The FilmArray Blood Culture Identification (BCID) Panel is a qualitative multiplexed nucleic acid-based in vitro diagnostic test intended for use with FilmArray systems. The FilmArray BCID Panel is capable of simultaneous detection and identification of multiple bacterial and yeast nucleic acids and select genetic determinants of antimicrobial resistance. The FilmArray BCID Panel assay is performed directly on blood culture samples identified as positive by a continuous monitoring blood culture system. Results are intended to be interpreted in conjunction with Gram stain results.

The following gram-positive bacteria, gram-negative bacteria, and yeast are identified using the FilmArray BCID Panel: Enterococci, Listeria monocytogenes, Staphylococci (including specific differentiation of Staphylococcus aureus), Streptococci (with specific differentiation of Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes), Acinetobacter baumannii, Enterobacteriaceae (including specific differentiation of the Enterobacter cloacae complex, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus, and Serratia marcescens), Haemophilus influenzae, Neisseria meningitidis (encapsulated), Pseudomonas aeruginosa, Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, and Candida tropicalis.

The FilmArray BCID Panel also contains assays for the detection of genetic determinants of resistance to methicillin (mecA), vancomycin (vanA and vanB), and carbapenems (blaxe) to aid in the identification of potentially antimicrobial resistant organisms in positive blood culture samples. The antimicrobial resistance gene detected may or may not be associated with the agent responsible for disease. Negative results for these select antimicrobial resistance gene assays do not indicate susceptibility, as multiple mechanisms of resistance to methicillin, vancomycin, and carbapenems exist.

FilmArray BCID Panel is indicated as an aid in the diagnosis of specific agents of bacteremia and fungemia and results should be used in conjunction with other clinical and laboratory findings. Positive FilmArray results do not rule out co-infection with organisms not included in the FilmArray BCID Panel. FilmArray BCID Panel is not intended to monitor treatment for bacteremia or fungemia.

Subculturing of positive blood cultures is necessary to recover organisms for susceptibility testing and epidemiological typing, to identify organisms in the blood culture that are not detected by the FilmArray BCID Panel, and for species determination of some Staphylococci, Enterococci, Streptococci, and Enterobacteriaceae that are not specifically identified by the FilmArray BCID Panel assays.

Device Description

The FilmArray Blood Culture Identification (BCID) Panel is a multiplex nucleic acid test designed to be used with a FilmArray system. The FilmArray BCID pouch contains freeze-dried reagents to perform nucleic acid purification and nested, multiplex PCR with DNA melt analysis. The FilmArray Blood Culture Identification (BCID) Panel simultaneously tests a single positive blood culture sample to provide results for 24 different organisms and organism groups that cause bloodstream infections and three genetic markers that are known to confer antimicrobial resistance (see Table 1).

A test is initiated by loading Hydration Solution and a positive blood culture sample mixed with the provided Sample Buffer into the FilmArray BCID pouch. The pouch contains all of the reagents required for specimen testing and analysis in a freeze-dried format; the addition of Hydration Solution and sample Buffer Mix rehydrates the reagents. After the pouch is prepared, the software guides the user though the steps of placing the pouch into the instrument. scanning the pouch barcode, entering the sample identification, and initiating the run.

The FilmArray instrument contains a coordinated system of inflatable bladders and seal points, which act on the pouch to control the movement of liquid between the pouch blisters. When a bladder is inflated over a reagent blister, it forces liquid from the blister into connecting channels. Alternatively, when a seal is placed over a connecting channel it acts as a valve to open or close a channel. In addition, electronically controlled pneumatic pistons are positioned over multiple plungers in order to deliver the rehydrated reagents into the blisters at the appropriate times. Two Peltier devices control heating and cooling of the pouch to drive the PCR reactions and the melt curve analysis.

