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 HER2 (4B5) 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 HER2 protein in formalin-fixed, paraffin-embedded normal and neoplastic tissue. This device is an accessory to Ventana Medical Systems, Inc. PATHWAY® anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody. The PATHWAY® anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody is indicated for use as an aid in the assessment of breast cancer patients for whom HERCEPTIN® (Trastuzumab) treatment is being considered.

NOTE: The IHC HER2 4B5 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 HER-2/neu receptor 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 PATHWAY® anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody assay used to assure the validity of the iScan System for IHC HER2 4B5 Digital Read and Image Analysis scores. The actual correlation of PATHWAY® anti-HER-2/neu (4B5) 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 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.

Software: 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

1. Table of Acceptance Criteria and Reported Device Performance:

Performance Metric	Acceptance Criteria (Implicit)	Reported Device Performance
Agreement (vs. Manual Method)
Digital Read vs. Manual	Not explicitly stated, but generally high agreement expected.	Site 1: 93% (CI: 87%-97%) Site 2: 83% (CI: 75%-88%) Site 3: 91% (CI: 84%-95%)
Image Analysis vs. Manual	Not explicitly stated, but generally high agreement expected.	Site 1: 92% (CI: 86%-96%) Site 2: 82% (CI: 74%-88%) Site 3: 88% (CI: 80%-92%)
Intra-Pathologist/Inter-Day Reproducibility
Digital Read	Not explicitly stated, but generally high agreement expected.	Ranged from 90% to 95% (Session 1 vs 2: 95%, Session 1 vs 3: 90%, Session 2 vs 3: 93%)
Image Analysis	Not explicitly stated, but 100% was achieved.	100% for each comparison (Session 1 vs 2: 100%, Session 1 vs 3: 100%, Session 2 vs 3: 100%)
Inter-Pathologist Reproducibility
Digital Read	Minimum requirement: 75%	Ranged from 90% to 92% (P1 vs P2: 92%, P1 vs P3: 91%, P2 vs P3: 90%)
Image Analysis	Minimum requirement: 75%	Ranged from 93% to 95% (P1 vs P2: 94%, P1 vs P3: 95%, P2 vs P3: 93%)
Scanner Precision (Image Analysis)	Not explicitly stated, but in excess of 90%.	In excess of 90% for every comparison (inter-site and intra-site/inter-day)

2. Sample Size and Data Provenance:

Test Set Sample Size:
- Agreement (Digital Read vs Manual): Site 1 (n = 119), Site 2 (n = 120), Site 3 (n = 118).
- Agreement (Image Analysis vs Manual): Site 1 (n = 117), Site 2 (n = 120), Site 3 (n = 120).
- Intra-Pathologist/Inter-Day Reproducibility: Exact number of cases not explicitly stated for individual sessions, but the confusion matrices show sums of around 40 cases for the comparisons (e.g., 40 cases for Session 1 digital read, 40 cases for Session 1 image analysis).
- Inter-Pathologist Reproducibility: Exact number of cases not explicitly stated for individual comparisons, but the confusion matrices show sums of around 120 cases for the comparisons (e.g., 120 cases for Site 1 manual, 120 cases for Site 1 digital read, 117 cases for Site 1 image analysis).
- Scanner Precision: A subset of 40 clinical cases from the primary study.
Data Provenance: Not explicitly stated (e.g., country of origin). The studies appear to be prospective, as they involved pathologists reviewing cases using the Virtuoso system and comparing them to manual methods, and also involved multiple sessions for reproducibility.

3. Number of Experts and Qualifications for Ground Truth:

Number of Experts: The study indicates that "each pathologist's Virtuoso digital read results were compared to their manual results," and also refers to "three pathologists." This suggests at least three pathologists were involved in generating the manual ground truth for the primary study.
Qualifications of Experts: "Qualified pathologist" is mentioned. Specific years of experience or subspecialty training are not provided.

4. Adjudication Method for the Test Set:

For the "Agreement" studies, the "Manual Method" by each pathologist served as the reference/ground truth. There is no mention of an adjudication process (e.g., 2+1, 3+1) to establish a consensus ground truth among multiple pathologists for the manual scores before comparison with the device. Each pathologist's manual read was compared to their own digital read/image analysis.
For "Reproducibility" studies, agreement was assessed between different sessions or different pathologists, but no formal adjudication to establish a "true" score for these comparisons is described.

