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The FilmArray Respiratory Panel (RP) is a multiplexed nucleic acid test intended for use with FilmArray systems for the simultaneous qualitative detection and identification of multiple respiratory viral and bacterial nucleic acids in nasopharyngeal swabs (NPS) obtained from individuals suspected of respiratory tract infections. The following organism types and subtypes are identified using the FilmArray RP: Adenovirus, Coronavirus 229E, Coronavirus HKU1, Coronavirus NL63, Coronavirus OC43, Human Metapneumovirus, Influenza A, Influenza A subtype H1, Influenza A subtype H3, Influenza A subtype 2009 H1, Influenza B, Parainfluenza Virus 1, Parainfluenza Virus 2, Parainfluenza Virus 3, Parainfluenza Virus 4, Human Rhinovirus/Enterovirus, Respiratory Syncytial Virus, Bordetella pertussis, Chlamydophila pneumoniae, and Mycoplasma pneumoniae. The detection and identification of specific viral and bacterial nucleic acids from individuals exhibiting signs and symptoms of a respiratory infection aids in the diagnosis of respiratory infection if used in conjunction with other clinical and epidemiological information. The results of this test should not be used as the sole basis for diagnosis, treatment, or other 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 or, lower respiratory tract infection that is not detected by a nasopharyngeal swab specimen. Positive results do not rule out co-infection with other organisms: the agent(s) detected by the Film Array RP 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 respiratory tract infection.

The FilmArray Respiratory Panel (RP) is a multiplexed nucleic acid test for the simultaneous qualitative detection and identification of multiple respiratory viral and bacterial nucleic acids in nasopharyngeal swabs (NPS) obtained from individuals suspected of respiratory tract infections. The FilmArray Respiratory Panel is designed to be used with FilmArray systems (currently FilmArray and FilmArray 2.0). This 510(k) modifies the Device by adding the FilmArray Torch as an additional instrument system for use with the FilmArray Respiratory Panel. The FilmArray RP pouch contains freeze-dried reagents to perform nucleic acid purification. reverse transcription, and nested, multiplex PCR with DNA melt analysis. FilmArray RP simultaneously conducts 20 tests for the identification of respiratory pathogens from nasopharyngeal swabs (NPS) obtained from individuals suspected of respiratory tract infections (Table 1). Results from the FilmArray RP test are available within about one hour.

A test is initiated by loading Hydration Solution and an unprocessed patient nasopharyngeal swab (NPS) specimen (i.e. specimen mixed with Sample Buffer) into the FilmArray RP pouch. The pouch contains all of the reagents required for specimen testing and analysis in a freezedried format; the addition of Hydration Solution and specimen/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.

FilmArray systems contain 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 Defense, LLC). The solution is then distributed to each well of the array. Array wells contain sets of primers designed specifically to amplify sequences internal to the PCR products generated during the first stage PCR reaction. The 2nd stage PCR, or nested PCR, is performed in singleplex fashion in each well of the array. At the conclusion of the 2nd stage PCR, the array is interrogated by melt curve analysis for the detection of signature amplicons denoting the presence of specific targets. A digital camera placed in front of the array captures fluorescent images of the PCR reactions and software interprets the data.

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

The provided text describes a Special 510(k) submission for the FilmArray Respiratory Panel (RP) for use with the FilmArray Torch system. This submission modifies the device by adding the FilmArray Torch as an additional instrument system for use with the already cleared FilmArray Respiratory Panel. Crucially, the reagent kit itself has not changed. Therefore, the performance characteristics demonstrated in the original clearance for the FilmArray RP on FilmArray and FilmArray 2.0 systems are largely relied upon.

The performance study described focuses on demonstrating reproducibility on the new FilmArray Torch system, rather than a full de novo clinical performance study for all targets.

Here's a breakdown of the requested information based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for this specific study, given the nature of the 510(k) (adding a new instrument to an existing assay), appears to be focused on reproducible detection at the Limit of Detection (LoD) and agreement with negative results.

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

• Test Set Sample Size: 90 replicates per analyte.
• Data Provenance: The study used contrived samples containing each FilmArray RP analyte at low positive levels (1x LoD). This implies laboratory-prepared samples, not clinical specimens. The study was conducted on three complete FilmArray Torch systems (12 FilmArray Torch Modules per system) over five days. This is a prospective laboratory study.

