FDA Perspective and Experience with Review of

AST Device Applications

Ribhi Shawar, Ph.D. (ABMM) Division of Microbiology Devices, CDRH, FDA

Antimicrobial Susceptibility and Resistance:

Addressing Challenges of Diagnostic Devices Workshop

September 13, 2017

2

Disclaimer

The contents of this presentation are for discussion and summary purposes only and do not describe the full extent of requirements applicable to devices under discussion in this workshop. Please see the Federal Food, Drug, and Cosmetic Act and Chapter I of Title 21 of the Code of Federal Regulations (CFR), especially Subchapter H that has requirements specific to medical devices

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Outline

Coordinated Development AST device review and experience with

reference broth microdilution (BMD) AST device review challenges and solutions

4

Improved Patient Care

Coordinated Development

Drug

Device

CDER

CDRH

5

Pre-sub supplement with Data

FDA Review

No additional

information needed

Submit 510(k) Clearance

Additional information

needed

Pre-sub supplement

Submit 510(k) Clearance

Coordination: Drug Developer/Device Manufacturer

Final Breakpoints and Indicated Organisms or

DRUG APPROVAL

Initial Pre-submission

Coordinated Development Submission Process

At least 75 days prior to

anticipated drug approval

Activities: September 2016 to Date Coordinated Development Draft Guidance Document and Workshop 9/16

Pre-sub MIC panel 12/16

Pre-sub Drug - 2/17

Pre-sub MIC Panel 5/17

Pre-sub Gradient Diffusion 5/17

Pre-sub Disk 5/17

Data Pre-sub MIC Panel 6/17

510k MIC panel 6/17

510(k) Gradient Diffusion 6/17

510(k) Disk 6/17

Pre-sub MIC Panel 6/17

510(k) MIC Panel 7/17

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Days Until 510(k) Clearance After Drug Approval

0 100 200 300 400 500 600 700 800 900

Device 1/CT

Device 2/CT

Device 3/CT

Device 4/CT

Device 1/New

Device 2/New

Device 3/New

Days Until Receipt First Round Days On Hold Second RoundDrug Approved

Three Devices Cleared 33-41 Days After Receipt and 44 Days After Drug Approval

FDA Data On File

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The 510(k) MDUFA Timeline

FDA Review max. 90

Days

Manufacturer Hold max. 180 Days

Total Max Days: 270

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From One 510(k) Come Many

Clearance for a drug/organism combination allows incorporation of that drug/organism combination on any

panel type manufactured by the sponsor.

Drug - Organism

Device 510(k)

Panel 1

Panel 2

Panel 3 Panel

4

Panel 5

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Assessment of BMD Variability

Reproducibility of the ref. BMD method is addressed in CLSI M23

Assessment of ref. BMD variability is important when

planning a new AST device for clearance Consider replicate testing of the reference method

Interactions between drug developers and device manufacturers are critical in understanding ref. BMD variability

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Results of Duplicate BMD Testing

0102030405060708090

100

Perc

ent

Drug/Organism

minus 2

minus 1

Exact

plus 1

plus 2

FDA Data On File

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0

1

2

3

4

5

6

7

8

9

10

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Repeat Testing of Ref. BMD

Testing multiple replicate of ref. BMD can be used as part of the study plan

Discordant analysis results cannot be used to change original performance

Repeat testing may be appropriate in cases where there was evidence of a technical error The data analysis is conducted using the repeat results

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AST Device Review Requirements, Challenges, and Solutions

Species spectrum and number of isolates Importance of evaluating CA, MAJ/VMJ errors

Adjustment of errors; Drugs without I BP Importance of on-scale MICs Evaluation of bias/trending Submission scenarios when BPs change

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Species Spectrum and Number of Isolates

All claimed species should be evaluated Isolates should predominantly be from the list

of organisms for which the drug has been shown to be active both in vitro and in clinical infections

FDA allows inclusion of isolates representing species from the in vitro only list in the FDA drug label

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Isolates for AST Testing

Isolate Type Total Number No. per

site Time from isolation Value

Fresh 75 25 7 days from isolation Real world conditions Not preselected

Recent 75 25 Up to one year from isolation On-scale organisms with MICs

near the breakpoints Organisms with currently

circulating resistance mechanisms

Because organisms to be tested are pre-selected, it is possible that isolates with better performance are presented in results of device evaluation

