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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

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.

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.

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.

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The ClearLLab 10C Panels are intended for in vitro diagnostic use for qualitative identification of cell populations by multiparameter immunophenotyping on the Navios EX 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, non-Hodgkin lymphoma, myeloma, myeloma, 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: TCRy8, 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, CD34, CD38, HLA-DR, CD19, CD45

The Navios 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, 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 Navios EX 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, and 405 mm) 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 new ClearLLab 10C reagent system is comprised of various components and is described below. Figures 2 and 3 illustrate the anticipated workflow from instrument setup through data analysis with a breakout of the standardization and Quality Control sequence for the new reagent system. As the figures show, the process is in-line with standard flow cytometry protocol.

• Four ClearLLab 10C Panels [B, T, M1 and M2]
• Navios and Navios EX flow cytometers [3 laser/10 color configurations]
• ClearLLab Compensation Kit
• ClearLLab Compensation Beads
• ClearLLab Control Cells, normal and abnormal
• Kaluza C data analysis software
• Flow-Check Pro Fluorospheres
• Flow-Set Pro Fluorospheres
• IOTest 3 Fixative Solution
• IOTest 3 Lysing Solution

The ClearLLab 10C reagent system is run on Beckman Coulter's Navios or Navios EX flow cytometer (3 Laser/10 Color configurations). 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 application, the indications for the Navios and Navios EX flow cytometers include all ten fluorescent detection channels and three laser configurations (blue, red and violet).

LMD data analysis is performed manually using the Kaluza C Analysis Software. This Analysis Software package is supplied separately from the Navios EX system softwares 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 OC data and sample data analysis. The Navios and Navios EX analysis software are NOT be recommended for use with this application (Note that QC data from Flow-Set Pro, Flow-Check Pro, 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 *.Imd files generated from flow cytometers.

Preset Kaluza C analysis templates for the ClearLLab 10c reagent system are provided.

The provided text describes the ClearLLab 10C Panels and associated Navios and Navios EX Flow Cytometers. Here's a breakdown of the acceptance criteria and study information:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly present a single table delineating acceptance criteria and reported device performance for each metric. Instead, it lists various studies performed, their objectives, and their results, which implicitly demonstrate an acceptance of performance. The "Testing Results" column in the tables effectively serves as the "Reported Device Performance," and the objective of each study implies the acceptance criteria (i.e., demonstrating stability, linearity, equivalency, specificity, etc.).

Below is a summary derived from the "Testing Results" section (pages 18-19):

ClearLLab 10C Panels, Navios and Navios EX Flow Cytometers Acceptance Criteria and Performance Summary

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

• Sample Size for Test Set: The document does not specify a distinct "test set" sample size for all studies. However, for the "Precision - Multi-Site with Clinical Specimens" and "Precision - Operator and Instrument Variability" studies, typical clinical specimens (both normal and abnormal) were used. The specific number of specimens for each study is not explicitly stated in the provided text.
• Data Provenance: The document does not explicitly state the country of origin. The "Clinical Accuracy" study mentions "the site's clinical diagnosis," indicating that the data likely came from clinical sites where the study was conducted. The studies appear to be prospective in nature, as they involve actively verifying performance, stability, and equivalency.

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

• For the "Clinical Accuracy" study, the comparison was made against "the site's clinical diagnosis of malignant or non-malignant outcome from the current standard of care." The interpretation of results for the device itself is stated to "be confirmed by a pathologist or equivalent professional in conjunction with other clinical and laboratory findings" (page 2). This indicates that pathologists or equivalent professionals establish the ground truth for clinical cases. The number of such experts is not specified.

4. Adjudication Method for the Test Set

• The document implies that the ground truth for "Clinical Accuracy" is established by "the site's clinical diagnosis...from the current standard of care" and confirmed by a "pathologist or equivalent professional." However, it does not explicitly describe an adjudication method (such as 2+1, 3+1, or none) for resolving discrepancies among multiple expert opinions on a specific case.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

• The provided text does not describe a multi-reader, multi-case (MRMC) comparative effectiveness study involving human readers with and without AI assistance (which is not relevant for this device as it's a diagnostic reagent and flow cytometer system, not an AI interpretative software for human review).

6. Standalone Performance Study

• The studies described, particularly those evaluating laser performance, instrument linearity, carryover, and reagent characteristics, are inherently standalone (algorithm/system only) performance studies. The system is evaluated on its ability to accurately detect and characterize cell populations. The "Clinical Accuracy" study also assesses the device's ability to identify abnormal populations against clinical outcomes, which is a standalone evaluation of its diagnostic capability.

7. Type of Ground Truth Used

• For various analytical studies (e.g., linearity, carryover, precision), the ground truth is established by reference standards, control materials, and comparative methods (e.g., predicate devices).
• For the "Clinical Accuracy" study, the ground truth is based on clinical diagnosis of malignant or non-malignant outcome from the current standard of care, confirmed by pathologist or equivalent professional consensus in conjunction with other clinical and laboratory findings.

