Automated scanning microscopy work station for histological identification of the enzyme leucocyte alkaline phosphatase in neutrophilic granulocytes to differentiate: Granulocytic leukemia; a malignant disease characterized by excessive overgrowth of granulocytes in bone marrow, and Reactions that resemble true leukemia, such as those occurring in severe infections.

Device Description

The MD, 2000 Digital Analyzer is an automated intelligent microscope cell locating device that detects, by color and pattern recognition techniques, cells stained with alkaline phosphatase reagent system FAST VIOLET B SALT. The system consists of software resident in computer memory and includes keyboard, color monitors, microscope, printer, and an automatic slide handling and scanning mechanism controlled and operated by a health care professional.

AI/ML Overview

The provided document describes the MDx 2000 Digital Analyzer, an automated intelligent microscope cell locating device. The document details the device's intended use and the clinical trials conducted to demonstrate its substantial equivalence to predicate devices. However, it does not explicitly state quantitative "acceptance criteria" for performance that the device was designed to meet. Instead, the study aims to show that the MDx 2000 performs "as well or better than the predicate devices."

Here's an analysis of the available information:

1. Table of Acceptance Criteria and Reported Device Performance

As mentioned, explicit, quantitative acceptance criteria are not presented in this summary. The evaluation focuses on demonstrating comparable performance and improvements over manual methods rather than meeting predefined numerical thresholds.

Feature Evaluated	Acceptance Criteria (Implicit)	Reported Device Performance
Precision	Similar to predicate devices	"Similar precision within site over 125 patients tested at 3 clinical sites."
Consistency (Between-Site)	Better than manual method	"Provided more between-site consistency in reported results than that for the comparative Sigma NAP kit manual method."
Between-Technologist Variability	Eliminated compared to manual method	"Eliminated the considerable between-technologist variability that occurred at each of the study sites."
Accuracy (Bias)	Comparable to manual method, or if bias exists, consistent and characterizable for adjustment.	"At two study sites, the results were directly comparable with little clinical bias between the two methods. At one of the study sites, there was considerable negative bias of the candidate device against the manual method, but this was consistent and characterizable, and is assumed to be removable by adjustment (calibration) of the local reference range."
Comparability at different sites with control slides	Comparable to predicate devices	"The candidate device was proved comparable to the candidate devices at the other sites by cross-validation with control slides."

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

Test Set Sample Size: 125 patients tested across 3 clinical sites.
Data Provenance: Clinical trials were conducted at three different sites. There is no explicit mention of the country of origin, but given the context of a 510(k) summary for the U.S. FDA, it is highly likely the data is from the United States. The study was prospective in nature, as indicated by the "written MicroVision Medical Systems, Inc. protocol" and controlled clinical trials.

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

The document mentions "qualified medical technologists examining the slides" for the manual comparison (The number of qualified medical technologists examining the slides). However, it does not specify the exact number of experts or their specific qualifications (e.g., years of experience) used to establish the ground truth for the test set.

4. Adjudication Method for the Test Set

The document states, "The design of the double blind study." While a double-blind study suggests measures to reduce bias, it does not explicitly describe an adjudication method (like 2+1 or 3+1). The "manual count" by qualified technologists serves as the reference, but the process for resolving discrepancies among manual readers (if multiple were involved in the ground truth) is not detailed.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and the Effect Size

The summary does not explicitly describe a Multi-Reader Multi-Case (MRMC) comparative effectiveness study in the typical sense of measuring human reader improvement with AI assistance versus without. The study primarily compares the automated device's performance to a manual method performed by technologists.

However, the findings imply an "effect size" related to variability:

The device "eliminated the considerable between-technologist variability that occurred at each of the study sites." This indicates a significant positive effect on consistency compared to unassisted human readers.
The device "provided more between-site consistency in reported results than that for the comparative Sigma NAP kit manual method." This also suggests an improvement in consistency over a purely manual process.
The document doesn't provide a quantitative effect size (e.g., percentage improvement in accuracy or reduction in reading time) due to AI assistance specifically.

6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done

Yes, the study primarily evaluates the standalone performance of the MDx 2000 Digital Analyzer algorithm (the "candidate device") against manual methods. The device is described as an "automated intelligent microscope cell locating device" that detects cells using "color and pattern recognition techniques." The assessments of precision, consistency, and accuracy are all of the automated system's output.

