1. Use of antibiotics in livestock production in the light of new FDA guidelines Chris Rademacher, DVM ISU Swine Extension Veterinarian

2. Agenda FDA Guidance 209/213 regulations VFD Regulations Veterinary-Client Patient Relationship (VCPR) Summary

3. Definitions VFD o Veterinary Feed Directive: Simply a prescription for feeding medically important antibiotics in animal feeds VCPR o Veterinary Client Patient Relationship: The established relationship between a livestock producer and their veterinarian who oversees the animal health for that operation FDA o Food and Drug Administration: Regulates all approvals of antibiotic usage. OTC o Over the Counter: Purchasing antibiotics without a prescription Rx o Prescription: For the purchase and use of an antibiotic from a veterinarian.

4. Antimicrobial Regulatory Environment 6 key areas of change in the next 5 years: 1.Withdrawal of growth promotion uses of antibiotics 2.Expansion of antimicrobial use reporting 3.Legislative initiatives to remove antimicrobial class for prevention or control of disease in food animals 4.Increased sensitivity of FSIS residue testing (LS-HPLC) Penicillin example 5.Use of the AMDUCA regulations as a regulatory tool to attempt to decrease use of targeted drug classes in food animals 6.Potential for FDA/CVM hearing on the hazard status of the use of tetracyclines and penicillins (likely other drugs) in animal feed. Source: Mike Apley (KSU) – Global Vet Link Webinar May 2014

5. So how did we get here??

6. Antibiotic Usage Reporting – FDA 2012 Annually, each drug manufacturer must report the sales and distribution of antibiotics that are approved for use in food animals. Is reported by pounds of active ingredient Limitations: Not actual usage data Some drugs approved for food animals AND companion animals Veterinarians are authorized to change dose in non-feed related antimicrobials Not species specific. Most antibiotic usage is in mass medication format.

7. Antibiotic Usage Reporting – FDA 2012 Most of the antibiotic usage does NOT require a prescription from a veterinarian Rx/VFD = Veterinary Oversight OTC = “Over the Counter” No veterinary oversight necessary Most antibiotic usage does not require oversight by a veterinarian.

8. Summary of FDA Guidance 209/213 1.Limits “medically important antibiotics” to therapeutic purposes (to protect animal health and well-being). – Therapeutic Purposes Treatment Control Prevention 2.Non-therapeutic uses of medically important antibiotics are ILLEGAL – Improved growth and feed conversion http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement /GuidanceforIndustry/ucm042450.htm

9. Antibiotic Label Indications for Use Treatment o Defined as the use of an antibiotic for the treatment of animals showing clinical signs of disease. Control o Defined as the use of an antibiotic for the treatment of a group of animals where a percentage (usually >10% are sick) and the remainder of the group are not showing clinical signs (yet). Prevention o Defined as the use of an antibiotic in a group of healthy animals that are known to be at risk for, or exposed to, disease agents. Growth Promotion o Improves growth or feed efficiency

10. Antibiotic Use in Swine by Route and Indication Use and Route TreatmentControlPreventionGrowth Promotion Injectable XX Water Soluble XXX Feed Grade XXX Treatment, Control, Prevention = Therapeutic Growth Promotion = Non-therapeutic

11. Summary of FDA Guidance 209/213 3.Also states the importance of veterinary oversight into all on- farm antibiotic decisions. – Veterinary oversight will now guide all antibiotic decisions on the farm. All “medically important” antibiotics used in mass medication (feed/water) will have to be scripted (Rx) in their use. – Eliminates “Over the Counter” usage of medically important antibiotics used in mass medication (Feed and/or Water). No longer be able to purchase “medically important” antibiotics without a prescription (Rx) from a licensed veterinarian.

12. Summary of FDA Guidance 209/213 This means changing marketing status from OTC to Rx (Scripted) or VFD (Veterinary Feed Directive) – Water soluble products to Rx – “medicated water” – Products used in or on feed to VFD – “medicated feed” DOES NOT APPLY to injectable antibiotics

13. How do you determine if an antibiotic is “medically” important? FDA Guidance #152 (2003) Risk assessment for veterinary drugs creating “potential” resistance issues for human medicine. All scientific assessments done to date have demonstrated that the risk is negligible. Classified all antibiotics into 2 classes: Medically Important for Human Use Non-medically Important for Human Use http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement /GuidanceforIndustry/ucm042450.htm

