FDA 510(k) Search - By Innolitics (SaMD and AI Experts)

The DxFLEX Flow Cytometer is intended for use as an in vitro diagnostic device for immunophenotyping using up to ten fluorescent detection channels using three lasers (488 nm, 638 nm and 405 nm) and two light scatter detection channels. It is intended for use with in vitro diagnostic (IVD) assays and software that are indicated for use with the instrument.

The ClearLab 10C Panels are intended for in vitro diagnostic use for qualitative identification of cell populations by multiparameter immunophenotyping on the Navios, Navios EX and DxFLEX flow cytometers. These reagents are used as an aid in the differential diagnosis of hematologically abnormal patients having, or suspected of having, the following hematopoietic neoplasms: chronic leukemia, acute leukemia, non-Hodgkin lymphoma, myelodysplastic syndrome (MDS), and/or myeloproliferative neoplasms (MPN). The reagents can be used with peripheral whole blood (collected in K2EDTA, Acid Citrate Dextrose (ACD) or Heparin), bone marrow (collected in K2EDTA, ACD or Heparin) and lymph node specimens. Interpretation of the results should be confirmed by a pathologist or equivalent professional in conjunction with other clinical and laboratory findings.

These reagents provide multiparameter, qualitative results for the surface antigens listed below:

ClearLLab 10C B Cell Tube: Kappa, Lambda, CD10, CD5, CD200, CD34, CD38, CD20, CD19, CD45
ClearLLab 10C T Cell Tube: TCRy6, CD4, CD2, CD56, CD5, CD34, CD3, CD8, CD7, CD45
ClearLLab 10C M1 Cell Tube: CD16, CD7, CD10, CD13, CD64, CD34, CD14, HLA-DR, CD11b, CD45
ClearLLab 10C M2 Cell Tube: CD15, CD123, CD117, CD13, CD33, CD34, CD38, HLA-DR, CD19, CD45

Device Description

The ClearLLab 10C Reagent System is currently cleared on the Navios EX Flow cytometer under K183592. Beckman Coulter has developed the DxFLEX Flow Cytometer, a next generation flow cytometer that offers enhanced performance in terms of optics and electronics, as well as more convenient installation and operation. The indications for use of the ClearLLab 10C Reagent System will be expanded to include its use on the DxFLEX Flow Cytometer. Furthermore, the indications for use will be clearly stated on labeling. The intended use of the ClearLLab 10C Reagent System will not be modified.

ClearLLab 10C Reagent System components that are included with use on the DxFLEX Flow Cytometer:

DxFLEX Flow Cytometer [3 laser/10 color configuration] [New]
DxFLEX Daily OC Fluorospheres [New]
ClearLLab 10C Panels [B, T, M1 and M2] [Modification to Existing]
ClearLLab Compensation Kit [Modification to Existing]
ClearLLab Compensation Beads [Modification to Existing]
ClearLLab Control Cells, normal and abnormal [Modification to Existing]
Kaluza C data analysis software [Existing]
IOTest 3 Fixative Solution [Existing]
IOTest 3 Lysing Solution [Existing]

The ClearLLab 10C Reagent System is run on Beckman Coulter's DxFLEX Flow Cytometer (3 Laser/10 Color configuration]. The DxFLEX Flow Cytometer includes the hardware and CytExpert for DxFLEX software. It requires off-line manual sample processing and use of the accompanying lysing reagent. As part of the ClearLLab 10C Reagent System, to allow proper utilization of this applications for the DxFLEX flow cytometers include ten fluorescent detection channels (FL1-FL10) and three laser configurations (blue, red and violet).

As with the workflow on the predicate system, LMD data analysis is performed manually using the Kaluza C Analysis Software. This Analysis Software package is supplied separately from the DxFLEX and must be installed on an independent computer workstation for off-line analysis of listmode files generated on the flow cytometer with the associated reagents and cytometer system software package, including Control Cell QC data and sample data analysis. The CvtExpert for DxFLEX software is NOT be recommended for analysis use with this application (Note that OC data DxFLEX Daily OC Fluorospheres and Compensation products will continue to be analyzed using the on-board instrument software).

