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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):

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.

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The BioFire® Global Fever Special Pathogens Panel is a qualitative, mucleic acid-based test intended for use with BioFire® FilmArray® 2.0 and BioFire® FilmArray® Torch Systems. The BioFire Global Fever Special Pathogens Panel is for the simultaneous qualitative detection and identification of multiple bacterial, viral, and protozoan nucleic acids directly from EDTA whole collected from individuals with signs and or symptoms of acute febrile illness and known or suspected exposure to the target pathogens described below.

Pathogens identified:
Chikungunya virus Dengue virus (serotypes 1, 2, 3 and 4) Leishmania spp. that cause visceral leishmaniasis (e.g., L. donovani and L. infantum) Leptospira spp. Plasmodium spp. (including species differentiation of Plasmodium falciparum and Plasmodium vivax/ovale) West Nile virus

Pathogens presumptively identified:
Bacillus anthracis Crimean-Congo hemorrhagic fever virus Ebolavirus spp. Francisella tularensis Lassa virus Marburgvirus Yellow fever virus Yersinia pestis

Pathogens for which the panel provides presumptive identification results resting and confirmation procedures in consultation with the appropriate public health authorities for whom reports may be necessary.

Positive results do not rule out co-infections with pathogens not included on the BioFire Global Fever Special Pathogens Panel. Not all pathogens that cause acute febrile illness are detected by this test, and nectude infection with the pathogens targeted by the device and should not be used as the sole basis for diagnosis, treatment, or other patient management decisions.

Evaluation for more common causes of acute illness (e.g., infections of the upper and lower respiratory tract or gastroenteritis, as well as non-infectious causes) should be considered prith this panel. 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 Global Fever Special Pathogens Panel as some pathogens are more common in certain geographical locations. Results are meant to be used in conjunction with other clinical, epidemiologic, and laboratory data, in accordance with the guided by the relevant public health authorities.

The BioFire Global Fever Special Pathogens Panel is indicatories having appropriate biosafety equipment, personal protective equipment (PPE), contamment facilities and persomel trained in the safe handling of diagnostic clinical specimens potentially containing any of the pathogens detected by this panel.

The BioFire Global Fever Special Pathogens Panel is indicated for use in laboratories that follow public health guidelines that address appropriate biosafety conditions, interpretation of test results, and coordination of findings with public health authorities.

For In Vitro Diagnostic Use.

The BioFire® Global Fever Special Pathogens Panel is a multiplexed nucleic acid-based test designed to be used with BioFire® FilmArray® Systems (BioFire® FilmArray® 2.0 or BioFire® FilmArray® Torch). The BioFire Global Fever Special Pathogens Panel pouch contains freezedried reagents to perform nucleic acid purification and nested, multiplexed polymerase chain reaction (PCR) with DNA melt analysis. The BioFire Global Fever Special Pathogens Panel conducts tests for the identification of bacterial, viral, and protozoan pathogens from whole blood specimens collected in EDTA tubes (Table 1). Results from the BioFire Global Fever Special Pathogens Panel are available in about 1 hour.

Here's a breakdown of the acceptance criteria and study information for the BioFire Global Fever Special Pathogens Panel:

1. Table of Acceptance Criteria and Reported Device Performance

The application does not explicitly state "acceptance criteria" for PPA and NPA. However, it presents the clinical performance results in a way that suggests these are the key metrics for evaluating agreement with comparator methods. The "Expected percent agreement was >95%" in the reproducibility study might be inferred as a general target for performance. For this table, I'll use the Reported Clinical Performance Summary (Tables 4, 5, 6) as the "Reported Device Performance" against an implied high standard of agreement.

Note on "Acceptance Criteria": The document provides performance results but doesn't explicitly state quantitative acceptance criteria (e.g., "PPA must be >95%"). However, the high percentages and confidence intervals presented imply that high sensitivity and specificity are expected for proper function. The "Reproducibility" section mentions ">95%", which can serve as a proxy for the general expectation of performance accuracy.

2. Sample size used for the test set and the data provenance

• Prospective Clinical Study Test Set:
  • Sample Size: 2139 prospectively collected whole blood specimens.
  • Data Provenance: The specimens were collected between March 2018 and March 2021 from 11 undisclosed sites. The country of origin is not explicitly stated, but the mention of "CDC Yellow Book" in the "Indications for Use" suggests a relevance to North American (US) context, although the pathogens detected indicate global relevance. The data is prospective.
• Archived Specimen Study Test Set:
  • Sample Size: 416 archived specimens.
  • Data Provenance: The specimens were collected from undisclosed sites (Site 01: 199, Site 02: 82, Site 03: 135). The country of origin is not explicitly stated. The data is retrospective.
• Contrived Specimen Study Test Set:
  • Sample Size: 50 replicates for each analyte for which archived specimens were unavailable or insufficient. This resulted in varying total number of specimens tested per analyte (e.g., CCHF virus and Marburgvirus sp. had 100 replicates, others had 50).
  • Data Provenance: Contrived specimens were prepared using residual human whole blood. This is a laboratory-based study.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

The document does not specify the number or qualifications of experts used to establish the ground truth for the test set. Ground truth was established using "plate-based PCR comparator methods" and "additional PCR" for discrepant results. For archived specimens, they had "known analyte content" or "high likelihood of containing a given analyte." For contrived specimens, the "known composition of the contrived specimen" was the ground truth.

