U.S. Food and Drug Administration

1. U.S. Food and Drug Administration Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

2. 21 CFR 558.15 “Studies”: A brief history Jeffrey M. Gilbert, Ph.D. Microbial Food Safety Team (HFV-157) Center for Veterinary Medicine

3. Situation in the 1960s Issue: What is the impact of antimicrobial drug use in animals on the potential development of antimicrobial resistant, zoonotic foodborne pathogens, and their subsequent transmission to humans as food contaminants?

4. In the 1970s... Antibiotic in Animal Feed Task Force (FDA) The task force was formed to address safety and effectiveness issues associated with antibiotics administered in animal feed.

5. Task force findings: • Therapeutic Abx used to relieve animal disease thought to pose a small risk (high dose/short duration in young animals) • The benefits to animals were thought to outweigh potential risks to humans • Identifiable need for using Abx in animals to relieve pain and suffering • Healthy animals = safer food supply

6. Task force conclusions: Pre-approval studies are needed to support microbiological safety of Abx in food-producing animals intended for sub-therapeutic uses only, including growth promotion and feed efficiency.

7. Title 21 CFR Part 558.15 1) Sponsors of Abx are required to submit study results demonstrating that their product does not promote bacterial drug resistance, only when their product is intended to be administered for greater than 14 days, and for non-prescription use in food-producing animals

8. 21 CFR 558.15 (b) (1) - (b) (3) 2) Sponsors are required to submit all information to the Agency on the impact of their drugs on the Salmonella reservoir in food-producing animals by specified dates depending on the drug class

9. 21 CFR 558.15 by July 19, 1973... “…records and reports of completed, ongoing, or planned studies, including protocols, on the tetracyclines, streptomycin, dihydrostreptomycin, penicillin, and the sulfonamides…”

10. 21 CFR 558.15 by October 17, 1973... “...records and reports of completed, ongoing, or planned studies, including protocols, on all other antibiotics…”

11. 21 CFR 558.15 by March 4, 1974... “...records and reports of completed, ongoing, or planned studies, including protocols, on nitrofurans…”

12. 21 CFR 558.15 by April 20, 1974... “...data from completed studies on the tetracyclines, streptomycin, dihydrostreptomycin, the sulfonamides, and penicillin assessing the effect of the subtherapeutic use of these drugs in the feed on the Salmonella reservoir in the target animal as compared to that in non-medicated controls…”

13. 21 CFR 558.15 by April 20, 1975... “...data satisfying all other specified criteria for safety and effectiveness, including the effect on the Salmonella reservoir for any antibiotic or sulfonamide drug approved for sub-therpeutic use in animal feeds…”

14. 21 CFR 558.15 by September 5, 1975... “...data satisfying all other specified criteria for safety and effectiveness, including the effect on the Salmonella reservoir for the nitrofuran drugs approved for sub-therapeutic use in animal feeds…”

15. 21 CFR 558.15 Study design • Studies were a set, including a shedding and resistance component • Studies included a negative control and a treated group • Animals were inoculated with a lab strain of Salmonella typhimurium (NAL resistant) • Strain free of transferable R elements

16. 21 CFR 558.15 Study design (cont’d) • Salmonella wereenumerated and tested for susceptibility • E. coli were tested for susceptibility • Studies were generally 8 weeks long • Test animals were not required to be near market age or weight

17. Parameters examined were: • Drug effect on pathogen quantity, prevalence, and duration of shedding • Drug effect on Salmonella antibiotic susceptibility • Drug effect on resident E. coli antibiotic susceptibility

18. FDA guidance on 558.15 studies • Guideline 18 - Human Health Safety Criteria • Guideline 19 - Animal Health Safety Criteria Guidelines were the product of the task force Guidelines can be found at: http://www.fda.gov/cvm

19. Integrity measurements evaluated: • Did the product have Abx properties? • Cross-contamination? • Animal numbers sufficient? • Enough drug consumed to test highest proposed dose? • Any other drug(s) given? • Any naturally occurring Salmonella present?

20. Integrity measurements evaluated (cont’d) • Salmonella marker stable? • Could Salmonella receive R factors? • Could Salmonella colonize the animals? • Appropriate micro methodology used? • What tissues were examined? • How often were samples taken? • Was study length adequate?

21. RESULTS (TOTALS reflective of final decision) Drug class Total Drug/Animal Pass Fail Reject ____________________________________________________________ Macro/Linco 9 4/3 4 2 3 Ionophores 13 7/3 10 0 3 Unclassified Gm+ 15 6/3 9 2 4 Streptogramins 1 1/1 1 0 0 Glycopeptides 2 2/1 1 0 1 Bambermycins 2 1/2 2 0 0 Broad spectrum 2 2/2 1 1 0 ____________________________________________________________ TOTALS 44 28 5 11

22. Studies REJECTED because... • Salmonella or coliform susceptibility results not submitted • Susceptibility test QC inadequate • Shedding too long to measure prevalence or duration • Environmental control animals contaminated or not included

23. Studies REJECTED because...(cont’d) • Animals failed to meet inclusion criteria • Data too disorganized to interpret • Too few animals in study

24. Problems identified following retrospective analysis: • Drug spectrum matched Salmonella and E. coli in 2/44 study sets • Limited info on susceptibility changes in naturally occurring flora • Artificially high inocula • Lab strain of Salmonella not representative • Small numbers of animals tested

25. Summary • Most studies that failed did so due to pathogen shedding • Problems with design and interpretation • Based on policy and regulation of the time • History helpful in steering current and future efforts on this topic