Predicate Devices

Reference Devices

AI/ML (Artificial Intelligence / Machine Learning)

No
The device description explicitly states that the software "makes no independent interpretations of the data and requires competent human intervention for all steps in the process." There is no mention of AI, ML, or related terms in the document.

Therapeutic

No
The device 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, and as an aid in the qualitative detection of progesterone receptor (PR) protein in tissue. It is an accessory to an antibody assay and is used for digital reading of stained slides to assist in the assessment of breast cancer patients for whom endocrine treatment is being considered, but it is not the sole basis for treatment. It does not provide therapy itself.

Diagnostic

Yes

Explanation: The "Intended Use / Indications for Use" section explicitly states, "It is intended for in vitro diagnostic use as an aid to the pathologist..." and later refers to it as an "accessory to Ventana Medical Systems, Inc. CONFIRM anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody assay," which is used as an "aid in the assessment of breast cancer patients." These statements confirm its role in diagnosis.

SaMD (Software as a Medical Device)

No

The device description explicitly states it is an "instrument-plus-software system" and lists hardware components including a slide scanner, computer, monitor, keyboard, and mouse.

IVD (In Vitro Diagnostic)

Yes, this device is an IVD (In Vitro Diagnostic).

Here's why:

Explicit Statement: The "Intended Use / Indications for Use" section explicitly states: "It is intended for in vitro diagnostic use as an aid to the pathologist..."
Purpose: The device is intended to be used on biological specimens (formalin-fixed, paraffin-embedded tissues) to provide information about a patient's health (qualitative detection of progesterone receptor protein). This aligns with the definition of an in vitro diagnostic device.
Aid to Diagnosis: The device is described as an "aid to the pathologist" in the detection, counting, review, and classification of tissues and cells of clinical interest, and specifically in the qualitative detection of PR protein. This indicates its role in the diagnostic process.
Accessory to an IVD Assay: The device is an accessory to the CONFIRM anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody assay, which is itself an IVD assay. This further reinforces its IVD nature.
Prescription Use Only: The "For prescription use only" statement is also a common characteristic of IVD devices.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

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.

Product codes (comma separated list FDA assigned to the subject device)

OEO

Device Description

The Virtuoso™ System is an instrument-plus-software system designed to assist the qualified pathologist in the consistent assessment of protein expression in immunohistochemically stained histologic sections from formalin-fixed, paraffinembedded normal and neoplastic tissues. The system consists of a slide scanner, 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 Comment
Associated materials for completing immunohistochemical staining according Comment 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

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Not Found

Anatomical Site

Formalin-fixed, paraffin-embedded normal and neoplastic tissue (breast cancer specimens)

Indicated Patient Age Range

Not Found

Intended User / Care Setting

Qualified pathologist / Not Found, but implies a pathology laboratory setting.

Description of the training set, sample size, data source, and annotation protocol

Not Found

Description of the test set, sample size, data source, and annotation protocol

A method comparison study evaluated agreement between a digital read (DR) application of the Virtuoso system and a manual read (MR) method (with a traditional microscope). This involved 3 pathologists and yielded 477 cases in total for analysis (Site 1: 159 cases, Site 2: 162 cases, Site 3: 156 cases). The data was categorized as "neg" (PR score of 0 to 0.99%) and "pos" (≥1%). Cases included were evaluable, meaning the investigator assigned a valid clinical score, confirmed acceptable morphology and background staining, and valid run controls. Some sites performed two independent MR scoring rounds, with data from the first MR round used for analysis.

A reproducibility study involved intra-pathologist/inter-day reproducibility and inter-pathologist reproducibility. For intra-pathologist reproducibility, 39 cases were evaluated three times by a single reader. For inter-pathologist, the agreement of PR clinical status between sites (readers) was examined for DR and MR methods, comparing each investigator's results for the PR clinical status [negative (0-0.99%) or positive (≥1%)] of the study cases to those of another reader using the same method.

A scanner precision study involved a subset of 40 clinical cases (both stainers) that were scanned two more times, and also scanned three times with two different scanners at two separate locations. This evaluated inter-scanner and intra-scanner/inter-day precision. Three FOVs were captured for each of the 40 cases (total 120 FOVs).

Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)

Study Type: Method comparison (agreement/concordance) study and a precision and reproducibility study.

Sample Size:

Method comparison: 477 cases (Site 1: 159, Site 2: 162, Site 3: 156)
Reproducibility (Intra-Pathologist/Inter-Day): 39 cases
Reproducibility (Inter-Pathologist): Not explicitly stated, but based on comparisons between 3 pathologists/sites after their individual reads.
Scanner Precision: 40 cases (scanned multi-times as described in test set)

AUC: Not Found.

MRMC: Not Found.

Standalone Performance: The study evaluated the agreement between the Virtuoso digital read and manual read, as well as reproducibility of the digital read and scanner precision. It did not present standalone performance metrics in isolation from reader interpretation.

Key Results:

Method Comparison (Agreement/Concordance) - Virtuoso Digital Read vs Manual Method:

Overall percent agreements across the three sites: 98.7% (Site 1), 88.9% (Site 2), and 96.2% (Site 3).
Overall agreement (n=477): Not explicitly stated, but implied to be high based on individual site results.
Site 1: Pos=107, Neg=50 (DR vs MR), OPA = 98.7% (95% CI: 95.5-99.7). PPA = 99.1% (95% CI: 94.9-99.8). NPA = 98.0% (95% CI: 89.7-99.7).
Site 2: Pos=72, Neg=72 (DR vs MR), OPA = 88.9% (95% CI: 83.1-92.9). PPA = 86.7% (95% CI: 77.8-92.4). NPA = 91.1% (95% CI: 82.8-95.6).
Site 3: Pos=68, Neg=82 (DR vs MR), OPA = 96.2% (95% CI: 91.9-98.2). PPA = 91.9% (95% CI: 83.4-96.2). NPA = 100.0% (95% CI: 95.5-100.0).

Reproducibility - Intra-Pathologist/Inter-Day (Digital Read):
OPA rates for the 3 pairwise comparisons (Read 1 vs Read 2, Read 1 vs Read 3, Read 2 vs Read 3) using 39 cases ranged from 89.7% to 97.4%.

Read 1 vs Read 2: OPA = 97.4% (95% CI: 86.8-99.5)
Read 1 vs Read 3: OPA = 89.7% (95% CI: 76.4-95.9)
Read 2 vs Read 3: OPA = 92.3% (95% CI: 79.7-97.3)

Reproducibility - Inter-Pathologist:

Manual Read: OPA rates for the 3 pairwise comparisons between pathologists ranged from 81.0% to 92.9%.
- Site 1 vs Site 2: OPA = 83.5% (95% CI: 77.0-88.5)
- Site 1 vs Site 3: OPA = 81.0% (95% CI: 74.1-86.5)
- Site 2 vs Site 3: OPA = 92.9% (95% CI: 87.7-96.0)
Digital Read: OPA rates for the 3 pairwise comparisons between pathologists ranged from 77.4% to 89.9%.
- Site 1 vs Site 2: OPA = 81.1% (95% CI: 74.3-86.5)
- Site 1 vs Site 3: OPA = 77.4% (95% CI: 70.2-83.3)
- Site 2 vs Site 3: OPA = 89.9% (95% CI: 84.2-93.7)

Scanner Precision:

Inter-scanner (Between Sites): Overall percent agreement (OPA) rates across 3 sites (all FOVs combined) ranged from 90.0% to 93.6%.
- Site 1 vs Site 2: OPA = 90.0% (95% CI: 86.5-92.7)
- Site 1 vs Site 3: OPA = 93.6% (95% CI: 90.6-95.7)
- Site 2 vs Site 3: OPA = 90.3% (95% CI: 86.8-92.9)
Intra-scanner (Between Days): Overall percent agreement (OPA) rates across 3 days (all FOVs combined) ranged from 90.8% to 92.2%.
- DAY 1 vs DAY 2: OPA = 92.2% (95% CI: 89.0-94.6)
- DAY 1 vs DAY 3: OPA = 90.8% (95% CI: 87.4-93.4)
- DAY 2 vs DAY 3: OPA = 90.8% (95% CI: 87.4-93.4)

Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)

OPA (Overall Percent Agreement)
PPA (Positive Percent Agreement)
NPA (Negative Percent Agreement)

Predicate Device(s)

K122143, K111869

Reference Device(s)

Not Found

Predetermined Change Control Plan (PCCP) - All Relevant Information

Not Found

Regulation Number and Section

§ 864.1860 Immunohistochemistry reagents and kits.

