Virtuoso System for IHC PR (1E2) using iScan HT

K142965 · Ventana Medical Systems, Inc. · OEO · Jul 16, 2015 · Hematology

Device Facts

• Record ID: K142965
• Device Name: Virtuoso System for IHC PR (1E2) using iScan HT
• Applicant: Ventana Medical Systems, Inc.
• Product Code: OEO · Hematology
• Decision Date: Jul 16, 2015
• 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) using the VENTANA iScan HT is for the digital read application. This particular Virtuoso system is intended for use as an aid to the pathologist in the qualitative detection 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).

Device Story

Virtuoso System for IHC PR (1E2) using VENTANA iScan HT is an instrument-plus-software digital pathology solution. Input: digitized images of FFPE breast tissue slides stained with CONFIRM anti-PR (1E2) antibody. Operation: iScan HT scanner captures images; Virtuoso software manages, displays, and allows pathologist to annotate/measure images on a computer monitor. Digital Read (DR) mode: pathologist manually scores PR expression (≥1% cut-off) based on digital images. No independent interpretation or automated scoring performed by software; requires human intervention. Used in pathology laboratories by qualified pathologists. Output: digital images and pathologist-generated reports. Benefit: facilitates digital review and reporting of IHC stained slides, supporting clinical decision-making regarding endocrine treatment for breast cancer patients.

Clinical Evidence

Clinical validation included method comparison (n=477) and precision/reproducibility studies. Method comparison between digital read (DR) and manual read (MR) showed overall percent agreement (OPA) ranging from 88.9% to 98.7% across three sites. Reproducibility studies evaluated intra-pathologist (DR OPA 89.7%-97.4%) and inter-pathologist agreement. Scanner precision (inter-scanner and intra-scanner/inter-day) was assessed using 40 cases across three sites/days, with OPA for clinical scoring categories ranging from 90.0% to 93.6% for inter-scanner and 90.8% to 92.2% for intra-scanner comparisons.

Technological Characteristics

System includes VENTANA iScan HT slide scanner, computer, monitor, and Virtuoso software. Scans FFPE breast tissue slides. Connectivity: networked/web-based interface. Software is non-automated for interpretation; requires human intervention. Calibration performed by manufacturer/service. Quality control includes image quality assessment module. Sterilization: N/A (instrument).

Indications for Use

Indicated for use as an aid to the pathologist in the qualitative detection of progesterone receptor (PR) protein in formalin-fixed, paraffin-embedded normal and neoplastic tissue, specifically for breast cancer patients being considered 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) [Benchmark ULTRA Stainer] (K122143)
• Virtuoso™ System for IHC PR (1E2) [Benchmark XT Stainer] (K111869)

Submission Summary (Full Text)

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

July 16, 2015

Ventana Medical Systems, Inc. Yassine Labiad, MS, RAC Regulatory Affairs Manager 203 Ravendale Drive Mountain View, CA 94043

Re: K142965

Trade/Device Name: Virtuoso™ System for IHC PR (1E2) using the VENTANA iScan HT Regulation Number: 21 CFR & 864.1860 Regulation Name: Immunohistochemistry reagents and kits Regulatory Class: Class II Product Code: OEO Dated: July 13, 2015 Received: July 14, 2015

Dear Mr. Labiad:

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

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

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set

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forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

If you desire specific advice for your device on our labeling regulation (21 CFR Part 801), please contact the Division of Industry and Consumer Education 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

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Sincerely yours,

# Reena Philip -S

Reena Philip, Ph.D. Director Division of Molecular Genetics and Pathology Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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# Indications for Use

510(k) Number (if known) K142965

#### Device Name

Virtuoso™ System for IHC PR (1E2) using the VENTANA iScan HT

#### Indications for Use (Describe)

The Virtuoso TM 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) using the VENTANA iScan HT is for the digital read application. This particular Virtuoso system is intended for use as an aid to the pathologist in the qualitative detection 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 application is an adjunctive computer-assisted methodology for the qualified pathologist in the acquisition and interpretation of images from microscope glass slides of breast cancer specimens stained for the presence of PR protein. 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 scores. The actual correlation of CONFIRM™ anti-PR antibody to clinical outcome has not been established. This device is intended for IHC slides stained on the BenchMark ULTRA stainers. For prescription use only.

| Type of Use (Select one or both, as applicable) |
|------------------------------------------------------------------------------------------|
| <span> Prescription Use (Part 21 CFR 801 Subpart D) </span> |
| <span> Over-The-Counter Use (21 CFR 801 Subpart C) </span> |

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

#### FOR FDA USE ONLY

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

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Image /page/4/Picture/0 description: The image shows the Ventana Medical Systems logo. The logo consists of a stylized sunburst symbol on the left and the word "VENTANA" in blue, sans-serif font on the right. Below the word "VENTANA" is the text "A Member of the Roche Group" in a smaller, lighter font.

