NECC2202: Formal Structure for the Minor Use Animal Drug Program
(Multistate Research Coordinating Committee and Information Exchange Group)
NECC2202: Formal Structure for the Minor Use Animal Drug Program
Duration: 10/01/2022 to 09/30/2027
Statement of Issues and Justification
The need, as indicated by Stakeholders.
The Minor Use Animal Drug Program (MUADP) currently has eight active projects in therapeutics and production devices for game birds, goats, sheep, and fish that have been requested and are supported by representative stakeholders. Through the nearly 39 years of the Program, stakeholders have requested work on 40 drug/species combinations. During this period the Program has published 43 Public Master Files (PMF) supporting 59 new label claims and has published 211 peer-reviewed, scientific articles. Moreover, 18 stakeholder drug requests continue to represent needy projects. Thus, the stakeholder needs exceed the current resources available to the Program.
The importance of the work, and what the consequences are if it is not done.
United States gross annual farm-gate income from the production of specialty animal species has been estimated by producer groups at over $4.8 billion. Further, these farm gate revenues produce an economic stimulus to the US Gross Domestic Product estimated at another $37 billion. Federal regulations over the concerns of human food safety, inappropriate drug usage, and antimicrobial resistance underscore the need for research in the approval of additional safe and effective therapeutics for our sheep, goat, farmed shrimp and fish, venison, honey, and game birds.
Moreover, recent increasing consumer demand for minor species in the diet will engender greater scrutiny of minor species foodstuffs. Much of our current commercial minor species food and fiber products, however, are imported. One-third of the lamb and 82% of venison consumed in the US comes from Australia and New Zealand. Nearly 90% of the commercially farmed shrimp are imported from Asia. Additionally, two-thirds of the honey consumed in the US is imported and half of that honey comes from China. The MUADP is the only initiative that endeavors to provide the US minor species animal producers with safe and effective therapeutics to compete in a global market while assuring US consumers a safe and wholesome food supply.
Improper drug use in animal agriculture has been identified as one of several major forces that are likely to impact the security of the US agriculture and food system enterprise in the coming years. The National Institute of Food and Agriculture (NIFA) has recognized that a major initiative to protect the biosecurity of our nation's food systems is timely, necessary, and worthwhile. The data provided by the MUADP is an essential part of the NIFA initiative and funding of the Program is critical to performing this function.
Loss of the MUADP will adversely affect the biosecurity and agricultural diversity of our nation's food systems, and create potentially serious disruptions to business and trade. Further, it will also diminish protections for producers, consumers, the food and agricultural system, and the national economy as a whole.
The technical feasibility of the research.
The Program has over 39 years of experience in the development of data to satisfy the U.S. Food and Drug Administration's Center for Veterinary Medicine (FDA/CVM) regulatory requirements for a minor species drug approval. Currently, the Program is comprised of a knowledgeable team with the skills and reputations to network with stakeholders, industry groups, and regulatory agencies. Its physical assets include university-based research facilities with up-to-date technology and a loyal stakeholder base with additional access to commercial production facilities for research support. The university-based structure of the Program provides personnel policies that establish quality performance. Its direct interaction with FDA/CVM personnel ensures adequate protocol design and timely review.
The MUADP accomplishments speak to the technical feasibility of the proposed research, which is structurally similar to its past. The Program has published 43 Public Master Files (PMF) supporting 59 new label claims and has published 211 peer-reviewed, scientific articles during the 39 years of the program.
The advantages for doing the work as a multistate effort.
There are several advantages for the MUADP to function as a multistate effort. These advantages emerge from the requirements of FDA/CVM to perform efficacy studies at multiple regional locations, and the geographically dispersed nature of commercial minor species farming throughout the country. As currently organized, the MUADP is staffed through regional laboratories at colleges of veterinary medicine in each of two regions, the Northeast and North Central. These regions are recognized centers of excellence for minor species. The Northeast is a center of excellence for aquaculture, while the North Central coordinates research in game birds, sheep, and goats. The Regional Coordinators and associated faculty at their colleges have professional relationships with commercial minor species farms in their respective regions. The Cornell University College of Veterinary Medicine has an excellent facility and have conducted many therapeutic trials with marine finfish species including three AQUI-S20E (10% eugenol) target animal safety studies over the last three summers utilizing artificial seawater. In 22Q3 the Northeast Region is funded to test the margin of study for AQUAFLOR (florfenicol) medicated feed on marine finfish as well. Thus, through these relationships, a multistate network of minor species stakeholders exists. Utilizing these networks, stakeholders provide input as to needed therapies and in-kind support for clinical trials. These professional, multistate networks have provided the basis for the dramatic efficiency of the Program.