Nucleic acid extraction occurs within the FilmArray pouch using mechanical lysis and standard magnetic bead technology. After extracting and purifying nucleic acids from the unprocessed sample, a nested multiplex PCR is executed in two stages. During the first stage, a single, large volume, highly multiplexed PCR reaction which includes all primers of the outer primer sets, is performed. The products from first stage PCR are then diluted and combined with a fresh, primer-free master mix and a fluorescent double stranded DNA binding dye (LC Green® Plus, BioFire Defense, LLC). The solution is then distributed to each well of the array. Array wells contain sets of primers designed specifically to amplify sequences internal to the PCR products generated during the first stage PCR reaction. The 2nd stage PCR, or nested PCR, is performed in singleplex fashion in each well of the array. At the conclusion of the 2nd stage PCR, the array is interrogated by melt curve analysis for the detection of signature amplicons denoting the presence of specific targets. A digital camera placed in front of the array captures fluorescent images of the PCR reactions and software interprets the data.

The FilmArray software automatically interprets the results of each DNA melt curve analysis and combines the data with the results of the internal pouch controls to provide a test result for each organism on the panel.

AI/ML Overview

The provided document is a 510(k) summary for a modification to an existing medical device, the FilmArray Blood Culture Identification (BCID) Panel. This submission primarily focuses on changes to the intended use and labeling, rather than a full re-evaluation of the device's original performance. As such, the document does not contain a typical study outlining comprehensive acceptance criteria and performance against those criteria in the same way an initial submission might.

However, based on the information provided, we can infer some "acceptance criteria" related to the changes being made and how the device meets them.

Here's an attempt to structure the information as requested, with caveats due to the nature of the document:

1. Table of Acceptance Criteria and Reported Device Performance

Since this is a modification submission, the "acceptance criteria" discussed are largely related to ensuring the changes (removal of false positive warnings, additional interference testing, and updated cross-reactivity information) do not negatively impact the device's overall performance as established by the predicate device.

Acceptance Criteria Category	Specific Acceptance Criteria (Inferred from study goals)	Reported Device Performance (Summary from this document)
Removal of False Positive Warnings (BioMérieux BacT/ALERT SN)	Ensure that the identified source of false positives for Enterococcus and Pseudomonas aeruginosa in bioMérieux BacT/ALERT SN bottles has been corrected and removed, and that the device no longer exhibits an increased risk of false positives with these bottles. The device should demonstrate reliable and accurate detection for these targets when tested in these specific bottles, on par with other approved blood culture bottles.	The source of false positive results has been identified, corrected, and removed. The limitation regarding increased risk of false positives for Pseudomonas aeruginosa and Enterococcus with bioMérieux BacT/ALERT SN bottles is being removed from the labeling as "no longer accurate."
Additional Interference Testing (New Blood Culture Bottles)	The device should not exhibit significant interference or unexpected invalid results when used with the newly added bioMerieux BacT/ALERT FA Plus and BacT/ALERT FN Plus blood culture media bottle types. Results obtained with these new bottle types should be comparable to those obtained with previously approved media.	"All 21 runs were valid with passed controls and no errors or unexpected results." The FilmArray BCID Panel Instruction Booklet will be updated to include these bottle types as acceptable.
Newly Identified Organism Cross-Reactivities	Accurately identify and characterize any newly discovered organism cross-reactivities. The updated labeling must reflect these findings to ensure users are aware of potential interpretations. (This is more an acceptance of identifying and reporting rather than a performance target per se)	New organism cross-reactivity findings (e.g., for Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Haemophilus influenzae, Listeria monocytogenes, Candida parapsilosis, Candida krusei, vanA/B) were identified and will be added to the Instruction Booklet.

2. Sample Size Used for the Test Set and Data Provenance

Due to the nature of this submission being a modification of use and labeling, the "test set" described is specifically for the interference testing. The document does not detail the full original clinical validation test set.

