X100 with Full Field Bone Marrow Aspirate (BMA) Application 2 X100HT with Full Field Bone Marrow Aspirate (BMA) Application

• K Number: DEN230034
• Device Name: X100 with Full Field Bone Marrow Aspirate (BMA) Application 2 X100HT with Full Field Bone Marrow Aspirate (BMA) Application
• Manufacturer: Scopio Labs Ltd.
• Date Cleared: 2024-03-22 ( 329 days)
• Product Code: SAL
• Regulation Number: 864.5261

Intended Use

The X100 with the Full Field Bone Marrow Aspirate (BMA) Application is an automated cell locating device, intended for in vitro use only. The Full Field BMA application automatically locates and presents images of hematopoietic cells to trained operators for visual evaluation of Romanowsky stained bone marrow aspirate (BMA) smears. The Full Field BMA application assists trained operators to perform bone marrow smear quality assessment, blast cell, plasma cell, and M:E ratio estimation. A qualified operator must review, confirm or modify classification of each cell according to type, and verify results before finalizing and releasing the report. The X100 with the Full Field Bone Marrow Aspirate (BMA) application presents images of Prussian Blue stained BMA smear. X100HT with Full Field BMA Application: The X100HT with the Full Field Bone Marrow Aspirate (Full Field BMA) Application is an automated cell locating device. intended for in vitro use only. The Full Field BMA application automatically locates and presents images of hematopoietic cells to trained operators for visual evaluation of Romanowsky stained bone marrow aspirate (BMA) smears. The Full Field BMA application assists trained operators to perform bone marrow smear quality assessment, blast cell, plasma cell, and M:E ratio estimation. A qualified operator must review, confirm or modify classification of each cell according to type, and verify results before finalizing and releasing the report. The X100HT with the Full Field Bone Marrow Aspirate (BMA) application presents images of Prussian Blue stained BMA smear.

Device Description

The X100 and X100HT instruments include a digital scanner and processing unit (computer) capable of acquiring high-resolution digital images from Romanowsky or Prussian Blue stained BMA slides with software application (Full Field Bone Marrow Aspirate (BMA) Application) for evaluation of acquired images. The X100 allows for three slides while X100HT comes with an additional component, a slide loader, a mechanical loading mechanism that holds up to 30 slides in three 10-slide cassettes and performs cover slipping and slide loading into the X100 scanner. The Full Field BMA application contains two scan modes - Romanowsky stain and Prussian Blue stain.

Predicate Devices

Not Found

Reference Devices

Not Found

AI/ML (Artificial Intelligence / Machine Learning)

No
The summary describes an "automated cell locating device" that "automatically locates and presents images" and "assists trained operators" in evaluation and estimation. While this involves automation and image processing, there is no mention of AI, ML, or any related terms like deep learning or neural networks. The emphasis is on presenting images for human review and classification, not on the device making autonomous classifications or learning from data.

Therapeutic

No

The device is intended for in vitro use only, specifically to locate and present images of hematopoietic cells for visual evaluation by trained operators to assist in diagnosis, not to provide therapy.

Diagnostic

Yes

Explanation: The device assists in the visual evaluation of bone marrow aspirate smears by locating and presenting images of hematopoietic cells, and helps in quality assessment, blast cell, plasma cell, and M:E ratio estimation. Although "a qualified operator must review, confirm or modify classification of each cell...and verify results before finalizing and releasing the report," the device provides information for diagnostic evaluation.

SaMD (Software as a Medical Device)

No

The device description explicitly states that the X100 and X100HT instruments include a digital scanner and processing unit (computer), and the X100HT includes a slide loader, which are hardware components. The software application runs on this hardware.

IVD (In Vitro Diagnostic)

Yes, this device is an IVD (In Vitro Diagnostic).

Here's why:

• Intended Use: The "Intended Use / Indications for Use" section explicitly states that the device is "intended for in vitro use only." This is a key characteristic of an IVD.
• Sample Type: The device analyzes "bone marrow aspirate (BMA) smears," which are biological specimens taken from the human body.
• Purpose: The device is used to "automatically locates and presents images of hematopoietic cells to trained operators for visual evaluation" and assists in "bone marrow smear quality assessment, blast cell, plasma cell, and M:E ratio estimation." These are diagnostic activities performed on biological samples.
• Clinical Context: The device is intended for use by "trained operators" in a "Clinical laboratory," which is the typical setting for IVD testing.
• Performance Studies: The document describes clinical studies comparing the device's performance to manual microscopy (a reference method) for diagnostic parameters like cell counts and quality assessment. This type of validation is required for IVDs.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

X100 with Full Field BMA Application:

The X100 with the Full Field Bone Marrow Aspirate (BMA) Application is an automated cell locating device, intended for in vitro use only. The Full Field BMA application automatically locates and presents images of hematopoietic cells to trained operators for visual evaluation of Romanowsky stained bone marrow aspirate (BMA) smears. The Full Field BMA application assists trained operators to perform bone marrow smear quality assessment, blast cell, plasma cell, and M:E ratio estimation. A qualified operator must review, confirm or modify classification of each cell according to type, and verify results before finalizing and releasing the report.

