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The FilmArray Global Fever Panel is a qualitative, multiplexed, nucleic acid-based in vitro diagnostic test intended for use with the FilmArray 2.0 system. The FilmArray Global Fever Panel detects and identifies selected bacterial, viral, and protozoan 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: Leptospira spp., chikungunya virus, dengue virus (serotypes 1, 2, 3 and 4), and Plasmodium spp. (including 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.

Positive results do not rule out co-infections with pathogens not included on the FilmArray Global Fever Panel. 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. Patient travel history and consultation of the CDC Yellow Book should be considered prior to use of the FilmArray Global Fever Panel as some pathogens are more common in certain geographical locations.

The FilmArrav Global Fever Panel is a multiplex nucleic acid-based test designed to be used with the FilmArray 2.0 system ("FilmArray system" or "FilmArray instrument"). The FilmArray Global Fever Panel includes a FilmArray Global Fever Panel pouch (pouch) which contains freeze-dried reagents to perform nucleic acid purification and nested, multiplex polymerase chain reaction (PCR) with DNA melt analysis. The FilmArray Global Fever Panel simultaneously conducts six tests for the identification of bacterial, viral, and protozoan organisms from whole blood specimens collected in EDTA tubes. Results from the FilmArray Global Fever Panel are available within about one hour.

A test is initiated by loading Hydration Solution into one port of the pouch and a whole blood or positive blood culture specimen mixed with the provided Sample Buffer and protease into the other port of the pouch and placing it in the FilmArray Instrument. The pouch contains all the reagents required for specimen testing and analysis in a freeze-dried format; the addition of Hydration Solution and the Sample Buffer rehvdrates the reagents. After the pouch is prepared, the FilmArray Software on the FilmArray system guides the user through the steps of placing the pouch into the instrument, scanning the pouch barcode, entering the sample identification, selecting the appropriate protocol, and initiating the run on the FilmArray system.

The FilmArray instruments contain a coordinated system of inflatable bladders and seal points. which act on the pouch to control the movement of liguid 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, 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 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 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 a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are generally demonstrated through the successful performance in the analytical and clinical studies. While explicit "acceptance criteria" are not listed in a separate table, the reported performance metrics (PPA, NPA, agreement rates) indicate the achieved levels that were deemed acceptable.

Study Design and Proof of Meeting Acceptance Criteria:

The detailed performance characteristics section (L. Performance Characteristics) outlines the studies conducted to demonstrate the device meets these criteria. The approval of the De Novo request signifies that the FDA found these results acceptable and the device adequately characterized for its intended use, with appropriate mitigations for identified risks.

2. Sample Sizes and Data Provenance

• Test Set (Clinical Study):

  • Total Eligible Specimens: 1875 whole blood specimens.
  • Category I (Prospective, Fresh): 1469 (78.3%) specimens.
  • Category II (Prospective, Frozen): 406 (21.7%) specimens.
  • Data Provenance: Multicenter study conducted at ten geographically distinct study sites, including two in the United States, and sites in Africa, Southeast Asia, and Central & South America. Data was collected prospectively (March 2018 - September 2019).

• Analytical Studies (Reproducibility, LoD, etc.): Sample sizes for these studies are distinct and smaller than the clinical study.

  • Reproducibility: 270 valid test results (90 replicates per sample, 3 samples, 3 sites, 5 days, 2 operators, 3 instruments, rotating pouch lots).
  • Detection Limit: "m replicates" tested for confirmation, and "x replicates" initially. Specific numerical values are redacted.
  • Inclusivity/Cross-reactivity/Interference: "replicates" (number often redacted) of spiked samples.

3. Number of Experts and Qualifications for Ground Truth

The document does not explicitly state the number or specific qualifications of experts used to establish the ground truth for the clinical test set.

• Clinical Study Ground Truth: The ground truth for the clinical samples was established using "well-validated nested PCR assays followed by bi-directional Sanger sequencing."