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

For this specific reproducibility study, the "ground truth" was inherently known because contrived samples were used. This means the researchers prepared samples with a known presence (at 1x LoD) or absence of each analyte. Therefore, no external experts were needed to establish ground truth for this particular test set.

4. Adjudication Method for the Test Set

Not applicable. Since contrived samples with known analytes (or their absence) were used, no adjudication method was required. The "ground truth" was established by the experimental design.

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

No. This document describes a reproducibility study for a new instrument platform, not a comparative effectiveness study involving human readers.

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

Yes, this study is inherently a standalone performance evaluation of the FilmArray RP assay run on the FilmArray Torch system. The device's software automatically interprets the results. While human operators initiate the test and prepare the pouch, the detection and interpretation are performed by the automated system.

7. The Type of Ground Truth Used

For this specific reproducibility study for the FilmArray Torch instrument, the ground truth was based on known composition of contrived samples. For the original FilmArray RP assay's clinical performance, the Indications for Use (and the full 510(k) typically details this) mention:

• "Performance characteristics for Bordetella pertussis, Coronavirus OC43, Influenza A H1, Influenza A H3, Influenza A H1-2009, Influenza B, Mycoplasma pneumoniae, Parainfluenza Virus 1, Parainfluenza Virus 2, and Parainfluenza Virus 4 were established primarily with retrospective clinical specimens."
• "Performance characteristics for Chlamydophila pneumoniae were established primarily using contrived clinical specimens."
• Initial clinical studies would have likely used a combination of culture, PCR, and other reference methods as ground truth for clinical specimens.

8. The Sample Size for the Training Set

The document does not specify a separate training set for the FilmArray RP performance on the Torch system. This submission is for a new instrument, not a new algorithm from scratch. The underlying FilmArray RP assay was already cleared. The study described focuses on verifying the performance of the already-developed assay on the new instrument.

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

Not explicitly stated for a training set in this particular document. Given that the reagent kit is unchanged, the "training" for the assay itself would have occurred during the development of the original FilmArray RP, for which detailed ground truth establishment methods (likely involving reference methods, clinical correlation, etc.) would have been described in its original K143080 submission.

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The FilmArray Respiratory Panel (RP) is a multiplexed nucleic acid test intended for use with FilmArray systems for the simultaneous qualitative detection and identification of multiple respiratory viral and bacterial nucleic acids in nasopharyngeal swabs (NPS) obtained from individuals suspected of respiratory tract infections. The following organism types and subtypes are identified using the FilmArray RP: Adenovirus 229E, Coronavirus HKU1, Coronavirus NL63, Coronavirus OC43, Human Metapneumovirus, Influenza A subtype H1, Influenza A subtype H3, Influenza A subtype 2009 H1, Influenza Virus 1, Parainfluenza Virus 2, Parainfluenza Virus 3, Parainfluenza Virus 4, Human Rhinovirus/Enterovirus, Respiratory Syncytial Virus, Bordetella pertussis, Chlamydophila pneumoniae, and Mycoplasma pneumoniae. The detection of specific viral and bacterial nucleic acids from individuals exhibiting signs and symptoms of a respiratory infection aids in the diagnosis of respiratory infection if used in conjunction with other clinical and epidemiological information. The results of this test should not be used as the sole basis for diagnosis, treatment, or other 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 or, lower respiratory tract infection that is not detected by a nasopharyngeal swab specimen. Positive results do not rule other organisms: the agent(s) detected by the Film Array RP may not be the definite cause of disease. Additional laboratory testing (e.g. bacterial and viral culturescence, and radiography) may be necessary when evaluating a patient with possible respiratory tract infection.

Due to the small number of positive specimens collected for certain organisms during the prospective clinical study, performance characteristics for Bordetella pertussis, Coronavirus OC43, Influenza A H1, Influenza A H3, Influenza A H1-2009, Influenza B, Mycoplasma pneumoniae, Parainfluenza Virus 1, Parainfluenza Virus 2, and Parainfluenza Virus 4 were established primarily with retrospective clinical specimens. Performance characteristics for Chlamydophila pneumoniae were established primarily using contrived clinical specimens.

