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Today’s Topic: 

Immediately - in - effect guidance: Antimicrobial Susceptibility Test (AST) 

System Devices – Updating Breakpoints in Device Labeling 

December 5, 2023
Immediately - in - effect guidance: Antimicrobial Susceptibility Test (AST) 

System Devices – Updating Breakpoints in Device Labeling

Ribhi Shawar, PhD (ABMM) 

Assistant Director 

Division of Microbiology Devices 

Office of In Vitro Diagnostics (OHT7) 

Office of Product Evaluation and Quality

Sarah Alsamarai, MD MS 

Medical Officer 

Division of Microbiology Devices

Office of In Vitro Diagnostics (OHT7)

Office of Product Evaluation and Quality

Natasha Griffin, PhD 

Team Lead

Division of Microbiology Devices 

Office of In Vitro Diagnostics (OHT7) 

Office of Product Evaluation and Quality

Center for Devices and Radiological Health 

U.S. Food and Drug Administration
Sarah Alsamarai, MD, MS 

Medical Officer

Division of Microbiology Devices

Office of In Vitro Diagnostics (OHT7)

Office of Product Evaluation and Quality

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Immediately-In-Effect (IIE) Guidance

Antimicrobial Susceptibility Test (AST) System 

Devices – Updating Breakpoints in Device 

Labeling issued on September 29, 2023 

www.fda.gov/regulatory-information/search-fda-guidancedocuments/antimicrobial-susceptibility-test-ast-system-devicesupdating-breakpoints-device-labeling

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Learning Objectives

• Discuss the clinical significance of using updated 

breakpoints with AST system devices 

• Describe the background and scope of the guidance 

• Describe the approaches outlined in the guidance for 

updating breakpoints in AST system devices 

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Clinical Significance of Breakpoints

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AST System Device

An in vitro diagnostic device in which results are used to: 

• Determine the susceptibility or resistance of a 

specific organism to a given antimicrobial agent

• Inform therapeutic decisions 

• Identify epidemiologic-trends of antimicrobialresistant organisms (such as emerging resistance) 

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Establishment and Use of Breakpoints

Breakpoints are: 

• well - established qualitative 

interpretations of quantitative results 

• determined based on microbiological, 

pharmacological and clinical evidence to 

correlate interpretive categories with 

clinical outcomes

• may be revised over time due to 

changing epidemiology and emerging 

resistance

Clinical

Breakpoint 

Determination

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Interpretive Categories (i.e., Breakpoints)

• Susceptible (S) 

• High likelihood of therapeutic success

• Intermediate (I) 

• Uncertain probability of therapeutic 

effect

• Resistant (R) 

• High likelihood of therapeutic failure

Clinical

Breakpoint 

Determination

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AST System Device Performance 

Evaluated with Breakpoints

Enterobacterales -

Ciprofloxacin

Breakpoints (S,I,R)

OLD NEW

MIC value (μg/mL) ≤1, 2, ≥4

≤0.25, 0.5, ≥1

OLD

0.03 0.06 0.12 0.25 0.5 1 2 4 8 16

Susceptible Resistant Intermediate

No growth 

inhibition

Complete 

growth 

inhibition

Antimicrobial 

concentration

(μg/mL)

0.03 0.06 0.12 0.25 0.5 1 2 4 8 16

Susceptible Resistant Intermediate

NEW

Susceptible

(High likelihood of therapeutic success )

Resistant

(High likelihood of therapeutic failure)

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Ribhi Shawar, PhD (ABMM) 

Assistant Director 

Division of Microbiology Devices 

Office of In Vitro Diagnostics (OHT7) 

Office of Product Evaluation and Quality

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Background and Scope

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Background

• FDA (CDER/CDRH) Labeling Update Guidance (2009) 

– Described an enforcement policy for updating STIC in AST system device labeling 

– Did not describe the procedures for using a breakpoint change protocol (BCP) 

– Withdrawn with issuance of IIE guidance 

• CDC & FDA Antimicrobial Resistance Isolate Bank (2015)

– Provides challenge isolates to verify/validate breakpoints 

• FDA - Recognized Antimicrobial Susceptibility Test Interpretive Criteria (STIC) website (2017) 

– Required by the 21st Century Cures Act to provide up - to - date breakpoint information online 

– Limited use of FDA - recognized breakpoints to those that appear on the FDA STIC webpage 

• FDA (CDER/CDRH) Coordinated Development Guidance (2019) 

– Outlined steps to facilitate timely availability of AST Devices in a timely manner at the time of drug approval or 

shortly thereafter. 

