VIRTUOSO SYSTEM FOR IHC KI-67 (30-9)

K111755 · Ventana Medical Systems, Inc. · NOT · Feb 22, 2012 · Hematology

Device Facts

• Record ID: K111755
• Device Name: VIRTUOSO SYSTEM FOR IHC KI-67 (30-9)
• Applicant: Ventana Medical Systems, Inc.
• Product Code: NOT · Hematology
• Decision Date: Feb 22, 2012
• 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 Ki67 (30-9) 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 Ki67 (30-9) protein in formalin-fixed, paraffin-embedded normal and neoplastic tissue. This device is an accessory to the Ventana Medical Systems, Inc. CONFIRM™ anti-Ki67 (30-9) Rabbit Monoclonal Primary Antibody assay. The Ventana Medical Systems, Inc. CONFIRM™ anti-Ki67 (30-9) assay is indicated for use in assessing the proliferative activity of normal and neoplastic breast tissue. When used with this assay, the Virtuoso™ System for Ki67 (30-9) is indicated for use as an aid in the assessment of Ki-67 status in breast cancer patients (but is not the sole basis for treatment). Note: The IHC Ki67 (30-9) 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 Ki67 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-Ki67 (30-9) Rabbit Monoclonal Primary Antibody assay to assure the validity of the Virtuoso™ System for Ki67 (30-9) Digital Read and Image Analysis scores. The actual correlation of CONFIRM™ anti-Ki67 (30-9) Rabbit Monoclonal Primary antibody assay to clinical outcome has not been established.

Device Story

Virtuoso System is an instrument-plus-software digital pathology solution for formalin-fixed, paraffin-embedded tissue slides. Hardware includes iScan slide scanner, computer, and monitor. Software provides two modes: Digital Read (pathologist scores digital image on monitor) and Image Analysis (automated algorithm-assisted scoring). Pathologist selects fields of view; system performs image enhancement, tissue/background separation, nuclear identification, and cell classification based on staining intensity/extent. Output is a semi-quantitative Ki67 score presented on-screen for pathologist verification. Used in pathology laboratories; operated by qualified pathologists. Device acts as an accessory to Ventana CONFIRM anti-Ki67 (30-9) assay. Benefits include consistent, reproducible assessment of proliferative activity in breast cancer specimens; requires human intervention for all analysis steps; software makes no independent clinical interpretations.

Clinical Evidence

Clinical validation included two studies. Study 1 (n=114-120 per site across 4 sites) compared Virtuoso digital read/image analysis to manual microscopy. Overall agreement ranged 81-92% for digital read and 81-88% for image analysis. Study 2 evaluated scanner precision and pathologist reproducibility. Intra-pathologist reproducibility (digital read) showed 98-100% agreement; image analysis showed 89-97% agreement. Inter-pathologist reproducibility (digital read) showed 71-85% agreement; image analysis showed 84-93% agreement. Scanner precision was ~90%.

Technological Characteristics

System includes iScan slide scanner, workstation (PC, monitor, keyboard, mouse), and web-based software. Operates on formalin-fixed, paraffin-embedded tissue slides stained with IHC reagents (DAB chromogen). Connectivity via Windows web browser-based interface. Software performs image quality assessment and quantitative analysis of nuclear staining. No specific ASTM material standards cited.

Indications for Use

Indicated for use as an aid to pathologists in the detection and semi-quantitative measurement of Ki67 (30-9) protein in formalin-fixed, paraffin-embedded normal and neoplastic breast tissue to assess proliferative activity in breast cancer patients. Not for use as the sole basis for treatment.

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

• PATHIAM™ System with iScan for p53 and Ki-67 (K092333)

Submission Summary (Full Text)

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VENTANA®
A Member of the Roche Group

# FEB 2 2 2012

# 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 K111755.

| 807.92 (a)(1): Name: | Ventana Digital Pathology |
|----------------------|------------------------------------------|
| Address: | 919 Hermosa Court<br>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 Ki-67 (30-9)

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

Classifications: 21 CFR § 864.1860- Immunohistochemistry reagents and kits

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

The Virtuoso System for IHC Ki-67 (30-9) is substantially equivalent to BioImagene's PATHIAMTM System with iScan for p53 and Ki-67 (BioImagene, Inc. [now Ventana Digital Pathology], Sunnyvale, CA), cleared under pre-market notification K092333 on October 27, 2010. Both devices are digital pathology and image analysis systems for the consistent assessment of pathology interpretations using immunohistochemically stained slides (in this case, stained for Ki-67 expression), and both systems include slide scanner hardware, and software that both automates the procedural steps and performs the analyses.