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

A comparative effectiveness study involving human readers with and without AI assistance is not explicitly described. The study focuses on the agreement of the AI (Virtuoso digital read and image analysis) with the manual method performed by pathologists. It also assesses inter- and intra-pathologist reproducibility of the Virtuoso system, but not a direct comparison of human performance with vs. without AI assistance. Therefore, an effect size of how much human readers improve with AI vs. without AI assistance is not provided.

6. Standalone (Algorithm Only) Performance:

Yes, the "Image Analysis" component of the Virtuoso system represents the standalone algorithm performance. The results for "Image Analysis vs Manual Method" (Agreements of 92%, 82%, 88%) and "Intra-Pathologist Image Analysis" (100% agreement for reproducibility) and "Inter-Pathologist Image Analysis" (93%-95% agreement) and "Scanner Precision" (in excess of 90%) directly reflect the algorithm's performance. The document states that the "image analysis application is the more sensitive of the two applications, and it generates an instrument-generated HER2 score that is not affected by memory bias as would be the case with human interpretations." This confirms it as an algorithm-only evaluation.

7. Type of Ground Truth Used:

The ground truth used was expert consensus (manual pathological assessment). The manual interpretation of HER2 protein expression by qualified pathologists using traditional microscopy was considered the "true score" against which the Virtuoso system's performance was measured.

8. Sample Size for the Training Set:

The document does not provide the sample size for the training set. It focuses solely on the clinical validation studies (test set).

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

The document does not provide information on how the ground truth for any potential training set was established.

Summary

{0}------------------------------------------------

Image /page/0/Picture/0 description: The image shows the date OCT 12 2011 at the top. Below the date is the Ventana logo, which includes a stylized sunburst design to the left of the word "VENTANA" in all caps. Underneath the logo is the text "A Member of the Roche Group".

SECTION 7 510(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 K111543.

807.92 (a)(1): Name:	Ventana Digital Pathology
Address:	919 Hermosa Court
Sunnyvale, CA 94085
Phone:	(408) 207-4200
FAX:	(408) 207-4299
Contact:	Mr. Indu Lakshman

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

Trade name: Virtuoso™ System for IHC HER2 (4B5)

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

Classifications: 21 CFR § 864.1860- Immunohistochemistry reagents and kits

Product Codes: OEO, NOT

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

The Virtuoso System for IHC HER2 (4B5) is substantially equivalent to the Aperio ScanScope® XT System (Aperio Technologies, Inc., Vista, CA) cleared under pre-market notification number K080654 on August 14, 2009. Both devices are digital pathology and image analysis systems for the consistent assessment of pathology interpretations using immunohistochemically stained slides; both systems include slide scanner hardware, and software that both automates the procedural steps and performs the analyses.

In terms of technology, the Virtuoso System for IHC HER2 (4B5) is also substantially equivalent to the BioImagene PATHIAM™ System with iScan for p53 and Ki-67 (Biolmagene, Inc., Sunnyvale, CA), cleared under pre-market notification K092333 on October 27, 2010. Both of these systems include the same slide scanner (iScan) and other hardware components. The software algorithms for the two systems is different, as this Virtuoso submission is for the breast tumor marker HER2, while the PATHIAM System is for the breast turnor markers p53 and Ki-67.

Page 1 of 10

{1}------------------------------------------------

Image /page/1/Picture/0 description: The image shows the logo for Ventana, a member of the Roche Group. The logo consists of a stylized sun-like symbol with eight arrow-shaped rays pointing inward, followed by the word "VENTANA" in bold, sans-serif font. Below the logo, the text "A Member of the Roche Group" is written in a smaller, serif font.

807.92 (a)(4): Device Description

General Description

Additional Materials Required:

Ventana PATHWAY® anti-HER2/neu (4B5) rabbit monoclonal primary . antibody
. Reagents for visualization, such as universal DAB chromogen
Associated materials for completing immunohistochemical staining according . 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:

{2}------------------------------------------------

Image /page/2/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" in a smaller font.

Summary of Procedure

Samples are obtained as formalin-fixed, paraffin-embedded tissue blocks. Histologic sections are prepared and mounted onto glass slides. Slides are reacted with the HER2 (4B5) primary antibody, and are then visualized using universal 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 semi-quantitative result of 0, 1+, 2+, or 3+, and the pathologist has the choice of accepting the result or overriding with his/her own score.