# SECTION 5 510(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 K142965.

| 807.92 (a)(1): | |
|----------------|---------------------------------------------|
| Name: | Ventana Digital Pathology |
| Address: | 203 Ravendale Rd<br>Mountain View, CA 94043 |
| Phone: | [phone] |
| FAX: | [phone] |
| Contact: | Mr. Yassine Labiad |

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

- Trade name: Virtuoso™ System for IHC PR (1E2) using the VENTANA iScan HT
- Common Name: IHC Digital pathology system for immunochemistry-stained slides
- 21 CFR § 864.1860- Immunohistochemistry reagents and kits Classifications:

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

This Virtuoso™ System for IHC PR (1E2) using the VENTANA iScan HT is substantially equivalent to its immediate predecessors cleared under K111869 on March 5, 2012, and K122143 on September 19, 2013. The only difference between the two is the use of a new scanner. The new iScan HT scanner is a powerful, high throughput bright field scanner that Ventana Medical Systems has decided to offer as an alternative to the iScan Coreo, which is a low to medium volume instrument currently employed for use with the Virtuoso™ System for IHC PR (1E2). Both the new and the predicate devices are digital pathology system for the consistent assessment of pathology interpretations using immunohistochemically stained slides (in this case. stained for PR 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

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immunohistochemically stained histologic sections from formalin-fixed, paraffinembedded normal and neoplastic tissues. The system consists of a slide scanner, computer, monitor, keyboard, and mouse 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 and generate reports.

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

The Virtuoso software is designed to complement the routine Software: workflow of a qualified pathologist in the review of immunohistochemically stained histologic slides. The software makes no independent interpretations of the data and requires competent human intervention for all steps in the process. Complete software information, following FDA's 2005 guidance document for software documentation required for regulatory submissions is being provided in Section 6 of this premarket notification.

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; this submission includes slides stained using both the Benchmark XT and Benchmark ULTRA stainers.
- . 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.

# Device Calibration:

The VENTANA iScan HT slide scanner is calibrated and verified at the manufacturing facility before shipment. Upon installation, calibrations are performed and verified by Roche Customer Support. No additional calibration or verification is required or performed by the end user. Annual preventive maintenance performed by Roche Customer Support is recommended to ensure that the VENTANA iScan HT slide scanner is operating as intended.

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Image /page/6/Picture/0 description: The image shows the Ventana Medical Systems logo. The logo consists of a stylized blue sunburst to the left of the word "VENTANA" in blue, with a registered trademark symbol to the right. Below the word "VENTANA" is the text "A Member of the Roche Group" in a smaller, gray font.

Summary of Procedure

Samples are obtained as formalin-fixed, paraffin-embedded tissue blocks. Histologic sections are prepared and mounted onto glass slides. Slides are reacted with the 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.

### 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) using the VENTANA iScan HT is for the digital read application. This particular Virtuoso system is intended for use as an aid to the pathologist in the qualitative detection 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 application is an adjunctive computerassisted methodology for the qualified pathologist in the acquisition and interpretation of images from microscope glass slides of breast cancer specimens stained for the presence of PR protein. 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 scores. The actual correlation of CONFIRMTM anti-PR antibody to clinical outcome has not been established. This device is intended for IHC slides stained on the BenchMark XT and BenchMark ULTRA stainers. For prescription use only.

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Image /page/7/Picture/0 description: The image shows the Ventana Medical Systems logo. The logo consists of a blue geometric shape on the left and the word "VENTANA" in blue on the right. Below the word "VENTANA" is the text "A Member of the Roche Group" in a smaller font size.

