Evaluating the Safety of Antimicrobial New Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to Their Animal Drugs with Regard to Their

Microbiological Effects on Bacteria of Human Microbiological Effects on Bacteria of Human Health Concern Health Concern

Qualitative Antimicrobial Resistance Risk Qualitative Antimicrobial Resistance Risk Assessment – Example of MiracinAssessment – Example of Miracin™™

Mary J. Bartholomew, Ph.D.Center for Veterinary Medicine

January 9, 2003

Risk Analysis ProcessRisk Analysis Process

The analysis process is intended to organize The analysis process is intended to organize and integrate an array of relevant information and integrate an array of relevant information and to provide guidance as to how this and to provide guidance as to how this information may be used to manage riskinformation may be used to manage risk

The process is composed of:The process is composed of: Hazard identificationHazard identification Qualitative antimicrobial resistance risk Qualitative antimicrobial resistance risk

assessmentassessmentRelease assessmentRelease assessmentExposure assessmentExposure assessmentConsequence assessmentConsequence assessmentRisk estimationRisk estimation

Risk managementRisk management

ExampleExampleHazard IdentificationHazard Identification

A.A. Drug/Product InformationDrug/Product Information1.1. Drug: Drug:

Miraclemycin, MiracinMiraclemycin, Miracin™™2.2. Class: Class:

22ndnd generation Curalloside; CAS 2002 generation Curalloside; CAS 20023.3. Use information:Use information:

A. Dosage regimenA. Dosage regimenMiracin is intended to be administered as Miracin is intended to be administered as an oral solution in drinking water for 5 daysan oral solution in drinking water for 5 days

B. Product indicationProduct indicationTreatment of swine respiratory disease Treatment of swine respiratory disease

C. Target speciesC. Target speciesSwineSwine

Release AssessmentRelease Assessment

Probability that resistant bacteria or resistance Probability that resistant bacteria or resistance determinants are present in the target animal as a determinants are present in the target animal as a consequence of the antimicrobial new animal drug consequence of the antimicrobial new animal drug useuse

Probability is ranked as Probability is ranked as LowLow, , MediumMedium, or , or HighHigh

Factors to Consider in Factors to Consider in Release AssessmentRelease Assessment

Product and drug substance descriptionProduct and drug substance descriptionMechanism and type of actionMechanism and type of actionSpectrum of activitySpectrum of activityPharmacokinetics/pharmacodynamicsPharmacokinetics/pharmacodynamicsResistance selection pressuresResistance selection pressuresPrevalence of resistance Prevalence of resistance Resistance mechanismsResistance mechanismsResistance transferResistance transferOther relevant information Other relevant information

ExampleExampleRelease Assessment of MiracinRelease Assessment of Miracin

What is the likelihood (What is the likelihood (high, medium, lowhigh, medium, low))that these factors favor resistance that these factors favor resistance emergence or of release of the hazardous emergence or of release of the hazardous agent?agent?

Miracin:Miracin:Bactericidal drug, some activity against Bactericidal drug, some activity against gram-positives; gram-positives; Campylobacter Campylobacter exhibit low MICs;exhibit low MICs;PK/PD parameters favorable for PK/PD parameters favorable for minimizing resistance release;minimizing resistance release;Transfer of resistance is infrequent;Transfer of resistance is infrequent;Low baseline resistance;Low baseline resistance;Low mutation rate.Low mutation rate.

The release assessment conclusionThe release assessment conclusionfor for MiracinMiracin would be a would be a low probability of low probability of releaserelease..