What the likely impacts will be from completing the work.
Continued maintenance of a formal structure for the MUADP will prevent the loss of the 88 Investigational New Animal Drug files (INADs) at the FDA/CVM that will be scheduled to terminate for lack of a sponsor. The loss of these INADs will result (1) in a collective loss of work estimated at over $5 million and (2) loss of stakeholder incentive to provide support for the Program.
Continued research on the current eight active projects in the program will introduce safe and effective therapeutics for gamebirds, goats, sheep, and fish. The resulting increase in domestic production will decrease the US reliance on imported foodstuffs and help protect the safety and food security of the domestic food supply.
Likely impacts of our current and anticipated projects include (1) protecting human food safety and security; (2) preventing and controlling local zoonotic diseases in both major and minor species; (3) stimulating small farm economy; (4) increasing the diversity of our agricultural base to include important specialty species; and (5) maintaining the health and welfare of agriculturally important specialty animal species in the US.
Provide the formal structure necessary to maintain the 88 investigational new animal drug INAD files held in the name of the MUADP.
Comments: Accomplishments to date: The 88 INAD files continue to remain active and support needed drug/species combinations for minor species. The MUADP is currently working with the Minor Use Minor Species (MUMS) program of CVM to obtain sponsors for these outstanding INAD files.
Continue Animal and Plant Health Inspection Service, U.S. Department of Agriculture funded research on cattle fever tick and sheep drug approvals.
Comments: Accomplishments to date: The cattle fever tick project has been completed and data have been shared with Animal and Plant Health Inspection Service, U.S. Department of Agriculture and the manufacturer is working with Food and Drug Administration/Center for Veterinary Medicine on an acceptable manufacturing process. Positive Feeds (The Sponsor) now needs to complete the Chemistry and Manufacturing Controls (CMC) Technical Section of the application. The CMC is only in its initial stages of preparation and should have been done significantly earlier in the study, but due to delays in sponsor submissions, this program has failed to advance. Both CVM and the Program are working to maintain project momentum. It is ideal to have the CMC approved prior to submission of the efficacy study report. The work of the Program is complete for this study. See attached Table 1 for a summary of MUADP active projects.
In conjunction with NIFA and stakeholders, identify a stable funding source to work with the FDA/CVM to facilitate their approval of animal health products and provide information for the safe and efficacious use of these materials in specialty animal species.
Comments: Accomplishments to date: Over the past 18 months, the Program has participated in the formation of the Tactical Sciences Network (TSN) under the direction of Dr. Martin A. Draper, Associate Dean, Research and Graduate Studies, College of Agriculture, Director, Research, K-State Research and Extension, Kansas State University. The TSN is intended to bring together independent projects that are all closely linked to directly benefit end users. The projects are largely associated with biosecurity, touching on plant health, animal health, antibiotic resistance, animal drugs for less common livestock species, tracking drug residues in livestock, food safety, education for disaster response and various levels of crop pest management which include researchers, regional clearinghouses or centers and state programs. Through this new association, the Program has submitted a budget of $2.5M per year to complete work on several of the current active projects. Funding is anticipated through NIFA.