807.92 (a)(5): Intended Use

{3}------------------------------------------------

Image /page/3/Picture/0 description: The image shows the Ventana logo, which consists of a stylized sun-like symbol on the left and the word "VENTANA" in bold, sans-serif font on the right. A registered trademark symbol is present next to the last letter. Below the logo, there is a line of text that reads "A Member of the Roche Group" in a smaller, serif font.

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

The similarities and differences among the analogous test systems are described below.

Characteristic	Virtuoso™ IHC HER2(4B5)	Aperio ScanScope® XTSystemK080564	PATHIAM™ with iScanfor p53 and Ki-67K092333
	This device is intended forin vitro diagnostic (IVD)use.	This device is intended forin vitro diagnostic (IVD)use.	This device is intended forin vitro diagnostic (IVD)use.
	The Virtuoso Systemprovides automated digitalslide creation, management,analysis, and viewing. It isintended for IVD use as anaid to the pathologist in thedisplay, detection, counting,review and classification oftissues and cells of clinicalinterest based on particularmorphology, color, size,intensity, pattern and shape.	The ScanScope® System isan automated digital slidecreation, management,viewing and analysissystem. It is intended forIVD use as an aid to thepathologist in the display,detection, counting andclassification of tissues andcells of clinical interestbased on particular color,intensity, size, pattern andshape.	The PATHIAM System isintended as an aid to thepathologist to detect, count,and classify cells of clinicalinterest based onrecognition of cellularobjects of particular color,size, and shape, usingappropriate controls toassure the validity of thescores.
IntendedUse/Indicationsfor Use	The IHC HER2 (4B5)Digital Read and ImageAnalysis applications areintended for use as an aid tothe pathologist in thedetection and semi-quantitative measurement ofHER2 protein in formalin-fixed, paraffin-embeddednormal and neoplastictissue. HER2 results areindicated for use as an aidin the management,prognosis and prediction oftherapy outcomes in breastcancer. When used withVentana Medical Systems,Inc. PATHWAY® anti-HER2/neu (4B5) RabbitMonoclonal PrimaryAntibody, it is indicated foruse as an aid in theassessment of breast cancer	The IHC HER2 TunableImage Analysis applicationis intended for use as anaccessory to the DakoHercepTest™ to aid in thedetection and semi-quantitative measurement ofHER2/neu (c-erbB-2) informalin-fixed, paraffin-embedded normal andneoplastic tissue. Whenused with the DakoHercepTest™, it isindicated for use as an aidin the assessment of breastcancer patients for whomHERCEPTIN®(Trastuzumab) treatment isbeing considered.	The p53/Ki-67 applicationsare intended for use as anaid to the pathologist toquantify the percentage ofpositively stained nuclei informalin-fixed, paraffin-embedded breast tissuespecimens stained withspecific monoclonalantibodies and visualizedwith DAB chromogen todetect both wild-type andmutant nuclear proteins, asspecified in the instructionsfor these reagents
	patients for whomHERCEPTIN®(Trastuzumab) treatment isbeing considered.
Characteristic	Virtuoso™ IHCHER2 (4B5)	Aperio ScanScope® XTSystemK080564	PATHIAMTM with iScanfor p53 and Ki-67-K092333
Specimen Type	Formalin-fixed, paraffin-embedded tissue stained byimmunohistochemicaltechnique	Same	Same
System Operation(Digital Read andImage Analysis)	Histologic observation by apathologist through theviewer and image analysissystems	N/A- also, the Aperiosystem utilizes a tunablemodel vs a pre-calibrated,locked model	Same as Virtuoso HER2(4B5)
Hardware andSoftware	BioImagene (now Ventana)iScan slide scanner,computer, color monitor,proprietary software forHER2 (4B5)	Automated digital slidescanner, computer, colormonitor, and image analysissoftware and digitalpathology informationmanagement software	BioImagene (now Ventana)iScan slide scanner,computer, color monitor,proprietary software for p53and Ki-67
Platform Components	mouse, keyboard, windowsweb browser.	mouse and keyboard	Same as Virtuoso HER2(4B5)
Primary Antibody(Assay) Reagent	Ventana PATHWAY HER2(4B5) (P990081 S003)	Dako Reagents for HER2	Dako p53) and Dako Ki-67(reagents are Class I. 510(k)exempt)
Ancillary Reagents	DAB chromogen kits	Same	Same
Localization ofIHC positive stain	Cytoplasmic membrane	Cytoplasmic membrane	Nucleus
Interpretation	Interpretation is performedby the pathologist.	Same	Same

{4}------------------------------------------------

Image /page/4/Picture/0 description: The image shows the Ventana Medical Systems logo. The logo consists of a stylized sun-like symbol on the left, followed by the word "VENTANA" in bold, uppercase letters. A registered trademark symbol is located to the upper right of the last letter.

