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510(k) Data Aggregation
(29 days)
FilmArray Blood Culture Identification (BCID) Panel
The FilmArray Blood Culture Identification (BCID) Panel is a qualitative multiplexed nucleic acid-based in vitro diagnostic test intended for use with FilmArray systems. The FilmArray BCID Panel is capable of simultaneous detection and identification of multiple bacterial and yeast nucleic acids and select genetic determinants of antimicrobial resistance. The FilmArray BCID Panel assay is performed directly on blood culture samples identified as positive by a continuous monitoring blood culture system. Results are intended to be interpreted in conjunction with Gram stain results.
The following gram-positive bacteria, gram-negative bacteria, and yeast are identified using the FilmArray BCID Panel: Enterococci, Listeria monocytogenes, Staphylococci (including specific differentiation of Staphylococcus aureus), Streptococci (with specific differentiation of Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes), Acinetobacter baumannii, Enterobacteriaceae (including specific differentiation of the Enterobacter cloacae complex, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus, and Serratia marcescens), Haemophilus influenzae, Neisseria meningitidis (encapsulated), Pseudomonas aeruginosa, Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, and Candida tropicalis.
The FilmArray BCID Panel also contains assays for the detection of genetic determinants of resistance to methicillin (mecA), vancomycin (vanA and vanB), and carbapenems (blaxe) to aid in the identification of potentially antimicrobial resistant organisms in positive blood culture samples. The antimicrobial resistance gene detected may or may not be associated with the agent responsible for disease. Negative results for these select antimicrobial resistance gene assays do not indicate susceptibility, as multiple mechanisms of resistance to methicillin, vancomycin, and carbapenems exist.
FilmArray BCID Panel is indicated as an aid in the diagnosis of specific agents of bacteremia and fungemia and results should be used in conjunction with other clinical and laboratory findings. Positive FilmArray results do not rule out co-infection with organisms not included in the FilmArray BCID Panel. FilmArray BCID Panel is not intended to monitor treatment for bacteremia or fungemia.
Subculturing of positive blood cultures is necessary to recover organisms for susceptibility testing and epidemiological typing, to identify organisms in the blood culture that are not detected by the FilmArray BCID Panel, and for species determination of some Staphylococci, Enterococci, Streptococci, and Enterobacteriaceae that are not specifically identified by the FilmArray BCID Panel assays.
The FilmArray Blood Culture Identification (BCID) Panel is a multiplex nucleic acid test designed to be used with a FilmArray system. The FilmArray BCID pouch contains freeze-dried reagents to perform nucleic acid purification and nested, multiplex PCR with DNA melt analysis. The FilmArray Blood Culture Identification (BCID) Panel simultaneously tests a single positive blood culture sample to provide results for 24 different organisms and organism groups that cause bloodstream infections and three genetic markers that are known to confer antimicrobial resistance (see Table 1).
A test is initiated by loading Hydration Solution and a positive blood culture sample mixed with the provided Sample Buffer into the FilmArray BCID pouch. 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 software guides the user though the steps of placing the pouch into the instrument. scanning the pouch barcode, entering the sample identification, and initiating the run.
The FilmArray instrument contains a coordinated system of inflatable bladders and seal points, which act on the pouch to control the movement of liquid between the pouch blisters. When a bladder is inflated over a reagent blister, it forces liquid from the blister into connecting channels. Alternatively, when a seal is placed over a connecting channel it acts as a valve to open or close a channel. In addition, electronically controlled pneumatic pistons are positioned over multiple plungers in order to deliver the rehydrated reagents into the blisters at the appropriate times. Two Peltier devices control heating and cooling of the pouch to drive the PCR reactions and the melt curve analysis.
Nucleic acid extraction occurs within the FilmArray pouch using mechanical lysis and 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 PCR reaction which includes all primers of the outer primer sets, 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 singleplex fashion in each well of the array. At the conclusion of the 2nd stage PCR, the array is interrogated by melt curve analysis for the detection of signature amplicons denoting the presence of specific targets. A digital camera placed in front of the array captures fluorescent images of the PCR reactions and software interprets the data.
The FilmArray software automatically interprets the results of each DNA melt curve analysis and combines the data with the results of the internal pouch controls to provide a test result for each organism on the panel.
The provided document is a 510(k) summary for a modification to an existing medical device, the FilmArray Blood Culture Identification (BCID) Panel. This submission primarily focuses on changes to the intended use and labeling, rather than a full re-evaluation of the device's original performance. As such, the document does not contain a typical study outlining comprehensive acceptance criteria and performance against those criteria in the same way an initial submission might.
However, based on the information provided, we can infer some "acceptance criteria" related to the changes being made and how the device meets them.
Here's an attempt to structure the information as requested, with caveats due to the nature of the document:
1. Table of Acceptance Criteria and Reported Device Performance
Since this is a modification submission, the "acceptance criteria" discussed are largely related to ensuring the changes (removal of false positive warnings, additional interference testing, and updated cross-reactivity information) do not negatively impact the device's overall performance as established by the predicate device.
