Predicate Devices

Reference Devices

AI/ML (Artificial Intelligence / Machine Learning)

Unknown
The document describes automated image analysis for detecting colonies but does not explicitly mention the use of AI or ML algorithms. While image analysis can be performed using traditional algorithms, it is also a common application for AI/ML in medical devices. Without explicit mention, it's impossible to confirm.

Therapeutic

No
Explanation: The device is an in vitro diagnostic system used for automated imaging and analysis of agar plates to detect the presence of MRSA colonies. It aids in screening for colonization but does not provide direct therapy or treatment.

Diagnostic

Yes

The "Intended Use / Indications for Use" section explicitly states, "The APAS Independence is an in vitro diagnostic system," and further, the "Device Description" section reiterates, "It is an in vitro diagnostic device." Its function involves detecting the presence of colonies suggestive of MRSA growth from patient samples (anterior nares swabs), which is a diagnostic purpose.

SaMD (Software as a Medical Device)

No

The device description explicitly states that the APAS Independence consists of an instrument with an automated plate handling mechanism and an imaging station, in addition to the software for image analysis. This indicates it is a system with both hardware and software components, not a software-only medical device.

IVD (In Vitro Diagnostic)

Yes, this device is an IVD (In Vitro Diagnostic).

The "Intended Use / Indications for Use" section explicitly states that the APAS Independence is an "in vitro diagnostic system".

Furthermore, the "Device Description" section also explicitly states, "It is an in vitro diagnostic device and has no direct contact with patients."

The device's function of analyzing biological samples (anterior nares swabs) on culture plates to detect the presence of MRSA colonies aligns with the definition of an in vitro diagnostic device, which is used to examine specimens derived from the human body to provide information for the diagnosis, prevention, or treatment of disease or for the assessment of health.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

The APAS Independence is an in vitro diagnostic system comprised of an instrument for automated imaging of agar plates and a software analysis module for the following uses:

The APAS Independence, when using its IC MRSA Chromogenic BD Analysis Module, automates culture plate imaging and interpretation to detect the presence of colonies with colors suggestive of methicillin-resistant Staphylococcus aureus (MRSA) growth on Beckton Dickson BBL™ CHROMagar™ MRSA II agar that has been inoculated with anterior nares swabs and incubated at 36°C ± 1°C for 24 hours. The APAS Independence, when using its IC MRSA Chromogenic BD Analysis Module, provides an aid in routine screening for colonization with MRSA. It provides one of two screening results: Presumptive MRSA or Negative. All culture plates that are identified as Presumptive MRSA by the APAS Independence, when using the IC MRSA Chromogenic BD Analysis Module require review by a trained microbiologist.
The APAS Independence, when using its IC MRSA Chromogenic TFS/S Analysis Module, automates culture plate imaging and interpretation to detect the presence of colonies with colors suggestive of methicillin-resistant Staphylococus aureus (MRSA) growth on Thermo-Fisher Spectra™ MRSA agar that has been inoculated with anterior nares swabs and incubated at 36°C ± 1°C for 24 hours. The APAS Independence, when using its IC MRSA Chromogenic TFS/S Analysis Module, provides an aid in routine screening for colonization with MRSA. It provides one of three screening results: Presumptive MRSA, Presumptive non-MRSA, or Negative. All culture plates that are identified as Presumptive MRSA or Presumptive non-MRSA by the APAS Independence, when using the IC MRSA Chromogenic TFS/S Analysis Module, require review by a trained microbiologist.

Product codes

QQY

Device Description

APAS Independence is a device designed to be used in a microbiology laboratory to automate the initial screening of specimens for the presence of growth on culture plates. It is an in vitro diagnostic device and has no direct contact with patients.

The APAS Independence consists of an automated plate handling mechanism to move culture plates through the instrument, an imaging station to capture images of culture plates, and software for image analysis (e.g., determination of growth) and presentation of reports.

The APAS Independence is intended to be installed with multiple software (analysis) modules, each of which will provide an assessment of growth for a specific clinical indication. More than one analysis module may be developed for the same indication to allow APAS to assess growth on culture plates from multiple agar manufacturers sold for the same indications.

This submission includes two MRSA analysis modules that have been developed for the same indication, which is to be used in a microbiology laboratory to automate the initial screening for the presence of presumptive methicillin-resistant Staphylococcus aureus (MRSA) growth on culture plates. It is indicated for the screening of MRSA colonization from swabs, where a specimen is collected from the anterior nares by non-invasive sampling techniques and plated onto specified chromogenic MRSA agars. No quantification of growth is required.

APAS Independence with IC MRSA Chromogenic BD Analysis Module is designed to interpret growth on BBL™ CHROMagar™ MRSA II agar from Becton Dickinson, and APAS Independence with IC MRSA Chromogenic TFS/S Analysis Module is designed to interpret growth on Spectra™ MRSA agar from Thermo Fisher Scientific (Remel).

Mentions image processing

Yes

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Charge Coupled Device (CCD) camera

Anatomical Site

Anterior nares

Indicated Patient Age Range

Not Found

Intended User / Care Setting

Microbiology laboratory

Description of the training set, sample size, data source, and annotation protocol

Not Found

Description of the test set, sample size, data source, and annotation protocol

Of the 1590 samples enrolled in the study (IVD Study), 13 were excluded due to defects in the agar and thus 1573 were analyzed for the IC MRSA Chromogenic BD Analysis Module, being 1118 non-simulated samples, 395 simulated MRSA-positive samples and 60 simulated negative MRSA samples. For the IC MRSA Chromogenic TFS/S Analysis Module, 10 samples were excluded due to defects in the agar, with a total of 1580 analyzed, being 1122 non-simulated samples, 398 simulated MRSA-positive samples and 60 simulated negative MRSA samples.
Left-over specimens from standard of care screening culture for colonization with MRSA were collected and inoculated onto chromogenic agar plates at a single site in Australia. The plates were then incubated and imaged with the APAS.
The APAS result for each image was compared against each of two reference results; one panel was located in the USA and the other in Australia. Each reference result was achieved using the majority result from the respective panel of 3 independent microbiologists.
Due to the low positivity rate for MRSA detection in the study population, simulated samples were prepared to supplement the study. The simulated swab samples were spiked with known MRSA and non-MRSA organisms. The use of simulated samples allowed the inclusion of unique strains of MRSA that provided global representation of the most common MRSA clades, including those found in the United States.

Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)

Digital Image Quality, Digital Image Interpretation Studies:
- Point (a) Reproducibility of plate image interpretations: Assessed by comparing individual assessments of plate images by three microbiologists with a single panel result (majority vote).
  - BD media: Microbiologists agreed with the panel 100% for presumptive MRSA, >97% for presumptive non-MRSA, and >95% for no growth. Combined averages: 100% (MRSA), 98.4% (non-MRSA), 98.1% (no growth).
  - TFS/S media: Microbiologists agreed with the panel >97% for presumptive MRSA, 93% for presumptive non-MRSA, and 98% for no growth. Combined averages: 97.7% (MRSA), 95.1% (non-MRSA), 99.0% (no growth).
- Point (b) Equivalency of Plate-in-Hand vs. Plate Image: Assessed by measuring percent agreement of a microbiologist's interpretations of the plate and image for presumptive MRSA, with an acceptance criterion of 95% for combined result. Plate-in-hand interpretation considered truth.
  - BD media: On average, microbiologists interpreted plate image equivalent to plate-in-hand >95% for each result designation (96.5% for No growth, 95.3% for Presumptive Non-MRSA, 95.9% for Presumptive MRSA for combined results).
  - TFS/S media: On average, microbiologists interpreted plate image equivalent to plate-in-hand

Regulation Number and Section

§ 866.2190 Automated image assessment system for microbial colonies on solid culture media.

