resistance with other classes 5) Limited risk of transmission of resistance elements within/across species of organisms Comments 3rd Gen Ceph C X X X Meningitis: Necrotizing enterocolitis Cefdinir Cefixime Cefoperazone Cefotaxime Cefpodoxime Ceftazidime Ceftibuten Ceftizoxme Ceftriaxone 4th Gen Ceph H X X Sole agent approved for use as empiric monotherapy for neutropenic fever Cefepime Cephamycins I X Cefotetan Cefoxitin Carbapenems H X X Infections due to multidrug resistant gram negative rods Imipenem Meropenem Ertapenem Monobactams I X Aztreonam Quinolones I X X Nalidixic Acid Cinoxacin Oxolinic Acid Pipemidic Acid Flouroquinolones C X X X X X Infections due to multidrug resistant gram negative rods Norfloxacin Ciprofloxacin Ofloxacin Enoxacin Levofloxacin Lomefloxacin Sparfloxacin Grepafloxacin Gatifloxacin Moxifloxacin Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Appendix A 32 Classification 1) Enteric pathogen responsible for foodborn disease 2) Sole/limited therapy or essential therapy for serious disease (See "Comments" for examples) 3) Used to treat enteric pathogens in non-foodborne disease 4) No cross-resistance within class/no linked cross-resistance with other classes 5) Limited risk of transmission of resistance elements within/across species of organisms Comments Aminoglycosides H X X Amikacin Gentamicin Enterococcal endocarditis Tobramycin Sole antimicrobial approved for aerosolized therapy in cystic fibrosis Kanamycin Streptomycin Infections due to Mycobacterium tuberculosis Neomycin Netilmicin Spectinomycin Infections due to Neisseria gonorrhoeae in pregnancy Macrolides C X X Legionnaire's disease: MAC/MAI prophylaxis and therapy Erythromycin Azithromycin Clarithromycin Clindamycin H X Serious infections due to Group A streptococci: Alternative therapy of infections due to Staphylococcus aureus in patients with serious beta lactam allergy Tetracyclines H X Rickettsial disease: Anthrax therapy/prophylaxis Tetracycline Chlorteracycline Demeclocycline Doxycycline Minocycline Glycopeptides H X Infections due to methicillin resistant Staphylococcus aureus Vancomycin Streptogramins H X Infections due to vancomycin resistant Enterococcus faecium Dalfopristin/quinupristin Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS Appendix A 33 Classification 1) Enteric pathogen responsible for foodborn disease 2) Sole/limited therapy or essential therapy for serious disease (See "Comments" for examples) 3) Used to treat enteric pathogens in non-food-borne disease 4) No crossresistance within class/no linked cross-resistance with other classes 5) Limited risk of transmission of resistance elements within/across species of organisms Comments Oxazolidones H X X Infections due to methicillin resistant Staphylococcus aureus and vancomycin resistant Enterococcus Linezolid Pyrazinamide H X Isoniazid H X Rifamycins H X Rifampin Rifabutin Chloramphenicol H X X Metronidazole H X Infection due to Clostridium difficile Trimeth/Sulfameth C X X X Infection due to Pneumocystis carinii Polymyxin B H X X Infections due to multidrug resistant gram negative rods Guidance #152 CONTAINS NON-BINDING RECOMMENDATIONS References 34 References 1. 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