  • "Two comparator assays were utilized for each assay target with positive result from both assays considered positive."
  • "If the results of the two comparator assays for a particular analyte disagreed, the samples were subjected to repeat comparator testing with samples determined as positive if at least 2/3 replicates were positive for a single comparator assay."
  • This implies a laboratory-based method for ground truth, rather than human expert consensus on clinical presentation.

• Assay Cut-off Validation (post-analytical/clinical studies): "a final validation of the melt ranges was performed and included review of data from the Inclusivity study and clinical studies. The observed sensitivity and specificity rates for the individual melt curves and assay calls as compared to expert annotation was greater than 99.8% and 99.9% respectively."

  • This indicates that "expert annotation" was used to validate the final melt ranges of the software's interpretation of results, suggesting these experts were likely highly specialized in nucleic acid analysis or molecular diagnostics. Specific number or qualifications are not provided beyond "expert annotation."

4. Adjudication Method for the Test Set

• The primary method for establishing ground truth for the clinical test set was through two comparator nested PCR assays followed by Sanger sequencing.
• Discrepancy Resolution/Adjudication: "Samples for which false positive and/or false negative results (i.e., discrepant results) were obtained when comparing the FilmArray Global Fever Panel results to the comparator method results were further investigated."
  • This investigation typically involved:
    1. Examination to determine if additional testing on Global Fever Panel or with comparator assays could detect the analyte (if near or below detection threshold).
    2. Evaluation by "at least one additional PCR test that used different primers than the Global Fever Panel assay or the comparator assays."
    3. When possible, "unresolved discrepancies were evaluated with additional PCR testing that could be verified by sequence analysis."
  • This describes a multi-step, laboratory-based adjudication process for discrepant results, leveraging additional molecular methods. It is not a 2+1 or 3+1 human reader adjudication, but rather a technical/laboratory adjudication.

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

• No, an MRMC comparative effectiveness study was not performed.
• This device is an in vitro diagnostic (IVD) nucleic acid amplification test, and its performance is evaluated against a molecular gold standard (comparator PCR and sequencing), not through human reader interpretation of images or other data. Therefore, the concept of "how much human readers improve with AI vs without AI assistance" does not apply here.

6. Standalone Performance

• Yes, the performance characteristics described in Section L (Performance Characteristics) represent the standalone performance of the FilmArray Global Fever Panel algorithm and system. This includes analytical performance (reproducibility, LoD, specificity, etc.) and the clinical performance (PPA, NPA) which compares the device's output directly to the "ground truth" established by the comparator molecular methods. The system automatically interprets the results of each DNA melt curve analysis and combines data with internal controls to provide a test result.

7. Type of Ground Truth Used

• For the clinical study, the primary ground truth was established by molecular comparator testing: "well-validated nested PCR assays followed by bi-directional Sanger sequencing." This is a highly objective, laboratory-based method for detecting and identifying specific nucleic acid sequences.

8. Sample Size for the Training Set

• The document does not explicitly state the sample size for a "training set".
• This is a molecular diagnostic assay where algorithms (e.g., for melt curve analysis) are likely developed based on known principles of PCR and fluorescence, and validated with a range of characterized samples (analytical studies). There isn't a traditional "training set" in the context of deep learning models for medical image analysis, which require large datasets for supervised learning. Instead, the "initial melt ranges" were determined by "mathematical modeling using known sequence variations... as well as data from testing of clinical specimens and known isolates."

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

• As a molecular diagnostic, the "training" (or development/refinement) data for the device's interpretive algorithm (e.g., Melt Detector software Tm values, fluorescence values, and melt curve analysis) would primarily come from:
  • Well-characterized isolates and contrived samples: Used to define expected melt curves, Tm values, and limits of detection. This includes the extensive analytical studies detailed (e.g., inclusivity, cross-reactivity, precision, LoD).
  • Mathematical modeling: Based on known sequence variations of target organisms.
  • Data from clinical specimens: Likely used to fine-tune and validate the interpretive algorithm (as indicated by the "final validation of the melt ranges" including "review of data from the Inclusivity study and clinical studies" against "expert annotation"). This implies that known positive and negative samples, rigorously characterized by molecular methods (and potentially expert review for complex cases), would inform the algorithm's development.