| Acceptance Criteria Category | Specific Acceptance Criteria (Inferred from study goals) | Reported Device Performance (Summary from this document) |
|---|---|---|
| Removal of False Positive Warnings (BioMérieux BacT/ALERT SN) | Ensure that the identified source of false positives for Enterococcus and Pseudomonas aeruginosa in bioMérieux BacT/ALERT SN bottles has been corrected and removed, and that the device no longer exhibits an increased risk of false positives with these bottles. The device should demonstrate reliable and accurate detection for these targets when tested in these specific bottles, on par with other approved blood culture bottles. | The source of false positive results has been identified, corrected, and removed. The limitation regarding increased risk of false positives for Pseudomonas aeruginosa and Enterococcus with bioMérieux BacT/ALERT SN bottles is being removed from the labeling as "no longer accurate." |
| Additional Interference Testing (New Blood Culture Bottles) | The device should not exhibit significant interference or unexpected invalid results when used with the newly added bioMerieux BacT/ALERT FA Plus and BacT/ALERT FN Plus blood culture media bottle types. Results obtained with these new bottle types should be comparable to those obtained with previously approved media. | "All 21 runs were valid with passed controls and no errors or unexpected results." The FilmArray BCID Panel Instruction Booklet will be updated to include these bottle types as acceptable. |
| Newly Identified Organism Cross-Reactivities | Accurately identify and characterize any newly discovered organism cross-reactivities. The updated labeling must reflect these findings to ensure users are aware of potential interpretations. (This is more an acceptance of identifying and reporting rather than a performance target per se) | New organism cross-reactivity findings (e.g., for Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Haemophilus influenzae, Listeria monocytogenes, Candida parapsilosis, Candida krusei, vanA/B) were identified and will be added to the Instruction Booklet. |
2. Sample Size Used for the Test Set and Data Provenance
Due to the nature of this submission being a modification of use and labeling, the "test set" described is specifically for the interference testing. The document does not detail the full original clinical validation test set.
-
Interference Testing (bioMerieux BacT/ALERT FA Plus and BacT/ALERT FN Plus bottles):
- Sample Size: 7 contrived blood culture samples (6 positive and 1 negative) per media type. As three media types were tested (BD BACTEC Plus Aerobic/F, BacT/ALERT FA Plus, BacT/ALERT FN Plus), this implies a total of 21 runs.
- Data Provenance: Not explicitly stated, but these were contrived samples prepared in a laboratory setting, likely at BioFire Diagnostics. Therefore, it's a prospective analytical study. Country of origin is implied to be within the US, where BioFire Diagnostics is located.
-
Cross-Reactivity Updates:
- The document notes that some cross-reactivities were observed "infrequently in pre-analytical studies and the clinical evaluation (estimated occurrence of ~0.25% of all Staphylococcus positive patient samples)," and "in contrived samples and/or clinical blood culture specimens."
- For Klebsiella quasipneumoniae, it's stated as a "new species (with subspecies) that is closely related to K. pneumoniae," implying some form of ongoing surveillance or re-evaluation. Similarly, Raoultella ornithinolytica cross-reactivity was "observed in clinical positive blood cultures."
- This suggests some data comes from retrospective analysis of previously collected clinical data or ongoing surveillance, as well as new analytical testing (contrived samples). Specific sample sizes for these cross-reactivity discoveries are not provided in this summary.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and the Qualifications of Those Experts
- Interference Testing: Not applicable in the same way as a clinical study. Ground truth for the contrived samples would have been precisely known based on their preparation. For example, a "positive" sample would have been spiked with a known organism at a known concentration.
- Cross-Reactivity: The document does not specify experts involved in establishing ground truth for the discovery of cross-reactivities. However, the identification of microorganisms and their genetic markers typically relies on established microbiology laboratory methods, often overseen by experienced microbiologists. Given the "in silico analysis" mentioned, bioinformatics experts would also be involved.
4. Adjudication Method for the Test Set
- Interference Testing: No formal adjudication method like "2+1" or "3+1" is mentioned or expected for this type of analytical validation using contrived samples. The results (valid runs, no errors, lack of interference) are directly observable from the instrument's output and comparison against expected results based on sample preparation.
- Cross-Reactivity: The document doesn't detail an adjudication process for identifying cross-reactivities, but it references "pre-analytical studies," "clinical evaluation," and "in silico analysis." This implies internal validation and expert review of results from various sources.
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, an MRMC comparative effectiveness study was not done. The FilmArray BCID Panel is an in vitro diagnostic (IVD) device that directly detects nucleic acids from blood culture samples and provides an automated interpretation. It is not an imaging AI device that "assists human readers" in the traditional sense. The device generates a definitive result (presence/absence of specific organisms/resistance genes), and while healthcare professionals interpret these results in conjunction with other clinical findings (like Gram stain), there isn't a human-in-the-loop "reading" task that the device is assisting.
6. If a Standalone (i.e. algorithm only without human-in-the loop performance) Was Done
- Yes, the primary performance of the FilmArray BCID Panel is standalone algorithm performance. The device performs nucleic acid extraction, PCR, and melt curve analysis, and its software automatically interprets the results. The "test interpretation" is described as "Automated test interpretation and report generation. User cannot access raw data." This confirms it's an algorithm-only, standalone performance. The document does not present separate standalone performance data for this specific submission as it is about modifications to an existing, already cleared device. The "performance" being demonstrated here is primarily the robustness of the existing system to new conditions (bottle types) and the transparent reporting of newly identified cross-reactivities. The performance of the predicate device (K160457) would have established its standalone performance.
7. The Type of Ground Truth Used
- Interference Testing: The ground truth for the contrived samples was known composition (i.e., specific organisms spiked at known concentrations, or negative controls).
- Cross-Reactivity: The ground truth for identified cross-reactivities likely came from a combination of:
- Analytical testing (e.g., testing known isolates/species in contrived samples).
- Clinical culture results (identifying organisms in patient samples that cross-reacted with the panel).
- In silico analysis (bioinformatics prediction based on sequence homology).
8. The Sample Size for the Training Set
- Not applicable for this modification submission. This document describes modifications to an existing device (K160457). The "training set" (if applicable from a machine learning perspective, which is unlikely for a PCR-based IVD) would have been part of the original development and validation of the predicate device, not detailed in this modification summary. The FilmArray panel design (primers, probes) itself is developed through a sophisticated "training" process involving bioinformatic analysis of target sequences, but the document does not provide details on specific sample sizes for that primer/probe design process.
