CVM VMAC Experience with 558.15 Studies

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CVM VMACExperience with 558.15 Studies

• Thomas R. Shryock, Ph.D.
• Elanco Animal Health
• January 23, 2002

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Discussion Outline

• 558.15 Study Protocol Review
• Actual experience with 558.15 salmonella shedding
  studies
• Limitations of salmonella shedding studies
• Lessons learned
• Relevance to Proposed Pathogen Load studies
• Conclusions

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21 CFR 558.15 Studies1970 FDA Task Force report
rationale to test test in-feed antimicrobials for
effects on salmonella
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21 CFR 558.15 StudiesObjectives

• For salmonella shedding studies a sponsor must
  show
• drug does not adversely impact quantities,
  prevalence or duration of salmonella shed (over
  baseline non-med control).
• Drug does not increase salmonella or coliform
  resistance (over baseline non-med control) to
  drugs used in either human or animal medicine
• 558.15 regulation gives no specifics in study
  design or expectations for the type of data to be
  submitted for CVM review. Sponsors were to
  consult with CVM

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Industry Experience with Conducting 558.15 Studies

• FDA required for feed additive for gt 14 days
• Salmonella shedding (Quantities, Prevalence,
  Duration) tissues at study end
• Antibiotic resistance of salmonellae and
  coliforms
• Most studies done by C.A.R.E. (Dr. Fagerberg)
• Initially a single study to assess all parameters
• Evolved to salmonella study separate coliform
  study
• Currently 3 studies
• Salmonella Quantitation (high dose challenge)
• Salmonella Prevalence Duration (lower challenge
  dose)
• Coliform Resistance Study

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General Study Timeline
Fast 12-24h Challenge 2X Feed (Med or Non-med)
High Challenge 1011 cfu Low Challenge 106 cfu
Day -14 -7 -1 0 1 4 7
14 21 28 35 42 49
56 Culture X X X X X
X X X X X X X
X Weigh X X Intake X X
X X X X X X
X X X X Clin ObX X X
X X X X X X X
X X X X Necropsy
X liver, spleen, MLN, cecal Note Quant-4 week
study, Prev/Dur 8 week study
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General Salmonella Study Design
Animals-SPF or Salmonella-free, lt20 baseline
resistance in E. coli Salmonella-NalR strain
specific to animal species on test Antibiotics-12
(AG, b-lactams, phenicol, quinolone, sulfa,
tet) MICs determined Feed- Requires validated
analytical feed assay Requires dose from
efficacy studies Requires formulated premix
product Study Groups 10-12 animals/group,
housed individually Med, Env. Control, Non-med.
Separate caretakers, strict biosecurity Isolati
on cage - minimal coprophagia GLP Study
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Industry Experience with 558.15 Studies
Discovery Development
Product Support
Submission
Approval
Find New Technology A. Target I.D. Screen
Dev B. Screen Opt Early SAR C. New Screens
Lead Optimization A. Select Final
Chemistry B. Formulation C. Candidate
Selection D. Toxicology

• Product
• Development
• Non Clinical
• Clinical
• Data for CMC

Registration Activities
Sales
558.15 studies
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General Coliform Resistance Study Design
Animals-SPF or Salmonella-free, lt20 baseline
resistance in E. coli No salmonella
challenge Antibiotics-12 (AG, b-lactams,
phenicol, quinolone, sulfa, tet) Feed-same ration
lot for medicated and non-medicated Study
Groups 10-12 animals/group, housed
individually Med, Non-med. Separate
caretakers, strict biosecurity Isolation cage -
minimal coprophagia
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Interpretation Issues Pass-Fail for Candidate

• Statistical significance vs. biological
  significance interpretation evolved from Larry
  Rollins, CVM
• Pass if med. Vs. non-med. Groups had
• Salm Quantitation lt 1-2 logs difference
• Salm Prevalence lt20-30 difference
• Salm Duration lt7-10 days difference
• Antibiotic Resistance Moot Point (no differences
  ever observed)
• Unclear if all 3 salmonella parameters, or just
  2, had to be within "bounds" to Pass the molecule
• No scientific evidence that these criteria
  actually relate to farms, meat, or illness

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Industry Experience with 558.15 Studies Failure
of 558.15 studies kills the candidate molecule in
late Development Phase
Discovery Development Product Support
Phase I Phase II Phase III
Phase lV
Submission
Approval
Find New Technology A. Target I.D. Screen
Dev B. Screen Opt Early SAR C. New Screens
Lead Optimization A. Select Final
Chemistry B. Formulation C. Candidate
Selection D. Toxicology