(a)
Identification. Immunohistochemistry test systems (IHC's) are in vitro diagnostic devices consisting of polyclonal or monoclonal antibodies labeled with directions for use and performance claims, which may be packaged with ancillary reagents in kits. Their intended use is to identify, by immunological techniques, antigens in tissues or cytologic specimens. Similar devices intended for use with flow cytometry devices are not considered IHC's.(b)
Classification of immunohistochemistry devices. (1) Class I (general controls). Except as described in paragraphs (b)(2) and (b)(3) of this section, these devices are exempt from the premarket notification requirements in part 807, subpart E of this chapter. This exemption applies to IHC's that provide the pathologist with adjunctive diagnostic information that may be incorporated into the pathologist's report, but that is not ordinarily reported to the clinician as an independent finding. These IHC's are used after the primary diagnosis of tumor (neoplasm) has been made by conventional histopathology using nonimmunologic histochemical stains, such as hematoxylin and eosin. Examples of class I IHC's are differentiation markers that are used as adjunctive tests to subclassify tumors, such as keratin.(2) Class II (special control, guidance document: “FDA Guidance for Submission of Immunohistochemistry Applications to the FDA,” Center for Devices and Radiologic Health, 1998). These IHC's are intended for the detection and/or measurement of certain target analytes in order to provide prognostic or predictive data that are not directly confirmed by routine histopathologic internal and external control specimens. These IHC's provide the pathologist with information that is ordinarily reported as independent diagnostic information to the ordering clinician, and the claims associated with these data are widely accepted and supported by valid scientific evidence. Examples of class II IHC's are those intended for semiquantitative measurement of an analyte, such as hormone receptors in breast cancer.
(3) Class III (premarket approval). IHC's intended for any use not described in paragraphs (b)(1) or (b)(2) of this section.
(c)
Date of PMA or notice of completion of a PDP is required. As of May 28, 1976, an approval under section 515 of the Federal Food, Drug, and Cosmetic Act is required for any device described in paragraph (b)(3) of this section before this device may be commercially distributed. See § 864.3.

Summary

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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 (800) 638-2041 or (301) 796-7100 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 Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

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

2

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

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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This section applies only to requirements of the Paperwork Reduction Act of 1995.

DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.

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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
Mountain View, CA 94043
Phone:	(408) 585-7949
FAX:	(408) 207-4299
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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Image /page/5/Picture/0 description: The image shows the Ventana Medical Systems logo. The logo consists of a blue geometric shape on the left, followed by the word "VENTANA" in blue, and the phrase "A Member of the Roche Group" in gray below. The geometric shape is made up of several blue triangles arranged in a circular pattern.