Interference Testing (bioMerieux BacT/ALERT FA Plus and BacT/ALERT FN Plus bottles):
- Sample Size: 7 contrived blood culture samples (6 positive and 1 negative) per media type. As three media types were tested (BD BACTEC Plus Aerobic/F, BacT/ALERT FA Plus, BacT/ALERT FN Plus), this implies a total of 21 runs.
- Data Provenance: Not explicitly stated, but these were contrived samples prepared in a laboratory setting, likely at BioFire Diagnostics. Therefore, it's a prospective analytical study. Country of origin is implied to be within the US, where BioFire Diagnostics is located.
Cross-Reactivity Updates:
- The document notes that some cross-reactivities were observed "infrequently in pre-analytical studies and the clinical evaluation (estimated occurrence of ~0.25% of all Staphylococcus positive patient samples)," and "in contrived samples and/or clinical blood culture specimens."
- For Klebsiella quasipneumoniae, it's stated as a "new species (with subspecies) that is closely related to K. pneumoniae," implying some form of ongoing surveillance or re-evaluation. Similarly, Raoultella ornithinolytica cross-reactivity was "observed in clinical positive blood cultures."
- This suggests some data comes from retrospective analysis of previously collected clinical data or ongoing surveillance, as well as new analytical testing (contrived samples). Specific sample sizes for these cross-reactivity discoveries are not provided in this summary.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and the Qualifications of Those Experts

Interference Testing: Not applicable in the same way as a clinical study. Ground truth for the contrived samples would have been precisely known based on their preparation. For example, a "positive" sample would have been spiked with a known organism at a known concentration.
Cross-Reactivity: The document does not specify experts involved in establishing ground truth for the discovery of cross-reactivities. However, the identification of microorganisms and their genetic markers typically relies on established microbiology laboratory methods, often overseen by experienced microbiologists. Given the "in silico analysis" mentioned, bioinformatics experts would also be involved.

4. Adjudication Method for the Test Set

Interference Testing: No formal adjudication method like "2+1" or "3+1" is mentioned or expected for this type of analytical validation using contrived samples. The results (valid runs, no errors, lack of interference) are directly observable from the instrument's output and comparison against expected results based on sample preparation.
Cross-Reactivity: The document doesn't detail an adjudication process for identifying cross-reactivities, but it references "pre-analytical studies," "clinical evaluation," and "in silico analysis." This implies internal validation and expert review of results from various sources.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study Was Done, If So, What Was the Effect Size of How Much Human Readers Improve with AI vs Without AI Assistance

No, an MRMC comparative effectiveness study was not done. The FilmArray BCID Panel is an in vitro diagnostic (IVD) device that directly detects nucleic acids from blood culture samples and provides an automated interpretation. It is not an imaging AI device that "assists human readers" in the traditional sense. The device generates a definitive result (presence/absence of specific organisms/resistance genes), and while healthcare professionals interpret these results in conjunction with other clinical findings (like Gram stain), there isn't a human-in-the-loop "reading" task that the device is assisting.

6. If a Standalone (i.e. algorithm only without human-in-the loop performance) Was Done

Yes, the primary performance of the FilmArray BCID Panel is standalone algorithm performance. The device performs nucleic acid extraction, PCR, and melt curve analysis, and its software automatically interprets the results. The "test interpretation" is described as "Automated test interpretation and report generation. User cannot access raw data." This confirms it's an algorithm-only, standalone performance. The document does not present separate standalone performance data for this specific submission as it is about modifications to an existing, already cleared device. The "performance" being demonstrated here is primarily the robustness of the existing system to new conditions (bottle types) and the transparent reporting of newly identified cross-reactivities. The performance of the predicate device (K160457) would have established its standalone performance.

7. The Type of Ground Truth Used

Interference Testing: The ground truth for the contrived samples was known composition (i.e., specific organisms spiked at known concentrations, or negative controls).
Cross-Reactivity: The ground truth for identified cross-reactivities likely came from a combination of:
- Analytical testing (e.g., testing known isolates/species in contrived samples).
- Clinical culture results (identifying organisms in patient samples that cross-reacted with the panel).
- In silico analysis (bioinformatics prediction based on sequence homology).

8. The Sample Size for the Training Set

Not applicable for this modification submission. This document describes modifications to an existing device (K160457). The "training set" (if applicable from a machine learning perspective, which is unlikely for a PCR-based IVD) would have been part of the original development and validation of the predicate device, not detailed in this modification summary. The FilmArray panel design (primers, probes) itself is developed through a sophisticated "training" process involving bioinformatic analysis of target sequences, but the document does not provide details on specific sample sizes for that primer/probe design process.