CDER – Center for Drug Evaluation and Research 

CDC – Centers for Disease Control and Prevention

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Paths to Update Breakpoints on AST 

System Devices

Pre-IIE Guidance Issuance

• Update AST device label using BCP

• To date, FDA has cleared >60 AST devices with BCPs and updated 

labels consistent with the BCP

• Only applied to AST devices cleared with a BCP

Post-IIE Guidance Issuance

• Update AST device label using predetermined change control plan (PCCP) 

or previously cleared BCP

• May be applied to legacy AST system devices

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Scope of Guidance

Limited to: 

• AST devices classified 

under the regulation 

numbers and with the 

product codes 

summarized in table 

• Modifications related to 

breakpoint updates

Regulation 

Number

Product 

Code Device Type 

21 CFR 

866.1640

LRG

Instrument For Auto Reader & 

Interpretation Of Overnight Suscept. 

Systems

JWY Manual Antimicrobial Susceptibility Test 

Systems

LTT Panels, Test, Susceptibility, Antimicrobial

JTT Susceptibility Test Powders, Antimicrobial

LTW Susceptibility Test Cards, Antimicrobial

NGZ Susceptibility Test Plate, Antifungal

21 CFR 

866.1645 LON System, Test, Automated, Antimicrobial Susceptibility, Short Incubation

21 CFR 

866.1650 PRH Positive Blood Culture Identification And Ast Kit

CFR – Code of Federal Regulations 15
Natasha Griffin, PhD 

Team Lead

Division of Microbiology Devices 

Office of In Vitro Diagnostics (OHT7) 

Office of Product Evaluation and Quality

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Policies Outlined in the Guidance

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Updating Breakpoints in AST System 

Device Labeling: PCCP

• A PCCP is documentation proposed in a premarket submission 

that proactively prespecifies and seeks premarket authorization 

– For AST system devices, this documentation was referred to as a 

BCP prior to issuance of the IIE guidance 

• IIE Guidance addresses updating AST system device labeling in 

the event of an FDA - recognized breakpoint change, as follows: 

– How to establish a PCCP 

– What content should be in a PCCP 

– How to utilize a PCCP 

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PCCP for AST System Devices 

Why: Approach to update breakpoints in AST devices without a new 510(k) 

What: Documentation for evaluating breakpoint changes 

Who: AST device manufacturer generates PCCP with FDA feedback 

When: Submitted for review and clearance with an AST device 510(k) submission 

How: PCCP is followed in the event of an FDA - recognized breakpoint change 

Result: If PCCP is appropriately followed (that is, no deviations), updated label sent 

to ASTdevices@fda.hhs.gov without a new 510(k). 

NOTE: BCPs are now being received and reviewed as PCCPs

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Establishing a PCCP

• AST device manufacturers can propose a PCCP to 

proactively seek clearance of updated breakpoints in 

labeling without the need for a new 510(k) 

• FDA recommends that all AST system device submissions 

include a PCCP in future submissions

• PCCP should contain procedures to help ensure that 

breakpoint updates do not significantly change the 

performance

See Section IV.A(1) of guidance for full establishment recommendations 20
Content of a PCCP 

• Description of Modifications 

– Describes the applicability to AST system devices with same technological 

characteristics 

– Updated breakpoints being adopted: 

• Identical to the relevant breakpoints on the FDA - recognized STIC website 

• Fall within the previously - cleared reporting range 

• Modification Protocol 

– Procedures to re - evaluate clinical data in most recent 510(k) clearance 

• Acceptable performance 

• Sufficient number of resistant isolates 

– Planned updates to AST labeling 

See Section IV.A(3) of guidance for full content recommendations 21
Utilizing a PCCP

• With a PCCP that has been reviewed and cleared in a 

510(k) for an AST system device: 

– Breakpoint update can be implemented according to the cleared 

PCCP 

• Refer to the FDA guidance “Deciding When to Submit a 510(k) for a Change to an 

Existing Device” for changes outside of the scope 

– Breakpoint update must be documented per the manufacturer’s 

quality system 

– Updated labeling should be emailed to ASTdevices@fda.hhs.gov

See Section IV.A(2) of guidance for full utilization recommendations 22
Approach to Update Breakpoints in AST 

System Devices with a PCCP

Scenario #1: Use PCCP with the AST system device it was cleared with 

Ciprofloxacin device 

cleared with PCCP

CDER recognizes 

updated breakpoints for 

ciprofloxacin

PCCP used and updated 

ciprofloxacin device label 

sent to 

ASTdevices@fda.hhs.gov

See Section IV.A(2) of guidance for full utilization recommendations 23
A Legacy AST System Device

• Compared to the device cleared with the BCP/PCCP, the 

legacy device should: 

– Be previously 510(k) cleared under the same classification 

regulation and product code, 

– Have the same intended use, and 

– Have the same technological characteristics

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Utilization of a BCP/PCCP for Legacy AST 

System Devices

• Breakpoint update should be implemented according to the cleared BCP/PCCP 

– Breakpoint updates that are not specified in, or implemented in accordance with, the 

cleared BCP/PCCP generally require submission of a 510(k) prior to updating the labeling

