(14 days)
The BIOFIRE Blood Culture Identification 2 (BCID2) Panel is a multiplexed nucleic acid test intended for use with BIOFIRE FILMARRAY 2.0 or BIOFIRE FILMARRAY TORCH Systems for the simultaneous qualitative detection and identification of multiple bacterial and yeast nucleic acids and select genetic determinants associated with antimicrobial resistance. The BIOFIRE BCID2 Panel test 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 organism types and subtypes are identified using the BIOFIRE BCID2 Panel: Gram Positive Bacteria Enterococcus faecalis Staphylococcus spp. Streptococcus spp. Enterococcus faecium Staphylococcus aureus Streptococcus agalactiae (Group B) Listeria monocytogenes Staphylococcus epidermidis Streptococcus pneumoniae Staphylococcus lugdunensis Streptococcus pyogenes (Group A) Gram Negative Bacteria Acinetobacter calcoaceticus-baumannii complex Enterobacterales Bacteroides fragilis Enterobacter cloacae complex Haemophilus influenzae Escherichia coli Neisseria meningitidis (encapsulated) Klebsiella aerogenes Pseudomonas aeruginosa Klebsiella oxytoca Stenotrophomonas maltophilia Klebsiella pneumoniae group Proteus spp. Salmonella spp. Serratia marcescens Yeast Candida albicans Candida krusei Cryptococcus neoformans/gattii Candida auris Candida parapsilosis Candida glabrata Candida tropicalis The BIOFIRE BCID2 Panel contains assays for the detection of genetic determinants associated with resistance to methicillin (mecA/C and mecA/C in conjunction with MREJ, vancomycin (vanA and vanB), ß-lactams including penicillins, cephalosporins, monobactams, and carbapenems (blaCTX-M, blaIMP, blaKPC, blaNDM, blaOXA48-like, blaVIM) to aid in the identification of potentially antimicrobial-resistant organisms in positive blood culture samples. In addition, the panel includes an assay for the mobilized genetic determinant mor-1, an emerging marker of public health importance. The antimicrobial resistance gene or may not be associated with the agent responsible for disease. Negative results for these select antimicrobial resistance gene and marker assays do not indicate susceptibility, as multiple mechanisms of resistance to methicillin, vancomycin, b-lactams, and colistin exist. Antimicrobial Resistance Genes CTX-M KPC mecA/C NDM vanA/B IMP mcr-1 mecA/C and MREJ (MRSA) OXA-48-like VIM The BIOFIRE BCID2 Panel is indicated as an aid in the diagnosis of bloodstream infection and results should be used in conjunction with other clinical and laboratory findings. Positive results do not rule out co-infection with organisms not included in the BIOFIRE BCID2 Panel. The BIOFIRE BCID2 Panel is not intended to monitor treatment for bloodstream infection. 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 BIOFIRE BCID2 Panel, and for determination of species detected but not identified within complexes, groups, or genera by the BIOFIRE BCID2 Panel assays.
The BIOFIRE Blood Culture Identification 2 (BCID2) Panel is designed to simultaneously identify 43 bacteria and yeast responsible for bloodstream infections, as well as select genetic determinants of antimicrobial resistance (see Table 1), in a timeframe (about an hour) that allows the test results to be used in determining appropriate patient treatment and management. The BIOFIRE BCID2 Panel is performed directly on positive blood culture samples. The BIOFIRE BCID2 Panel is compatible with BioFire's PCR-based in vitro diagnostic BIOFIRE FILMARRAY 2.0 and FILMARRAY TORCH systems for infectious disease testing. A specific software module (i.e., BIOFIRE BCID2 Panel pouch module) is used to perform BIOFIRE BCID2 Panel testing on these systems. A test is initiated by loading Hydration Solution into one port of the BIOFIRE pouch and positive blood culture specimen mixed with the provided Sample Buffer into the other port of the BIOFIRE BCID2 Panel pouch and placing it in a BIOFIRE System. The pouch contains all 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 BIOFIRE Software guides the user though the steps of placing the 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 (rt-PCR) reaction. The products from first stage PCR are then diluted 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 2nd stage PCR, or nested PCR, is performed in single plex fashion in each well of the array. At 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.
Here's a breakdown of the acceptance criteria and the study information based on the provided FDA 510(k) summary for the BioFire Blood Culture Identification 2 (BCID2) Panel:
1. Table of Acceptance Criteria and Reported Device Performance:
The document primarily focuses on a software update to mitigate a risk of false negative results for C. tropicalis specifically. It states that the re-analysis with the modified software led to a "very minor adjustment to clinical sensitivity for S. epidermidis from 96.5% [93.0-98.2%] to 96.9%".
The summary does not provide a comprehensive table of acceptance criteria and the overall device performance for all targets. Instead, it highlights the impact of the software update on C. tropicalis detection and the resulting minor change in S. epidermidis sensitivity.