7. The Type of Ground Truth Used

The ground truth for the clinical trials was established by:

Expert Consensus/Manual Count: The "average manual count" performed by "qualified medical technologists" based on "a scoring procedure... from ratings from zero to 4+ on the basis of quantity and intensity of precipitated dye within the cytoplasm of the cells." This manual method was based on established cytochemical techniques and a "scoring procedure" detailed in referenced literature.

8. The Sample Size for the Training Set

The document does not provide information on the sample size used for the training set. The focus of this 510(k) summary is on the clinical validation of the device, not its development or training process.

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

Since the document does not mention the training set size, it also does not specify how the ground truth for the training set was established. We can infer that the device's "color and pattern recognition techniques" would have been developed using some form of labeled data, likely derived from expert analysis of stained cells, but the specifics are not included in this regulatory submission summary.

Summary

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Appendix C

510(k) Summary of Substantial Equivalence MicroVision Medical Systems, Inc. (MDx 2000 Digital Analyzer)

This summary of substantial equivalence information is furnished in accordance with 21 CFR 807.92 as follows:

21 CFR 807.92(a) :

21 CFR 807.92(a) (1) :

Submitter's name and address:

MicroVision Medical Systems, Inc. 33171 Paseo Cerveza San Juan Capistrano, California 92675

- Submitter's telephone number: (714) 443-3366

Contact person:

Michael Schneider Mr. MicroVision Medical Systems, Inc. 33171 Paseo Cerveza San Juan Capistrano, California 92675

Date this 510(k) summary was prepared: March 4, 1997

21 CFR 807.92(a) (2) :

Trade/proprietary name of the device: MDx 2000 Digital Analyzer
Classification name: Automated microscopy cell locating workstation

21 CFR 807.92(a)(3): Legally marketed predicate devices to which substantial equivalence is claimed:

Nikon Biostation

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510(k) Summary of Substantial Equivalence MicroVision Medical Systems, Inc. (MD, 2000 Digital Analyzer)

Intelligent Imaging, Inc. Model IMS-200 automated cell locating device.
Siqma Diaqnostics' alkaline phosphatase reagent system FAST VIOLET B SALT catalog No. 85-1.

21 CFR 807.92(a) (4) : Description of the device that is the subject of this premarket notification:

The MD, 2000 Digital Analyzer is an automated intelligent microscope cell locating device that detects, by color and pattern recognition techniques, cells stained with alkaline The system phosphatase reagent system FAST VIOLET B SALT. consists of software resident in computer memory and includes keyboard, color monitors, microscope, printer, and an automatic slide handling and scanning mechanism controlled and operated by a health care professional.

21 CFR 807.92(a) (5) : Intended use and labeled indications for use :

Automated scanning microscopy work station for histological identification of the enzyme leucocyte alkaline phosphatase in neutrophilic granulocytes to differentiate:

Granulocytic leukemia; a malignant disease characterized by excessive overgrowth of granulocytes in bone marrow, and
Reactions that resemble true leukemia, such as those occurring in severe infections.

21 CFR 807.92 (a) (6) : Technological characteristics :

The design, construction, energy source, and other characteristics of the MDx 2000 candidate device are considered to be substantially equivalent to the relevant features of the predicate devices. A summary of the

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510(k) Summary of Substantial Equivalence MicroVision Medical Systems, Inc. (MDx 2000 Digital Analyzer)

technological characteristics of the MDx 2000 candidate device in comparison to those of the predicate devices follows:

The reagent system is identical to * Reagent system: Sigma Diagnostics' alkaline phosphatase reagent system FAST VIOLET B SALT, catalog No. 85-1.

Method of cell detection: The same as the predicate devices; i.e., colorimetric pattern recognition by microscopic examination of prepared cells by size, shape, hue, and intensity as observed by an automated computer controlled microscope and/or by visual observation by a health care professional.
System components: The system components comprising the candidate device are the same as those in the Intelligent Medical Imaging, Inc. and/or Nikon predicate devices; i.e., computer, microscope, color monitor(s), keyboard, printer, automatic loading and positioning of prepared sample on microscope stage, automatic focusing of microscope, and automatic storage of acquired images.
Energy source: The electrical service is 120 VAC 60 HZ, the same as the Intelligent Medical Imaging, Inc. and Nikon predicate devices.

21 CFR 807.92(b): 510(k) summaries for those premarket submissions in which a determination of substantial equivalence is also based on performance data shall contain the following information:

21 CFR 807.92(b)(1): Brief discussion of the non-clinical tests submitted, referenced, or relied upon in this premarket notification submission:

There were no nonclinical tests submitted, referenced, or

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510(k) Summary of Substantial Equivalence MicroVision Medical Systems, Inc. (MD, 2000 Digital Analyzer)

relied upon in this submission.

