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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 2009 H1, Influenza B, Parainfluenza Virus 1, Parainfluenza Virus 2, Parainfluenza Virus 3, Parainfluenza Virus 4, 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 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 20 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 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, 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.

Acceptance Criteria and Device Performance Study for FilmArray® Respiratory Panel (RP)

This document describes the acceptance criteria and supporting studies for the FilmArray® Respiratory Panel (RP) device with added assays for Coronavirus OC43, Coronavirus 229E, Bordetella pertussis, Mycoplasma pneumoniae, and Chlamydophila pneumoniae.

1. Table of Acceptance Criteria and Reported Device Performance

The provided document does not explicitly state pre-defined acceptance criteria (e.g., "sensitivity must be >90%"). Instead, the clinical performance is presented as observed Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) with 95% confidence intervals. The reproducibility study shows percent agreement with expected results at various concentrations. For clarity, we will present the key performance metrics observed in the clinical and archived specimen studies as "reported device performance."

(N/A - Not Applicable, LoD - Limit of Detection)

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

The evaluation for the newly added assays was conducted through a combination of prospective clinical studies, retrospective testing of archived clinical specimens, and contrived specimens.

• Prospective Clinical Study:

  • Sample Size: 1117 subjects (initially 1144 enrolled, 27 withdrawn or omitted).
  • Data Provenance: 3 U.S. clinical sites.
  • Retrospective or Prospective: Prospective. The study spanned two respiratory seasons (December 2009 - May 2010 and September 2010 - January 2011).

• Archived Specimens Study (for B. pertussis, Coronavirus 229E, Coronavirus OC43, or M. pneumoniae):

  • Sample Size: 305 total specimens.
  • Data Provenance: Not explicitly stated but implied to be from various sources, likely within the U.S., as they were "preselected archived samples."
  • Retrospective or Prospective: Retrospective.

• Contrived C. pneumoniae Specimens Study:

  • Sample Size: 100 specimens (50 spiked, 50 unspiked).
  • Data Provenance: Residual specimens from the prospective clinical study, spiked with C. pneumoniae.
  • Retrospective or Prospective: Contrived/Spiked.

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

The document describes the reference/comparator methods used to establish the ground truth, rather than directly mentioning "experts" in the context of adjudication for individual test results.

• Method: For Coronavirus 229E, Coronavirus OC43, B. pertussis, C. pneumoniae, and M. pneumoniae, the ground truth was established by composite comparator methods consisting of two analytically validated PCR assays followed by bi-directional sequencing.
  • "True" positives were defined as samples with bi-directional sequencing data meeting pre-defined quality acceptance criteria and matching NCBI GenBank database sequences.
  • "True" negatives were defined as samples negative by both comparator PCR assays.
• Number of Experts: Not explicitly stated as a number of human experts adjudicating each case. The "experts" implied are the skilled laboratory personnel performing and interpreting the bi-directional sequencing, which is a highly technical molecular biology method. Their qualifications would implicitly be in molecular diagnostics and sequence analysis.

4. Adjudication Method for the Test Set

The adjudication method relies on the described composite comparator methods:

• Method: Two independent PCR assays targeting different sequences, followed by bi-directional sequencing for confirmation.
• Rule: "True" positives were confirmed by sequencing matching GenBank. "True" negatives were confirmed by negativity in both PCR assays. Discrepant results between the FilmArray RP and the initial comparator PCRs were further investigated using bi-directional sequencing (as seen in the footnotes for discrepancy investigations in Table 4).

This is a form of adjudicated ground truth based on a robust laboratory method rather than human consensus interpretation of device output.

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 device is an automated multiplex nucleic acid test. Its performance is evaluated against reference laboratory methods, not by comparing human reader performance with and without AI assistance. The readout is qualitative (presence/absence of target nucleic acid), and interpretation is automated by the device's software.

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

Yes, a standalone performance study was done.

The clinical performance data (PPA, NPA) presented in Tables 4, 8, and 9 reflects the performance of the FilmArray RP system (including the algorithm responsible for interpreting the raw data and providing a result) operating independently without human modification or interpretation of the final result. The system's software automatically interprets results based on melting curve analysis and internal controls.

7. The Type of Ground Truth Used

The primary type of ground truth used was expert-defined laboratory gold standard:

• Clinical and Archived Specimen Studies: Ground truth was established using composite comparator methods comprising two analytically validated PCR assays followed by bi-directional sequencing. This is a highly robust and specific laboratory reference method.
• Contrived C. pneumoniae Specimens: Ground truth was established by spiking known concentrations of the pathogen into clinical matrix, and also by using unspiked controls.

8. The Sample Size for the Training Set

The document does not explicitly state the sample size for the training set used to develop the FilmArray RP algorithms for the newly added assays. Regulatory submissions typically focus on the performance of the final, locked algorithm on independent test sets (as described in this document), rather than detailing the internal development and training processes.

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

As the document does not provide details on a specific "training set," it also does not describe how the ground truth for any training set was established. It's common for diagnostic device development to use well-characterized positive and negative specimens, often confirmed by highly sensitive and specific laboratory methods (similar to the comparator methods described for the test set), for initial algorithm development and optimization.