Acceptance Criteria (Implied / Pre-established for Original Device):
While not explicitly stated as "acceptance criteria" in this specific document, the overall context of a 510(k) clearance implies that the device must demonstrate comparable performance to its predicate. The key focus of this Special 510(k) is to show that the software update does not adversely affect, and in fact, improves, the device's performance, particularly concerning the false negative C. tropicalis issue. The acceptance criterion for this update seems to be that the corrected software resolves the C. tropicalis issue and does not significantly degrade performance on other targets.
| Target Organism / Metric | Pre-update Reported Performance (where available) | Post-update Reported Performance (where available) | Implied Acceptance Criteria (for the update) |
|---|---|---|---|
| C. tropicalis detection | Intermittent false negatives with control M416 | Resolved (no false negatives with control M416) | Elimination of intermittent false negatives for C. tropicalis with external control M416. |
| S. epidermidis sensitivity | 96.5% [93.0-98.2%] | 96.9% | Maintain or slightly improve sensitivity, without degradation. |
| Overall clinical performance | Cleared in K193519 (predicate) | No overall change in study conclusions or claims | Performance remains "as well as the predicate device." |
2. Sample Size Used for the Test Set and Data Provenance:
- Test Set Sample Size: The document refers to "reanalysis of the performance data (clinical and non-clinical studies) with the modified pouch module software." It explicitly mentions that the C. tropicalis issue was identified during testing of Maine Molecular Quality Controls, Inc. (MMQC) FilmArray BCID2 Control Panel M416. While the specific number of tests performed on this control or other test sets with the modified software is not given in this summary, the "reanalysis of the performance data" implies that the original clinical and non-clinical study data from the predicate device (K193519) was re-evaluated using the new software.
- Data Provenance: The issue was identified through testing with an external control material (C. tropicalis synthetic control material). The "reanalysis of the performance data (clinical and non-clinical studies)" implies that data from the original (K193519) approval was used, which would have primarily involved prospective clinical samples from various geographic locations. However, this specific document does not detail the provenance of the original clinical data. The new data generated to address the C. tropicalis issue was from synthetic control material.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and the Qualifications of Those Experts:
- This information is not provided in the given FDA summary. The document focuses on a software update to an already cleared device, addressing a technical issue related to melting temperature analysis. The ground truth for the original clinical studies would have been established through a combination of clinical methods (e.g., standard microbiological culture and identification, susceptibility testing), but those details are not part of this specific Special 510(k) summary.
4. Adjudication Method for the Test Set:
- This information is not provided in the given FDA summary. For the original clinical studies related to the predicate device, an adjudication method (e.g., expert panel review of discrepancies) would likely have been employed, but this specific document does not detail it.
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:
- This is not applicable. The device (BIOFIRE Blood Culture Identification 2 Panel) is a fully automated multiplex nucleic acid test. It does not involve human readers interpreting results in the same way an imaging AI device would. Therefore, an MRMC study with human readers and AI assistance is not relevant to this device.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done:
- Yes. The BIOFIRE BCID2 Panel operates as a standalone diagnostic system. The "pouch module software" automatically interprets the melt curve analysis and combines data with internal controls to generate a test result. 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." There is no "human-in-the-loop" performance component for result generation, although clinical interpretation of results in conjunction with Gram stain and other findings is required.
7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.):
- For the specific issue addressed in this Special 510(k) regarding C. tropicalis, the ground truth was known composition of synthetic control material.
- For the broader re-analysis of "clinical and non-clinical studies" (referring to the original predicate data), the ground truth for microbial identification in blood cultures typically involves standard microbiological culture (subculturing) and definitive identification methods (e.g., biochemical tests, mass spectrometry, sequencing), often supplemented by clinical context. The document emphasizes that "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 BIOFIRE BCID2 Panel, and for determination of species detected but not identified within complexes, groups, or genera by the BIOFIRE BCID2 Panel assays," highlighting the role of traditional microbiology as a gold standard.
8. The Sample Size for the Training Set:
- This information is not provided in the given FDA summary, as the nature of this submission is a software update to an existing device, not a de novo algorithm development. The "pouch module software" utilizes pre-defined melting temperature (Tm) ranges and analysis parameters. The "reanalysis to include data generated from synthetic control materials" effectively served to refine or "retrain" specific parameters (Tm ranges) within the existing analytical framework, but the original training set size for the entire panel's algorithm is not detailed here.
9. How the Ground Truth for the Training Set Was Established:
- This information is not provided in the given FDA summary. For the original development of the BIOFIRE BCID2 Panel, the ground truth for establishing the algorithms' detection parameters and Tm ranges would have been based on extensive analytical studies using well-characterized microbial isolates (strains with confirmed identities) at various concentrations, likely identified by definitive culture-based methods and sequencing. The update specifically states that "Data from the synthetic control material(s) had not been included in the establishment and validation of the assay Tm ranges used for analysis by the pouch module software," indicating that the "training" for the C. tropicalis Tm range was incomplete previously and was corrected by incorporating this synthetic control material data.
§ 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).