14. Medically Important Feed Grade Antibiotics Antimicrobial ClassSpecific drugs approved for use in feed AminoglycosidesApramycin, Hygromycin B, Neomycin, Streptomycin DiaminopyrimidinesOrmetoprim LincosamidesLincomycin MacrolidesErythromycin, Oleandomycin, Tylosin PenicillinsPenicillin StreptograminsVirginiamycin SulfasSulfadimethoxine, Sulfamerazine, Sulfamethazine, Sulfaquinoxaline TetracyclineChlortetracycline, Oxytetracycline

15. Medically Important Water Soluble Antibiotics Antimicrobial ClassSpecific drugs approved for use in water AminoglycosidesApramycin, Gentamicin, Neomycin, Spectinomycin, Streptomycin LincosamidesLincomycin MacrolidesCarbomycin, Erythromycin, Tylosin PenicillinsPenicillin SulfasSulfachloropyrazine, Sulfachlorpyridazine, Sulfadimethoxine, Sulfamerazine, Sulfamethazine, Sulfaquinoxaline TetracyclineChlortetracycline, Oxytetracycline, Tetracycline

16. Antibiotics that are already VFD (Rx) based –avilamycin, florfenicol, tilmicosin; or Rx - Tylosin. Antibiotics that are not medically important: –Ionophores (monensin, lasalocid, narasin (Skycis,etc. ) –Bacitracin (BMD, bacitracin zinc) –Bambermycins (Flavomycin) Other drugs (that are not antibiotics), including: –Anthelmentics: Coumaphos, Fenbendazole, Ivermectin –Beta agonists: Ractopamine, Zilpaterol –Coccidiostats: Clopidol, Decoquinate, Diclazuril 16 Antibiotics NOT affected by Guidance 209/213

17. Injectable and Oral Antibiotics For Use In Swine Yellow = Medically Important Green = Non-medically Important

18. Swine Feed Grade Antibiotics Yellow = Medically Important Green = Non-medically Important (BMD) (Mecadox) (CTC – Aureomycin/Pennchlor 64) (OTC – Terramycin/LA 200/Pennox) (Denagard) (Stafac) (Flavomycin) Narasin (Skycis)

19. Drug*ManufacturerDoseCurrent Label Lincomycin®Zoetis20 g/TonIncreased rate of weight gain in growing-finishing swine Tylan®Elanco10-20 g/TonIncreased rate of weight gain in growing-finishing swine Stafac®Phibro5-10 g/TonIncreased rate of weight gain and improved feed efficiency So what feed grade antibiotic claims will be phased out? * Same for generic equivalents

20. Veterinary Feed Directive (VFD) Basically, it is a prescription for utilizing “medically important” antibiotics in animal feed. – Not technically a script, but functionally works the same It requires a VFD from a veterinarian who the producer has a valid VCPR with for their operation. – Veterinarian is responsible for filling it our correctly, based on the correct information the producer gets to them. Then the producer (or the veterinarian) will need to get the VFD to the feed mill to manufacture the feed.

21. Current VFD Drugs (2015) Currently Approved VFD Drugs Approved for Use in the Following Species Avilamycin (Kavault®) Swine – reduction of diarrhea – E. coli. Florfenicol (Nuflor®) Fish – control of mortality (various diseases by fish type) Swine – control of SRD Tilmicosin (Pulmotil®) Cattle – control of BRD Swine – control of SRD

22. Veterinary Feed Directive (VFD) Current requirements for Current Drugs (2015) o Written for amount of feed to be consumed in a time period o Original document required to the feed mill within 5 days o VCPR o Refills not straightforward o Keep records (mill, veterinarian, farmer) for two years

23. Veterinary Feed Directive (VFD) New requirements: o Vet name, address, phone o Client name, address, phone o Premises o Date of issuance o Expiration date - no longer than 6 months o number of refills (if allowed by label) o Drug/indication/dose/duration o Species and production class to be fed o Approximate number of animals to be treated

24. Veterinary Feed Directive (VFD) New Requirements: o VCPR o At discretion of State Pharmacy or Veterinary Practice Acts o Electronic signature and transmittal acceptable o Telephone VFDs will still not be allowed o Estimate of tons of feed no longer require o Replaced by number of days on feed

25. VFD Final Rule Previous Rule 2 year record retention Original document to mill No extra-label use Order for tons of feed No refills, unless on label Written for one group of animals on a premise VCPR required Revised Rule 2 year record retention May email or fax document No extra-label use Order for number of days No refills, unless on label Attached list of premises – For each mill State VCPR* required Max of 6 mo. expiration

