(26 days)
The FilmArray® Pneumonia Panel is a multiplexed nucleic acid test intended for use with FilmArray® 2.0 or FilmArray® Torch systems for the simultaneous detection of 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 suspected of lower respiratory tract infection.
The following bacteria are reported semi-quantitatively with bins representing approximately 10^4, 10^5 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
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-Mycoplasma pneumoniae
Viruses -Adenovirus -
-Coronavirus
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-Human Metapneumovirus
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-Human Rhinovirus/Enterovirus
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-Influenza A
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-Influenza B
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-Parainfluenza Virus
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-Respiratory Syncytial Virus
Antimicrobial Resistance Genes -CTX-M -IMP -KPC -NDM -OXA-48-like -VIM -mecA/C and MREJ
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 FilmArray 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 FilmArray Pneumonia Panel 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 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 FilmArray 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.
The FilmArray Pneumonia (PN) Panel is designed to simultaneously identify 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 with signs and/or symptoms of lower respiratory tract infection in a time (~1 hour) that allows the test results to be used in determining appropriate patient treatment and management. FilmArray PN Panel is compatible with BioFire Diagnostics' (BioFire) PCR-based in vitro diagnostic FilmArray 2.0 (K143178) and FilmArray Torch (K160068) systems for infectious disease testing. A specific software module (i.e. FilmArray PN Panel pouch module) is used to perform FilmArray PN Panel testing on these systems.
Bacteria - Quantitative Results: 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
Bacteria (Atypical) - Qualitative Results: Chlamydia pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae
Antimicrobial Resistance Genes: blaCTX-M (Extended spectrum beta-lactamase (ESBL)), blaIMP (Carbapenem resistance), blaKPC (Carbapenem resistance), mecA/mecC and MREJ (Methicillin resistance), blaNDM (Carbapenem resistance), blaOXA48-like (Carbapenem resistance), blaVIM (Carbapenem resistance)
Viruses: Adenovirus, Coronavirus, Human Metapneumovirus, Human Rhinovirus/Enterovirus, Influenza A, Influenza B, Parainfluenza Virus, Respiratory Syncytial Virus
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 PN Panel 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 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. 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 single plex 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 feature of the FilmArray PN Panel 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.
Here's an analysis of the provided text regarding the FilmArray Pneumonia Panel, focusing on the acceptance criteria and study details. It's important to note that this document is a Special 510(k) Summary for a labeling modification related to a previously cleared device. Therefore, it primarily discusses the change and its impact on the device's labeling, rather than presenting a comprehensive de novo validation study.
Key takeaway: The document describes a labeling modification due to a stability issue with the Adenovirus2 assay (specifically for Adenovirus C) within 6 months of the pouch expiration date. It does not provide details of an initial, full validation study with acceptance criteria and reported performance for all analytes, as that would have been part of the original K180966 submission. The information below is extracted from what's available in this specific document regarding the impact of the noted issue.
1. Table of Acceptance Criteria and Reported Device Performance
This document does not present a table of general acceptance criteria and reported performance for all analytes of the FilmArray Pneumonia Panel since it's a labeling modification submission. The focus is specifically on the change in performance for Adenovirus C due to stability.
The "acceptance criteria" discussed here are essentially the observed degradation in sensitivity and the resulting limitation on the use of the device for Adenovirus C detection under specific conditions.
| Analyte (Specific Focus) | Acceptance Criteria (Original expectation) | Reported Device Performance (Under specific conditions) |
|---|---|---|
| Adenovirus C (when pouch is within 6 months of expiration) | Consistent sensitivity | LoD for adenovirus species C is 10 – 100 x impaired (loss in sensitivity) when pouches are within 6 months of expiration. Increased risk of false negative Adenovirus results. |
| All other analytes / Adenovirus C (when pouch is > 6 months from expiration) | Consistent sensitivity | Performance is not impacted. |
Note: The original acceptance criteria for the initial clearance (K180966) would have included specific sensitivity (Limit of Detection - LoD) and specificity targets, which are not detailed in this specific document.
2. Sample Size Used for the Test Set and Data Provenance
The document does not specify a "test set" in the context of a de novo validation study. Instead, it refers to a stability study where the issue with Adenovirus2 assay's performance was discovered.
- Sample Size for Test Set: Not explicitly stated as a separate test set. The issue was identified during a stability study of the device pouches.
- Data Provenance: The issue was identified through internal stability study results conducted by BioFire Diagnostics, LLC. No country of origin for clinical samples is mentioned, as the data appears to be from analytical testing (stability of laboratory-manufactured pouches). The study type is retrospective in the sense that previously manufactured pouches were being tested for stability over time.
3. Number of Experts Used to Establish Ground Truth and Qualifications
Not applicable. This document does not describe a study involving expert consensus to establish ground truth for clinical cases. The issue identified was an analytical performance degradation discovered during internal stability testing.