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The FilmArray® Global Fever Panel External Control Kit contains Positive External Controls intended for use as assayed quality controls to monitor the performance of in vitro diagnostic laboratory nucleic acid testing procedures for the qualitative detection of FilmArray® Global Fever Panel targets on FilmArray® 2.0 systems. The Global Fever Panel External Control Kit is designed for and intended to be used solely with the FilmArray Global Fever Panel. This product does not replace manufacturer internal controls provided as part of the Global Fever Panel device.

The FilmArray Global Fever Panel External Control Kit contains Positive and Negative External Controls. The Positive External Control has been optimized to be detected by all pathogen assays contained in the Global Fever Panel (Table 1). The Negative External Control contains no nucleic acid and a successful run will be negative for all assays on the panel. These controls are not intended to replace the internal FilmArray Global Fever Panel pouch controls (RNA process control and second stage PCR array control). The Global Fever Panel External Control Kit contains no biological hazards and is 100% non-infectious.

The External Controls are referenced in the Ouick Guide and product literature as Control Injection Vials. The use of room-temperature stable External Controls contained within an injection vial simplifies the workflow and allows for use of the External Controls in settings where access to refrigeration may be limited. Each individually packaged, ready-to-use FilmArray Global Fever External Control is processed separately according to the Instructions for Use, and follows the procedure as outlined in the Quick Guide for the FilmArray Global Fever External Control Kit. Each External Control Injection Vial is intended for a single use.

The Global Fever Panel External Control Kit is designed to mitigate the risk of control contamination and misuse when evaluating clinical samples on the FilmArray 2.0 System.

• Negative External Controls are tested using the Negative External Control protocol, which monitors for contamination from both external control material and target pathogens; it will fail if either is detected.
• The Positive External Contains DNA sequences that produce signature amplicon melting temperature (Tm) values distinct from the amplicon Tm values produced by each of the pathogens detected by the Global Fever Panel. By design, the Positive ECM will not be detected when using the Global Fever Panel Whole Blood Protocol, and reciprocally, amplified pathogen-specific nucleic acid will not be detected when using the Positive External Control Protocol. Through modification of the sequence between the inner primers for each ECM target, the Tm value of the amplicon is shifted to higher or lower Tm values relative to the expected Global Fever Panel target amplicon while running the same Global Fever Panel pouches with the same physical pouch manipulation in the FilmArray 2.0 Instrument. Positive External Control-specific pouch module software detects the expected shifted Tm values as being from ECM amplicon, thereby evaluating the performance of the FilmArray 2.0 System. Also, the modification of the ECM sequence mitigates possible contamination events and does not cause false positives in clinical samples. In the unlikely event that Positive ECM or ECM amplicon is introduced into a patient sample, the resulting amplification Tm value(s) is not detected within the pathogen(s) Tm window in the Global Fever Panel Whole Blood Protocol. where different Tm windows are used to detect amplified pathogen sequence.

Here's an analysis of the provided text regarding the acceptance criteria and study for the FilmArray Global Fever Panel External Control Kit:

Note: This document describes an external control kit for an in vitro diagnostic device, not a diagnostic device itself. As such, some of the typical criteria for diagnostic devices (like sensitivity, specificity for patient outcomes, or MRMC studies) are not directly applicable or reported in the same way. The focus here is on the performance of the control kit in monitoring the primary diagnostic device.

Acceptance Criteria and Device Performance for FilmArray Global Fever Panel External Control Kit

1. Table of Acceptance Criteria and Reported Device Performance

Explanations of Implicit Criteria:

• For a quality control material, the primary acceptance criteria are its ability to consistently produce the expected positive or negative results, and for negative controls, its ability to detect contamination.
• The document implies that a "passed" rate of ≥95% is acceptable for field performance and multi-site reproducibility. For repeatability, 100% pass rates are shown, indicating a high standard for within-lab consistency.
• Low Tm standard deviation and CV for positive controls are implicit acceptance criteria for consistent amplification and melting characteristics.

