Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to Their Microbiological Effects on Bacteria of Human Health Concern Qualitative Antimicrobial Resistance Risk Assessment

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Evaluating the Safety of Antimicrobial New Animal
Drugs with Regard to Their Microbiological
Effects on Bacteria of Human Health Concern
Qualitative Antimicrobial Resistance Risk
Assessment Example of Miracin

• Mary J. Bartholomew, Ph.D.
• Center for Veterinary Medicine
• January 9, 2003

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Risk Analysis Process

• The analysis process is intended to organize and
  integrate an array of relevant information and to
  provide guidance as to how this information may
  be used to manage risk
• The process is composed of
• Hazard identification
• Qualitative antimicrobial resistance risk
  assessment
• Release assessment
• Exposure assessment
• Consequence assessment
• Risk estimation
• Risk management

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Example

• Hazard Identification
• Drug/Product Information
• Drug
• Miraclemycin, Miracin
• Class
• 2nd generation Curalloside CAS 2002
• Use information
• A. Dosage regimen
• Miracin is intended to be administered as an
  oral solution in drinking water for 5 days
• B. Product indication
• Treatment of swine respiratory disease
• C. Target species
• Swine

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Release Assessment

• Probability that resistant bacteria or resistance
  determinants are present in the target animal as
  a consequence of the antimicrobial new animal
  drug use
• Probability is ranked as Low, Medium, or High

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Factors to Consider in Release Assessment

• Product and drug substance description
• Mechanism and type of action
• Spectrum of activity
• Pharmacokinetics/pharmacodynamics
• Resistance selection pressures
• Prevalence of resistance
• Resistance mechanisms
• Resistance transfer
• Other relevant information

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ExampleRelease Assessment of Miracin
What is the likelihood (high, medium, low) that
these factors favor resistance emergence or of
release of the hazardous agent? Miracin Bacteri
cidal drug, some activity against gram-positives
Campylobacter exhibit low MICs PK/PD parameters
favorable for minimizing resistance
release Transfer of resistance is
infrequent Low baseline resistance Low mutation
rate. The release assessment conclusion for
Miracin would be a low probability of
release.
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Exposure Assessment

• Probability for humans to ingest the resistant
  bacteria/resistance determinants in question from
  the particular relevant food commodity
• Probability is ranked as Low, Medium, or High

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Exposure Assessment

• Factors to Consider
• The probability for humans to be exposed to given
  bacteria via a particular food commodity
• Probability that bacteria of interest (to which
  humans are exposed) are resistant to a particular
  antimicrobial drug or possess associated
  resistance determinants

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Example Exposure Assessment of Miracin

• The probability for humans to be exposed to given
  bacteria via a particular food commodity
• Estimated by considerations of
• Per capita consumption of the food commodity
  (pork)
• e.g., USDA Economic Research Service reports
• Probability of contamination of pork by bacteria
  of interest (Campylobacter)
• e.g., USDA Food Safety and Inspection Service
  data

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Example Exposure Assessment of Miracin

• Consumption ranking and contamination ranking are
  merged to derive qualitative ranking for
  probability that a human is exposed to
  Campylobacter on pork

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Example Summarizing Exposure Assessment of
Miracin for Use in Swine

• Exposure assessment ranking
• Derived by integrating the ranking for
  probability of human exposure (through food) to
  the bacteria in question
• High from previous slide
• With the probability that the bacteria will be
  resistant to the antimicrobial drug in question
• Low from release assessment

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Example Summarizing Exposure Assessment of
Miracin for Use in Swine
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Consequence Assessment

• Probability that human exposure to resistant
  bacteria/determinants results in an adverse human
  health consequence
• Based on the medical importance of the
  antimicrobial drug under review
• Ranked as Low, Medium, or High

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Example Consequence Assessment of Miracin

• Appendix A provides ranking of antimicrobial
  drugs developed by FDA CDER
• Miracin is determined to be high from the table
  of antimicrobial drug rankings

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Risk Estimation

• Integration of the results from the release
  assessment, exposure assessment, and consequence
  assessment
• Result is low, medium, or high risk for human
  health to be adversely impacted by emergence of
  antimicrobial resistance associated with the use
  of the drug in animals

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Risk Estimation

• Low - Low rankings on all three assessments or
  two low and one medium
• High- High rankings on all three assessments or
  two high and one medium
• Medium-All intermediate combinations of the three
  assessments

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Example

• Miracin Oral Solution for swine
• Release assessment - low
• Exposure assessment - medium
• Consequence assessment high
• Overall Risk Estimate medium (Category 2)

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SummaryPossible Risk Management Steps
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Example

• Miracin Oral Solution for swine
• Conditions/limitations proposed by sponsor
• Limited to prescription use only (use by or under
  the order of a licensed veterinarian)
• Limited to therapy of select pens/groups of
  animals
• Limited to 5 days of administration

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Example

• Miracin Oral Solution for swine
• Based on the risk assessment and the drug
  application as a whole, FDA concludes that the
  antimicrobial new animal drug, Miracin, is safe
• That is, there is a reasonable certainty of no
  harm when the drug is approved under the defined
  use conditions.

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• Questions ?