(a)
Identification. An automated image assessment system for microbial colonies on solid culture media is a system that is intended to assess the presence or absence of microbial colonies on solid microbiological culture medium, and to interpret their number, and phenotypic and morphologic characteristics through analysis of two dimensional digital images as an aid in diagnosis of infectious disease.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include a detailed description of the device, including the technology employed, components and software modules, as well as a detailed explanation of the result algorithms and any expert rules that are used to assess colony characteristics and enumerate colonies from image capture through end result.
(2) Premarket notification submissions must include detailed documentation of the analytical studies performed to characterize device performance to support the intended use, as appropriate.
(3) Premarket notification submissions must include detailed documentation from clinical studies performed on a population that is consistent with the intended use population.
(i) The clinical studies must establish the device performance based on comparison to results obtained by an acceptable reference method, as appropriate.
(ii) The clinical study documentation must include the study protocol with a predefined statistical analysis plan and the final report documenting support for the Indications for Use and the results of the statistical analysis, as appropriate.
(4) Premarket notification submissions must include detailed documentation for device software, including but not limited to software applications and hardware based components that incorporate software, and any decision-making thresholds used to generate results for the device. If a part of a Total Laboratory Automation System, the premarket notification submission must include detailed documentation addressing the instrument and software system integration.
(5) Premarket notification submissions must include detailed documentation of appropriate instructions for use regarding the intended user's device quality control procedures for the instrument system and components, as appropriate.
(6) The 21 CFR 809.10 compliant device labeling must include:
(i) Detailed user instructions to mitigate the risk of failure to operate the instrument correctly.
(ii) A detailed explanation of the interpretation of results and limitations regarding the need for review of culture plates by a qualified microbiologist, as appropriate.
(iii) A summary of performance data obtained from the analytical studies used to support device performance, as appropriate.
(iv) A summary of performance data obtained from clinical studies performed on a population that is consistent with the intended use population, as appropriate.
(7) Under 21 CFR 820.30 compliant design control, device manufacturers must, as appropriate:
(i) Conduct human factors/usability validation testing with the final version of the labeling and related materials to adequately mitigate the risk of failure to operate the instrument correctly.
(ii) Document a device training program that will be offered to the end user to adequately mitigate the risk of failure to operate the instrument correctly.

Summary

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Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which is a blue square with the letters "FDA" in white. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.

October 28, 2021

Clever Culture Systems Julie Winson Regulatory Affairs Manager Seestrasse 204a Bach. CH-8806 Switzerland

Re: K200839

Trade/Device Name: APAS Independence with IC Chromogenic MRSA BD Analysis Module; APAS Independence with IC Chromogenic MRSA TFS/S Analysis Module Regulation Number: 21 CFR 866.2190 Regulation Name: Automated Image Assessment System For Microbial Colonies On Solid Culture Media Regulatory Class: Class II Product Code: QQY Dated: March 27, 2020 Received: March 31, 2020

Dear Julie Winson:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's

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requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

Ribhi Shawar, Ph.D. (ABMM) Chief. General Bacteriology and Antimicrobial Susceptibility Branch Division of Microbiology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

2

Indications for Use

510(k) Number (if known) K200839

Device Name

APAS Independence with IC MRSA Chromogenic BD Analysis Module APAS Independence with IC MRSA Chromogenic TFS/S Analysis Module

Indications for Use (Describe)

The APAS Independence is an in vitro diagnostic system comprised of an instrument for automated imaging of agar plates and a software analysis module for the following uses:

The APAS Independence, when using its IC MRSA Chromogenic BD Analysis Module, automates culture plate imaging and interpretation to detect the presence of colonies with colors suggestive of methicillin-resistant Staphylococcus aureus (MRSA) growth on Beckton Dickson BBL™ CHROMagar™ MRSA II agar that has been inoculated with anterior nares swabs and incubated at 36°C ± 1°C for 24 hours. The APAS Independence, when using its IC MRSA Chromogenic BD Analysis Module, provides an aid in routine screening for colonization with MRSA. It provides one of two screening results: Presumptive MRSA or Negative. All culture plates that are identified as Presumptive MRSA by the APAS Independence, when using the IC MRSA Chromogenic BD Analysis Module require review by a trained microbiologist.
The APAS Independence, when using its IC MRSA Chromogenic TFS/S Analysis Module, automates culture plate imaging and interpretation to detect the presence of colonies with colors suggestive of methicillin-resistant Staphylococus aureus (MRSA) growth on Thermo-Fisher Spectra™ MRSA agar that has been inoculated with anterior nares swabs and incubated at 36°C ± 1°C for 24 hours. The APAS Independence, when using its IC MRSA Chromogenic TFS/S Analysis Module, provides an aid in routine screening for colonization with MRSA. It provides one of three screening results: Presumptive MRSA, Presumptive non-MRSA, or Negative. All culture plates that are identified as Presumptive MRSA or Presumptive non-MRSA by the APAS Independence, when using the IC MRSA Chromogenic TFS/S Analysis Module, require review by a trained microbiologist.

Type of Use (Select one or both, as applicable)
☑ Prescription Use (Part 21 CFR 801 Subpart D)	☐ Over-The-Counter Use (21 CFR 801 Subpart C)

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Image /page/3/Picture/0 description: The image contains the logo for Clever Culture Systems. The logo consists of a red icon resembling interconnected nodes, followed by the text "CLEVER CULTURE SYSTEMS" in a bold, sans-serif font. To the right of the logo, the text "Traditional 510(k) APAS Independence with MRSA Analysis Module" is displayed, indicating the company's focus on traditional medical device clearance pathways and its expertise in automated plate assessment systems for MRSA analysis.

5.510(k) Summary

5.1 Submitter

Clever Culture Systems AG Seestrasse 204a, CH-8806 Bach, Switzerland

Contact person: Julie Winson

Telephone +61 88 2771555

e-mail: Julie.Winson@cleverculturesystems.com

Date prepared: 19 October 2021

5.2 Device

The information presented in this 510(k) premarket notification submission is for two devices, as follows:

| Name of Devices | APAS Independence with IC MRSA Chromogenic BD Analysis Module
APAS Independence with IC MRSA Chromogenic TFS/S Analysis Module |
|----------------------|------------------------------------------------------------------------------------------------------------------------------------------------------|
| Model Numbers | AI-16001 - APAS Independence instrument
AI-16053 - IC MRSA Chromogenic BD Analysis Module
AI-16057 - IC MRSA Chromogenic TFS/S Analysis Module |
| Common or Usual Name | (Both Devices)
APAS Independence with MRSA Analysis Module |
| Classification Name: | Automated image assessment system for microbial colonies on solid culture media (21 CFR 866.2190). |
| Regulatory Class: | II (special controls). |
| Product Code | QQY |

5.3 Predicate Device

The predicate device is APAS Independence with Urine Analysis Module, K183648.

This predicate has not been subject to a design related recall.

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5.4 Device Description

APAS Independence is a device designed to be used in a microbiology laboratory to automate the initial screening of specimens for the presence of growth on culture plates. It is an in vitro diagnostic device and has no direct contact with patients.

The APAS Independence consists of an automated plate handling mechanism to move culture plates through the instrument, an imaging station to capture images of culture plates, and software for image analysis (e.g., determination of growth) and presentation of reports.

The APAS Independence is intended to be installed with multiple software (analysis) modules, each of which will provide an assessment of growth for a specific clinical indication. More than one analysis module may be developed for the same indication to allow APAS to assess growth on culture plates from multiple agar manufacturers sold for the same indications.

This submission includes two MRSA analysis modules that have been developed for the same indication, which is to be used in a microbiology laboratory to automate the initial screening for the presence of presumptive methicillin-resistant Staphylococcus aureus (MRSA) growth on culture plates. It is indicated for the screening of MRSA colonization from swabs, where a specimen is collected from the anterior nares by non-invasive sampling techniques and plated onto specified chromogenic MRSA agars. No quantification of growth is required.

APAS Independence with IC MRSA Chromogenic BD Analysis Module is designed to interpret growth on BBL™ CHROMagar™ MRSA II agar from Becton Dickinson, and APAS Independence with IC MRSA Chromogenic TFS/S Analysis Module is designed to interpret growth on Spectra™ MRSA agar from Thermo Fisher Scientific (Remel).

Table 5-1. shows reported final plate designation and relationship to plate interpretation result for each module. respectively.

| Chromogenic Agar
Result | Chromogenic Agar
Description | IC Chromogenic Analysis Modules | |
|--------------------------------|----------------------------------------------|---------------------------------|---------------------------------|
| | | BD Analysis Module
Result | TFS/S Analysis
Module Result |
| Presumptive MRSA
Growth | Colonies or growth
suggestive of MRSA | Presumptive MRSA | Presumptive MRSA |
| Presumptive non-MRSA
Growth | Colonies or growth not
suggestive of MRSA | Negative | Presumptive non-MRSA |
| No Growth | No colonies or growth | Negative | Negative |

Table 5-1: APAS final designation

Both modules provide a triaqing step within the workflow of a microbiology laboratory. Each module takes two key inputs (agar plate images and flags) and computes a final plate designation so that the plate can be efficiently and appropriately routed to the next step in the laboratory workflow.

For APAS Independence with IC MRSA Chromogenic BD Analysis Module, the final designation will be either Presumptive MRSA or Negative.