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

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

| | Predicate 1 | Predicate 2 | New Device |
|----------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Characteristic | Virtuoso™ System for IHC PR<br>(1E2) | Virtuoso™ System for<br>IHC PR (1E2) | Virtuoso™ System for IHC<br>PR (1E2)<br>Using the VENTANA iScan HT |
| | [Benchmark ULTRA Stainer]<br>K122143 | [Benchmark XT Stainer]<br>K111869 | |
| Intended<br>Use/Indications<br>for Use | The Virtuoso System provides<br>automated digital slide creation,<br>management, analysis, and<br>viewing. It is intended for IVD<br>use as an aid to the pathologist in<br>the 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. | SAME | The Virtuoso™ system<br>provides automated digital slide<br>creation, management, analysis,<br>and viewing. It is intended for<br>in vitro diagnostic use as an aid<br>to the pathologist in the display,<br>detection, counting, review and<br>classification of tissues and<br>cells of clinical interest based<br>on particular morphology,<br>color, intensity, size, pattern<br>and shape. |
| | The Virtuoso™ System for IHC<br>PR (1E2) is for digital read and<br>image analysis applications. This<br>particular Virtuoso system is<br>intended for use as an aid to the<br>pathologist in the detection and<br>semi-quantitative measurement<br>of progesterone receptor (PR)<br>protein in formalin-fixed,<br>paraffin-embedded normal and<br>neoplastic tissue. This device is<br>an accessory to Ventana Medical<br>Systems, Inc. CONFIRMTM anti-<br>Progesterone Receptor (PR)<br>(1E2) Rabbit Monoclonal<br>Primary Antibody assay. The<br>CONFIRM™ anti-Progesterone<br>Receptor (PR) (1E2) Rabbit<br>Monoclonal Primary Antibody<br>assay is indicated for use as an<br>aid in the assessment of breast | SAME | and shape.<br>The Virtuoso™ System for IHC<br>PR (1E2) using the VENTANA<br>iScan HT is for the digital read<br>application. This particular<br>Virtuoso system is intended for<br>use as an aid to the pathologist<br>in the qualitative detection of<br>progesterone receptor (PR)<br>protein in formalin-fixed,<br>paraffin-embedded normal and<br>neoplastic tissue. This device is<br>an accessory to Ventana<br>Medical Systems, Inc.<br>CONFIRM™ anti-Progesterone<br>Receptor (PR) (1E2) Rabbit<br>Monoclonal Primary Antibody<br>assay. The CONFIRM™ anti-<br>Progesterone Receptor (PR)<br>(1E2) Rabbit Monoclonal<br>Primary Antibody assay is |
| | cancer patients for whom<br>endocrine treatment is being<br>considered (but is not the sole<br>basis for treatment).<br>Note: The IHC PR (1E2) Digital<br>Read and Image Analysis<br>applications are adjunctive<br>computer- assisted | | indicated for use as an aid in<br>the assessment of breast cancer<br>patients for whom endocrine<br>treatment is being considered<br>(but is not the sole basis for<br>treatment).<br>Note: The IHC PR (1E2) |
| | Predicate 1 | Predicate 2 | New Device |
| Characteristic | Virtuoso™ System for IHC PR<br>(1E2)<br>[Benchmark ULTRA Stainer]<br>K122143 | Virtuoso™ System for<br>IHC PR (1E2)<br>[Benchmark XT Stainer]<br>K111869 | Virtuoso™ System for IHC<br>PR (1E2)<br>Using the VENTANA iScan<br>HT |
| | methodologies for the qualified<br>pathologist in the acquisition and<br>measurement of images from<br>microscope glass slides of breast<br>cancer specimens stained for the<br>presence of PR protein. The<br>pathologist should verify<br>agreement with the Image<br>Analysis software application<br>score. The accuracy of the test<br>results depends on the quality of<br>the immunohistochemical<br>staining. It is the responsibility<br>of a qualified pathologist to<br>employ appropriate<br>morphological studies and<br>controls as specified in the<br>instructions for the<br>CONFIRM™ anti-Progesterone<br>Receptor (PR) (1E2) Rabbit<br>Monoclonal Primary Antibody<br>used to assure the validity of the<br>Virtuoso System for IHC PR<br>Digital Read and Image Analysis<br>scores. The actual correlation of<br>CONFIRM™ anti-PR antibody<br>to clinical outcome has not been<br>established. This device is<br>intended for IHC slides stained<br>on the BenchMark XT and<br>BenchMark ULTRA stainers.<br>For prescription use only. | Same | Digital Read application is an<br>adjunctive computer-assisted<br>methodology for the qualified<br>pathologist in the acquisition<br>and interpretation of images<br>from microscope glass slides of<br>breast cancer specimens stained<br>for the presence of PR protein.<br>The accuracy of the test results<br>depends on the quality of the<br>immunohistochemical staining.<br>It is the responsibility of a<br>qualified pathologist to employ<br>appropriate morphological<br>studies and controls as<br>specified in the instructions for<br>the CONFIRMTM anti-<br>Progesterone Receptor (PR)<br>(1E2) Rabbit Monoclonal<br>Primary Antibody used to<br>assure the validity of the<br>Virtuoso System for IHC PR<br>Digital Read score. The actual<br>correlation of CONFIRM™<br>anti-PR antibody to clinical<br>outcome has not been<br>established. This device is<br>intended for IHC slides stained<br>on the BenchMark XT and<br>BenchMark ULTRA stainers.<br>For prescription use only. |
| Specimen Type | Formalin-fixed, paraffin-<br>embedded tissue stained by<br>immunohistochemical technique | Same | Same |
| System Operation<br>(Digital Read and<br>Image Analysis) | Histologic observation by a<br>pathologist through the image<br>viewer and image analysis<br>systems | Same | Histologic observation by a<br>pathologist through the image<br>viewer system. |
| Hardware and<br>Software | Ventana iScan slide scanner,<br>computer, color monitor,<br>proprietary software for PR<br>(1E2) | Same | Ventana iScan HT scanner,<br>computer, color monitor,<br>proprietary software for PR<br>(1E2) |
| Platform | Mouse, keyboard, windows web | Same | Same |
| Characteristic | Predicate 1<br>Virtuoso™ System for IHC PR<br>(1E2)<br>[Benchmark ULTRA Stainer]<br>K122143 | Predicate 2<br>Virtuoso™ System for<br>IHC PR (1E2)<br>[Benchmark XT Stainer]<br>K111869 | New Device<br>Virtuoso™ System for IHC<br>PR (1E2)<br>Using the VENTANA iScan<br>HT |
| Components | browser. | | |
| Primary Antibody<br>(Assay) Reagent | Ventana CONFIRM™ anti-<br>Progesterone Receptor (PR)<br>(1E2) Rabbit Monoclonal<br>Primary Antibody | Same | Same |
| Ancillary<br>Reagents/Stainers | DAB universal chromogen kits,<br>Slides stained with Benchmark<br>ULTRA stainer | DAB universal chromogen<br>kits, slides stained with<br>Benchmark XT stainer | DAB universal chromogen kits,<br>slides stained with Benchmark<br>XT and ULTRA stainers |
| Localization of<br>IHC positive stain | Nucleus | Same | Same |
| Interpretation | Interpretation is performed by<br>the pathologist. | Same | Same |