Low mutation rateRelated to other curallosides used in human medicine

Other factors1

ModerateSelection pressure

Infrequent (no evidence of transfer)Resistance transfer

Multiple mechanisms (DNA point mutations most relevant)

Resistance mechanism(s)

Serum concentration > MIC for 6 hours; in vivo PAE = 3.5 hoursPharmacodynamics

Rapid absorption, high distribution to tissues

Pharmacokinetics

Gram-positive and some Gram-negative activity;Appropriate zoonotic pathogens display low MICs

Spectrum of activity

Inhibition of protein synthesis;Bactericidal

Mechanism of activity

Comments and conclusions regarding factors

Extent to which relevant factors favor resistance emergenceRelevant parameters

Exposure AssessmentExposure Assessment

Probability for humans to ingest the resistant Probability for humans to ingest the resistant bacteria/resistance determinants in question bacteria/resistance determinants in question from the particular relevant food commodityfrom the particular relevant food commodity

Probability is ranked as Probability is ranked as LowLow, , MediumMedium, or , or HighHigh

Exposure AssessmentExposure Assessment

Factors to Consider:Factors to Consider:

The probability for humans to be exposed to The probability for humans to be exposed to given bacteria via a particular food given bacteria via a particular food commoditycommodity

Probability that bacteria of interest (to which Probability that bacteria of interest (to which humans are exposed) are resistant to a humans are exposed) are resistant to a particular antimicrobial drug or possess particular antimicrobial drug or possess associated resistance determinantsassociated resistance determinants

ExampleExample Exposure Assessment of MiracinExposure Assessment of Miracin

The probability for humans to be exposed to The probability for humans to be exposed to given bacteria via a particular food given bacteria via a particular food commoditycommodity Estimated by considerations of:Estimated by considerations of:

Per capita consumption of the food commodityPer capita consumption of the food commodity ((pork)pork)

e.g., USDA Economic Research Service reportse.g., USDA Economic Research Service reports

Probability of contamination ofProbability of contamination of porkpork by bacteria of by bacteria of interestinterest ((Campylobacter)Campylobacter)

e.g., USDA Food Safety and Inspection Service datae.g., USDA Food Safety and Inspection Service data

ExampleExample Exposure Assessment of MiracinExposure Assessment of Miracin

Consumption ranking and contamination ranking are Consumption ranking and contamination ranking are merged to derive qualitative ranking for probability that a merged to derive qualitative ranking for probability that a human is exposed to human is exposed to CampylobacterCampylobacter on on porkpork

TTaabbllee BB44.. PPoossssiibbllee pprroocceessss ffoorr rraannkkiinngg qquuaalliittaattiivveellyy tthheepprroobbaabbiilliittyy ooff hhuummaann eexxppoossuurree ttoo aa ggiivveenn bbaacctteerriiaa iinn aaggiivveenn ffoooodd ccoommmmooddiittyy

Probability of human exposure togiven bacteria

ppeerr ccaappiittaa ccoonnssuummppttiioonn ooff tthhee ffooooddccoommmmooddiittyy

PPrroobbaabbiilliittyy ooffffoooodd

ccoommmmooddiittyyccoonnttaammiinnaattiioonn

HHiigghh MMeeddiiuumm LLooww

HHiigghh HH HH MM

MMeeddiiuumm HH MM LL

LLooww MM LL LL

Example Example Summarizing Exposure Assessment of Summarizing Exposure Assessment of

Miracin for Use in SwineMiracin for Use in Swine

Exposure assessment rankingExposure assessment ranking Derived by integrating the ranking for Derived by integrating the ranking for

probability of human exposure (through food) probability of human exposure (through food) to the bacteria in questionto the bacteria in question

HighHigh from previous slide from previous slide With the probability that the bacteria will be With the probability that the bacteria will be

resistant to the antimicrobial drug in questionresistant to the antimicrobial drug in questionLowLow from release assessment from release assessment

Example Example Summarizing Exposure Assessment of Summarizing Exposure Assessment of

Miracin for Use in SwineMiracin for Use in SwineTTaabbllee 22.. PPrroocceessss ffoorr cchhaarraacctteerriizziinngg tthhee pprroobbaabbiilliittyy ooff hhuummaanneexxppoossuurree ttoo tthhee iiddeennttiiffiieedd hhaazzaarrddoouuss aaggeenntt ((ii..ee..,, ssppeecciiffiieedd rreessiissttaannttbbaacctteerriiaa oorr rreessiissttaannccee ddeetteerrmmiinnaannttss))..

