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 p53 (DO-7) 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 p53 (DO-7) protein in formalin-fixed, paraffin-embedded normal and neoplastic tissue. This device is an accessory to the Ventana Medical Systems, Inc. CONFIRM™ anti-p53 (DO-7) Mouse Monoclonal Primary Antibody assay. The Ventana Medical Systems, Inc. CONFIRM™ anti-p53 assay is indicated for the assessment of p53 protein where mutations have been linked to tumor proliferation. When used with this assay, the Virtuoso™ System for p53 (DO-7) is indicated for use as an aid in the assessment of p53 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, paraffin-embedded 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

Acceptance Criteria and Device Performance Study for Virtuoso™ System for IHC p53 (DO-7)

The information provided describes clinical validation studies for the Virtuoso™ System for IHC p53 (DO-7), first with the Benchmark XT stainer (predicate device's studies essentially) and then with the Benchmark ULTRA stainer (for this specific submission). The acceptance criteria are implicitly derived from the reported performance in these studies, focusing on agreement between the device's digital read (DR) and image analysis (IA) with manual microscopic assessment.

1. Table of Acceptance Criteria and Reported Device Performance

Note: The provided document does not explicitly state predefined "acceptance criteria" but rather reports the observed performance and concludes that the system is "safe and effective for its intended use" based on these results. Therefore, the "Acceptance Criteria" below are inferred from the reported performance figures that led to regulatory clearance.

Performance Metric	Acceptance Criteria (Inferred from reported performance)	Reported Device Performance (Benchmark XT Stainer)	Reported Device Performance (Benchmark ULTRA Stainer)
Digital Read (DR) vs. Manual Method - Overall Agreement	> 80% (based on lowest reported site performance)	Site 1: 93% (87-97% CI) Site 2: 95% (89-98% CI) Site 3: 94% (88-97% CI) Site 4: 82% (73-88% CI)	88.3% (81.4-92.9% CI)
Digital Read (DR) vs. Manual Method - Negative Agreement	> 70% (based on lowest reported site performance)	Site 1: 100% (95-100% CI) Site 2: 93% (86-97% CI) Site 3: 95% (87-98% CI) Site 4: 74% (63-82% CI)	83.7% (74.5-90.0% CI)
Digital Read (DR) vs. Manual Method - Positive Agreement	> 65% (based on lowest reported site performance)	Site 1: 83% (69-91% CI) Site 2: 100% (89-100% CI) Site 3: 93% (81-98% CI) Site 4: 97% (87-100% CI)	100.0% (89.8-100.0% CI)
Image Analysis (IA) vs. Manual Method - Overall Agreement	> 90% (based on lowest reported site performance)	Site 1: 92% (85-95% CI) Site 2: 97% (92-99% CI) Site 3: 91% (84-95% CI) Site 4: 90% (83-95% CI)	95.0% (89.5-97.7% CI)
Image Analysis (IA) vs. Manual Method - Negative Agreement	> 90% (based on lowest reported site performance)	Site 1: 99% (93-100% CI) Site 2: 95% (89-98% CI) Site 3: 95% (87-98% CI) Site 4: 91% (82-96% CI)	95.3% (88.6-98.2% CI)
Image Analysis (IA) vs. Manual Method - Positive Agreement	> 80% (based on lowest reported site performance)	Site 1: 80% (67-89% CI) Site 2: 100% (89-100% CI) Site 3: 83% (69-92% CI) Site 4: 89% (76-96% CI)	94.1% (80.9-98.4% CI)
Intra-Pathologist/Inter-Day Digital Read Agreement	> 90% (based on lowest reported performance)	90% - 95%	Not applicable (study focused on concordance for ULTRA stainer)
Intra-Pathologist/Inter-Day Image Analysis Agreement	> 80% (based on lowest reported performance)	80% - 93%	Not applicable (study focused on concordance for ULTRA stainer)
Inter-Pathologist Digital Read Agreement	> 94% (based on lowest reported performance)	94% - 99%	Not applicable (study focused on concordance for ULTRA stainer)
Inter-Pathologist Image Analysis Agreement	> 94% (based on lowest reported performance)	94% - 97%	Not applicable (study focused on concordance for ULTRA stainer)

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

For predicate device (Benchmark XT stainer):

