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

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

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

Here's a breakdown of the acceptance criteria and the study details for the VENTANA Virtuoso™ System for IHC Ki-67 (30-9), based on the provided 510(k) summary:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined "acceptance criteria" in terms of specific thresholds that needed to be met for agreement percentages. Instead, it presents the results of concordance and reproducibility studies. The performance reported below serves as the demonstrated effectiveness of the device.

Performance Metric	Acceptance Criteria (Implied by reported results)	Reported Device Performance
Concordance - Digital Read vs. Manual	High agreement between digital read and manual method for Ki-67 classification (≤10% neg, >10% pos).	Overall agreements: 92%, 81%, 86%, 87% across four sites.
	Negative % Agreement (Digital Read vs. Manual)	79% (Site 1), 100% (Site 2), 94% (Site 3), 92% (Site 4)
	Positive % Agreement (Digital Read vs. Manual)	100% (Site 1), 69% (Site 2), 80% (Site 3), 81% (Site 4)
Concordance - Image Analysis vs. Manual	High agreement between image analysis and manual method for Ki-67 classification.	Overall agreements: 88%, 86%, 86%, 81% across four sites.
	Negative % Agreement (Image Analysis vs. Manual)	79% (Site 1), 95% (Site 2), 86% (Site 3), 65% (Site 4)
	Positive % Agreement (Image Analysis vs. Manual)	93% (Site 1), 81% (Site 2), 86% (Site 3), 100% (Site 4)
Reproducibility - Intra-Pathologist/Inter-Day (Digital Read)	High agreement between repeated digital readings by the same pathologist on different days.	Total agreements ranged from 98% to 100% (across 3 session comparisons).
Reproducibility - Intra-Pathologist/Inter-Day (Image Analysis)	High agreement between repeated image analyses by the same pathologist on different days.	Total agreements ranged from 89% to 97% (across 3 session comparisons).
Reproducibility - Inter-Pathologist (Digital Read)	Acceptable agreement between digital readings by different pathologists.	Total agreements ranged from 71% to 85%.
Reproducibility - Inter-Pathologist (Image Analysis)	Acceptable agreement between image analysis interpretations by different pathologists.	Total agreements ranged from 84% to 93%.
Scanner Precision	High percentage agreement for image analysis fields of views across inter-site and intra-site/inter-day scans.	Approximately 90% for every comparison.

2. Sample Size Used for the Test Set and Data Provenance

Sample Size:
- Concordance studies:
  - Site 1: n = 120
  - Site 2: n = 118 (Digital Read), n = 117 (Image Analysis)
  - Site 3: n = 114
  - Site 4: n = 118 (Digital Read), n = 117 (Image Analysis)
- Reproducibility studies (intra-pathologist):
  - The confusion matrices show cell counts of 37-38 for positive and 1-8 for negative detections in Session 1, suggesting a smaller sample size per pathologist for this specific part, but the total number of cases for reproducibility is not explicitly stated.
- Reproducibility studies (inter-pathologist): The confusion matrices show cell counts of ~30-60 for negative and positive detections per site/pathologist comparison, again implying a specific sample size for this portion of the study that is not explicitly stated as a total N.
Data Provenance: The document does not specify the country of origin of the data. The study was a "primary study" that "evaluated overall system performance across four sites," implying a multi-center study. It does not explicitly state if the data was retrospective or prospective. Given it's a clinical validation study, it would typically be prospective, but this is not confirmed.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications

The ground truth for the concordance studies (Digital Read vs. Manual, Image Analysis vs. Manual) was established by pathologists performing a "manual method (with a traditional microscope)".
The number of pathologists involved in establishing the "manual method" ground truth for the test set is not explicitly stated, but it implies at least one pathologist per site for the concordance studies (four sites) and three pathologists for the reproducibility studies.
Qualifications: Referred to as "qualified pathologist[s]". Specific years of experience or sub-specialty are not provided.

4. Adjudication Method for the Test Set

The document does not describe a formal adjudication method (e.g., 2+1 or 3+1 consensus) for establishing the ground truth from the manual method. It simply states the comparison was made against the pathologist's manual results. For the reproducibility studies, it measures agreement between pathologists or within a pathologist over time, not a specific ground truth adjudication process for the test set itself.