Probability of human exposure to thehazardous agent

Probability of human exposure to given bacteria2

PPrroobbaabbiilliittyytthhaatt bbaacctteerriiaaooff iinntteerreesstt aarreerreessiissttaanntt11

HHiigghh MMeeddiiuumm LLooww

HHiigghh H H M

MMeeddiiuumm H M L

LLooww M L L1May be based on susceptibility data on bacterial isolates from foodcommodity or on the outcome of the Release Assessment

2Ranking from Table B4 in Appendix B

Consequence AssessmentConsequence Assessment

Probability that human exposure to Probability that human exposure to resistant bacteria/determinants results in resistant bacteria/determinants results in an adverse human health consequencean adverse human health consequence

Based on the medical importance of the Based on the medical importance of the antimicrobial drug under reviewantimicrobial drug under review

Ranked as Ranked as LowLow, , MediumMedium, or , or HighHigh

Example Example Consequence Assessment of MiracinConsequence Assessment of Miracin

Appendix A provides ranking of Appendix A provides ranking of antimicrobial drugs developed by FDA antimicrobial drugs developed by FDA CDERCDER

Miracin is determined to be high from the Miracin is determined to be high from the table of antimicrobial drug rankingstable of antimicrobial drug rankings

Risk EstimationRisk Estimation

Integration of the results from the release Integration of the results from the release assessment, exposure assessment, and assessment, exposure assessment, and consequence assessmentconsequence assessment

Result is Result is lowlow, , mediummedium, or , or highhigh risk for risk for human health to be adversely impacted by human health to be adversely impacted by emergence of antimicrobial resistance emergence of antimicrobial resistance associated with the use of the drug in associated with the use of the drug in animalsanimals

Risk EstimationRisk Estimation

Low - Low rankings on all three Low - Low rankings on all three assessments assessments oror two low and one medium two low and one medium

High- High rankings on all three High- High rankings on all three assessments assessments oror two high and one medium two high and one medium

Medium-All intermediate combinations of Medium-All intermediate combinations of the three assessmentsthe three assessments

ExampleExample

MiracinMiracin™™ Oral Solution for swine Oral Solution for swine

Release assessment - Release assessment - lowlow

Exposure assessment - Exposure assessment - mediummedium

Consequence assessment – Consequence assessment – highhigh

Overall Risk Estimate – mediumOverall Risk Estimate – medium (Category 2)(Category 2)

SummarySummaryPossible Risk Management StepsPossible 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

Marketing Status1 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

Advisory committee review considered

Yes In certain cases3 No

1Prescription (Rx), Veterinary Feed Directive (VFD), Over-the-counter (OTC)

2See Table 4 for characterization of extent of use 3These 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.

ExampleExample

MiracinMiracin™™ Oral Solution for swine Oral Solution for swine

Conditions/limitations proposed by sponsor:Conditions/limitations proposed by sponsor:

Limited to prescription use only (use by or under Limited to prescription use only (use by or under the order of a licensed veterinarian)the order of a licensed veterinarian)

Limited to therapy of select pens/groups of Limited to therapy of select pens/groups of animalsanimals

Limited to 5 days of administrationLimited to 5 days of administration

ExampleExample

MiracinMiracin™™ Oral Solution for swine Oral Solution for swineBased on the risk assessment and the drug Based on the risk assessment and the drug application as a whole, FDA concludes that application as a whole, FDA concludes that the antimicrobial new animal drug, the antimicrobial new animal drug, MiracinMiracin™™,, is safe is safe

That is, there is a reasonable certainty of no That is, there is a reasonable certainty of no harm when the drug is approved under the harm when the drug is approved under the defined use conditions. defined use conditions.

Questions ?Questions ?