The FilmArray Meningitis/Encephalitis (ME) Panel is a qualitative multiplexed nucleic acid-based in vitro diagnostic test intended for use with FilmArray, FilmArray Torch systems. The FilmArray ME Panel is capable of simultaneous detection and identification of multiple bacterial, viral, and yeast nucleic acids directly from cerebrospinal fluid (CSF) specimens obtained via lumbar puncture from individuals with signs and/or symptoms of meningitis and/or encephalitis. The following organisms are identified using the FilmArray ME Panel:

Bacteria:

· Escherichia coli K 1
· Haemophilus influenzae
· Listeria monocytogenes
· Neisseria meningitidis (encapsulated)
· Streptococcus agalactiae
Streptococcus pneumoniae

Viruses:

· Cytomegalovirus
· Enterovirus
Herpes simplex virus 1
Herpes simplex virus 2
· Human herpesvirus 6
Human parechovirus
Varicella zoster virus

Yeast:

· Cryptococcus neoformans/gattii
The FilmArray ME Panel is indicated as an aid in the diagnosis of meningitis and/or encephalitis and results are meant to be used in conjunction with other clinical, epidemiological, and laboratory data. Results from the FilmArray ME Panel are not intended to be used as the sole basis for diagnosis, treatment, or other patient management decisions. Positive results do not rule out co-infection with organisms not included in the agent detected may not be the definite cause of the disease. Negative results do not preclude central nervous system (CNS) infection. Not all agents of CNS infection are detected by this test and sensitivity in clinical use may differ from that described in the package insert.

The FilmArray ME Panel is not intended for testing of specimens collected from indwelling CNS medical devices.

The FilmArray ME Panel is intended to be used in conjunction with standard of care culture for organism recovery, serotyping, and antimicrobial susceptibility testing.

Device Description

The FilmArray Meningitis/Encephalitis (ME) Panel is a multiplex nucleic acid test designed to be used with FilmArray systems. The FilmArray ME pouch contains freeze-dried reagents to perform nucleic acid purification and nested, multiplex PCR with DNA melt analysis. The FilmArray Meningitis/Encephalitis (ME) Panel simultaneously conducts 14 tests for the identification of potential CNS pathogens from CSF specimens obtained via lumbar puncture (Table 1). Results from the FilmArray ME Panel test are available within about one hour.

A test is initiated by loading Hydration Solution into one port of the FilmArray pouch and a CSF sample mixed with the provided Sample Buffer into the other port of the FilmArray ME pouch and placing it in the FilmArray Instrument. 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 FilmArray Software guides the user through the steps of placing 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 valye 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 and chemical lysis followed by purification using 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 reverse transcription PCR (rt-PCR) reaction 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 21d stage PCR, or nested PCR, is performed in each well of the array. At the conclusion of the 21d 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 PCR2 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

Here's the breakdown of the acceptance criteria and study information for the FilmArray Meningitis/Encephalitis (ME) Panel when used with the FilmArray Torch system, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" in a table format with specific thresholds. Instead, it describes performance in terms of reproducible detection at LoD (Limit of Detection) and agreement with expected negative results.

Performance Metric	Acceptance Criteria (Implied)	Reported Device Performance
Reproducible detection at LoD (1x LoD)	≥ 95% (common industry standard for LoD reproducibility)	≥ 95.6% of samples tested for each analyte on FilmArray Torch systems
Agreement with expected negative results	> 95% (common industry standard for specificity/negative agreement)	> 98% for each analyte

Note: The acceptance criteria in the "Implied" column are based on common industry practices for diagnostic assay performance and reproducibility, as the document doesn't provide explicit numerical targets directly labeled as "acceptance criteria."

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

Sample Size: 30 replicates per analyte per system, tested on three complete FilmArray Torch systems, resulting in a total of 90 replicates per analyte.
Data Provenance: The study involved contrived samples containing each FilmArray ME Panel analyte at low positive levels (1x LoD) and expected negative results. The document does not specify the country of origin, but given the submission to the FDA, it's likely the testing was conducted in the US. This was a prospective study, as samples were specifically prepared and tested to evaluate the new instrument.

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

The document does not mention the use of experts to establish ground truth for this particular study. The ground truth for the test set was established by the contrived nature of the samples, meaning the researchers intentionally prepared samples with known positive (at 1x LoD) and negative results.