Sample Size (Agreement/Concordance):
- Site 1: n = 119
- Site 2: n = 119
- Site 3: n = 117
- Site 4: n = 114 (for Digital Read), n = 105 (for Image Analysis)
- Total across sites: Approximately 469 unique cases for Digital Read, and 460 unique cases for Image Analysis.
Sample Size (Reproducibility - Intra-Pathologist/Inter-Day and Inter-Pathologist): The document reports agreement percentages but does not explicitly state the number of cases (n) used for these specific reproducibility comparisons in the summary table. However, confusion matrices for intra-pathologist reproducibility show "Session 1 Neg" count for example, which implies a smaller, constant set of cases (e.g., 40 cases if (26+14) for neg and (1+25) for pos in Session 1 for Digital Read).
Data Provenance: The document states "across four sites". No country of origin is specified. The studies are clinical validation studies, suggesting prospective data collection for the validation phase.

For new device (Benchmark ULTRA stainer):

Sample Size (Agreement/Concordance): 120 cases
Data Provenance: "one pathologist at one site". No country of origin is specified. This was a concordance study.

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

For predicate device (Benchmark XT stainer):

Number of Experts: The agreement/concordance study involved "Each pathologist's Virtuoso digital read results were compared to their manual results." This implies that the ground truth was established by the same pathologists who then used the digital system. The reproducibility studies involved three pathologists.
Qualifications: "qualified pathologist." No specific years of experience or sub-specialty are explicitly mentioned beyond being "qualified."

For new device (Benchmark ULTRA stainer):

Number of Experts: "one pathologist at one site."
Qualifications: "qualified pathologist." No specific years of experience or sub-specialty are explicitly mentioned beyond being "qualified."

4. Adjudication Method for the Test Set

The document does not explicitly describe a formal adjudication method (e.g., 2+1, 3+1). For the agreement studies, the manual microscopic reading by the "qualified pathologist" appears to be the reference standard against which the digital read and image analysis results are compared. This suggests that the pathologist's own manual score served as the definitive ground truth for their comparative analysis, not an independent adjudicated ground truth from multiple experts for each case before comparison.

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

Yes, a form of MRMC study was done for reproducibility purposes for the predicate device (Benchmark XT stainer).
- "Inter-Pathologist/Site" study: This evaluated the reproducibility among three pathologists for digital read and image analysis.
- However, this was a reproducibility study among AI-assisted reads, not a direct comparison of human readers with AI vs. without AI assistance to measure an "effect size" of improvement. The primary concordance studies compared each pathologist's digital/IA read to their own manual read.
Effect Size of human reader improvement: The document does not report an effect size for how much human readers improve with AI vs. without AI assistance in the format of a comparative effectiveness study showing gain in performance. Instead, it measures the agreement between the AI-assisted read and the manual read, and the reproducibility of the AI-assisted reads among multiple pathologists and over time for a single pathologist.

6. Standalone (Algorithm Only) Performance Study

Yes, a standalone performance was done for Image Analysis (IA). The "Image Analysis vs Manual Method" sections provide data on the algorithm's performance (standalone, as it generates the quantitative score) compared to the manual method. While a human selects the fields of view, the scoring itself is algorithmic.

7. Type of Ground Truth Used

Expert Consensus / Pathology (Manual Read): The ground truth for the predicate device studies and the new device study was established by a "qualified pathologist" performing a "manual method" with a traditional microscope. This is described as the "reference manual method" or "manual score (reference result)."

8. Sample Size for the Training Set

The document does not provide information on the sample size used for the training set for the Virtuoso™ system's image analysis algorithms. The studies described are clinical validation studies using test sets, not details about the algorithm development or training data.

9. How the Ground Truth for the Training Set Was Established

As the document does not provide details on the training set, it does not specify how the ground truth for the training set was established.

Summary

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510(k) Summary

807.92 (a)(1): Name:	Ventana Digital Pathology	JUN - 1 2012
Address:	919 Hermosa CourtSunnyvale, CA 94085
Phone:	(520) 229-4184
FAX:	(520) 229-5960
Contact:	Mr. Troy Quander

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

Trade name: Virtuoso™ System for IHC p53( DO-7)

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

Classifications: 21 CFR § 864.1860- Immunohistochemistry reagents and kits

Product Codes: NOT, NQN, OEO

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

This Virtuoso System for IHC p53 (DO-7) is substantially equivalent to its immediate predecessor with the same name, cleared under K111872 on April 19, 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 p53 submission qualified the Benchmark XT stainer, and this current submission qualified a second automatic stainer, the Benchmark ULTRA stainer.