. Presumptive MRSA designation indicates that the culture plate was determined to contain colored colonies which are suspected to be MRSA. Investigation and confirmation by a microbiologist are required.
. Negative designation indicates that the culture plate was determined to not contain colored colonies indicative of MRSA. No further investigations will be required.

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Figure 5-1 provides an illustration of the expected workflow after the IC MRSA Chromogenic BD Analysis Module has produced a screening result.

Figure 5-1: Typical workflow of APAS Independence with IC MRSA Chromogenic BD analysis module

Image /page/5/Figure/3 description: This image is a flowchart describing a laboratory process. The process starts with an incubated sample on media, which then goes through APAS. From APAS, the sample can either be presumptive MRSA or negative. If the sample is presumptive MRSA, it goes through laboratory protocols for confirmation, and then it is reported to LIS. If the sample is negative, no further work is needed, and it is reported to LIS, but a flag is set to indicate that the sample is negative.

When APAS Independence with IC MRSA Chromogenic BD analysis module completes the analysis of each plate, the APAS-generated result is sent to the LIS. In the case of a Negative designation which does not require any further work, the final laboratory report can be issued according to standard reporting protocols without any investigation. Any Presumptive MRSA designations, however, will require investigation according to laboratory protocols for confirmation.

For APAS Independence with IC MRSA Chromogenic TFS/S Analysis Module the final designation will be either Presumptive MRSA, Presumptive non-MRSA, or Negative.

. Presumptive MRSA designation indicates that the culture is likely to contain colored colonies which are suspected to be MRSA. Investigation and confirmation by a microbiologist are required.
. Presumptive non-MRSA designation indicates that the culture is likely to contain growth of organisms not typically suspected to be MRSA. Review is required by a microbiologist.
Negative designation indicates that no growth is present on the plate. No further . investigations will be required.

Figure 5-2 provides an illustration of the expected workflow after the IC MRSA Chromogenic TFS/S Analysis Module has produced a screening result.

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Image /page/6/Picture/0 description: The image features the logo of Clever Culture Systems on the left. To the right of the logo is the text "CLEVER CULTURE SYSTEMS" in bold font. Below this text is the phrase "Traditional 510(k) APAS Independence with MRSA Analysis Module". The text is horizontally aligned.

Image /page/6/Figure/1 description: The image is titled "Figure 5-2: Typical workflow of APAS Independence with IC MRSA Chromogenic TFS/S analysis module". The image is a figure that describes the typical workflow of APAS Independence. The figure includes IC MRSA Chromogenic TFS/S analysis module.

Image /page/6/Figure/2 description: This image is a flowchart describing a laboratory process. The process starts with an incubated sample on media, which then goes through APAS. From APAS, there are three possible outcomes: Presumptive MRSA, Presumptive non-MRSA, and Negative. The Presumptive MRSA outcome leads to following laboratory protocols for confirmation, while the Presumptive non-MRSA outcome leads to laboratory assessment, and the Negative outcome leads to no further work needed. Both the laboratory assessment and the follow laboratory protocols for confirmation outcomes lead to reporting to LIS.

When APAS Independence with IC MRSA Chromogenic TFS/S analysis module completes the analysis of each plate, the APAS-generated result is sent to the LIS. In the case of a Negative designation, which does not require any further work, the final laboratory report can be issued according to standard reporting protocols without any investigation. Any Presumptive MRSA or Presumptive non-MRSA designation, however, will require investigation according to laboratory protocols for confirmation prior to a laboratory report being issued.

Figure 5-3 shows a photograph of the instrument from the front. It shows the input area on the left, the imaging area in the middle and the output area on the right. The user controls the instrument via the screen at the top middle of the instrument.

Image /page/6/Picture/5 description: The image shows a laboratory instrument called APAS Independence. The instrument is white and gray and has a touch screen on the front. There are several containers on the right side of the instrument, and a drawer on the left side. The instrument is sitting on a black base.

Figure 5-3: APAS Independence

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5.5 Intended Use

The APAS Independence is an in vitro diagnostic system comprised of an instrument and software analysis module(s) for specific indications that are used to automate imaging and interpretation of microbial colonies on plates of solid culture media.

5.6 Indications for Use

The indication for use for APAS Independence, when using one of the MRSA analysis modules included in this application, is one of the following:

APAS Independence with IC MRSA Chromogenic BD Analysis Module 5.6.1

The APAS Independence is an in vitro diagnostic system comprised of an instrument for automated imaging of agar plates and a software analysis module for the following use:

The APAS Independence, when using its IC MRSA Chromogenic BD analysis module, automates culture plate imaging and interpretation to detect the presence of colonies with colors suggestive of methicillin-resistant Staphylococcus aureus (MRSA) growth on Beckton Dickson BBL ™ CHROMagar™ MRSA II agar that has been inoculated with anterior nares swabs and incubated at 36°C ± 1°C for 24 hours.

The APAS Independence, when using its IC MRSA Chromogenic BD analysis module, provides an aid in routine screening for colonization with MRSA. It provides one of two screening results: Presumptive MRSA or Negative. All culture plates that are identified as Presumptive MRSA by the APAS Independence, when using the IC MRSA Chromogenic BD analysis module require review by a trained microbiologist.

5.6.2 APAS Independence with IC MRSA Chromogenic TFS/S Analysis Module

The APAS Independence is an in vitro diagnostic system comprised of an instrument for automated imaging of agar plates and a software analysis module for the following use:

The APAS Independence, when using its IC MRSA Chromogenic TFS/S analysis module, automates culture plate imaging and interpretation to detect the presence of colonies with colors suggestive of methicillin-resistant Staphylococcus aureus (MRSA) growth on Thermo-Fisher Spectra™ MRSA agar that has been inoculated with anterior nares swabs and incubated at 36°C ± 1°C for 24 hours.

The APAS Independence, when using its IC MRSA Chromogenic TFS/S analysis module, provides an aid in routine screening for colonization with MRSA. It provides one of three screening results: Presumptive MRSA, Presumptive non-MRSA, or Negative. All culture plates that are identified as Presumptive MRSA or Presumptive non-MRSA by the APAS Independence, when using the IC MRSA Chromogenic TFS/S analysis module, require review by a trained microbiologist.

5.6.3 Predicate device APAS Independence with Urine Analysis Module

The indication for use of the predicate device, which is the APAS Independence with Urine Analysis Module, is as follows:

The APAS Independence is an in vitro diagnostic system comprised of an instrument for automated imaging of agar culture plates and a software analysis module for the following use:

The APAS Independence, when usinq its urine analysis module, automates urine culture plate imaging and interpretation to detect the presence of microbial growth on sheep blood and MacConkey agar culture plates that are inoculated with a 1uL sample volume. The

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APAS Independence, when using its urine analysis module, provides a semi-quantitative assessment of colony counts that are used as an aid in the diagnosis of urinary tract infection. All urine culture plates that are identified as positive for growth by the APAS Independence, when using its urine analysis module, must be reviewed by a trained microbiologist.

The difference in indications for use reflects the different therapeutic screening purposes supported by APAS. Neither the predicate urine analysis module nor either of the MRSA analysis modules provide a final diagnostic result; for each module, a positive screening result is confirmed by a microbiologist.

The same questions of safety and effectiveness for all analysis modules are addressed by fulfilling the requirements of the Special Controls for automated image assessment systems for microbial colonies on solid culture media.

5.7 Comparison of Technological Characteristics with the Predicate Device

The nominated predicate device is the APAS Independence with Urine Analysis Module which was cleared via application K183648.

APAS Independence when using both MRSA analysis modules included in this submission uses the same technology and methods to provide an interpretation of growth from anterior nares swabs taken by non-invasive techniques and cultured for screening for specific indications.

Both devices have been developed by Clever Culture Systems (CCS). Table 5-2 provides a side-byside comparison of the main components of APAS Independence as used in the predicate and the two new devices, showing that no changes were necessary to accommodate the two new modules.

Component	Predicate Device	Subject Devices
Hardware	APAS Independence with Urine Analysis Module (K183648)	APAS Independence with IC MRSA Chromogenic BD Analysis Module
And
APAS Independence with IC MRSA Chromogenic TFS/S Analysis Module
	Imaging Station	Light Emitting Diode (LED) illumination of culture plates and image capture using a Charge Coupled Device (CCD) camera	Same
	Plate Handling Mechanism	An automated system that accepts input carriers of multiple plates, moves plates through the instrument and sorts them to output carriers and stacks based on the analysis result.
Accurately positions the plate for imaging	Same
Software	APAS Controller PC	Controls image capture, analysis, report generation and result storage	Same

Table 5-2: Comparison of Main Components Between Predicate and Subject Device

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Image /page/9/Picture/0 description: The image shows the logo for Clever Culture Systems. The logo consists of a red circle with a white molecular structure inside, followed by the text "CLEVER CULTURE" in bold black letters above the text "SYSTEMS" in bold black letters. The logo is simple and modern, and it is likely used to represent a company that is involved in science or technology.