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

The Virtuoso System for IHC HER2 (4B5) was clinically validated via two studies. The first (primary) study evaluated overall system performance in terms of: (1) agreement between the reference manual method (with a traditional microscope) and both the digital read (DR) and image analysis (IA) applications of the Virtuoso system, (2) intra-pathologist/inter-day reproducibility of the two Virtuoso applications, and (3) inter-pathologist reproducibility of the two Virtuoso applications.

In the second study, scanner precision was evaluated in an isolated fashion via a cross-over design from the primary study. In this second study, a subset of the clinical cases (n = 40) was scanned two more times with two different scanners at two separate locations. This study evaluated scanner precision of the image analysis application only for both inter-scanner precision and intra-

{5}------------------------------------------------

Image /page/5/Picture/0 description: The image shows the word "VENTANA" in bold, black letters. To the left of the word is a symbol that looks like a sun made of arrows. A registered trademark symbol is to the right of the word.

scanner/inter-day precision, as the image analysis application is the more sensitive of the two applications, and it generates an instrument-generated HER2 score that is not affected by memory bias as would be the case with human interpretations. The data from both studies are summarized below.

Agreement/Concordance

Virtuoso Digital Read vs Manual Method a.
Each pathologist's Virtuoso digital read results were compared to their manual results. The data were categorized as "neg" and "pos" using HER2 classifications of 0 and 1+ to describe negative, and 2+ and 3+ to describe positive. The overall agreements across the three sites were: 93%, 83%, and 91%, respectively. The data, with the 95% confidence intervals (CI) around the agreements are shown below.

2 x 2 Table
Confusion Matrix	Digital
	Site 1(n = 119)	Site 2(n = 120)	Site 3(n = 118)
	Neg Pos	Neg Pos	Neg Pos
Manual	Neg (0, 1+)	64	4	51	1	54	4
	Pos (2+, 3+)	4	47	20	48	7	53
	% Agreement	93%		83%		91%
	(95% CI)	(87% - 97%)		(75% - 88%)		(84% - 95%)

Agreement: Digital Read vs Manual (manual = true score)

b. Virtuoso Image Analysis vs Manual Method

The same analysis as performed for digital read was performed for image analysis. The overall agreements across the three sites were: 92%, 82%, and 88%, respectively. That data table, along with the 95% Cls, is presented below.

Agreement: Image Analysis vs Manual (manual = true score)

2 x 2 Table

{6}------------------------------------------------

Image /page/6/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 capital letters. A registered trademark symbol is present to the right of the word "VENTANA".

Confusion Matrix	Image Analysis
	Site 1	Site 2	Site 3
	(n = 117)	(n = 120)	(n = 120)
	Neg	Pos	Neg	Pos	Neg	Pos
Manual	Neg (0, 1+)	67	0	52	0	59	1
	Pos (2+, 3+)	9	41	22	46	14	46
	% Agreement	92%		82%		88%
	(95% CI)	(86% -	96%)	(74% -	88%)	(80% -	92%)

Reproducibility

a. Intra-Pathologist/Inter-Day (pair-wise comparisons, Session 1 vs Session 2, Session 1 vs Session 3, Session 2 vs Session 3)

Digital Read

The agreements between each of the three comparisons across three sessions with the same pathologist are shown below. The total agreements ranged from 90% to 95%, and the data (with 95% CIs) are shown below.

Intra-Pathologist Digital
Confusion Matrix	Session 2		Session 3		Session 3
	Neg	Pos	Neg	Pos	Neg	Pos
Session 1	Neg	17	17	0	17	0
	Pos	22	2	20	4	18
Session 2	Neg	19					19	0
	Pos	21					3	18
% Agreement		95%		90%		93%
(95% CI)		(83% - 99%)		(76% - 96%)		(80% - 97%)

Image Analysis

The agreements between each of the three comparisons across three sessions with the same pathologist are shown below. The agreements were 100% for each comparison.

