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The BIOFIRE FILMARRAY Pneumonia Panel (BIOFIRE Pneumonia Panel) 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 of multiple respiratory viral and bacterial nucleic acids, as well as select antimicrobial resistance genes, in sputum-like speciorated sputum, or endotracheal aspirates) or bronchoalveolar lavage (BAL)-like specimens (BAL) obtained from individuals suspected of lower respiratory tract infection.

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
• · Klebsiella oxytoca
• · Serratia marcescens
• · Enterobacter cloacae complex
• Klebsiella pneumoniae group
• · 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:

Atypical Bacteria

• Chlamydia pneumoniae
• · Legionella pneumophila
• Mycoplasma pneumoniae

Viruses

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

• Human metapneumovirus

• Influenza B 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, as well as the estimation of relative abundance of nucleic acid from common bacterial analytes, within specimens collected from individuals exhibiting signs and/or symptoms of a respiratory infection, aids in the diagnosis of lower respiratory infection with other clinical and epidemiological information. The results of this test should not be used as for diagnosis, treatment, or other patient management decisions.

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 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 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 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, 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.

BIOFIRE FILMARRAY Pneumonia Panel plus:

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. Thical signs and symptoms assocated 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 influenzae
• 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

• · KPC

• 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 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 BAL-like specimens from individuals with early infection and from asymptomatic MERS-CoV carriers 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.

The BIOFIRE® FILMARRAY® Pneumonia Panel and BIOFIRE® FILMARRAY® Pneumonia Panel plus use nested, multiplex reverse transcription polymerase chain reaction (PCR), followed by melting curve analysis for the detection of select organisms and antimicrobial resistance (AMR) genes in sputum-like (induced and expectorated sputum as well as endotracheal aspirate, ETA) and bronchoalveolar lavage (BAL)-like (BAL and mini-BAL) specimens. The panels allow for the identification of specific bacteria, atypical bacteria, viruses, and AMR genes as indicated in Table 1. The BIOFIRE Pneumonia Panel and BIOFIRE Pneumonia Panel plus pouches are identical, but the BIOFIRE Pneumonia Panel plus includes reporting of Middle East Respiratory Syndrome Coronavirus (MERS-CoV), which is not included in the BIOFIRE Pneumonia Panel. Reporting of MERS-CoV is controlled through software masking of the MERS-CoV result for the BIOFIRE Pneumonia Panel.

The BIOFIRE Pneumonia Panels are compatible with bioMérieux's PCR-based in vitro diagnostic BIOFIRE® FILMARRAY® 2.0 and BIOFIRE® FILMARRAY® TORCH Systems for infectious disease testing. Specific software module (i.e. BIOFIRE Pneumonia Panel Pouch Module Software) are used to perform BIOFIRE Pneumonia Panels testing on these systems.

This document refers to a 510(k) premarket notification for a medical device (BIOFIRE FILMARRAY Pneumonia Panel and BIOFIRE FILMARRAY Pneumonia Panel plus). This type of submission focuses on demonstrating substantial equivalence to a legally marketed predicate device rather than presenting a full de novo study with strict acceptance criteria and performance validation against a test set. The document clearly states that the submission is for software updates to mitigate false positive Coronavirus and CTX-M results and that "Reanalysis of the performance data with the modified pouch module software did not result in an overall change of the study conclusions or performance claims for non-clinical/analytical studies."

Therefore, the information typically requested in your prompt regarding acceptance criteria, study details, sample sizes, expert ground truth establishment, MRMC studies, and standalone performance might not be explicitly detailed in this type of FDA submission as it would be for a de novo marketing authorization. However, I can extract what is available and clarify what is not.

Based on the provided text, here's a breakdown of the requested information:

1. A table of acceptance criteria and the reported device performance

The document does not explicitly state formal "acceptance criteria" in a quantitative table format as might be seen for a new device submission. Instead, the focus is on the impact of the software update on existing performance. The relevant performance change mentioned is:

The document implies that these updated specificities are acceptable because they represent an improvement in mitigating false positives and "did not result in an overall change of the study conclusions or performance claims for non-clinical/analytical studies."