9. How the Ground Truth for the Training Set Was Established
- Also not applicable for this modification submission as a "training set" for an algorithm in the machine learning sense isn't detailed, nor is its ground truth establishment. For the original development of the PCR panel, the ground truth for probe design and target identification would have been established through extensive genomic sequencing data, validated microbial culture collections, and molecular characterization methods.
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(25 days)
FilmArray Blood Culture Identification (BCID) panel for use with FilmArray Torch
The FilmArray Blood Culture Identification (BCID) Panel is a qualitative multiplexed nucleic acid-based in vitro diagnostic test intended for use with FilmArray BCID Panel is capable of simultaneous detection and identification of multiple bacterial and yeast nucleic acids and select genetic determinants of antimicrobial resistance. The BCID assay is performed directly on blood culture samples identified as positive by a continuous monitoring blood culture system that demonstrate the presence of organisms as determined by Gram stain.
The following gram-positive bacteria, gram-negative bacteria, and yeast are identified using the FilmArray BCD Panel: Enterococci, Listeria monocytogenes, Staphylococci (including specific differentiation of Staphylococcus aureus), Streptococci (with specific differentiation of Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes), Acinetobacter baumannii, Enterobacteriaceae (including specific differentiation of the Enterchacter cloacae complex, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus, and Serratia marcescens), Haemophilus influenzae, Neisseria meningitidis (encapsulated), Pseudomonas aeruginosa, Candida glabrata, Candida krusei, Candida parapsilosis, and Candida tropicalis.
The FilmArray BCID Panel also contains assays for the determinants of resistance to methicillin (mecA), vancomycin (vanA and vanB), and carbapenems (blaKPC) to aid in the identification of potentially antimicrobial resistant organisms in positive blood culture samples. The antimicrobial resistance gene detected may or may not be associated with the agent responsible for disease. Negative results for these select antimicrobial resistance gene assays do not indicate susceptibility, as multiple mechanisms of resistance to methicillin, vancomycin, and carbapenens exist. FilmArray BCID is indicated as an aid in the diagnosis of bacteremia and fungemia and results should be used in conjunction with other clinical and laboratory findings. Positive FilmArray results do not rule out co-infection with organisms not included in the FilmArray BCID Panel. FilmArray BCID is not intended to monitor treatment for bacteremia or fungemia.
Subculturing of positive blood cultures is necessary to recover organisms for susceptibility testing and epidemiological typing, to identify organisms in the blood culture that are not detected by the FilmArray BCID Panel, and for species determination of some Staphylococci, Streptococci, Streptococci, and Enterobacteriaceae that are not specifically identified by the FilmArray BCID Panel assays.
The FilmArray Blood Culture Identification (BCID) Panel is a multiplex nucleic acid test designed to be used with a FilmArray system. The FilmArray BCID pouch contains freeze-dried reagents to perform nucleic acid purification and nested, multiplex PCR with DNA melt analysis. The FilmArray Blood Culture Identification (BCID) Panel simultaneously tests a single positive blood culture sample to provide results for 24 different organisms and organism groups that cause bloodstream infections and three genetic markers that are known to confer antimicrobial resistance (see Table 1).
A test is initiated by loading Hydration Solution and a positive blood culture sample mixed with the provided Sample Buffer into the FilmArray BCID pouch. 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 software guides the user though the steps of placing the pouch into the instrument. scanning the pouch barcode, entering the sample identification, and initiating the run.
The FilmArray instrument contains a coordinated system of inflatable bladders and seal points, which act on the pouch to control the movement of liquid between the pouch blisters. When a bladder is inflated over a reagent blister, it forces liquid from the blister into connecting channels. Alternatively, when a seal is placed over a connecting channel it acts as a valve to open or close a channel. In addition, electronically controlled pneumatic pistons are positioned over multiple plungers in order to deliver the rehydrated reagents into the blisters at the appropriate times. Two Peltier devices control heating and cooling of the pouch to drive the PCR reactions and the melt curve analysis.
Nucleic acid extraction occurs within the FilmArray pouch using mechanical lysis and 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 PCR reaction which includes all primers of the outer primer sets, 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 singleplex fashion in each well of the array. At the conclusion of the 2nd stage PCR, the array is interrogated by melt curve analysis for the detection of signature amplicons denoting the presence of specific targets. A digital camera placed in front of the array captures fluorescent images of the PCR reactions and software interprets the data.
The FilmArray software automatically interprets the results of each DNA melt curve analysis and combines the data with the results of the internal pouch controls to provide a test result for each organism on the panel.
Here's a breakdown of the acceptance criteria and study information for the FilmArray Blood Culture Identification (BCID) Panel for use with FilmArray Torch, based on the provided document:
Acceptance Criteria and Device Performance
The document doesn't explicitly state numerical acceptance criteria in a dedicated section with thresholds. However, it describes the performance goal and the reported device performance as follows:
| Acceptance Criteria / Performance Goal | Reported Device Performance |
|---|---|
| Reproducible detection of each FilmArray BCID analyte (including antibiotic resistance markers) at concentrations consistent with levels in positive blood culture bottles at initial positivity. | Reproducible detection was confirmed for each FilmArray BCID analyte. 100% of samples tested on FilmArray Torch systems yielded the expected "Detected" results. |
| Agreement with expected negative results ("Not Detected") for each analyte. | Agreement with the expected negative results (Not Detected) was >98% for each analyte. |
| Substantial equivalence in performance characteristics (including reproducibility) to the predicate device (FilmArray BCID Panel on FilmArray and FilmArray 2.0 systems). | "Non-clinical validation studies have established that the performance characteristics of FilmArray BCID, including reproducibility, are substantially equivalent on FilmArray, FilmArray 2.0, and FilmArray Torch." (This is a qualitative statement of equivalence based on the quantitative results above). |
Study Information
2. Sample size used for the test set and the data provenance:
- Sample Size: 30 replicates per analyte per system for 90 total replicates per analyte. (The document doesn't specify how many analytes are on the panel, but Table 1 lists 24 organism targets and 4 resistance markers, implying a total of 28 analytes. So, for each of these 28 analytes, 90 samples were tested).
