Transcript Document 7201991

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
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
Example
Hazard Identification
A. Drug/Product Information
1. Drug:
Miraclemycin, Miracin™
2. Class:
2nd generation Curalloside; CAS 2002
3. 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
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
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
Example
Release Assessment of Miracin
Relevant parameters
Extent to which relevant factors
favor resistance emergence
Comments and conclusions
regarding factors
Mechanism of activity
Inhibition of protein synthesis;
Bactericidal
Spectrum of activity
Gram-positive and some Gramnegative activity;
Appropriate zoonotic pathogens
display low MICs
Pharmacokinetics
Rapid absorption, high distribution
to tissues
Pharmacodynamics
Serum concentration > MIC for 6
hours; in vivo PAE = 3.5 hours
Resistance
mechanism(s)
Multiple mechanisms (DNA point
mutations most relevant)
Resistance transfer
Infrequent (no evidence of transfer)
Selection pressure
Moderate
Other
factors1
Low mutation rate
Related to other curallosides used
in human medicine
What is the likelihood (high, medium, low)
that these factors favor resistance
emergence or of release of the hazardous
agent?
Miracin:
Bactericidal 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.
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
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
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
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
Table B4. Possible process for ranking qualitatively the
probability of human exposure to a given bacteria in a
given food commodity
Probability of human exposure to
given bacteria
per capita consumption of the food
commodity
Probability of
food
commodity
contamination
High
Medium
Low
High
H
H
M
Medium
H
M
L
Low
M
L
L
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
Example
Summarizing Exposure Assessment of
Miracin for Use in Swine
Table 2. Process for characterizing the probability of human
exposure to the identified hazardous agent (i.e., specified resistant
bacteria or resistance determinants).
Probability of human exposure to the
hazardous agent
Probability of human exposure to given bacteria2
Probability
that bacteria
of interest are
resistant1
High
Medium
Low
High
H
H
M
Medium
H
M
L
Low
M
L
L
1
May be based on susceptibility data on bacterial isolates from food
commodity or on the outcome of the Release Assessment
2
Ranking from Table B4 in Appendix B
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
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
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
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
Example
Miracin™ Oral Solution for swine
Release assessment - low
Exposure assessment - medium
Consequence assessment – high
Overall Risk Estimate – medium
(Category 2)
Summary
Possible Risk Management Steps
Table 5. Examples of potential risk management steps associated with the approval of
antimicrobial new animal drugs in food-producing animals based on the level of concern (1,
2, or 3) as estimated by a qualitative antimicrobial resistance risk assessment.
Category of concern
Approval
conditions
Category 1
Category 2
Category 3
Rx
Rx/VFD
Rx/VFD/OTC
Extra-label use
(ELU)
No ELU
Restricted in some
cases3
ELU permitted
Extent of use2
Low
Low, medium
Low, medium, high
Post-approval
monitoring
NARMS
NARMS
NARMS
Yes
In certain cases3
No
Marketing Status1
Advisory
committee review
considered
1
Prescription (Rx), Veterinary Feed Directive (VFD), Over-the-counter (OTC)
2
See Table 4 for characterization of extent of use
3
These risk management steps may be appropriate for certain Category 2 drugs that were ranked
high for consequence assessment and ranked “high” for release or exposure assessment.
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
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.
Questions ?