807.92 (a)(4): Device Description

General Description

The Virtuoso™ System is an instrument-plus-software system designed to assist the qualified pathologist in the consistent assessment of protein expression in immunohistochemically stained histologic sections from formalin-fixed, paraffin-embedded normal and neoplastic tissues. The system consists of a slide scanner (iScan), computer, monitor, kevboard, 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

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annotations, make measurements, perform image analysis, and generate reports.

Additional Materials Required:

Ventana CONFIRM™ p53 (DO-7) rabbit monoclonal primary antibody
Reagents for visualization, such as universal DAB chromogen
Associated materials for completing immunohistochemical staining according to the appropriate package insert
Color printer if user wishes to print color copies.

Device Quality Control

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

Summary of Procedure

Samples are obtained as formalin-fixed, paraffin-embedded tissue blocks. Histologic sections are prepared and mounted onto glass slides. Slides are reacted with the p53 (DO-7) 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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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.

Note: The IHC p53 (DO-7) 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 p53 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-p53 (DO-7) Mouse Monoclonal Primary Antibody assay used to assure the validity of the Virtuoso System for IHC p53 Digital Read and Image Analysis scores. The actual correlation of CONFIRM™ anti-p53 (DO-7) Mouse Monoclonal Primary Antibody to clinical outcome has not been established.

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

Characteristic	Virtuoso™ IHC p53 (DO-7)[Benchmark ULTRA Stainer]	Virtuoso™ IHC p53 (DO-7)[Benchmark XT Stainer) K111872
	This device is intended for in vitro diagnostic(IVD) use.	SAME
	The Virtuoso system provides automateddigital slide creation, management, analysis,and viewing. It is intended for in vitrodiagnostic use as an aid to the pathologist inthe display, detection, counting, review andclassification of tissues and cells of clinicalinterest based on particular morphology,color, intensity, size, pattern and shape.	SAME
IntendedUse/Indicationsfor Use	The Virtuoso™ System for p53 (DO-7) is fordigital read and image analysis applications.This particular Virtuoso system is intended foruse as an aid to the pathologist in the detectionand semi-quantitative measurement of p53(DO-7) protein in formalin-fixed, paraffin-embedded normal and neoplastic tissue. Thisdevice is an accessory to the Ventana MedicalSystems, Inc. CONFIRM™ anti-p53 (DO-7)Mouse Monoclonal Primary Antibody assay.The Ventana Medical Systems, Inc.CONFIRM™ anti-p53 assay is indicated forthe assessment of p53 protein where mutationshave been linked to tumor proliferation.When used with this assay, the Virtuoso™System for p53 (DO-7) is indicated for use asan aid in the assessment of p53 status in breastcancer patients (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 p53 (DO-7))	Same
Platform Components	mouse, keyboard, windows web browser.	Same
Primary Antibody(Assay) Reagent	Ventana CONFIRM™ p53 (DO-7)(reagent is Class I, 510(k) exempt)	Same
Characteristic	Virtuoso™ IHC p53 (DO-7)[Benchmark ULTRA Stainer]	Virtuoso™ IHC p53 (DO-7)[Benchmark XT Stainer] K111872
AncillaryReagents/Stainers	DAB universal chromogen kits,Slides stained with Benchmark ULTRAstainer	DAB universal chromogen kits,Slides stained with Benchmark XTstainer
Localization ofIHC positive stain	Nucleus	Same
Interpretation	Interpretation is performed by the pathologist.	Same

The following chart describes similarities and differences hetween the two test systems

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

The Virtuoso System for IHC p53 (DO-7) with the Benchmark XT stainer was clinically validated via two studies. The first (primary) study evaluated overall system performance (concordance) 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, system reproducibility was evaluated among three pathologists for interpathologist reproducibility of the two Virtuoso applications: also, intrapathologist/inter-day reproducibility of the two Virtuoso applications was 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 p53 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: 93%, 95%, 94%, and 82%, respectively. The data, with the 95% confidence intervals (CI) aroundthe agreements, and negative and positive agreements, are shown below.