Due to the genetic similarity between Human Rhinovirus, the FilmArray RP cannot reliably differentiate them. A positive FilmArray RP Rhinovirus result should be followed-up using an alternate method (e.g., cell culture or sequence analysis).

The FilmArray RP assay for Coronavirus OC43 may cross-react with some isolates of Coronavirus HKU1. A dual positive result may be due to cross-reactivity or may indicate a co-infection.

Performance characteristics for Influenza A were established when Influenza A 2009 HIN1, 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 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 is a multiplex nucleic acid test designed to be used with FilmArray systems. The FilmArray RP pouch contains freeze-dried reagents to perform nucleic acid purification, reverse transcription, and nested, multiplex PCR with DNA melt analysis. FilmArray RP simultaneously conducts 20 tests for the identification of respiratory pathogens from nasopharyngeal swabs (NPS) obtained from individuals suspected of respiratory tract infections (Table 1). Results from the FilmArray RP test are available within about one hour.

A test is initiated by loading Hydration Solution and an unprocessed patient nasopharyngeal swab (NPS) specimen (i.e. specimen mixed with Sample Buffer) into the FilmArray RP pouch. The pouch contains all of the reagents required for specimen testing and analysis in a freezedried format; the addition of Hydration Solution and specimen/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. 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 Ivsis followed by purification using standard magnetic bead technology. After extracting and purifying nucleic acids from the unprocessed sample, a nested multiplex PCR is executed in two stages. During the first stage, a single, large volume, highly multiplexed reverse transcription PCR (rt-PCR) reaction is performed. The products from first stage PCR are then diluted and combined with a fresh, primer-free master mix and a fluorescent double stranded DNA binding dye (LC Green® Plus, BioFire Defense, LLC). The solution is then distributed to each well of the array. Array wells contain sets of primers designed specifically to amplify sequences internal to the PCR products generated during the first stage PCR reaction. The 2nd stage PCR, or nested PCR, is performed in singleplex fashion in each well of the array. At the conclusion of the 2ª0 stage PCR, the array is interrogated by melt curve analysis for the detection of signature amplicons denoting the presence of specific targets. A digital camera placed in front of the array captures fluorescent images of the PCR reactions and software interprets the data.

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

Here's a summary of the acceptance criteria and study details for the FilmArray Respiratory Panel (RP), based on the provided document:

The study is designed to demonstrate that the performance of the FilmArray RP on the new FilmArray 2.0 system and with the new injection vial loading method is equivalent to its performance on the original FilmArray system with syringe loading.

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" in a table format with pass/fail metrics. Instead, it presents performance data (Positive Percent Agreement - PPA, Negative Percent Agreement - NPA, and % Detection) and implies that 100% concordance for most analytes and overall PPA of ≥96.8% and NPA of ≥99.2% are considered acceptable. For some analytes, slightly lower, but statistically comparable, performance with overlapping 95% CIs is accepted.

For the Low Analyte study, the implied acceptance criterion is equivalent detection on all three configurations, evidenced by >95% detection or overlapping 2-sided 95% confidence intervals and comparable amplification/detection in titration series.
For the Tm values, the acceptance criterion is that the mean Tm values for all FilmArray RP assays on the modified configurations should be ±0.5°C or less compared to the same samples tested on the current configuration.
For the Reproducibility study, the implied acceptance criterion is high reproducibility and consistency with previously collected data on the single-instrument system, demonstrated by high percentage agreement with expected results and low standard deviations for Tm values.

Here's a table summarizing the reported device performance, which the manufacturer presents as evidence of meeting their equivalence criteria:

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

Clinical Performance Study:

• Sample Size: A total of 102 specimens were selected for testing.
• Data Provenance: The specimens were:
  • Previously obtained during the FilmArray RP prospective clinical evaluations.
  • Supplemented with other archived specimens collected from external medical facilities and reference laboratories.
  • This indicates a mix of prospective and retrospective clinical specimens from various unspecified countries/regions (implied to be from clinical facilities).

Low Analyte Study:

• Sample Size:
  • Titration series: Samples at concentrations above, at, and below (10x, 1x, 0.1x, and 0.01x) LoD (specific number of samples not given, but likely multiple for each concentration and analyte).
  • Additional side-by-side testing at LoD: 20 replicates per analyte on each system.
• Data Provenance: Not specified, but given the nature of the study, these were likely contrived samples made in a laboratory setting, not clinical specimens.