9. How the Ground Truth for the Training Set Was Established

Also not applicable for this modification submission as a "training set" for an algorithm in the machine learning sense isn't detailed, nor is its ground truth establishment. For the original development of the PCR panel, the ground truth for probe design and target identification would have been established through extensive genomic sequencing data, validated microbial culture collections, and molecular characterization methods.

Summary

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Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). The logo consists of two parts: the Department of Health and Human Services logo on the left and the FDA logo on the right. The FDA logo is a blue square with the letters "FDA" in white, followed by the words "U.S. Food & Drug Administration" in blue.

July 5, 2018

BioFire Diagnostics, LLC Kristen Kanack Senior Vice President, Regulatory & Clinical Affairs 515 Colorow Drive Salt Lake City, Utah 84108

Re: K181493

Trade/Device Name: FilmArray Blood Culture Identification (BCID) Panel Regulation Number: 21 CFR 866.3365 Regulation Name: Multiplex nucleic acid assay for identification of microorganisms and resistance markers from positive blood cultures. Regulatory Class: Class II Product Code: PEN, PAM Dated: June 5, 2018 Received: June 6, 2018

Dear Kristen Kanack:

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. 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 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); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR

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Part 820); 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 http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm.

For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). 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 (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

for

Uwe Scherf, Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known)

Device Name

Indications for Use (Describe)

Prescription Use (Part 21 CFR 801 Subpart D)

| Over-The-Counter Use (21 CFR 801 Subpart C)

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Special 510(k) Summary BioFire Diagnostics, LLC

FilmArray Blood Culture Identification (BCID) Panel

Introduction: According to the requirements of 21 CFR 807.92, the following information provides sufficient detail to understand the basis for a determination of substantial equivalence.

Submitted by:

BioFire Diagnostics, LLC 515 Colorow Drive Salt Lake City, UT 84108

Contact:

Kristen J. Kanack, Ph.D. Telephone: 801-736-6354. ext. 1330 Fax: 801-588-0507 Email: Kristen.kanack@biofiredx.com

Date Submitted:

June 5, 2018

Trade Name: FilmArray Blood Culture Identification (BCID) Panel

Classification Name:

Multiplex devices that use DNA hybridization to detect bacteria and their resistance markers. (21 CFR 866.3365)

Predicate Device:

K160457 - FilmArray Blood Culture Identification (BCID) Panel

Intended Use:

BioFire Diagnostics, LLC Special 510(k) FilmArray BCID Panel Modification

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Proteus, and Serratia marcescens), Haemophilus influenzae, Neisseria meningitidis (encapsulated), Pseudomonas aeruginosa, Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, and Candida tropicalis.

Device Description:

Gram-Positive Bacteria	Gram-Negative Bacteria	Yeast
Enterococcus	Acinetobacter baumannii	Candida albicans
Listeria monocytogenes	Enterobacteriaceae	Candida glabrata
Staphylococcus	Enterobacter cloacae complex	Candida krusei
Staphylococcus aureus	Escherichia coli	Candida parapsilosis
Streptococcus	Klebsiella oxytoca	Candida tropicalis
Streptococcus agalactiae	Klebsiella pneumoniae	Antimicrobial resistance genes
Streptococcus pneumoniae	Proteus	mecA – methicillin resistance
Streptococcus pyogenes	Serratia marcescens	vanA/B - vancomycin resistance
	Haemophilus influenzae	blaKPC - carbapenem resistance
	Neisseria meningitidis (encapsulated)
	Pseudomonas aeruginosa

Table 1. FilmArray BCID Panel Test Results.

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Device Comparison:

The purpose of this submission is to modify the intended use and labeling of the FilmArray Blood Culture Identification (BCID) Panel. The previously cleared FilmArray BCID Panel test was intended to be performed directly on blood culture samples identified as positive by a continuous monitoring blood culture system that demonstrate the presence of organisms as determined by Gram stain. The intended use is being modified so that results can instead be used in conjunction with Gram stain results.

