(27 days)
The BIOFIRE FILMARRA Y Tropical Fever (TF) Panel is an automated qualitative, multiplexed, polymerase chain reaction (PCR) test intended for use with BIOFIRE FILMARRAY 2.0 and BIOFIRE FILMARRAY TORCH Systems. The BIOFIRE FILMARRAY TF Panel detects and identifies selected bacterial, viral, and parasitic nucleic acids directly from EDTA whole blood collected from individuals with signs and/or symptoms of acute febrile illness or recent acute febrile illness and known or suspected exposure to the following target pathogens: chikungunya virus, dengue virus (serotypes 1, 2, 3 and 4), Leptospira spp., and Plasmodium species differentiation of Plasmodium falciparum and Plasmodium vivax/ovale).
Evaluation for more common causes of acute febrile illness (e.g., infections of the upper and lower respiratory tract or gastroenteritis, as well as non-infectious causes) should be considered prior to evaluation with this panel. Results are meant to be used in conjunction with other clinical, epidemiologic, and laboratory data, in accordance with the guidelines provided by the relevant public health authorities.
The BIOFIRE FILMARRA Y TF Panel is not intended to be used as the sole basis for diagnosis, treatment, or other management decisions. Positive results do not rule out co-infection with other organisms not included on the BIOFIRE FILMARRA Y TF Panel, nor do negative results rule out infection. Negative results from the BIOFIRE FILMARRA Y TF Panel may require additional testing if clinically indicated. Not all pathogens that cause acute febrile illness are detected by this test, and negative results do not rule out the presence of other infections.
In the United States, patient travel history, exposure risk, and consultation of the CDC Yellow Book should be considered prior to use of the BIOFIRE FILMARRAY TF Panel as some pathogens are more common in certain geographical locations.
The BIOFIRE FILMARRAY TF Panel is a rebranded version of the BioFire Global Fever Panel. It is designed to simultaneously identify 6 pathogens from whole blood specimens collected in EDTA tubes. The BIOFIRE FILMARRAY TF Panel is compatible with BioFire's PCR-based in vitro diaqnostic BIOFIRE® FILMARRAY® 2.0 and BIOFIRE® FILMARRAY® TORCH Systems for infectious disease testing. A panel-specific software module (i.e., BIOFIRE FILMARRAY TF Panel pouch module software) is used to perform BIOFIRE FILMARRAY TF Panel testing on these systems. Results from the BIOFIRE FILMARRAY TF Panel test are available within about one hour.
A test is initiated by loading Hydration into one port of the pouch and a whole blood or positive blood culture specimen mixed with the provided Sample Buffer into the port of the BIOFIRE FILMARRAY TF Panel pouch and placing it in a BIOFIRE System. The pouch contains all the reacents required for speciment testing and analysis in a freezedried format; the addition of Hydration and Sample/Buffer Mix rehydrates the reagents. After the pouch is prepared, the BIOFIRE Software quides the user though the pouch into the instrument, scanning the pouch barcode, entering the sample identification, and initiating the run.
The BIOFIRE System 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 BIOFIRE 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 BIOFIRE system performs a nested multiplex PCR that is executed in two stages. During the first stage, the BIOFIRE System performs a single, large volume, highly multiplexed reverse transcription 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. The solution is then distributed to each wells contain sets of primers designed specifically to amplify sequences internal to the PCR products generated during the first stage PCR reaction. The 2nd stage PCR, or nested PCR, is performed in single plex fashion in each well of the end of the 2nd stage PCR, the array is interrogated by melt curve analysis for the detection of signature amplicons denoting the presence of specific targets. A digital camera placed in front of the 2nd stage PCR captures fluorescent images of the PCR reactions and software interprets the data.
The BIOFIRE 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.
This document describes the BIOFIRE FILMARRAY Tropical Fever (TF) Panel, a rebranded version of the BioFire Global Fever Panel (K220870). The submission is a Special 510(k), indicating that the modifications are minor and do not affect the fundamental scientific technology, performance claims, or risk of the device. Therefore, the acceptance criteria and study proving its performance are based on the predicate device, the BioFire Global Fever Panel (K220870), as the performance claims of the rebranded panel remain identical.
1. Table of Acceptance Criteria and Reported Device Performance
Since this is a re-branding with identical performance claims, the "acceptance criteria" for the BIOFIRE FILMARRAY TF Panel are implicitly met by demonstrating substantial equivalence to the predicate device, which has already met its own acceptance criteria. The document states: "The performance claims of the BIOFIRE FILMARRAY TF Panel remain identical to the predicate BioFire Global Fever Panel."