2. Sample sizes used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

The document mentions a "Clinical Prospective Study" for which the Coronavirus specificity numbers are reported. It does not provide the exact sample size for this specific study, nor does it explicitly state the country of origin. It indicates that the reanalysis of existing performance data was done.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

This information is not provided in the document. As this is a molecular diagnostic test, ground truth would typically be established by highly sensitive and specific laboratory methods (e.g., PCR, sequencing, culture) rather than expert human interpretation in the way radiologists interpret images.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set

This information is not provided.

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

An MRMC study is not applicable here as this is a molecular diagnostic device, not an AI-assisted diagnostic imaging device that involves human reader interpretation.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

This refers to the performance of the assay itself. The document implicitly discusses the "standalone" performance of the BIOFIRE FILMARRAY Pneumonia Panel and Panel Plus, which is a molecular diagnostic test. The reported specificities are a measure of this standalone performance. The software update is an internal modification to the assay's interpretation logic.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)

The document implies that the ground truth for the clinical performance evaluations was established through highly sensitive and specific methods for pathogen detection, as is standard clinical laboratory practice for molecular diagnostics. It does not explicitly state the specific ground truth methods but mentions that "Culture is required to obtain isolates for antimicrobial susceptibility testing, and BIOFIRE Pneumonia Panel results should be used in conjunction with culture results for determination of bacterial susceptibility or resistance." This suggests that culture and other definitive laboratory tests would be part of the ground truth establishment, particularly for bacterial analytes and antimicrobial resistance genes.

8. The sample size for the training set

This document describes a software update to an already cleared device. It does not provide details about a "training set" in the context of machine learning model development. The software update appears to be a rule-based or algorithmic adjustment to optimize melting curve analysis and mitigate cross-reactivity with human genomic DNA, rather than a re-training of a complex AI model. The modification was driven by "routine post-market monitoring and complaint investigations combined with concurrent findings from an internal product development study."

9. How the ground truth for the training set was established

As there's no mention of a traditional "training set" in the context of an AI model, this information is not provided. The "ground truth" that informed the software change was likely observations of false positives in clinical samples, identified through investigations and potentially confirmed by orthogonal testing or characterization of the offending interactions (cross-reactivity with hgDNA).

Ask a specific question about this device

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.

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.

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

Study Details (Based on the information provided)

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

Ask a specific question about this device

The FilmArray® Pneumonia Panel plus is a multiplexed nucleic acid test intended for use with FilmArray® 2.0, or FilmArray® Torch systems for the simultaneous detection 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) obtained from individuals meeting MERS-CoV clinical and/or epidemiological criteria.

Testing with FilmArray Pneumonia Panel plus should not be performed unless the patient meets clinical and/or epidemiologic criteria for testing suspecimens. 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 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

• · Adenovirus
• · Coronavirus
• Human Metapneumovirus
• · Human Rhinovirus/Enterovirus
• · Influenza A
• · Influenza B
• · Parainfluenza Virus
• · Respiratory Syncytial Virus

Antimicrobial Resistance Genes

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

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.

FilmArray 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.

FilmArray Pneumonia Panel plus MERS-CoV negative results, even in the context of a FilmArray 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 carriers are not well understood. A negative FilmArray 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 FilmArray 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 FilmArray 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 FilmArray Pneumonia Panel plus are not equivalent to CFU/mL and do not consistently correlate with the quantity of bacterial analytes compared to CFUmL. 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 FilmArray Pneumonia Panel plus results should be used in conjunction with culture results for deterial 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 FilmArray 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.

The FilmArray Pneumonia Panel plus is designed to simultaneously identify Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and 26 other potential pathogens of lower respiratory tract infection (LRTI) and seven 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) that allows the test results to be used in determining appropriate patient treatment and management.

The FilmArray Pneumonia Panel plus is compatible with BioFire's PCR-based in vitro diagnostic FilmArray, FilmArray 2.0, and FilmArray Torch systems for infectious disease testing. A specific software module (i.e. FilmArray Pneumonia Panel pouch module) is used to perform FilmArray Pneumonia Panel testing on these systems.