Reproducibility Study:

• Sample Size: Contrived nasopharyngeal swab samples spiked with four different RP analytes (Bordetella pertussis, Adenovirus Species C, Influenza A H1N1-2009, Respiratory Syncytial Virus Type A). Each analyte was evaluated at three concentrations (Negative, Low Positive, Moderate Positive).
  • 90 data points per sample, per loading procedure. This equates to 90 runs for each of the 4 analytes x 3 concentrations x 2 loading procedures = 2160 individual results.
  • For the single-instrument comparison, the total negative replicates were 540, and positive were 60-180 depending on the analyte.
• Data Provenance: Contrived nasopharyngeal swab samples, likely prepared in a laboratory setting.

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

The document does not provide information on the number or qualifications of experts used to establish the ground truth for the test sets. It refers to specimens being "originally characterized" for the clinical performance study and "expected result" for the reproducibility study. In the context of in-vitro diagnostics, the ground truth for clinical specimens is typically established by well-characterized reference methods (e.g., culture, sequencing) at the originating clinical or reference laboratories. For contrived samples, the truth is known by design.

4. Adjudication Method for the Test Set

The document does not explicitly describe an adjudication method for the test set results. For the clinical performance study, it notes "occasional discrepant results were observed where an analyte was detected by one or two out of three runs; in all cases the discrepant results were attributed to analyte levels below the limit of detection (LoD) for a particular assay in specimens that had previously been characterized as positive for that analyte, or due to a known cross-reactivity." This suggests internal review and technical explanation for discrepancies rather than an independent expert adjudication process as might be seen for imaging studies.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This document describes the validation of an in vitro diagnostic device (a molecular diagnostic test), not an imaging or AI-assisted diagnostic tool that would involve human readers. The study compares the device's performance across different system configurations and loading methods, not human reader performance with or without AI assistance.

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

The studies described are for a standalone diagnostic device (the FilmArray Respiratory Panel cartridge and system). The system automatically interprets the results of the DNA melt curve analysis and combines data with internal controls to provide a test result. Human interaction is primarily for loading the sample and initiating the run, not for interpreting raw data or making diagnostic decisions that the device output alone would provide. Therefore, the device operates autonomously in terms of result generation.

7. The Type of Ground Truth Used

• Clinical Performance Study:
  • For positive specimens: "originally characterized as positive for that analyte" or "not been reported as present in these specimens by the source laboratory." This implies ground truth was established by reference methods (e.g., other molecular tests, culture, sequencing) at the originating labs, or clinical diagnosis.
  • For low-level positives/cross-reactivity: explanations are provided for discrepancies.
• Low Analyte Study: Ground truth was established by contriving samples with known concentrations of analytes.
• Reproducibility Study: Ground truth was established by contriving samples with known analytes and concentrations (Negative, Low Positive, Moderate Positive).

8. The Sample Size for the Training Set

The document does not mention a training set sample size. This is expected because the FilmArray Respiratory Panel is a molecular diagnostic assay using PCR and melt curve analysis, not an AI/machine learning algorithm that requires a separate training set for model development. The assays are designed based on known genetic sequences for the pathogens.

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

As there is no explicit training set for an AI/machine learning model, this question is not applicable to the FilmArray RP device described in this document. The "training" for such a device would be the extensive R&D process to design and optimize the primers, probes, and reaction conditions for each target pathogen, along with establishing detection thresholds, likely validated against characterized reference materials and strains.