• Breakpoint update must be documented per the manufacturer’s quality system 

• Internal documentation should include: 

– Reference to 510(k) submission number of cleared BCP/PCCP 

– Summary that the protocol was appropriately followed 

– Determination that update falls within the enforcement policy outlined in this guidance 

• Updated label and referenced 510(k) submission number should be emailed to 

ASTdevices@fda.hhs.gov

See Section IV.B of guidance for full recommendations for legacy AST devices 25
Approach to Update Breakpoints in Legacy

AST System Devices

Scenario #2: Use cleared BCP/PCCP with legacy AST system device 

Piperacillin-tazobactam 

device cleared

Ciprofloxacin device 

cleared with BCP/PCCP

CDER recognizes updated 

breakpoints for 

piperacillin-tazobactam

BCP/PCCP (cleared for 

ciprofloxacin device) used

and updated piperacillintazobactam device label 

sent to 

ASTdevices@fda.hhs.gov

See Section IV.B of guidance for full recommendations for legacy AST devices 26
Utilization of a BCP/PCCP incorporated by 

reference for AST System Devices

• Manufacturers may reference cleared BCP/PCCP with new 510(k) 

submissions 

– New AST device should have the same intended use and technological characteristics as 

the device cleared with the BCP/PCCP 

– Submission should include the 510(k) submission number of the cleared BCP/PCCP 

• Breakpoint update should be implemented according to the cleared 

BCP/PCCP 

• Breakpoint update should be documented per the manufacturer’s 

quality system 

• Updated label should be emailed to ASTdevices@fda.hhs.gov

See Section IV.C of guidance for full recommendations to incorporate by reference 27
Approach to Update Breakpoints in AST 

System Devices with a referenced BCP/PCCP

Scenario #3: Use a cleared BCP/PCCP that was incorporated by 

reference with an AST system device clearance 

Ciprofloxacin device 

cleared with BCP/PCCP

Sulbactam-durlobactam

device cleared with 

referenced BCP/PCCP

CDER recognizes updated 

breakpoints for 

sulbactam-durlobactam

BCP/PCCP (cleared for 

ciprofloxacin device) used

and updated sulbactamdurlobactam device label 

sent to 

ASTdevices@fda.hhs.gov

See Section IV.C of guidance for full recommendations to incorporate by reference 28
Summary

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• Use of AST devices with updated breakpoints is essential to provide accurate 

results for patient care and to monitor emergence of resistance 

• BCPs have been successfully used to update breakpoints in AST devices 

• IIE guidance provides least burdensome recommendations to update 

breakpoints in AST devices, including legacy AST devices 

• Manufacturers of AST devices with a cleared BCP can immediately begin 

applying it to legacy AST devices 

• Manufacturers of AST devices without a cleared BCP should submit a 510(k) 

submission for an AST device and include a PCCP for review 

– After clearance, the PCCP can be used to update breakpoints for legacy AST 

devices, as outlined in the guidance 
Resources

Slide 

Number

Cited Resource URL

13 Antimicrobial Susceptibility Test (AST) 

Systems - Class II Special Controls 

Guidance for Industry and FDA

www.fda.gov/medical-devices/guidance-documents-medical-devices-andradiation-emitting-products/antimicrobial-susceptibility-test-ast-systemsclass-ii-special-controls-guidance-industry-and-fda

13 FDA - Recognized Antimicrobial 

Susceptibility Test Interpretive Criteria

www.fda.gov/drugs/development-resources/fda-recognized-antimicrobialsusceptibility-test-interpretive-criteria

13 21st Century Cures Act www.fda.gov/regulatory-information/selected-amendments-fdc-act/21stcentury-cures-act

13 Coordinated Development www.fda.gov/media/124382/download

13 CDC & FDA Antimicrobial Resistance (AR) 

Isolate Bank

www.cdc.gov/drugresistance/resistance-bank/index.html

22 Deciding When to Submit a 510(k) for a 

Change to an Existing Device

www.fda.gov/regulatory-information/search-fda-guidancedocuments/deciding-when-submit-510k-change-existing-device

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Submit Comments to Docket

• Although implemented without prior public comment, 

comments may be submitted to the docket number 

FDA - 2023 - D - 4045 (www.regulations.gov/docket/FDA2023-D-4045), in accordance with the Agency’s good 

guidance practices. 

• FDA will consider all comments received and revise the 

guidance as appropriate.

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Let’s Take Your Questions

• To Ask a Question: 

• Raise your hand in Zoom 

• Moderator will announce your name and invite you to ask your question 

• Unmute yourself when prompted in Zoom to ask your question 

• When Asking a Question: 

• Ask one question only 

• Keep question short 

• No questions about specific submissions 

• After Question is Answered: 

• Mute yourself and lower your hand 

• If you have more questions - raise your hand again

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