Procedures and Activities
Dr. Rodman G. Getchell has obtained funding of $200,000 over two years through U.S. Department of Agriculture (USDA), National Institute of Food and Agriculture (NIFA), and Agriculture and Food Research Initiative (AFRI): USDA-NIFA-AFRI-Funding Opportunity Number 007052 in the animal health program area under “Therapeutic interventions for disease reduction or treatment.” Researchers within the Cornell University Aquatic Animal Health Program and USFWS Aquatic Animal Drug Approval Partnership (AADAP) program will continue a collaboration to conduct studies to increase the number of safe and effective drugs that can be used to benefit the U.S. aquaculture community. Trials will be conducted with Florfenicol (AQUAFLOR®), Oxytetracycline (TM200), and Hydrogen peroxide (Perox-Aid®), which are used to treat diseases and parasites of fish.
Drs. Griffith and Kreuder have been granted $500,000 over two years: Kreuder AJ, Plummer PJ, Smith JS, Griffith RW. Efficacy of tulathromycin for treatment of respiratory disease in goats: a final step towards label approval. USDA NIFA. 7/1/21 - 6/30/23. $499,872.
Work accomplished under the original project
- As part of the coordinated effort to generate data to support approval by FDA/CVM, Cornell University researchers has conducted a series of studies under a recently submitted protocol to FDA/CVM (AQS20E-18-SEA-TAS.2b) to evaluate the safety of AQUI-S®20E (10% eugenol) used to sedate marine fish to the handleable stage of anesthesia in saltwater. The objective of these studies is to evaluate the safety of AQUI-S®20E to saltwater-reared marine finfish when overexposed to either the HEC (1×) or 1.5× the highest proposed efficacious dose. The results of these safety studies will be used to complete the target animal safety (TAS) technical section data requirements for marine finfish and ultimately support a New Animal Drug Application to FDA/CVM to approve the use of AQUI-S®20E for sedation in all finfish.
- The Striped Bass Final Study Report has been prepared and submitted to the FD/CVMA "drug sponsor", which is different from the NIFA funding support. The report, photos, and summary tables are 160 pages long and the appendices with additional tables, figures, data analyses, and histopathology and quality assurances reports are included in the next 700 pages. This large document is required as part of the technical section for addressing animal safety, which is needed for eventual licensing of the new sedative under study in this project.
- In the second year of our USDA NIFA study titled, “The Safety of AQUI-S®20E as a Sedative on a Variety of Marine Finfish at Cornell University” we have made major progress responding to FDA requests for information about our data from the striped bass trials we collected in 2019 and we were able to conduct the Florida pompano trials even with the delays getting access to our laboratories because of COVID-19. We have completed the histological evaluations, most of the data analysis, final study report writing, and presenting our results to our stakeholders during the virtual AADAP Meeting that occurred August 27-29, 2021. Manuscript preparation has started, but is waiting for all the second-year data to be tabulated and analyzed.
- The Target Animal Safety technical section entitled, The Safety of AQUI-S® 20E as a Sedative on a Variety of Marine Finfish” at Cornell University. (Study Number 2019-001) was accepted at FDA/CVM and the Summary Freedom of Information document is being prepared at the Agency.
- Strontium Chloride immersion for salmon: MUADP continues collaboration with our research partner, Syndel USA, to generate the data necessary to obtain FDA approval of strontium chloride hexahydrate immersion for the skeletal marking of freshwater salmonid fry and fingerlings.Fishery managers need a method to chemically mark salmon to determine migration patterns while avoiding the stress of tagging or other physical markings. While there are other drug products approved for skeletal marking in salmon, this project provides a non-antimicrobial alternative.
- Target Animal Safety: Dr. Rod Getchell, Northeast Regional Coordinator for the MUADP, completed a GLP Target Animal Safety study evaluating strontium chloride hexahydrate immersion for the skeletal marking of freshwater salmonid fry and fingerlings.
- In May 2019, CVM determined that the Target Animal Safety technical section was complete for this indication.
- Fenbendazole in quail: MUADP continues collaboration with our research partners, Dr. Ron Kendall of Texas Tech University and Merck Animal Health, to generate the data necessary to obtain FDA approval of fenbendazole-medicated feed for the treatment of nematodes in quail. This project has impact for both wild quail and farmed quail. Wild quail populations have declined by more than 85% in the last five decades. While many causes for the decline have been proposed, this project addresses the potential role of parasitism. Field studies conducted by Dr. Kendall have shown that fenbendazole is effective against common parasites in quail. The ongoing research will also support FDA approval for the use of fenbendazole in farmed quail. There are currently no anthelmintics approved for use in quail. Successful completion of this project will provide access to a class of therapeutic drugs previously unavailable to quail farmers.