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FilmArray® Respiratory Panel (RP) is a multiplexed nucleic acid test intended for use with the FilmArray Instrument for the simultaneous qualitative detection and identification of multiple respiratory viral and bacterial nucleic acids in nasopharyngeal swabs (NPS) obtained from individuals suspected of respiratory tract infections. The following organism types and subtypes are identified using the FilmArray RP: Adenovirus, Coronavirus 229E, Coronavirus HKU1, Coronavirus NL63, Coronavirus OC43, Human Metapneumovirus, Influenza A, Influenza A subtype H1, Influenza A subtype H3, Influenza A subtype H1-2009, Influenza B, Parainfluenza Virus 1, Parainfluenza Virus 2, Parainfluenza Virus 3, Parainfluenza Virus 4, Human Rhinovirus/Enterovirus, Respiratory Syncytial Virus, Bordetella pertussis, Chlamydophila pneumoniae, and Mycoplasma pneumoniae. The detection and identification of specific viral and bacterial nucleic acids from individuals exhibiting signs and symptoms of a respiratory infection aids in the diagnosis of respiratory infection if used in conjunction with other clinical and epidemiological information. The results of this test should not be used as the sole basis for diagnosis, treatment, or other 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 or, lower respiratory tract infection that is not detected by a nasopharyngeal swab specimen. Positive results do not rule out co-infection with other organisms: the agent(s) detected by the Film Array RP 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 respiratory tract infection.

The FilmArray RP System is a multiplex nucleic acid test system composed of the FilmArray instrument, the FilmArray software (preinstalled on a laptop computer) and the FilmArray RP pouch. The FilmArray RP reagent pouch contains freeze-dried reagents to perform nucleic acid purification, reverse transcription, and nested, multiplex PCR with DNA melt analysis. The RP identifies 20 respiratory pathogens as shown in the following table.

Organisms Detected by the FilmArray Respiratory Panel

A test is initiated by loading Hydration Solution and an unprocessed patient nasopharyngeal swab (NPS) specimen (i.e., specimen mixed with Sample Buffer) into the FilmArray RP pouch. The pouch contains all of the reagents required for specimen testing and analysis in a freeze-dried format; the addition of Hydration Solution and specimen/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 reverse transcription reactions, the PCR reactions, and the melting curve analysis.

Nucleic acid extraction occurs within the FilmArray pouch using mechanical lysis and standard magnetic bead technology. After extracting and purifying nucleic acids from the unprocessed sample, 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). This second master mix 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 second stage PCR, or nested PCR, is performed in singleplex fashion in each well of the array. At the conclusion of the 200 stage PCR, the array is interrogated by melting curve analysis for the detection of signature amplicons denoting the presence of specific viral or bacterial targets. A digital camera placed in front of the second stage PCR captures fluorescent images of the PCR reactions in real time.

The FilmArray software automatically interprets the results of each DNA melting 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.

Here's a summary of the acceptance criteria and the study details for the FilmArray® Respiratory Panel (RP) device, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance (Focusing on Adenovirus, as this is a modification)

The primary acceptance criteria for the modification appear to be improved detection of Adenovirus and equivalent performance for other analytes. Since specific numerical targets for "acceptance criteria" are not explicitly stated in percentages for agreement, the reported performance metrics (PPA and NPA) from the clinical comparison serve as the de facto demonstration of meeting the required performance for regulatory clearance.

2. Sample Size and Data Provenance for the Test Set

• Test Set Sample Size:

  • Clinical Comparison (Archived Specimens): 222 de-identified archived nasopharyngeal swab (NPS) specimens.
  • Contrived Clinical Specimens: 44 specimens (10 AdVC2, 10 AdVC6, 10 C. pneumoniae, and 14 M. pneumoniae).
  • Analytical Sensitivity (LoD): 20 replicates for each of four Adenovirus serotypes (AdVC1, AdVC2, AdVE4, AdVC6) at the estimated LoD.
  • Analytical Reactivity (Inclusivity): 22 Adenovirus serotypes (various species) were tested.
  • Analytical Specificity (Cross-reactivity/Exclusivity): High concentrations of 20 RP organisms and an exclusivity panel of 26 bacteria, 6 viruses, and 1 yeast.
  • Competitive Interference: 5 different virus combinations (co-infections), each tested with two viral components at varying concentrations.

• Data Provenance:

  • Archived Specimens: Retrospective, collected between 2008 and 2011 throughout the United States (at least 8 geographically distinct locations) and Scotland (at least 1 location).
  • Contrived Clinical Specimens: Spiked NPS specimens.
  • Analytical Studies (LoD, Reactivity, Specificity, Interference): Laboratory-generated data using quantified cultures and spiked samples.

3. Number of Experts and Qualifications for Ground Truth of the Test Set

The document does not specify the number or qualifications of experts used to establish the ground truth for the test set.