Traditional 510(k) APAS Independence with MRSA Analysis Module

Component	Predicate Device	Subject Devices
	APAS Independence with Urine
Analysis Module (K183648)	APAS Independence with IC MRSA
Chromogenic BD Analysis Module
And
APAS Independence with IC MRSA
Chromogenic TFS/S Analysis
Module
	Instrument
Controller PC	User interface for operation of the APAS
Independence.
Oversight of plate movements	Same
	Analysis
Module	Installed on the APAS Controller PC to
provide the configuration and
instructions for image capture and
analysis	Same
	Laboratory
Information
System (LIS)
Interface	Analysis result for each plate sent to the
LIS.
Sample ID details retrieved from the
LIS.	Same
	Laboratory
Network
Interactions	Interfaces with an external LIS.
Optionally interfaces with NTP, LDAP,
DNS and DHCP servers.	Same
QC	Qualification
Tools	Color Check Tool: - Multicolored disk for
checking and correcting color of the
system optics.
System Check Tool: - A pair of disks
with small dots replicating colonies for
checking overall system functionality
and associated software	Same

Table 5-3 and Table 5-4 provide a side-by-side comparison of the main characteristics of the Analysis Modules used in the predicate and subject devices. The differences do not raise different questions about safety and effectiveness, which are addressed by determining analytical performance and clinical performance.

Table 5-3: Comparison of Characteristics Between Predicate and Subject Analysis Modules
-----------------------------------------------------------------------------------------	--

Characteristic	Predicate Device	Subject Device
Intended Use	The APAS Independence is an in vitro
diagnostic system comprised of an
instrument and software analysis
module(s) for specific indications that
are used to automate imaging and
interpretation of microbial colonies on
plates of solid culture media.	Same
Target population	All patients	Same
Anatomical site	Biological samples taken by non-
invasive techniques	Same
Sample Type	Urine samples	Anterior nares swab samples
Where used	Microbiology laboratory	Same

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Characteristic	Predicate Device	Subject Device
Media used	Urine analysis module uses media manufactured by Remel, USA:
Trypticase Soy Agar with 5% sheep blood, Product Code R01202A MacConkey Agar with crystal violet, Product Code R01552A	IC MRSA Chromogenic BD analysis module uses media manufactured by Beckton Dickinson
BBLTM CHROMagarTM MRSA II, Product Codes 215228 (20pk) and 215229 (120pk) IC MRSA Chromogenic TFS/S analysis module uses media manufactured by Thermo Fisher Scientific SpectraTM MRSA, Product Codes R01821(A) (10pk) and R01822(A) (100pk)

Table 5-4: Comparison of Indications for Use Between Predicate and Subject Analysis Modules

Predicate Urine Analysis	IC MRSA Chromogenic BD	IC MRSA Chromogenic TF/S
Module	analysis module	analysis module
The APAS Independence is an in	The APAS Independence is an in	The APAS Independence is an in
vitro diagnostic system comprised	vitro diagnostic system comprised	vitro diagnostic system comprised
of an instrument for automated	of an instrument for automated	of an instrument for automated
imaging of agar culture plates and	imaging of agar plates and a	imaging of agar plates and a
a software analysis module for the	software analysis module for the	software analysis module for the
following use:	following use:	following use:
The APAS Independence, when	The APAS Independence, when	The APAS Independence, when
using its urine analysis module,	using its IC MRSA Chromogenic BD	using its IC MRSA Chromogenic
automates urine culture plate	analysis module, automates	TFS/S analysis module, automates
imaging and interpretation to	culture plate imaging and	culture plate imaging and
detect the presence or absence of	interpretation to detect the	interpretation to detect the
microbial growth on sheep blood	presence or absence of colonies	presence or absence of colonies
and MacConkey agar culture	with colors suggestive of	with colors suggestive of
plates that are inoculated with a	methicillin-resistant	methicillin-resistant
1µL sample volume.	Staphylococcus aureus (MRSA)	Staphylococcus aureus (MRSA)
The APAS Independence, when	growth on Beckton Dickson BBL™	growth on Thermo-Fisher
using its urine analysis module,	CHROMagar™ MRSA II agar that	Spectra™ MRSA agar that has
provides a semi-quantitative	has been inoculated with anterior	been inoculated with anterior
assessment of colony counts that	nares swabs and incubated at	nares swabs and incubated at
are used as an aid in the diagnosis	36°C ± 1°C for 24 hours.	36°C ± 1°C for 24 hours.
of urinary tract infection. All urine	The APAS Independence, when	The APAS Independence, when
culture plates that are identified
as positive for growth by the APAS
Independence, when using its
urine analysis module, must be
reviewed by a trained
microbiologist.	using its IC MRSA Chromogenic BD
analysis module, provides an aid in
routine screening for colonization
with MRSA. It provides one of two
screening results: Presumptive
MRSA or Negative. All culture
plates that are identified as
Presumptive MRSA by the APAS
Independence, when using the IC
MRSA Chromogenic BD analysis
module require review by a trained
microbiologist.	using its IC MRSA Chromogenic
TFS/S analysis module, provides
an aid in routine screening for
colonization with MRSA. It
provides one of three screening
results: Presumptive MRSA,
Presumptive non-MRSA, or
Negative. All culture plates that
are identified as Presumptive
MRSA or Presumptive non-MRSA
by the APAS Independence, when
using the IC MRSA Chromogenic
TFS/S analysis module, require
review by a trained microbiologist.

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5.8 Performance Data

This section addresses the software verification and validation conducted for each MRSA analysis module, and the performance requirements specified as Special Controls for a device of this type, which require that pre-market notification submissions include:

1. detailed documentation of the analytical studies performed to characterize device performance to support the intended use, as appropriate.
1. detailed documentation from clinical studies performed on a population that is consistent with the intended use population.
- a) The clinical studies must establish the device performance based on comparison to results obtained by an acceptable reference method, as appropriate.
- b) The clinical study documentation must include the study protocol with a predefined statistical analysis plan and the final report documenting support for the Indications for Use and the results of the statistical analysis, as appropriate.

5.8.1 Analysis Module Software Verification and Validation

Software verification and validation testing were conducted, and documentation was provided as recommended by FDA's Guidance for Industry and Staff, Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices. The software for this device was considered as a "moderate" level of concern as a malfunction of, or latent design flaw in the software could lead to an erroneous diagnosis or a delay in delivery of appropriate medical care that would likely lead to a Minor injury to the patient. See Section 16 for additional details.

Digital Image Quality, Digital Image Interpretation 5.8.2

When conducting clinical studies and some analytical performance studies, the reference result against which APAS performance was compared was generated by microbiologists interpreting growth on digital images of plates (plate image) rather than from the physical plate (plate-in-hand). Studies were conducted to determine:

a) If the interpretation of the digital imaqe of the same plate is reproducible across microbiologists, as this is the method used to generate performance data in support of the current 510(k) application.
b) Whether the plate-in-hand interpretation and plate image interpretation of the same plate are equivalent across microbiologists to determine if a microbiologist can equivalently interpret presumptive MRSA on the plate and the digital image, as this provide confidence that the diqital image interpretation is a true representation of the agar plate interpretation.

5.8.2.1 Point (a) Reproducibility of plate image interpretations

The reproducibility of plate image interpretations was assessed by comparing the individual assessments of plate images by three microbiologists with a single panel result (i.e., majority vote) for each image. Table 5-5 shows the percent agreement of the three microbiologists with the panel result for detection of presumptive MRSA, presumptive non-MRSA, and no growth on each of the BD BBL and TFS Spectra media.