The X100 with the Full Field Bone Marrow Aspirate (BMA) application presents images of Prussian Blue stained BMA smear.

X100HT with Full Field BMA Application:

The X100HT with the Full Field Bone Marrow Aspirate (Full Field BMA) Application is an automated cell locating device. intended for in vitro use only. The Full Field BMA application automatically locates and presents images of hematopoietic cells to trained operators for visual evaluation of Romanowsky stained bone marrow aspirate (BMA) smears. The Full Field BMA application assists trained operators to perform bone marrow smear quality assessment, blast cell, plasma cell, and M:E ratio estimation. A qualified operator must review, confirm or modify classification of each cell according to type, and verify results before finalizing and releasing the report.

The X100HT with the Full Field Bone Marrow Aspirate (BMA) application presents images of Prussian Blue stained BMA smear.

Product codes (comma separated list FDA assigned to the subject device)

SAL

Device Description

The X100 and X100HT instruments include a digital scanner and processing unit (computer) capable of acquiring high-resolution digital images from Romanowsky or Prussian Blue stained BMA slides with software application (Full Field Bone Marrow Aspirate (BMA) Application) for evaluation of acquired images. The X100 allows for three slides while X100HT comes with an additional component, a slide loader, a mechanical loading mechanism that holds up to 30 slides in three 10-slide cassettes and performs cover slipping and slide loading into the X100 scanner. The Full Field BMA application contains two scan modes - Romanowsky stain and Prussian Blue stain.

Mentions image processing

Yes

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

High-resolution digital images from Romanowsky or Prussian Blue stained BMA slides.

Anatomical Site

Bone Marrow Aspirate (BMA)

Indicated Patient Age Range

Not Found

Intended User / Care Setting

Trained operators / clinical laboratories

Description of the training set, sample size, data source, and annotation protocol

Not Found

Description of the test set, sample size, data source, and annotation protocol

Precision (Repeatability):

• Sample size: 12 Romanowsky stained slides
• Data source: Randomly selected from clinical groups: residual morphologic hematologic neoplasm (R), morphologic hematologic neoplasm (M), and normal morphology marrow (N).
• Annotation protocol: Samples were tested over 20 days with two runs per day, and two replicate scans for each run. 960 scans were analyzed to evaluate repeatability, between-run, between-day, and within-laboratory precision using the device DSS pre-classified results without operator reclassification.

Precision (Reproducibility):

• Sample size: 9 Romanowsky stained slides
• Data source: Randomly selected from clinical groups: residual morphologic hematologic neoplasm (R), morphologic hematologic neoplasm (M), and normal morphology marrow (N).
• Annotation protocol: Study performed at three sites with three runs per day over five days on four devices (three X100 and one X100HT) by four operators, with three replicate scans for each slide. 540 scans were analyzed to evaluate repeatability, within-laboratory, between-day, between-site, and reproducibility using the DSS pre-classified results without operator reclassification.

Clinical Study (Clinical Sensitivity and Specificity - Comparison to manual microscopy):

• Sample size: 615 Romanowsky stained slides
• Data source: Samples encompassing multiple diseases grouped into five clinical categories. Slides were randomly selected and blinded.
• Annotation protocol: Evaluated by two operators at each of three sites. Operators were qualified to review bone marrow aspirates. Sample slides evaluated by test method and then by reference method (manual microscopy) with a 3-week washout period. DSS suggested results were reviewed and confirmed or reclassified by operators as necessary.

Clinical Study (Comparison of candidate device to de-identified medical data):

• Sample size: Subset of 615 slides
• Data source: De-identified medical records data retrieved from two of the three sites used in the clinical study.
• Annotation protocol: Not explicitly detailed beyond comparison to the de-identified medical data.

Expected Values/Reference Range Validation:

• Sample size: 40 specimens
• Data source: Banked normal morphology BMA smears from U.S. individuals for which BMA has been deemed non-abnormal during routine lab evaluation, collected from two sites. One Romanowsky stained BMA slide was obtained from each individual.
• Annotation protocol: Each sample was reviewed by two investigators (out of four participating). Means of the two differential counts were used in validation of results, which were compared to pre-defined reference intervals.

Further Clinical Sensitivity and Specificity (Manually Classified Parameters):

• Sample size: 795 slides (615 Romanowsky stained, and 180 Prussian Blue stained)
• Data source: Not specified whether new samples or from previous sets, but covers Romanowsky and Prussian Blue stained BMA smears.
• Annotation protocol: Manual microscopy was reference. Slides were randomly selected, blinded, evaluated by two operators at each of three sites. Sample slides evaluated by test method, then reference method with 3-week washout. Images reviewed and cell types classified by operators.

Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)

Precision (Repeatability):

• Study type: Repeatability precision study
• Sample size: 12 Romanowsky stained slides, resulting in 960 scans.
• Key results: Results met pre-defined acceptance criteria for repeatability, between-run, between-day, and within-laboratory precision for Blasts, Plasma Cells, and M:E Ratio (qualitative grading).

Precision (Reproducibility):

• Study type: Reproducibility precision study
• Sample size: 9 Romanowsky stained slides, resulting in 540 scans.
• Key results: Results met predefined acceptance criteria for repeatability, within-laboratory, between-day, between-site, and reproducibility for Blasts, Plasma Cells, and M:E Ratio (qualitative grading).

