The Virtuoso system provides automated digital slide creation, management, analysis, and viewing. It is intended for in vitro diagnostic use as an aid to the pathologist in the display, detection, counting, review and classification of tissues and cells of clinical interest based on particular morphology, color, intensity, size, pattern and shape.

The Virtuoso™ System for IHC PR (1E2) is for digital read and image analysis applications. This particular Virtuoso system is intended for use as an aid to the pathologist in the detection and semi-quantitative measurement of progesterone receptor (PR) protein in formalin-fixed, paraffin-embedded normal and neoplastic tissue. This device is an accessory to Ventana Medical Systems, Inc. CONFIRM™ anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody assay. The CONFIRM™ anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody assay is indicated for use as an aid in the assessment of breast cancer patients for whom endocrine treatment is being considered (but is not the sole basis for treatment).

Note: The IHC PR (1E2) Digital Read and Image Analysis applications are adjunctive computer-assisted methodologies for the qualified pathologist in the acquisition and measurement of images from microscope glass slides of breast cancer specimens stained for the presence of PR protein. The pathologist should verify agreement with the Image Analysis software application score. The accuracy of the test results depends on the quality of the immunohistochemical staining. It is the responsibility of a qualified pathologist to employ appropriate morphological studies and controls as specified in the instructions for the CONFIRM™ anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody used to assure the validity of the Virtuoso System for IHC PR Digital Read and Image Analysis scores. The actual correlation of CONFIRM™ anti-PR antibody to clinical outcome has not been established.

Device Description

The Virtuoso™ System is an instrument-plus-software system designed to assist the qualified pathologist in the consistent assessment of protein expression in immunohistochemically stained histologic sections from formalin-fixed, paraffinembedded normal and neoplastic tissues. The system consists of a slide scanner (iScan), computer, monitor, keyboard, mouse, image analysis algorithms for specific immunohistochemical markers, and software with a Windows web browser-based user interface. Virtuoso is a web-based, end-to-end, digital pathology software solution that allows pathology laboratories to acquire, manage, view, analyze, share, and report digital images of pathology specimens. Using the Virtuoso software, the pathologist can view digital images, add annotations, make measurements, perform image analysis, and generate reports.

The iScan slide scanning device captures digital images of formalin-fixed, paraffin-embedded tissues that are suitable for storage and viewing. The device includes a digital slide scanner, racks for loading glass slides, computer, scanner software, keyboard, mouse and monitor.

The Virtuoso software is designed to complement the routine workflow of a qualified pathologist in the review of immunohistochemically stained histologic slides. It allows the user to select fields of view (FOVs) in the digital image for analysis and provides quantitative data on these FOVs to assist with interpretation. The software makes no independent interpretations of the data and requires competent human intervention for all steps in the analysis process.

AI/ML Overview

Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided text:

Acceptance Criteria and Device Performance

Metric	Acceptance Criteria (Predetermined)	Reported Device Performance (Digital Read)	Reported Device Performance (Image Analysis)
Positive Percent Agreement (PPA)	75%	94.4% (95% CI: 86.6-97.8)	95.9% (95% CI: 88.7-98.6)
Negative Percent Agreement (NPA)	75%	97.6% (95% CI: 87.4-99.6)	97.5% (95% CI: 87.1-99.6)
Overall Percent Agreement (OPA)	75%	95.6% (95% CI: 90.1-98.1)	96.5% (95% CI: 91.3-98.6)

As stated in the document, "The overall agreement between the digital read and the manual read was 95.6%, the overall agreement between image analysis and the manual read was 96.5%, and the predetermined acceptance criterion for each measurement of 75% has been met."

Study Details

2. Sample size used for the test set and the data provenance

Sample Size: Approximately 120 cases. For the Digital Read analysis, 113 cases were analyzed. For the Image Analysis, 114 cases were analyzed.
Data Provenance: The document does not explicitly state the country of origin. It was a retrospective study as it compares different assessment methods of already prepared slides.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

Number of Experts: One pathologist.
Qualifications of Experts: The document specifies "one pathologist" but does not explicitly state their experience level (e.g., "10 years of experience"). It implies they are a "qualified pathologist."