- Data Provenance: The study used "contrived samples" containing analytes at specific concentrations. This indicates a prospective, laboratory-controlled study, rather than retrospective clinical data. No country of origin is explicitly stated, but the submission is to the FDA (USA).
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- This study evaluates an in vitro diagnostic (IVD) device that directly detects nucleic acids. The ground truth for the contrived samples would be established by the known composition and concentration of the analytes spiked into the samples during their preparation, not by human expert interpretation. Therefore, no external human experts were involved in establishing the ground truth for this specific test set.
4. Adjudication method (e.g. 2+1, 3+1, none) for the test set:
- Not applicable. As this is an IVD device testing contrived samples against known concentrations, there is no need for expert adjudication. The result is either "Detected" or "Not Detected" compared to the known content of the contrived sample.
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 an automated IVD and does not involve human readers interpreting results in the same way an AI for image analysis would. Its output is an automated interpretation of molecular detection.
6. If a standalone (i.e. algorithm only without human-in-the loop performance) was done:
- Yes, this was effectively a standalone performance evaluation of the FilmArray Torch system running the BCID Panel. The "algorithm" (the automated processes and software interpretation within the FilmArray system) directly processed the samples and generated results without human interpretation of raw data; the user only sees automated test interpretation and report generation.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- For the test set, the ground truth was known composition and/or spiking of analytes (nucleic acids) at specific concentrations in the contrived samples.
8. The sample size for the training set:
- The document describes a submission for a modified device (FilmArray Torch) to be used with an existing reagent panel (FilmArray BCID Panel). It states "There have been no changes to the previously cleared FilmArray BCID Panel reagent kit itself." Therefore, the training of the assay (the BCID Panel's detection algorithms) would have occurred during the development and clearance of the original K143171 predicate device. This document does not provide details on the training set for that original assay, as the focus here is on the new instrument's equivalence. The study described (using 90 replicates per analyte) is a validation/test set, not a training set.
9. How the ground truth for the training set was established:
- As noted above, details about the training set for the original BCID Panel assay are not provided in this document. For molecular diagnostic assays like this, training data would typically involve:
- Known positive samples: Samples containing confirmed target organisms/genes (e.g., pure cultures, reference materials).
- Known negative samples: Samples confirmed to lack the target organisms/genes.
- Specificity panels: Samples containing closely related organisms or common co-infecting agents to ensure accurate differentiation and minimize cross-reactivity.
- The ground truth would be established through gold standard microbiology methods (e.g., culture, sequencing, validated reference PCRs) for organisms, and often sequencing or known genetic constructs for resistance genes.
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(87 days)
FilmArray Blood Culture Identification (BCID) Panel for use with the FilmArray 2.0
The FilmArray Blood Culture Identification (BCID) Panel is a qualitative multiplexed nucleic acid-based in vitro diagnostic test intended for use with FilmArray systems. The FilmArray BCID Panel is capable of simultaneous detection and identification of multiple bacterial and yeast nucleic acids and select genetic determinants of antimicrobial resistance. The BCID assay is performed directly on blood culture samples identified as positive by a continuous monitoring blood culture system that demonstrate the presence of organisms as determined by Gram stain.
The following gram-positive bacteria, gram-negative bacteria, and yeast are identified using the FilmArray BCID Panel: Enterococci, Listeria monocytogenes, Staphylococci (including specific differentiation of Staphylococcus aureus), Streptococci (with specific differentiation of Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes), Acinetobacter baumannii, Enterobacteriaceae (including specific differentiation of the Enterobacter cloacae complex, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus, and Serratia marcescens), Haemophilus influenzae, Neisseria meningitidis (encapsulated), Pseudomonas aeruginosa, Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, and Candida tropicalis.
The FilmArray BCID Panel also contains assays for the detection of genetic determinants of resistance to methicillin (mecA), vancomycin (vanA and vanB), and carbapenems (blakpr) to aid in the identification of potentially antimicrobial resistant organisms in positive blood culture samples. The antimicrobial resistance gene detected may or may not be associated with the agent responsible for disease. Negative results for these select antimicrobial resistance gene assays do not indicate susceptibility, as multiple mechanisms of resistance to methicillin, vancomycin, and carbapenems exist.
FilmArray BCID is indicated as an aid in the diagnosis of specific agents of bacteremia and fungemia and results should be used in conjunction with other clinical and laboratory findings. Positive FilmArray results do not rule out co-infection with organisms not included in the FilmArray BCID Panel. FilmArray BCID is not intended to monitor treatment for bacteremia or fungemia.
Subculturing of positive blood cultures is necessary to recover organisms for susceptibility testing and epidemiological typing, to identify organisms in the blood culture that are not detected by the FilmArray BCID Panel, and for species determination of some Staphylococci, Enterococci, Streptococci, and Enterobacteriaceae that are not specifically identified by the FilmArray BCID Panel assays.
The FilmArray Blood Culture Identification (BCID) Panel is a multiplex nucleic acid test designed to be used with a FilmArray system. The FilmArray BCID pouch contains freeze-dried reagents to perform nucleic acid purification and nested, multiplex PCR with DNA melt analysis. The FilmArray Blood Culture Identification (BCID) Panel simultaneously tests a single positive blood culture sample to provide results for 24 different organisms and organism groups that cause bloodstream infections and three genetic markers that are known to confer antimicrobial resistance (see Table 1).
