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 IHC Ki-67 (30-9) Digital Read and Image Analysis applications are intended for use as an aid to the pathologist in the detection and semi-quantitative measurement of Ki-67 protein in formalin-fixed, paraffin-embedded normal and neoplastic tissue. Ki-67 results are indicated for use in assessing the proliferative activity of normal and neoplastic breast tissue. When used with Ventana Medical Systems, Inc. CONFIRM™ anti-Ki-67 (30-9) Rabbit Monoclonal Primary Antibody Assay, it is indicated for use as an aid in the assessment of Ki-67 status in breast cancer patients (but is not the sole basis for treatment).

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 (iScan), computer, monitor, keyboard, mouse, image analysis algorithms for specific immunohistochemical markers, and software with a Windows web browser-based user interface. Virtuoso is a web-based, end-to-end, digital pathology software solution that allows pathology laboratories to acquire, manage, view, analyze, share, and report digital images of pathology specimens. Using the Virtuoso software, the pathologist can view digital images, add annotations, make measurements, perform image analysis, and generate reports.

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

Software: The Virtuoso software is designed to complement the routine workflow of a qualified pathologist in the review of immunohistochemically stained histologic slides. It allows the user to select fields of view (FOVs) in the digital image for analysis and provides quantitative data on these FOVs to assist with interpretation. The software makes no independent interpretations of the data and requires competent human intervention for all steps in the analysis process.

AI/ML Overview

The Ventana Virtuoso™ System for IHC Ki-67 (30-9) was tested for its performance in both digital reading (DR) and image analysis (IA) of Ki-67 stained slides. The overall acceptance criterion for each measurement was 75% overall percent agreement (OPA) with manual microscopic reads.

1. Table of Acceptance Criteria and Reported Device Performance

Performance Metric	Acceptance Criteria (Overall Percent Agreement)	Reported Device Performance (Overall Percent Agreement)
Digital Read (DR) vs. Manual Read	≥ 75%	90.0% (95% CI: 83.3-94.2)
Image Analysis (IA) vs. Manual Read (Overall)	≥ 75%	78.0% (95% CI: 69.7-84.5)
Image Analysis (IA) vs. Manual Read (Site 1)	≥ 75%	86.6% (95% CI: 79.1-91.7)
Image Analysis (IA) vs. Manual Read (Site 2)	≥ 75%	90.8% (95% CI: 84.2-94.8)

2. Sample Size and Data Provenance for the Test Set

Digital Read (DR) Test Set: 120 cases.
Image Analysis (IA) Test Set: 120 cases.
Data Provenance: The document does not explicitly state the country of origin. The studies appear to be prospective concordance studies where new data was generated for validation.

3. Number of Experts and Qualifications for Ground Truth Establishment (Test Set)

Digital Read (DR): "one pathologist at one site" established the manual score (reference result). No specific qualifications are provided beyond "pathologist".
Image Analysis (IA): "three pathologists at three sites" established the manual score (reference result). No specific qualifications are provided beyond "pathologists".

4. Adjudication Method for the Test Set

The document describes concordance studies where manual scores were compared to device scores. It does not mention any formal adjudication method beyond establishing the "manual score (reference result)" by one or more pathologists. This implies a single expert's opinion served as the ground truth for each case initially, rather than multiple experts with a specific adjudication process.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No formal MRMC comparative effectiveness study is described where human readers' performance with and without AI assistance is directly compared to quantify an effect size. The studies focus on the agreement between the device alone (digital read or image analysis) and manual reads.

6. Standalone (Algorithm Only) Performance

Yes, standalone performance was done for both Digital Read and Image Analysis:

Digital Read Performance: This section describes the agreement between the digital image reviewed by a pathologist ("Digital Read") and the manual microscopic read. While a pathologist is involved in the "Digital Read," the intent is to show that replacing the physical microscope with a digital image viewer (which is part of the system) does not negatively impact the pathologist's ability to score the cases.
Image Analysis Performance: This section directly assesses the agreement between the Virtuoso Image Analysis application's output and the manual microscopic read. This represents the algorithm-only performance in providing a quantitative score before any potential human override.

7. Type of Ground Truth Used

The ground truth used for both the Digital Read and Image Analysis studies was expert consensus (specifically, manual microscopic reads) by qualified pathologists. The manual score was explicitly stated as the "reference result" or "true score."

