(389 days)
FilmArray Respiratory Panel EZ (RP EZ) is a multiplexed nucleic acid test intended for use with the FilmArray 2.0 EZ Configuration 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 are identified using the FilmArray RP EZ: Adenovirus, Coronavirus, Human Metapneumovirus, Influenza A subtype H1, Influenza A subtype H3, Influenza A subtype H1-2009, Influenza Virus, 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 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 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 FilmArray RP EZ 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 EZ (RP EZ) is a multiplex nucleic acid test designed to be used with the FilmArray 2.0 EZ Configuration instrument. The FilmArray RP pouch (a component of the FilmArray RP EZ test system) contains freeze-dried reagents to perform nucleic acid purification, reverse transcription, and nested, multiplex PCR with DNA melt analysis. FilmArray RP EZ simultaneously conducts 14 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 EZ 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. 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 RPpouch 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 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 (LCGreen® 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 200 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.
Acceptance Criteria and Device Performance for FilmArray® Respiratory Panel EZ (RP EZ)
The provided document describes the FilmArray® Respiratory Panel EZ (RP EZ), a multiplexed nucleic acid test for the simultaneous detection and identification of multiple respiratory viral and bacterial nucleic acids. The information primarily focuses on establishing substantial equivalence to a predicate device and validating the device's performance in a CLIA-waived setting for external control testing.
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state quantitative acceptance criteria for clinical performance (e.g., sensitivity, specificity for each pathogen) in the same way a direct clinical trial report might. Instead, the "acceptance criteria" presented are implied through validation studies demonstrating the device's intended use and substantial equivalence to a previously cleared device.
However, the document does report on a study for external control testing, for which we can infer an acceptance criterion.
| Aspect of Performance | Acceptance Criteria (Implied) | Reported Device Performance |
|---|---|---|
| External Control Testing Accuracy | Intended users should accurately acquire and interpret results for positive and negative external controls. | 98.9% (178/180) overall correct control test results |
| Positive Control Recognition | 100% of positive controls should be correctly identified. | 100% (90/90) of positive controls correctly identified |
| Negative Control Recognition | High percentage of negative controls should be correctly identified. | 97.8% (88/90) of negative controls correctly identified |
| Functional Equivalence to Predicate Device | Device should operate with similar technological principles and provide comparable results to the predicate. | Demonstrated through comparison table and V&V of software. |
Study Proving Device Meets Acceptance Criteria (External Control Testing)
2. Sample Size Used for the Test Set and Data Provenance:
- Sample Size: A total of 182 external controls were tested (91 positive and 91 negative). Two tests were excluded due to invalid results, resulting in 180 control tests for analysis.
- Data Provenance: The study was conducted at "three locations" (sites) by "multiple operators" with "training and educational backgrounds consistent with those in the CLIA-waived testing environment." The document does not specify the country of origin, but given the FDA submission, it is likely the USA. The study design appears to be prospective, specifically designed for this validation.
3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications of Those Experts:
This study focused on validating the ability of intended users to perform external control testing. The "ground truth" for the external controls (i.e., whether they were positive or negative for all analytes) was established by the manufacturer (Maine Molecular Quality Controls, Inc., and BioFire Diagnostics) during their manufacturing and quality control processes. No independent experts were used to establish the ground truth for these pre-defined control materials in this particular user study.
4. Adjudication Method for the Test Set:
Not applicable. The study evaluated the direct interpretation of the device results by the users against the known composition of the external controls. There was no need for expert adjudication over user interpretations as the controls have a fixed "ground truth."
5. If a multi-reader, multi-case (MRMC) comparative effectiveness study was done:
No, an MRMC comparative effectiveness study was not done. This study solely assessed the ability of individual users (readers) to correctly operate the device and interpret the results of pre-defined external controls in a CLIA-waived setting. It did not compare the effectiveness of human readers with or without AI assistance, as the device itself is a diagnostic test, not an AI interpretative tool for human readers.
6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done:
Yes, in a sense. The FilmArray RP EZ is a fully automated, standalone diagnostic system. The "algorithm only" performance is inherent in the device's ability to process the sample, perform PCR, and interpret the melt curve analysis to generate a result. The external control study demonstrated that the device itself (operated by an intended user) accurately produced results for known control materials. The results reported (e.g., 98.9% overall correct) represent the standalone performance of the device when operated by its intended user, as the interpretation of the results is automated by the device's software.
7. The Type of Ground Truth Used:
For the external control testing, the ground truth was known composition of control materials. The external controls (M265, M266, M267) were manufactured with a defined positive (containing all FilmArray RP EZ analytes) or negative (containing no analytes) composition.
8. The Sample Size for the Training Set:
The document explicitly states that "User training on use of the FilmArray RP EZ was limited to the training video and quick guide provided with the EZ system." There isn't a formally described "training set" in the context of machine learning model development. The users in this study received standard instructional materials provided with the device.
9. How the Ground Truth for the Training Set Was Established:
As there was no formal "training set" in the machine learning sense, this question is not directly applicable. The "training" for the human users was provided through the manufacturer's training video and quick guide, which would convey the correct operational procedures and interpretation guidelines for the device. The ground truth for the device's internal algorithm (which is the "AI" component here, though not explicitly termed AI) was established through extensive analytical and clinical studies described in previous 510(k) submissions (K103175, K110764, K120267, K123620, K143080), as referenced in the document. These foundational studies would have leveraged expert consensus, comparator methods (like PCR, culture, and sequencing), and clinical outcomes data to establish the ground truth for pathogen detection.
§ 866.3980 Respiratory viral panel multiplex nucleic acid assay.
(a)
Identification. A respiratory viral panel multiplex nucleic acid assay is a qualitative in vitro diagnostic device intended to simultaneously detect and identify multiple viral nucleic acids extracted from human respiratory specimens or viral culture. The detection and identification of a specific viral nucleic acid from individuals exhibiting signs and symptoms of respiratory infection aids in the diagnosis of respiratory viral infection when used in conjunction with other clinical and laboratory findings. The device is intended for detection and identification of a combination of the following viruses:(1) Influenza A and Influenza B;
(2) Influenza A subtype H1 and Influenza A subtype H3;
(3) Respiratory Syncytial Virus subtype A and Respiratory Syncytial Virus subtype B;
(4) Parainfluenza 1, Parainfluenza 2, and Parainfluenza 3 virus;
(5) Human Metapneumovirus;
(6) Rhinovirus; and
(7) Adenovirus.
(b)
Classification. Class II (special controls). The special controls are:(1) FDA's guidance document entitled “Class II Special Controls Guidance Document: Respiratory Viral Panel Multiplex Nucleic Acid Assay;”
(2) For a device that detects and identifies Human Metapneumovirus, FDA's guidance document entitled “Class II Special Controls Guidance Document: Testing for Human Metapneumovirus (hMPV) Using Nucleic Acid Assays;” and
(3) For a device that detects and differentiates Influenza A subtype H1 and subtype H3, FDA's guidance document entitled “Class II Special Controls Guidance Document: Testing for Detection and Differentiation of Influenza A Virus Subtypes Using Multiplex Nucleic Acid Assays.” See § 866.1(e) for the availability of these guidance documents.