A test is initiated by loading Hydration Solution and a positive blood culture sample mixed with the provided Sample Buffer into the FilmArray BCID pouch. 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 software guides the user though the steps of placing the pouch into the instrument, scanning the pouch barcode, entering the sample identification, and initiating the run.
The instrument contains a coordinated system of inflatable bladders and seal points, which act on the pouch to control the movement of liquid between the pouch blisters. When a bladder is inflated over a reagent blister, it forces liquid from the blister into connecting channels. Alternatively, when a seal is placed over a connecting channel it acts as a valve to open or close a channel. In addition, electronically controlled pneumatic pistons are positioned over multiple plungers in order to deliver the rehydrated reagents into the blisters at the appropriate times. Two Peltier devices control heating and cooling of the pouch to drive the PCR reactions and the melt curve analysis.
Nucleic acid extraction occurs within the FilmArray pouch using mechanical lysis and 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 PCR reaction which includes all primers of the outer primer sets, 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 singleplex fashion in each well of the array. At the conclusion of the 21th stage PCR, the array is interrogated by melt curve analysis for the detection of signature amplicons denoting the presence of specific targets. A digital camera placed in front of the array captures fluorescent images of the PCR reactions and software interprets the data.
The 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 an analysis of the provided text regarding the acceptance criteria and study for the FilmArray Blood Culture Identification (BCID) Panel:
The document describes a 510(k) premarket notification for the FilmArray BCID Panel for use with the FilmArray 2.0 system, claiming substantial equivalence to a previously cleared device (K130914). The studies discussed are primarily focused on demonstrating this equivalence rather than establishing wholly new acceptance criteria for the device itself. The acceptance criteria essentially align with the performance of the predicate device.
1. A table of acceptance criteria and the reported device performance
The acceptance criteria are implicitly based on demonstrating comparable performance to the predicate FilmArray BCID Panel on the original FilmArray system. The reported performance for the new device (FilmArray BCID Panel on FilmArray 2.0) is effectively the validation that it meets these implicit acceptance criteria.
| Acceptance Criteria (Implicit) | Reported Device Performance (FilmArray 2.0 with both loading procedures) |
|---|---|
| Maintain overall PPA (Positive Percent Agreement) ≥ 95.3% as seen with the predicate. | Overall PPA ≥ 99.1% (Lower bound 95% CI ≥ 95.3%) |
| Maintain overall NPA (Negative Percent Agreement) ≥ 99.7% as seen with the predicate. | Overall NPA ≥ 99.9% (Lower bound 95% CI ≥ 99.7%) |
| Achieve 100% agreement for most analytes across various comparisons (system, loading tools). | 100% concordance observed for most analytes across all comparisons. Occasional discrepancies attributed to analyte levels well below typical positive blood culture levels. |
| Maintain a Tm (melting temperature) variation of ±0.5°C or less compared to the predicate system. | Mean Tm values for all FilmArray BCID assays on modified configurations were ±0.5°C or less compared to the current configuration. |
| Reproducibility for positive and negative results with expected agreement. | High reproducibility (100% or very close to 100%) for majority of analytes across sites and loading procedures. (See Table 6 for detailed percentages per analyte). Lower bounds of 95% CI for overall concordance were consistently high (e.g., 96.0%-100%, 92.2%-99.7%). |
| Tm reproducibility (within-site/system and overall) within acceptable standard deviations. | Tm standard deviations were consistently low, generally ±0.1 to ±0.4 degrees Celsius, indicating high reproducibility. (See Table 7 for detailed values). |
2. Sample sized used for the test set and the data provenance
- Clinical Performance Study Test Set:
- Sample Size: 100 specimens (plus 2 additional runs for the modified system, totaling 102 runs for the current system and 202 for the modified system). These were selected such that each analyte (and antibiotic resistance marker) was represented 3-5 times.
- Data Provenance: Retrospective. Specimens were "previously obtained during the FilmArray BCID prospective clinical evaluation." Seeded blood cultures (remnant from the prospective BCID clinical study) were used for rare BCID analytes. The country of origin is not explicitly stated, but the FDA submission and company location (Salt Lake City, UT, USA) suggest it is likely US-based data.
- Low Analyte (Titration) Study Test Set:
- Sample Size: Not explicitly stated as a single number, but involves dilution series of samples for various analytes. Each test level for each organism was tested with 5 replicates (e.g., 5/5 (100%) in Table 4). The total number of tests for each analyte across the dilution series is 20 (5 replicates x 4 dilutions). With ~30 analytes, this implies hundreds of individual tests.
- Data Provenance: This appears to be an analytical study using contrived samples (dilution series of samples containing a mix of BCID analytes), not directly clinical specimens. Country of origin not specified, but likely internal lab data.
- Reproducibility Study Test Set:
- Sample Size: For each analyte, at each test level (Positive/Negative), 30 tests were performed at each of 3 sites, for a total of 90 data points per analyte/test level/loading procedure combination. This was then done for both syringe and injection vial loading procedures, effectively 180 data points per analyte/test level. There were 6 organisms with 2 test levels each for the most detailed analysis (positive/negative), and several other analytes with only negative test levels contributing to overall statistics.
- Data Provenance: Contrived blood culture samples spiked with various concentrations of BCID organisms, tested across three different test sites (likely in the US based on the submission).
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts
The document does not mention the use of experts to establish ground truth for the test sets. For the clinical performance study, the ground truth for previously collected clinical specimens would have been established by standard clinical microbiology methods. For the seeded blood cultures and contrived samples, the ground truth is inherently known by the study design (i.e., what organisms were spiked into the samples). This is a common approach for in vitro diagnostic (IVD) device studies.