4. Adjudication Method for the Test Set

Since the ground truth was established by preparing contrived samples with known concentrations (1x LoD) or known absence of analytes, there was no adjudication method described or necessary. The "ground truth" was inherent in the sample preparation.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study was Done

No, an MRMC comparative effectiveness study was not done. This study focused on verifying the performance of the existing FilmArray ME Panel when used with a new instrument system (FilmArray Torch). It was not designed to assess human reader performance with or without AI assistance.

6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done

Yes, a standalone performance study was done. The described performance evaluation tests the FilmArray ME Panel (an in vitro diagnostic device with an automated test interpretation algorithm) on the FilmArray Torch system directly. The results are automatically interpreted by the FilmArray software, and the user "cannot access raw data," indicating an algorithm-only or standalone performance evaluation.

7. The Type of Ground Truth Used

The ground truth used was based on contrived samples with known positive (1x LoD) and negative results. This is a form of analytical truth established by precise sample preparation.

8. The Sample Size for the Training Set

The document does not provide information on the sample size for the training set. This K160462 submission is for a special 510(k) to add a new instrument (FilmArray Torch) for an already cleared device (FilmArray ME Panel, cleared under DEN150013). Therefore, the reagent kit and its underlying algorithm were presumably developed and trained prior to this submission, and that information is not detailed here.

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

Similarly, the document does not describe how the ground truth for the training set was established. This information would have been part of the original 510(k) submission (DEN150013) for the FilmArray ME Panel itself, which is not provided in this excerpt.

Summary

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Public Health Service

March 17, 2016

Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

BIOFIRE DIAGNOSTICS, LLC KRISTEN KANACK, PHD VICE PRESIDENT, REGULATED PRODUCTS & CLINICAL AFFAIRS 390 WAKARA WAY SALT LAKE CITY UT 84108

Re: K160462

Trade/Device Name: FilmArray Meningitis/Encephalitis (ME) Panel for use with FilmArray Torch Regulation Number: 21 CFR 866.3970 Regulation Name: Device to detect and identify microbial pathogen nucleic acids in cerebrospinal fluid Regulatory Class: II Product Code: PLO Dated: February 18, 2016 Received: February 19, 2016

Dear Dr. 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 Parts 801 and 809); medical device reporting (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 Part 820); and if applicable, the

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electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm. 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 the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely yours,

Steven R. Gitterman -S

For Uwe Scherf, M.Sc., 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) K160462

Device Name

FilmArray Meningitis/Encephalitis (ME) Panel

Indications for Use (Describe)

Bacteria:

· Escherichia coli K 1
· Haemophilus influenzae
· Listeria monocytogenes
· Neisseria meningitidis (encapsulated)
· Streptococcus agalactiae
Streptococcus pneumoniae

Viruses:

· Cytomegalovirus
· Enterovirus
Herpes simplex virus 1
Herpes simplex virus 2
· Human herpesvirus 6
Human parechovirus
Varicella zoster virus

Yeast:

· Cryptococcus neoformans/gattii
The FilmArray ME Panel is indicated as an aid in the diagnosis of meningitis and/or encephalitis and results are meant to be used in conjunction with other clinical, epidemiological, and laboratory data. Results from the FilmArray ME Panel are not intended to be used as the sole basis for diagnosis, treatment, or other patient management decisions. Positive results do not rule out co-infection with organisms not included in the agent detected may not be the definite cause of the disease. Negative results do not preclude central nervous system (CNS) infection. Not all agents of CNS infection are detected by this test and sensitivity in clinical use may differ from that described in the package insert.

The FilmArray ME Panel is not intended for testing of specimens collected from indwelling CNS medical devices.

The FilmArray ME Panel is intended to be used in conjunction with standard of care culture for organism recovery, serotyping, and antimicrobial susceptibility testing.

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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Special 510(k) Summary BioFire Diagnostics, LLC

FilmArray Meningitis/Encephalitis (ME) Panel for use with FilmArray Torch

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 390 Wakara Way Salt Lake City, UT 84108

Contact:

Kristen J. Kanack, Ph.D. Telephone: 801-736-6354, ext. 330 Fax: 801-588-0507 Email: Kristen.kanack@biofiredx.com

Date Submitted:

February 18, 2016

Trade Name: FilmArray Meningitis/Encephalitis (ME) Panel

Classification Name:

21 CFR 866.3970 – Device to detect and identify microbial pathogen nucleic acids in cerebrospinal fluid.

Predicate Device: DEN150013 - FilmArray Meningitis/Encephalitis (ME) Panel

Intended Use:

The FilmArray Meningitis/Encephalitis (ME) Panel is a qualitative multiplexed nucleic acidbased in vitro diagnostic test intended for use with FilmArray systems. The FilmArray ME Panel is capable of simultaneous detection and identification of multiple bacterial, viral, and yeast nucleic acids directly from cerebrospinal fluid (CSF) specimens obtained via lumbar puncture from individuals with signs and/or symptoms of meningitis and/or encephalitis. The following organisms are identified using the FilmArray ME Panel:

Bacteria:

Escherichia coli K1 .
Haemophilus influenzae
Listeria monocytogenes
Neisseria meningitidis (encapsulated)
. Streptococcus agalactiae
. Streptococcus pneumoniae

BioFire Diagnostics, LLC Special 510(k) FilmArray Torch ME Panel

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Viruses:

. Cytomegalovirus
Enterovirus
Herpes simplex virus 1
Herpes simplex virus 2 .
Human herpesvirus 6
Human parechovirus ●
. Varicella zoster virus

Yeast:

. Cryptococcus neoformans/gattii
The FilmArray ME Panel is indicated as an aid in the diagnosis of specific agents of meningitis and/or encephalitis and results are meant to be used in conjunction with other clinical, epidemiological, and laboratory data. Results from the FilmArray ME Panel are not intended to be used as the sole basis for diagnosis, treatment, or other patient management decisions. Positive results do not rule out co-infection with organisms not included in the FilmArray ME Panel. The agent detected may not be the definite cause of the disease. Negative results do not preclude central nervous system (CNS) infection. Not all agents of CNS infection are detected by this test and sensitivity in clinical use may differ from that described in the package insert.

The FilmArray ME Panel is not intended for testing of specimens collected from indwelling CNS medical devices.

The FilmArray ME Panel is intended to be used in conjunction with standard of care culture for organism recovery, serotyping, and antimicrobial susceptibility testing.

Device Description:

Bacteria	Viruses
Escherichia coli K1	Cytomegalovirus (CMV)
Haemophilus influenzae	Enterovirus (EV)
Listeria monocytogenes	Herpes simplex virus 1 (HSV 1)
Neisseria meningitidis	Herpes simplex virus 2 (HSV 2)
Streptococcus agalactiae	Human herpesvirus 6 (HHV-6)
Streptococcus pneumoniae	Human parechovirus (HPeV)
Yeast	Varicella zoster virus (VZV)
Cryptococcus neoformans/gattii

Table 1. Analytes identified by the FilmArray ME Panel

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Nucleic acid extraction occurs within the FilmArray pouch using mechanical and chemical lysis followed by purification using 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 reverse transcription PCR (rt-PCR) reaction 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 each well of the array. At the conclusion of the 21d 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 PCR2 reactions and software interprets the data.

Device Comparison:

The purpose of this submission is to add FilmArray Torch as an additional instrument system for use with the FilmArray Meningitis/Encephalitis (ME) Panel. There have been no changes to the previously cleared FilmArray ME Panel reagent kit itself. In order to increase throughput capacity, the FilmArray 2.0 was modified to develop the FilmArray Torch by organizing densely packaged instruments (now called FilmArray Torch Modules) into a "tower" configuration having the computer with touchscreen interface incorporated into the system base. Pouches are now inserted horizontally rather than from the top. This configuration allows the FilmArray Torch Modules to be stacked directly on top of each other to minimize system footprint.

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The following table compares the FilmArray ME Panel for use with the FilmArray Torch to the previously cleared FilmArray ME Panel for Use with the FilmArray 2.0 (DEN150013). The table outlines the similarities and differences between the two systems.

Element	Modified Device:FilmArray Meningitis/Encephalitis (ME)Panel for use with FilmArray Torch	Predicate:FilmArray Meningitis/Encephalitis (ME)Panel for use with FilmArray 2.0(DEN150013)
OrganismsDetected	Bacteria:• Escherichia coli K1• Haemophilus influenzae• Listeria monocytogenes• Neisseria meningitidis(encapsulated)• Streptococcus agalactiae• Streptococcus pneumoniaeViruses:• Cytomegalovirus• Enterovirus• Herpes simplex virus 1• Herpes simplex virus 2• Human herpesvirus 6• Human parechovirus• Varicella zoster virusYeast:• Cryptococcus neoformans/gattii	Same
Analyte	RNA/DNA	Same
Specimen Types	Cerebrospinal Fluid	Same
TechnologicalPrinciples	Nested multiplex RT-PCR followed by highresolution melting analysis to confirmidentity of amplified product.	Same
Instrumentation	Single instrument FilmArray System,FilmArray 2.0 System, orFilmArray Torch System	Single instrument FilmArray system orFilmArray 2.0 system
Instrument-SoftwareCommunication	Communication for multiple FilmArrayTorch Modules travels via Ethernetcable/port.	Same (multiple instruments)
Time to result	About 1 hour	Same
TestInterpretation	Automated test interpretation and reportgeneration. User cannot access raw data.	Same
ReagentHydration andSample Loading	FilmArray Injection Vial-based loadingprocedure	Same
Sample	Sample Processing is automated in the	Same

