VIRTUOSO (TM) SYSTEM FOR IHC HER2 (4B5)

K111543 · Ventana Medical Systems, Inc. · NOT · Oct 12, 2011 · Hematology

Device Facts

• Record ID: K111543
• Device Name: VIRTUOSO (TM) SYSTEM FOR IHC HER2 (4B5)
• Applicant: Ventana Medical Systems, Inc.
• Product Code: NOT · Hematology
• Decision Date: Oct 12, 2011
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 864.1860
• Device Class: Class 2

Intended Use

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 the 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.

Device Story

Virtuoso System is an instrument-plus-software digital pathology solution for IHC-stained slides. Inputs: digital images of formalin-fixed, paraffin-embedded tissue slides captured by iScan scanner. Operation: pathologist selects fields of view (FOVs) for analysis; software provides quantitative data and semi-quantitative HER2 scores (0, 1+, 2+, 3+). Context: used in pathology labs; operated by qualified pathologists. Output: digital images, annotations, measurements, and semi-quantitative HER2 scores displayed on monitor. Decision-making: pathologist reviews software-generated scores and accepts or overrides them; software is adjunctive and requires human intervention. Benefit: provides consistent, quantitative assessment of HER2 protein expression to aid in breast cancer therapy decisions.

Clinical Evidence

Validation included three-site study (n=120 specimens) comparing manual microscopy (reference) to Digital Read (DR) and Image Analysis (IA). Overall agreement for DR vs. manual ranged 83-93%; IA vs. manual ranged 82-92%. Reproducibility study (n=40) assessed intra-pathologist/inter-day and inter-pathologist concordance; all met ≥75% acceptance criteria. Scanner precision study (n=40) evaluated inter-scanner and intra-scanner/inter-day performance, showing >90% agreement for IA fields of view.

Technological Characteristics

System includes iScan slide scanner, computer, monitor, keyboard, mouse, and proprietary software. Uses Windows web browser-based interface. Analyzes formalin-fixed, paraffin-embedded tissue stained with DAB chromogen. Software performs image quality assessment and quantitative analysis of HER2 protein expression. Connectivity is networked/web-based.

Indications for Use

Indicated for use as an aid to pathologists in the detection and semi-quantitative measurement of HER2 protein in formalin-fixed, paraffin-embedded normal and neoplastic breast tissue. Used as an accessory to the PATHWAY anti-HER2/neu (4B5) antibody to assist in the assessment of breast cancer patients being considered for HERCEPTIN (Trastuzumab) therapy.

Regulatory Classification

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.

Special Controls

(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.

Predicate Devices

• Aperio ScanScope® XT System (k080564)
• PATHIAM™ with iScan for p53 and Ki-67 (k092333)

Submission Summary (Full Text)

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# 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: | [phone] |
| FAX: | [phone] |
| 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.

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#### 807.92 (a)(4): Device Description

#### General 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.

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:

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#### 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

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.