4. Adjudication method for the test set
Not applicable, as ground truth was established by microbiological culture or by design (for contrived samples), not by expert opinion requiring adjudication.
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
Not applicable. This is an in vitro diagnostic (IVD) device, not an AI-assisted diagnostic imaging system that uses human readers. The "reader" here is the instrument and its software, and the comparison is between two versions of the instrument/software system, and different loading methods.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
Yes, the device (FilmArray BCID Panel) performs as a standalone algorithm/instrument system to detect and identify nucleic acids. There is no human interpretation of raw data; "The 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."
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)
- Clinical Performance Study: Ground truth for patient specimens would have been established by conventional microbiology methods (culture, identification, susceptibility testing). For seeded blood cultures, the ground truth was based on the known spiked organisms.
- Low Analyte Study: Ground truth was based on the known composition and concentration of the spiked organisms in the contrived samples.
- Reproducibility Study: Ground truth was based on the known composition and expected detection of the spiked organisms in the contrived samples.
8. The sample size for the training set
The document does not provide information about a separate "training set" in the context of device development or any machine learning approach. This is an IVD device based on molecular biology principles (PCR and melt analysis), not a machine learning algorithm that typically requires explicit training datasets. The development and optimization of the assays would have involved extensive R&D, but not in the "training set" sense of AI/ML.
9. How the ground truth for the training set was established
As noted in point 8, the concept of a "training set" in the AI/ML sense is not directly applicable to this type of IVD device. The ground truth for developing and validating the PCR assays would involve standard molecular biology and microbiology techniques to confirm the presence and identity of target organisms and resistance genes.
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(80 days)
FILMARRAY BLOOD CULTURE IDENTIFICATION (BCID) PANEL
The FilmArray Blood Culture Identification (BCID) Panel is a qualitative multiplexed nucleic acid-based in vitro diagnostic test intended for use with the FilmArray Instrument. The FilmArray BCID Panel is capable of simultaneous detection and identification of multiple bacterial and yeast nucleic acids and select genetic determinants of antimicrobial resistance. The BCID assay is performed directly on blood culture samples identified as positive by a continuous monitoring blood culture system that demonstrates the presence of organisms as determined by Gram stain.
The following gram-positive bacteria, gram-negative bacteria, and yeast are identified using the FilmArray BCID Panel: Enterococci, Listeria monocytogenes, commonly encountered Staphylococci (including specific differentiation of Staphylococcus aureus), commonly encountered Streptococci (with specific differentiation of Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes), Acinetobacter baumannii, commonly encountered Enterobacteriaceae (including specific differentiation of the Enterobacter cloacae complex, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus, and Serratia marcescens), Haemophilus influenzae, Neisseria meningitidis (encapsulated), Pseudomonas aeruginosa, Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, and Candida tropicalis.
The FilmArray BCID Panel also contains assays for the detection of genetic determinants of resistance to methicillin (mecA), vancomycin (vanA and vanB), and carbapenems (blaKPC) to aid in the identification of potentially antimicrobial resistant organisms in positive blood culture samples. The antimicrobial resistance gene detected may or may not be associated with the agent responsible for disease. Negative results for these select antimicrobial resistance gene assays do not indicate susceptibility, as multiple mechanisms of resistance to methicillin, vancomycin, and carbapenems exist.
FilmArray BCID is indicated as an aid in the diagnosis of specific agents of bacteremia and fungemia and results should be used in conjunction with other clinical and laboratory findings. Positive FilmArray results do not rule out co-infection with organisms not included in the FilmArray BCID Panel. FilmArray BCID is not intended to monitor treatment for bacteremia or fungemia.
Subculturing of positive blood cultures is necessary to recover organisms for susceptibility testing and epidemiological typing, to identify organisms in the blood culture that are not detected by the FilmArray BCID Panel, and for species determination of some Staphylococci, Enterococci, Streptococci, and Enterobacteriaceae that are not specifically identified by the FilmArray BCID Panel assays.
The FilmArray Blood Culture Identification (BCID) Panel is a multiplex nucleic acid test designed to be used with the FilmArray Instrument. The FilmArray BCID pouch contains freeze-dried reagents to perform nucleic acid purification and nested, multiplex PCR with DNA melt analysis. The FilmArray Blood Culture Identification (BCID) Panel simultaneously tests a single positive blood culture sample to provide results for 24 different organisms and organism groups that cause bloodstream infections and three genetic markers that are known to confer antimicrobial resistance (see Table 1).
A test is initiated by loading Hydration Solution and a positive blood culture sample mixed with the provided Sample Buffer into the FilmArray BCID pouch. 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 though the steps of placing the pouch into the instrument, scanning the pouch barcode, entering the sample identification, and initiating the run.
The FilmArray Instrument contains a coordinated system of inflatable bladders and seal points, which act on the pouch to control the movement of liquid between the pouch blisters. When a bladder is inflated over a reagent blister. it forces liquid from the blister into connecting channels. Alternatively, when a seal is placed over a connecting channel it acts as a valve to open or close a channel. In addition, electronically controlled pneumatic pistons are positioned over multiple plungers in order to deliver the rehydrated reagents into the blisters at the appropriate times. Two Peltier devices control heating and cooling of the pouch to drive the PCR reactions and the melt curve analysis.