Therefore, the performance data provided would be from the studies conducted for the predicate device, K220870 (BioFire Global Fever Panel). While the specific performance table demonstrating these results is not directly included in the provided text, the implication is that the predicate met the necessary performance metrics (e.g., sensitivity, specificity, accuracy for each target pathogen).
For illustrative purposes, if this were a new device submission, a table would look like this (conceptual, based on the device type):
| Pathogen/Performance Metric | Acceptance Criteria (e.g., % Sensitivity, % Specificity) | Reported Device Performance (from K220870 studies) |
|---|---|---|
| Chikungunya virus Sensitivity | ≥ X% | Y% |
| Chikungunya virus Specificity | ≥ X% | Y% |
| Dengue virus (all serotypes) Sensitivity | ≥ X% | Y% |
| Dengue virus (all serotypes) Specificity | ≥ X% | Y% |
| Leptospira spp. Sensitivity | ≥ X% | Y% |
| Leptospira spp. Specificity | ≥ X% | Y% |
| Plasmodium falciparum Sensitivity | ≥ X% | Y% |
| Plasmodium falciparum Specificity | ≥ X% | Y% |
| Plasmodium vivax/ovale Sensitivity | ≥ X% | Y% |
| Plasmodium vivax/ovale Specificity | ≥ X% | Y% |
| Overall Agreement/Accuracy | ≥ X% | Y% |
The document explicitly states that the performance claims are identical to the predicate, meaning the predicate's performance metrics serve as the "acceptance criteria" implicitly met by this re-branding.
2. Sample Size Used for the Test Set and Data Provenance
The provided text does not contain the specific sample sizes used for the clinical/test set for the predicate device (K220870). It also does not explicitly state the country of origin of the data or whether it was retrospective or prospective. Such details would typically be found in the original 510(k) submission for K220870 or its associated clinical study reports.
However, given it's a panel for tropical fevers, it's highly probable that the data would be from regions where these pathogens are endemic, and likely include both prospective and/or retrospective samples to
cover various disease states and prevalence.
3. Number of Experts Used to Establish Ground Truth for the Test Set and Their Qualifications
For an in vitro diagnostic (IVD) device like the BIOFIRE FILMARRAY TF Panel, especially one that detects nucleic acids, the "ground truth" for the test set is typically established through a combination of:
- Clinical Diagnosis: Based on patient symptoms, travel history, other laboratory findings, and epidemiological data.
- Confirmatory Laboratory Testing: Often using highly sensitive and specific reference methods (e.g., CDC-validated PCR assays, sequencing, culture where applicable) for the target pathogens.
This process generally does not involve a "number of experts" in the same way an imaging AI ground truth would. Instead, it relies on validated laboratory methods and comprehensive clinical assessment. The qualifications would be laboratory professionals using validated reference methods and clinicians making diagnoses based on standard medical practice. The text does not provide specific details on the number or qualifications of experts involved in establishing ground truth for the predicate device.
4. Adjudication Method for the Test Set
As the ground truth for an IVD device like this is primarily established by laboratory reference methods and clinical outcomes, an "adjudication method" in the sense of multiple human readers resolving disagreements (common in imaging AI) is not directly applicable. The resolution of discrepancies would involve retesting by reference methods, review of patient charts, or further clinical investigation, rather than expert consensus reading of images.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size
No, an MRMC comparative effectiveness study was not done, and is not applicable for this type of IVD device. MRMC studies are primarily used for medical imaging AI devices to assess the impact of AI assistance on human reader performance. This device is a qualitative, multiplexed PCR test that provides automated results, not an imaging diagnostic that assists human readers.
6. If a Standalone (i.e., Algorithm Only Without Human-in-the-Loop Performance) Was Done
Yes, the performance study for this device (or its predicate) is inherently a standalone performance assessment. The BIOFIRE FILMARRAY TF Panel is an automated test. The "algorithm" (the instrument's software interpreting PCR data) provides the final qualitative result (positive/negative for each pathogen) without a human interpreting raw data or images. The results are automatically interpreted and reported. The human "in the loop" is the lab technician who performs the test and interprets the results in a clinical context, but not one who influences the primary diagnostic output of the device itself.
The description explicitly states: "The BIOFIRE 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." This confirms its standalone nature.
7. The Type of Ground Truth Used
The ground truth for an IVD diagnostic like this is typically established by:
- Reference Laboratory Methods: Gold standard molecular assays (e.g., highly sensitive and specific PCR assays, sometimes developed or validated by national reference labs like the CDC), possibly combined with sequencing.
- Clinical Data and Outcomes: Patient symptoms, travel history, other clinical laboratory findings, and sometimes follow-up data to confirm true positive or true negative status.