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

Yes, elements of an MRMC study were conducted:
- The "Agreement/Concordance" section compares the Virtuoso Digital Read and Image Analysis applications against a "Manual Method" performed by pathologists. Each pathologist's Virtuoso digital read results were compared to their manual results. This is a comparison of human performance (manual) against human-assisted performance (digital read and IA).
- The "Reproducibility" section directly assesses inter-pathologist and intra-pathologist variability with the Virtuoso system.
Effect Size of Human Readers' Improvement with AI vs. Without AI Assistance: The document does not provide a direct "effect size" in terms of how much human readers improve with AI assistance compared to solely manual reading. Instead, it measures the agreement between the AI-assisted methods (Digital Read, Image Analysis) and the "manual method" (considered the true score). For instance, overall agreements for Digital Read vs. Manual ranged from 81-92%, and for Image Analysis vs. Manual ranged from 81-88%. This indicates a high level of agreement, but not an improvement factor in diagnostic accuracy or efficiency.

6. Standalone Algorithm Performance

Yes, in part. The "Image Analysis" application results (e.g., in the "Virtuoso Image Analysis vs Manual Method" section) represent the performance of the algorithm itself, providing quantitative scores. However, the device description emphasizes that "The software makes no independent interpretations of the data and requires competent human intervention for all steps in the analysis process." The pathologist selects the fields of view and can accept or override the software's score. Therefore, while the algorithm provides a standalone score, its final clinical performance is inherently linked to human interaction. The "Digital Read" performance also represents an AI-assisted mode where the human reads the digital image.

7. Type of Ground Truth Used

Expert Consensus / Pathologist Interpretation (Manual Method): The ground truth was established by pathologists performing a "manual method (with a traditional microscope)". This means the manual pathological interpretation served as the reference standard against which the digital read and image analysis results were compared.

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 algorithms.

9. How the 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. It only describes the validation studies for the device.

Summary

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VENTANA®
A Member of the Roche Group

FEB 2 2 2012

510(k) SUMMARY

This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92. The assigned 510(k) number is K111755.

807.92 (a)(1): Name:	Ventana Digital Pathology
Address:	919 Hermosa CourtSunnyvale, CA 94085
Phone:	(408) 207-4200
FAX:	(408) 207-4299
Contact:	Mr. Indu Lakshman

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

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

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

Classifications: 21 CFR § 864.1860- Immunohistochemistry reagents and kits

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

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

807.92 (a)(4): Device Description

General Description

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A Member of the Roche Group

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

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

Additional Materials Required:

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

Device Quality Control

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

Summary of Procedure

Samples are obtained as formalin-fixed, paraffin-embedded tissue blocks. Histologic sections are prepared and mounted onto glass slides. Slides are reacted with the p53 (DO7) primary antibody, and are then visualized using DAB. Prepared slides are loaded into the Virtuoso system scanner and scanned. The resulting digital images are reviewed by the pathologist on a computer monitor, and appropriate fields of view (FOVs) are then selected for analysis by the Virtuoso software. The Virtuoso software produces a quantitative score for the FOV and an aggregate score over all the FOVs for the whole slide. The pathologist has the choice of accepting the result or overriding with his/her own score for some or all FOVs.

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

807.92 (a)(5): Intended Use/ Indication(s) for Use:

Note: The IHC Ki67 (30-9) Digital Read and Image Analysis applications are adjunctive computer-assisted methodologies for the qualified pathologist in the acquisition and measurement of images from microscope glass slides of breast cancer specimens stained for the presence of Ki67 protein. The pathologist should verify agreement with the Image Analysis software application score. The accuracy of the test results depends on the quality of the immunohistochemical staining. It is the responsibility of a qualified pathologist to employ appropriate morphological studies and controls as specified in the instructions for the CONFIRMTM anti-Ki67 (30-9) Rabbit Monoclonal Primary Antibody assay to assure the validity of the Virtuoso™ System for Ki67 (30-9) Digital Read and Image Analysis scores. The actual correlation of CONFIRM™ anti-Ki67 (30-9) Rabbit Monoclonal Primary antibody assay to clinical outcome has not been established.