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Image /page/8/Picture/0 description: The image shows the Ventana logo. The logo consists of a blue geometric shape on the left and the word "VENTANA" in blue capital letters on the right. Below the word "VENTANA" is the text "A Member of the Roche Group".

A Member of the Roche Group

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Image /page/9/Picture/0 description: The image shows the Ventana Medical Systems logo. The logo consists of a stylized blue sunburst to the left of the word "VENTANA" in blue capital letters. Below the word "VENTANA" is the text "A Member of the Roche Group".

A Member of the Roche Group

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

The Virtuosond System for IHC PR (1E2) using the VENTANA iScan HT was clinically validated via a method comparison (agreement/concordance) study and a precision and reproducibility study. The method comparison study evaluated overall system performance in terms of agreement between the reference manual method (with a traditional microscope) and the digital read (DR) application of the Virtuoso system. Two sets of statistical analyses were performed for the method comparison study: 1) Initial analysis: This analysis involved the primary endpoint analysis for each of the 3 pathologists participating in the study. The primary end points included the overall percent agreement (OPA), positive percent agreement (PPA), and negative percent agreement (NPA) between the Digital Read (DR) method and Manual Read (MR) method. 2) The additional analysis employed the Generalized Linear Mixed Model (GLMM) analysis methodology for the primary endpoint analysis. This additional analysis was associated with model-based results. which enabled appropriate estimation within a repeated-measures design of the average reader performance using the comparator device. The GLMM analysis included all 3 pathologists' data.

The reproducibility components of the studies involved the intrapathologist/inter-day reproducibility evaluation as well the inter-pathologist reproducibility of the DR Virtuoso application.

