The BioFire® FilmArray® Pneumonia Panel plus (BioFire Pneumonia Panel plus) is a multiplexed nucleic acid test intended for use with BioFire® FilmArray® 2.0 (BioFire® FilmArray® Torch (BioFire Torch) systems for the simultaneous detection and identification of nucleic acids from Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and multiple respiratory viral and bacterial nucleic acids, as well as select antimicrobial resistance genes, in sputum-like specimens (induced or expectorated sputum, or endotracheal aspirates) or bronchoalveolar lavage (BAL)-like specimens (BAL or mini-BAL) obtained from individuals meeting MERS-CoV clinical and/or epidemiological criteria.

Testing with BioFire Pneumonia Panel plus should not be performed unless the patient meets clinical and/or epidemiologic criteria for testing suspected MERS-CoV specimens. This includes: clinical signs and symptoms associated with MERS-CoV infection, contact with a probable or confirmed MERS-CoV case, history of travel to geographic locations where MERS-CoV cases were detected, or other epidemiological links for which MERS-CoV testing may be indicated.

The following bacteria are reported semi-quantitatively with bins representing approximately 10^4, 10^5, or ≥10^7 genomic copies of bacterial nucleic acid per milliliter (copies/mL) of specimen, to aid in estimating relative abundance of nucleic acid from these common bacteria within a specimen:

Bacteria reported with bins of 10^4, 10^5, 10^6, or ≥10^7 copies/mL

· Acinetobacter calcoaceticus-baumannii complex
· Enterobacter cloacae complex
· Escherichia coli
· Haemophilus influenza
· Klebsiella aerogenes
· Klebsiella oxytoca
· Klebsiella pneumoniae group
· Moraxella catarrhalis
· Proteus spp.
· Pseudomonas aeruginosa
· Serratia marcescens
· Staphylococcus aureus
· Streptococcus agalactiae
· Streptococcus pneumoniae
· Streptococcus pyogenes

The following atypical bacteria, viruses, and antimicrobial resistance genes are reported qualitatively:

Atypical Bacteria

· Chlamydia pneumoniae
· Legionella pneumophila
· Mycoplasma pneumoniae

Viruses
· Middle East respiratory syndrome coronavirus (MERS-CoV)

· Adenovirus
· Coronavirus
· Human metapneumovirus
· Human rhinovirus/enterovirus
· Influenza A virus
· Influenza B virus
· Parainfluenza virus
· Respiratory syncytial virus

Antimicrobial Resistance Genes

· CTX-M
· IMP
· КРС
· NDM
· OXA-48-like
· VIM
· mecA/C and MREJ (MRSA)

The detection and identification of specific viral and bacterial nucleic acids from MERS-CoV and other respiratory pathogens, as well as the estimation of relative abundance of nucleic acid from common bacterial analytes, within specimens collected from individuals meeting MERS-CoV clinical and/or epidemiological criteria aids in the differential diagnosis of MERS-CoV infection, if used in conjunction with other clinical and epidemiological information in accordance with the guidelines provided by the appropriate public health authorities.

BioFire Pneumonia Panel plus MERS-CoV positive results are for the identification of MERS-CoV. The definitive identification of MERS-CoV requires additional testing and confirmation procedures in consultation with the appropriate public health authorities (e.g., local or state public health departments, etc.) for whom reporting is necessary. The diagnosis of MERS-CoV infection must be made based on history, signs, symptoms, exposure likelihood, and other laboratory evidence in addition to the identification of MERS-CoV.

BioFire Pneumonia Panel plus MERS-CoV negative results, even in the context of a BioFire Pneumonia Panel plus positive result for one or more of the common respiratory pathogens, do not preclude MERS-CoV infection and should not be used as the sole basis for patient management decisions. The levels of MERS-CoV that would be present in sputum-like or BAL-like specimens from individuals with early infection and from asymptomatic MERS-CoV cariers are not well understood. A negative BioFire Pneumonia Panel plus MERS-CoV result in an asymptomatic individual does not rule out the possibility of future illness and does not demonstrate that the individual is not infectious.

Viral culture should not be attempted on specimens with positive BioFire Pneumonia Panel plus results for MERS-CoV unless a BSL 3 facility is available to receive and culture specimens.

Negative results in the setting of a respiratory illness may be due to infection with pathogens that are not detected by this test, pathogens below the limit of detection, or in the case of bacterial analytes, present at levels below the lowest reported 10^4 copies/mL bin. Detection of analytes does not rule out co-infection with other organisms; the agent(s) detected by the BioFire Pneumonia Panel plus may not be the definite cause of disease. Additional laboratory testing (e.g. bacterial and viral culture, immunofluorescence, and radiography) may be necessary when evaluating a patient with possible lower respiratory tract infection.

Detection of bacterial nucleic acid may be indicative of colonizing or normal respiratory flora and may not indicate the causative agent of pneumonia. Semi-quantitative Bin (copies/mL) results generated by the BioFire Pneumonia Panel plus are not equivalent to CFU/mL and do not consistently correlate with the quantity of bacterial analytes compared to CFU/ mL. For specimens with multiple bacteria detected, the relative abundance of nucleic acids (copies/mL) may not correlate with the relative abundance of bacteria as determined by culture (CFU/mL). Clinical correlation is advised to determine significance of semi-quantitative Bin (copies/mL) for clinical management.