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

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

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

Characteristic	Virtuoso™ IHC Ki-67 (30-9)	PATHIAM™ with iScan forp53 and Ki-67 K092333
IntendedUse/Indicationsfor Use	This device is intended for in vitrodiagnostic (IVD) use.The Virtuoso System provides automateddigital slide creation, management,analysis, and viewing. It is intended forIVD use as an aid to the pathologist in thedisplay, detection, counting, review andclassification of tissues and cells of clinicalinterest based on particular morphology,color, size, intensity, pattern and shape.The IHC Ki-67 (30-9) Digital Read andImage Analysis applications are intendedfor use as an aid to the pathologist in thedetection and quantitative measurement ofKi-67 protein in formalin-fixed, paraffin-embedded normal and neoplastic tissue.When used with Ventana MedicalSystems, Inc. CONFIRM™ anti-Ki-67(30-9) Rabbit Monoclonal PrimaryAntibody, it is indicated for use as an aidin the assessment p53 protein of breastcancer patients (but is not the sole basis fortreatment).	This device is intended for in vitrodiagnostic (IVD) use.The PATHIAM System is intended as anaid to the pathologist to detect, count, andclassify cells of clinical interest based onrecognition of cellular objects of particularcolor, size, and shape, using appropriatecontrols to assure the validity of the scores.The p53/Ki-67 applications are intendedfor use as an aid to the pathologist toquantify the percentage of positivelystained nuclei in formalin-fixed, paraffin-embedded breast tissue specimens stainedwith specific monoclonal antibodies andvisualized with DAB chromogen to detectboth wild-type and mutant nuclearproteins, as specified in the instructions forthese reagents
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	BioImagene (now Ventana) iScan slidescanner, computer, color monitor,proprietary software for Ki-67 (30-9)	BioImagene (now Ventana) iScan slidescanner, computer, color monitor,proprietary software for p53 and Ki-67
Platform Components	mouse, keyboard, windows web browser.	Same
Primary Antibody(Assay) Reagent	Ventana CONFIRM™ Ki-67 (30-9)(reagent is Class I, 510(k) exempt)	Dako p53 and Dako Ki-67(reagents are Class I, 510(k) exempt)
Ancillary Reagents	DAB chromogen kits	Same
Localization ofIHC positive stain	Nucleus	Nucleus
Interpretation	Interpretation is performed by thepathologist.	Same

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

The Virtuoso System for IHC KI-67 (30-9) was clinically validated via two studies. The first (primary) study evaluated overall system performance across four sites in terms of agreement between the reference manual method (with a traditional microscope) and both the digital read (DR) and image analysis (IA) applications of the Virtuoso system. In the second study, scanner precision was evaluated in an isolated fashion among three pathologists for inter-pathologist reproducibility of the two Virtuoso applications, and intra-pathologist/inter-day reproducibility of the two Virtuoso applications was also evaluated. The data from both studies are summarized below.

Agreement/Concordance

Virtuoso Digital Read vs Manual Method a.
Each pathologist's Virtuoso digital read results were compared to their manual results. The data were categorized as "neg" and "pos" using Ki-67 classifications of less than or equal to 10% staining to describe negative, and greater than 10% to describe positive. The overall agreements across the four sites were: 92%, 81%, 86%, and 87%, respectively. The data, with the 95% confidence intervals (CI) around the agreements are shown below.

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

Ki-67 Agreement: Digital Read vs Manual (manual = true score)

b. Virtuoso Image Analysis vs Manual Method

The same analysis as performed for digital read was performed for image analysis. The overall agreements across the three sites were: 88%, 86% and 81%, respectively. That data table, along with the 95% Cls, is presented below.

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Image /page/5/Picture/0 description: The image shows the logo for Ventana. The logo consists of a stylized sun-like symbol on the left, followed by the word "VENTANA" in all caps. A registered trademark symbol is located to the right of the word. The text "A Member of the Roche Group" is located below the logo.