4. Adjudication Method for the Test Set

The document does not describe an adjudication method for the test set results. The comparison is directly between the original FilmArray RP and the modified FilmArray RP. For discrepant results (e.g., in the archived specimen study), bidirectional sequence analysis was used for confirmation, which serves as a form of "ground truth" establishment for those specific cases, but not a general adjudication process between human readers.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not conducted. This study focuses on "algorithm only" or "device only" performance in comparison to a previous version of the device, not on human reader performance with or without AI assistance.

6. Standalone (Algorithm Only) Performance Study

Yes, a standalone performance study was done. The entire submission details the performance of the modified FilmArray RP (an algorithm-driven diagnostic device) itself, comparing its output to that of the original FilmArray RP and, in discrepant cases or for analytical metrics, to direct molecular confirmation (e.g., sequencing) or known spiked concentrations. There is no human-in-the-loop component described in the performance evaluation.

7. Type of Ground Truth Used

The ground truth for the test samples was established using a combination of methods:

• Original FilmArray RP Results: Performance of the modified device was primarily compared against the results of the previously cleared original FilmArray RP.
• Bidirectional Sequence Analysis: Used to confirm discrepant Adenovirus detections in archived specimens and contrived specimens. Also used to categorize Adenovirus serotypes. This is a highly specific molecular method.
• Known Spiked Concentrations: For contrived specimens and analytical studies (Limit of Detection, Analytical Reactivity, Analytical Specificity, Competitive Interference), the ground truth was the known presence and concentration of the spiked organisms.

8. Sample Size for the Training Set

The document does not specify a sample size for a training set. This is typical for in-vitro diagnostic devices where validation might focus more on analytical performance and clinical concordance rather than a separate "training" of a machine learning algorithm in the same sense as an AI/ML product for image analysis, for example. The "training" of such a system would likely involve extensive internal development and optimization based on known strains and clinical samples, but these are not typically referred to as a "training set" in the context of regulatory submissions unless they are explicitly for an adaptive AI algorithm.

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

As no specific "training set" is mentioned in the context of the regulatory submission, the method for establishing its ground truth is not described. The device's underlying technology relies on primer design and DNA melt analysis, which are developed and optimized through laboratory experiments rather than a distinct "training set" in the AI/ML sense.

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The FilmArray Respiratory Panel (RP) is a multiplexed nucleic acid test intended for use with the FilmArray instrument for the simultaneous qualitative detection and identification of multiple respiratory viral nucleic acids in nasopharyngeal swabs (NPS) obtained from individuals suspected of respiratory tract infections. The following virus types and subtypes are identified using the FilmArray RP: Adenovirus, Coronavirus HKU1, Coronavirus NL63, Human Metapneumovirus, Influenza A, Influenza A subtype H1, Influenza A subtype H3, Influenza A subtype 2009 H1, Influenza B, Parainfluenza virus 3, Rhinovirus/Enterovirus, and Respiratory Syncytial Virus. The detection and identification of specific viral nucleic acids from individuals exhibiting signs and symptoms of a respiratory infection aids in the diagnosis of respiratory infection if used in conjunction with other clinical and epidemiological information. Negative results do not preclude respiratory infection and should not be used as the sole basis for diagnosis, treatment or other management decisions. Positive results do not rule out bacterial infection or co-infection with other organisms. The agent detected may not be the definite cause of disease. The use of additional laboratory testing (e.g. bacterial and viral culture, immunofluorescence, and radiography) and clinical presentation must be taken into consideration in order to obtain the final diagnosis of respiratory infection.

Due to seasonal prevalence, performance characteristics for Influenza A/H1, Influenza A/H3, Influenza A/2009 H1, and Influenza B were established primarily with retrospective clinical specimens.

Due to the genetic similarity between human Rhinovirus and Enterovirus, the FilmArray RP cannot reliably differentiate them. A positive FilmArray RP Rhinovirus/Enterovirus result should be followed-up using an alternate method (e.g. cell culture or sequence analysis).

The FilmArray RP detects Adenovirus species C serotype 6 with reduced sensitivity. It is recommended that specimens found to be negative for Adenovirus after examination using FilmArray RP be confirmed by an alternate method (e.g. FDA cleared molecular test or cell culture).