Clinical Sensitivity and Specificity (Comparison to manual microscopy):

• Study type: Clinical study comparing candidate device to manual microscopy (reference method).
• Sample size: 615 Romanowsky stained slides.
• Key results:
  • Specimen Quality Assessment (Qualitative):
    • Sample Quality (Adequate/Inadequate): Sensitivity 88.72%, Specificity 99.36%, Accuracy 98.21%
    • Stripped Cells (Normal/Increased): Sensitivity 66.67%, Specificity 95.45%, Accuracy 93.99%
  • Specimen Quality Assessment (Semi-Quantitative):
    • Sample quality (Particulate/Pauciparticulate/Aparticulate): Sensitivity 90.86%, Specificity 99.42%, Agreement 97.64%
    • Sample quality (Bloody tap/Diluted BM/Adequate BM): Sensitivity 91.88%, Specificity 99.06%, Agreement 96.25%
  • Count Estimation:
    • Blast Estimation (Normal/Increased): Sensitivity 93.29%, Specificity 87.39%, Accuracy 89.08%
    • Blast Estimation (20%): Sensitivity 91.67%, Specificity 96.34%, Accuracy 95.41%
    • Plasma Cell Estimation (

Regulation Number and Section

N/A

Summary

0

Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). The logo consists of two parts: a symbol on the left and the text "FDA U.S. FOOD & DRUG ADMINISTRATION" on the right. The symbol is a stylized representation of a caduceus, a traditional symbol of medicine. The text is in blue and is arranged in three lines, with "FDA" in a larger font size than the rest of the text.

EVALUATION OF AUTOMATIC CLASS III DESIGNATION FOR X100 with Full Field Bone Marrow Aspirate (BMA) Application X100HT with Full Field Bone Marrow Aspirate (BMA) Application. DECISION SUMMARY

I Background Information:

A De Novo Number

DEN230034

B Applicant

Scopio Labs Ltd.

C Proprietary and Established Names

X100 with Full Field Bone Marrow Aspirate (BMA) Application, X100HT with Full Field Bone Marrow Aspirate (BMA) Application

D Regulatory Information

| Product
Code(s) | Classification | Regulation
Section | Panel |
|--------------------|----------------|-----------------------|------------|
| SAL | II | 864.5261 | Hematology |

II Submission/Device Overview:

A Purpose for Submission:

De Novo request for evaluation of automatic class III designation for X100 with Full Field Bone Marrow Aspirate (BMA) Application and X100HT with Full Field Bone Marrow Aspirate (BMA) Application

B Measurand:

Specimen quality, blast cells, plasma cells, myeloid:erythroid (M:E) ratio

C Type of Test:

Sample quality assessment, blast and plasma cell estimation, and evaluation of myeloid lineage to erythroid lineage ratio estimation

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III Indications for Use:

A Intended Use(s):

See Indications for Use below.

B Indication(s) for Use:

X100 with Full Field BMA Application:

The X100 with the Full Field Bone Marrow Aspirate (BMA) Application is an automated cell locating device, intended for in vitro use only. The Full Field BMA application automatically locates and presents images of hematopoietic cells to trained operators for visual evaluation of Romanowsky stained bone marrow aspirate (BMA) smears. The Full Field BMA application assists trained operators to perform bone marrow smear quality assessment, blast cell, plasma cell, and M:E ratio estimation. A qualified operator must review, confirm or modify classification of each cell according to type, and verify results before finalizing and releasing the report.

The X100 with the Full Field Bone Marrow Aspirate (BMA) application presents images of Prussian Blue stained BMA smear.

X100HT with Full Field BMA Application:

The X100HT with the Full Field Bone Marrow Aspirate (Full Field BMA) Application is an automated cell locating device. intended for in vitro use only. The Full Field BMA application automatically locates and presents images of hematopoietic cells to trained operators for visual evaluation of Romanowsky stained bone marrow aspirate (BMA) smears. The Full Field BMA application assists trained operators to perform bone marrow smear quality assessment, blast cell, plasma cell, and M:E ratio estimation. A qualified operator must review, confirm or modify classification of each cell according to type, and verify results before finalizing and releasing the report.

The X100HT with the Full Field Bone Marrow Aspirate (BMA) application presents images of Prussian Blue stained BMA smear.

C Special Conditions for Use Statement(s):

Rx - For Prescription Use Only

D Special Instrument Requirements:

X100 and X100HT Instruments

IV Device/System Characteristics:

A Device Description:

2

The X100 and X100HT instruments include a digital scanner and processing unit (computer) capable of acquiring high-resolution digital images from Romanowsky or Prussian Blue stained BMA slides with software application (Full Field Bone Marrow Aspirate (BMA) Application) for evaluation of acquired images. The X100 allows for three slides while X100HT comes with an additional component, a slide loader, a mechanical loading mechanism that holds up to 30 slides in three 10-slide cassettes and performs cover slipping and slide loading into the X100 scanner. The Full Field BMA application contains two scan modes - Romanowsky stain and Prussian Blue stain.