8. Sample Size for the Training Set

• The document does not explicitly mention a "training set" as the devices described are diagnostic reagents and flow cytometers, not AI models that require specific training data in the context of machine learning. The studies listed are for performance verification and validation.

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

• As there is no explicit mention of a "training set" in the context of an AI/machine learning model, this information is not applicable and is not provided in the document.

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The ClearLLab reagents are intended for in vitro diagnostic use as a panel for qualitative identification of cell populations by multiparameter immunophenotyping on an FC 500 flow cytometer. 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, myeloma, myelodysplastic syndrome (MDS), and/or myeloproliferative neoplasms (MPN). The reagents can be used with peripheral whole blood collected in EDTA (K2 and K3EDTA), Acid Citrate Dextrose 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 Cluster of Differentiation (CD) parameters listed below:

• ClearLLab T1: CD2, CD56, CD7, CD5, CD7, CD5, CD45
• ClearLLab T2: CD8, CD4, CD3, CD45
• ClearLLab B1: Kappa, Lambda, CD19, CD5, CD45
• ClearLLab B2: CD20, CD10, CD10, CD19, CD38, CD45
• ClearLLab M: CD7, CD13, CD34, CD33, CD45

The Clear LLab Reagents panel is used with the following reagents with their respective indicated uses. A description of the reagents provided is described below in Table 1.

The ClearLLab Reagents are intended for in vitro diagnostic use as a panel for qualitative identification of cell populations by multiparameter immunophenotyping on an FC 500 flow cytometer. These reagents are used as an aid in the differential diagnosis of hematologically abnormal patients having, or suspected of having hematopoietic neoplasms.

1. A table of acceptance criteria and the reported device performance:

2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective):

• Test Set Sample Size: A total of 279 abnormal hematologic specimens were enrolled in the clinical performance study.
  • 137 hematologically abnormal but no malignancy.
  • 142 with hematolymphoid malignancy (23 Acute Leukemia, 36 Chronic Leukemia, 62 Lymphoma, 8 Plasma Cell Neoplasm, 13 Others: MDS/MPN).
  • An additional analysis was performed on 160 whole blood specimens (78 hematologically abnormal with no malignancy and 82 with hematolymphoid malignancy) from this larger set.
• Data Provenance: The study was a multi-center, retrospective study conducted at four sites. While the document does not explicitly state the country of origin, the reference to "WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues" suggests an international context for clinical guidelines, but the specific locations of the four sites are not detailed.

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):

• Number of Experts: Two qualified flow experts evaluated the ClearLLab flow cytometry results.
• Qualifications of Experts: The document states "Two qualified flow experts evaluated the ClearLLab flow cytometry results independently of each other..." However, specific details on their years of experience or exact professional titles (e.g., "radiologist with 10 years of experience") are not provided. It does state that "The device labeling states that interpretation of specimens should be performed by a pathologist or equivalent professional who has the appropriate training." This implies the experts would hold such qualifications.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set:

• Adjudication Method: The two flow experts evaluated the ClearLLab results independently of each other and were blinded to the final diagnosis. There is no mention of an adjudication method like 2+1 or 3+1 to resolve discrepancies between the two experts' interpretations of the ClearLLab device output. However, the expert interpretations of the ClearLLab results were then compared against the clinical outcome ("malignant" or "non-malignant") established by the clinical sites' final patient diagnosis.

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 study did not appear to be an MRMC comparative effectiveness study in the context of human readers improving "with AI vs without AI assistance." The ClearLLab Reagents are a device for qualitative identification of cell populations using flow cytometry for aid in diagnosis. The study focused on the performance of these reagents (a diagnostic tool), interpreted by human experts, against clinical diagnosis. There is no mention of AI assistance in the interpretation of the device results or a comparison of human reader performance with and without such assistance.

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

• No, a standalone (algorithm only) performance was not done. The ClearLLab Reagents are a diagnostic tool that produces flow cytometry data. The interpretation of this data by human "flow experts" was an integral part of the clinical performance study. The device's output itself isn't a definitive diagnosis but an aid, requiring expert interpretation.

7. The type of ground truth used (expert concensus, pathology, outcomes data, etc):

• The ground truth used was the clinical outcome of "malignant" or "non-malignant" based on the clinical sites' final patient diagnosis. This diagnosis was established by a pathologist or equivalent professional in conjunction with other clinical and laboratory findings, adhering to WHO guidelines. This can be categorized as a form of outcomes data or established clinical diagnosis, rather than simply expert consensus on the device's output.

8. The sample size for the training set:

• The document focuses on the performance of the ClearLLab Reagents and associated interpretive processes. There is no mention of a "training set" in the context of an algorithm or AI model development, as this device submission is for reagents and their clinical performance when interpreted by human experts, not an AI diagnostic algorithm.

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

• As there is no mention of a "training set" for an algorithm or AI model in this document, the method for establishing its ground truth is not applicable or described.

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