(27 days)
The FilmArray Meningitis/Encephalitis (ME) Panel is a qualitative multiplexed nucleic acid-based in vitro diagnostic test intended for use with FilmArray, FilmArray Torch systems. The FilmArray ME Panel is capable of simultaneous detection and identification of multiple bacterial, viral, and yeast nucleic acids directly from cerebrospinal fluid (CSF) specimens obtained via lumbar puncture from individuals with signs and/or symptoms of meningitis and/or encephalitis. The following organisms are identified using the FilmArray ME Panel:
Bacteria:
- · Escherichia coli K 1
- · Haemophilus influenzae
- · Listeria monocytogenes
- · Neisseria meningitidis (encapsulated)
- · Streptococcus agalactiae
- Streptococcus pneumoniae
Viruses:
- · Cytomegalovirus
- · Enterovirus
- Herpes simplex virus 1
- Herpes simplex virus 2
- · Human herpesvirus 6
- Human parechovirus
- Varicella zoster virus
Yeast:
- · Cryptococcus neoformans/gattii
The FilmArray ME Panel is indicated as an aid in the diagnosis of meningitis and/or encephalitis and results are meant to be used in conjunction with other clinical, epidemiological, and laboratory data. Results from the FilmArray ME Panel are not intended to be used as the sole basis for diagnosis, treatment, or other patient management decisions. Positive results do not rule out co-infection with organisms not included in the agent detected may not be the definite cause of the disease. Negative results do not preclude central nervous system (CNS) infection. Not all agents of CNS infection are detected by this test and sensitivity in clinical use may differ from that described in the package insert.
The FilmArray ME Panel is not intended for testing of specimens collected from indwelling CNS medical devices.
The FilmArray ME Panel is intended to be used in conjunction with standard of care culture for organism recovery, serotyping, and antimicrobial susceptibility testing.
The FilmArray Meningitis/Encephalitis (ME) Panel is a multiplex nucleic acid test designed to be used with FilmArray systems. The FilmArray ME pouch contains freeze-dried reagents to perform nucleic acid purification and nested, multiplex PCR with DNA melt analysis. The FilmArray Meningitis/Encephalitis (ME) Panel simultaneously conducts 14 tests for the identification of potential CNS pathogens from CSF specimens obtained via lumbar puncture (Table 1). Results from the FilmArray ME Panel test are available within about one hour.
A test is initiated by loading Hydration Solution into one port of the FilmArray pouch and a CSF sample mixed with the provided Sample Buffer into the other port of the FilmArray ME pouch and placing it in the FilmArray Instrument. The pouch contains all of the reagents required for specimen testing and analysis in a freeze-dried format; the addition of Hydration Solution and Sample/Buffer Mix rehydrates the reagents. After the pouch is prepared, the FilmArray Software guides the user through the steps of placing the instrument, scanning the pouch barcode, entering the sample identification, and initiating the run.
The FilmArray 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 valye 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, 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 21d stage PCR, or nested PCR, is performed in each well of the array. At the conclusion of the 21d 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 PCR2 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 the breakdown of the acceptance criteria and study information for the FilmArray Meningitis/Encephalitis (ME) Panel when used with the FilmArray Torch system, based on the provided document:
1. Table of Acceptance Criteria and Reported Device Performance
The document doesn't explicitly state "acceptance criteria" in a table format with specific thresholds. Instead, it describes performance in terms of reproducible detection at LoD (Limit of Detection) and agreement with expected negative results.
| Performance Metric | Acceptance Criteria (Implied) | Reported Device Performance |
|---|---|---|
| Reproducible detection at LoD (1x LoD) | ≥ 95% (common industry standard for LoD reproducibility) | ≥ 95.6% of samples tested for each analyte on FilmArray Torch systems |
| Agreement with expected negative results | > 95% (common industry standard for specificity/negative agreement) | > 98% for each analyte |
Note: The acceptance criteria in the "Implied" column are based on common industry practices for diagnostic assay performance and reproducibility, as the document doesn't provide explicit numerical targets directly labeled as "acceptance criteria."
2. Sample Size Used for the Test Set and Data Provenance
- Sample Size: 30 replicates per analyte per system, tested on three complete FilmArray Torch systems, resulting in a total of 90 replicates per analyte.