B Principle of Operation

The X100 / X100HT Scanner acquires image resolution that is equivalent to a manual microscope high power field magnification (100x). To acquire a high-resolution image, the sample slide is moved by the device's positioning stage under its main optic tube, which has a microscope objective with a tube lens and a high-resolution camera. An illumination system illuminates a light through the sample which is then collected by an optic tube is located on a vertical stage which assures focus throughout the scan. The device captures multiple images of the sample under a plurality of illumination conditions (different durations, illumination angles, illumination patterns, and wavelengths). The software application, Full Field Bone Marrow Aspirate (Full Field BMA) Application, suggests an analysis area, while taking into account the particulates in the area.

For Romanowsky-stained slides, the Full Field BMA Application automatically locates and presents images of hematopoietic cells on BMA smears. The Full Field BMA Application provides a Decision Support System (DSS) to assist in the evaluation of specimen quality, blast cell estimate, plasma cell estimate, and M:E ratio estimation. The DSS highlights a suggested result output for these parameters which a qualified operator would review and confirm before finalizing the report.

Parameter	How the parameter is evaluated	Results output
Specimen quality
Sample quality	Qualitative	Adequate / Inadequate
Particulate / Pauciparticulate / Aparticulate
Adequate bone marrow / Diluted bone marrow (Hemodilute) / Bloody tap (Peripheral blood)
Stripped cells	Qualitative	Normal (50% / Too few to
assess (less than 50 erythroid cells)
Myeloid lineage
Eosinophil estimation	Qualitative	Normal (50% / Too few to
assess (less than 50 myeloid
cells)
Mast cell estimation	Qualitative	Normal (50%
Lymphocytes morphology	Qualitative	Normal / Abnormal
Plasma cell morphology	Qualitative	Normal / Abnormal
Prussian Blue stain smear analysis
Storage iron - Specimen Quality -	Qualitative	Adequate / Inadequate
Storage iron - Iron Stores	Qualitative	Normal / Abnormal
Storage iron - Iron Stores	Qualitative	Decreased / Normal / Increased
Storage iron - Ring sideroblasts	Qualitative	No (15%

4

For Prussian Blue stained slides, the Full Field BMA Application also scans and displays highresolution images acquired from fixed and Prussian blue stained BMA smears. The scan is used by skilled users to provide grading of iron stores and ring sideroblasts based on Prussian Blue staining of the aspirate sample, without DSS suggestions.

The qualified user can either utilize the DSS suggestions or hide the DSS suggestions and work independently, by viewing the digital copy of the patient sample and performing a visual assessment of the various findings, as they would using an analog microscope, while documenting their findings in the digital report format provided by the Full Field BMA

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Application. A qualified operator must review, confirm or modify classification of each cell according to type, and verify results before finalizing and releasing the report.

C Instrument Description Information

• 1. Instrument Name:
     The X100 The X100HT
• 2. Specimen Identification:
     The slide's barcode is captured automatically and assigned to each case. The device also supports typing the barcode manually.
• 3. Specimen Sampling and Handling:
     A BMA smear is prepared within four hours following aspiration according to the protocols and procedures used per laboratory procedure. The slides are stained using Romanowsky or Prussian Blue stains. The BMA smear is covered with a cover slip using a clear mounting medium. The face of the slide should be cleaned in order to remove residues, oil and/or dust.
• 4. Calibration:
     The device is calibrated by a trained technician at the factory on a BMA slide. Re-calibration can also be performed by a certified technician if a problem arises during the daily quality control (QC) testing, which is determined as a calibration issue. The installation calibration tests consist of memory availability assessment, Z calibration to determine the exact height limit of the objective lens to obtain focused image, stage alignment calibration, movement calibration, and vibration testing.

5. Quality Control:

The Full Field BMA software automatically initiates a OC test the first time a case is reviewed, to verify the quality of the sample preparation and the precision of the system. A daily OC is also conducted to verify that the system is working as expected. Both types of QC tests verify that the system's automatic detection process has properly detected the following:

• . The location of the particles by properly placing a bounding box around them.
• Identification of megakaryocytes in the sample, without false detections. .

V Standards/Guidance Documents Referenced:

• . CLSI EP17-A2- Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures: Approved Guideline - Second Edition

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• CLSI EP05-A3- Evaluation of Precision of Quantitative Measurement Procedures; . Approved Guideline - Third Edition
• . CLSI EP12-A2- User Protocol for Evaluation of Qualitative Test Performance; Approved Guideline - Second Edition
• ISO 15223-1 Fourth edition 2021-07: Medical devices Symbols to be used with . information to be supplied by the manufacturer - Part 1: General requirements
• ISO 7000 Sixth edition 2019-07; Graphical symbols for use on equipment Registered . symbols
• . IEC 62366-1 Edition 1.1 2020-06 CONSOLIDATED VERSION Medical devices - Part 1: Application of usability engineering to medical devices
• ISO 14971: 2019; Medical devices Applications of risk management to medical devices .
• . IEC 62304:2006/A1:2016; Medical device software - Software life cycle processes [Including Amendment 1 (2016)]
• . IEC 60601-1-2:2014; 4th Edition: Medical electrical equipment - Part 1-2: General requirements for basic safety and essential performance - Collateral Standard: Electromagnetic disturbances - Requirements and tests
• IEC 62471 First edition 2006-07; Photobiological N/A safety of lamps and lamp systems .
• IEC 61010-1 3rd Ed. dated May 12, 2012 with revision through July 19, 2019; Standard . for Safety for Electrical Equipment For Measurement, Control and Laboratory Use; Part 1: General Requirements, FDA recognition number: 19-41
• . IEC 61010-2-101: 2015, EN 61010-2-101:2017, Safety requirements for electrical equipment for measurement, control and laboratory use. Part 2-101: Particular requirements for in vitro diagnostic (IVD) medical equipment
• . IEC 61010-1:2010/AMD1:2016, EN 61010-1:2010/A1:2019, Safety requirements for electrical equipment for measurement, control, and laboratory use - Part 1: General requirements