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

Adjudication Method: Not explicitly stated as a formal adjudication process involving multiple pathologists. The ground truth ("manual score") was established by a single pathologist performing a routine microscopic read.

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

MRMC Study: No, a multi-reader, multi-case (MRMC) comparative effectiveness study was not explicitly described. The study involved one pathologist evaluating cases in three different ways (manual, digital read, image analysis).
Effect Size of Human Improvement with AI: This study does not provide data on the effect size of how much human readers improve with AI assistance. It focuses on the concordance between the digital methods (digital read and image analysis) and the manual read by a single pathologist.

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

Standalone Performance: Yes, the "Image Analysis Read" data in the table represents the performance of the algorithm as an aid to the pathologist. While the pathologist selected the fields of view, the scores themselves are generated by the software. The document also states "The software makes no independent interpretations of the data and requires competent human intervention for all steps in the analysis process." This implies it's not a purely standalone, fully automated system without human oversight, but the "Image Analysis Read" itself is the algorithmic output.

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

Type of Ground Truth: Expert individual pathologist's manual microscopic read ("manual score").

8. The sample size for the training set

Training Set Sample Size: The document does not provide information about the sample size used for the training set of the Virtuoso software. The study described is a clinical validation study, not a development or training study.

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

Ground Truth for Training Set: The document does not explain how the ground truth for the training set was established, as it does not detail the training phase of the algorithm.

Summary

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K122143

VENTANA®

A Member of the Roche Group

SEP 1 9 2013

SECTION 6 510(k) SUMMARY

This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92. The assigned 510(k) number is K122143.

807.92 (a)(1): Name:	Ventana Digital Pathology
Address:	203 Ravendale DriveMountain View, CA 94043
Phone:	(408) 207-4201
FAX:	(408) 207-4299
Contact:	Mr. Mort Minaee

807.92 (a)(2): Device name- trade name and common name, and classification

Trade name: VirtuosoTM System for IHC PR (1E2)

Common Name: Digital pathology and image analysis system for immunochemistry-stained slides

Classifications: 21 CFR & 864.1860- Immunohistochemistry reagents and kits

Product Codes: NOT, NON, OEO

807.92 (a)(3): Identification of the legally marketed predicate devices

This Virtuoso System for IHC PR (IE2) is substantially equivalent to its immediate predecessor with the same name, cleared under K111869 on March 5. 2012. The two Virtuoso systems are identical, with the sole difference being the automatic stainer that can be used with the reagents to stain the glass slides. The first PR submission qualified the Benchmark XT stainer, and this current submission qualified a second automatic stainer, the Benchmark ULTRA stainer.

807.92 (a)(4): Device Description

General Description

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Image /page/1/Picture/0 description: The image shows the logo for Ventana. The logo consists of a stylized sun-like symbol on the left, followed by the word "VENTANA" in bold, sans-serif font. A registered trademark symbol is located to the right of the word.

A Member of the Roche Group

browser-based user interface. Virtuoso is a web-based, end-to-end, digital pathology software solution that allows pathology laboratories to acquire, manage, view, analyze, share, and report digital images of pathology specimens. Using the Virtuoso software, the pathologist can view digital images, add annotations, make measurements, perform image analysis, and generate reports.

The iScan slide scanning device captures digital images of Hardware: formalin-fixed, paraffin-embedded tissues that are suitable for storage and viewing. The device includes a digital slide scanner, racks for loading glass slides, computer, scanner software, keyboard, mouse and monitor.

The Virtuoso software is designed to complement the routine Software: workflow of a qualified pathologist in the review of immunohistochemically stained histologic slides. It allows the user to select fields of view (FOVs) in the digital image for analysis and provides quantitative data on these FOVs to assist with interpretation. The software makes no independent interpretations of the data and requires competent human intervention for all steps in the analysis process.

Additional Materials Required:

Ventana CONFIRM™ anti-Progesterone Receptor (PR) (1E2) Rabbit . Monoclonal Primary Antibody
Reagents for visualization, such as DAB chromogen .
Associated materials for completing immunohistochemical staining according 0 to the appropriate package insert
Color printer if user wishes to print color copies .

Device Quality Control

The quality of results depends on the laboratory following the quality control instructions recommended in the labeling of the immunohistochemistry (IHC) reagents. The software also performs a quality check on the digital images to determine if they are suitable for further analysis using "Image Quality Assessment" algorithms.

