VIRTUOSO SYSTEM FOR IHC HER2 (4B5)

K121516 · Ventana Medical Systems, Inc. · NQN · Sep 26, 2013 · Hematology

Device Facts

• Record ID: K121516
• Device Name: VIRTUOSO SYSTEM FOR IHC HER2 (4B5)
• Applicant: Ventana Medical Systems, Inc.
• Product Code: NQN · Hematology
• Decision Date: Sep 26, 2013
• 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 PR (1E2) is for digital read and image analysis applications. This particular Virtuoso system is intended for use as an aid to the pathologist in the detection and semi-quantitative measurement of progesterone receptor (PR) protein in formalin-fixed, paraffin-embedded normal and neoplastic tissue. This device is an accessory to Ventana Medical Systems, Inc. CONFIRM™ anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody assay. The CONFIRM™ anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody assay is indicated for use as an aid in the assessment of breast cancer patients for whom endocrine treatment is being considered (but is not the sole basis for treatment). Note: The IHC PR (1E2) Digital Read and Image Analysis applications are adjunctive computer-assisted methodologies for the qualified pathologist in the acquisition and measurement of images from microscope glass slides of breast cancer specimens stained for the presence of PR protein. The pathologist should verify agreement with the Image Analysis software application score. The accuracy of the test results depends on the quality of the immunohistochemical staining. It is the responsibility of a qualified pathologist to employ appropriate morphological studies and controls as specified in the instructions for the CONFIRM™ anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody used to assure the validity of the Virtuoso System for IHC PR Digital Read and Image Analysis scores. The actual correlation of CONFIRM™ anti-PR antibody to clinical outcome has not been established.

Device Story

Virtuoso System provides automated digital slide creation, management, analysis, and viewing for IHC-stained tissue slides. Device inputs include digital images of formalin-fixed, paraffin-embedded breast cancer tissue specimens stained with PATHWAY anti-HER2/neu (4B5) antibody. System utilizes digital read and image analysis applications to assist pathologists in detecting and measuring HER2 protein expression. Operated by laboratory personnel; results reviewed by qualified pathologists to aid clinical decision-making regarding HERCEPTIN treatment. System functions as an accessory to the staining process, now validated for use with Benchmark ULTRA stainer. Pathologist verifies agreement between image analysis scores and manual microscopic assessment. Benefits include standardized digital review and semi-quantitative measurement of HER2 status.

Clinical Evidence

Concordance study of ~120 cases evaluated by one pathologist at one site. Comparison of manual microscopic read vs. digital read and image analysis. Results: Digital Read PPA 94.4% (86.6-97.8), NPA 97.6% (87.4-99.6), OPA 95.6% (90.1-98.1). Image Analysis PPA 95.9% (88.7-98.6), NPA 97.5% (87.1-99.6), OPA 96.5% (91.3-98.6). Acceptance criterion of 75% met.

Technological Characteristics

System includes iScan slide scanner, computer, monitor, and proprietary software. Analyzes formalin-fixed, paraffin-embedded tissue stained with DAB chromogen. Software performs image quality assessment and quantitative analysis of PR protein expression. Web-based user interface.

Indications for Use

Indicated for use as an aid to pathologists in the detection and semi-quantitative measurement of progesterone receptor (PR) protein in formalin-fixed, paraffin-embedded normal and neoplastic breast cancer tissue to assist in assessing patients for endocrine 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

• Virtuoso System for IHC PR (1E2) (K111869)

Submission Summary (Full Text)

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A Member of the Roche Group

# SECTION 6 510(k) SUMMARY

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

| 807.92 (a)(1): | Name: | Ventana Digital Pathology | SEP 2 6 2013 |
|----------------|----------|------------------------------------------------|--------------|
| | Address: | 203 Ravendale Drive<br>Mountain View, CA 94043 | |
| | Phone: | [phone] | |
| | FAX: | [phone] | |
| | Contact: | Mr. Mort Minaee | |

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

Trade name: Virtuoso™ System for IHC PR (IE2)

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

Classifications: 21 CFR § 864.1860- Immunohistochemistry reagents and kits

Product Codes: NOT, NON, OEO

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

This Virtuoso System for IHC PR (1E2) is substantially equivalent to its immediate predecessor with the same name, cleared under K-111869 on March 5, 2012. The two Virtuoso systems are identical, with the sole difference being the automatic stainer that can be used with the reagents to stain the glass slides. The first PR submission qualified the Benchmark XT stainer, and this current submission qualified a second automatic stainer, the Benchmark ULTRA stainer,

# 807.92 (a)(4): Device Description

General Description

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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Ventana Digital Pathology | 203 Ravendale Drive, Mountain View, CA 94043 |T: 408 207 4299 www.ventanadigitalpathology.com

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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 circle made of arrows pointing inward. 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.

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. ...

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™ anti-Progesterone Receptor (PR) (1E2) Rabbit . Monoclonal Primary Antibody
- Reagents for visualization, such as 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.