Stock 150 50 Up to three years from isolation

Challenge 75 75 (one site)

Not specified

Total 375 - -

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Importance of Evaluating Categorical Agreement/Errors

Evaluation of category agreement is implied in the regulations regarding AST devices (866.1640 and 866.1645): Results from AST tests are used to determine the

antimicrobial agent of choice to treat bacterial disease Test reporting must provide the interpretive criteria users

should use for each antimicrobial agent

The interpretive category (S,I,R) is a component of device labelling that is provided in patient report Physicians and HCP are familiar with S,I,R results in the patient reports

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Reference

Device

Susceptible Resistant

0.5 1 2 4 >4

0.5

1 12 8 3

2 1 11 9

4 1 7

>4 1 2 287

Total 13 9 4 13 303

Very major errors

Major errors

In EA

Not in EA

Not in EA

Total Resistant = 316 No. vmj errors = 20 (6.3%) No. vmj in EA = 11 Adjusted vmj = 9 (2.8%)* *acceptable per Table 8 AST Special Controls Document

Adjustment of Errors/No I BP

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Examples of Cleared Devices Evaluable On-Scale Results

0100200300400500600700800

Tot No. Isolates

Eval Tot

AST Special Controls Guidance: The new device and the reference panel should include a sufficient number of two-fold dilutions around the S and R thresholds

With limited evaluable data, FDA is unable to determine true EA FDA may request additional testing and/or a footnote in labeling

FDA Data On File

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P. aeruginosa ATCC 27853

Example of On-scale and Off-Scale QC Ranges-Ceftazidime

Device Range

S. aureus ATCC 29213

E. coli ATCC 25922

0.06 0.12 0.25 32 2 4 8 16 1 0.5 64 128

K. pneumoniae ATCC 700603

g/mL Dilutions

There should be at least one QC organism that will produce on-scale results for each antimicrobial/media

Concentration/reporting ranges on the panel should allow on-scale evaluation of the selected QC strains

Some device designs may not fully cover the range Assess the need to validate new strain (e.g. CLSI M23-type studies)

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MIC Trending Analysis

FDA AST Guidance Recommends Evaluation of Trending to assess impact on interpretation of patient results

FDA requests the following footnote in labeling: The device MIC values tended to be higher by one or more dilution compared to the reference method

020406080

Perc

ent

Dilution Difference

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Different Scenarios When Breakpoints Change

1. Previously collected data exists that includes resistant organisms and new breakpoints are covered in drug concentrations on the device

No device modifications needed Recalculate performance with new breakpoints If performance acceptable submit If performance unacceptable conduct a new study

Device modifications needed Conduct a new study

2. Previously collected data exists that includes resistant organisms and new breakpoints are not covered in the drug concentrations on the device Conduct a new study

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Future Direction

Implementation of 21st Century Cures Act Implications for AST submissions and reviews

Address comments on Coordinated Development Guidance with the goal to finalize

Interacting with STMA and other stakeholders FDA is planning a Frequently Asked Questions

Guidance to address common issues and streamline submissions and reviews

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Thank You!

Slide Number 1DisclaimerOutlineSlide Number 4Slide Number 5Activities: September 2016 to DateDays Until 510(k) Clearance After Drug ApprovalThe 510(k) MDUFA TimelineFrom One 510(k) Come ManyAssessment of BMD VariabilityResults of Duplicate BMD TestingHigh % Essential Agreement: Data From 34 Cleared Devices, 2014-2017Repeat Testing of Ref. BMDAST Device Review Requirements, Challenges, and SolutionsSpecies Spectrum and Number of IsolatesIsolates for AST TestingImportance of Evaluating Categorical Agreement/ErrorsAdjustment of Errors/No I BPExamples of Cleared Devices Evaluable On-Scale ResultsExample of On-scale and Off-Scale QC Ranges-CeftazidimeMIC Trending AnalysisDifferent Scenarios When Breakpoints ChangeFuture DirectionSlide Number 24