Performance characteristics for influenza A were established when influenza A/2009 H1N1, A/H1, and A/H3 were the predominant influenza A viruses in circulation. When other influenza A viruses are emerging, performance characteristics may vary. 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 RP System is multiplex nucleic acid test system composed of the FilmArray instrument, the FilmArray software (preinstalled on a laptop computer) and the FilmArray RP pouch. The FilmArray RP pouch contains freeze-dried reagents to perform nucleic acid purification, reverse transcription, and nested, multiplex PCR with DNA melt analysis. The Respiratory Panel (RP) pouch identifies 12 common and emerging viral respiratory pathogens (see Table 1).

A test is initiated by loading Hydration Solution and an unprocessed patient nasopharyngeal swab (NPS) specimen (i.e. specimen mixed with Sample Buffer) into the FilmArray RP pouch. The pouch contains all of the reagents required for specimen testing and analysis in a freeze-dried format; the addition of Hydration Solution and Sample/Buffer Mix rehydrates the reagents. After the pouch is prepared, the FilmArrav 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 reverse transcription reactions, the PCR reactions, and the melting curve analysis.

Nucleic acid extraction occurs within the FilmArray pouch using mechanical lysis and standard magnetic bead technology. After extracting and purifying nucleic acids from the unprocessed sample, 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, Idaho Technology). This second master mix 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 second stage PCR, or nested PCR, is performed in singleplex fashion in each well of the array. At the conclusion of the 200 stage PCR, the array is interrogated by melting curve analysis for the detection of signature amplicons denoting the presence of specific viral or bacterial targets A digital camera placed in front of the second stage PCR captures fluorescent images of the PCR reactions in real time.

The FilmArray software automatically interprets the results of each DNA melting 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.

Here's an analysis of the provided text, focusing on acceptance criteria and supporting study details:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined "acceptance criteria" in a numerical target for metrics like sensitivity or specificity. However, it presents the reported clinical sensitivity (Positive Percent Agreement - PPA) and specificity (Negative Percent Agreement - NPA) for each detected organism from two studies: a prospective clinical study and an archived specimen study. The implicit acceptance criteria would be for these values to be high, ideally close to 100%, and for the 95% Confidence Intervals (CI) to be acceptably narrow.

Table: Reported Device Performance (Clinical Studies)

2. Sample Sizes and Data Provenance

• Test Set (Clinical Performance):
  • Prospective Clinical Study:
    • Sample Size: 853 subjects (from an initial enrollment of 857).
    • Data Provenance: 3 U.S. clinical sites, prospective data collected from December 2009 through May 2010.
  • Archived Specimen Study:
    • Sample Size: 349 archived clinical NPS specimens were confirmed to contain or lack the analyte of interest (from 400 initially selected).
    • Data Provenance: Retrospective, preselected archived clinical NPS specimens. Age demographics provided (e.g., 89 (25.5%) ≤5 years, 188 (53.9%) unknown age from a pediatric hospital). Country of origin is implied to be U.S. from clinical sites and some strains are from particular US states, but not explicitly stated for all archived samples.

3. Number of Experts and Qualifications for Ground Truth (Test Set)

The document primarily relies on comparator methods for establishing ground truth, rather than a direct count of human expert consensus.

• For Adenovirus, Influenza A, Influenza B, Parainfluenza virus 3, Respiratory Syncytial Virus (Prospective Study):
  • Ground Truth Method: Viral culture followed by DFA (Fluorescent Antibody) identification. "True" positives/negatives were defined based on these comparator methods.
• For FluA/H1, FluA/H3, FluA/2009 H1 (Prospective Study):
  • Ground Truth Method: Viral culture followed by one analytically validated PCR assay with bi-directional sequence confirmation. The comparator PCR assays were designed to amplify different sequences than the FilmArray assays. "True" positives/negatives were based on cultural positivity for Influenza A and bi-directional sequencing results matching NCBI GenBank entries.
• For Human Rhinovirus, Coronavirus NL63, Coronavirus HKU1, Human Metapneumovirus (Prospective Study):
  • Ground Truth Method: A "predetermined algorithm that used composite comparator methods" consisting of two analytically validated PCR assays followed by bi-directional sequencing. "True" positives/negatives were based on bi-directional sequencing data matching NCBI GenBank entries or negative results from both comparator PCR assays.
• For Archived Specimen Study:
  • Ground Truth Method: Analyte-specific PCR and bi-directional sequencing were used to confirm the presence or absence of the analyte of interest in each specimen prior to FilmArray RP testing.