The Scanner precision study involved a subset of the clinical cases (n = 40, both stainers) that were scanned two more times, and also scanned three times with two different scanners at two separate locations. This study evaluated scanner precision for both inter-scanner precision and intra-scanner/inter-day precision.

The data from both method comparison and precision/reproducibility studies are summarized below.

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# Method comparison (Agreement/Concordance)

## Virtuoso Digital Read vs Manual Method

Each pathologist's Virtuoso digital read results were compared to their manual results. The data were categorized as "neg" and "pos" using the PR score of 0 to 0.99% positive staining to describe negative, and ≥1% positive staining to describe positive. The overall percent agreements using negative and positive, as defined above, across the three sites were: 98.7%, 88.9%, and 96.2%, respectively. The overall, negative, and positive percent agreements, with the 95% confidence intervals (CI) around the agreements are shown below.

## Table: PR Clinical Status Agreement6550 Between DR and MR[6], By Site (Reader)

| | | Manual Read | | | | | | | |
|----------------------------------------|-------|---------------------|-----|---------------------|-----|-----------------------|-----|----------------------|-----|
| | | SITE 1<br>(n =159) | | SITE 2<br>(n =162) | | SITE 3<br>(n =156) | | Overall<br>(n = 477) | |
| | | Pos | Neg | Pos | Neg | Pos | Neg | Pos | Neg |
| Digital Read | Pos | 107 | 1 | 72 | 7 | 68 | 0 | 247 | 8 |
| | Neg | 1 | 50 | 11 | 72 | 6 | 82 | 18 | 204 |
| | Total | 108 | 51 | 83 | 79 | 74 | 82 | 265 | 212 |
| Overall agreement (%)<br>(95% CI) [d] | | 98.7<br>(95.5-99.7) | | 88.9<br>(83.1-92.9) | | 96.2<br>(91.9-98.2) | | | |
| Positive Agreement (%)<br>(95% CI) [d] | | 99.1<br>(94.9-99.8) | | 86.7<br>(77.8-92.4) | | 91.9<br>(83.4-96.2) | | | |
| Negative agreement (%)<br>(95% CI) [d] | | 98.0<br>(89.7-99.7) | | 91.1<br>(82.8-95.6) | | 100.0<br>(95.5-100.0) | | | |

[a] Clinical status: positive = clinical scoring category of 1-10% or >10%; negative = clinical scoring category of 0-0.99%.

[b] Only cases with evaluable results are included this analysis. For a case result to be evaluable, the investigator must have assigned a valid clinical score (status) to the case and must have confirmed that the case morphology and background staining were acceptable and that the run controls were valid.

ld For sites that performed two independent MR scoring rounds, these data are from the first MR round.

[d] Two-sided 95% confidence interval calculated using the score method.

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# Reproducibility

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

In the primary analysis of DR intra-reader reproducibility, the PR clinical status [negative (0-0.99%) or positive (≥1%)] was compared across three individual DR evaluations of the same set of 39 cases by the Reader. The 2 × 2 comparisons for the 3 reading sessions (reads) are shown in the following table with the respective agreement values. OPA rates for the 3 pairwise comparisons ranged from 89.7% to 97.4%. During the second and third reads for the DR reproducibility evaluation, Reader 3 investigator identified one case as unevaluable.

| READ 1 vs READ 2 | | | Read 2 Clinical Assessment | | | Read 1 vs Read 2 Agreement Rates | | | |
|-------------------------------|-------|----|----------------------------|-----|-------|----------------------------------|------|------------|-----------|
| | | | Pos | Neg | Total | Rate | n/N | % | 95% CI[b] |
| Read 1 Clinical<br>Assessment | Pos | 19 | 1 | 20 | APA | 38/39 | 97.4 | 90.9-100.0 | |
| | Neg | 0 | 19 | 19 | ANA | 38/39 | 97.4 | 90.7-100.0 | |
| | Total | 19 | 20 | 39 | OPA | 38/39 | 97.4 | 86.8-99.5 | |
| READ 1 vs READ 3 | | | Read 3 Clinical Assessment | | | Read 1 vs Read 3 Agreement Rates | | | |
| | | | Pos | Neg | Total | Rate | n/N | % | 95% CI[b] |
| Read 1 Clinical<br>Assessment | Pos | 18 | 2 | 20 | APA | 36/40 | 90.0 | 78.0-97.9 | |
| | Neg | 2 | 17 | 19 | ANA | 34/38 | 89.5 | 76.5-97.8 | |
| | Total | 20 | 19 | 39 | OPA | 35/39 | 89.7 | 76.4-95.9 | |
| READ 2 vs READ 3 | | | Read 3 Clinical Assessment | | | Read 2 vs Read 3 Agreement Rates | | | |
| | | | Pos | Neg | Total | Rate | n/N | % | 95% CI[b] |
| Read 2 Clinical<br>Assessment | Pos | 18 | 1 | 19 | APA | 36/39 | 92.3 | 81.3-100.0 | |
| | Neg | 2 | 18 | 20 | ANA | 36/39 | 92.3 | 81.3-100.0 | |
| | Total | 20 | 19 | 39 | OPA | 36/39 | 92.3 | 79.7-97.3 | |