{7}------------------------------------------------

Image /page/7/Picture/0 description: The image shows the word "VENTANA" in all caps with a registered trademark symbol. To the left of the word is a symbol that looks like a sun or asterisk. The font is sans-serif and the text is black on a white background.

Intra-Pathologist Image Analysis
Confusion Matrix	Session 2		Session 3		Session 3
	Neg	Pos	Neg	Pos	Neg	Pos
Session 1	Neg	24	24	23	23	23	23
	Pos	16	0	0	0	0	16
Session 2	Neg	24				23	0
	Pos	16				0	16
% Agreement			100%		100%		100%
(95% CI)			(91% - 100%)		(91% - 100%)		(91% - 100%)

b. Inter-Pathologist (pair-wise comparisons, Pathologist 1 vs Pathologist 2, Pathologist 1 vs Pathologist 3, Pathologist 2 vs Pathologist 3)

Manual Read

The three manual readings across the three pathologists were compared to each other. There was no acceptance criterion for this evaluation, as this aspect of the study assesses the differences in the human component of IHC interpretations. The agreements ranged from 85% to 90%, indicating commonality among the three pathologists.

Inter-Pathologist Manual
	Site 2		Site 3		Site 3
	Confusion Matrix	Neg	Pos	Neg	Pos	Neg	Pos
Site 1	Neg	51	17	58	10	60	60
	Pos	1	50	2	49	60	60
Site 2	Neg	52	68	60	60	48	4
	Pos	68	51	2	49	12	56
% Agreement		85%		90%		87%
(95% CI)		(77% - 90%)		(83% - 94%)		(79% - 92%)

Digital Read

The reproducibility in the Virtuoso digital readings among the three pathologists is shown below, along with the 95% CIs. The percent total agreements ranged from 90% to 92%, satisfying the minimum requirement of 75%.

{8}------------------------------------------------

Image /page/8/Picture/0 description: The image shows the Ventana Medical Systems logo. The logo consists of a stylized sun-like symbol on the left, followed by the word "VENTANA" in bold, sans-serif font, with a registered trademark symbol. Below the word "VENTANA" is the text "A Member of the Roche Group" in a smaller font size.

Inter-Pathologist Digital
Confusion Matrix			Site 2		Site 3		Site 3
			Neg	Pos	Neg	Pos	Neg	Pos
Site 1	Neg	68	71	49	61	57	61	57
	Pos	51	65	3	58	8
Site 2	Neg		71				59	10
	Pos		49				2	47
% Agreement				92%		91%	90%
(95% CI)				(86% - 96%)		(84% - 95%)	(83% - 94%)

Page 9 of 10

{9}------------------------------------------------

Image /page/9/Picture/0 description: The image shows the Ventana logo, which includes a stylized sun-like symbol on the left and the word "VENTANA" in bold, sans-serif font to the right. A registered trademark symbol is present next to the last "A" in "VENTANA". Below the logo, the text "A Member of the Roche Group" is displayed in a smaller, serif font, indicating Ventana's affiliation with the Roche Group.

Image Analysis

The reproducibility in the Virtuoso image analysis interpretations among the three pathologists is shown below, along with the 95% Cls. The percent agreements ranged from 93% to 95%, satisfying the minimum requirement of 75%.

Inter-Pathologist Image Analysis
Confusion Matrix	Site 2		Site 3		Site 3
	Neg	Pos	Neg	Pos	Neg	Pos
Site 1	Neg	71	5	71	5
	Pos	2	40	1	41
Site 2	Neg					69	5
	Pos					4	42
% Agreement		94%		95%		93%
(95% CI)		(88% - 97%)		(89% - 98%)		(86% - 96%)
	76	74	46	73	47	73	47
	42	74	46

Scanner Precision

When the iScan scanner was evaluated for inter-site and intra-site/inter-day precision, the percent agreements for three image analysis filed of views were in excess of 90% for every comparison.

807.92 (b)(3): Conclusions from Clinical Testing

Concordance, reproducibility, and precision studies were performed for the Virtuoso System for IHC HER2 (4B5). The test system was shown to be safe and effective for its intended use.

{10}------------------------------------------------

DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/10/Picture/1 description: The image shows the logo for the United States Department of Health and Human Services. The logo features a stylized depiction of a human figure with outstretched arms, symbolizing care and protection. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged in a circular pattern around the figure.