Summary of Procedure

Samples are obtained as formalin-fixed, paraffin-embedded tissue blocks. Histologic sections are prepared and mounted onto glass slides are reacted with the PR (1E2) primary antibody, and are then visualized using DAB. Prepared slides are loaded into the Virtuoso system scanner and scanned. The resulting digital images are reviewed by the pathologist on a computer monitor, and appropriate fields of view (FOVs) are then selected for analysis by the Virtuoso software. The Virtuoso software produces a quantitative score for the FOV and an aggregate score over all the FOVs for the whole slide. The pathologist has the

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A Member of the Roche Group

choice of accepting the result or overriding with his/her own score for some or all FOVs.

807.92 (a)(5): Intended Use

Note: The IHC PR (1E2) Digital Read and Image Analysis applications are adjunctive computer-assisted methodologies for the qualified pathologist in the acquisition and measurement of images from microscope glass slides of breast cancer specimens stained for the presence of PR protein. The pathologist should verify agreement with the Image Analysis software application score. The accuracy of the test results depends on the quality of the immunohistochemical staining. It is the responsibility of a qualified pathologist to employ appropriate morphological studies and controls as specified in the instructions for the CONFIRMTM anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody used to assure the validity of the Virtuoso System for IHC PR Digital Read and Image Analysis scores. The actual correlation of CONFIRM™ anti-PR antibody to clinical outcome has not been established.

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Image /page/3/Picture/0 description: The image shows the Ventana logo. The logo consists of a stylized sun-like symbol on the left, followed by the word "VENTANA" in bold, sans-serif font. To the right of the word is a registered trademark symbol. Below the logo is the text "A Member of the Roche Group".

Characteristic	Virtuoso™ IHC HER2 (4B5)[Benchmark ULTRA Stainer]	Virtuoso™ IHC PR (1E2)[Benchmark XT Stainer] K111869
	This device is intended for in vitro diagnostic(IVD) use.	SAME
	The Virtuoso System provides automated digitalslide creation, management, analysis, and viewing.It is intended for IVD use as an aid to thepathologist in the display, detection, counting,review and classification of tissues and cells ofclinical interest based on particular morphology,color, size, intensity, pattern and shape.	SAME
Intended Use/Indicationsfor Use	The Virtuoso™ System for IHC PR (1E2) is fordigital read and image analysis applications. Thisparticular Virtuoso system is intended for use as anaid to the pathologist in the detection and semi-quantitative measurement of progesterone receptor(PR) protein in formalin-fixed, paraffin-embeddednormal and neoplastic tissue. This device is anaccessory to Ventana Medical Systems, Inc.CONFIRM™ anti-Progesterone Receptor (PR)(1E2) Rabbit Monoclonal Primary Antibody assay.The CONFIRM™ anti-Progesterone Receptor(PR) (1E2) Rabbit Monoclonal Primary Antibodyassay is indicated for use as an aid in theassessment of breast cancer patients for whomendocrine treatment is being considered (but is notthe sole basis for treatment).	SAME
Specimen Type	Formalin-fixed, paraffin-embedded tissue stainedby immunohistochemical technique	Same
System Operation(Digital Read andImage Analysis)	Histologic observation by a pathologist throughthe viewer and image analysis systems	Same
Hardware andSoftware	Ventana iScan slide scanner, computer, colormonitor, proprietary software for PR (1E2)	Same
Platform Components	mouse, keyboard, windows web browser.	Same
Primary Antibody(Assay) Reagent	Ventana CONFIRM™ anti-Progesterone Receptor(PR) (1E2) Rabbit Monoclonal Primary Antibody	Same
AncillaryReagents/Stainers	DAB universal chromogen kits,Slides stained with Benchmark ULTRA stainer	DAB universal chromogen kits,Slides stained with Benchmark XTstainer
Localization ofIHC positive stain	Nucleus	Same

807.92 (a)(6): Technological Similarities and Differences to the Predicate Devices

The following chart describes similarities and differences between the two test systems.