Other work completed or ongoing
Human Food Safety = COMPLETE
Target Animal Safety = COMPLETE
Environmental Impact = FDA/CVM reviewing the Environmental Assessment
Controlled Internal Drug Release (CIDR) device that releases progesterone /goats:
Human Food Safety = COMPLETE
Target Animal Safety = COMPLETE
Environmental Impact = COMPLETE
Effectiveness = Current plan is to write up the study and submit to FDA/CVM
Human Food Safety = COMPLETE
Target Animal Safety = COMPLETE
Environmental Impact = Environmental assessment requires administrative revisions
Effectiveness = Work ongoing on White Paper to reaffirm the technical section complete letter received in 1998, so that the indication can be broadened to all salmonids, as opposed to only Chinook
Work that is incomplete, or areas in need of further investigation
- The first year of our AQUI-S 20E target animal safety study with Yellow Clownfish is underway.
- Tulathromycin study to demonstrate efficacy in sheep and goats.
- Lasalocid develop residue method and resubmit target animal safety.
- The Program will continue to review and prioritize active projects in conjunction with stakeholder needs.
- Establish stronger outreach to stakeholders as drug approvals continue to increase; and coordinate with CVM Minor Use Minor Species (MUMS) program to work with new, interested sponsors to address some of the 88 outstanding files.
Getchell, Rodman G., D.M. Scott, B.M. Chambers, N. Wandelear, P.R. Bowser, P. Baneux, D. Kirby, H. Marquis, and M. Blair. 2020. The Safety of AQUI-S® 20E (10% Eugenol) as a sedative on marine fish. Aquaculture America 2020, February 9-12, 2020, Honolulu, HI.
Getchell, Rodman G., Danielle M. Scott, Brian M. Chambers, Niccole Wandelear, Paul R. Bowser, Philippe Baneux, Drew Kirby, Hélène Marquis, and Marilyn Blair. 2019. The safety of AQUI-S® 20E (10% Eugenol) as a sedative on a marine finfish. Aquatic Animal Drug Approval Partnership (AADAP) Program U.S. Fish and Wildlife Service,August 31, 2019 Bozeman, MT
Gorden P, Ydstie J, Kleinhenz M, et al.: Comparative plasma and interstitial fluid pharmacokinetics and tissue residues of ceftiofur crystalline‐free acid in cattle with induced coliform mastitis. Journal of Veterinary Pharmacology and Therapeutics. 2018;41.
Smith J, Borts D, Griffith R, Mochel J: Pharmacokinetics of tulathromycin in healthy goats and goats with induced Pasteurella multocida pneumonia2018.
Smith J, Mochel J, Borts D, Griffith R: Effects of experimentally induced respiratory disease on the pharmacokinetics and tissue residues of tulathromycin in meat goats. Journal of Veterinary Pharmacology and Therapeutics. 2019;42.
Smith J, Mochel J, Seo Y-J, Ahrens A, Griffith R: Evaluation of a Pasteurella multocida Respiratory Disease Induction Model for Goats (Capra aegagrus hircus). Vol 702020.
Smith J, Viall A, Breuer R, et al.: Preliminary Investigation of Bovine Whole Blood Xenotransfusion as a Therapeutic Modality for the Treatment of Anemia in Goats. Frontiers in Veterinary Science. 2021;8:1-7.
Xia J, Pang J, Tang Y, et al.: High prevalence of fluoroquinolone-resistant Campylobacter in sheep and increased Campylobacter counts in the bile and gallbladder of sheep medicated with tetracycline in feed. Applied and Environmental Microbiology. 2019;85.
Yaeger M, Mochel J, Wu Z, et al.: Pharmacokinetics of tulathromycin in pregnant ewes (Ovis aries) challenged with Campylobacter jejuni. PLOS ONE. 2021;16:e0256862.