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

• Clinical Testing (Field Use):
  • Sample Size: 317 External Control tests (160 Positive, 157 Negative).
  • Data Provenance: Prospective, collected between July 2019 and January 2020, from "six sites" (implied to be clinical laboratories). The country of origin is not explicitly stated but assumed to be the US based on FDA submission.
• Repeatability:
  • Sample Size: 90 External Control tests (45 Positive, 45 Negative).
  • Data Provenance: In-house study, one operator, one kit lot, one instrument, over 14 days. Retrospective based on experimental design.
• Multi-Site Reproducibility:
  • Sample Size: 270 External Control tests (135 Positive, 135 Negative).
  • Data Provenance: Multi-site study involving "three sites," "three External Control kits," "three reagent pouch lots," "two operators and three FilmArray 2.0 instruments at each site." This is a prospective experimental study.

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

• This device is an external control kit, not a diagnostic device for patient samples. Therefore, the "ground truth" is based on the expected output of the control material (i.e., Positive Control = "Passed" with expected amplicon melts, Negative Control = "Passed" with no amplicon melts/no pathogen detection).
• The "truth" is inherent in the design of the control material (synthetic DNA designed to produce specific signals or no signal) and the proper functioning of the FilmArray 2.0 system. No human experts were used to establish ground truth in the traditional sense of disease diagnosis for these control materials. The system itself determines "passed" or "failed" based on pre-programmed criteria for the control.

4. Adjudication Method for the Test Set

• Not applicable in the traditional sense. The device (FilmArray 2.0 System) with its specific "External Control-specific protocols" internally adjudicates whether a run "passed" or "failed" based on expected amplicon melt curves (for positive) or absence of melts and pathogen detection (for negative). The results are "overall passed or failed results."
• For the clinical testing study, if a control failed, the site "immediately tested a new External Control and obtained the expected result," suggesting internal site-level re-testing but not a formal expert adjudication of the initial failed result. The cause of failure (e.g., user error, contamination) was noted where apparent.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

• No MRMC study was done. This is an in vitro diagnostic control kit, not an AI-assisted diagnostic imaging or pathology device. The "reader" here is the automated FilmArray 2.0 system. The study focuses on the performance and reliability of the control kit itself.

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

• The performance data presented could be considered standalone algorithm performance in the context of the FilmArray 2.0 instrument processing the control material. The instrument's software interprets the results of the control runs and determines if they "passed" or "failed" based on programmed criteria for the specific control and panel. Human intervention is primarily in performing the test, not in interpreting the primary outcome of the control run.

7. The Type of Ground Truth Used

• The ground truth used is expert design specification and expected performance for a quality control material.
  • Positive Controls: Designed with "dried synthetic DNA segments" to produce expected amplicon melting temperature (Tm) values, specific for the External Control melt range and distinct from pathogen Tm values. Ground truth is that these segments should amplify and produce these specific Tm values.
  • Negative Controls: Designed to contain "no DNA" and be non-reactive. Ground truth is that these should not produce any amplification or pathogen detection.
• This is not pathology, outcomes data, or expert consensus on clinical findings, but rather a verification that the control material itself performs as designed and intended to monitor the system's performance.

8. The Sample Size for the Training Set

• Not applicable / No specific training set mentioned. For an in vitro diagnostic control kit, the "training" typically involves the development and calibration of the control material and the associated instrument software during the design phase. The document describes verification and validation studies (clinical, repeatability, reproducibility), which assess the final product's performance, rather than a separate training set for a machine learning algorithm.

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

• Not applicable. As the device is not an AI/ML algorithm that undergoes a training process with a specific ground truth dataset, this question does not directly apply. The "ground truth" for the development of the control kit and its interpretation by the FilmArray system would have been established internally during product development based on molecular biology principles, assay design, synthetic DNA characteristics, and instrument calibration standards.

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