#### 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

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Image /page/1/Picture/0 description: The image shows the word "VENTANA" in all capital letters. To the left of the word is a symbol that looks like a star made up of arrowheads. To the right of the word is a registered trademark symbol.

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.

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 CONFIRM™ Ki-67 (30-9) rabbit monoclonal primary antibody .
- Reagents for visualization, such as universal DAB universal 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.

#### 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 p53 (DO7) 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 choice of accepting the result or overriding with his/her own score for some or all FOVs.

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Image /page/2/Picture/0 description: The image shows the Ventana logo. The logo consists of a stylized sunburst symbol to the left of the word "VENTANA", with a registered trademark symbol next to the last "A". Below the word "VENTANA" is the text "A Member of the Roche Group".

### 807.92 (a)(5): Intended Use/ Indication(s) 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 Ki67 (30-9) 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 Ki67 (30-9) protein in formalin-fixed, paraffin-embedded normal and neoplastic tissue. This device is an accessory to the Ventana Medical Systems, Inc. CONFIRM™ anti-Ki67 (30-9) Rabbit Monoclonal Primary Antibody assay. The Ventana Medical Systems, Inc. CONFIRM™ anti-Ki67 (30-9) assay is indicated for use in assessing the proliferative activity of normal and neoplastic breast tissue. When used with this assay, the Virtuoso™ System for Ki67 (30-9) is indicated for use as an aid in the assessment of Ki-67 status in breast cancer patients (but is not the sole basis for treatment).

Note: The IHC Ki67 (30-9) 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 Ki67 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-Ki67 (30-9) Rabbit Monoclonal Primary Antibody assay to assure the validity of the Virtuoso™ System for Ki67 (30-9) Digital Read and Image Analysis scores. The actual correlation of CONFIRM™ anti-Ki67 (30-9) Rabbit Monoclonal Primary antibody assay to clinical outcome has not been established.

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Image /page/3/Picture/0 description: The image shows the logo for Ventana, a member of the Roche Group. The logo consists of a stylized sunburst symbol to the left, followed by the word "VENTANA" in bold, uppercase letters. Below the word "VENTANA" is the text "A Member of the Roche Group" in a smaller, italicized font.

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

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

| Characteristic | Virtuoso™ IHC Ki-67 (30-9) | PATHIAM™ with iScan for<br>p53 and Ki-67 K092333 |
|----------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended<br>Use/Indications<br>for Use | This device is intended for in vitro<br>diagnostic (IVD) use.<br><br>The Virtuoso System provides automated<br>digital slide creation, management,<br>analysis, and viewing. It is intended for<br>IVD use as an aid to the pathologist in the<br>display, detection, counting, review and<br>classification of tissues and cells of clinical<br>interest based on particular morphology,<br>color, size, intensity, pattern and shape.<br><br>The IHC Ki-67 (30-9) Digital Read and<br>Image Analysis applications are intended<br>for use as an aid to the pathologist in the<br>detection and quantitative measurement of<br>Ki-67 protein in formalin-fixed, paraffin-<br>embedded normal and neoplastic tissue.<br>When used with Ventana Medical<br>Systems, Inc. CONFIRM™ anti-Ki-67<br>(30-9) Rabbit Monoclonal Primary<br>Antibody, it is indicated for use as an aid<br>in the assessment p53 protein of breast<br>cancer patients (but is not the sole basis for<br>treatment). | This device is intended for in vitro<br>diagnostic (IVD) use.<br><br>The PATHIAM System is intended as an<br>aid to the pathologist to detect, count, and<br>classify cells of clinical interest based on<br>recognition of cellular objects of particular<br>color, size, and shape, using appropriate<br>controls to assure the validity of the scores.<br><br>The p53/Ki-67 applications are intended<br>for use as an aid to the pathologist to<br>quantify the percentage of positively<br>stained nuclei in formalin-fixed, paraffin-<br>embedded breast tissue specimens stained<br>with specific monoclonal antibodies and<br>visualized with DAB chromogen to detect<br>both wild-type and mutant nuclear<br>proteins, as specified in the instructions for<br>these reagents |
| Specimen Type | Formalin-fixed, paraffin-embedded tissue<br>stained by immunohistochemical technique | Same |
| System Operation<br>(Digital Read and<br>Image Analysis) | Histologic observation by a pathologist<br>through the viewer and image analysis<br>systems | Same |
| Hardware and<br>Software | BioImagene (now Ventana) iScan slide<br>scanner, computer, color monitor,<br>proprietary software for Ki-67 (30-9) | BioImagene (now Ventana) iScan slide<br>scanner, computer, color monitor,<br>proprietary software for p53 and Ki-67 |
| Platform Components | mouse, keyboard, windows web browser. | Same |
| Primary Antibody<br>(Assay) Reagent | Ventana CONFIRM™ Ki-67 (30-9)<br>(reagent is Class I, 510(k) exempt) | Dako p53 and Dako Ki-67<br>(reagents are Class I, 510(k) exempt) |
| Ancillary Reagents | DAB chromogen kits | Same |
| Localization of<br>IHC positive stain | Nucleus | Nucleus |
| Interpretation | Interpretation is performed by the<br>pathologist. | Same |

