(29 days)
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.
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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.
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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.
§ 866.3365 Multiplex nucleic acid assay for identification of microorganisms and resistance markers from positive blood cultures.
(a)
Identification. A multiplex nucleic acid assay for identification of microorganisms and resistance markers from positive blood cultures is a qualitative in vitro device intended to simultaneously detect and identify microorganism nucleic acids from blood cultures that test positive by Gram stain or other microbiological stains. The device detects specific nucleic acid sequences for microorganism identification as well as for antimicrobial resistance. This device aids in the diagnosis of bloodstream infections when used in conjunction with other clinical and laboratory findings. However, the device does not replace traditional methods for culture and susceptibility testing.(b)
Classification. Class II (special controls). The special control for this device is FDA's guideline document entitled “Class II Special Controls Guideline: Multiplex Nucleic Acid Assay for Identification of Microorganisms and Resistance Markers from Positive Blood Cultures.” For availability of the guideline document, see § 866.1(e).