The document states: "The BIOFIRE FILMARRAY TF Panel is not intended to be used as the sole basis for diagnosis, treatment, or other management decisions. Positive results do not rule out co-infection with other organisms... nor do negative results rule out infection. Negative results... may require additional testing if clinically indicated." This implies that while the device offers a direct result, the final clinical diagnosis relies on a broader set of information, and the device's performance is validated against established methods or confirmed clinical diagnoses.
8. The Sample Size for the Training Set
The document does not provide details on the training set for the algorithm (software). For PCR-based IVD devices, the "training" analogous to machine learning often involves significant laboratory work to:
- Design and optimize primers/probes: Extensive testing with known positive and negative samples, various concentrations of targets, and interfering substances.
- Establish cutoff values: For determining positive vs. negative results based on fluorescence thresholds and melt curve characteristics.
- Verify analytical performance: Limit of detection (LoD), inclusivity, exclusivity, cross-reactivity, precision, etc.
This "training" or development process heavily relies on characterized biological samples (clinically relevant strains, spiked samples, negative controls). The specific number of samples for each stage of this development is not given in this document, as it focuses on the equivalence to a predicate.
9. How the Ground Truth for the Training Set Was Established
For IVD development, the ground truth for training/development samples is established through:
- Well-characterized Isolates/Strains: Using verified pathogen cultures or nucleic acid extracts with confirmed identity and quantification.
- Spiking Studies: Adding known amounts of target nucleic acids into clinical matrix (e.g., whole blood) from healthy donors.
- Known Clinical Samples: Samples previously characterized by highly accurate reference methods or confirmed clinical diagnosis.
This process ensures that the assay design (e.g., primer selection, PCR conditions, interpretation algorithms) effectively detects and differentiates the target pathogens from non-targets and in the presence of various confounding factors. The specific methodology for ground truth establishment for the training set of the predicate is not detailed in the provided text.
§ 866.3966 Device to detect and identify selected microbial agents that cause acute febrile illness.
(a)
Identification. A device to detect and identify selected microbial agents that cause acute febrile illness is identified as an in vitro device intended for the detection and identification of microbial agents in human clinical specimens from patients with signs and symptoms of acute febrile illness who are at risk for exposure or who may have been exposed to these agents. It is intended to aid in the diagnosis of acute febrile illness in conjunction with other clinical, epidemiologic, and laboratory data, including patient travel, pathogen endemicity, or other risk factors.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Any sample collection device used must be FDA-cleared, -approved, or -classified as 510(k) exempt (standalone or as part of a test system) for the collection of specimen types claimed by this device; alternatively, the sample collection device must be cleared in a premarket submission as a part of this device.
(2) The labeling required under § 809.10(b) of this chapter must include:
(i) An intended use that includes a detailed description of targets the device detects and measures, the results provided to the user, the clinical indications appropriate for test use, and the specific population(s) for which the device is intended.
(ii) Limiting statements indicating:
(A) Not all pathogens that cause febrile illness are detected by this test and negative results do not rule out the presence of other infections;
(B) Evaluation of more common causes of acute febrile illness should be considered prior to evaluation with this test;
(C) Test results are to be interpreted in conjunction with other clinical, epidemiologic, and laboratory data available to the clinician; and
(D) When using this test, consider patient travel history and exposure risk, as some pathogens are more common in certain geographical locations.
(iii) A detailed device description, including reagents, instruments, ancillary materials, all control elements, and a detailed explanation of the methodology, including all pre-analytical methods for processing of specimens.
(iv) Detailed discussion of the performance characteristics of the device for all claimed specimen types as shown by the analytical and clinical studies required under paragraphs (b)(3)(ii) and (iii) of this section, except specimen stability performance characteristics.
(v) A statement that nationally notifiable results are to be reported to public health authorities in accordance with local, state, and federal law.
(3) Design verification and validation must include:
(i) A detailed device description (
e.g., all device parts, control elements incorporated into the test procedure, reagents required but not provided, the principle of device operation and test methodology), and the computational path from collected raw data to reported result (e.g., how collected raw signals are converted into a reported result).(ii) Detailed documentation of analytical studies, including those demonstrating Limit of Detection (LoD), inclusivity, cross-reactivity, microbial interference, interfering substances, competitive inhibition, carryover/cross contamination, specimen stability, within lab precision, and reproducibility, as appropriate.
(iii) Detailed documentation and performance results from a clinical study that includes prospective (sequentially collected) samples for each claimed specimen type and, when determined to be appropriate by FDA, additional characterized clinical samples. The study must be performed on a study population consistent with the intended use population and compare the device performance to results obtained from FDA-accepted comparator methods. Documentation from the clinical studies must include the clinical study protocol (including a predefined statistical analysis plan), study report, testing results, and results of all statistical analyses.
(iv) A detailed description of the impact of any software, including software applications and hardware-based devices that incorporate software, on the device's functions.