#### 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 PR (1E2) primary antibody, and are then visualized using DAB. Prepared slides are loaded into the Virtuoso system scanner and scanned. The resulting digital images are reviewed by the pathologist on a computer monitor, and appropriate fields of view (FOVs) are then selected for analysis by the Virtuoso software. The Virtuoso software produces a quantitative score for the FOV and an aggregate score over all the FOVs for the whole slide. The pathologist has the

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

A Member of the Roche Group

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

## 807.92 (a)(5): Intended Use

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

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

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

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

A Member of the Roche Group

| Characteristic | Virtuoso™ IHC HER2 (4B5)<br>[Benchmark ULTRA Stainer] | Virtuoso™ IHC PR (1E2)<br>[Benchmark XT Stainer] K111869 |
|----------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------|
| | This device is intended for in vitro diagnostic<br>(IVD) use. | SAME |
| | The Virtuoso System provides automated digital<br>slide creation, management, analysis, and viewing.<br>It is intended for IVD use as an aid to the<br>pathologist in the display, detection, counting,<br>review and classification of tissues and cells of<br>clinical interest based on particular morphology,<br>color, size, intensity, pattern and shape. | SAME |
| Intended<br>Use/Indications<br>for Use | The Virtuoso™ System for IHC PR (1E2) is for<br>digital read and image analysis applications. This<br>particular Virtuoso system is intended for use as an<br>aid to the pathologist in the detection and semi-<br>quantitative measurement of progesterone receptor<br>(PR) protein in formalin-fixed, paraffin-embedded<br>normal and neoplastic tissue. This device is an<br>accessory to Ventana Medical Systems, Inc.<br>CONFIRM™ anti-Progesterone Receptor (PR)<br>(1E2) Rabbit Monoclonal Primary Antibody assay.<br>The CONFIRM™ anti-Progesterone Receptor<br>(PR) (1E2) Rabbit Monoclonal Primary Antibody<br>assay is indicated for use as an aid in the<br>assessment of breast cancer patients for whom<br>endocrine treatment is being considered (but is not<br>the sole basis for treatment). | SAME |
| Specimen Type | Formalin-fixed, paraffin-embedded tissue stained<br>by immunohistochemical technique | Same |
| System Operation<br>(Digital Read and<br>Image Analysis) | Histologic observation by a pathologist through<br>the viewer and image analysis systems | Same |
| Hardware and<br>Software | Ventana iScan slide scanner, computer, color<br>monitor, proprietary software for PR (1E2) | Same |
| Platform Components | mouse, keyboard, windows web browser. | Same |
| Primary Antibody<br>(Assay) Reagent | Ventana CONFIRM™ anti-Progesterone Receptor<br>(PR) (1E2) Rabbit Monoclonal Primary Antibody | Same |
| Ancillary<br>Reagents/Stainers | DAB universal chromogen kits,<br>Slides stained with Benchmark ULTRA stainer | DAB universal chromogen kits,<br>Slides stained with Benchmark XT<br>stainer |
| Localization of<br>IHC positive stain | Nucleus | Same |

# 807.92 (a)(6): Technological Similarities and Differences to the Predicate Devices The following chart describes similarities and differences between the two test systems.

Ventana Digital Pathology | 203 Ravendale Drive, Mountain View, CA 94043 |T: 408 207 4200|F: 408 207 4299 www.ventanadigitalpathology.com

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

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

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

## Digital Read

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

#### Image Analysis

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

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

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

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#### DEPARTMENT OF HEALTH & HUMAN SERVICES

Food and Drug Administration 19903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

September 26, 2013

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

Re: K121516

Trade/Device Name: Ventana Virtuoso System for IHC Her2 (4B5) Regulation Number: 21 CFR 864.1860 Regulation Name: Immunohistochemistry reagents and kits Regulatory Class: II Product Code: NQN, NOT, OEO Dated: August 21, 2013 Received: August 22, 2013

Dear Ms. Ammirati:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The I ou mayy arovisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

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

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act that I DA has made a colorialiations administered by other Federal agencies. You must of any reachardies and regisments, including, but not limited to: registration and listing (21 Comply with an the Not of CFR Parts 801 and 809); medical device reporting (reporting of CIN I an 007), adomig (21 CFR 803); good manufacturing practice requirements medical device-rolation as relies of the regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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Page 2-Ms. Erika Ammirati

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

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

You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number [phone] or [phone] or at its Internet address http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm.

Sincerely yours,

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

Enclosure

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#### DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration

#### Indications for Use

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

#### 510(k) Number (if known) KI21516

#### Device Name

Virtuoso™ System for IHC HER2 (4B5)

#### Indications for Use (Describe)

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

The Virtuoso™ System for IHC HER2 (4BS) 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 messurement of HER2 protein in formatin-fixed, paraffin-embedded normal and neoplastic tissue. This device is an accessory to Ventana Medical Systems, Inc. PATHWA Y & anti-HER2heu (4B5) Rabit Monoclonal Primary Antibody. The PATHWAY® ani-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody is indicated for use as an aid in the assessment of breast cancer pairents for whom HERCEPTIN® (Treatment is being considered.

NOTE: The IHC HER2 4BS Digital Read and Image Analysis applications are adjunctive computer-assisted methodologics for the qualified pathologist in the aquisition and measurement of images from microscope glass slices of breast stained for the presence of HER-2/neu receptor protein. The pathologiss should vith the Image Analysis software application score. The accuracy of the test results depends on the immunohistochemical staining. It is the responsibility of a quilified pathologist to employ appropriate morphological sudies and controls as specified in the PATH WAY W anti-HER-2/neu (4BS) Rabbit Monoclonal Primary Anibody assay used to assure the validity of the iSean System for IHC HER2 4B5 Digital Read and image Analysis scores. The actual correlation of PATHWAY® anti-HER-2/new (4BS) to clinical outcome has not been established.

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

Prescription Use (Part 21 CFR 801 Subpart D)

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

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

EN FOR FOR A STATE OF CONSTITUTION FOR FOR FOR FOR FOR FOR FOR FOR . . . . . . . . .

Concurrence of Center for Devices and Radiological Health (CDRH) (Signature)

Maria Howan -S

FORM FDA 3881 (6/13)