Additional labeling modifications are also being incorporated, including:

. Removal of false positive warnings for manufacturer-specific (bioMérieux BacT/ALERT SN) blood culture bottles.
Additional interference testing to include bioMérieux BacT/ALERT FA plus and FN plus ● blood culture bottles

BioFire Diagnostics, LLC Special 510(k) FilmArray BCID Panel Modification

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Addition of newly identified organism cross-reactivity ●
The following table compares the modified FilmArray BCID Panel to the previously cleared FilmArray BCID Panel (K160457). The table outlines the similarities and differences between the two panels.

Table 2. Comparison of the FilmArray Blood Culture Identification (BCID) Panel with modified intended use and labeling to the current FilmArray Blood Culture Identification (BCID) Panel.

Element	Modified Device:FilmArray BCID Panel (with modified intendeduse and labeling)	Predicate:FilmArray BCID Panel(K160457)
OrganismsDetected	Enterococci, Listeria monocytogenes, Staphylococci(including specific differentiation of Staphylococcusaureus), Streptococci (with specific differentiation ofStreptococcus agalactiae, Streptococcus pneumoniae,and Streptococcus pyogenes), Acinetobacterbaumannii, Enterobacteriaceae (including specificdifferentiation of the Enterobacter cloacae complex,Escherichia coli, Klebsiella oxytoca, Klebsiellapneumoniae, Proteus, and Serratia marcescens),Haemophilus influenzae, Neisseria meningitidis(encapsulated), Pseudomonas aeruginosa, Candidaalbicans, Candida glabrata, Candida krusei,Candida parapsilosis, Candida tropicalis, andresistance markers mecA, vanA, vanB, and blakpc(KPC)	Same
Analyte	DNA	Same
Specimen Types	Positive blood culture samples.	Same
TechnologicalPrinciples	Nested multiplex PCR followed by high resolutionmelting analysis to confirm identity of amplifiedproduct.	Same
Instrumentation	Single instrument FilmArray System, FilmArray 2.0System, or FilmArray Torch System	Same
Time to result	About 1 hour	Same
TestInterpretation	Automated test interpretation and report generation.User cannot access raw data.	Same
ReagentHydration andSample Loading	FilmArray Injection Vial-based loading procedure	Same
SamplePreparationMethod	Sample Processing is automated in the FilmArrayBCID pouch.	Same
Reagent Storage	Reagents are stored at room temperature.	Same
Controls	Two controls are included in each reagent pouch tocontrol for sample processing and both stages of PCRand melt analysis.	Same
UserComplexity	Moderate/Low	Same

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Updates to the FilmArray BCID Panel Instruction Booklet

Removal of False Positive Warnings for Manufacturer-Specific Blood Culture Bottles

In 2014, BioFire reported an increased risk of false positive results (specifically for Enterococcus and Pseudomonas aeruginosa) when the FilmArray BCID Panel is used with bioMérieux BacT/ALERT Standard Anaerobic (SN) blood culture bottles (Recall Event ID 68352). The source of these false positive results has been identified, corrected, and removed. Therefore, the following limitation, along with similar warnings throughout the Instruction Booklet is being removed, as it is no longer accurate:

-There is an increased risk of false positive test results for Pseudomonas aeruginosa and Enterococcus when the FilmArray BCID Panel is used to test bioMérieux BacT/ALERT SN standard anaerobic blood culture bottles. If the FilmArray BCID Panel is used with these bottles, then positive results for Pseudomonas aeruginosa and Enterococcus should be confirmed by another method prior to reporting the test results.

Additional Interference Testing

BioFire performed additional interference testing of two bioMerieux blood culture media bottle types (BacT/ALERT FA Plus and BacT/ALERT FN Plus) in order to add them as acceptable bottle types for use with the FilmArray BCID Panel.

Seven contrived blood culture samples (six positive and one negative) were prepared in each of three media or bottle types and subsequently tested with the FilmArray BCID Panel. The aim was to compare results obtained from samples prepared with a control or reference media (BD BACTEC Plus Aerobic/F) to those from samples prepared with aerobic and anaerobic media/bottle types which contain resin for antibiotic adsorption (BacT/ALERT FA Plus and BacT/ALERT FN Plus). Samples prepared in the BD BACTEC Plus Aerobic/F and BacT/ALERT FA Plus media had been evaluated in the original study, though the BacT/ALERT FA Plus bottles used in the study were obtained from the manufacturer (Biomerieux) prior to IVD labeling and use of the bottles in the United States. Testing of samples in BacT/ALERT FN Plus media was not performed in the original study.