Public Health Service

Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993

Ventana Digital Pathology c/o Mr. Indu Lakshman Senior Director QA/ RA 919 Hermosa Court Sunnyvale, CA 94085

OCT 1 2 2011

Re: K111543

Trade/Device Name: Ventana Virtuoso™ System for HER2 (4B5) Regulation Number: 21 CFR §864.1860 Regulation Name: Immunohistochemistry reagents and kits Regulatory Class: Class II Product Codes: NOT, OEO Dated: September 27, 2011 Received: September 28, 2011

Dear Mr. Lakshman:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determind the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predically quivalent (for the industions for prior to May 28, 1976, the enactment date of the Medical Devices marketed in interstate commerce
have been reclassified in accordance with the maintents, 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.

If your device is classified (see above) into class II (Special Controls), it may be subject to such i additional controls. Existing major regulations affecting your device to such
additional controls. Existing major regulations affecting your device can be found in Title 21 of Federal Regulations (CFR), Parts 800 to 895. In addition, FDA may publish firsther 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 administed by other Fequirements of the Act or
all the Act's requirements including, but not limited to all the Act's requirements, including by oner Federal agencies. You must comply with labeling (21 CFR Parts 801 and 809); medical device reporting (21 CFR Part 807);
adverse events) (21 CFR 801); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); and good manufacturing of medical device-relation quality systems (QS) regulation (21 CFR Part 820). This letter will allow you to begin maketing and of the ( ( ( ) a gamest (11 OF IT all 820). This letter will allow you to begin makes
your device as described in your Section 510(k) premarket notification. The FDA f

{11}------------------------------------------------

Page 2 – Mr. Indu Lakshman

substantial equivalence of your device to a legally marketed predicate device results in a classification for your device to a legally marketed proceed to the market.

If you desire specific advice for your device on our labeling regulation (21 CFR Parts 801 and 809), and 809), and 809), and please contact the Office of your device on our labeling regulation (21 CFR Parts 801 and 800
Also, please note the requiried. "Mich and in all result and Safety at (301) 796 Also, please note the regulation and Sate Device Evaluation and Satety at (301) 796-5450.
CFR Part 807 97) For questions roceding the only of reference to premarket notific CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR
regulation (21 CFR Part 803), please go to 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 on your responsibilities under the Act from the Division the Division 638-2041 or (301) 796-7100 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html.

Sincerely yours,

for Reena Philip
Maria M. Chan, Ph.D.

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

Enclosure

{12}------------------------------------------------

INDICATIONS FOR USE

510(k) Number (if Known):

111543

Device Name: Virtuoso™ System for IHC HER2 (4B5)

Indications for Use

The Virtuoso™ System for IHC HER2 (4B5) is for digital read and image analysis applications. This particular Virtuoso system is intended for use as an aid to the pathologist in the detections. and semi-quantitative measurement of HER2 protein in formalin-fixed, paraffin-mbedded normal and neoplastic tissue. This device is an accessory to Ventana Medical Systems, Inc. PATHWAY® anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody. The PATHMS, Inc.
PATHWA Y® anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody. The PATHWAY® anti-HER2/neu (4B5) Rabit Monoclonal Primary Antibody is indicated for use as an aid in the assessment of breast cancer patients for whom HERCEPTIN® (Trastuzumab) treatment is being

The IHC HER2 4B5 Digital Read and Image Analysis applications are adjunctive NOTE: computer-assisted methodologies for the qualified pathologist in the acquisitions are adjunctive measurement of images from microscope glass slides of breast cancer specimens stained for the presence of HER-2/neu receptor 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 PATHWAY® anti-HER-2/neu (4B5) Rabbit Monocloal Primary Antibody assay used to the the validity of the iScan System for IHC HERZ 4BS Digital Read and Image Analysis soces The actual correlation of PATHWAY® anti-HER-2/neu (4B5) to clinical outcome has not been established.

Prescription Use	X
(Part 21 CFR 801 Subpart D)

AND/OR

Over-The-Counter Use (21 CFR 801 Subpart C)

(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)

Concurrence of CDRH, Office of In Vitro Diagnostics (OIVD) Division Sign-Off
Office of In Vitro Diagnostic Device Evaluation and Safety
510K	K111543

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.