Nucleic acid extraction occurs within the FilmArray pouch using mechanical lysis and standard magnetic bead technology. After extracting and purifying nucleic acids from the unprocessed sample, the FilmArray performs a nested multiplex PCR that is exceuted in two stages. During the first stage, the FilmArray performs a single, large volume, highly multiplexed PCR reaction which includes all primers of the outer primer sets. 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 Diagnostics). The solution is then distributed to each well of the array. Array wells contain sets of primers designed specifically to amplify sequences internal to the PCR products generated during the first stage PCR reaction. The 200 stage PCR, or nested PCR, is performed in singleplex fashion in each well of the array. At the conclusion of the 2" 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 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 and antimicrobial resistance gene on the panel.
Here's a breakdown of the acceptance criteria and study information for the FilmArray Blood Culture Identification (BCID) Panel, based on the provided text:
FilmArray Blood Culture Identification (BCID) Panel
1. Table of Acceptance Criteria and Reported Device Performance:
The document doesn't explicitly state quantitative acceptance criteria in a dedicated section. However, the "Clinical Performance" and "Reproducibility" sections present performance metrics (sensitivity, specificity, positive percent agreement, negative percent agreement, and percent agreement with expected results) that act as the de facto acceptance criteria. I'll present the overall clinical performance from Tables 6, 7, 8, 9, and 10 and the overall reproducibility from Tables 59 and 60.
Overall Clinical Performance (Aggregated from Prospective and Seeded Arms)
| Analyte Group | Performance Metric | Value | 95% Confidence Interval |
|---|---|---|---|
| Gram-Positive Organisms (Overall) | |||
| Enterococcus | Sensitivity/PPA | 97.7% | 93.4-99.5% |
| Specificity/NPA | 99.8% | 99.5-99.9% | |
| Listeria monocytogenes | Sensitivity/PPA | 100% | 90.3-100% |
| Specificity/NPA | 100% | 99.8-100% | |
| Staphylococcus | Sensitivity/PPA | 96.5% | 95.0-97.7% |
| Specificity/NPA | 99.1% | 98.5-99.6% | |
| Staphylococcus aureus | Sensitivity/PPA | 98.4% | 96.1-99.6% |
| Specificity/NPA | 99.8% | 99.5-99.9% | |
| Streptococcus | Sensitivity/PPA | 97.5% | 94.3-99.2% |
| Specificity/NPA | 99.8% | 99.4-99.9% | |
| Streptococcus agalactiae | Sensitivity/PPA | 100% | 90.3-100% |
| Specificity/NPA | 100% | 99.8-100% | |
| Streptococcus pneumoniae | Sensitivity/PPA | 97.3% | 85.8-99.9% |
| Specificity/NPA | 99.9% | 99.7-100% | |
| Streptococcus pyogenes | Sensitivity/PPA | 100% | 90.7-100% |
| Specificity/NPA | 99.9% | 99.7-100% | |
| Gram-Negative Organisms (Overall) | |||
| Acinetobacter baumannii | Sensitivity/PPA | 100% | 93.0-100% |
| Specificity/NPA | 99.8% | 99.5-99.9% | |
| Enterobacteriaceae | Sensitivity/PPA | 98.4% | 96.9-99.3% |
| Specificity/NPA | 99.8% | 99.4-99.9% | |
| Enterobacter cloacae complex | Sensitivity/PPA | 97.4% | 86.5-99.9% |
| Specificity/NPA | 99.9% | 99.6-100% | |
| Escherichia coli | Sensitivity/PPA | 98% | 94.4-99.6% |
| Specificity/NPA | 99.8% | 99.4-99.9% | |
| Klebsiella oxytoca | Sensitivity/PPA | 92.2% | 82.7-97.4% |
| Specificity/NPA | 99.9% | 99.7-100% | |
| Klebsiella pneumoniae | Sensitivity/PPA | 97.1% | 91.9-99.4% |
| Specificity/NPA | 99.6% | 99.2-99.8% | |
| Proteus | Sensitivity/PPA | 100% | 91.0-100% |
| Specificity/NPA | 100% | 99.8-100% | |
| Serratia marcescens | Sensitivity/PPA | 98.7% | 93.0-100% |
| Specificity/NPA | 99.9% | 99.7-100% | |
| Haemophilus influenzae | Sensitivity/PPA | 100% | 91.8-100% |
| Specificity/NPA | 100% | 99.8-100% | |
| Neisseria meningitidis | Sensitivity/PPA | 100% | 90.3-100% |
| Specificity/NPA | 100% | 99.8-100% | |
| Pseudomonas aeruginosa | Sensitivity/PPA | 98.1% | 89.7-100% |
| Specificity/NPA | 99.9% | 99.7-100% | |
| Yeast (Overall) | |||
| Candida albicans | Sensitivity/PPA | 100% | 94.4-100% |
| Specificity/NPA | 99.8% | 99.5-99.9% | |
| Candida glabrata | Sensitivity/PPA | 100% | 92.7-100% |
| Specificity/NPA | 99.9% | 99.7-100% | |
| Candida krusei | Sensitivity/PPA | 100% | 90.5-100% |
| Specificity/NPA | 100% | 99.8-100% | |
| Candida parapsilosis | Sensitivity/PPA | 96.7% | 88.7-99.6% |
| Specificity/NPA | 99.9% | 99.7-100% | |
| Candida tropicalis | Sensitivity/PPA | 100% | 91.0-100% |
| Specificity/NPA | 100% | 99.8-100% | |
| Antimicrobial Resistance Genes (PCR/Sequencing Direct from Blood Culture) | |||
| mecA (All Staphylococcus) | Sensitivity/PPA | 98.4% | 96.8-99.3% |
| Specificity/NPA | 98.3% | 96.0-99.4% | |
| vanA/B (Enterococcus) | Sensitivity/PPA | 100% | 94.4-100% |
| Specificity/NPA | 100% | 94.6-100% | |
| KPC (Enterobacteriaceae & others) | Sensitivity/PPA | 100% | 91.0-100% |
| Specificity/NPA | 100% | 99.3-100% | |
| Antimicrobial Resistance Genes (PCR/Sequencing of Cultured Isolates) | |||
| mecA (All Staphylococcus) | Positive Percent Agreement | 98.9% | 97.5-99.6% |
| Negative Percent Agreement | 87.9% | 83.9-91.3% | |
| vanA/B (Enterococcus) | Positive Percent Agreement | 100% | 94.0-100% |
| Negative Percent Agreement | 94.4% | 86.2-98.4% | |
| KPC (Enterobacteriaceae & others) | Positive Percent Agreement | 100% | 91.0-100% |
| Negative Percent Agreement | 100% | 99.3-100% |
Overall Reproducibility (All Sites, Across All Analytes Tested)
| Performance Metric | Value | 95% Confidence Interval |
|---|---|---|
| Organism Assays (% Agreement) | ~100% | (Min: 98.0%, Max: 100%) |
| Antimicrobial Resistance Assays (% Agreement) | ~100% | (Min: 98.0%, Max: 100%) |
2. Sample Sizes and Data Provenance for the Test Set:
- Total Test Set Sample Size: 2207 blood cultures
- Prospective Arm: 1568 specimens
- 67 specimens excluded (e.g., >8 hours past positivity, incomplete reference data, previous specimen from same subject).