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Image /page/4/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. Below the word "VENTANA" is the text "A Member of the Roche Group" in a smaller font size.

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

The Virtuoso System for IHC KI-67 (30-9) was clinically validated via two studies. The first (primary) study evaluated overall system performance across four sites in terms of 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. In the second study, scanner precision was evaluated in an isolated fashion among three pathologists for inter-pathologist reproducibility of the two Virtuoso applications, and intra-pathologist/inter-day reproducibility of the two Virtuoso applications was also evaluated. 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 Ki-67 classifications of less than or equal to 10% staining to describe negative, and greater than 10% to describe positive. The overall agreements across the four sites were: 92%, 81%, 86%, and 87%, respectively. The data, with the 95% confidence intervals (CI) around the agreements are shown below.

| Confusion Matrix | Site 1<br>(n = 120) | | Site 2<br>(n = 118) | | Site 3<br>(n = 114) | | Site 4<br>(n = 118) | | |
|----------------------|---------------------|----------------------|---------------------|----------------------|---------------------|--------------------|---------------------|--------------------|----|
| | Neg | Pos | Neg | Pos | Neg | Pos | Neg | Pos | |
| Manual | Neg (≤10%) | 37 | 10 | 43 | 0 | 46 | 3 | 59 | 5 |
| | Pos (>10%) | 0 | 73 | 23 | 52 | 13 | 52 | 10 | 44 |
| Manual | % Agreement | 92%<br>(85% - 95%) | | 81%<br>(72% - 87%) | | 86%<br>(78% - 91%) | | 87%<br>(80% - 92%) | |
| | (95% CI) | | | | | | | | |
| Negative % Agreement | | 79%<br>(65% - 88%) | | 100%<br>(92% - 100%) | | 94%<br>(83% - 98%) | | 92%<br>(83% - 97%) | |
| Positive % Agreement | | 100%<br>(95% - 100%) | | 69%<br>(58% - 79%) | | 80%<br>(69% - 88%) | | 81%<br>(69% - 90%) | |

#### Ki-67 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: 88%, 86% and 81%, respectively. That data table, along with the 95% Cls, is presented below.

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Image /page/5/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 all caps. A registered trademark symbol is located to the right of the word. The text "A Member of the Roche Group" is located below the logo.