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Confusion Matrix	Site 1(n = 119)		Site 2(n = 119)		Site 3(n = 117)		Site 4(n = 114)
	Neg	Po	Neg	Po	Neg	Po	Neg	Po
Manual	Neg (≤10%)	73	S0	82	S6	71	S4	56	S20
	Pos (>10%)	8	38	0	31	3	39	1	37
	% Agreement	93%		95%		94%		82%
	(95% CI)	(87% -	97%)	(89% -	98%)	(88% -	97%)	(73% -	88%)
Negative % Agreement		100%		93%		95%		74%
(95% CI)		(95% -	100%)	(86% -	97%)	(87% -	98%)	(63% -	82%)
Positive % Agreement		83%		100%		93%		97%
(95% CI)		(69% -	91%)	(89% -	100%)	(81% -	98%)	(87% -	100%)

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 four sites were: 92%, 97%, 91% and 90%, respectively. That data table, along with the 95% CIs, and the negative and positive percent agreements, is presented below.

		Site 1(n = 119)		Site 2(n = 119)		Site 3(n = 117)		Site 4(n = 105)
Confusion Matrix	P53 (DO-7) Image Analysis	Neg	Po	Neg	Po	Neg	Po	Neg	Po
Manual	Neg (≤10%)	72	s1	84	s4	71	s4	61	s6
	Pos (>10%)	9	37	0	31	7	35	4	34
	% Agreement	92%	97%	91%	90%
	(95% CI)	(85% - 95%)	(92% - 99%)	(84% - 95%)	(83% - 95%)
Negative % Agreement		99%	95%	95%	91%
(95% CI)		(93% - 100%)	(89% - 98%)	(87% - 98%)	(82% - 96%)
Positive % Agreement		80%	100%	83%	89%
(95% CI)		(67% - 89%)	(89% - 100%)	(69% - 92%)	(76% - 96%)

Reproducibility

a. Intra-Pathologist/Inter-Day (pair-wise comparisons, Session 1 vs Session 2, Session 1 vs Session 3, Session 2 vs Session 3, using the 10% cutoff) -

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Digital Read

The agreements between each of three comparisons across three sessions with the same pathologist are shown below. The total agreements ranged from 90% to 95%, and the data (with 95% CIs) are shown below.

p53 Intra-Pathologist Digital- 10%
Confusion Matrix	Session 2		Session 3		Session 3
	Neg	Pos	Neg	Pos	Neg	Pos
Session 1	Neg	26	14	25	15	25	15
	Pos	26	1	25	2
Session 2	Neg	27	0	0	13
	Pos	13	13			24	2
% Agreement		98%		95%		93%
(95% CI)		(87% - 100%)		(83% - 99%)		(80% - 97%)

Image Analysis

The agreements between each of the three comparisons across three sessions with the same pathologist are shown below. The agreements ranged from 80% to 93%, and the data (with 95% CIs) are shown below.

p53 Intra-Pathologist Image Analysis- 10%
Confusion Matrix			Session 2		Session 3		Session 3
			Neg	Pos	Neg	Pos	Neg	Pos
Session 1	Neg	25	24	1	24	1
	Pos	15	2	13	1	14
Session 2	Neg	26					25	1
	Pos	14					0	14
% Agreement				93%		95%		98%
(95% CI)			(80% -	97%)	(83% -	99%)	(87% -	100%)

b. Inter-Pathologist/Site (pair-wise comparisons, Pathologist 1 vs Pathologist 2, Pathologist 1 vs Pathologist 3, Pathologist 2 vs Pathologist 3, using 10% cutoff)

Digital Read

The reproducibility in the Virtuoso digital readings among three pathologists/sites is shown below, along with the 95% Cls. The percent total agreements ranged from 94% to 99%.

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Inter-Pathologist Digital p53 (DO-7)
	Site 2		Site 3		Site 3
Confusion Matrix	Neg	Po	Neg	Po	Neg	Po
Site 1	Neg	81	81	0	74	6
	Po	38	1	37	1	37
Site 2	Neg	82		75	6
	Po	37		0	37
% Agreement		99%	94%	95%
(95% CI)		(95% - 100%)	(88% - 97%)	(89% - 98%)

Image Analysis

The reproducibility in the Virtuoso image analysis interpretations among three pathologists is shown below, along with the 95% Cls. The percent agreements ranged from 94% to 97%.