The antimicrobial resistance gene detected may or may not be associated with the agent(s) responsible for disease. Negative results for these antimicrobial resistance gene assays do not indicate susceptibility to corresponding classes of antimicrobials, as multiple mechanisms of antimicrobial resistance exist.

Antimicrobial resistance can occur via multiple mechanisms. A "Not Detected" result for a genetic marker of antimicrobial resistance does not indicate susceptibility to associated antimicrobial drugs or drug classes. A "Detected" result for a genetic marker of antimicrobial resistance cannot be definitively linked to the microorganism(s) detected. Culture is required to obtain isolates for antimicrobial susceptibility testing, and BioFire Pneumonia Panel plus results should be used in conjunction with culture results for determination of bacterial susceptibility or resistance.

Due to the genetic similarity between human rhinovirus and enterovirus, the test cannot reliably differentiate them. A positive Rhinovirus/Enterovirus result should be followed up using an alternate method (e.g., cell culture or sequence analysis) if differentiation is required.

Culture is required to identify pathogens not detected by the BioFire Pneumonia Panel plus, to further speciate analytes in genus, complex, or group results if desired, to identify bacterial pathogens present below the 10°4 copies/mL bin if desired, and for antimicrobial susceptibility testing.

Device Description

The FilmArray Pneumonia Panel plus is designed to simultaneously identify MERS-CoV and 26 potential pathogens of lower respiratory tract infection (LRTI) and associated antimicrobial resistance (AMR) genes from a sputum-like (induced and expectorated sputum as well as endotracheal aspirate, ETA) or bronchoalveolar lavage (BAL)-like (BAL and mini-BAL) specimens obtained from individuals meeting MERS-CoV clinical and/or epidemiological criteria in a time (~1 hour). The FilmArray Pneumonia Panel plus is compatible with BioFire Diagnostics' (BioFire) PCR-based in vitro diagnostic BioFire FilmArray 2.0 (K143178) and BioFire FilmArray Torch (K160068) systems for infectious disease testing. A specific software module (i.e., FilmArray Pneumonia Panel plus pouch module) is used to perform FilmArray Pneumonia Panel plus testing on these systems.

A test is initiated by loading Hydration Solution into one port of the FilmArrav pouch and a soutumlike or BAL-like sample mixed with the provided Sample Buffer into the port of the FilmArray Pneumonia Panel plus pouch and placing it in a FilmArray instrument. The pouch contains all 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 quides 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 and chemical lvsis followed by purification using standard magnetic bead technology. After extracting and purifying nucleic acids from the unprocessed sample, the FilmArray performs a nested multiplex PCR that is executed in two stages. During the first stage, the FilmArray performs a single, large volume, highly multiplexed reverse transcription PCR (rt-PCR) reaction. 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 Diagnostics). 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 end 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 2nd stage PCR 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 text is a summary of a Special 510(k) submission for the BioFire FilmArray Pneumonia Panel plus. The purpose of this submission is solely to modify the labeling of the device to include new limitations regarding the Adenovirus2 assay's performance closer to its expiration date.

Therefore, the document does not describe a new study to prove device performance against acceptance criteria. Instead, it refers to a problem identified through stability studies and a voluntary recall. The premise of this 510(k) submission is that because there are no changes to the actual device, its fundamental scientific technology, performance, and risk are unchanged from the legally marketed predicate device (K181324).

The acceptance criteria table below is inferred from the identified issue and the proposed label modifications, not from a performance study demonstrating device capabilities.

Acceptance Criteria and Reported Device Performance

Acceptance Criteria	Reported Device Performance (from stability study and recall)
Adenovirus C Detection Sensitivity (within 6 months of expiration)	Impaired: For Adenovirus species C, when pouches are within 6 months of expiration, there is an increased risk of false negative results due to a 10-100x loss in sensitivity (i.e., impairment leading to an increase in the Limit of Detection - LoD). This led to a voluntary recall (Recall Event 88117/ Z-2039-2021, Z-2040-2021).
Adenovirus C Detection Sensitivity (more than 6 months from expiration)	Unimpacted: The test performance for Adenovirus species C for pouches more than 6 months from the expiration date is not impacted.
Other Adenovirus Species Detection Performance	Unimpacted: Performance for other adenovirus species is not impacted regardless of the pouch's proximity to the expiration date.
General Device Performance (excluding identified Adenovirus C issue)	Unchanged/Equivalent to Predicate: "The fundamental scientific technology, performance, and risk of the FilmArray Pneumonia Panel plus is unchanged from the legally marketed FilmArray Pneumonia Panel plus." This implies that for all other analytes and under normal conditions (i.e., pouches not within 6 months of expiration for Adenovirus C detection), the device performance meets the established criteria of the predicate device (K181324).