All 21 runs were valid with passed controls and no errors or unexpected results. The FilmArray BCID Panel Instruction Booklet will be updated to include these bottle types as shown in Table 3 below in red (refer to Table 77 in the Instruction Booklet).

EndogenousSubstances	Exogenous Substances		Technique-SpecificSubstances
Hemoglobin	Fluconazole	Ceftriaxone	Bleach
Triglycerides	Vancomycin	Tetracycline	Ethanol
Bilirubin	Ciprofloxacin	Amoxicillin/Clavulanate
γ-globulin	Gentamicin sulfate	Heparin
Human Genomic DNA	Imipenem	Sodium Polyanetholesulfonate (SPS)
On-Panel Competing Microorganisms		Off-Panel Competing Microorganisms
Staphylococcus epidermidis		Corynebacterium jeikeium
Escherichia coli		Bacillus cereus
Streptococcus mitis		Micrococcus luteus
		Clostridium perfringens
		Propionibacterium acnes

Table 3. Potentially Interfering Substances Tested (No Interference Observed)

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Blood Culture Media/Bottle Types
BACTEC Plus Aerobic/F	BacT/ ALERT SA Standard Aerobic	VersaTREK REDOX 1
BACTEC Standard Aerobic	BacT/ ALERT SN Standard Anaerobic	VersaTREK REDOX 2
BACTEC Standard Anaerobic	BacT/ ALERT FA Aerobic FAN
BACTEC Plus Anaerobic/F	BacT/ ALERT FN Anaerobic FAN
BACTEC Pediatric Plus	BacT/ ALERT PF Pediatric FAN
BACTEC Lytic/10 Anaerobic/F	BacT/ALERT FA Plus Aerobic
	BacT/ALERT FN Anaerobic

Note: While not shown to interfere in this evaluation, blood culture bottles that contain charcoal have the potential to generate false positive results presumably due to the presence of nucleic acids from non-viable organisms and are listed as contraindicated for use with the FilmArray BCID Panel system.

Newly Identified Organism Cross-Reactivities

BioFire has identified new organism cross-reactivity not previously found during premarket analytical and clinical studies. These findings will be added to the FilmArray BCID Panel Instruction Booklet where appropriate, including Table 4 listed below - updates show in red (see Table 72 in Instruction Booklet).

FilmArray BCID Panel Result	Cross-Reactive Organism(s)/Isolate(s)/Gene
Gram-positive Bacteria
Enterococcus	Some coagulase-negative Staphylococcia
Gram-negative Bacteria
Acinetobacter baumannii	Acinetobacter calcoaceticus-baumannii (ACB) complex species:Acinetobacter calcoaceticus (ssp. anitratus) bAcinetobacter pittii (formerly genomospecies 3)bAcinetobacter seifertii b,c
Escherichia coli/Enterobacteriaceae	Escherichia fergusonniiShigella species (S. boydii, S. dysenteriae, S. flexneri, S. sonnei)
Enterobacter cloacae complex/Enterobacteriaceae	Pantoea (Enterobacter) agglomerans c
Klebsiella oxytoca/Enterobacteriaceae	Klebsiella michiganensis d
Klebsiella pneumoniae/Enterobacteriaceae	Klebsiella quasipneumoniae eKlebsiella variicola (aka Klebsiella pneumoniae variant 342)Enterobacter aerogenes (reclassified as Klebsiella aerogenes)Raoultella ornithinolytica
Serratia marcescens/Enterobacteriaceae	Serratia species (S. entomophilaa, S. ficaria, S. odoriferaa, and S. rubidaeaa)Raoultella ornithinolyticaPseudomonas aeruginosa (ATCC 25619) hSome Pseudomonas species (e.g. P. putida, P. poae, and P. veronii) iSome Pantoea species (e.g. P. calida, P. gavinia, and P. septica)i
Haemophilus influenzae	Some Haemophilus species (H. haemolyticus, H. sputorum, and H. influenzae biotypeIV (H. quentini)) j
Listeria monocytogenes	Listeria innocua c
Yeast
Candida parapsilosis	Candida orthopsilosis (Group III Candida parapsilosis) lCandida multigemmis c
Candida krusei	Some Streptococcus species (S. mitis, S. pneumoniae, S. dysgalactiae, S. equi, S.oralis, S. parauberis, S. pyogenes, S. salivarious, and S. thermophilus) l
Antimicrobial Resistance Genes
vanA/B	vanMm