21 CFR 807.92(b)(2) : Brief discussion of the clinical tests submitted, referenced, or relied upon in this premarket notification submission:

This premarket notification relies on both referenced literature and clinical tests performed. A brief discussion of the results and conclusions of the performance of naphthol as phosphate as a reagent in the cytochemical demonstration of alkaline phosphatase activity on thin smears of human blood is first discussed. This discussion is followed by a brief discussion of the results and conclusions from clinical trials conducted:

1. Referenced literature:

Cytochemistry of Leukocyte Alkaline Phosphatase; Use of Complex Naphthol as Phosphates in Azo Dye-Coupling Technics.

Leonard S. Kaplow, M.D. With the technical assistance of Mrs. Charlotte Ladd, M.T. (ASCP) Department of Pathology, Medical College of Virginia

The American Journal of Clinical Pathology Vol. 39, No. 5, pp. 439-449, May 1963

Summary:

Upon preparation of blood smear slides as described in the literature, examination of negative and positive controls at 100X magnification disclosed the theoretical sites of enzyme activity were represented by distinct pink granulations varying in color from very pale pink to a brilliant ruby The precipitation took the form of minute dots or red. larger granules or rod shaped structures. The contrast of the red cytoplasm with the blue-black nuclei was striking. Localization appeared far more precise, although similar in pattern, than that seen with older technics.

A scoring procedure was established from ratings from zero

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510 (k) Summary of Substantial Equivalence MicroVision Medical Systems, Inc. (MDx 2000 Digital Analyzer)

to 4+ on the basis of quantity and intensity of precipitated dye within the cytoplasm of the cells. The sum of the reading of 100 observed cells was regarded as the "score" for a given blood smear. The ratings were based on the number, size, and intensity of staining of the granules.

Conclusion:

The value of assessing leukocyte alkaline phosphatase activity as an aid in the diagnosis of certain hematologic diseases is now well established. Such assessment is particularly valuable in distinguishing chronic granulocytic leukemia from leukemoid reactions and from other myeloproliferative diseases as well as in distinguishing polycythemia vera from secondary polycythemia.

Cytochemical technics are suitable staining methods and have been used in many laboratories as routine procedures. By means of these staining methods and in conjunction with a "scoring" procedure, it is possible to obtain a numerical representation of the degree of enzyme activity of leukocytes on a given blood smear and thus to compare enzyme activity disease states with the normal.

Clinical trials: 2 .

Description of clinical sites and devices used:

The results of clinical trials were used to obtain data to compare the analytical performance, accuracy, and precision of the MDx 2000 candidate device to that of the predicate The clinical trials were conducted in accordance devices. with a written MicroVision Medical Systems, Inc. protocol and were conducted on a model MDx 2000 device (three different devices; not the same device) at three different sites.

* Description of the scientific methods used:

The following characteristics of the clinical trials

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510(k) Summary of Substantial Equivalence MicroVision Medical Systems, Inc. (MDx 2000 Digital Analyzer)

conducted were carefully selected to help ensure the conducted were carefaring and statistically valid:

The number of clinical sites
The quantity of patient samples per site
The quantity of stained smears examined
The number of times a smear stained slide was examined
The number of qualified medical technologists examining the slides
The design of the double blind study
The number of times the same "control" slide(s) was run on each of the three devices to determine was full on caon on for each "control" slide
- The number of times the same "control" slide(s) was run on each of the three devices to establish was full on out on of the neutrophil alkaline phosphatase (NAP)
- Running the "control" slide(s) on each device at Ruming che - and end of each daily run on each of the beginning and the candidate devices to evaluate the consistency of the devices

* Methods of statistical analysis:

Statistical analyses of the data included:

The use of parametric and/or non-parametric statistical methods to analyze the data
Pooling/combining data from the three clinical roofing, only if statistically justified based on equivalent results

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510(k) Summary of Substantial Equivalence MicroVision Medical Systems, Inc. (MD, 2000 Digital Analyzer)

Assessment of bias (accuracy) and imprecision as generally described in the National Committee for Clinical Laboratory Standards (NCCLS) documents EP9-A and EP5-T

Bias of the MD, 2000 candidate device compared with the predicate devices was based on the use of linear regression comparison of the averages of the devices versus the average manual count.

Statistical assessment of the estimated bias using the appropriate t-test.
- Analysis of variance of the data to estimate the variance contributions of the technologists, slides, replication, and other variables.