4. Adjudication method for the test set

The document describes "discrepancy testing" for samples where the BioFire Global Fever Special Pathogens Panel results differed from the initial comparator method results. For example:

• For Chikungunya virus, "Evidence of Chikungunya virus was found in 2/2 FP specimens by additional PCR."
• For Dengue virus, "15/17 FN specimens were positive upon BioFire Global Fever Special Pathogens Panel retest and by additional PCR, two were positive Global Fever Special Pathogens Panel retest, and eight were detected only by additional PCR."
• For Leptospira spp., "Evidence of Leptospira spp. was found in 1/1 FN specimens by BioFire Global Fever Special Pathogens Panel retest and by additional PCR, and in 3/4 FP specimens by additional PCR."
• For Plasmodium spp., similar retesting by the BioFire panel and "additional PCR" or "species-level comparator assay" was used.

This indicates an adjudication method that involves retesting with the device and/or additional PCR/comparator methods for discrepant results, rather than explicitly stating an "X+Y" consensus model among human experts.

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, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This device is a diagnostic assay (nucleic acid-based test), not an AI-assisted interpretation tool for human readers. Therefore, the concept of "human readers improve with AI vs without AI assistance" does not apply to this submission.

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

Yes, the performance studies (clinical, archived, contrived) evaluate the BioFire Global Fever Special Pathogens Panel as a standalone device (algorithm only). The device provides automated test interpretation and report generation, and the "user cannot access raw data" (Table 2). This means the performance metrics (PPA, NPA) reflect the algorithm's detection capabilities without human intervention in the interpretation process.

7. The type of ground truth used

The ground truth for the test sets was primarily established by:

• Comparator methods (e.g., plate-based PCR/additional PCR): For both prospective clinical and archived specimens.
• Known composition: For contrived specimens, where the analytes were intentionally spiked into the samples.
• Discrepancy testing: For cases where the device result and initial comparator result differed, further testing (usually additional PCR) was performed to resolve the discrepancy and establish the final ground truth.

8. The sample size for the training set

The document does not specify the sample size for a training set. The BioFire Global Fever Special Pathogens Panel is a diagnostic assay, and while its development would involve internal validation and optimization, the provided performance data relates to its analytical and clinical performance after development, rather than the data used for machine learning model training.

9. How the ground truth for the training set was established

Since a "training set" in the context of the requested information (e.g., for an AI model) is not explicitly mentioned or relevant to this type of device submission, the document does not describe how ground truth for a training set was established. The performance studies presented are for the finished device's evaluation against established laboratory methods.

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The BioFire® Global Fever Panel is a qualitative, multiplexed, nucleic acid-based in vitro diagnostic test intended for use with BioFire® FilmArray® 2.0 and BioFire® FilmArray® Torch Systems. The BioFire 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 illness or recent acute febrile illness and known or suspected exposure to the following target pathogens: chikungunya virus (serotypes 1, 2, 3 and 4), Leptospira spp., 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 BioFire 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. In the United States, patient travel history and consultation of the CDC Yellow Book should be considered prior to use of the BioFire Global Fever Panel as some pathogens are more common in certain geographical locations.

For In Vitro Diagnostic Use.

The BioFire Global Fever Panel is a multiplexed nucleic acid-based test for the detection and identification of six pathogens which cause acute febrile illness (AFI) from whole blood specimens on BioFire FilmArray systems. The BioFire Global Fever Panel detects and identifies the following pathogens: chikungunya virus, dengue virus, Leptospira spp., and Plasmodium spp., including species differentiation between P. falciparum and P. vivax/ovale. The BioFire Global Fever Panel was originally described and was granted De Novo classification in DEN200043.

The BIOFIRE SHIELD Control Kit for the BioFire Global Fever Panel is an assayed quality control intended for monitoring the diagnostic performance of the BioFire Global Fever Panel. The Control Kit consists of Positive and Negative External Controls in a FilmArray Control Injection Vial format. The Positive External Control contains external assayed quality control material consisting of a set of non-infectious DNA segments dried on the filter of a FilmArray Control Injection Vial and detected by the Global Fever Panel. The Negative External Control contains no DNA and is also provided in the Control Injection Vial format. Analysis of the controls is carried out by specific pouch modules that are included in the BioFire Global Fever Panel Pouch Module Package. The BIOFIRE SHIELD Control Kit for the BioFire Global Fever Panel was fully described and cleared in K202382.