Inter-Pathologist Image Analysis p53 (DO-7)
Confusion Matrix			Site 2		Site 3		Site 3
			Neg	Po	Neg	Po	Neg	Po
		84	જ્વેર	79	ਝੇ ਰੇ	79	ಜ್ಞಾರಿ
Site 1	Neg	81	81	0	76	4
	Po	38	3	રેર	3	રે રેણવાડી તેમ જ દૂધની ડેરી જેવી સવલતો પ્રાપ્ય થયેલી છે. આ ગામનાં પ્રાથમિક શાળા, આંગણવાડી તેમ જ દૂધની ડેરી જેવી સવલતો પ્રાપ્ય થયેલી છે. આ ગામનાં પ્રાથમિક શાળા, આંગણવાડી તેમ
Site 2	Neg	84					79	4
	Po	ਤੇ ਤੇ					0	ਤੇ ਤੇ
% Agreement		97%		94%		97%
(95% CI)		(93% -	99%)	(88% -	197%)	(92% -	99%)

PERFORMANCE with a SECONDARY STAINER (Benchmark ULTRA)

The Virtuoso System for IHC p53 (DO-7) with the Benchmark ULTRA stainer was clinically validated via a concordance study where 120 cases were evaluated three ways by one pathologist at one site. Each case was scored (1) manually with a routine microscope, (2) as a digital image, and (3) by way of the image analysis application. The manual score (reference result) was compared to both the digital read result and the image analysis result.

The data were evaluated as positive or negative for p53 status using up to 10% positive staining to define negative, and >10% to define positive. The data summaries follow, first for digital readings, and followed by image analyses.

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			Negative= 0-10%; Positive=>10%
	Manual Microscopic Read
Digital Read	Positive	Negative	Total
Positive	34	14	48
Negative	0	72	72
Total	34	86	120
Positive Percent Agreement (PPA) n/N (%) (95%CI)	34/34 (100.0) (89.8-100.0)
Negative Percent Agreement (NPA) n/N (%) (95%CI)	72/86 (83.7) (74.5-90.0)
Overall Percent Agreement (OPA) n/N (%) (95%CI)	106/120 (88.3) (81.4-92.9)

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

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

	Manual Microscopic Read
Image Analysis	Positive	Negative	Total
Positive	32	4	36
Negative	2	82	84
Total	34	86	120
Positive Percent Agreement (PPA) n/N (%) (95% CI)	32/34 (94.1) (80.9-98.4)
Negative Percent Agreement (NPA) n/N (%) (95% CI)	82/86 (95.3) (88.6-98.2)
Overall Percent Agreement (OPA) n/N (%) (95% CI)	114/120 (95.0) (89.5-97.7)

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

Concordance studies and reproducibility studies were performed for the Virtuoso System for IHC p53 (DO-7) with the Benchmark XT stainer. Concordance studies were performed for the Virtuoso System for IHC p53 (DO-7) with a secondary stainer, the Benchmark ULTRA stainer. The test system was shown to be safe and effective for its intended use.

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/9/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a circular seal with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES • USA" around the perimeter. Inside the circle is an abstract symbol that resembles a stylized caduceus or a representation of human figures.

Public Health Service

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

Ventana Medical Systems, Inc. c/o Ms. Erika B. Ammirati, RAC, MT(ASCP) Ammirati Regulatory Consulting 575 Shirlynn Court Los Altos, CA 94022

JUN 0 1 2012

Re: K121350

Trade/Device Name: Virtuoso™ System for IHC p53 (DO-7) Regulation Number: 21 CFR § 864.1860 Regulation Name: Immunohistochemistry reagents and kits Regulatory Class: Class II Product Code: NOT, NON, OEO Dated: May 3, 2012 Received: May 4, 2012

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.

If your device is classified (see above) into class II (Special Controls), it may be subject to such additional controls. Existing major regulations affecting your device can be found in Title 21, Code of Federal Regulations (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 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); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820). This letter

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Page 2 - Ms. Erika Ammirati

will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device 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 809), please contact the Office of 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 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/cdrh/industry/support/index.html.

Sincerely yours.

. In leni

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):

K121350

Device Name:

Virtuoso™ System for IHC p53 (DO-7)

Indications for Use

Note: The IHC p53 (DO-7) 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 p53 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-p53 (DO-7) Mouse Monoclonal Primary Antibody assay used to assure the validity of the Virtuoso System for IHC p53 Digital Read and Image Analysis scores. The actual correlation of CONFIRM™ anti-p53 (DO-7) Mouse Monoclonal Primary Antibody to clinical outcome has not been established.

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

510(k)

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

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Concurrence of CDRH, Office of In Vitro Diagnostics (OIVD)
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Division Sign-Off
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Office of In Vitro Diagnostic
Device Evaluation and Safety

K12.1350
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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.