Ventuna Digital Pathology | 203 Ravendale Drive. Mountain View. CA 94043 |T: 408 207 4299 ww.vemanadigitalpathology.com

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Image /page/4/Picture/0 description: The image shows the Ventana logo. The logo consists of a circular design made up of arrow-like shapes pointing inward, followed by the word "VENTANA" in bold, sans-serif font, with a registered trademark symbol next to the last "A". Below the logo, the text "A Member of the Roche Group" is displayed in a smaller, italicized font.

807.92 (b)(1/2): Brief Description of Clinical Data (Non-clinical data N/A)

The Virtuoso System for IHC PR (1E2) with the Benchmark ULTRA stainer was clinically validated via a concordance study where approximately 120 cases were evaluated three ways by one pathologist at one site in a blinded fashion. Each case was scored (1) manually with a routine microscope, (2) as a digital image, and (3) by way of the image analysis application using a different order of slide presentation for each round. The manual score (reference result) was compared to both the digital read result and the image analysis result.

The data were evaluated as positive or negative for PR status using 0% to 0.99% positive staining as negative status, and at least 1% positive staininbg as positive status for both digital read and image analysis methods. The data for positive percent agreement, negative percent agreement, and overall agreement, plus the 95% confidence intervals, are shown below.

Digital Read

	Manual Microscopic Read
Digital Read	Positive	Negative	Total
Positive	68	1	69
Negative	4	40	44
Total	72	41	113
Positive Percent Agreement (PPA) n/N (%) (95% CI)	68/72 (94.4) (86.6-97.8)
Negative Percent Agreement (NPA) n/N (%) (95% CI)	40/41 (97.6) (87.4-99.6)
Overall Percent Agreement (OPA) n/N (%) (95% CI)	108/113 (95.6) (90.1-98.1)

Image Analysis

	Manual Microscopic Read
Image Analysis Read	Positive	Negative	Total
Positive:	71	1	72
Negative:	3	39	42
Total	74	40	114
Positive Percent Agreement (PPA) n/N (%) (95% CI)	71/74 (95.9) (88.7-98.6)
Negative Percent Agreement (NPA) n/N (%) (95% CI)	39/40 (97.5) (87.1-99.6)
Overall Percent Agreement (OPA) n/N (%) (95% CI)	110/114 (96.5) (91.3-98.6)

807,92 (b)(3): Conclusions from Clinical Testing

Concordance studies were performed for the Virtuoso System for IHC PR (1E2) with the Benchmark ULTRA stainer. The overall agreement between the digital read and the manual read was 95.6%, the overall agreement between image analysis and the manual read was 96.5%, and the predetermined acceptance criterion for each measurement of 75% has been met.

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Image /page/5/Picture/0 description: The image shows a logo for the U.S. Department of Health & Human Services. The logo consists of a circular seal with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES USA" around the perimeter. Inside the circle is a stylized symbol that resembles an abstract human figure or a caduceus, which is a symbol often associated with healthcare.

DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

September 19, 2013

VENTANA MEDICAL SYSTEMS, INC. C/O MS. ERIKA AMMIRATI AMMIRATI REGULATORY CONSULTING 575 SHIRLYNN COURT LOS ALTOS CA 94022

Re: K122143

Trade/Device Name: Virtuoso System For IHC Pr (1e2) Benchmark Ultra Stainer Regulation Number: 21 CFR 864.1860 Regulation Name: Immunohistochemistry reagents and kits Regulatory Class: II Product Code: NQN, NOT, OEO Dated: August 21, 2013 Received: August 22, 2013

Dear Ms. Ammirati:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate 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) that do not require approval of a premarket approval application (PMA). 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. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must of any 1 outh all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the as set form in the quality of control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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Page 2-Ms. Ammirati

If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to

http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm.

Sincerely yours,

Maria M. Chan -S

Maria M. Chan, Ph.D. Director Division of Immunology and Hematology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K122143

Device Name

Virtuosom System for IHC PR (11:2)

Indications for Use (Describe)

The Virtueso system provides antomated digital slide creation, management, and viewing, It is intended for in vitro diagnostic use as an aid to the pathologias, detection, counting, review and classiliention of tissues and ethis of clinical interest based on particular morphology , color, intensity , size, pattern and shape.