4. Adjudication Method
Not applicable. This document is not describing a study that required adjudication of complex clinical cases or image interpretations. The "adjudication" was the internal assessment of stability study results and the determination that the performance characteristic (LoD for Adenovirus C) had degraded under specific conditions.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
Not applicable. The device is an in vitro diagnostic (IVD) based on molecular detection, not one requiring human interpretation of results. Therefore, an MRMC study is not relevant to this type of device.
6. Standalone (Algorithm Only) Performance
Yes, the information presented relates to standalone performance of the device. The reported impairment in LoD for Adenovirus C was determined through analytical testing of the device itself (the assay in the pouch) under specific storage conditions. There is no human-in-the-loop component in the detection process of the FilmArray Pneumonia Panel.
7. Type of Ground Truth Used
The ground truth used for identifying this issue was analytical performance data (stability study results) and the degradation of the Limit of Detection (LoD) for Adenovirus C, which represents a quantifiable measure of the assay's sensitivity. This is akin to a "spike-in" experiment or testing known positive controls at various concentrations across the shelf-life of the product.
8. Sample Size for the Training Set
Not applicable. This document describes a stability issue with an already-cleared device and a subsequent labeling modification. It does not refer to a "training set" in the context of an algorithm or AI development. The device pre-dates common AI/ML nomenclature in medical device submissions for IVDs.
9. How the Ground Truth for the Training Set Was Established
Not applicable, as there is no "training set" described in this document.
§ 866.3985 Device to detect and identify microorganisms and associated resistance marker nucleic acids directly in respiratory specimens.
(a)
Identification. A device to detect and identify microorganisms and associated resistance marker nucleic acids directly from respiratory specimens is an in vitro diagnostic device intended for the detection and identification of microorganisms and associated resistance markers in respiratory specimens collected from patients with signs or symptoms of respiratory infection. The device is intended to aid in the diagnosis of respiratory infection in conjunction with clinical signs and symptoms and other laboratory findings. These devices do not provide confirmation of antibiotic susceptibility since mechanisms of resistance may exist other than those detected by the device.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The intended use for the 21 CFR 809.10 labeling must include a detailed description of what the device detects, the type of results provided to the user, the clinical indications appropriate for test use, and the specific population(s) for which the device is intended.
(2) The 21 CFR 809.10(b) labeling must include:
(i) A detailed device description, including all device components, control elements incorporated into the test procedure, instrument requirements, ancillary reagents required but not provided, and a detailed explanation of the methodology, including all pre-analytical methods for processing of specimens.
(ii) Performance characteristics from analytical studies, including, but not limited to, limit of detection, inclusivity, reproducibility, cross reactivity, interfering substances, competitive inhibition, carryover/cross contamination, specimen stability, and linearity, as applicable.
(iii) A limiting statement that the device is intended to be used in conjunction with clinical history, signs and symptoms, and results of other diagnostic tests, including culture and antimicrobial susceptibility testing.
(iv) A detailed explanation of the interpretation of test results for clinical specimens and acceptance criteria for any quality control testing.
(v) A limiting statement that negative results for microorganisms do not preclude the possibility of infection, and should not be used as the sole basis for diagnosis, treatment, or other patient management decisions.
(vi) If applicable, a limiting statement that detected microorganisms may not be the cause of lower respiratory tract infection and may be indicative of colonizing or normal respiratory flora.
(vii) If applicable, a limiting statement that detection of resistance markers cannot be definitively linked to specific microorganisms and that the source of a detected resistance marker may be an organism not detected by the assay, including colonizing flora.
(viii) If applicable, a limiting statement that detection of antibiotic resistance markers may not correlate with phenotypic gene expression.
(3) The 21 CFR 809.10(b) labeling and any test report generated by the device must include a limiting statement that negative results for resistance markers do not indicate susceptibility of detected microorganisms.
(4) Design verification and validation must include:
(i) Performance characteristics from clinical studies that include prospective (sequential) samples and, if appropriate, additional characterized samples. The study must be performed on a study population consistent with the intended use population and compare the device performance to results obtained from an FDA accepted reference method and/or FDA accepted comparator method, as appropriate. Results from the clinical studies must include the clinical study protocol (including predefined statistical analysis plan, if applicable), clinical study report, and results of all statistical analyses.
(ii) A detailed device description including the following:
(A) Thorough description of the assay methodology including, but not limited to, primer/probe sequences, primer/probe design, and rationale for target sequence selection, as applicable.
(B) Algorithm used to generate a final result from raw data (e.g., how raw signals are converted into a reported result).
(iii) A detailed description of device software, including, but not limited to, validation activities and outcomes.
(iv) As part of the risk management activities, an appropriate end user device training program must be offered as an effort to mitigate the risk of failure from user error.