Yaeger M, Wu Z, Plummer P, et al.: Experimental evaluation of tulathromycin as a treatment for Campylobacter jejuni abortion in pregnant ewes. American journal of veterinary research. 2020;81:205-209.
Publication in preparation
Getchell, Rodman G., et al.: Three AQUI-S20E (10% eugenol) target animal safety studies are in preparation for publication in 2022, and the AQUAFLOR (50% florfenicol) marine finfish safety research will be submitted for publishing in 2023-2024.
Expected Outcomes and Impacts
- The Program will continue to work with the TSN under the direction of Dr. Martin A. Draper, to establish a more reasonable and secure source of funding through National Institute of Food and Agriculture.
- The continued development of drug approvals for minor species through the MUADP will contribute to addressing critical issues as noted below. Comments: • Protect human food safety and biosecurity • Prevent and control local zoonotic diseases in both major and minor species • Stimulate small farm economy • Increase the diversity of our agricultural base to include important specialty species • Ensure the health and welfare of agriculturally important specialty animal species in the US.
Projected ParticipationView Appendix E: Participation
Education of stakeholder groups through peer-reviewed publications and presentations of data generated by the Program are used to combat the disinformation on minor species therapeutics and husbandry generated through social media. These efforts create feedback loops enabling robust stakeholder interactions thereby increasing cross collaborations/coordination between different minor species organizations.
The Program also provides educational opportunities for graduate students, interns and summer fellows. For example, the 2019 AQUAVET® Summer Fellow, DVM student Danielle Scott returned for a second summer and took on evenmore responsibility conducting the target animal safety study utilizing Good Laboratory Practices. Ms. Scott has drafted the materials and method section of the upcoming journal publication. A second DVM, Kyara Moran Cornell Class of 2023, completed many of the 2020 data tables during COVID from her home in Miami.
The recommended Standard Governance for multistate research activities includes the election of a Chair, a Chair-elect, and a Secretary (Dr. John Babish). All officers have maintained their positions over the course of the Program and will continue through the next term to provide continuity. Administrative guidance is provided by an Administrative Advisor, Dr. Margaret Smith, and a NIFA Representative, Dr. Tim Sullivan.
The interrelationship of the groups involved is represented schematically in Figure 1 (see attachments). The Coordinating Committee in Figure 1 consists of representatives of the universities, and stakeholders (FDA/CVM, producers and pharma). Responsibilities of the Coordinating Committee include the selection of drug/species research and consulting on progress of the studies. Members also disseminate information on the program through presentations, publications and social media. Zoom meetings of AA, NIFA, FDA/CVM and university personnel are held roughly every six to eight weeks. Program representatives also participate in Zoom meetings of the Tactical Sciences Network under the direction of Dr. Martin A. Draper, Associate Dean, Research and Graduate Studies, College of Agriculture, Director, Research, K-State Research and Extension, Kansas State University.
All MUADP studies are conducted under a series of government regulations and standards. These include FDA Good Laboratory Practice for Nonclinical Laboratory Studies (GLP), Good Clinical Laboratory Practice (GCLP), and Institutional Animal Care and Use Committee (IACUC) regulations. Few academically-based programs have qualified to meet such an array of regulations successfully.
Tactical Sciences Network proposal: [https://portal.nifa.usda.gov/web/crisprojectpages/1019623-tactical-sciences-coordination-network-to-enhance-plant-and-animal-health-and- biosecurity.html]
U.S. total lamb and mutton imports and exports from 2006 to 2021 [https://www.statista.com/statistics/194707/us-total-lamb-and-mutton-imports-and-exports-since-2001/]
US Shrimp Imports - Study of Shrimp Market with Shrimp Buyers in US [https://www.exportgenius.in/blog/us-shrimp-imports-study-of-shrimp-market-with-shrimp-buyers-in-usa285.php#:~:text=Shrimp%2C%20which%20comes%20under%20HS%20Code%20030617%2C%20is,metric%20tons%20of%20shrimps%20from%20the%20global%20countries]
USA imports 60% of its honey [https://soltegra.com.mx/en/the-united-states-leads-the-world-in-honey-imports/]