• Product
• Development
• Non Clinical
• Clinical
• Data for CMC

Registration Activities
Sales
558.15 studies (GLP) Formulated Premix
(GMP) Validated analytical feed assay method Dose
selected
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Industry Experience with Conducting 558.15 Studies

• Most drugs tested were G active, all in-feed
• Baseline resistance (lt20 rule) in coliforms in
  test animals is difficult to achieve
• 73 Pass rate variety of antibiotic classes
• Failure of studies may be due more to
  interpretation of "borderline" data than a
  biologically significant "shedding"
• A failed study could be repeated and be passed
• If Pass in one species, usually pass in others
• "Study Creep"
• One initial study became 3 separate studies
• Separate series of studies for each species of use

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Study Limitations

• Relationship of test model results to commercial
  farms has not been established
• Relationship of test model results to carcass
  contamination levels was not established
• Relationship of test model results to public
  health was not established
• Only one strain of salmonella tested for
  "shedding"
• Salmonella given prior to medication would
  sequester intracellularly, bypassing normal flora
  (minimized by fasting).
• High-challenge dose is unrealistic exposure
• Overcomes protective flora, causes disease
• Sick animals don't eat as much

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Model Study vs. Field Situation

• The field situation is considerably different
• Animals previously exposed (immune) or no
  salmonella present
• Natural, continuous exposure, often at young age
• Small proportion of herd/flock culture positive,
  many undetected carriers
• Antibiotic superimposed in presence of low levels
  of shedding
• Antibiotic administered to diseased and stressed
  animals
• Housing, biosecurity, environment are not
  "research grade" status
• Model study cannot "factor in" these real world
  situations, nor predict what will happen there.

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558.15 Lessons to apply to Proposed Pathogen Load
Studies

• Only database so far is for in-feed medication
  for multi-week studies with salmonella challenge
• No experience with higher doses, other routes,
  shorter durations or post-medication withdrawal
  effects
• Therapeutic drugs usually given weeks to months
  before slaughter. When to sample? Relevance?
• No experience with other foodborne pathogens-will
  multiple studies be needed ("study creep")?
• Very little experience with broad-spectrum drugs
• G- spectrum likely to decrease shedding!
• Biological variation occurs in individual
  animals results may not always be clear-cut for
  interpretation.

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Other Lessons to apply to Proposed Pathogen Load
Studies

• CVM Pre-approval Workshop groups found no value
  to conducting Pathogen Load studies
• Exponent Report found no consistent evidence to
  indicate an association of salmonella shedding
  with antibiotics
• FDA Task Force recommendations did not include
  therapeutic drugs
• A standardized, validated protocol, with clear
  interpretation of results does not exist for
  Pathogen Load studies. A modify-as-you-go
  approach, as was done for 558.15 studies, is
  unacceptable.
• De facto implementation of Pathogen Load studies
  has already begun as CVM is asking sponsors to
  conduct these studies for therapeutic drugs

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Pathogen Load Study Relevance

• 8 of US Swine salmonella positive, HACCP pork
  carcass baseline is 8. Feed additive use is 90.
• The magnitude of salmonella for these food animal
  species is already quite low.
• How would pre-approval pathogen load studies on
  therapeutic uses of new antibiotics be relevant?
• Six of top ten human salmonella serotypes differ
  from those recovered from food animals
• How can Pathogen Load studies be designed to be
  predictive of public health impact?

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Pathogen Load Study Relevance

• Salmonella "load" in intestinal tract increases
  from farm to slaughter plant different serotypes
  emerge
• Pathogen load is more affected near slaughter by
  transport, stress, feed, environment than prior
  antibiotic use.
• Contamination post-slaughter can occur but
  on-farm origin assumed
• Effective interventions occur at/after slaughter
  plant (HACCP, cooking, etc.) to minimize
  foodborne pathogen contamination of carcasses
• Muscle is sterile upon arrival- meat is
  contaminated upon cut-up so containment is
  especially important

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Conclusions

• 558.15 remains in place for in-feed antibiotic
  products
• Pathogen Load studies for therapeutic antibiotics
  cannot be designed to have relevance to on-farm
  practices, meat contamination and subsequent
  human illness
• Pathogen Load study requirements are an
  unnecessary impediment to the development of new
  food animal therapeutic antibiotics.