The Virtunson™ Sestem for 111, PR (1E2) is for digital read and image analysis applications. This particular Virtuaso system is intended for use as an aid to the nathologist in the detection and sem-ouantitative measurement of provincine receptor (PR) provin in formalin-fixed, paraffinembedded normal and news is un accessors to Venuna Medical Systems. Inc. CONFIRM™ ani-Progesterne Recentor (PR) ( ) E2) Rubbit Monocloud Primars Antibody ussus. The CONFIRM™ anti-Progesterone Receptur (PR) ( 11:2) Rabhi Monoclonal Primary Antibody assay is indicated for use as an aid in the assessment of breast cancer patients for whom endocrine treasment is being considered (hat is not the sole basis for treatment).

Note: The HIC PR (11:2) Digital Read and Integrations are adjunctive computer-assisted methodologics for the ouslified pathologist in the acquisition of images from microscope plass slides of breast cancer specimens stained for the presence of PR postein. The pathologist should vith the Image Analysis software application same. The accuracy of the test results depends on the immunumistochenical staining. It is the responsibility of a qualified pathologist in employ uppropriate morphological studies and controls specified in the instructions for the CONFIRM™ ani-Progesterent Receptor (PR) (1F.2) Rabbit Minner Antinody used to assure the vulidity of the Virtueso System for IIIC PR Digital Read and Image Analysis scores. The actual correlation of CONFIRM™ anti-PR antibrogy to clinical nutcome has not been established.

Type of Use (Select one or both, as applicable)

X Prescription Use (Pan 21 CFR 801 Subpart D)

801

Prescription Use (Part 21 CFR 801 Subpart D)

Over-The-Counter Use (21 CFR-807-Subpart C)

PLEASE DO NOT WRITE BELOW THIS LINE - CONTINUE ON A SEPARATE PAGE IF NEEDED.

FOR FDA USE ONLY

nd Radiological Health (CDRH) (Signature) Concurrence of Cente

FORM FDA 3881 (6/13)

'I'm looking forward to it, sir.'

Form Approved. OMB No. 0910-0120 Expiration Date: December 31, 2013 See PRA Statement on last page

Regulation Number and Section

§ 864.1860 Immunohistochemistry reagents and kits.

(a)
Identification. Immunohistochemistry test systems (IHC's) are in vitro diagnostic devices consisting of polyclonal or monoclonal antibodies labeled with directions for use and performance claims, which may be packaged with ancillary reagents in kits. Their intended use is to identify, by immunological techniques, antigens in tissues or cytologic specimens. Similar devices intended for use with flow cytometry devices are not considered IHC's.(b)
Classification of immunohistochemistry devices. (1) Class I (general controls). Except as described in paragraphs (b)(2) and (b)(3) of this section, these devices are exempt from the premarket notification requirements in part 807, subpart E of this chapter. This exemption applies to IHC's that provide the pathologist with adjunctive diagnostic information that may be incorporated into the pathologist's report, but that is not ordinarily reported to the clinician as an independent finding. These IHC's are used after the primary diagnosis of tumor (neoplasm) has been made by conventional histopathology using nonimmunologic histochemical stains, such as hematoxylin and eosin. Examples of class I IHC's are differentiation markers that are used as adjunctive tests to subclassify tumors, such as keratin.(2) Class II (special control, guidance document: “FDA Guidance for Submission of Immunohistochemistry Applications to the FDA,” Center for Devices and Radiologic Health, 1998). These IHC's are intended for the detection and/or measurement of certain target analytes in order to provide prognostic or predictive data that are not directly confirmed by routine histopathologic internal and external control specimens. These IHC's provide the pathologist with information that is ordinarily reported as independent diagnostic information to the ordering clinician, and the claims associated with these data are widely accepted and supported by valid scientific evidence. Examples of class II IHC's are those intended for semiquantitative measurement of an analyte, such as hormone receptors in breast cancer.
(3) Class III (premarket approval). IHC's intended for any use not described in paragraphs (b)(1) or (b)(2) of this section.
(c)
Date of PMA or notice of completion of a PDP is required. As of May 28, 1976, an approval under section 515 of the Federal Food, Drug, and Cosmetic Act is required for any device described in paragraph (b)(3) of this section before this device may be commercially distributed. See § 864.3.