Kaluza C Software is a software tool designed to work with *.fcs and *.lmd files generated from flow cytometers. The advantages of using the Kaluza C over the CytExpert for DxFLEX software are listed below:

Powerful processing speed allows fast analysis of listmode data, including real-time updating of gating and compensation
Plot displays are more versatile allowing linear, logarithmic and 'Logicle' (linear/log hybrid) axes as well as configurable scaling and zooming options
Range of compensation options
QC reporting includes Levey-Jennings plots and highlighted pass/fail criteria on results displays

Preset Kaluza C analysis templates for the ClearLLab 10C reagent system will be provided. The total WBC gate is defined in the histogram of SS vs. CD45-KO525-A by the inclusion of all CD45+ events with low, medium and high Side Scatter after the exclusion of the cells that were compromised and/or aggregated. A subsequent histogram defines specific leukocyte subset such as lymphocytes, monocytes, granulocytes. The low SS/bright CD45+ population identifies lymphocytes. Applicable markers are then displayed in subsequent histograms gated on lymphocytes. This process is repeated for mid SS/medium CD45+ populations to identify monocytes and for high SS/medium CD45+ to identify granulocytes.

AI/ML Overview

The provided document describes the ClearLLab 10C Reagent System on the DxFLEX Flow Cytometer and its substantial equivalence to the predicate device, the ClearLLab 10C Reagent System on the Navios EX Flow Cytometer.

Here's an analysis of the acceptance criteria and study data based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly present a single table labeled "Acceptance Criteria" and "Reported Device Performance" side-by-side with specific numerical thresholds for each criterion. Instead, it lists various studies, their objectives, and the "Testing Results" which indicate whether the device met the performance requirements.

However, we can infer the acceptance criteria from the objectives of the studies and the "Testing Results" column. The reported device performance is stated as meeting these requirements.

Study (Criterion)	Objective (Implied Acceptance Criteria)	Reported Device Performance
Laser Performance Characteristics	Verify stability of the laser performance of the DxFLEX Flow Cytometer over time. (Acceptance: Laser performance is stable over time.)	Analysis of the data collected demonstrates that the DxFLEX Flow Cytometer laser performance is stable over time.
Instrument Carryover (Fluorospheres)	To verify carryover of the DxFLEX Daily QC Fluorospheres in specimens on the DxFLEX Flow Cytometer after running the required daily clean. (Acceptance: Meets carryover performance requirements for fluorospheres.)	Analysis of the data collected demonstrates that the DxFLEX Flow Cytometer meets the carryover performance requirements.
Instrument Linearity	Verify fluorescence detection is linear using standard DxFLEX Flow Cytometer settings. (Acceptance: Fluorescence detection is linear.)	Linearity of fluorescence measurements was demonstrated.
Carryover - Specimen and Reagent	To verify carryover of specimen and reagents on the DxFLEX Flow Cytometer meets performance specifications. (Acceptance: Meets carryover performance requirements for specimens and reagents.)	Analysis of the data collected demonstrates that the DxFLEX Flow Cytometer meets carryover performance requirements.
Detection Capability	To verify that the ClearLLab 10C Reagent System on the DxFLEX Flow Cytometer meet the performance requirements for the ability to differentiate between abnormal and normal populations. (Acceptance: Meets performance requirements for differentiating abnormal and normal populations.)	Analysis of the data collected demonstrates that the ClearLLab 10C Reagent System on the DxFLEX Flow Cytometer meet the performance requirements for Detection Capability.
Precision - Control Material	Demonstrate system imprecision using control material as a surrogate for a stabilized sample. (Acceptance: Meets performance requirements for repeatability and reproducibility with control material.)	Analysis of the data collected demonstrates that the ClearLLab 10C Reagent System on the DxFLEX Flow Cytometer meets performance requirements for repeatability and reproducibility.
Precision - Multi-Site with Clinical Specimens	Demonstrate assay repeatability and reproducibility using both normal and clinical specimens. (Acceptance: Meets performance requirements for repeatability and reproducibility with normal and clinical specimens.)	Analysis of the data collected demonstrates that the ClearLLab 10C Reagent System on the DxFLEX Flow Cytometer meets performance requirements for repeatability and reproducibility.
Precision - Operator and Instrument Variability	Demonstrate system imprecision performance of the ClearLLab 10C Reagent System on the DxFLEX Flow Cytometer using the same specimen prepared by three (3) operators, twice a day, on two (2) DxFLEX Flow Cytometers. (Acceptance: Acceptable precision performance and met acceptance criteria across operators and instruments.)	The ClearLLab 10C Reagent System, when run on each specimen type by different operators on different DxFLEX Flow Cytometers, demonstrated acceptable precision performance and met acceptance criteria.
Clinical Accuracy	Demonstrate the performance equivalency between ClearLLab 10C Reagent System on DxFLEX cytometers (Test Method) and Navios EX flow cytometers (Predicate Method) by a multi-site evaluation of the qualitative immunophenotype agreement between the two systems using specimens from donors in the intended use population. (Acceptance: Able to identify the abnormal population when compared to the predicate.)	Analysis of the data collected demonstrates that the ClearLLab 10C panels are able identify the abnormal population when compared to the predicate.
DxFLEX Daily QC Fluorospheres Analyte Value Assignment	Define DxFLEX Daily QC Fluorospheres Target Value ranges for use with the ClearLLab 10C Reagent System and define a process for ranges transfer from one lot of DxFLEX Daily QC Fluorospheres. (Acceptance: Appropriate target value ranges are defined, and a process for range transfer is in place.)	Analysis of the data collected demonstrates that appropriate DxFLEX Daily QC Fluorospheres Target Value ranges are defined for use with the ClearLLab 10C Reagent System and that a process for range transfer from one lot of DxFLEX Daily QC Fluorospheres to another one is in place.