Performance Characteristics: VI

A Analytical Performance:

1) Precision

• a) Repeatability: The study was conducted using one instrument (X100) at one site, with 12 Romanowsky stained slides (hereafter referred to as samples) that were randomly selected within the following three clinical groups: residual morphologic hematologic neoplasm (R), morphologic hematologic neoplasm (M), and normal morphology marrow (N). Samples were tested over 20 days with two runs per day, and two replicate scans for each run. In total. 960 scans were analyzed to evaluate repeatability, between-run. between-day, and within-laboratory precision using the device DSS pre-classified results without operator reclassification. The results met the pre-defined acceptance criteria.
  Blasts

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Sample	N	Mean (%)	Repeatability		Between-Run		Between-Day		Within-Laboratory
			SD (%)	%CV	SD (%)	%CV	SD (%)	%CV	SD (%)	%CV
R1	80	9.43	0.69	7.28	0.59	6.26	0.00	0.00	0.91	9.60
R2	80	18.01	1.23	6.85	0.74	4.10	0.38	2.11	1.49	8.26
R3	80	8.04	0.78	9.75	1.32	16.4	0.00	0.00	1.54	19.11
R4	80	1.44	0.46	32.09	0.00	0.00	0.15	10.27	0.48	33.69
M1	80	64.78	1.84	2.83	0.58	0.89	0.51	0.79	1.99	3.07
M2	80	22.57	1.94	8.60	1.87	8.29	0.68	3.03	2.78	12.32
M3	80	6.79	0.67	9.81	0.35	5.15	0.00	0.00	0.75	11.08
M4	80	12.23	4.06	33.21	0.00	0.00	1.52	12.46	4.34	35.47
M5	80	7.92	1.42	17.94	0.57	7.15	0.35	4.42	1.57	19.81
M6	80	6.51	0.53	8.16	0.16	2.48	0.28	4.29	0.62	9.55
N1	80	4.35	0.36	8.38	0.33	7.57	0.00	0.00	0.49	11.30
N2	80	3.12	0.34	10.88	0.00	0.00	0.13	4.05	0.36	11.61

Plasma Cells

Sample	N	Mean (%)	Repeatability		Between-Run		Between-Day		Within-Laboratory
			SD (%)	%CV	SD (%)	%CV	SD (%)	%CV	SD (%)	%CV
R1	80	3.80	0.34	9.01	0.25	6.69	0.11	2.91	0.44	11.60
R2	80	1.17	0.32	27.14	0.00	0.00	0.12	10.47	0.34	29.09
R3	80	2.94	0.53	17.93	0.32	11.07	0.18	6.19	0.64	21.96
R4	80	0.07	0.09	N/A	0.04	N/A	0.00	0.00	0.10	N/A
M1	80	4.94	0.94	19.04	0.94	18.96	0.00	0.00	1.33	26.87
M2	80	42.98	2.30	5.36	1.93	4.49	0.00	0.00	3.0	6.99
M3	80	0.24	0.07	N/A	0.00	0.00	0.03	N/A	0.08	N/A
M4	80	53.81	2.63	4.89	2.08	3.87	0.00	0.00	3.36	6.24
M5	80	24.48	3.39	13.86	0.00	0.00	2.39	9.77	4.15	16.95
M6	80	13.23	2.91	21.97	0.00	0.00	0.00	0.00	2.91	21.97
N1	80	1.05	0.27	25.35	0.14	13.67	0.04	3.96	0.30	29.07
N2	80	0.27	0.10	N/A	0.03	N/A	0.00	0.00	0.10	N/A

M:E Ratio

	Grade
Specimen	Normal	Abnormal	Too Few
to Assess	True Grade	Agreement
R1	80	0	0	Normal	100%
R2	0	80	0	Abnormal	100%
R3	3	77	0	Abnormal	96%
R4	0	80	0	Abnormal	100%
M1	0	80	0	Abnormal	100%
M2	0	4	76	Too Few to Assess	95%
M3	0	0	80	Too Few to Assess	100%

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	Grade
Specimen	Normal	Abnormal	Too Few
to Assess	True Grade	Agreement
M4	0	0	80	Too Few to Assess	100%
M5	4	76	0	Abnormal	95%
M6	79	0	1	Normal	99%
N1	77	3	0	Normal	96%
N2	80	0	0	Normal	100%

• a) Reproducibility: The study was conducted using nine Romanowsky stained slides randomly selected from the following three clinical groups: residual morphologic hematologic neoplasm (R), morphologic hematologic neoplasm (M), and normal morphology marrow (N), with three replicate scans for each slide. The study was performed at three sites with three runs per day over five days on four devices (three X100 and one X100HT) and four operators. In total, 540 scans were analyzed to evaluate repeatability, within-laboratory, between-day, between-site, and reproducibility using the DSS pre-classified results without operator reclassification. The results met the predefined acceptance criteria.