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
(1E2)	Virtuoso™ System for
IHC PR (1E2)	Virtuoso™ System for IHC
PR (1E2)
Using the VENTANA iScan HT
	[Benchmark ULTRA Stainer]
K122143	[Benchmark XT Stainer]
K111869
Intended
Use/Indications
for Use	The Virtuoso System provides
automated digital slide creation,
management, analysis, and
viewing. It is intended for IVD
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, size,
intensity, pattern and shape.	SAME	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	SAME	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
	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		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)
	Predicate 1	Predicate 2	New Device
Characteristic	Virtuoso™ System for IHC PR
(1E2)
[Benchmark ULTRA Stainer]
K122143	Virtuoso™ System for
IHC PR (1E2)
[Benchmark XT Stainer]
K111869	Virtuoso™ System for IHC
PR (1E2)
Using the VENTANA iScan
HT
	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. This device is
intended for IHC slides stained
on the BenchMark XT and
BenchMark ULTRA stainers.
For prescription use only.	Same	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 CONFIRMTM anti-
Progesterone Receptor (PR)
(1E2) Rabbit Monoclonal
Primary Antibody used to
assure the validity of the
Virtuoso System for IHC PR
Digital Read score. 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 XT and
BenchMark ULTRA stainers.
For prescription use only.
Specimen Type	Formalin-fixed, paraffin-
embedded tissue stained by
immunohistochemical technique	Same	Same
System Operation
(Digital Read and
Image Analysis)	Histologic observation by a
pathologist through the image
viewer and image analysis
systems	Same	Histologic observation by a
pathologist through the image
viewer system.
Hardware and
Software	Ventana iScan slide scanner,
computer, color monitor,
proprietary software for PR
(1E2)	Same	Ventana iScan HT scanner,
computer, color monitor,
proprietary software for PR
(1E2)
Platform	Mouse, keyboard, windows web	Same	Same
Characteristic	Predicate 1
Virtuoso™ System for IHC PR
(1E2)
[Benchmark ULTRA Stainer]
K122143	Predicate 2
Virtuoso™ System for
IHC PR (1E2)
[Benchmark XT Stainer]
K111869	New Device
Virtuoso™ System for IHC
PR (1E2)
Using the VENTANA iScan
HT
Components	browser.
Primary Antibody
(Assay) Reagent	Ventana CONFIRM™ anti-
Progesterone Receptor (PR)
(1E2) Rabbit Monoclonal
Primary Antibody	Same	Same
Ancillary
Reagents/Stainers	DAB universal chromogen kits,
Slides stained with Benchmark
ULTRA stainer	DAB universal chromogen
kits, slides stained with
Benchmark XT stainer	DAB universal chromogen kits,
slides stained with Benchmark
XT and ULTRA stainers
Localization of
IHC positive stain	Nucleus	Same	Same
Interpretation	Interpretation is performed by
the pathologist.	Same	Same

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A Member of the Roche Group

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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
(n =159)		SITE 2
(n =162)		SITE 3
(n =156)		Overall
(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 (%)
(95% CI) [d]		98.7
(95.5-99.7)		88.9
(83.1-92.9)		96.2
(91.9-98.2)
Positive Agreement (%)
(95% CI) [d]		99.1
(94.9-99.8)		86.7
(77.8-92.4)		91.9
(83.4-96.2)
Negative agreement (%)
(95% CI) [d]		98.0
(89.7-99.7)		91.1
(82.8-95.6)		100.0
(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
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
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
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
Clinical Assessment				Rate	n/N	%	95% CI [d] (%)
Site 1
Clinical
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
Clinical Assessment				Rate	n/N	%	95% CI [d] (%)
Site 1
Clinical
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
Clinical Assessment				Rate	n/N	%	95% CI [d] (%)
Site 2
Clinical
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
Clinical Assessment | | | Site 1-vs-Site 2 Agreement Rates | | | |
|-------------------------------|-------|-------------------------------|-----|-------|----------------------------------|---------|------|----------------|
| | | Pos | Neg | Total | Rate | n/N | % | 95% CI [d] (%) |
| Site 1 Clinical
Assessment | Pos | 79 | 29 | 108 | APA | 158/188 | 84.0 | 78.0-89.6 |
| Site 1 Clinical
Assessment | Neg | 1 | 50 | 51 | ANA | 100/130 | 76.9 | 68.8-84.6 |
| Site 1 Clinical
Assessment | Total | 80 | 79 | 159 | OPA | 129/159 | 81.1 | 74.3-86.5 |
| SITE 1 vs. SITE 3 | | Site 3
Clinical Assessment | | | Site 1-vs-Site 3 Agreement Rates | | | |
| | | Pos | Neg | Total | Rate | n/N | % | 95% CI [d] (%) |
| Site 1 Clinical
Assessment | Pos | 70 | 35 | 105 | APA | 140/175 | 80.0 | 73.4-86.3 |
| Site 1 Clinical
Assessment | Neg | 0 | 50 | 50 | ANA | 100/135 | 74.1 | 65.6-81.8 |
| Site 1 Clinical
Assessment | Total | 70 | 85 | 155 | OPA | 120/155 | 77.4 | 70.2-83.3 |
| SITE 2 vs. SITE 3 | | Site 3
Clinical Assessment | | | Site 2-vs-Site 3 Agreement Rates | | | |
| | | Pos | Neg | Total | Rate | n/N | % | 95% CI [d] (%) |
| Site 2 Clinical
Assessment | Pos | 65 | 11 | 76 | APA | 130/146 | 89.0 | 83.5-93.8 |
| Site 2 Clinical
Assessment | Neg | 5 | 77 | 82 | ANA | 154/170 | 90.6 | 85.7-94.7 |
| Site 2 Clinical
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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Scanner Precision