A Member of the Roche Group

| Confusion Matrix | Image Analysis | | Site 1 | | Site 2 | | Site 3 | | Site 4 | |
|----------------------|----------------|--------------------|-----------|--------------------|-----------|--------------------|-----------|----------------------|-----------|-----|
| | | | (n = 120) | | (n = 117) | | (n = 114) | | (n = 117) | |
| | | | Neg | Pos | Neg | Pos | Neg | Pos | Neg | Pos |
| Manual | Neg (≤10%) | 37 | 10 | 40 | 2 | 42 | 7 | 41 | 22 | |
| | Pos (>10%) | 5 | 68 | 14 | 61 | 9 | 56 | 0 | 54 | |
| % Agreement | | 88%<br>(80% - 92%) | | 86%<br>(79% - 91%) | | 86%<br>(78% - 91%) | | 81%<br>(73% - 87%) | | |
| Negative % Agreement | | 79%<br>(65% - 88%) | | 95%<br>(84% - 99%) | | 86%<br>(73% - 93%) | | 65%<br>(53% - 76%) | | |
| Positive % Agreement | | 93%<br>(85% - 97%) | | 81%<br>(71% - 89%) | | 86%<br>(76% - 93%) | | 100%<br>(93% - 100%) | | |

## Ki-67 Agreement: Image Analysis vs Manual (manual = true score)

#### 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 98% to 100%, 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 | 3 | 2 | 1 | 1 | 1 | 1 |
| | Pos | 37 | 0 | 37 | 0 | 36 | |
| Session 2 | Neg | 2 | | | | 1 | 0 |
| | Pos | 38 | | | | 0 | 37 |
| % Agreement | | | 98% | | 97% | | 100% |
| (95% CI) | | | (87% - 100%) | | (87% - 100%) | | (91% - 100%) |

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Image /page/6/Picture/0 description: The image shows the word "VENTANA" in all caps, with a registered trademark symbol next to the last letter. To the left of the word is a circular design made up of arrow shapes pointing inward. Below the word "VENTANA" is the text "A Member of the Roche Group".

#### Image Analysis

The agreements between each of the three comparisons across three sessions with the same pathologist are shown below. The agreements ranged from 89% to 97%, and the data (with 95% CIs) are shown below.

| Intra-Pathologist Image Analysis | | | | | | | |
|----------------------------------|-----|-----------|-------------|-----------|--------------|-----------|-------------|
| Confusion Matrix | | Session 2 | | Session 3 | | Session 3 | |
| | | Neg | Pos | Neg | Pos | Neg | Pos |
| Session 1 | Neg | 8 | 5 | 7 | 3 | 7 | 1 |
| | Pos | 30 | 1 | 0 | 29 | 0 | 30 |
| Session 2 | Neg | 6 | 32 | | | 5 | 1 |
| | Pos | 32 | | | | 2 | 30 |
| % Agreement | | | 89% | | 97% | | 92% |
| (95% CI) | | | (76% - 96%) | | (87% - 100%) | | (79% - 97%) |

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

The reproducibility in the Virtuoso digital readings among three pathologists is shown below, along with the 95% CIs. The percent total agreements ranged from 71% to 85%.

| Inter-Pathologist Digital | | | | | | | | |
|---------------------------|--------|-----|--------|------|--------|------|-------|------|
| Confusion Matrix | Site 2 | | Site 3 | | Site 3 | | | |
| | Neg | Pos | Neg | Pos | Neg | Pos | | |
| | 66 | 52 | 61 | 55 | 61 | 55 | | |
| Site 1 | Neg | 37 | 35 | 0 | 30 | 3 | | |
| | Pos | 83 | 31 | 52 | 31 | 52 | | |
| Site 2 | Neg | 66 | | | | 54 | 10 | |
| | Pos | 52 | | | | 7 | 45 | |
| % Agreement | | | 74% | | 71% | | 85% | |
| (95% CI) | | | (65%- | 81%) | (62%- | 78%) | (78%- | 91%) |

#### Image Analysis

The reproducibility in the Virtuoso image analysis interpretations among three pathologists is shown below, along with the 95% CIs. The percent agreements ranged from 84% to 93%.

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Image /page/7/Picture/0 description: The image shows the word "VENTANA" in all capital letters. To the left of the word is a symbol that looks like a star made of arrows. A registered trademark symbol is to the right of the last letter.