Blasts:

| Sample | N | Mean
Value (%) | Repeatability | | Between-Day | | Between-instrument/site | | Reproducibility | |
|--------|----|-------------------|---------------|-------|-------------|-------|-------------------------|-------|-----------------|-------|
| | | | SD (%) | %CV | SD (%) | %CV | SD (%) | %CV | SD (%) | %CV |
| R1 | 60 | 16.73 | 1.13 | 6.75 | 0.69 | 4.10 | 1.20 | 7.19 | 1.79 | 10.67 |
| R2 | 60 | 8.41 | 1.30 | 15.50 | 0.93 | 11.05 | 1.61 | 19.14 | 2.27 | 26.99 |
| R4 | 60 | 1.41 | 0.60 | 42.66 | 0.29 | 20.81 | 0.12 | 8.19 | 0.68 | 48.17 |
| M1 | 60 | 61.02 | 1.94 | 3.18 | 0.81 | 1.33 | 4.06 | 6.65 | 4.57 | 7.49 |
| M2 | 60 | 8.02 | 0.99 | 12.39 | 0.33 | 4.17 | 0.95 | 11.89 | 1.42 | 17.67 |
| M4 | 60 | 11.64 | 2.47 | 21.24 | 1.12 | 9.59 | 0.00 | 0.00 | 2.71 | 23.30 |
| M5 | 60 | 9.37 | 2.94 | 31.39 | 1.72 | 18.41 | 1.34 | 14.26 | 3.66 | 39.08 |
| M6 | 60 | 6.51 | 0.58 | 8.86 | 0.10 | 1.55 | 0.00 | 0.00 | 0.59 | 8.99 |
| N1 | 60 | 4.58 | 0.51 | 11.03 | 0.00 | 0.00 | 0.76 | 16.59 | 0.91 | 19.92 |

Plasma Cells:

Sample	N	Mean Value (%)	Repeatability		Between-Day		Between-Instrument/site		Reproducibility
			SD (%)	%CV	SD (%)	%CV	SD (%)	%CV	SD (%)	%CV
R1	60	1.01	0.29	28.60	0.07	6.83	0.68	67.42	0.75	73.55

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| Sample | N | Mean
Value
(%) | Repeatability | | Between-Day | | Between-
Instrument/site | | Reproducibility | |
|--------|----|----------------------|---------------|-------|-------------|-------|-----------------------------|-------|-----------------|-------|
| | | | SD (%) | %CV | SD (%) | %CV | SD (%) | %CV | SD (%) | %CV |
| R2 | 60 | 2.71 | 0.81 | 29.80 | 0.92 | 33.99 | 2.03 | 74.89 | 2.37 | 87.47 |
| R4 | 60 | 0.07 | 0.11 | N/A | 0.00 | 0.00 | 0.04 | N/A | 0.12 | N/A |
| M1 | 60 | 3.76 | 0.72 | 19.03 | 0.31 | 8.30 | 2.90 | 77.06 | 3.00 | 79.81 |
| M2 | 60 | 0.64 | 0.32 | N/A | 0.29 | N/A | 0.60 | N/A | 0.74 | N/A |
| M4 | 60 | 49.56 | 5.35 | 10.79 | 2.92 | 5.90 | 0.89 | 1.79 | 6.16 | 12.43 |
| M5 | 60 | 22.24 | 5.81 | 26.13 | 2.15 | 9.68 | 0.88 | 3.97 | 6.26 | 28.15 |
| M6 | 60 | 13.80 | 2.45 | 17.72 | 1.67 | 12.09 | 0.84 | 6.07 | 3.08 | 22.29 |
| N1 | 60 | 1.02 | 0.25 | 24.62 | 0.07 | 7.26 | 0.72 | 71.13 | 0.77 | 75.63 |

M:E Ratio

	Grade
Specimen	Normal	Abnormal	*Too Few to
Assess	True Grade	Agreement
R2	0	60	0	Abnormal	100%
R3	10	50	0	Abnormal	83%
R4	0	60	0	Increased	100%
M1	0	60	0	Abnormal	100%
M2	0	0	60	Too Few to Assess	100%
M4	0	3	57	Too Few to Assess	95%
M5	0	32	28	Increased	53%
M6	59	0	1	Normal	98%
N1	58	2	0	Normal	97%

*Too Few to Assess (TFTA): Insufficient information to determine a characteristic's grading

2) Linearity:

Not applicable

3) Analytical Specificity/Interference:

Not applicable

• 4. Assay Reportable Range:

10

Not applicable

• 5. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):
     Not applicable
• 6. Detection Limit:
     Not applicable
• 7. Assay Cut-Off:
     Not applicable
• 8. Accuracy (Instrument):
     See Clinical studies section below.
• 9. Carry-Over:
     Not applicable