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		Percent Agreement
		No growth	Presumptive non-MRSA	Presumptive MRSA
BD	Microbiologist 1	98.9% (260/263)	97.6% (80/82)	100.0% (55/55)
	Microbiologist 2	100.0% (263/263)	97.6% (80/82)	100.0% (55/55)
	Microbiologist 3	95.4% (251/263)	100.0% (82/82)	100.0% (55/55)
	Combined	98.1% (774/789)	98.4% (242/246)	100.0% (165/165)
TFS/S	Microbiologist 1	98.0% (192/196)	95.1% (98/103)	98.0% (99/101)
	Microbiologist 2	100.0% (196/196)	93.2% (96/103)	97.0% (98/101)
	Microbiologist 3	99.0% (194/196)	97.1% (100/103)	98.0% (99/101)
	Combined	99.0% (582/588)	95.1% (294/309)	97.7% (296/303)

Table 5-5: Microbiologist agreement with panel result

Table 5-5 shows that for BD media, when interpreting growth from digital images, microbiologists agree with the panel 100% of the time for detection of presumptive MRSA, over 97% of the time for presumptive non-MRSA, and over 95% of the time for no growth. Combining (averaging) these results yields 100%, 98.4% and 98.1%, respectively. These results support the use of digital images by a panel of microbiologists to establish a reference result against which the APAS result can be compared.

Table 5-5 shows that for TFS/S media, when interpreting growth from digital images, microbiologists agree with the panel more than 97% of the time for detection of presumptive MRSA, 93% of the time for presumptive non-MRSA, and 98% of the time for no growth. Combining (averaging) these results yields 97.7%, 95.1% and 99.0%, respectively. These results support the use of digital images by a panel of microbiologists to establish a reference result against which the APAS result can be compared.

5.8.2.2 Point (b) Equivalency of Plate-in-Hand vs. Plate Image

The equivalency of plate-in-hand vs. plate image measurements were assessed by measuring the percent of time a microbiologist's interpretations of the plate and image were in agreement for presumptive MRSA and applying an acceptance criterion of 95% for the combined result. In this comparison, the plate-in-hand interpretation is considered to be the truth state.

		Percent Agreement Microbiologist Image vs Plate-in-Hand
		No growth	Presumptive Non-MRSA	Presumptive MRSA
BD	Microbiologist 1	95.8% (252/263)	89.6% (69/77)	91.7% (55/60)
	Microbiologist 2	98.1% (264/269)	98.7% (74/75)	98.2% (55/56)
	Microbiologist 3	95.4% (250/262)	97.6% (82/84)	98.1% (53/54)
	Combined	96.5% (766/794)	95.3% (225/236)	95.9% (163/170)
TFS/S	Microbiologist 1	93.8% (182/194)	87.1% (88/101)	92.4% (97/105)
	Microbiologist 2	96.0% (193/201)	90.8% (89/98)	92.1% (93/101)
	Microbiologist 3	94.2% (180/191)	86.8% (92/106)	96.1% (99/103)
	Combined	94.7% (555/586)	88.2% (269/305)	93.5% (289/309)

Table 5-6: Microbiologist Image vs. Plate-in-hand agreement

Table 5-6 shows that on average, microbiologists interpret the plate image equivalent to the plate-inhand using the BD media >95% of the time for each result designation. Presumptive MRSA

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agreement is >95%, supporting the use of a 2-designation approach (Presumptive MRSA and Negative) with this media.

Table 5-6 shows that on average, microbiologists interpret the plate image equivalent to the plate-inhand using the TFS media 95% of the time was identified as the smallest colony size for each organism (bolded result).

Results of the study demonstrated that the smallest MRSA colony size that can be detected 95% of the time by APAS is 0.82 mm for MRSA wild strain and 0.91 mm for MRSA ATCC 43300 using the BD module (Table 5-11) and 0.63 mm for MRSA wild strain and 0.54 mm for MRSA ATCC 43300 using the TFS/S module (Table 5-12).

Colony Size (Diameter)		Detection Rate¹
Pixels	Extrapolated
mm	MRSA Wild Strain	MRSA ATCC 43300
1-3	0.09-0.27	0.0% (0/399)	0.4% (1/264)
4-5	0.36-0.45	1.5% (4/258)	1.7% (3/175)
6	0.54	5.2% (7/135)	9.7% (9/93)
7	0.63	18.6% (21/113)	22.8% (18/79)
8	0.72	72.5% (66/91)	42.9% (36/84)
9	0.82	95.1% (117/123)	67.6% (50/74)
10	0.91	98.0% (147/150)	97.7% (84/86)
11	1.00	100.0% (130/130)	99.0% (95/96)
12	1.09	100.0% (156/156)	100.0% (90/90)

Table 5-11: LoD of Colony Size - IC MRSA Chromogenic BD

1 Value calculated by dividing the number of presumptive MRSA colonies detected by APAS by the total number of colonies located by a microbiologist.

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Colony Size (Diameter)		Detection Rate1
Pixels	Extrapolated
mm	MRSA Wild Strain 1	MRSA ATCC 43300
1-3	0.09-0.27	0.0% (0/285)	1.8% (3/163)
4-5	0.36-0.45	7.6% (12/159)	43.0% (98/228)
6	0.54	70.8% (63/89)	97.7% (129/132)
7	0.63	98.0% (145/148)	100.0% (100/100)
8	0.72	99.5% (197/198)	100.0% (71/71)
9	0.82	100.0% (167/167)	100.0% (43/43)
10	0.91	100.0% (103/103)	100.0% (12/12)
11	1.00	100.0% (21/21)	100.0% (2/2)

Table 5-12: LoD of Colony Size - IC MRSA Chromogenic TFS/S

1 Value calculated by dividing the number of presumptive MRSA colonies detected by APAS by the total number of colonies located by a microbiologist.

5.8.4.4 Analytical Sensitivity - Detection of MRSA in Mixtures

This test evaluated the ability of APAS to detect small amounts (1-100 colonies) and large amounts (>100 colonies) of MRSA when in the presence of other growth (>100 white colonies) after incubation for 24 hours.

Five, 10-fold dilutions of a 0.5 McFarland suspension were prepared with two strains of MRSA, one strain of S. haemolyticus, and one strain of S. warneri, all of which had been isolated from the wild. A 1:1 mixture and a 1:10 mixture of MRSA with a non-MRSA orqanism were prepared for two different combinations of MRSA and non-MRSA. The plates were incubated at 36℃ ± 1℃ for 24 hours. The images were read and interpreted by APAS and by 3 microbiologists, each of whom recorded the presence or absence of MRSA colonies on the plate. The majority vote was taken as the truth state against which the APAS result was compared.

The results for APAS Independence with IC Chromogenic MRSA BD Analysis Module are shown in Table 5-13 and show that APAS correctly identifies the presence of MRSA colonies ≥95% of the time at 24 hours.

The results for APAS Independence with IC Chromogenic MRSA TFS/S Analysis Module are shown in Table 5-14. and show that APAS correctly identifies the presence of MRSA colonies ≥95% of the time at 24 hours.

20

| Organisms
Plated | Mixture
Ratios | CFU | | Agreement1 | |
|-------------------------------------------|-------------------|-------|-------|-----------------------------------|-------------------------------------|
| | | MRSA | Other | Presence or
absence
of MRSA | Presence or
absence
of Growth |
| MRSA (Strain 1)
S. haemolyticus | 1:1 | >100 | >100 | 100.0% (5/5) | 100.0% (5/5) |
| | 1:100 | 1-100 | >100 | 100.0% (5/5) | 100.0% (5/5) |
| MRSA (Strain 2)
S. warneri | 1:1 | >100 | >100 | 100.0% (5/5) | 100.0% (5/5) |
| | 1:100 | 1-100 | >100 | 100.0% (5/5) | 100.0% (5/5) |

Table 5-13: Detection of MRSA in Mixtures - IC MRSA Chromogenic BD

1 Agreement between majority panel microbiologist result (i.e., truth state) and APAS result.

Table 5-14: Detection of MRSA in Mixtures - IC MRSA Chromogenic TFS/S

Organisms Plated	Mixture Ratios	CFU		Agreement1
		MRSA	Other	Presence or absence of MRSA	Presence or absence of Growth
MRSA (Strain 1)
S. haemolyticus
(Strain 2)	1:1	>100	>100	100.0% (5/5)	100.0% (5/5)
	1:100	1-100	>100	100.0% (5/5)	100.0% (5/5)
MRSA (Strain 2)
S. warneri	1:1	>100	>100	100.0% (5/5)	100.0% (5/5)
	1:100	1-100	>100	100.0% (5/5)	100.0% (5/5)

1 Agreement between majority panel microbiologist result (i.e., truth state) and APAS result.

5.8.4.5 Analytical Specificity - Limit of Blank

This test examined the ability of APAS to correctly identify when there is no growth present on the agar, and therefore determine the likelihood of false positives caused by known interferences.