- Tested either fresh (821 specimens) or frozen (747 specimens).
- Seeded Arm: 639 specimens
- 77 cultures excluded (e.g., >8 hours past positivity, not positive by automated blood culture, contaminated).
- Tested either fresh (419 specimens) or frozen (220 specimens).
- Prospective Arm: 1568 specimens
- Data Provenance: The study was a "two-armed clinical study" conducted at eight U.S. clinical sites. This indicates the data is prospective for the clinical arm and retrospective/contrived for the seeded arm (as isolates were seeded into blood culture bottles).
3. Number of Experts and Qualifications for Ground Truth - Test Set:
The document does not explicitly state the number of experts used to establish the ground truth for the test set, nor their specific qualifications (e.g., "radiologist with 10 years of experience").
Instead, the ground truth for organism detection was established using "Standard manual and automated microbiological/biochemical identification methods." For Acinetobacter baumannii, this was supplemented with "16S PCR with bi-directional sequencing."
For antimicrobial resistance genes, the ground truth involved "PCR with bi-directional sequencing for specific resistance gene - direct from blood culture" or "PCR with bi-directional sequencing for specific resistance gene from - appropriate cultured isolates." Additionally, "Standard manual and automated phenotypic antimicrobial susceptibility testing of appropriate cultured isolates" was performed for informational purposes.
While these are standard laboratory methods typically performed by trained microbiologists or laboratory technicians, the number and specific qualifications of the experts overseeing or performing these reference methods are not detailed.
4. Adjudication Method for the Test Set:
The document does not explicitly describe an adjudication method (like 2+1 or 3+1) for discrepant results in the test set.
However, the detailed tables of results often include footnotes explaining discrepancies. For instance, for Acinetobacter baumannii, isolates misidentified by phenotypic methods were subjected to 16S PCR and bi-directional sequencing for definitive characterization. Similarly, for other organisms and resistance genes, bidirectional sequencing was used to investigate false positive and false negative results. This implies an investigative process to reconcile differences, rather than a formal, predefined expert adjudication panel for every case.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:
A Multi-Reader Multi-Case (MRMC) comparative effectiveness study was NOT done for this device. The study evaluated the standalone performance of the FilmArray BCID Panel against reference laboratory methods, not its impact on human reader performance or diagnostic accuracy with AI assistance.
6. Standalone Performance Study:
Yes, a standalone study was performed. The entire "Clinical Performance" section (Tables 6-10) reports the performance of the FilmArray BCID Panel as a standalone diagnostic device. The results (sensitivity, specificity, PPA, NPA) are presented for the algorithm/device only, without human-in-the-loop interaction, compared against established laboratory reference methods. The "Reproducibility" section also evaluates the device's technical consistency in a standalone capacity.
7. Type of Ground Truth Used:
The ground truth primarily used was:
- Expert Consensus/Reference Laboratory Methods:
- Standard manual and automated microbiological/biochemical identification methods for all organism detections.
- 16S PCR with bi-directional sequencing for A. baumannii speciation.
- PCR with bi-directional sequencing for antimicrobial resistance gene detection (from blood culture or cultured isolates).
- Pathology: Not explicitly mentioned as a primary ground truth for organism identification in this context, which focuses on molecular/microbial identification.
- Outcomes Data: Not used as ground truth for diagnostic accuracy in this study.
8. Sample Size for the Training Set:
The document does not explicitly specify a sample size for a "training set." The studies primarily focus on clinical validation (prospective and seeded arms) and analytical validation (inclusivity, exclusivity, reproducibility). While the device's algorithm undoubtedly relies on an underlying model, information regarding its specific training data and size is not provided in this regulatory submission summary. The inclusivity studies involve testing a "diverse collection of 303 isolates," which could be considered part of the data informing the assay's design and optimization, but it's not explicitly labeled as a "training set" in the context of a machine learning model.
9. How the Ground Truth for the Training Set Was Established:
As the document does not explicitly identify a "training set" in the context of a machine learning model with corresponding ground truth establishment, this information is not provided. The inclusivity and exclusivity studies, which evaluate the assay's breadth and specificity, likely contribute to the "training" or development of the assay's detection capabilities. The ground truth for these analytical studies was established by known characteristics of the isolates (e.g., ATCC strains, clinical isolates with confirmed identity), and confirmed through standard microbiological identification and sequencing methods.
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