Study Details (Based on the information provided)

Sample size used for the test set and the data provenance:
- The document does not explicitly state the sample size of the test set used in the stability study that identified the Adenovirus C issue.
- The data provenance is from stability studies conducted by BioFire Diagnostics, LLC. It is retrospective in the sense that the issue was discovered after initial marketing and through ongoing stability monitoring of manufactured product.
Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- This information is not provided as the document describes a stability study related to device shelf-life rather than a diagnostic performance study against a clinical ground truth. The "ground truth" here would have been the presence/absence and concentration of adenovirus species C in the stability samples, likely confirmed by a reference method in a laboratory setting. Details on experts or their qualifications are not given.
Adjudication method for the test set:
- This information is not provided. Given it's a stability study on a diagnostic assay, adjudication in the context of expert consensus on clinical cases is not directly applicable. The determination of "false negative" would have been based on comparison to expected results or a reference method.
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. This device is a multiplexed nucleic acid test (an in vitro diagnostic device), not an imaging AI device that involves human readers.
If a standalone (i.e., algorithm only without human-in-the-loop performance) was done:
- The FilmArray Pneumonia Panel plus is an automated diagnostic assay. Its performance (detection of nucleic acids) is inherently "standalone" in the sense that the instrument and software interpret the results without human interpretation of raw data. The stability study assessed this standalone performance.
The type of ground truth used:
- For the stability studies that identified the issue, the ground truth was likely analytical truth (known presence, absence, and concentration of specific analytes like Adenovirus species C) in manufactured control samples or spiked specimens. This is standard for stability testing of IVD assays.
The sample size for the training set:
- This document describes a modification to labeling based on post-market stability findings, not a de novo development or training of an algorithm. Therefore, information about a "training set" is not applicable and not provided.
How the ground truth for the training set was established:
- As there is no mention of a training set for an algorithm, this information is not applicable.

Summary

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October 27, 2022

BioFire Diagnostics, LLC Kevin Bourzac Vice President, Regulatory & Clinical Affairs 515 Colorow Drive Salt Lake City, Utah 84108

Re: K222601

Trade/Device Name: FilmArray Pneumonia Panel plus Regulation Number: 21 CFR 866.4001 Regulation Name: A Multiplex Respiratory Panel To Detect And Identify Emerging Respiratory Pathogen(S) And Common Respiratory Pathogens In Human Clinical Specimens Regulatory Class: Class II Product Code: QDS Dated: August 25, 2022 Received: August 29, 2022

Dear Kevin Bourzac:

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

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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) 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 (QS) 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 medical devices and radiation-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,

for

Noel Gerald Branch Chief DMD: Division of Microbiology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K181324

Device Name BioFire FilmArray Pneumonia Panel plus

Indications for Use (Describe)

The following bacteria are reported semi-quantitatively with bins representing approximately 10°4, 10°5, or ≥10°7 genomic copies of bacterial nucleic acid per milliliter (copies/mL) of specimen, to aid in estimating relative abundance of nucleic acid from these common bacteria within a specimen:

Bacteria reported with bins of 10^4, 10^5, 10^6, or ≥10^7 copies/mL

· Acinetobacter calcoaceticus-baumannii complex
· Enterobacter cloacae complex
· Escherichia coli
· Haemophilus influenza
· Klebsiella aerogenes
· Klebsiella oxytoca
· Klebsiella pneumoniae group
· Moraxella catarrhalis
· Proteus spp.
· Pseudomonas aeruginosa
· Serratia marcescens
· Staphylococcus aureus
· Streptococcus agalactiae
· Streptococcus pneumoniae
· Streptococcus pyogenes

The following atypical bacteria, viruses, and antimicrobial resistance genes are reported qualitatively:

Atypical Bacteria

· Chlamydia pneumoniae
· Legionella pneumophila
· Mycoplasma pneumoniae

Viruses

· Middle East respiratory syndrome coronavirus (MERS-CoV)

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· Adenovirus
· Coronavirus
· Human metapneumovirus
· Human rhinovirus/enterovirus
· Influenza A virus
· Influenza B virus
· Parainfluenza virus
· Respiratory syncytial virus

Antimicrobial Resistance Genes

· CTX-M
· IMP
· КРС
· NDM
· OXA-48-like
· VIM
· mecA/C and MREJ (MRSA)

Viral culture should not be attempted on specimens with positive BioFire Pneumonia Panel plus results for MERS-CoV unless a BSL 3 facility is available to receive and culture specimens.

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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

FilmArrav Pneumonia Panel plus

Introduction:

Purpose

The content of this Special 510(k) submission is limited to obtaining FDA clearance for the FilmArray Pneumonia Panel plus (K181324) with modified labeling to address stability results of the adenovirus2 assay used for the detection of adenovirus C species.

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.

Background

Stability study results showed that the Adenovirus2 assay on Pneumonia Panels (Pneumonia Panel and Pneumonia Panel plus) exhibited an increased rate of unexpected Negative results in pouches that were more than 6 months from the date of manufacture (i.e. within 6 months of expiration). As a result of the stability testing, BioFire conducted a voluntary recall of the FilmArray Pneumonia Panels (Part No. RFIT-ASY-0142, RFIT-ASY-0143, RFIT-ASY-0144, and RFIT-ASY-0145) in June 2021 (refer to Recall Event 88117/ Z-2039-2021, Z-2040-2021).