Forty (40) cases representing the useful categories of 10% | 1–10% | 0–0.99% | Total | n/N | % | 95% CI[c] |
| Site 1 Clinical
Scoring
Category | >10% | 113 | 8 | 0 | 121 | 324/360 | 90.0 | 86.5-92.7 | |
| | 1–10% | 3 | 30 | 15 | 48 | | | | |
| | 0–0.99% | 0 | 10 | 181 | 191 | | | | |
| Total | | 116 | 48 | 196 | 360 | | | | |
| SITE 1 vs SITE 3 [b] | | | | Site 3 Clinical Scoring Category | | | OPA | | |
| | | | >10% | 1–10% | 0–0.99% | Total | n/N | % | 95% CI[c] |
| Site 1 Clinical
Scoring
Category | >10% | 119 | 2 | 0 | 121 | 337/360 | 93.6 | 90.6-95.7 | |
| | 1–10% | 4 | 34 | 10 | 48 | | | | |
| | 0–0.99% | 0 | 7 | 184 | 191 | | | | |
| Total | | 123 | 43 | 194 | 360 | | | | |
| SITE 2 vs SITE 3 [b] | | | | Site 3 Clinical Scoring Category | | | OPA | | |
| | | | >10% | 1–10% | 0–0.99% | Total | n/N | % | 95% CI[c] |
| Site 2 Clinical
Scoring
Category | >10% | 115 | 1 | 0 | 116 | 325/360 | 90.3 | 86.8-92.9 | |
| | 1–10% | 8 | 28 | 12 | 48 | | | | |
| | 0–0.99% | 0 | 14 | 182 | 196 | | | | |
| Total | | 123 | 43 | 194 | 360 | | | | |

[a] PR clinical scoring categories of: 0 – 0.99% (negative), 1–10% (positive), and ≥ 10% (positive). [b] This analysis is based on the results of pooling all days.

l Two-sided 95% Cls for OPA of each site (reader) pair (not pooled for all site-pairs) are calculated using the score method. Two-sided 95% Cls for OPA with all site-pairs pooled are calculated using the percentile bootstrap method.

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PR Clinical Scoring Category [3] Agreement Within Scanners (Between Days): All FOVs Combined

DAY 1 vs DAY 2 [b]				OPA
	>10%	1-10%	0-0.99%	Total	n/N	%	95% CI[c]
Day 1 Clinical
Scoring
Category	>10%	117	4	0	121	332/360	92.2	89.0-94.6
	1-10%	1	33	11	45
	0-0.99%	1	11	182	194
	Total	119	48	193	360
DAY 1 vs DAY 3 [b]				OPA
	>10%	1-10%	0-0.99%	Total	n/N	%	95% CI[c]
Day 1 Clinical
Scoring
Category	>10%	118	3	0	121	327/360	90.8	87.4-93.4
	1-10%	2	29	14	45
	0-0.99%	0	14	180	194
	Total	120	46	194	360
DAY 2 vs DAY 3 [b]				OPA
	>10%	1-10%	0-0.99%	Total	n/N	%	95% CI[c]
Day 2 Clinical
Scoring
Category	>10%	115	3	1	119	327/360	90.8	87.4-93.4
	1-10%	5	31	12	48
	0-0.99%	0	12	181	193
	Total	120	46	194	360

[a] PR clinical scoring categories of: 0 – 0.99% (negative), 1–10% (positive), and ≥ 10% (positive). [b] This analysis is based on the results of pooling all FOVs and all sites.

[0 Two-sided 95% Cls for OPA of each day pair (not pooled for all day-pairs) are calculated using the score method. Two-sided 95% Cls for OPA with all day-pairs pooled are calculated using the percentile bootstrap method.

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

Concordance, reproducibility, and precision studies were performed for the Virtuoso System for IHC PR (1E2) using the VENTANA iScan HT. The test system was shown to be as safe and effective (therefore substantially equivalent) as the predicate devices for its intended use.