1. FDA Perspective on the development and use of Epidemiological cut-off values (ECVs)
Simone M. Shurland, Ph.D.,
Division of Anti-Infective Products
Office of Antimicrobial Products
Office of New Drugs
Center for Drug Evaluation and Research
Food and Drug Administration

2. Disclosures
None

3. Epidemiological Cut-off Values
Epidemiological cut-off value distinguishes wild-type population from those with acquired or selected resistance mechanisms.
Wild type are strains that harbor no acquired resistance mechanism, specifically no resistance attributable to
Mutation (target alteration)
Enzymatic inactivation
Up-regulation of efflux pump
Up-regulation of target production
Metabolic bypass
Any combination of the above

4. Clinical Breakpoint
A classification based on an in vitro response of an organism (MIC or zone diameter) to an antimicrobial drug at concentrations corresponding to blood or tissue levels usually attainable at the site of infection with a prescribed labeled dosing regimen.
Antimicrobial susceptibility test interpretive criteria are provided to healthcare providers as
Susceptible
Intermediate
Resistant

5. Data used to derive ECVs v. CB
Microbiological
In vitro data (MIC distributions and wild type cut-offs)
In vitro resistance markers (both phenotypic and genotypic)
Clinical Breakpoints (CB)
Microbiological
In vitro data (MIC distributions and wild type cut-offs)
In vitro resistance markers (both phenotypic and genotypic)
Pharmacokinetic/ Pharmacodynamic (PK/PD)
Evaluation of PK/PD relationships from animal models of infection
Clinical Trial
Microbiologic and/or Clinical Outcome by MIC
Asin-Prieto et al., J. Infect Chemo 2015

6. Development programs to address Unmet Need
Data expected in such programs …
Evidence of in vitro activity and activity in relevant animal models of infection
Human PK-PD data
Establish MIC breakpoints supported by PK exposure
Confirm appropriateness of dosage adjustments/exposures in relevant and special populations
Human safety information and non-clinical safety data
Smaller clinical datasets with less clinical data likely to be available

7. ECVs – Pros and Cons Examples of uses of microbiological distributions
Ideal
“Splitting” the Wildtype
Non-Wildtype Population

8. Example 1 – Ideal ECV Distribution

9. Example 2 - “Splitting” the Wild Type Population

10. Example 2 – Importance of Non-Wild Type Distribution
MIC
Microbiological Eradication
Clinical Cure
Probability of Target Attainment
≤0.06
98%
100%
0.12
92%
0.25
100%*
0.5 1 -- 2 4 8 16
94%
32*
39%

11. Perspective on Potential Concerns
Detection and Characterization of Resistance Mechanism
Some genotypic resistance may not be expressed phenotypically
>1 mutation may be required before resistance is expressed clinically or in the laboratory
Not all molecular mechanisms responsible for antimicrobial resistance are known
Clinical Significance
Small shifts upward/downward in MICs may not manifest clinically
Downgrade the potential of good drugs
Overuse of “reserve” antibacterial drugs
Establishing Susceptibility Criteria for Drugs Developed to Treat Resistant Infections
The use of ECVs may be limited in establishing breakpoints for drugs designed to overcome resistance mechanisms

12. Summary ECVs and CBs have different potential uses. Establishing CBs
Microbiologic distribution data is one of the data elements
Supportive evidence of other data elements (for instance PK/PD, animal studies) especially in developmental programs with limited clinical data
Establishing putative ECVs based on microbiological distribution data will pose challenges.