A test is initiated by loading Hydration Solution into one port of the FilmArray pouch and a sputum-like or BAL-like sample mixed with the provided Sample Buffer into the other port of the FilmArray Pneumonia Panel plus pouch and placing it in a 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 instruments contain coordinated systems 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, electronicallycontrolled 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, 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 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 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.

A new feature of the FilmArray Pneumonia Panel plus is the reporting of organism abundance for common bacteria in discrete bins representing 10^4, 10^5, 10^6, and ≥10^7 genomic copies/mL. The panel accomplishes this by comparing the amplification of the bacterial assays with that of a Quantified Standard Material (QSM) present in the pouch.

The provided text describes the performance study for the FilmArray Pneumonia Panel plus, a multiplex nucleic acid test. Below is a structured summary addressing the requested points.

Acceptance Criteria and Device Performance Study

The acceptance criteria for the FilmArray Pneumonia Panel plus are indirectly demonstrated through the clinical and analytical performance studies, showing the device's ability to accurately detect a wide range of respiratory pathogens and antimicrobial resistance genes in specific clinical samples. The study proves the device meets these criteria through robust empirical testing and in silico analyses.

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" in a go/no-go format for each analyte, but rather presents the performance (Sensitivity/PPA and Specificity/NPA) from the clinical study as evidence of meeting regulatory requirements. The implicit acceptance criteria would likely be high agreement percentages and confidence intervals.

Table 1: Summary of Reported Device Performance (Clinical Study - BAL Specimens)

Note: Performance for Sputum specimens presented in Table 5.
Note: PPA = Positive Percent Agreement (Sensitivity), NPA = Negative Percent Agreement (Specificity).
Note: '-' indicates TP/(TP+FN) or TN/(TN+FP) was 0/0, thus percentage and CI could not be calculated.

2. Sample Sizes and Data Provenance

• Test Set (Clinical Performance):
  • Sample Size: 846 BAL specimens (including mini-BAL) and 836 sputum specimens (including ETA).
  • Data Provenance: Multi-center study conducted at eight geographically distinct U.S. study sites. The study was prospective in nature, collecting specimens from October 2016 to July 2017. Additionally, archived retrospective specimens were used for low-prevalence analytes, including 8 BAL and 10 sputum specimens from a 2015 MERS-CoV outbreak in South Korea, and 171 archived specimens from external laboratories (139 BAL, 14 sputum, and negative controls). Contrived specimens were also used (1225 total, N=625 BAL, N=600 sputum for main contrived study; N=60 BAL, N=60 sputum for polymicrobial contrived study).

3. Number of Experts and Qualifications for Ground Truth

The document does not specify the exact number and qualifications of experts establishing the ground truth for the test set. Instead, it details the reference methods used for ground truth:

• Bacterial Analytes: Quantitative reference culture (qRefCx) with a threshold of ≥ 3162 (10^3.5) CFU/mL. Discrepancies were further investigated using single PCR assays followed by quantitative molecular assay including sequencing (qMol), and additional molecular assays followed by sequence analysis where needed.
• Atypical Bacteria and Viruses: Two conventional PCR assays followed by bidirectional sequencing. A specimen was considered positive if bidirectional sequencing data met predefined quality acceptance criteria and matched organism-specific sequences in the NCBI GenBank database.
• AMR Genes: Single PCR assay followed by sequencing (qMol) from the specimen, combined with phenotypic AST (antimicrobial susceptibility testing) via qRefCx performed in conjunction with current CLSI guidelines for correlation.
• MERS-CoV: For clinical specimens, it was assumed they were negative as the virus was not circulating in the US during enrollment. For archived specimens, previous laboratory results (from South Korea during the 2015 outbreak) served as ground truth.