8. Sample Size for the Training Set

The document does not provide any information regarding the sample size used for the training set of the Virtuoso™ System's image analysis algorithms. This information is typically found in the development and validation sections, which are not detailed in this 510(k) summary.

9. How Ground Truth for the Training Set Was Established

The document does not provide any information on how the ground truth for the training set was established.

Summary

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K121033

Image /page/0/Picture/1 description: The image shows the logo for Ventana, a member of the Roche Group. The logo consists of a stylized sun-like symbol on the left, followed by the word "VENTANA" in bold, uppercase letters. The words "A Member of the Roche Group" are written in a smaller font size below the main logo.

SECTION 6 510(k) SUMMARY

This 510(k) Summary is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92. The assigned 510(k) number is K121033.

Name:	Ventana Digital Pathology
Address:	c/o Ammirati Regulatory ConsultingLos Altos, CA 94043
Phone:	(650) 949-2768	SEP 06 2012
FAX:	(650) 949-5347
Contact:	Erika B. Ammirati
	Consultant to Ventana Medical Systems, Inc.

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

Trade name: Virtuoso™ System for IHC Ki-67 (30-9)

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

Classifications: 21 CFR § 864.1860- Immunohistochemistry reagents and kits

Product Codes: NOT, NON, OEO

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

This Virtuoso System for IHC Ki-67 (30-9) is substantially equivalent to its immediate predecessor with the same name, cleared under K111755 on February 22, 2012. The two Virtuoso systems are identical, with the sole difference being the automatic stainer that can be used with the reagents to stain the glass slides. The first Ki-67 submission qualified the Benchmark XT stainer, and this current submission qualified a second automatic stainer, the Benchmark ULTRA stainer.

807.92 (a)(4): Device Description

General Description

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Ventana Digital Pathology | 203 Ravendale Dr., Mountain View. CA 94043ff. 408 207 4200fF: 408 207 4299 ww.ventanadigitalpathology.com

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A Member of the Roche Group

specific immunohistochemical markers, and software with a Windows web browser-based user interface. Virtuoso is a web-based, end-to-end, digital pathology software solution that allows pathology laboratories to acquire, manage, view, analyze, share, and report digital images of pathology specimens. Using the Virtuoso software, the pathologist can view digital images, add annotations, make measurements, perform image analysis, and generate reports.

The Virtuoso software is designed to complement the routine Software: workflow of a qualified pathologist in the review of immunohistochemically stained histologic slides. It allows the user to select fields of view (FOVs) in the digital image for analysis and provides quantitative data on these FOVs to assist with interpretation. The software makes no independent interpretations of the data and requires competent human intervention for all steps in the analysis process.

Additional Materials Required:

Ventana CONFIRMIM Ki-67 (30-9) rabbit monoclonal primary antibody .
Reagents for visualization, such as universal DAB chromogen o
. Associated materials for completing immunohistochemical staining according to the appropriate package insert
o Color printer if user wishes to print color copies

Device Quality Control

The quality of results depends on the laboratory following the quality control instructions recommended in the labeling of the immunohistochemistry (IHC) reagents. The software also performs a quality check on the digital images to determine if they are suitable for further analysis using "Image Quality Assessment" algorithms.

Summary of Procedure

Samples are obtained as formalin-fixed, paraffin-embedded tissue blocks. Histologic sections are prepared and mounted onto glass slides are reacted with the Ki-67 (30-9) primary antibody, and are then visualized using DAB. Prepared slides are loaded into the Virtuoso system scanner and scanned. The resulting digital images are reviewed by the pathologist on a computer monitor, and appropriate fields of view (FOVs) are then selected for analysis by the Virtuoso software. The Virtuoso software produces a quantitative score for the FOV and an aggregate score over all the FOVs for the whole slide. The

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Ventana Digital Pathology | 203 Ravendale Dr., Mountain View, CA 9404317; 408 207 4299 www.ventanadigitalpathology.com

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ENTANA A Member of the Roche Group

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

807.92 (a)(5): Intended Use

Note: The IHC Ki-67 (30-9) Digital Read and Image Analysis applications are adjunctive computer-assisted methodologies for the qualified pathologist in the acquisition and measurement of images from microscope glass slides of breast cancer specimens stained for the presence of Ki-67 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- Ki-67 (30-9) Rabbit Monoclonal Primary Antibody assay used to assure the validity of the Virtuoso System for IHC Ki-67 Digital Read and Image Analysis scores. The actual correlation of CONFIRM™ anti-Ki-67 (30-9) Rabbit Monoclonal Primary Antibody to clinical outcome has not been established.