In addition, and as a corrective action, the FilmArray Pneumonia Panel 'Limitations' section in the instructions for use was modified to include new limitations as well as an additional footnote on the analytical Limit of Detection (LoD) table that addresses the detection of adenovirus in the FilmArray Pneumonia Panel within 6 months of expiration. This corrective action was accepted and cleared under special 510(k) K212727.

BioFire would now like to clear the same limitations for the FilmArray Pneumonia Panel plus instructions for use (this submission).

Submitted by:

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

Contact:

Kevin Bourzac, Ph.D. Telephone: 801-736-6354, ext. 1358 Fax: 801-588-0507 Email: kevin.bourzac@biomerieux.com

Date Submitted:

August 25, 2022

BioFire Diagnostics, LLC Special 510(k) FilmArray Pneumonia Panel plus - Label Modification Page 1

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Trade Name: FilmArray Pneumonia Panel plus

Classification Name:

21 CFR 866.4001 - MERS-CoV and common respiratory pathogens multiplex nucleic acid detection system

Predicate Device:

K181324 - FilmArray Pneumonia Panel plus

Intended Use:

The BIOFIRE® FILMARRAY® Pneumonia Panel plus (BIOFIRE Pneumonia Panel plus) is a multiplexed nucleic acid test intended for use with BIOFIRE® FILMARRAY® 2.0 (BIOFIRE 2.0) or BIOFIRE® FILMARRAY® TORCH (BIOFIRE TORCH) systems for the simultaneous detection and identification of nucleic acids from Middle East respiratory syndrome coronavirus (MERS-CoV) and multiple respiratory viral and bacterial nucleic acids, as well as select antimicrobial resistance genes, in sputum-like specimens (induced or expectorated sputum, or endotracheal aspirates) or bronchoalveolar lavage (BAL)-like specimens (BAL or mini-BAL) obtained from individuals meeting MERS-CoV clinical and/or epidemiological criteria.

Testing with BIOFIRE Pneumonia Panel plus should not be performed unless the patient meets clinical and/or epidemiologic criteria for testing suspected MERS-CoV specimens. This includes: clinical signs and symptoms associated with MERS-CoV infection, contact with a probable or confirmed MERS-CoV case, history of travel to geographic locations where MERS-CoV cases were detected, or other epidemiological links for which MERS-CoV testing may be indicated.

The following bacteria are reported semi-quantitatively with bins representing approximately 10^4, 10^5, 10^6, or ≥10^7 genomic copies of bacterial nucleic acid per millliter (copies/mL) of specimen, to aid in estimating relative abundance of nucleic acid from these common bacteria within a specimen:

Bacteria reported with bins of $10^4$ , $10^5$ , $10^6$ , or $\geq 10^7$ copies/mL
Acinetobacter calcoaceticus-baumanniicomplex	Klebsiella oxytoca	Serratia marcescens
Enterobacter cloacae complex	Klebsiella pneumoniaegroup	Staphylococcus aureus
Escherichia coli	Moraxella catarrhalis	Streptococcus agalactiae
Haemophilus influenzae	Proteus spp.	Streptococcus pneumoniae
Klebsiella aerogenes	Pseudomonas aeruginosa	Streptococcus pyogenes

The following atypical bacteria, viruses, and antimicrobial resistance genes are reported qualitatively:

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Atypical Bacteria
Chlamydia pneumoniae	Legionella pneumophila	Mycoplasma pneumoniae
Viruses
Middle East respiratory syndrome coronavirus (MERS-CoV)
Adenovirus	Human rhinovirus/enterovirus	Parainfluenza virus
Coronavirus	Influenza A virus	Respiratory syncytial virus
Human metapneumovirus	Influenza B virus
Antimicrobial Resistance Genes
CTX-M	NDM	mecA/C and MREJ (MRSA)
IMP	OXA-48-like
KPC	VIM

BIOFIRE Pneumonia Panel plus MERS-CoV positive results are for the presumptive identification of MERS-CoV. The definitive identification of MERS-CoV requires additional testing and confirmation procedures in consultation with the appropriate public health authorities (e.g., local or state public health departments, etc.) for whom reporting is necessary. The diagnosis of MERS-CoV infection must be made based on history, signs, symptoms, exposure likelihood, and other laboratory evidence in addition to the identification of MERS-CoV.

BIOFIRE Pneumonia Panel plus MERS-CoV negative results, even in the context of a BIOFIRE Pneumonia Panel plus positive result for one or more of the common respiratory pathogens, do not preclude MERS-CoV infection and should not be used as the sole basis for patient management decisions. The levels of MERS-CoV that would be present in sputum-like or BALlike specimens from individuals with early infection and from asymptomatic MERS-CoV cariers are not well understood. A negative BIOFIRE Pneumonia Panel plus MERS-CoV result in an asymptomatic individual does not rule out the possibility of future illness and does not demonstrate that the individual is not infectious.