Additional Requested Information:

2. Sample sized used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)
- Sample Size: The document doesn't explicitly state the specific sample sizes for all test sets. For "Precision - Operator and Instrument Variability," it mentions "the same specimen prepared by three (3) operators, twice a day, on two (2) DxFLEX Flow Cytometers." For "Clinical Accuracy," it mentions "specimens from donors in the intended use population" evaluated in a "multi-site evaluation."
- Data Provenance: The document does not specify the country of origin of the data. The "Clinical Accuracy" study states it used "specimens from donors in the intended use population," implying clinical samples. It does not state if the studies were retrospective or prospective, though "Multi-Site with Clinical Specimens" and "Clinical Accuracy" studies usually imply prospective collection for validation.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)
- The document states for the "Indications for Use" of the ClearLLab 10C Panels: "Interpretation of the results should be confirmed by a pathologist or equivalent professional in conjunction with other clinical and laboratory findings."
- However, regarding the studies themselves, and specifically for establishing the ground truth for the test set used in the evaluations (e.g., in the Clinical Accuracy study), the document does not specify the number of experts, their qualifications, or their role in establishing ground truth. The "Clinical Accuracy" study compared the DxFLEX system to the predicate Navios EX, implying the predicate's results served as a comparative reference rather than an independent expert ground truth being explicitly defined for the DxFLEX data.
4. Adjudication method (e.g. 2+1, 3+1, none) for the test set
- The document does not describe any adjudication method used for the test set.
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 device is a flow cytometer and reagent system, not an AI-assisted diagnostic tool. Therefore, an MRMC comparative effectiveness study involving human readers and AI assistance is not applicable and was not performed or mentioned in this document. The "Clinical Accuracy" study compared the new device to a predicate device, which is a different type of comparative study.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
- The device described is an in vitro diagnostic device (flow cytometer and reagents) that generates qualitative data for immunophenotyping. The data analysis uses "Kaluza C data analysis software," but the "Interpretation of the results should be confirmed by a pathologist or equivalent professional." This indicates it is not a standalone algorithm in the sense of providing a final diagnosis without human interpretation. Performance studies were largely focused on the instrument and reagent's analytical capabilities, not a standalone diagnostic algorithm.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)
- For the "Clinical Accuracy" study, the ground truth was essentially implied by comparison to the predicate device (Navios EX flow cytometer). The study aimed to demonstrate "performance equivalency" and "qualitative immunophenotype agreement" between the DxFLEX system and the cleared Navios EX system. While pathologists confirm interpretations, the studies described herein validate the device's performance against established methods, rather than generating a de novo ground truth from pathology and outcomes for every case.
8. The sample size for the training set
- The document does not mention a training set or its sample size. This type of submission (for a flow cytometer and reagent system) typically focuses on analytical and clinical validation studies, rather than machine learning model training.
9. How the ground truth for the training set was established
- As no training set is mentioned, information on how its ground truth was established is not provided.

Summary

Regulation Number and Section

§ 864.5220 Automated differential cell counter.

(a)
Identification. An automated differential cell counter is a device used to identify one or more of the formed elements of the blood. The device may also have the capability to flag, count, or classify immature or abnormal hematopoietic cells of the blood, bone marrow, or other body fluids. These devices may combine an electronic particle counting method, optical method, or a flow cytometric method utilizing monoclonal CD (cluster designation) markers. The device includes accessory CD markers.(b)
Classification. Class II (special controls). The special control for this device is the FDA document entitled “Class II Special Controls Guidance Document: Premarket Notifications for Automated Differential Cell Counters for Immature or Abnormal Blood Cells; Final Guidance for Industry and FDA.”