Table 4. Predicted and Observed Cross-Reactivity with On-Panel or Off-Panel Organisms

BioFire Diagnostics, LLC Special 510(k) FilmArray BCID Panel Modification

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3 Cross-reactivity was not observed in analytical sesting, but is predicted by in silico analysis to occur only with some species (i.e. S. epidermis, S. capitis and S. haemolyticus) when present in a sample at very high levels. The predicted cross-reactivity was observed infrequently in pre-analytical studies and the clinical evaluation (estimated occurrence of -0.25% of all Staphylococus positive patient samples).

Acinetobacter calcoaceticus-baumannii (ACB) complex species are often mis-identified as A. baumannii by automated and manual microbial identification methods.

· Detection was not observed in analytical specificity testing and/or sequence analysis predicts that detection due to cross-

reactivity may be possible at higher concentrations. d Identified as a new species that is closely related to K. oxytoca [82].
e Identified as a new species (with subspecies) that is closely related to K. pneumoniae [83].

l Cross-reactivity was not observed when ATCC 31898 was tested at a concentration ~1x10 CFU/mL, but cross-reactivity was observed in clinical positive blood cultures containing R. ornithinolytica.

9 Cross-reactivity was observed only at high organism concentration (≥10° CFU/mL); rare human pathogens.

1 No cross-reactivity was observed with five other Pseudomonas aeruginosa isolates tested at ≥10° CFU/mL

I Primarily environmental microorganisms, may cause rare opportunistic infections in humans. The potential for cross-reactivity was identified in contrived samples and/or clinical blood culture specimens.

l Haemophilus spp. that are infrequently isolated from human blood culture and are difficult to distinguish from H. influenzae by automated and manual microbial identification methods. The potential for cross-reactivity with H. sputorum and H. quentini was identified in clinical blood culture specimens.

Candida orthopsilosis is mis-identified as C. parapsilosis by automated and manual microbial identification methods.

l Cross-reactivity was not observed in analytical specificity testing, but inefficient cross-reactivity with high levels of select streptococi (S.

mitis and S. pneumoniae) has been identified via investigation of false results in silico analysis also predicts potential

cross-reactivity with S. dysgalactiae, S. equi, S. oralis, S. parauberis, S. salivarius, and S. thermophilus.

m Identified from a vancomycin-resistant Enterococcus faecium isolated in Asia, 2011; vanBresistance phenotype.

Conclusion:

The fundamental scientific technology, performance, and risk of the FilmArray BCID Panel is unchanged from the legally marketed FilmArray BCID Panel. There is no change to the product itself, only to the intended use and the labeling (Instruction Booklet). Therefore, the modified FilmArray BCID Panel performs as well as the predicate device.

Regulation Number and Section

§ 866.3365 Multiplex nucleic acid assay for identification of microorganisms and resistance markers from positive blood cultures.

(a)
Identification. A multiplex nucleic acid assay for identification of microorganisms and resistance markers from positive blood cultures is a qualitative in vitro device intended to simultaneously detect and identify microorganism nucleic acids from blood cultures that test positive by Gram stain or other microbiological stains. The device detects specific nucleic acid sequences for microorganism identification as well as for antimicrobial resistance. This device aids in the diagnosis of bloodstream infections when used in conjunction with other clinical and laboratory findings. However, the device does not replace traditional methods for culture and susceptibility testing.(b)
Classification. Class II (special controls). The special control for this device is FDA's guideline document entitled “Class II Special Controls Guideline: Multiplex Nucleic Acid Assay for Identification of Microorganisms and Resistance Markers from Positive Blood Cultures.” For availability of the guideline document, see § 866.1(e).