26. Examples of “medically important” feed-use antibiotics that are expected to transition to VFD status Antimicrobial ClassSpecific drugs approved for use in feed AminoglycosidesApramycin, Neomycin, Streptomycin DiaminopyrimidinesOrmetoprim Hygromycin B LincosamidesLincomycin MacrolidesErythromycin, Oleandomycin, Tylosin PenicillinsPenicillin - Currently only production uses. StreptograminsVirginiamycin SulfasSulfadimethoxine, Sulfamerazine, Sulfamethazine, Sulfaquinoxaline TetracyclineChlortetracycline, Oxytetracycline

27. Expiration Date on VFD Expiration Date – o Specifies the period of time for which the VFD authorization is valid o A VFD feed should not be fed after the expiration date (i.e., after VFD authorization expires) o May be specified on the product label o If not – it cannot exceed 6 months after the date of issuance. o The veterinarian can use his or her medical judgment to determine whether a more limited period is warranted

28. Duration of Use for VFD Duration of Use: o A separate concept from the expiration date o The length of time that the animal feed containing the VFD drug is allowed to be fed to the animals o Established as part of the approval, conditional approval, or index listing process o If the VFD order will expire before completing the duration of use on the order, the client should contact his/her veterinarian to request a new VFD order http://www.fda.gov/animalveterinary/products/ animalfoodfeeds/medicatedfeed/bluebirdlabels /default.htm

29. Current VFD Drugs Currently Approved VFD Drugs Approved for Use in the Following Species VFD Expiration Date Duration of Use Avilamycin (Kavault®) Swine – reduction of diarrhea – E. coli.42 d21 d Florfenicol (Nuflor®) Fish – control of mortality (various diseases by fish type) 15 d10 d Swine – control of SRD90 d5 d Tilmicosin (Pulmotil®) Swine – control of SRD90 d21 d Cattle – control of BRD 45 d14 d

30. What about “combination drugs”? Combination drugs o An FDA approved label for the combination of different drugs into animal feed, whereby at least one of the antibiotics is classified as a “VFD drug” o VFD drug = “Medically important antibiotic” Example: Denagard® Plus o Tiamulin (Denagard®)– Not medically important antibiotic o Chlortetracycline (CTC) – Medically important antibiotic (VFD Drug) This combination is considered to be a VFD drug.

31. What is a Distributor? A ‘‘distributor’’ means any person who distributes a medicated feed containing a VFD drug to another person. – Such other person may be another distributor or the client-recipient of the VFD medicated feed. – There are two kinds of distributors: Only distributes VFD feed Manufactures and distributes VFD Feed Distributors must notify FDA: – Prior to the first time they distribute animal feed containing a VFD drug Acknowledgement letter sent to the FDA – Within 30 days of any change of ownership, business name, or business address

32. Distributor Responsibilities: File a one time notice with the FDA on intent to distribute FDA drugs – Must notify FDA if change in ownership, name or address Fill a VFD order, only if all the required information is present Retain all VFD orders for 2 years from date of issuance Retain records of the receipt and distribution of all medicated feeds containing VFD drugs for 2 years Obtain and hold for 2 years the acknowledgement letter if shipping feed containing VFD drugs to another distributor.

33. What about On Farm Feed Manufacturing? Will not need to register as a distributor unless producing feed for commerce Will need VFD to buy medicated premix (Type B) Will not be able to have medicated feed in bin after expiration of the VFD

34. Implementation Timeline Summary January 1, 2017 – Target for all medically important antimicrobials for use in or on feed to require a VFD – December 2016 – Target for drug sponsors to implement changes to use conditions of products affected by GFI #213 34

35. Vulnerabilities Antibiotic usage is going to be tracked NPB, NPPC and AASV are working with FDA to better define. Concerned that just modifying or even eliminating feed grade antibiotics for growth promotion won’t move the needle much. Will get challenged on prevention and control claims next. Need to sure you have good documentation for justification Water antibiotic usage is a weakness Easily managed at the site or service manager level. Easier to treat the group vs. pro-actively do individual pig treatments.

36. Summary FDA Guidance 209, 213, VFD already being implemented No growth promotion of medically important antibiotics More veterinary oversight into antibiotic usage (VFD) VFD will be required for all “medically important antibiotics” to be used in feed. These regulations will be fully into effect by January 1, 2017 We have less than a year to get these changes in place.

37. Acknowledgements: Dr. Liz Wagstrom – NPPC Veterinarian Dr. Mike Murphy – FDA/CVM