- Data Provenance: The study involved contrived samples containing each FilmArray ME Panel analyte at low positive levels (1x LoD) and expected negative results. The document does not specify the country of origin, but given the submission to the FDA, it's likely the testing was conducted in the US. This was a prospective study, as samples were specifically prepared and tested to evaluate the new instrument.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
The document does not mention the use of experts to establish ground truth for this particular study. The ground truth for the test set was established by the contrived nature of the samples, meaning the researchers intentionally prepared samples with known positive (at 1x LoD) and negative results.
4. Adjudication Method for the Test Set
Since the ground truth was established by preparing contrived samples with known concentrations (1x LoD) or known absence of analytes, there was no adjudication method described or necessary. The "ground truth" was inherent in the sample preparation.
5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study was Done
No, an MRMC comparative effectiveness study was not done. This study focused on verifying the performance of the existing FilmArray ME Panel when used with a new instrument system (FilmArray Torch). It was not designed to assess human reader performance with or without AI assistance.
6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done
Yes, a standalone performance study was done. The described performance evaluation tests the FilmArray ME Panel (an in vitro diagnostic device with an automated test interpretation algorithm) on the FilmArray Torch system directly. The results are automatically interpreted by the FilmArray software, and the user "cannot access raw data," indicating an algorithm-only or standalone performance evaluation.
7. The Type of Ground Truth Used
The ground truth used was based on contrived samples with known positive (1x LoD) and negative results. This is a form of analytical truth established by precise sample preparation.
8. The Sample Size for the Training Set
The document does not provide information on the sample size for the training set. This K160462 submission is for a special 510(k) to add a new instrument (FilmArray Torch) for an already cleared device (FilmArray ME Panel, cleared under DEN150013). Therefore, the reagent kit and its underlying algorithm were presumably developed and trained prior to this submission, and that information is not detailed here.
9. How the Ground Truth for the Training Set Was Established
Similarly, the document does not describe how the ground truth for the training set was established. This information would have been part of the original 510(k) submission (DEN150013) for the FilmArray ME Panel itself, which is not provided in this excerpt.
§ 866.3970 Device to detect and identify microbial pathogen nucleic acids in cerebrospinal fluid.
(a)
Identification. A device to detect and identify microbial pathogen nucleic acids in cerebrospinal fluid is a qualitative in vitro device intended for the detection and identification of microbial-associated nucleic acid sequences from patients suspected of meningitis or encephalitis. A device to detect and identify microbial pathogen nucleic acids in cerebrospinal fluid is intended to aid in the diagnosis of meningitis or encephalitis when used in conjunction with clinical signs and symptoms and other clinical and laboratory findings.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include detailed device description documentation, including the device components, ancillary reagents required but not provided, and a detailed explanation of the methodology, including primer/probe sequence, design, and rationale for sequence selection.
(2) Premarket notification submissions must include detailed documentation from the following analytical studies: Analytical sensitivity (limit of detection), inclusivity, reproducibility, interference, cross reactivity, and specimen stability.
(3) Premarket notification submissions must include detailed documentation from a clinical study. The study, performed on a study population consistent with the intended use population, must compare the device performance to results obtained from well-accepted comparator methods.
(4) Premarket notification submissions must include detailed documentation for device software, including, but not limited to, software applications and hardware-based devices that incorporate software.
(5) The Intended Use statement in the device labeling must include a statement that the device is intended to be used in conjunction with standard of care culture.
(6) A detailed explanation of the interpretation of results and acceptance criteria must be included in the device's 21 CFR 809.10(b)(9) compliant labeling.
(7) The device labeling must include a limitation stating that the negative results do not preclude the possibility of central nervous system infection.
(8) The device labeling must include a limitation stating that device results are not intended to be used as the sole basis for diagnosis, treatment, or other patient management decisions.
(9) The device labeling must include a limitation stating that positive results do not mean that the organism detected is infectious or is the causative agent for clinical symptoms.
(10) As part of the risk management activities performed as part of your 21 CFR 820.30 design controls, you must document an appropriate end user device training program that will be offered as part of your efforts to mitigate the risk of failure to correctly operate the instrument.