Viral culture should not be attempted on specimens with positive BIOFIRE Pneumonia Panel plus results for MERS-CoV unless a BSL 3 facility is available to receive and culture specimens.

Negative results in the setting of a respiratory illness may be due to infection with pathogens that are not detected by this test, pathogens below the limit of detection, or in the case of bacterial analytes, present at levels below the lowest reported 10^4 copies/mL bin. Detection of analytes does not rule out co-infection with other organisms; the agent(s) detected by the BIOFIRE Pneumonia Panel plus may not be the definite cause of disease. Additional laboratory testing (e.q. bacterial and viral culture, immunofluorescence, and radiography) may be necessary when evaluating a patient with possible lower respiratory tract infection.

BioFire Diagnostics, LLC Special 510(k) FilmArray Pneumonia Panel plus - Label Modification

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Detection of bacterial nucleic acid may be indicative of colonizing or normal respiratory flora and may not indicate the causative agent of pneumonia. Semi-quantitative Bin (copies/mL) results generated by the BIOFIRE Pneumonia Panel plus are not equivalent to CFU/mL and do not consistently correlate with the quantity of bacterial analytes compared to CFU/mL. For specimens with multiple bacteria detected, the relative abundance of nucleic acids (copies/mL) may not correlate with the relative abundance of bacteria as determined by culture (CFU/mL). Clinical correlation is advised to determine significance of semi-quantitative Bin (copies/mL) for clinical management.

Antimicrobial resistance can occur via multiple mechanisms. A "Not Detected" result for a genetic marker of antimicrobial resistance does not indicate susceptibility to associated antimicrobial drugs or drug classes. A "Detected" result for a genetic marker of antimicrobial resistance cannot be definitively linked to the microorganism(s) detected. Culture is required to obtain isolates for antimicrobial susceptibility testing, and BIOFIRE Pneumonia Panel plus results should be used in conjunction with culture results for determination of bacterial susceptibility or resistance.

Culture is required to identify pathogens not detected by the BIOFIRE Pneumonia Panel plus, to further speciate analytes in genus, complex, or group results if desired, to identify bacterial pathogens present below the 10^4 copies/mL bin if desired, and for antimicrobial susceptibility testing.

Device Description:

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the FilmArray Software quides the user though the steps of placing the pouch into the instrument, scanning the pouch barcode, entering the sample identification, and initiating the run.

Device Comparison:

Table 1 outlines the similarities and differences between the two panels.

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Table 1 Comparison of the FilmArray Pneumonia Panel plus with modified labeling to the current FilmArray Pneumonia Panel plus.

Element	Modified Device:FilmArray Pneumonia Panel plus (withmodified labeling)	Predicate:FilmArray Pneumonia Panelplus(K181324)
OrganismsDetected	Bacteria: Acinetobacter calcoaceticus-baumanniicomplex, Enterobacter aerogenes, Enterobactercloacae complex, Escherichia coli, Haemophilusinfluenzae, Klebsiella oxytoca, Klebsiellapneumoniae group, Moraxella catarrhalis,Proteus spp., Pseudomonas aeruginosa, Serratiamarcescens, Staphylococcus aureus,Streptococcus agalactiae, Streptococcuspneumoniae, Streptococcus pyogenesAtypical Bacteria: Chlamydia pneumoniae,Legionella pneumophila, Mycoplasmapneumoniae	Same
	Antimicrobial Resistance Genes: CTX-M, IMP,KPC, mecA/C + MREJ, NDM, Oxa48-like, VIM
	Viruses: Middle East Respiratory SyndromeCoronavirus, Adenovirus, Coronavirus, HumanMetapneumovirus, HumanRhinovirus/Enterovirus, Influenza A, Influenza B,Parainfluenza virus,Respiratory Syncytial virus
Analyte	DNA/RNA	Same
SpecimenTypes	Positive blood culture samples containing gram-positive or gram-negative bacteria and/or yeast.	Same
TechnologicalPrinciples	Nested multiplex PCR followed by high resolutionmelting analysis to confirm the identity ofamplified product.	Same
Instrumentation	Single instrument FilmArray 2.0 System, orFilmArray Torch System	Same
Time to result	About 1 hour	Same
TestInterpretation	Automated test interpretation and reportgeneration. User cannot access raw data.	Same
SamplePreparationMethod	Sample Processing is automated in the BioFireFilmArray PN pouch.	Same
ReagentStorage	Reagents are stored at room temperature.	Same
Shelf-Life	12 months from Date of Manufacture (DOM)*	Same
Element	Modified Device:FilmArray Pneumonia Panel plus (withmodified labeling)	Predicate:FilmArray Pneumonia Panelplus(K181324)
Controls	Two controls are included in each reagent pouchto control for sample processing and both stagesof PCR and melt analysis.	Same
UserComplexity	Moderate/High	Same

BioFire Diagnostics, LLC Special 510(k)

FilmArray Pneumonia Panel plus - Label Modification

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LoD for adenovirus species C is 10 - 100 x impaired when pouches are within 6 months of expiration

The purpose of this submission is to modify the labeling of the FilmArray Pneumonia Panel plus to include the following limitations in the instructions for use:

There is an increased risk of false negative Adenovirus results for adenovirus species C when using a pouch that is within 6 months of the expiration date due to a 10-100 x loss in sensitivity (i.e. impairment leading to an increase in the LoD). The test performance is not impacted if kits are more than 6 months from expiration date. Performance for other adenovirus species is not impacted.