4. Adjudication Method for the Test Set

The adjudication method for discrepant results between the FilmArray Pneumonia Panel plus and the primary comparator method varied:

• For bacterial analytes, discrepancies were first examined to see if the qRefCx or FilmArray observed the analyte but below the detection threshold. If unresolved, qMol testing results were considered. If still unresolved, multiple additional molecular assays followed by sequence analysis were used.
• For other analytes (atypical bacteria, viruses, AMR genes), molecular comparator results (two conventional PCR assays followed by bidirectional sequencing) were used. If the two assays agreed, that was the ground truth. If they disagreed, additional molecular assays followed by sequence analysis were performed. The results of "SOC testing" (Standard of Care) were also considered.

This suggests an algorithm-mediated adjudication with expert review for difficult cases (discrepancies), rather than a fixed "2+1" or "3+1" expert consensus model initially. The ground truth itself often involved molecular methods, which are considered highly accurate for nucleic acid detection.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

There is no MRMC comparative effectiveness study described in the provided text. The study focuses on comparing the device's performance against reference laboratory methods (molecular and culture-based) for direct detection, not on evaluating how human readers' performance might improve with or without AI assistance. The device is an in vitro diagnostic (IVD) test, not an AI-assisted diagnostic imaging tool.

6. Standalone (Algorithm Only) Performance

The entire performance study described is essentially a standalone (algorithm only without human-in-the-loop) performance evaluation for the FilmArray Pneumonia Panel plus. The results for sensitivity/PPA and specificity/NPA directly report the device's accuracy in detecting various pathogens and AMR genes compared to established reference methods.

7. Type of Ground Truth Used

The ground truth used varied by analyte:

• Bacterial Analytes: Quantitative Reference Culture (qRefCx) for primary evaluation. Discrepancies were resolved using quantitative molecular assays (qMol) and subsequent sequencing/additional molecular assays.
• Atypical Bacteria, Viruses (excluding MERS-CoV in US clinical samples): Two conventional PCR assays followed by bidirectional sequencing. Discrepancies resolved with additional molecular assays and sequencing.
• MERS-CoV (archived specimens): Previous laboratory results (implicitly molecular/viral culture confirmation) from the outbreak.
• Antimicrobial Resistance Genes: Single PCR assay followed by sequencing (qMol) directly from the specimen, and correlation with phenotypic AST from cultured isolates.

Therefore, the ground truth is a combination of expert-interpreted molecular data (PCR/sequencing), quantitative culture, and phenotypic AST, with further discrepancy resolution protocols.

8. Sample Size for the Training Set

The document focuses solely on the performance evaluation of the FilmArray Pneumonia Panel plus device. It states that the device is "designed to simultaneously identify Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and 26 other potential pathogens of lower respiratory tract infection (LRTI) and seven associated antimicrobial resistance (AMR) genes." It describes analytical and clinical validation studies but does not provide information on a "training set" sample size for an AI/ML model, as this is a molecular diagnostic device not explicitly using an AI/ML component in its core diagnostic algorithm. The phrase "FilmArray Software automatically interprets the results" implies a deterministic algorithm, not a trainable machine learning model.

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

Since no training set for an AI/ML model is mentioned, there is no information provided on how its ground truth was established. The document describes the validation/test set ground truth as outlined in point 7.

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The FilmArray Respiratory Panel 2 plus (RP2plus) is a multiplexed nucleic acid test intended for use with FilmArray 2.0 or FilmArray Torch systems for the simultaneous qualitative detection and identification of nucleic acids from Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and multiple common viral and bacterial respiratory pathogens in nasopharyngeal swabs (NPS) obtained from individuals meeting MERS-CoV clinical and/or epidemiological criteria.

Testing with the FilmArray RP2plus 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 FilmArray RP2plus identifies:

• Middle East Respiratory Syndrome Coronavirus (MERS-CoV) ●
  And the following viral and bacterial respiratory pathogen types and subtypes:

• Adenovirus

• Coronavirus 229E ●

• Coronavirus HKU1 ●

• Coronavirus NL63

• Coronavirus OC43 ●

• Human Metapneumovirus

• Human Rhinovirus/Enterovirus ●

• Influenza A. including subtypes H1. H1-2009, and H3 ●

• Influenza B

• Parainfluenza Virus 1

• Parainfluenza Virus 2

• Parainfluenza Virus 3 ●

• Parainfluenza Virus 4

• Respiratory Syncytial Virus ●

• Bordetella parapertussis (IS 1001) ●

• Bordetella pertussis (ptxP)

• . Chlamydia pneumoniae

• . Mycoplasma pneumoniae

The detection and identification of specific viral and bacterial nucleic acids from MERS-CoV and other respiratory pathogens in 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.