A Member of the Roche Group

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

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

Reproducibility

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

Digital Read

The agreements between each of the three comparisons across three sessions with the same pathologist are shown below. The total agreements ranged from 98% to 100%, and the data (with 95% CIs) are shown below.

Intra-Pathologist Digital
Confusion Matrix	Session 2		Session 3		Session 3
	Neg	Pos	Neg	Pos	Neg	Pos
Session 1	Neg	3	2	1	1	1	1
	Pos	37	0	37	0	36
Session 2	Neg	2				1	0
	Pos	38				0	37
% Agreement			98%		97%		100%
(95% CI)			(87% - 100%)		(87% - 100%)		(91% - 100%)

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Image Analysis

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

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

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

Digital Read

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

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

Image Analysis

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

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A Member of the Roche Group

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

Scanner Precision

When the iScan scanner was evaluated for inter-site and intra-site/inter-day precision, the percent agreements for three image analysis fields of views were in approximately 90% for every comparison.

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

Concordance, reproducibility, and precision studies were performed for the Virtuoso System for IHC Ki-67 (30-9). The test system was shown to be safe and effective for its intended use.

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

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

FEB 2 2 2012

Re: K111755 Virtuoso™ System for IHC Ki-67 (30-9) Trade/Device Name: 21 CFR §864.1860 Regulation Number: Immunohistrochemistry reagents and kits Regulation Name: Class II Regulatory Class: NON, NOT, OEO Product Code: January 18, 2012 Dated: January 19, 2012 Received:

Dear Mr. Quander:

We have reviewed your Section 510(k) premarket notification of intent to market the device we nave reviewed your becomen on the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate for use starcu in the onerobate) to region of the Medical Device Amendments, or to commerce provision in May 20, 1978, the eccordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). and Cosmetic Herefore, market the device, subject to the general controls provisions of the Act. The T ou may, merelore, manel the act include requirements for annual registration, listing of general controls provisions of the rice, labeling, and prohibitions against misbranding and adulteration.

If your device is classified (see above) into class II (Special Controls), it may be subject to such If your device is elassified (boo abor regulations affecting your device can be found in Title 21, additional controllo. Entitions (CFR), Parts 800 to 895. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean Please be advised that I DA 3 issuates Cra business with other requirements of the Act that I Drivias made a and regulations administered by other Federal agencies.

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

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Page 2 - Mr. Troy Quander

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

If you desire specific advice for your device on our labeling regulation (21 CFR Parts 801 and 11 you desire openite and In Vitro Diagnostic Device Evaluation and Safety at (301) 796-5450. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Tou thay of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html.

Sincerely yours,

for Maria M. Chan, Ph.D.

Director Division of Immunology and Hematology Devices Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health

Enclosure

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INDICATIONS FOR USE

510(k) Number (if Known):

K111755

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

Indications for Use

Indication(s) for Use:

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

Note: The IHC Ki67 (30-9) Digital Read and Image Analysis applications are adjunctive computer-assisted methodologies for the qualified pathologist in the acquisition and measurement of images from microscope glass slides of breast cancer specimens stained for the presence of Ki67 protein. The pathologist should verify agreement with the Image Analysis software application score. The accuracy of the test results depends on the quality of the immunohistochemical staining. It is the responsibility of a qualified pathologist to employ appropriate morphological studies and controls as specified in the instructions for the CONFIRM™ anti-Ki67 (30-9) Rabbit Monoclonal Primary Antibody assay to assure the validity of the Virtuoso™ System for Ki67 (30-9) Digital Read and Image Analysis scores. The actual correlation of CONFIRM™ anti-Ki67 (30-9) Rabbit Monoclonal Primary antibody assay to clinical outcome has not been established.

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

Over-The-Counter Use _________________________________________________________________________________________________________________________________________________________ (21 CFR 801 Subpart C)

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

Concurrence of CDRH, Office of In Vitro Diagnostics (OIVD)

Section 2- Indications for Use

Page 1 of 2

Office of In Vitro Dia Device Evaluation and

510(k) K111755.

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.