A test matrix of plates with no growth were prepared using 3 different applicators (flocked swab, cotton swab and 10μL loop) to inoculate plates using 3 different media (Stuart Transport, Amies Transport and saline) and no media (dry). The plates were labelled with one of 4 different labels applied to the base or side and were either marked with felt-tip pen or not. The test therefore consisted of a matrix of 96 plates (3 applicators x 4 media x 4 labels x 2 marks).

Table 5-15 shows that for APAS with IC MRSA Chromogenic BD, there was qood agreement that colored colonies indicative of MRSA were not present. The table also shows that growth may be detected, but that it was unlikely to be reported as presumptive MRSA.

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| Interference
Mechanism | Interference
Variable | Total number of
Images evaluated | Agreement that
no growth is
present (%)1 | Agreement that no
colored colonies
are present (%)2 |
|---------------------------|--------------------------|-------------------------------------|------------------------------------------------|-----------------------------------------------------------|
| Label Type | Paper, 1D, Base | 24 | 83.3 (20/24) | 100.0 (24/24) |
| Label Type | Paper, 2D, Base | 24 | 79.2 (19/24) | 95.8 (23/24) |
| Label Type | Plastic, 2D, Base | 24 | 75.0 (18/24) | 100.0 (24/24) |
| Label Type | Paper, 1D, Side | 24 | 70.8 (17/24) | 100.0 (24/24) |
| Applicator | Cotton swab | 32 | 65.6 (21/32) | 96.9 (31/32) |
| Applicator | Flocked swab | 32 | 84.4 (27/32) | 100.0 (32/32) |
| Applicator | 10uL Loop | 32 | 81.2 (26/32) | 100.0 (32/32) |
| Transport Media | Amies Transport | 24 | 91.7 (22/24) | 100.0 (24/24) |
| Transport Media | Dry | 24 | 75.0 (18/24) | 100.0 (24/24) |
| Transport Media | Saline | 24 | 87.5 (21/24) | 100.0 (24/24) |
| Transport Media | Stuart Transport | 24 | 54.2 (13/24) | 95.8 (23/24) |
| Pen | Present | 48 | 79.2 (38/48) | 100.0 (48/48) |
| Pen | Absent | 48 | 75.0 (36/48) | 97.9 (47/48) |

Table 5-15: Limit of Blank - IC MRSA Chromogenic BD

1 Value calculated by dividing the number of images with no detected growth by the total number of images

2 Value calculated by dividing the number of images with zero detected colored colonies by the total number of images

Table 5-16 shows that for APAS with IC MRSA Chromogenic TFS/S, there was good agreement that colored colonies indicative of MRSA were not present. The table also shows that growth may be detected, but that it was unlikely to be reported as presumptive MRSA.

Table 5-16: Limit of Blank - IC MRSA Chromogenic TFS/S

| Interference
Mechanism | Interference
Variable | Total number of
Images evaluated | Agreement that
no growth is
present (%)1 | Agreement that no
colored colonies
are present (%)2 |
|---------------------------|--------------------------|-------------------------------------|------------------------------------------------|-----------------------------------------------------------|
| Label Type | Paper, 1D, Base | 24 | 58.3 (14/24) | 100.0 (24/24) |
| | Paper, 2D, Base | 24 | 66.7 (16/24) | 100.0 (24/24) |
| | Plastic, 2D, Base | 24 | 54.2 (13/24) | 100.0 (24/24) |
| | Paper, 1D, Side | 24 | 58.3 (14/24) | 91.7 (22/24) |
| Applicator | Cotton swab | 32 | 62.5 (20/32) | 100.0 (32/32) |
| | Flocked swab | 32 | 50.0 (16/32) | 93.8 (30/32) |
| | 10uL Loop | 32 | 65.6 (21/32) | 100.0 (32/32) |
| Transport
Media | Amies Transport | 24 | 62.5 (15/24) | 95.8 (23/24) |
| | Dry | 24 | 70.8 (17/24) | 100.0 (24/24) |
| | Saline | 24 | 91.7 (22/24) | 100.0 (24/24) |
| | Stuart Transport | 24 | 12.5 (3/24) | 95.8 (23/24) |
| Pen | Present | 48 | 56.2 (27/48) | 97.9 (47/48) |
| | Absent | 48 | 62.5 (30/48) | 97.9 (47/48) |

1 Value calculated by dividing the number of images with no detected growth by the total number of images

2 Value calculated by dividing the number of images with zero detected colored colonies by the total number of images

22

5.8.4.6 Analytical Specificity - Interference with detection of MRSA

This test evaluated the ability of APAS to correctly detect MRSA in the presence of known interferences and to determine if a heavy growth of non-MRSA is detected by APAS as MRSA, as heavy growth of some non-MRSA orqanisms may display a chromogen reaction.

Pure 0.5 McFarland suspensions of MRSA and S. haemolyticus (representing non-MRSA) were serially diluted to produce an inoculum for each organism which would produce predominantly isolated colonies of MRSA and heavy growth of S. haemolyticus when cultured.

A test matrix of plates per organism was quadrant streaked using 3 different applicators (flocked swab, cotton swab and 10μL loop) to inoculate plates using 2 different media (Stuart Transport and Amies Transport), The plates were labelled with one of 4 different labels applied to the base or side and were either marked with felt-tip pen or not. The test therefore consisted of 48 plates (3 applicators x 2 media x 4 labels x 2 marks) per organism. The inoculated plates were incubated at 36℃ ± 1℃ for 24 hours and then imaged.

The images were processed to generate the APAS report for each plate and then the reported presence or absence of MRSA and non-MRSA were compared with the expected result for growth and color, which was the presence of colored growth and no colored growth, respectively.

The results for APAS Independence with IC MRSA Chromogenic BD Analysis Module are shown in Table 5-17. These results show that the interference modes tested had minimal impact on the ability of APAS to detect the presence of MRSA. The results also show that when a heavy inoculum of S. haemolyticus is present, false positive detections as presumptive MRSA occurred in this interference study.

| Organism | Interferenc
e
Mechanism | Interference
Variable | Total number of
Images
evaluated | Agreement with
Expected Growth¹
(%) | Agreement with
Expected Color²
(%) |
|------------------------------------------|-------------------------------|--------------------------|----------------------------------------|-------------------------------------------|------------------------------------------|
| MRSA | Label Type | Paper, 1D,
Base | 12 | 100.0 (12/12) | 100.0 (12/12) |
| | | Paper, 2D,
Base | 12 | 100.0 (12/12) | 100.0 (12/12) |
| | | Plastic, 2D,
Base | 12 | 100.0 (12/12) | 100.0 (12/12) |
| | | Paper, 1D, Side | 12 | 100.0 (12/12) | 100.0 (12/12) |
| | Applicator | Cotton swab | 16 | 100.0 (16/16) | 100.0 (16/16) |
| | | Flocked swab | 16 | 100.0 (16/16) | 100.0 (16/16) |
| | | 10uL Loop | 16 | 100.0 (16/16) | 100.0 (16/16) |
| | Transport
Media | Amies
Transport | 24 | 100.0 (24/24) | 100.0 (24/24) |
| | | Stuart
Transport | 24 | 100.0 (24/24) | 100.0 (24/24) |
| | Pen | Present | 24 | 100.0 (24/24) | 100.0 (24/24) |
| | | Absent | 24 | 100.0 (24/24) | 100.0 (24/24) |
| S.
haemolyticu
s (heavy
growth) | Label Type | Paper, 1D,
Base | 12 | 100.0 (12/12) | 41.7 (5/12) |
| | | Paper, 2D,
Base | 12 | 100.0 (12/12) | 16.7 (2/12) |
| | | Plastic, 2D,
Base | 12 | 100.0 (12/12) | 50.0 (6/12) |
| | | Paper, 1D, Side | 12 | 100.0 (12/12) | 100.0 (12/12) |

Table 5-17: Analytical Specificity - Interference - IC MRSA Chromogenic BD

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Traditional 510(k) APAS Independence with MRSA Analysis Module

| Organism | Interferenc
e
Mechanism | Interference
Variable | Total number of
Images
evaluated | Agreement with
Expected Growth1
(%) | Agreement with
Expected Color2
(%) |
|----------|-------------------------------|--------------------------|----------------------------------------|-------------------------------------------|------------------------------------------|
| | Applicator | Cotton swab | 16 | 100.0 (16/16) | 43.8 (7/16) |
| | | Flocked swab | 16 | 100.0 (16/16) | 50.0 (8/16) |
| | | 10uL Loop | 16 | 100.0 (16/16) | 62.5 (10/16) |
| | Transport
Media | Amies
Transport | 24 | 100.0 (24/24) | 50.0 (12/24) |
| | | Stuart
Transport | 24 | 100.0 (24/24) | 54.2 (13/24) |
| | Pen | Present | 24 | 100.0 (24/24) | 50.0 (12/24) |
| | | Absent | 24 | 100.0 (24/24) | 54.2 (13/24) |

1 Value calculated by dividing the number of images with detected growth by the total number of images

² Value calculated by dividing the number of images where the detection or non-detection of colored colonies matches expectation, by the total number of images

The results for APAS Independence with IC MRSA Chromogenic TFS/S Analysis Module are shown in Table 5-18. These results show that the interference modes tested had minimal impact on the ability of APAS to detect the presence of MRSA. The results also show that the heavy growth of S. haemolyticus did not cause false detections of presumptive MRSA on this media.