B Comparison Studies:

• 1. Method Comparison:
     See Clinical Study Section below.
• 2. Matrix Comparison:
     Not applicable

C Clinical Studies:

• 1. Clinical Sensitivity and Specificity: The study was conducted at three sites with 615 Romanowsky stained slides. Manual microscopy was used as the reference method. The samples encompass multiple diseases that can be grouped into five clinical categories, as shown in the table below. The slides were randomly selected, blinded, and evaluated by two operators at each site. The operators were qualified to review bone marrow aspirates. The sample slides were evaluated by the test method and then by the reference method with a 3week washout period in between. The DSS suggested results for the cell types/parameters were reviewed and confirmed or reclassified by the operators as necessary. The results met the pre-defined acceptance criteria.

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Additional performance analysis was conducted for a subset of the 615 slides comparing the results of the candidate device with de-identified medical records data retrieved from two of the three sites.

Staining Method	Clinical Condition	Number of slides
Romanowsky Stain	Morphologic Hematologic neoplasm	180
	Residual morphologic hematologic neoplasm	180
	Benign	15
	Normal morphology marrow	180
	Others: Inadequate / Hemodiluted aspirate	60
Total		615

Clinical conditions distribution:

Romanowsky Stain:

• 1. Comparison of candidate device to manual microscopy

Specimen Quality Assessment

Qualitative analysis	Sensitivity (95%CI)	Specificity (95% CI)	Accuracy (95% CI)
Sample Quality
(Adequate/Inadequate)	88.72%
(82.22%, 93.05%)	99.36%
(98.69%, 99.69%)	98.21%
(97.31%, 98.82%)
Stripped Cells (Normal
(20%)	91.67%
(87.21%, 94.66%)	96.34%
(94.88%, 97.39%)	95.41%
(94.00%, 96.50%)
Plasma Cell
Estimation (1 M. E. Pollyea, "NCCN guidelines insights: acute myeloid leukemia, version 2.2021: featured updates to the NCCN guidelines," Journal of the National Comprehensive Cancer Network, vol. 19, no. 1, pp. 16-27, 2021.

2 S. Parmentier et al., "Reevaluation of reference values for bone marrow differential counts in 236 healthy bone marrow donors," Ann Hematol, vol. 99, no. 12, pp. 2723- 2729, 2020.

3 A. Orazi, D. P. O'Malley and D. A. Arber, "The normal bone marrow and an approach to bone marrow evaluation of neoplastic and proliferative processes," in Illustrated Pathology of the Bone Marrow, Cambridge University Press, 2006, pp. 5-15.

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• 2. Clinical Sensitivity and Specificity: Assessment of the manually classified parameters were also conducted in the clinical study with three sites and 795 slides (615 Romanowsky stained, and 180 Prussian Blue stained). Manual microscopy was used as the reference method. The slides were randomly selected, blinded, and evaluated by two operators at each site. The sample slides were evaluated by the test method and then by the reference method with a 3-week washout period in between. The images were reviewed and cell types were classified by the operators. For Romanowsky stained BMA smears, count estimation was assessed for basophils. eosinophils. Ivmphocytes, megakaryocytes, and mast cells while Maturation and Morphology was assessed for blast auer rods detections, blast nucleus morphology, blast granulation detections, erythropoiesis maturation, erythropoiesis morphology, myelopoiesis maturation, myelopoiesis morphology, lymphocyte morphology, megakaryocytes maturation, megakaryocytes morphology, monocyte morphology, and plasma cell morphology. For Prussian blue stained BMA smears, iron specimen quality, iron stores, and ring sideroblasts detections were assessed. The results demonstrated that the images provided for manual determination of the cell categories was appropriate.

Staining Method	Clinical Condition	Number of slides
Romanowsky Stain	Morphologic Hematologic neoplasm	180
	Residual morphologic hematologic neoplasm	180
	Benign	15
	Normal morphology marrow	180
	Others: Inadequate / Hemodiluted aspirate	60
Prussian Blue Stain	Others: Evaluation of Iron Stores	180
Total		795

Clinical conditions distribution:

• 3. Too Few to Assess (TFTA) Grading: TFTA grading was used when an investigator identified that they did not have enough information to determine a characteristic's grading. During the Clinical Study, the users performed the same evaluation with regards to TFTA for both manual microscopy and Full Field BMA device. The criteria indicated below were used to assess TFTA. In total, out of 7,662 cases that were assessed using the manual microscope as TFTA. 94.53% were also assessed using Scopio Labs Full Field BMA as too few to assess.
     Criteria for TFTA Evaluation