Ventana Digital Pathology | 203 Ravendale Dr., Mountain View, CA 9404311: 408 207 4200F: 408 207 4299 ww.ventanadigitalpathology.com

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

Characteristic	Virtuoso™ IHC Ki-67 (30-9)[Benchmark ULTRA Stainer]	Virtuoso™ IHC Ki-67 (30-9)[Benchmark XT Stainer] K111755
	This device is intended for in vitro diagnostic(IVD) use.	SAME
IntendedUse/Indicationsfor Use	The Virtuoso System provides automateddigital slide creation, management, analysis,and viewing. It is intended for IVD use as anaid to the pathologist in the display, detection,counting, review and classification of tissuesand cells of clinical interest based onparticular morphology, color, size, intensity,pattern and shape.	SAME
	The IHC Ki-67 (30-9) Digital Read and ImageAnalysis applications are intended for use asan aid to the pathologist in the detection andsemi-quantitative measurement of Ki-67protein in formalin-fixed, paraffin-embeddednormal and neoplastic tissue. When used withVentana Medical Systems, Inc. CONFIRM™anti-Ki-67 (30-9) Rabbit Monoclonal PrimaryAntibody, it is indicated for use as an aid inthe assessment Ki-67 protein of breast cancerpatients (but is not the sole basis fortreatment).	SAME
Specimen Type	Formalin-fixed, paraffin-embedded tissuestained by immunohistochemical technique	Same
System Operation(Digital Read andImage Analysis)	Histologic observation by a pathologistthrough the viewer and image analysissystems	Same
Hardware andSoftware	Ventana iScan slide scanner, computer, colormonitor, proprietary software for Ki-67 (30-9)	Same
Platform Components	mouse, keyboard, windows web browser.	Same
Primary Antibody(Assay) Reagent	Ventana CONFIRM™ Ki-67 (30-9)(reagent is Class 1, 510(k) exempt)	Same
AncillaryReagents/Stainers	DAB universal chromogen kits,Slides stained with Benchmark ULTRAstainer	DAB universal chromogen kitsSlides stained with Benchmark XTstainer
Localization ofIHC positive stain	Nucleus	Same
	Interpretation is performed by the pathologist.

The following chart describes similarities and differences between the two test systems.

Ventana Digital Pathology | 203 Ravendale Dr., Mountain View. CA 94043fT: 408 207 4200fF: 408 207 4299 ww.ventanadigitalpathology.com

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

DIGITAL READ PERFORMANCE

The Virtuoso System for IHC Ki-67 (30-9) with the Benchmark ULTRA stainer was clinically validated for digital reading (DR) via a concordance study where 120 cases were evaluated by the manual and DR methods by one pathologist at one site. Each case was scored manually with a routine microscope and as a digital image. The manual score (reference result) was compared to the digital read result.

The data were evaluated as positive or negative for Ki-67 status using 0% to 10% as negative status, and >10% as positive status.

Agreement: Digital Read vs Manual (manual = true score) (ULTRA stainer) Negative= 0-10%; Positive=>10%

	Manual Microscopic Read
Digital Read	Positive	Negative	Total
Positive	52	12	64
Negative	0	56	56
Total	52	68	120
Positive Percent Agreement (PPA) n/N (%) (95% CI)	52/52 (100.0) (93.1-100)
Negative Percent Agreement (NPA) n/N (%) (95% CI)	56/68 (82.4) (71.6-89.6)
Overall Percent Agreement (OPA) n/N (%) (95% CI)	108/120 (90.0) (83.3-94.2)

IMAGE ANALYSIS PERFORMANCE

The Virtuoso System for IHC Ki-67 (30-9) with the Benchmark ULTRA stainer was clinically validated for image analysis (IA) via a concordance study where 120 cases were evaluated by the manual and IA methods by three pathologists at three sites. Each case was scored manually with a routine microscope and by using the Virtuoso IA application. The manual score (reference result) was compared to the IA result.

The data were evaluated as positive or negative for Ki-67 status using 0% to 10% as negative status, and >10% as positive status.