If using a pouch that is within 6 months of expiration when a patient is suspected of adenovirus C infection, confirm all negative Adenovirus results using another method prior to reporting the result, or alternatively, do not report a negative Adenovirus result.

An additional footnote in the Analytical LoD section (Table 63) of the Pneumonia Panel plus instructions for use will also be included.

Conclusion:

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

Regulation Number and Section

§ 866.4001 A multiplex respiratory panel to detect and identify emerging respiratory pathogen(s) and common respiratory pathogens in human clinical specimens.

(a)
Identification. A multiplex respiratory panel to detect and identify emerging respiratory pathogen(s) and common respiratory pathogens in human clinical specimens is identified as an in vitro diagnostic device intended for the qualitative detection and identification of both emerging and common respiratory pathogens from individuals meeting specific emerging respiratory pathogen clinical and/or epidemiological criteria. For example, clinical signs and symptoms associated with infection of the emerging respiratory pathogen, contact with a probable or confirmed emerging respiratory pathogen case, history of travel to geographic locations where cases of the emerging respiratory pathogen were detected, or other epidemiological links for which testing of the emerging respiratory pathogen may be indicated. A device to detect and identify emerging respiratory pathogen(s) and common respiratory pathogens in human clinical specimens, and in turn to distinguish emerging respiratory pathogen(s) from common respiratory pathogens, is intended to aid in the differential diagnosis of the emerging respiratory pathogen infection, in conjunction with other clinical, epidemiologic, and laboratory data, in accordance with the guidelines provided by the appropriate public health authorities.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The intended use for the labeling required under § 809.10 of this chapter must include a description of what the device detects and measures, the specimen types, the results provided to the user, the clinical indications for which the test is to be used, the specific intended population(s), the testing location(s) where the device is to be used (if applicable), and other conditions of use as appropriate.
(2) The labeling required under § 809.10 of this chapter must include:
(i) A device description, including the parts that make up the device, ancillary reagents required but not provided, and an explanation of the methodology.
(ii) Performance characteristics from analytical studies, including cut-off (if applicable), analytical sensitivity (
i.e., limit of detection), inclusivity, reproducibility, interference, cross-reactivity, instrument carryover/cross-contamination (if applicable), and specimen stability.(iii) Detailed instructions for minimizing the risk of potential users' exposure to the emerging respiratory pathogen(s) that may be present in test specimens and those used as control materials.
(iv) Detailed instructions for minimizing the risk of generating false positive test results due to carry-over contamination from positive test specimens and/or positive control materials.
(v) A warning statement that the interpretation of test results requires experienced healthcare professionals who have training in principles and use of infectious disease diagnostics and reporting of results, in conjunction with the patient's medical history, clinical signs and symptoms, and the results of other diagnostic tests.
(vi) A warning statement that culture should not be attempted in cases of positive results for an emerging respiratory pathogen unless a facility with an appropriate level of laboratory biosafety (
e.g., BSL 3 and BSL 3+) is available to receive and culture specimens.(vii) A warning statement that device positive results for one or more common respiratory pathogens do not rule out bacterial infection, or co-infection with other common respiratory pathogens.
(viii) A warning statement that respiratory pathogen(s) detected may not be the definite cause of disease.
(ix) A warning statement that the use of additional laboratory testing (
e.g. bacterial culture, immunofluorescence, x-ray findings) and clinical presentation must be taken into consideration in order to obtain the final diagnosis of a respiratory infection.(x) A limiting statement that device negative results for the common respiratory pathogens do not preclude infection of a respiratory pathogen and should not be used as the sole basis for diagnosis, treatment, or other patient management decisions.
(xi) A limiting statement that analyte targets (
e.g., pathogen nucleic acid sequences or other molecular signatures) may persist in vivo, independent of organism viability. Detection of analyte target(s) does not imply that the corresponding pathogen(s) is infectious, nor is the causative agent(s) for clinical symptoms.(xii) A limiting statement that detection of pathogen nucleic acid sequences or other molecular signatures is dependent upon proper specimen collection, handling, transportation, storage and preparation. Failure to observe proper procedures in any one of these steps can lead to incorrect results. There is a risk of false negative values resulting from improperly collected, transported, or handled specimens.
(xiii) A limiting statement that there is a risk of false positive values resulting from cross-contamination by target organisms, their nucleic acids or amplified product, or from non-specific signals in the assay.
(xiv) A limiting statement that there is a risk of false negative results due to the presence of nucleic acid sequence variants in the pathogen targets of the device.
(xv) A limiting statement that device performance was not established in immunocompromised patients.
(xvi) A limiting statement that positive and negative predictive values are highly dependent on prevalence. The device performance was established during one or more specific respiratory seasons. The performance for some respiratory pathogens may vary depending on the prevalence and patient population tested. False positive test results are likely when prevalence of disease due to a particular respiratory pathogen is low or non-existent in a community.
(xvii) In situations where the performance of the device was estimated based largely on testing pre-selected banked retrospective clinical specimens and/or contrived clinical specimen, a limiting statement that the estimated device performance of that specific pathogen or pathogen subtype may not reflect the performance or prevalence in the intended use population.