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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<br>(4B5) | Aperio ScanScope® XT<br>System<br>K080564 | PATHIAM™ with iScan<br>for p53 and Ki-67<br>K092333 |
|----------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| | This device is intended for<br>in vitro diagnostic (IVD)<br>use. | This device is intended for<br>in vitro diagnostic (IVD)<br>use. | This device is intended for<br>in vitro diagnostic (IVD)<br>use. |
| | The Virtuoso System<br>provides automated digital<br>slide creation, management,<br>analysis, and viewing. It is<br>intended for IVD use as an<br>aid to the pathologist in the<br>display, detection, counting,<br>review and classification of<br>tissues and cells of clinical<br>interest based on particular<br>morphology, color, size,<br>intensity, pattern and shape. | The ScanScope® System is<br>an automated digital slide<br>creation, management,<br>viewing and analysis<br>system. It is intended for<br>IVD use as an aid to the<br>pathologist in the display,<br>detection, counting and<br>classification of tissues and<br>cells of clinical interest<br>based on particular color,<br>intensity, size, pattern and<br>shape. | The PATHIAM System is<br>intended as an aid to the<br>pathologist to detect, count,<br>and classify cells of clinical<br>interest based on<br>recognition of cellular<br>objects of particular color,<br>size, and shape, using<br>appropriate controls to<br>assure the validity of the<br>scores. |
| Intended<br>Use/Indications<br>for Use | The IHC HER2 (4B5)<br>Digital Read and Image<br>Analysis applications are<br>intended for use as an aid to<br>the pathologist in the<br>detection and semi-<br>quantitative measurement of<br>HER2 protein in formalin-<br>fixed, paraffin-embedded<br>normal and neoplastic<br>tissue. HER2 results are<br>indicated for use as an aid<br>in the management,<br>prognosis and prediction of<br>therapy outcomes in breast<br>cancer. When used with<br>Ventana Medical Systems,<br>Inc. PATHWAY® anti-<br>HER2/neu (4B5) Rabbit<br>Monoclonal Primary<br>Antibody, it is indicated for<br>use as an aid in the<br>assessment of breast cancer | The IHC HER2 Tunable<br>Image Analysis application<br>is intended for use as an<br>accessory to the Dako<br>HercepTest™ to aid in the<br>detection and semi-<br>quantitative measurement of<br>HER2/neu (c-erbB-2) in<br>formalin-fixed, paraffin-<br>embedded normal and<br>neoplastic tissue. When<br>used with the Dako<br>HercepTest™, it is<br>indicated for use as an aid<br>in the assessment of breast<br>cancer patients for whom<br>HERCEPTIN®<br>(Trastuzumab) treatment is<br>being considered. | The p53/Ki-67 applications<br>are intended for use as an<br>aid to the pathologist to<br>quantify the percentage of<br>positively stained nuclei in<br>formalin-fixed, paraffin-<br>embedded breast tissue<br>specimens stained with<br>specific monoclonal<br>antibodies and visualized<br>with DAB chromogen to<br>detect both wild-type and<br>mutant nuclear proteins, as<br>specified in the instructions<br>for these reagents |
| | patients for whom<br>HERCEPTIN®<br>(Trastuzumab) treatment is<br>being considered. | | |
| Characteristic | Virtuoso™ IHC<br>HER2 (4B5) | Aperio ScanScope® XT<br>System<br>K080564 | PATHIAMTM with iScan<br>for p53 and Ki-67-<br>K092333 |
| Specimen Type | Formalin-fixed, paraffin-<br>embedded tissue stained by<br>immunohistochemical<br>technique | Same | Same |
| System Operation<br>(Digital Read and<br>Image Analysis) | Histologic observation by a<br>pathologist through the<br>viewer and image analysis<br>systems | N/A- also, the Aperio<br>system utilizes a tunable<br>model vs a pre-calibrated,<br>locked model | Same as Virtuoso HER2<br>(4B5) |
| Hardware and<br>Software | BioImagene (now Ventana)<br>iScan slide scanner,<br>computer, color monitor,<br>proprietary software for<br>HER2 (4B5) | Automated digital slide<br>scanner, computer, color<br>monitor, and image analysis<br>software and digital<br>pathology information<br>management software | BioImagene (now Ventana)<br>iScan slide scanner,<br>computer, color monitor,<br>proprietary software for p53<br>and Ki-67 |
| Platform Components | mouse, keyboard, windows<br>web browser. | mouse and keyboard | Same as Virtuoso HER2<br>(4B5) |
| Primary Antibody<br>(Assay) Reagent | Ventana PATHWAY HER2<br>(4B5) (P990081 S003) | Dako Reagents for HER2 | Dako p53) and Dako Ki-67<br>(reagents are Class I. 510(k)<br>exempt) |
| Ancillary Reagents | DAB chromogen kits | Same | Same |
| Localization of<br>IHC positive stain | Cytoplasmic membrane | Cytoplasmic membrane | Nucleus |
| Interpretation | Interpretation is performed<br>by the pathologist. | Same | Same |

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## 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-

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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<br>(n = 119) | Site 2<br>(n = 120) | Site 3<br>(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

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| 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.

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| 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%.

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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%) | |

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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.

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# 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

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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 [phone].
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 [phone] 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 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 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 |