# PR clinical Status [3] Agreement Within Reader (Digital Read)

Clinical assessment (ie, PR status): positive = clinical score of 1—10%; negative = clinical score of 0 –

wo-sided 95% Cls for OPA of each read pair (not pooled for all read-pairs) are calculated using the score nethod. The other Cls are calculated using the percentile bootstrap method.

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- b. Inter-Pathologist (pair-wise comparisons, Pathologist 1 vs Pathologist 2, Pathologist 1 vs Pathologist 3, Pathologist 2 vs Pathologist 3)
The agreement of PR clinical status between sites (readers) was examined separately for DR and MR. Each investigator's results for the PR clinical status [negative (0-0.99%) or positive (≥1%)] of the study cases were compared to those of another reader using the same reading method. The agreement rates and 95% CIs are shown in the following tables, respectively, for each reading method (DR and MR).

## Manual Read

The three manual readings across the three pathologists (sites) were compared to each other. The reproducibility in the manual readings among the three pathologists (sites) is shown below, along with the 95% CIs. The OPA rates for the 3 pairwise comparisons ranged from 81.0% to 92.9%.

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| SITE 1 vs. SITE 2 | | | | | Site 1-vs-Site 2 Agreement Rates | | | |
|----------------------------------|-------------------------------|----|----|-----|----------------------------------|---------|------|----------------|
| | Site 2<br>Clinical Assessment | | | | Rate | n/N | % | 95% CI [d] (%) |
| Site 1<br>Clinical<br>Assessment | Pos | 82 | 25 | 107 | APA | 164/190 | 86.3 | 80.7-91.2 |
| | Neg | 1 | 50 | 51 | ANA | 100/126 | 79.4 | 71.1-86.6 |
| | Total | 83 | 75 | 158 | OPA | 132/158 | 83.5 | 77.0-88.5 |
| SITE 1 vs. SITE 3 | | | | | Site 1-vs-Site 3 Agreement Rates | | | |
| | Site 3<br>Clinical Assessment | | | | Rate | n/N | % | 95% CI [d] (%) |
| Site 1<br>Clinical<br>Assessment | Pos | 74 | 29 | 103 | APA | 148/177 | 83.6 | 77.2-89.4 |
| | Neg | 0 | 50 | 50 | ANA | 100/129 | 77.5 | 68.8-85.1 |
| | Total | 74 | 79 | 153 | OPA | 124/153 | 81.0 | 74.1-86.5 |
| SITE 2 vs. SITE 3 | | | | | Site 2-vs-Site 3 Agreement Rates | | | |
| | Site 3<br>Clinical Assessment | | | | Rate | n/N | % | 95% CI [d] (%) |
| Site 2<br>Clinical<br>Assessment | Pos | 70 | 8 | 78 | APA | 140/151 | 92.7 | 88.0-96.7 |
| | Neg | 3 | 74 | 77 | ANA | 148/159 | 93.1 | 88.6-96.8 |
| | Total | 73 | 82 | 155 | OPA | 144/155 | 92.9 | 87.7-96.0 |

## PR Clinical Status Agreement[8]] Between Sites (Readers): Manual Read

[a] Clinical status: positive = clinical scoring category of 1–10%; negative = clinical scoring category of 0 - 0.99%.

[b] Only cases with evaluable results are included this analysis. For a case result to be evaluable, the investigator must have assigned a valid clinical score (status) to the case and must have confirmed that the case morphology and background staining were acceptable and that the run controls were valid.