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| Cell | Evaluation
parameter | Prerequisite for
determination | TFTA Criteria |
|----------------|-------------------------|------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------|
| Erythropoiesis | Maturation | Presence of Erythroid cells | Less than 50 Erythroid
cells are detected |
| | Morphology | Presence of abnormal
Erythroid cells | Less than 50 Erythroid
cells are detected |
| M:E Ratio | Estimation | Presence of Myeloid and Erythroid
cells | Total count of Myeloid and
Erythroid out of the total
number of cells is less than
50% |
| Megakaryocytes | Maturation | Determination by Megakaryocytes
cells size | Less than 30
Megakaryocytes are detected |
| | Morphology | Presence of abnormal
Megakaryocytes, marked manually
by the users as abnormal during the
review process | Less than 30 Megakaryocytes
are detected |
| Monocytes | Morphology | Presence of abnormal Monocytes,
marked manually by the users as
abnormal during the review process | Less than 20 Monocytes are
detected |
| Myelopoiesis | Maturation | Presence of Myeloid cells | Less than 50 Myeloid
cells are detected |
| | Morphology | Presence of abnormal Myeloid cells
marked manually by the users as
abnormal during the review process | Less than 50 Myeloid cells are
detected |

• 4. Inadequate Samples Quality: The number of samples for which users chose 'inadequate' in the Sample Quality primary characteristic in each of the methods was compared. Users marked 1,450 cases as adequate using Scopio Labs Full Field BMA, and in 98.76% of the times they were also marked as adequate when using the manual microscope.
• 5. Scanning Area Performance: The comparison used the percentage (%) of the combined particle areas falling within the suggested scan area as a metric. An overall score was defined as the average score of all Romanowsky stained cases which were not characterized by the user as "Inadequate" or "Aparticulate" using the reference method. An overall score of 91.10% was obtained.
• 6. Inter-User Agreement: Samples were reviewed separately by each of the two users at the sites. Each of the user's results in the test method were compared to the same user's results in the reference method. Agreement between the two users' results when using a manual

16

microscope was calculated, and the agreement between the two users' results when using the test method.

VII Proposed Labeling:

The labeling supports the decision to grant the De Novo request for this device.

Identified Risks and Mitigations: VIII

Risks to Health	Mitigation Measures
Clinical action based on false positive results
may lead to misdiagnosis, inappropriate patient
management, or unnecessary treatments.	Certain design verification and validation,
including documentation of certain analytical
studies and clinical studies.

Certain labeling information, including
limitations. |
| Clinical action based on false negative results
may lead to delayed diagnosis, missed
diagnosis, or delay in treatment. | Certain design verification and validation,
including documentation of certain analytical
studies and clinical studies.

Certain labeling information, including
limitations. |

IX Benefit/Risk Assessment:

A Summary of the Assessment of Benefit:

There is currently no FDA authorized automated cell locating device for evaluating cell types in bone marrow aspirates (BMA). Currently, to perform analysis of BMA smears, laboratories use manual microscopy, or a camera mounted on a manual microscope to perform 500-1000 nucleated cell differentials at 100x resolution. The X100 and X100HT instruments with software application (Full Field BMA Application) is intended to perform the same functions in a digital workflow. The Full Field BMA application can provide the intended users with pre-classification results for slide quality, blasts, plasma cells and M/E ratio. The level of blasts in bone marrow is particularly important. Having at least 20% blasts in the bone marrow is required for the diagnosis of acute myeloid leukemia. Blast count of 5% is an important diagnostic threshold for the sub-classification of myelodysplastic syndrome. In patients with multiple myeloma, abnormal clonal plasma cells make up at least 10% of the cells in the bone marrow. M:E ratio compares the relative numbers of myeloid precursors to erythroid precursors. Together with overall bone marrow cellularity, M:E ratio helps assess changes in the myeloid and erythroid cell populations. The Full Field BMA application can generate qualitative or semiquantitative preclassification results based on clinically relevant medical decision levels (e.g., 5% and 20% for blasts). Comparing to manual smear review, the device shows favorable sensitivities in detecting samples with abnormally increased cell counts. The performances for analytical validations of

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these parameters are acceptable benefits of the pre-classification functions include facilitating more effective BMA assessment and reducing potential user errors such as underestimating blast counts.

B Summary of the Assessment of Risk:

The risks of the device include false negative or false positive results due to incorrect suggestions offered to the user by the system's DSS (Decision Support System) in the scaming and/or analysis stages. This risk can occur in the selection of the scanned area (the user may not see all the relevant areas in the slide), in the selection of optimal NDC-ROI (region of interest for nucleated differential count) where the user may not review all the relevant cells, and in the cells' pre-classification stage (which can lead to inaccurate lineage assessment being presented to the user). Incorrect suggestions offered by the system may lead to delayed diagnosis, missed diagnosis, or delay in treatment.

C Patient Perspectives:

This submission did not include specific information on patient perspectives for this device.

D Summary of the Assessment of Benefit-Risk:

There is probable risk associated with an erroneous result. To mitigate the risks, analytical and clinical studies are performed for verification and validation. Labeling information, including limitations and user training are included such as the labeling clearly states that the user must verify and revise the suggested results as needed. The intended users of the device are qualified in BMA assessment, who have the expertise to evaluate the system's DSS suggestions. The risk mitigation strategies and special controls are sufficient to mitigate the risks. While general controls are not sufficient to mitigate the risks, in light of the special controls, the benefits of the device outweigh the risks.

X Conclusion:

The De Novo request is granted and the device is classified under the following and subject to the special controls identified in the letter granting the De Novo request:

Product Code(s): SAL Device Type: Automated cell-locating device for bone marrow aspirate Class: II Regulation: 21 CFR 864.5261