Ventana Digital Pathology | 203 Ravendale Dr., Mountain View. CA 9404377: 408 207 4299 www.ventanadigitalpathology.com

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	Manual Microscopic Read
Image Analysis	Positive	Negative	Total
Positive	52	1	53
Negative	25	40	65
Total	77	41	118
Positive Percent Agreement (PPA) n/N (%) (95% CI)	52/77 (67.5) (56.5-76.9)
Negative Percent Agreement (NPA) n/N (%) (95% CI)	40/41 (97.6) (87.4-99.6)
Overall Percent Agreement (OPA) n/N (%) (95% CI)	92/118 (78.0) (69.7-84.5)

Agreement: Site 1 Image Analysis vs Manual (manual = true score) Negative= 0-10%; Positive= >10%

Agreement: Site 2 Image Analysis vs Manual (manual = true score) Negative= 0-10%; Positive=>10%

		Manual Microscopic Read
Image Analysis	Positive	Negative	Total
Positive: >10%	54	2	56
Negative: 0-10%	13	43	56
Total	67	45	112
Positive Percent Agreement (PPA) n/N (%) (95% CI)	54/67 (80.6) (69.6-88.3)
Negative Percent Agreement (NPA) n/N (%) (95% CI)	43/45 (95.6) (85.2-98.8)
Overall Percent Agreement (OPA) n/N (%) (95% CI)	97/112 (86.6) (79.1-91.7)

Agreement: Site 3 Image Analysis vs Manual (manual = true score) Negative= 0-10%; Positive=>10%

	Manual Microscopic Read
Image Analysis	Positive	Negative	Total
Positive: >10%	59	1	60
Negative: 0 - 10%	10	49	59
Total	69	50	119
Positive Percent Agreement (PPA) n/N (%) (95% CI)	59/69 (85.5) (75.3-91.9)
Negative Percent Agreement (NPA) n/N (%) (95% CI)	49/50 (98.0) (89.5-99.6)
Overall Percent Agreement (OPA) n/N (%) (95% CI)	108/119 (90.8) (84.2-94.8)

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

Concordance studies were performed for the Virtuoso System for IHC Ki-67 (30-9) with the Benchmark ULTRA stainer. The overall agreement between the digital read and the manual read at one site was 90.0%, and the overall agreements between image analysis and the manual read across three sites were 78.0%, 86.6%, and 90.8%, and the predetermined acceptance criterion for each measurement of 75% has been met.

Ventana Digital Pathology | 203 Ravendale Dr., Mountain View, CA 94043JT: 408 207 4299 ww.ventanadigitalpathology.com

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

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

September 6, 2013

VENTANA MEDICAL SYSTEMS INC. C/O MS. ERIKA AMMIRATI CONSULTANT 575 SHIRL YNN COURT LOS ALTOS CA 94022

Re: K121033

Trade/Device Name: Ventana Virtuoso System for IHC Ki67 (30-9) Regulation Number: 21 CFR 864.1860 Regulation Name: Immunohistochemistry reagents and kits Regulatory Class: II Product Code: NQN, NOT, OEO Dated: August 21, 2013 Received: August 22, 2013

Dear Ms. Ammirati:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The 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 Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set 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.

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Page 2-Ms. Erika Ammirati

If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (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 Small Manufacturers, International and Consumer Assistance 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,

Maria M. Chan -S

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

Enclosure

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Indications for Use

510(k) Number (if known): K121033.

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

Indications For Use:

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

The IHC Ki-67 (30-9) Digital Read and Image Analysis applications are intended for use as an aid to the pathologist in the detection and semi-quantitative measurement of Ki-67 protein in formalin-fixed, paraffin-embedded normal and neoplastic tissue. K667 results are indicated for use in assessing the proliferative activity of normal and neoplastic breast tissue. When used with Ventana Medical Systems, Inc. CONFIRM™ anti-Ki-67 (30-9) Rabbit Monoclonal Primary Antibody Assay, it is indicated for use as an aid in the assessment of Ki-67 status in breast cancer patients (but is not the sole basis for treatment).

Prescription Use _ X (Part 21 CFR 801 Subpart D) AND/OR

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

(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)

Concurrence of CDRH; Office of in Vitro Diagnostics and Radiological Health (OIR)

Maria M. Chan -S

Division Sign-Off Office of In Vitro Diagnostics and Radiological Health

510(k): K121033

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.