FilmArray RP2plus 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.

FilmArray RP2plus MERS-CoV negative results, even in the context of a FilmArray RP2plus 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 NPS specimens from individuals with early infection and from asymptomatic MERS-CoV carriers are not well understood. The FilmArray RP2plus MERS-CoV negative results may also be due to lower respiratory tract infection with MERS-CoV that may not be detected by an NPS specimen. In this context, collection of lower respiratory and serum specimens (if possible) for MERS-CoV testing using other laboratory tests is highly recommended in addition to testing for MERS-CoV RNA in NPS specimens (i.e., upper respiratory specimens) using the FilmArray RP2plus. A negative FilmArray RP2plus 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 in the cases of positive FilmArray RP2plus results for MERS-CoV unless a BSL 3 facility is available to receive and culture specimens.

Negative FilmArray RP2plus results in the setting of a respiratory illness may be due to infection with pathogens that are not detected by this test, or other pathogens that may not be detected by an NPS specimen. Positive FilmArray RP2plus results do not rule out coinfection with other organisms: the agent(s) detected by the FilmArray RP2plus may not be the definite cause of disease.

Due to the genetic similarity between Human Rhinovirus and Enterovirus, the FilmArrav RP2plus cannot reliably differentiate them. A positive FilmArray RP2plus Rhinovirus/Enterovirus result should be followed up using an alternate method (e.g., cell culture or sequence analysis) if differentiation is required.

Performance characteristics for Influenza A were established when Influenza A H1-2009, A H1, and A H3 were the predominant Influenza A viruses in circulation. Performance of detecting Influenza A may vary if other Influenza A strains are circulating or a novel Influenza A virus emerges. 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.

The FilmArray Respiratory Panel 2 plus (RP2plus) is designed to simultaneously detect and identify MERS-CoV and 21 different common pathogens (see the Indications for Use section) of respiratory tract infection from a single NPS specimen in a time frame (~45 minutes) that may allow the test results to be used as an aid in determining appropriate patient treatment and management. FilmArray RP2plus is compatible with BioFire Diagnostics' (BioFire) PCR-based in vitro diagnostic FilmArray 2.0 and FilmArray Torch systems for infectious disease testing. A specific software module (i.e., FilmArray RP2plus pouch module) is used to perform FilmArray RP2plus testing on these systems.

A test is initiated by loading Hydration Solution into one port of the FilmArray pouch and a NPS sample (in transport media) mixed with the provided Sample Buffer into the other port of the FilmArray RP2plus pouch and placing it in a FilmArray instrument. The FilmArray 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 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 and chemical lysis 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, PCR1. The products from first stage PCR are then diluted and combined with a fresh, primerfree master mix and a fluorescent double stranded DNA binding dye (LC Green Plus, BioFire Diagnostics, 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, PCR2. 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 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.

Table of Acceptance Criteria and Reported Device Performance:

2. Sample sizes used for the test set and the data provenance:

• Reproducibility Study Test Set: 120 data points per sample, across 4 contrived NPS samples, totaling 480 valid runs. The data was from a combined total of 15 different FilmArray 2.0 instruments and 19 different FilmArray Torch modules at three testing sites. The samples were contrived NPS samples in simulated VTM.
• LoD Confirmation Test Set: For each analyte, 40 replicates (20 on FilmArray 2.0, 20 on FilmArray Torch) at 1xLoD, and 40 replicates at 0.1xLoD. Samples were contrived in simulated NPS in VTM.
• Analytical Reactivity Test Set: Each isolate/strain was tested in triplicate (one replicate on each of three different reagent lots) near 3xLoD. Tested at 10xLoD or higher if not reliably detected. Samples were contrived in Remel M4 Transport Medium.
• Analytical Specificity/Cross-Reactivity Test Set: Each organism tested in triplicate on three different lots of FilmArray RP2plus pouches at high concentrations (typically ≥1.0E+06 CFU/ml for bacteria and fungi and ≥1.0E+05 TCID50/mL for viruses). Samples were in Remel M4 transport medium.
• Interfering Substances Test Set: Each test substance added to a contrived sample containing a mix of five analytes (each near LoD).
• Comparator Assay for B. parapertussis: Validation testing of the PCR followed by sequencing assays used samples (nature and number not specified beyond demonstrating equivalent analytical sensitivity to RP2plus).
• MERS-CoV Comparative Analytical Sensitivity: A MERS-CoV proficiency test panel (QCMD, U.S. government contracted) containing MERS-CoV samples and common coronaviruses.
• Prospective Clinical Study Test Set: 1612 residual NPS specimens in VTM after exclusions. Data provenance: Three geographically distinct U.S. study sites (Salt Lake City, UT; Chicago, IL; Columbus, OH) during portions of the 2015-2016 and 2016-2017 respiratory illness seasons. Samples were retrospective (archived/frozen) and prospective (fresh).
• Retrospective Clinical Study - Common Respiratory Pathogens Test Set: A total of 214 archived NPS in VTM specimens after exclusions. These were preselected specimens previously tested positive at the source laboratory. Data provenance: BioFire Diagnostics (testing site), specimens were archived from various source laboratories (presumably US-based).
• Retrospective Clinical Study - MERS-CoV Test Set: 3 archived retrospective NPS in VTM specimens from confirmed cases of MERS-CoV infection. Data provenance: Laboratory in South Korea during the 2015 MERS-CoV outbreak.
• Contrived Clinical Specimens Test Set: 50 MERS-CoV positive contrived specimens, 48 Influenza A H1 positive contrived specimens, and 50 un-spiked negative specimens. Samples were prepared using unique residual NPS specimens that previously tested negative from a clinical site. Data provenance: One of the three clinical sites from the prospective evaluation.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

• Analytical Studies (Reproducibility, LoD, Analytical Reactivity, Analytical Specificity, Interfering Substances, MERS-CoV Comparative Analytical Sensitivity): The document does not specify a number of "experts" for ground truth outside of the internal process for developing the melt detector algorithm. Ground truth for these was established using known concentrations of cultured isolates, molecular quantification (qPCR/RT-PCR), or known positive/negative status of contrived samples. The melt detector algorithm's performance was compared to "expert annotation," but the number and qualifications of these experts are not explicitly stated.
• Prospective Clinical Study: Ground truth was established by an FDA-cleared multiplexed respiratory pathogens panel (for most analytes) and two analytically-validated PCR followed by bidirectional sequencing assays (for B. parapertussis). For MERS-CoV, the ground truth was the expected negative result in this population. The performance of these comparator methods, acting as the reference standard, generally implies expert oversight in their validation and historical use, but no specific human experts are mentioned for establishing the ground truth for this particular study.
• Retrospective Clinical Study - Common Respiratory Pathogens: Ground truth was established by the same comparator methods as the prospective study (FDA-cleared multiplexed respiratory pathogens panel and B. parapertussis PCR/sequencing).
• Retrospective Clinical Study - MERS-CoV: Ground truth was established by standard of care methods, specifically two rRT-PCR assays targeting upE and ORF1A (based on WHO primer/probe sequences) used during the 2015 MERS-CoV outbreak. These methods would have been operated by trained laboratory personnel, implying expertise, but no specific number or qualification of experts is provided for creating the ground truth for this study.
• Contrived Clinical Specimens: Ground truth was based on the known spiking of negative specimens with quantified isolates of Influenza A H1 and MERS-CoV.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set:

• Analytical Studies: Adjudication methods are not explicitly described for discrepancies in analytical tests. Deviations from expected results (e.g., non-detection at 3xLoD) led to retesting at higher concentrations. The Melt Detector algorithm validation involved comparison to "expert annotation" without a specified adjudication protocol.
• Clinical Studies (Prospective and Retrospective - Common Respiratory Pathogens): Discrepant results (FilmArray RP2plus vs. comparator method) were subjected to further investigation. The discrepancy investigation was mainly conducted by performing independent molecular methods with primers different from the FilmArray RP2plus and/or comparator method retesting. This indicates a form of adjudication, where a third, independent method or re-run of the comparator served to resolve the discrepancy, but a specific "X+Y" voting method (like 2+1) is not detailed.
• Retrospective Clinical Study - MERS-CoV: This study involved only three positive samples, and the FilmArray RP2plus showed 100% agreement. No discrepancies were observed, so no adjudication method was needed or described.
• Contrived Clinical Specimens: Ground truth was defined by the known spiking protocol. Any deviations from expected results were analyzed for causes (e.g., presence of a specific strain of Influenza A/Weiss/43 leading to equivocal result).

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?

This document describes the evaluation of a fully automated in vitro diagnostic (IVD) device (FilmArray Respiratory Panel 2 plus), which is a nucleic acid amplification test. It is not an AI-assisted diagnostic device where human readers interact with AI. Therefore, a multi-reader multi-case (MRMC) comparative effectiveness study evaluating human reader performance with and without AI assistance was not applicable and not performed. The device itself performs the analysis and provides a result without human interpretation of raw data.

6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done?

Yes, a standalone performance evaluation was done. The entire submission details the performance of the FilmArray RP2plus, which is described as a "multiplexed nucleic acid test intended for use with FilmArray 2.0 or FilmArray Torch systems for the simultaneous qualitative detection and identification of nucleic acids..." (Section D). The device "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" (Section I). This clearly indicates an algorithm-only (standalone) performance. The clinical studies compare the device's output directly to comparator methods, not to human interpretations that the device might aid.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc):

• Analytical Studies (Reproducibility, LoD, Analytical Reactivity, Analytical Specificity, Interfering Substances): The ground truth was primarily based on known concentrations of cultured isolates, molecular quantification (e.g., qPCR/RT-PCR), or the inherent design of contrived samples. For the internal Melt Detector validation, it was compared to "expert annotation."
• Prospective Clinical Study: The ground truth was established using a combination of FDA-cleared multiplexed respiratory pathogen panels (molecular comparator devices) and analytically-validated PCR followed by bidirectional sequencing assays for B. parapertussis. For MERS-CoV, the ground truth was the expected negative result in the general study population. Discrepancies were further investigated using independent molecular methods.
• Retrospective Clinical Study - Common Respiratory Pathogens: The ground truth was established by the same comparator methods as the prospective study (FDA-cleared multiplexed respiratory pathogen panels and B. parapertussis PCR/sequencing).
• Retrospective Clinical Study - MERS-CoV: The ground truth was established by standard of care reference molecular methods (two rRT-PCR assays based on WHO primer/probe sequences) used during the 2015 MERS-CoV outbreak, confirming positive MERS-CoV infection.
• Contrived Clinical Specimens: The ground truth was based on the known positive status due to spiking with quantified isolates and the known negative status of un-spiked specimens.

8. The sample size for the training set:

• Melt Detector Algorithm: The "Melt Detector" algorithm was "tuned against a large data set comprising typical and atypical melting curves... with expert annotation (positive or negative calls) during the development of the original FilmArray RP." A specific number for this training set is not explicitly provided in the given text, but it's described as "large" and stemming from the development of the original FilmArray RP.
• Other aspects of the FilmArray RP2plus development: The document hints at iterative development and testing, but a distinct "training set" in the context of machine learning for all aspects of the device is not detailed. The performance evaluations presented are essentially "test set" evaluations against defined ground truths.

9. How the ground truth for the training set was established:

• Melt Detector Algorithm Training: The ground truth for the "large data set comprising typical and atypical melting curves" used to tune the Melt Detector algorithm was established through "expert annotation (positive or negative calls)." The qualifications of these experts are not explicitly stated.

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