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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 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 1, Parainfluenza Virus 2, Parainfluenza Virus 3, Parainfluenza Virus 4, 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 viral infection if used in conjunction with other clinical and epidemiological information. Negative results do not preclude respiratory viral 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, Influenza B, Parainfluenza Virus 1, Parainfluenza Virus 2, and Parainfluenza Virus 4 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 2 and 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 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 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 15 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 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 dve (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 a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided text:

Device: FilmArray Respiratory Panel (RP) System

Purpose of 510(k) submission: To support unmasking of test results for the Parainfluenza Virus 1, 2, and 4 (PIV1, PIV2, PIV4) assays in the FilmArray RP.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are generally implied standards for diagnostic tests (e.g., high sensitivity and specificity). The reported device performance is directly from the study results.

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

Clinical Performance Study (Prospective):

• Sample Size: 1117 subjects (after exclusions) from an initial enrollment of 1144.
• Data Provenance: Prospective study conducted at 3 U.S. clinical sites. Enrollment spanned December 2009 - May 2010 and September 2010 - January 2011 (two respiratory seasons).

Archived Specimens Study (Retrospective):

• Sample Size: 147 confirmed specimens tested (from 168 initially selected).
• Data Provenance: Retrospective study using preselected archived clinical nasopharyngeal swab (NPS) specimens. The origin of these archived samples is not specified beyond being "preselected" and from "one source" (a pediatric hospital mentioned for age range).

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

The term "experts" in the context of diagnostic assay ground truth typically refers to reference laboratory personnel or clinicians involved in the gold standard method. The document describes the methods used to establish ground truth rather than explicitly stating the number and qualifications of individuals.

For Parainfluenza Virus 1 and 2 (Clinical Study):

• Ground Truth Method: Viral culture followed by DFA (Direct Fluorescent Antibody) identification.
• Implicit Expertise: Laboratory technicians/virologists skilled in viral culture techniques and DFA interpretation. No specific number or qualifications (e.g., years of experience) mentioned.

For Parainfluenza Virus 4 (Clinical Study):

• Ground Truth Method: Viral culture followed by one analytically validated PCR assay with bi-directional sequence confirmation.
• Implicit Expertise: Laboratory technicians/virologists skilled in viral culture, PCR amplification, and sequence analysis. No specific number or qualifications mentioned.

For Archived Specimens Study:

• Ground Truth Method: Analyte-specific PCR and bi-directional sequencing.
• Implicit Expertise: Laboratory personnel proficient in molecular diagnostic techniques and sequence analysis. No specific number or qualifications mentioned.

4. Adjudication Method for the Test Set

The document does not explicitly describe an "adjudication method" in the typical sense of multiple experts reviewing discordant results. Instead, it describes how "true" positive/negative status was determined based on the outcomes of the reference methods:

• Clinical Study (PIV1, PIV2, PIV4):
  • For PIV1 and PIV2, "True" positives/negatives were defined by the viral culture with DFA results.
  • For PIV4, "True" positives were defined by bi-directional sequencing data matching NCBI GenBank sequences from viral culture material. "True" negatives were defined by negative results from the comparator PCR assay on viral culture material.
  • Discrepancies between the FilmArray RP and comparator methods were sometimes further investigated (e.g., PIV1 was identified in one discordant specimen by bi-directional sequence analysis; PIV2 in false positive specimens by bi-directional sequencing). This suggests a form of post-hoc review for discrepant results, but not a front-end adjudication process by multiple independent experts defining ground truth prior to or independent of the reference method.
• Archived Specimens Study: Ground truth was established by "analyte specific PCR and bi-directional sequencing" prior to FilmArray RP testing. The study design meant users testing with FilmArray RP were "blinded as to the expected test result." This indicates the ground truth was predetermined by molecular methods.

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 performed. This study focuses on the diagnostic performance of the device itself against reference methods, not on comparing human reader performance with and without AI assistance. The FilmArray RP is an automated diagnostic system, not an AI-assisted interpretation tool for human readers.

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

Yes, the study describes the standalone performance of the FilmArray RP System.

• The FilmArray RP is a fully automated system from specimen loading to result interpretation. 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."
• The clinical sensitivity, specificity, and analytical studies (LoD, inclusivity, specificity, precision, interference) all evaluate the performance of this automated system directly against established reference methods or controlled conditions, without human interpretation as part of the primary diagnostic output.

7. The Type of Ground Truth Used

• Clinical Performance Study:
  • Expert Consensus: Not explicitly stated as consensus among multiple experts. The ground truth was established by viral culture followed by DFA (PIV1, PIV2) and viral culture followed by analytically validated PCR with bi-directional sequence confirmation (PIV4). These are established laboratory diagnostic methods often considered gold standards for viral detection at the time.
  • Pathology: Not applicable, as this is a viral detection assay, not tissue pathology.
  • Outcomes Data: Not primarily outcomes data, but a direct comparison to laboratory reference methods for pathogen presence.
• Archived Specimens Study:
  • Molecular Confirmation: Ground truth was established using analyte-specific PCR and bi-directional sequencing. This is a highly specific molecular method for confirming the presence or absence of viral nucleic acid.

8. The Sample Size for the Training Set

The document does not specify a training set size because it describes a diagnostic device validation study, not a machine learning model development study with separate training and testing sets. The FilmArray RP is a molecular diagnostic assay using pre-programmed algorithms for interpretation, not a learnable AI algorithm that requires a "training set" in the machine learning sense. The device's internal algorithms and reagents are developed, and then validated with the clinical and analytical performance studies described.

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

As noted above, there is no "training set" in the context of machine learning for this device. The device's operational parameters and interpretive logic are presumably established during its development phase using a combination of scientific principles, laboratory experiments, and internal validation, rather than through labeled training data as used in AI.

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