A Member of the Roche Group

| Inter-Pathologist Image Analysis | | | | | | |
|----------------------------------|-------------|-----|-------------|-----|-------------|-----|
| Confusion Matrix | Site 2 | | Site 3 | | Site 3 | |
| | Neg | Pos | Neg | Pos | Neg | Pos |
| | 54 | 63 | 52 | 63 | 52 | 63 |
| Site 1 | 37 | 2 | 36 | 1 | | |
| | 17 | 61 | 16 | 62 | | |
| Site 2 | | | | | 48 | 4 |
| | | | | | 4 | 59 |
| % Agreement | 84% | | 85% | | 93% | |
| (95% CI) | (76% - 89%) | | (78% - 91%) | | (87% - 96%) | |

#### Scanner Precision

When the iScan scanner was evaluated for inter-site and intra-site/inter-day precision, the percent agreements for three image analysis fields of views were in approximately 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 Ki-67 (30-9). The test system was shown to be safe and effective for its intended use.

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Image /page/8/Picture/1 description: The image shows the 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 image of three human profiles facing to the right, with flowing lines suggesting movement or connection.

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

Mr. Troy Quander Vice President, Regulatory Affairs Ventana Medical Systems, Inc. 1910 E. Innovation Park Drive Tuscon, Arizona 85755

# FEB 2 2 2012

Re: k111755 Virtuoso™ System for IHC Ki-67 (30-9) Trade/Device Name: 21 CFR §864.1860 Regulation Number: Immunohistrochemistry reagents and kits Regulation Name: Class II Regulatory Class: NON, NOT, OEO Product Code: January 18, 2012 Dated: January 19, 2012 Received:

Dear Mr. Quander:

We have reviewed your Section 510(k) premarket notification of intent to market the device we nave reviewed your becomen on the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate for use starcu in the onerobate) to region of the Medical Device Amendments, or to commerce provision in May 20, 1978, the eccordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). and Cosmetic Herefore, market the device, subject to the general controls provisions of the Act. The T ou may, merelore, manel the act include requirements for annual registration, listing of general controls provisions of the rice, 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 If your device is elassified (boo abor regulations affecting your device can be found in Title 21, additional controllo. Entitions (CFR), Parts 800 to 895. 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 Please be advised that I DA 3 issuates Cra business with other requirements of the Act that I Drivias made a and regulations administered by other Federal agencies.

You must comply with all the Act's requirements, including, but not limited to: registration and r ou must comply with an the Fiel CFR Parts 801 and 809); medical device reporting Ilsung (21 CFR Part 007); laooinig (21 verse events) (21 CFR 803); and good manufacturing of 1920); (reporting of inculcal device relation as releases (QS) regulation (21 CFR Part 200). This practice requirements as bet relax teting your device as described in your Section 510(k)

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Page 2 - Mr. Troy Quander

premarket notification. The FDA finding of substantial equivalence of your device to a legally premarked notification - results in a classification for your device and thus, permits your device to proceed to the market.

If you desire specific advice for your device on our labeling regulation (21 CFR Parts 801 and 11 you desire openite and In Vitro Diagnostic Device Evaluation and Safety at [phone]. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 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 Tou thay of Small Manufacturers, International and Consumer Assistance at its toll-free number [phone] or [phone] or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html.

Sincerely yours,

for 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

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# INDICATIONS FOR USE

510(k) Number (if Known):

K111755

Virtuoso™ System for IHC Ki-67 (30-9) Device Name:

#### Indications for Use

Indication(s) 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 Ki67 (30-9) 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 Ki67 (30-9); protein in formalin-fixed, paraffin-embedded normal and neoplastic tissue. This device is an accessory to the Ventana Medical Systems, Inc. CONFIRM™ anti-Ki67 (30-9) Rabbit Monoclonal Primary Antibody assay. The Ventana Medical Systems, Inc. CONFIRM™ anti-Ki67 (30-9) assay is indicated for use in assessing the proliferative activity of normal and neoplastic breast tissue. When used with this assay, the Virtuoso™ System for Ki67 (30-9) is indicated for use as an aid in the assessment of Ki-67 status in breast cancer patients (but is not the sole basis for treatment).

Note: The IHC Ki67 (30-9) 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 Ki67 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-Ki67 (30-9) Rabbit Monoclonal Primary Antibody assay to assure the validity of the Virtuoso™ System for Ki67 (30-9) Digital Read and Image Analysis scores. The actual correlation of CONFIRM™ anti-Ki67 (30-9) Rabbit Monoclonal Primary antibody assay 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)

Section 2- Indications for Use

Page 1 of 2

Office of In Vitro Dia Device Evaluation and

510(k) K111755.