(xviii) For devices with an intended use that includes detection of emerging respiratory pathogen(s), a limiting statement that testing with the device should not be performed unless the patient meets clinical and/or epidemiologic criteria for testing suspected specimens of the emerging respiratory pathogen.
(xix) For devices with an intended use that includes detection of emerging respiratory pathogen(s), a limiting statement that positive results obtained with the device for the emerging respiratory pathogen are for the presumptive identification of that pathogen and that the definitive identification of the emerging respiratory pathogen requires additional testing and confirmation procedures in consultation with the appropriate public health authorities (
e.g., local or state public health departments) for whom reporting is necessary.(xx) For devices with an intended use that includes detection of emerging respiratory pathogen(s), a limiting statement that negative results for the emerging respiratory pathogen, even in the context of device positive results for one or more of the common respiratory pathogens, do not preclude infection with the emerging respiratory pathogen and should not be used as the sole basis for patient management decisions.
(xxi) For devices with an intended use that includes detection of emerging respiratory pathogen(s), a limiting statement that negative results for the emerging respiratory pathogen may be due to infection of the emerging respiratory pathogen at a specific respiratory tract location that may not be detected by a particular clinical specimen type. A negative result for the emerging respiratory pathogen in an asymptomatic individual does not rule out the possibility of future illness and does not demonstrate that the individual is not infectious.
(xxii) For devices with an intended use that includes detection of emerging respiratory pathogen(s), a limiting statement that a nationally notifiable Rare Disease of Public Health Significance caused by an emerging respiratory pathogen must be reported, as appropriate, to public health authorities in accordance with local, state, and federal law.
(3) Design verification and validation must include:
(i) Performance results of an appropriate clinical study (
e.g., a prospective clinical study) for each specimen type, and, if appropriate, results from additional characterized samples. The clinical study must be performed on a study population consistent with the intended use population and must compare the device performance to results obtained using FDA-accepted comparator methods or to expected negative results if the infection is not generally expected in the intended use population. Clinical specimens evaluated in the study must contain relevant organism concentrations applicable to the specimen type(s) and the targeted analyte(s). Detailed documentation must be kept of that study and its results, including the study protocol, study report for the proposed intended use, testing results, and results of all statistical analyses.(ii) For devices with an intended use that includes detection of emerging respiratory pathogen(s) for which an FDA recommended panel is available, design verification and validation must include the performance results of an analytical study testing an FDA recommended reference panel of characterized samples that contain the emerging respiratory pathogen. Detailed documentation must be kept of that study and its results, including the study protocol, study report for the proposed intended use, testing results, and results of all statistical analyses.
(iii) An appropriate risk mitigation strategy, including a detailed description of all procedures and methods, for the post-market identification of genetic mutations and/or novel respiratory pathogen isolates or strains (
e.g., regular review of published literature and annual in silico analysis of target sequences to detect possible mismatches. The required documentation for this device must also include all of the results, including any findings, from the application of this post-market mitigation strategy.(iv) For devices with an intended use that includes detection of multiple common respiratory pathogens, in addition to detecting emerging respiratory pathogen(s) in human clinical specimens, a detailed description of the identity, phylogenetic relationship, or other recognized characterization of the common respiratory pathogens that the device is designed to detect is addressed. Also, address in detail how the device results might be used in a diagnostic algorithm and other measures that might be needed for a laboratory diagnosis of respiratory tract infection. Perform an evaluation of the device compared to a currently appropriate and FDA accepted comparator method. Detailed documentation must be kept of that study and its results, including the study protocol, study report for the proposed intended use, testing results, and results of all statistical analyses.
(v) A detailed device description, including the parts that make up the device, ancillary reagents required but not provided, and a detailed explanation of the methodology, including molecular target(s) for each analyte, design of target detection reagents, rationale for target selection, limiting factors of the device (
e.g., saturation level of hybridization and maximum amplification and detection cycle number), internal and external controls, and computational path from collected raw data to reported result (e.g., how collected raw signals are converted into a reported signal and result), as applicable and appropriate.(vi) A detailed description of the device software, including software applications and hardware-based devices that incorporate software.
(vii) For devices with an intended use that includes detection of Influenza A and Influenza B viruses and/or detection and differentiate between the Influenza A virus subtypes in human clinical specimens, in addition to detecting emerging respiratory pathogen(s), a detailed description of the identity, phylogenetic relationship, or other recognized characterization of the Influenza A and B viruses that the device is designed to detect, a description of how the device results might be used in a diagnostic algorithm and other measures that might be needed for a laboratory identification of Influenza A or B virus and of specific Influenza A virus subtypes, and a description of the clinical and epidemiological parameters that are relevant to a patient case diagnosis of Influenza A or B and of specific Influenza A virus subtypes. Perform an evaluation of the device compared to a currently appropriate and FDA accepted comparator method. Detailed documentation must be kept of that study and its results, including the study protocol, study report for the proposed intended use, testing results, and results of all statistical analyses.