21 CFR 807.92(b)(3): The conclusion drawn from the non-clinical and/or clinical tests that demonstrate the MDx 2000 candidate device is as safe, is as effective, and performs as well or better than the predicate devices:

The MD, 2000 Digital Analyzer candidate device was found to provide neurophilic alkaline phosphatase (NAP) measurements that had similar precision within site over 125 patients tested at 3 clinical sites. Use of the candidate device provided more between-site consistency in reported results than that for the comparative Sigma NAP kit manual method, and eliminated the considerable between-technologist variability that occurred at each of the study sites.

The accuracy of the MD, 2000 Digital Analyzer candidate device data was assessed by method comparison linear regression against the manual method. At two study sites, the results were directly comparable with little clinical bias between the two methods. At one of the study sites, there was considerable negative bias of the candidate device against the manual method, but this was consistent and characterizable, and is assumed to be removable by adjustment (calibration) of the local reference range.

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510 (k) Summary of Substantial Equivalence MicroVision Medical Systems, Inc. (MD, 2000 Digital Analyzer)

The candidate device was proved comparable to the candidate devices at the other sites by cross-validation with control slides. The difference in bias relationship at the different sites was not unanticipated, based on the labeling of the Sigma Diagnostics predicate device/kit and the National Committee for Clinical Laboratory Standards publication H-22P, Histological Method for Leukocyte Alkaline Phosphatase, that warn of considerable subjective differences in technologist and site expected values.

END OF 510(k) SUMMARY ....

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Image /page/8/Picture/0 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo is circular and contains the words "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" around the perimeter. Inside the circle is an abstract symbol that resembles an eagle or bird-like figure with three curved lines above it.

DEPARTMENT OF HEALTH & HUMAN SERVICES

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Mr. Michael Schneider Official Correspondent MicroVision Medical Systems, Inc. 33171 Paseo Cerveza San Juan Capistrano, California 92675

MAY 30 1997

Re: K970824 Trade Name: MD, 2000 Digital Analyzer Regulatory Class: II Product Code: JOY Dated: March 5, 1997 Received: March 6, 1997

Dear Mr. Schneider:

We have reviewed your Section 510(k) notification of intent to market the device referenced above and we have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration.

If your device is classified (see above) into either class II (Special Controls) or class III (Premarket Approval), it may be subject to such additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 895. A substantially equivalent determination assumes compliance with the Good Manufacturing Practice for Medical Devices: General (GMP) regulation (21 CFR Part 820) and that, through periodic GMP inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP regulation may result in regulatory action. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please note: this response to your premarket notification submission does not affect any obligation you night have under sections 531 through 542 of the Act for devices under the Electronic Product Radiation Control provisions, or other Federal Laws or Regulations.

Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), this device may require a CLIA complexity categorization. To determine if it does, you should contact the Centers for Disease Control and Prevention (CDC) at (770)488-7655.

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This letter will allow you to begin marketing your device as described in your 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.

If you desire specific advice for your device on our labeling regulation (21 CFR Part 801 and additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at (301) -594-4588. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers Assistance at its toll free number (800) 638-2041 or at (301) 443-6597 or at its internet address "http://www.fda.gov/cdrh/dsmamain.html"

Sincerely yours.

Steven Putman

Steven I. Gutman, M.D., M.B.A. Director Division of Clinical Laboratory Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure

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Page 1 of 1 510(k) number (if known): Unknown; not yet assigned by FDA. Device name: Model MDx 2000 Digital Analyzer Indications for use for the device: Automated scanning microscopy work station for histological identification of the enzyme leucocyte niscologicur rase in neutrophilic granulocytes to differentiate: * Granulocytic leukemia, a malignant disease characterized by excessive overgrowth of granulocytes in bone marrow, and * Reactions that resemble true leukemia, such as those occurring in severe infections. Concurrence of CDRH, Office of Device Evaluation (ODE) Over-the-Counter Use or Prescription Use ﻟﻠﺘﻌﻠﻴﻘﺎﺕ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤ (Per 21 CFR 801.109) (Optional format 1-2-96) ని XL7.10

Regulation Number and Section

§ 864.5260 Automated cell-locating device.

(a)
Identification. An automated cell-locating device is a device used to locate blood cells on a peripheral blood smear, allowing the operator to identify and classify each cell according to type. (Peripheral blood is blood circulating in one of the body's extremities, such as the arm.)(b)
Classification. Class II (performance standards).