The purpose of this submission is to add BioFire FilmArray Torch as an additional instrument system for use with the BioFire Global Fever Panel and BIOFIRE SHIELD Control Kit for the BioFire Global Fever Panel, which were previously marketed for use with BioFire FilmArray 2.0 Systems. The FilmArray Torch is a modular configuration of the FilmArray 2.0 that minimizes instrument footprint by stacking up to twelve individual FilmArray Torch Modules on top of a single FilmArray Torch System Base. This 510(k) request describes modifications to the BioFire Global Fever Panel Pouch Module Package software and validation efforts to support adding FilmArray Torch Systems to the intended use of both the BioFire Global Fever Panel and associated BIOFIRE SHIELD Control Kit.

Here's an analysis of the provided text, focusing on the acceptance criteria and the study details:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state formal "acceptance criteria" in a separate section. Instead, the performance data is presented as a comparison to the predicate device (BioFire FilmArray 2.0 system), implying that non-inferiority or comparable performance to the established predicate is the implicit acceptance criterion.

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

• Test Set for BioFire Global Fever Panel (Table 3):

  • Sample Size: For each analyte (e.g., Leptospira interrogans), there were 3 concentrations tested (Moderate Positive, Low Positive, Negative). Each concentration was tested with 3 FilmArray 2.0 systems and 3 FilmArray Torch systems. On each system, 30 replicates were run.
    • For a single analyte and concentration, 30 replicates/system * 3 systems = 90 replicates for each platform.
    • Total replicates per analyte (3 concentrations): 90 replicates/platform * 3 concentrations = 270 replicates for each platform.
    • Total replicates across all analytes and concentrations for comparison: 1080 replicates on FilmArray 2.0 and 1080 replicates on FilmArray Torch.
    • The exact number of unique "samples" (batches of contrived material) is not specified, but the number of test runs is clear.
  • Data Provenance: The replicates are "contrived samples containing representative pathogens... at concentrations near the limit of detection (LoD)" and "negative samples containing no analyte." The exact country of origin is not stated, but the study was conducted by BioFire Defense, LLC (Salt Lake City, UT, USA). It is a prospective study as new testing was performed to evaluate the FilmArray Torch system.

• Test Set for BIOFIRE SHIELD Control Kit (Table 4):

  • Sample Size:
    • Positive External Controls: 135 replicates (45 replicates/system * 3 FilmArray Torch systems).
    • Negative External Controls: 135 replicates (45 replicates/system * 3 FilmArray Torch systems).
    • Total: 270 replicates.
  • Data Provenance: Details are for the BioFire FilmArray Torch platform only. The data is prospective, generated specifically for this evaluation.

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

For both studies (BioFire Global Fever Panel and BIOFIRE SHIELD Control Kit), the ground truth was established by the known concentration/presence of the analyte in the contrived samples or controls. While operators performed the tests, there is no mention of "experts" establishing the ground truth of the test material, as it's an analytical performance study using characterized samples.

4. Adjudication Method for the Test Set

There is no mention of an adjudication method in the context of expert review. The "expected result" for each test run (Detected/Not Detected) was based on the known composition of the contrived samples or control materials.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was Done, What was the Effect Size of How Much Human Readers Improve with AI vs. Without AI Assistance?

This type of study was not performed, nor is it applicable. The device is an in vitro diagnostic test that provides automated interpretation and report generation. There is no "human reader" component in the interpretation of the results to be improved by AI assistance. The document explicitly states: "Automated test interpretation and report generation; user cannot access raw data."

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

Yes, a standalone study was done. The BioFire Global Fever Panel runs on the FilmArray system, which is an automated device. The performance data presented in Table 3 and Table 4 reflects the algorithm's performance (i.e., the device's ability to detect and identify targets) directly on the FilmArray Torch system, without human intervention in the result interpretation. The objective of this submission was to evaluate the performance of the existing panel on a new instrument system (FilmArray Torch), which itself is automated.

7. The Type of Ground Truth Used

The ground truth used was known composition of contrived samples/controls. This means:

• For positive samples, the specific analytes and their concentrations (e.g., 3xLoD, 1xLoD) were pre-determined.
• For negative samples and controls, the absence of the target analyte was pre-determined.

8. The Sample Size for the Training Set

The document does not provide information on a training set. This submission is for adding a new instrument system (BioFire FilmArray Torch) for an already existing and cleared device (BioFire Global Fever Panel). The "BioFire Global Fever Panel was originally described and was granted De Novo classification in DEN200043." Therefore, any initial development and potential "training" (if applicable for the underlying algorithm) would have occurred during the development phase for DEN200043, and those details are not part of this 510(k) summary. The current study is a verification/validation for expanded instrument compatibility.

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

As no training set information is provided in this document, the method for establishing its ground truth is also not available here.

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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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