(4) For devices with an intended use that includes detection of Influenza A and Influenza B viruses and/or detection and differentiate between the Influenza A virus subtypes in human clinical specimens, in addition to detecting emerging respiratory pathogen(s), the labeling required under § 809.10 of this chapter must include the following:
(i) Where applicable, a limiting statement that performance characteristics for Influenza A were established when Influenza A/H3 and A/H1-2009 (or other pertinent Influenza A subtypes) were the predominant Influenza A viruses in circulation. When other Influenza A viruses are emerging, performance characteristics may vary.
(ii) Where applicable, a warning statement that reads if infection with a novel Influenza A virus is suspected based on current clinical and epidemiological screening criteria recommended by public health authorities, specimens should be collected with appropriate infection control precautions for novel virulent influenza viruses and sent to state or local health departments for testing. Viral culture should not be attempted in these cases unless a BSL 3+ facility is available to receive and culture specimens.
(iii) Where the device results interpretation involves combining the outputs of several targets to get the final results, such as a device that both detects Influenza A and differentiates all known Influenza A subtypes that are currently circulating, the device's labeling required under § 809.10(b)(9) of this chapter must include a clear interpretation instruction for all valid and invalid output combinations, and recommendations for any required follow up actions or retesting in the case of an unusual or unexpected device result.
(iv) A limiting statement that if a specimen yields a positive result for Influenza A, but produces negative test results for all specific influenza A subtypes intended to be differentiated (
e.g., H1-2009 and H3), this result requires notification of appropriate local, state, or federal public health authorities to determine necessary measures for verification and to further determine whether the specimen represents a novel strain of Influenza A.(5) The manufacturer must perform annual analytical reactivity testing of the device with contemporary influenza strains. This annual analytical reactivity testing must meet the following criteria:
(i) The appropriate strains to be tested will be identified by FDA in consultation with the Centers for Disease Control and Prevention (CDC) and sourced from CDC or an FDA designated source. If the annual strains are not available from CDC, FDA will identify an alternative source for obtaining the requisite strains.
(ii) The testing must be conducted according to a standardized protocol considered and determined by FDA to be acceptable and appropriate.
(iii) By July 31 of each calendar year, the results of the last 3 years of annual analytical reactivity testing must be included as part of the device's labeling. If a device has not been on the market long enough for 3 years of annual analytical reactivity testing to have been conducted since the device received marketing authorization from FDA, then the results of every annual analytical reactivity testing since the device received marketing authorization from FDA must be included. The results must be presented as part of the device's labeling in a tabular format, which includes the detailed information for each virus tested as described in the certificate of authentication, either by:
(A) Placing the results directly in the device's labeling required under § 809.10(b) of this chapter that physically accompanies the device in a separate section of the labeling where the analytical reactivity testing data can be found; or
(B) In the device's label or in other labeling that physically accompanies the device, prominently providing a hyperlink to the manufacturer's public website where the analytical reactivity testing data can be found. The manufacturer's home page, as well as the primary part of the manufacturer's website that discusses the device, must provide a prominently placed hyperlink to the web page containing this information and must allow unrestricted viewing access.
(6) If one of the actions listed at section 564(b)(1)(A)-(D) of the FD&C Act occurs with respect to an influenza viral strain, or if the Secretary of Health and Human Services (HHS) determines, under section 319(a) of the Public Health Service Act, that a disease or disorder presents a public health emergency, or that a public health emergency otherwise exists, with respect to an influenza viral strain:
(i) Within 30 days from the date that FDA notifies manufacturers that characterized viral samples are available for test evaluation, the manufacturer must have testing performed on the device with those viral samples in accordance with a standardized protocol considered and determined by FDA to be acceptable and appropriate. The procedure and location of testing may depend on the nature of the emerging virus.
(ii) Within 60 days from the date that FDA notifies manufacturers that characterized viral samples are available for test evaluation and continuing until 3 years from that date, the results of the influenza emergency analytical reactivity testing, including the detailed information for the virus tested as described in the certificate of authentication, must be included as part of the device's labeling in a tabular format, either by:
(A) Placing the results directly in the device's labeling required under § 809.10(b) of this chapter that physically accompanies the device in a separate section of the labeling where analytical reactivity testing data can be found, but separate from the annual analytical reactivity testing results; or
(B) In a section of the device's label or in other labeling that physically accompanies the device, prominently providing a hyperlink to the manufacturer's public website where the analytical reactivity testing data can be found. The manufacturer's home page, as well as the primary part of the manufacturer's website that discusses the device, must provide a prominently placed hyperlink to the web page containing this information and must allow unrestricted viewing access.