Table 2. Comparison of the FilmArray Meningitis/Encephalitis Panel for use with the FilmArray Torch to the
current FilmArray Meningitis/Encephalitis Panel.

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Element	Modified Device:FilmArray Meningitis/Encephalitis (ME)Panel for use with FilmArray Torch	Predicate:FilmArray Meningitis/Encephalitis (ME)Panel for use with FilmArray 2.0(DEN150013)
PreparationMethod	FilmArray ME pouch.
Reagent Storage	Reagents are stored at room temperature.	Same
Controls	Two controls are included in each reagentpouch to control for sample processing andboth stages of PCR and melt analysis.	Same
UserComplexity	Moderate/Low	Same

Performance Characteristics of FilmArray ME Panel on FilmArray Torch

Contrived samples containing each FilmArray ME Panel analyte at low positive levels (1x LoD) were tested on three complete FilmArray Torch systems (12 FilmArray Torch Modules per system) over five days (30 replicates per analyte per system for 90 total replicates per analyte). Reproducible detection at LOD was confirmed for each FilmArray ME analyte with the expected Detected results for ≥95.6% of samples tested on FilmArray Torch systems. Agreement with the expected negative results (Not Detected) was >98% for each analyte.

Conclusion:

The intended use and fundamental scientific technology of the FilmArray ME Panel used with the modified device, FilmArray Torch, is unchanged from use of the legally marketed FilmArray ME Panel on FilmArray and FilmArray 2.0 systems. Non-clinical validation studies have established that the performance characteristics of FilmArray ME, including reproducibility, are substantially equivalent on FilmArray, FilmArray 2.0, and FilmArray Torch. These data demonstrate that the device performs as well as the predicate device.

Regulation Number and Section

§ 866.3970 Device to detect and identify microbial pathogen nucleic acids in cerebrospinal fluid.

(a)
Identification. A device to detect and identify microbial pathogen nucleic acids in cerebrospinal fluid is a qualitative in vitro device intended for the detection and identification of microbial-associated nucleic acid sequences from patients suspected of meningitis or encephalitis. A device to detect and identify microbial pathogen nucleic acids in cerebrospinal fluid is intended to aid in the diagnosis of meningitis or encephalitis when used in conjunction with clinical signs and symptoms and other clinical and laboratory findings.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include detailed device description documentation, including the device components, ancillary reagents required but not provided, and a detailed explanation of the methodology, including primer/probe sequence, design, and rationale for sequence selection.
(2) Premarket notification submissions must include detailed documentation from the following analytical studies: Analytical sensitivity (limit of detection), inclusivity, reproducibility, interference, cross reactivity, and specimen stability.
(3) Premarket notification submissions must include detailed documentation from a clinical study. The study, performed on a study population consistent with the intended use population, must compare the device performance to results obtained from well-accepted comparator methods.
(4) Premarket notification submissions must include detailed documentation for device software, including, but not limited to, software applications and hardware-based devices that incorporate software.
(5) The Intended Use statement in the device labeling must include a statement that the device is intended to be used in conjunction with standard of care culture.
(6) A detailed explanation of the interpretation of results and acceptance criteria must be included in the device's 21 CFR 809.10(b)(9) compliant labeling.
(7) The device labeling must include a limitation stating that the negative results do not preclude the possibility of central nervous system infection.
(8) The device labeling must include a limitation stating that device results are not intended to be used as the sole basis for diagnosis, treatment, or other patient management decisions.
(9) The device labeling must include a limitation stating that positive results do not mean that the organism detected is infectious or is the causative agent for clinical symptoms.
(10) As part of the risk management activities performed as part of your 21 CFR 820.30 design controls, you must document an appropriate end user device training program that will be offered as part of your efforts to mitigate the risk of failure to correctly operate the instrument.