[c] Two-sided 95% confidence interval for OPA of each site (reader) pair (not pooled for all sites) are calculated using the score method. The other Cls are calculated using the percentile bootstrap method.

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# Digital Read

The reproducibility in the Virtuoso digital readings among the three pathologists (sites) is shown below, along with the 95% Cls. The overall percent agreements ranged from 77.4% to 89.9%.

## PR Clinical Status Agreement439) Between Sites (Readers): Digital Read

| SITE 1 vs. SITE 2 | | Site 2<br>Clinical Assessment | | | Site 1-vs-Site 2 Agreement Rates | | | |
|-------------------------------|-------|-------------------------------|-----|-------|----------------------------------|---------|------|----------------|
| | | Pos | Neg | Total | Rate | n/N | % | 95% CI [d] (%) |
| Site 1 Clinical<br>Assessment | Pos | 79 | 29 | 108 | APA | 158/188 | 84.0 | 78.0-89.6 |
| Site 1 Clinical<br>Assessment | Neg | 1 | 50 | 51 | ANA | 100/130 | 76.9 | 68.8-84.6 |
| Site 1 Clinical<br>Assessment | Total | 80 | 79 | 159 | OPA | 129/159 | 81.1 | 74.3-86.5 |
| SITE 1 vs. SITE 3 | | Site 3<br>Clinical Assessment | | | Site 1-vs-Site 3 Agreement Rates | | | |
| | | Pos | Neg | Total | Rate | n/N | % | 95% CI [d] (%) |
| Site 1 Clinical<br>Assessment | Pos | 70 | 35 | 105 | APA | 140/175 | 80.0 | 73.4-86.3 |
| Site 1 Clinical<br>Assessment | Neg | 0 | 50 | 50 | ANA | 100/135 | 74.1 | 65.6-81.8 |
| Site 1 Clinical<br>Assessment | Total | 70 | 85 | 155 | OPA | 120/155 | 77.4 | 70.2-83.3 |
| SITE 2 vs. SITE 3 | | Site 3<br>Clinical Assessment | | | Site 2-vs-Site 3 Agreement Rates | | | |
| | | Pos | Neg | Total | Rate | n/N | % | 95% CI [d] (%) |
| Site 2 Clinical<br>Assessment | Pos | 65 | 11 | 76 | APA | 130/146 | 89.0 | 83.5-93.8 |
| Site 2 Clinical<br>Assessment | Neg | 5 | 77 | 82 | ANA | 154/170 | 90.6 | 85.7-94.7 |
| Site 2 Clinical<br>Assessment | Total | 70 | 88 | 158 | OPA | 142/158 | 89.9 | 84.2-93.7 |

[a] Clinical status: positive = clinical scoring category of 1–10% or ≥ 10%; negative = clinical scoring category of 0 – 0.99%.

[b] Only cases with evaluable results are included this analysis. For a case result to be evaluable, the investigator must have assigned a valid clinical score (status) to the case and must have confirmed that the case morphology and background staining were acceptable and that the run controls were valid.

[c] Two-sided 95% confidence interval for OPA of each site (reader) pair (not pooled for all sites) are calculated using the score method. The other Cls are calculated using the percentile bootstrap method.

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Image /page/16/Picture/0 description: The image shows the Ventana Medical Systems logo. The logo consists of a blue geometric design to the left, followed by the word "VENTANA" in blue, and the phrase "A Member of the Roche Group" in gray below the word "VENTANA". The geometric design is a circle made up of several arrow-like shapes pointing inward.

# Scanner Precision

Forty (40) cases representing the useful categories of <1%, 1-10%, and 10% positive staining for PR were scanned on three different scanners at three different sites to assess inter-scanner precision, and three FOVs were captured (total = 120) and evaluated. Similarly, these same 40 cases were scanned on three different days by the same scanner, and the same FOVs were applied to the appropriate cases to assess intra-scanner/inter day precision.

Pairwise comparisons were performed between each of the three sites (interscanner), and between each of the three days (sessions, intra-scanner). The precision tables are found below.

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Image /page/17/Picture/0 description: The image shows the Ventana Medical Systems logo. The logo consists of a blue geometric design to the left of the word "VENTANA" in blue, with a registered trademark symbol next to it. Below the logo, in a smaller font, is the text "A Member of the Roche…