		Table 5-18: Analytical Specificity - Interference - IC MRSA Chromogenic TFS/S
--	--	-------------------------------------------------------------------------------	--

| Organism | Interference
Mechanism | Interference
Variable | Total number of
Images
evaluated | Agreement with
Expected Growth¹
(%) | Agreement with
Expected Color²
(%) |
|----------------------------------------------------|---------------------------|--------------------------|----------------------------------------|-------------------------------------------|------------------------------------------|
| MRSA | Label Type | Paper, 1D, Base | 12 | 100.0 (12/12) | 100.0 (12/12) |
| | | Paper, 2D, Base | 12 | 100.0 (12/12) | 100.0 (12/12) |
| | | Plastic, 2D, Base | 12 | 100.0 (12/12) | 100.0 (12/12) |
| | | Paper, 1D, Side | 12 | 100.0 (12/12) | 100.0 (12/12) |
| | Applicator | Cotton swab | 16 | 100.0 (16/16) | 100.0 (16/16) |
| | | Flocked swab | 16 | 100.0 (16/16) | 100.0 (16/16) |
| | | 10uL Loop | 16 | 100.0 (16/16) | 100.0 (16/16) |
| | Transport
Media | Amies
Transport | 24 | 100.0 (24/24) | 100.0 (24/24) |
| | | Stuart
Transport | 24 | 100.0 (24/24) | 100.0 (24/24) |
| | Pen | Present | 24 | 100.0 (24/24) | 100.0 (24/24) |
| | | Absent | 24 | 100.0 (24/24) | 100.0 (24/24) |
| S.
haemolyticus (heavy
growth) | Label Type | Paper, 1D, Base | 12 | 100.0 (12/12) | 100.0 (12/12) |
| | | Paper, 2D, Base | 12 | 100.0 (12/12) | 100.0 (12/12) |
| | | Plastic, 2D, Base | 12 | 100.0 (12/12) | 100.0 (12/12) |
| | | Paper, 1D, Side | 12 | 100.0 (12/12) | 91.7 (11/12) |
| | Applicator | Cotton swab | 16 | 100.0 (16/16) | 93.8 (15/16) |
| | | Flocked swab | 16 | 100.0 (16/16) | 100.0 (16/16) |
| | | 10uL Loop | 16 | 100.0 (16/16) | 100.0 (16/16) |

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Image /page/24/Picture/0 description: The image contains the logo for Clever Culture Systems. On the left is a red circle with a white abstract design inside. To the right of the circle are the words "CLEVER CULTURE" in bold, black letters on the top line, and "SYSTEMS" in bold, black letters on the bottom line.

Traditional 510(k) APAS Independence with MRSA Analysis Module

| Organism | Interferenc
e
Mechanism | Interference
Variable | Total number of
Images
evaluated | Agreement with
Expected Growth1
(%) | Agreement with
Expected Color2
(%) |
|----------|-------------------------------|--------------------------|----------------------------------------|-------------------------------------------|------------------------------------------|
| | Transport
Media | Amies
Transport | 24 | 100.0 (24/24) | 100.0 (24/24) |
| | | Stuart
Transport | 24 | 100.0 (24/24) | 95.8 (23/24) |
| Pen | | Present | 24 | 100.0 (24/24) | 95.8 (23/24) |
| | | Absent | 24 | 100.0 (24/24) | 100.0 (24/24) |

1 Value calculated by dividing the number of images with detected growth by the total number of images

2 Value calculated by dividing the number of images where the detection or non-detection of colored colonies matches expectation, by the total number of images

IVD Studies 5.8.5

The clinical performance of each analysis module was assessed in a prospective study, where the performance of APAS with each analysis module was evaluated separately aqainst two reference panels of 3 clinical microbiologists interpreting growth from the same APAS-generated digital image.

Device	Agar	Growth interpreted by;
APAS Independence with IC MRSA
Chromogenic BD Analysis Module	BBL CHROMagar MRSA II
From Becton Dickinson	APAS and Reference Panel
APAS Independence with IC MRSA
Chromogenic TFS/S Analysis
Module	Spectra™ MRSA
From Thermo Fisher Scientific (Remel)	APAS and Reference Panel

Left-over specimens from standard of care screening culture for colonization with MRSA were collected and inoculated onto chromogenic agar plates at a single site in Australia. The plates were then incubated and imaged with the APAS.

The APAS result for each image was compared against each of two reference results; one panel was located in the USA and the other in Australia. Each reference result was achieved using the majority result from the respective panel of 3 independent microbiologists.

Due to the low positivity rate for MRSA detection in the study population, simulated samples were prepared to supplement the study. The simulated swab samples were spiked with known MRSA and non-MRSA organisms. The use of simulated samples allowed the inclusion of unique strains of MRSA that provided global representation of the most common MRSA clades, including those found in the United States.

The total number of both clinical and simulated samples included in the final analysis for the IC MRSA Chromogenic BD Analysis Module (BD) and IC MRSA Chromogenic TFS/S Analysis Module (TFS/S) from the 1590 enrolled samples is shown in Table 5-19, stratified by the proportions of clinical and simulated samples.

Type	Samples recruited / included	Plates Imaged (BD)	Plates imaged (TFS/S)
PCR- MRSA Negative	1100	1093	1097
PCR- MRSA Positive	25	25	25
Simulated Negative	60	60	60
Simulated Positive	405	395	398
Total	1590	1573	1580

Table 5-19: Number of samples per specimen category

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Each specimen and simulated sample were inoculated onto a culture plate and incubated for 24 hours at 36±1ºC prior to analysis by APAS Independence and by the reference panels.

Performance was assessed by comparing the final interpretation of digital plate images established by the microbiologists (reference method) with the corresponding interpretation by APAS. The primary performance objective was positive percent agreement of presumptive MRSA growth.

Results - IC MRSA Chromogenic BD 5.8.5.1

Of the 1590 samples enrolled in the study, 13 were excluded due to defects in the agar and thus 1573 were analyzed, being 1118 non-simulated samples, 395 simulated MRSA-positive samples and 60 simulated negative MRSA samples. The study results are shown in Table 5-21 and Table 5-22.

Table 5-20: APAS Performance against Australian Reference Panel - IC MRSA Chromogenic BD

		AU Panel Result
		Presumptive
MRSA	Presumptive
non-MRSA	Negative	Total
APAS Result	Presumptive MRSA	393	30	3	426
	Presumptive non-MRSA	0	226	156	382
	Negative	0	11	754	765
	Total	393	267	913	1573
Presumptive MRSA
Agreement	100.0% (393/393: 95% CI 99.0% - 100.0%)
Presumptive Non-MRSA
Agreement	84.6% (226/267: 95% CI 79.8% - 88.5%)
Negative Agreement	82.6% (754/913: 95% CI 80.0% - 84.9%)

Table 5-21: APAS Performance against US Reference Panel - IC MRSA Chromogenic BD

		US Panel Result
		Presumptive MRSA	Presumptive non-MRSA	Negative	Total
APAS Result	Presumptive MRSA	390	33	3	426
	Presumptive non-MRSA	1	226	155	382
	Negative	0	10	755	765
	Total	391	269	913	1573
Presumptive MRSA Agreement	99.7% (390/391: 95% CI 98.6% - 100.0%)
Presumptive Non-MRSA Agreement	84.0% (226/269: 95% CI 79.2% - 87.9%)
Negative Agreement	82.7% (755/913: 95% CI 80.1% - 85.0%)

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Image /page/26/Picture/0 description: The image contains the logo for Clever Culture Systems. The logo consists of a red circle with a white molecular-like structure inside, followed by the company name "CLEVER CULTURE" in bold, black letters. Below the company name is the word "SYSTEMS", also in bold, black letters.