The document does not specify the number of experts or their qualifications for interpreting the DFA, viral culture, PCR, or sequencing results. It states these are "analytically validated" assays, implying expert input in their validation and interpretation, but provides no direct detail on the human experts involved in establishing the ground truth for this specific study.

4. Adjudication Method for the Test Set

The document describes comparator methods for defining "true" positive/negative results. For the clinical performance sections:

• For categories like Adenovirus through RSV in the prospective study, ground truth was set by viral culture + DFA. Discrepancies between FilmArray RP and the comparator method were further investigated (e.g., footnoted retesting and bi-directional sequence analysis for false positives/negatives). For example, "Adenoviruses were identified in 13/14 false positive specimens using bi-directional sequence analysis." This implies adjudication by molecular methods (PCR and sequencing) was used to resolve discrepancies or to further confirm findings where FilmArray differed from the initial comparator method.
• For Influenza A subtypes and other viruses (Rhinovirus, etc.), the ground truth was already a composite of PCR and bi-directional sequencing, suggesting internal resolution of complex cases within that ground truth establishment process.

The "archived specimen study" explicitly states that the presence or absence of the analyte was confirmed using analyte-specific PCR and bi-directional sequencing prior to FilmArray RP testing, which serves as a highly robust ground truth.

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

No. The study is a diagnostic performance evaluation comparing the device (FilmArray RP) against established laboratory methods (viral culture, PCR, sequencing) for detecting respiratory pathogens. It does not involve human readers interpreting results with or without AI assistance, or quantify the effect size of human improvement. This is a standalone diagnostic test evaluation.

6. Standalone Performance Study (Algorithm Only)

Yes, the clinical performance studies (prospective and archived specimen) describe the standalone performance of the FilmArray RP system. The device is automated with "automated test interpretation and report generation" where the "User cannot access raw data" (Table 3), indicating the algorithm's interpretation delivers the final result.

7. Type of Ground Truth Used

The ground truth used is a combination of:

• Expert Consensus/Reference Methods (Viral Culture + DFA, PCR + Bi-directional Sequencing): This reflects standard laboratory diagnostic methods considered to be gold standards or highly accurate comparators at the time.
  • "True" positives/negatives were determined by these reference methods.
  • For discrepancies, especially for "false positives" or "false negatives" where the FilmArray RP result differed from the initial comparator, further molecular analysis (bi-directional sequence analysis) was often performed, indicating a robust process to confirm ground truth when needed.

8. Sample Size for the Training Set

The document explicitly describes studies for clinical performance evaluation and analytical validation (LoD, inclusivity, specificity, precision, interference). It does not provide details on a specific "training set" or its size, as would be typical for machine learning models. This suggests that the FilmArray RP system's interpretive algorithm (which automatically interprets melting curve analysis results) was developed and validated internally using methods not detailed in this summary (e.g., extensive analytical testing, algorithm tuning, and potentially internal datasets before these formal clinical studies). The "analytical studies" sections (LoD, inclusivity, etc.) would contribute to refining and confirming the algorithm's performance.

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

Since a "training set" is not explicitly defined or detailed in this summary, the method for establishing its ground truth is also not provided. However, based on the analytical studies described:

• LoD (Limit of Detection): Established by testing limiting dilutions of live, quantified viruses (or clinical specimens in one case) where the presence and concentration are precisely known.
• Analytical Reactivity (Inclusivity): Evaluated using known strains/isolates, often quantified. Bi-directional sequencing and bioinformatics (in silico analyses) were used to confirm specific viral identities and predict reactivity.
• Analytical Specificity (Cross-reactivity and Exclusivity): Tested against high concentrations of known interfering organisms or substances.

These analytical studies established ground truth for known viral identities and concentrations under controlled conditions, which would underpin the fundamental ability of the algorithm to accurately detect and identify targets. While not a "training set" in the modern ML sense, these analytical validations serve a similar purpose in confirming the algorithm's foundational accuracy against known truths.

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