| Panel | Population | Statistic | Cases | Correct | Estimate | Lower
95% CI | Upper
95% CI |
|-------|---------------|-----------|-------|---------|---------------|-----------------|-----------------|
| US | All | PPA1 | 391 | 390 | 99.7% | 98.6% | 100.0% |
| | All | NPA2 | 1182 | 1146 | 97.0% | 95.8% | 97.8% |
| | Simulated | PPA | 358 | 358 | 100.0% | 98.9% | 100.0% |
| | Simulated | NPA | 97 | 79 | 81.4% | 72.6% | 87.9% |
| | Non-simulated | PPA | 33 | 32 | 97.0% | 84.7% | 99.5% |
| | Non-simulated | NPA | 1085 | 1067 | 98.3% | 97.4% | 98.9% |
| AU | All | PPA | 393 | 393 | 100.0% | 99.0% | 100.0% |
| | All | NPA | 1180 | 1147 | 97.2% | 96.1% | 98.0% |
| | Simulated | PPA | 359 | 359 | 100.0% | 98.9% | 100.0% |
| | Simulated | NPA | 96 | 79 | 82.3% | 73.5% | 88.6% |
| | Non-simulated | PPA | 34 | 34 | 100.0% | 89.8% | 100.0% |
| | Non-simulated | NPA | 1084 | 1068 | 98.5% | 97.6% | 99.1% |

Table 5-22. Presumptive MRSA agreement results stratified by sample type – IC MRSA Chromogenic BD

1 Positive percent agreement with the panel that presumptive MRSA is present

2Negative percent agreement. APAS agreement with the panel that presumptive MRSA is absent

5.8.5.2 Results - IC MRSA Chromogenic TFS/S

Of the 1590 samples enrolled in the study, 10 were excluded due to defects in the agar so that a total of 1580 was analyzed, being 1122 non-simulated samples, 398 simulated MRSA-positive samples and 60 simulated negative MRSA samples.

The study results are shown in Table 5-23 Table 5-24 and Table 5-25

Table 5-23: Performance against Australian Reference Panel - IC MRSA Chromogenic TFS/S

	AU Panel Result
		Presumptive MRSA	Presumptive non-MRSA	Negative	Total
APAS Result	Presumptive MRSA	476	69	1	546
	Presumptive non-MRSA	3	383	116	502
	Negative	1	5	526	532
	Total	480	457	643	1580
Presumptive MRSA Agreement		99.2% (476/480: 95% CI 97.9% - 99.7%)
Presumptive Non-MRSA Agreement		83.8% (383/457: 95% CI 80.2% - 86.9%)
Negative Agreement		81.8% (526/643: 95% CI 78.6% - 84.6%)

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			US Panel Result
			Presumptive
MRSA	Presumptive
non-MRSA	Negative	Total
APAS Result	Presumptive MRSA	434	110	2	546
	Presumptive non-MRSA	1	369	132	502
	Negative	1	4	527	532
Total		436	483	661	158
Presumptive MRSA
Agreement		99.5% (434/436: 95% CI 98.3% - 99.9%)
Presumptive Non-MRSA
Agreement		76.4% (369/483: 95% CI 72.4% - 80.0%)
Negative Agreement		79.7% (527/661; 95% CI 76.5% - 82.6%)

Table 5-24: Performance against US Reference Panel - IC MRSA Chromogenic TFS/S

Table 5-25: Presumptive MRSA agreement stratified by sample type for MRSA performance – IC MRSA Chromogenic TFS/S

Panel	Population	Statistic	Cases	Correct	Estimate	Lower 95% CI	Upper 95% CI
All	All	PPA1	436	434	99.5%	98.3%	99.9%
	All	NPA2	1144	1032	90.2%	88.4%	91.8%
US	Simulated	PPA	362	362	100.0%	98.9%	100.0%
		NPA	96	88	91.7%	84.4%	95.7%
US	Non-simulated	PPA	74	72	97.3%	90.7%	99.3%
		NPA	1048	944	90.1%	88.1%	91.7%
AU	All	PPA	479	475	99.2%	97.9%	99.7%
	All	NPA	1101	1030	93.6%	91.9%	94.9%
AU	Simulated	PPA	362	362	100.0%	98.9%	100.0%
		NPA	96	88	91.7%	84.4%	95.7%
AU	Non-simulated	PPA	117	113	96.6%	91.5%	98.7%
		NPA	1005	942	93.7%	92.1%	95.1%

1 Positive percent agreement with the panel that presumptive MRSA is present 2Negative percent agreement. APAS agreement with the panel that presumptive MRSA is absent

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5.8.5.3 Agreement between the Australian and US reference panels

An analysis of the results from the Australian and US panels of microbiologists was performed to determine the extent of agreement in interpretation of the same digital images. This data is presented in Table 5-26 and Table 5-27 where the AU panel result is treated as being the truth.

		AU Microbiologist panel
		MRSA Growth	Non-MRSA Growth	No growth	Total
US Microbiologist panel	MRSA Growth	390	1	0	391
	Non-MRSA Growth	3	253	13	269
	No growth	0	13	900	913
	Total	393	267	913	1573
Agreement - Presumptive
MRSA	99.2% (390/393: 95% CI 97.8% - 99.7%)
Agreement - Presumptive
Non-MRSA	94.8% (253/267: 95% CI 91.4% - 96.9%)
Agreement - No growth	98.6% (900/913: 95% CI 97.6% - 99.2%)

Table 5-26: Aqreement of US panel with Australian panel - images of BD plates

Table 5-27: Agreement of US panel with Australian panel - images of TFS plates

		AU Microbiologist
		MRSA Growth	Non-MRSA Growth	No growth	Total
US Microbiologist	MRSA Growth	435	1	0	436
	Non-MRSA Growth	45	432	6	483
	No growth	0	24	637	661
	Total	480	457	643	1580
Agreement - Presumptive
MRSA	90.6% (435/480: 95% CI 87.7% - 92.9%)
Agreement - Presumptive
Non-MRSA	94.5% (432/457: 95% CI 92.0% - 96.3%)
Agreement - No growth	99.1% (637/643: 95% CI 98.0% - 99.6%)

The tables show that the US panel had 99.8% agreement with the Australian panel for presumptive MRSA when interpreting images of BD plates and 90.6% agreement for images of TFS plates, indicating that the Australian panel reported more MRSA than the US panel.

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Image /page/29/Picture/0 description: The image features the logo for Clever Culture Systems, which includes a stylized red atom-like graphic to the left of the company name. To the right of the logo is the text "Traditional 510(k) APAS Independence with MRSA Analysis Module". The text describes the company's focus on traditional 510(k) APAS independence and its MRSA analysis module.

5.9 Conclusions

5.9.1 2 vs 3 Designation Rule Set

The overall performances for the BD MRSA and TFS/S MRSA analysis modules have been evaluated to determine the possible claims that could be supported and how performance issues could be mitigated. As a result, considering data and supportive metrics from other studies, it was concluded that either a two-designation rule set (i.e., presumptive MRSA growth and negative) or a threedesignation rule set (i.e., presumptive MRSA growth, presumptive non-MRSA growth, and negative) would be appropriate.

The overall performance of the BD MRSA analysis module for detection of presumptive MRSA growth (both in the analytical studies and clinical study) is acceptable to support a two-designation rule set (i.e., presumptive MRSA growth and negative). As such, only plates with "presumptive MRSA growth" require review by a microbiologist. The acceptability of the two-designation rule set is based on the following performance metrics:

95% agreement for "presumptive MRSA growth" (95.9%, Table 5-6) in the digital image ● quality study
98% agreement for "presumptive MRSA growth" in the Australian (100.0%, Table 5-20) and . US clinical studies (99.7%, Table 5-21)
95% agreement for "presumptive MRSA growth" when comparing the Australian and US . microbiologist panel results (99.2%, Table 5-26)

The overall performance of the TFS/S MRSA analysis modules for detection of presumptive MRSA growth (both in the analytical studies and clinical study) is acceptable to support a three-designation rule set (i.e., presumptive MRSA growth, presumptive non-MRSA growth, and negative). As such, all plates with growth ("presumptive MRSA growth" or "presumptive non-MRSA growth) require review by a microbiologist. The acceptability of the three-designation rule set is based on the following performance metrics:

98% agreement for "presumptive MRSA growth" in the Australian reference panel (99.2%, . Table 5-23) and US clinical studies (99.5%, Table 5-24)
.