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).

Note: The IHC p53 (D0-7) 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.

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 an analysis of the acceptance criteria and study details for the Virtuoso™ System for IHC p53 (DO-7), based on the provided document:

Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria with specific thresholds for agreement percentages. Instead, it presents the results of several agreement and reproducibility studies. For the purpose of this summary, the reported performance values themselves are considered against an implicit expectation of high agreement.

Metric	Acceptance Criteria (Implicit from context)	Reported Device Performance (Virtuoso System)
Agreement: Virtuoso Digital Read vs Manual	High agreement desirable (e.g., >90%)	Site 1: 93% (CI 87-97%)Site 2: 95% (CI 89-98%)Site 3: 94% (CI 88-97%)Site 4: 82% (CI 73-88%)
Agreement: Virtuoso Image Analysis vs Manual	High agreement desirable (e.g., >90%)	Site 1: 92% (CI 85-95%)Site 2: 97% (CI 92-99%)Site 3: 91% (CI 84-95%)Site 4: 90% (CI 83-95%)
Intra-Pathologist/Inter-Day Reproducibility (Digital Read)	High agreement desirable (e.g., >90%)	Total agreements ranging from 90% to 95%
Intra-Pathologist/Inter-Day Reproducibility (Image Analysis)	High agreement desirable (e.g., >80-90%)	Total agreements ranging from 80% to 93%
Inter-Pathologist Reproducibility (Digital Read)	High agreement desirable (e.g., >90%)	Total agreements ranging from 94% to 99%
Inter-Pathologist Reproducibility (Image Analysis)	High agreement desirable (e.g., >90%)	Total agreements ranging from 94% to 97%
Scanner Precision (Image Analysis)	High agreement desirable (e.g., >90%)	Approximately 90% for every comparison across three image analysis FOVs

Study Details

The evaluation involved two studies: a primary study for overall system performance and a secondary study for scanner precision.

Sample size used for the test set and the data provenance:
- Agreement Studies (Virtuoso vs Manual): The sample sizes for the primary agreement study were 119 cases for Site 1, 119 cases for Site 2, 117 cases for Site 3, and 114 cases for Site 4 for the Digital Read analysis. For Image Analysis, Site 4 had 105 cases.
- Reproducibility Studies: The sample sizes for reproducibility studies are not explicitly stated as total number of cases. However, the confusion matrices for intra-pathologist reproducibility (pages 5 & 6) suggest working with sample sizes in the range of 30-40 cases across sessions (e.g., for Digital Read: 27 Neg, 13 Pos in Session 1, implying around 40 cases). For inter-pathologist reproducibility (pages 6 & 7), the sample sizes range from 119 to ~120 (e.g., Site 1 vs Site 2 had counts summing to 119).
- Scanner Precision Study: A subset of 40 clinical cases from the primary study was used.
- Data Provenance: Not explicitly stated, but the mention of "four sites" suggests data was collected from multiple clinical institutions. It is a clinical validation study and, given the nature of regulatory submissions, is almost certainly retrospective analysis of previously collected and stained slides. No country of origin is specified, but the submission is to the US FDA, implying US (and potentially international) clinical data.
Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- Number of Experts: For the primary study, at least three pathologists were involved for inter-pathologist reproducibility, and each of them performed manual readings for comparison. For the agreement with the manual method, "Each pathologist's Virtuoso digital read results were compared to their manual results." This implies that the manual reading by the same pathologist served as a direct comparison for their digital (DR or IA) reading.
- Qualifications of Experts: The document states the device is "designed to assist the qualified pathologist" and requires "competent human intervention." While specific years of experience are not mentioned, it is implicit that these were qualified pathologists using traditional diagnostic methods.
Adjudication method (e.g., 2+1, 3+1, none) for the test set:
- The primary study compared the Virtuoso system's readings (Digital Read and Image Analysis) against the manual method findings of the same pathologist. This means the pathologist's own manual interpretation served as the reference for their digital assessment, rather than an independent adjudicated ground truth from multiple experts.
- The inter-pathologist agreement section compares readings among three pathologists but does not describe an explicit adjudication process (like 2+1 majority vote) to establish a single "ground truth" across them for the reproducibility analysis itself. Instead, it measures the agreement between them.
If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:
- This document does not describe a MRMC comparative effectiveness study that measures the improvement of human readers with AI assistance vs. without AI assistance.
- Instead, it evaluates the agreement of the AI system's outputs (Digital Read and Image Analysis) with human manual readings, and the reproducibility of human readings, both with and without the digital system (manual vs. digital read, IA vs. manual). It's more of a validation of the digital system as an equivalent tool, rather than an AI-assisted improvement study.
If a standalone (i.e. algorithm only, without human-in-the-loop performance) was done:
- The "Image Analysis" portion of the Virtuoso system represents the algorithm's standalone performance, albeit within a workflow where a pathologist selects the fields of view. The software "produces a quantitative score for the FOV and an aggregate score over all the FOVs for the whole slide," and "the pathologist has the choice of accepting the result or overriding with his/her own score."
- The agreement of "Virtuoso Image Analysis vs Manual Method" (page 5) effectively serves as an evaluation of the algorithm's standalone performance (after FOV selection), compared to a human's manual assessment.
The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- The ground truth for comparison was established by the manual interpretation of qualified pathologists using traditional microscopy. This is termed the "reference manual method."
- The p53 classifications were "less than or equal to 10% to describe negative, and greater than 10% to describe positive." This threshold-based binary classification was applied by the pathologists.
The sample size for the training set:
- The document does not provide any information about the sample size used for the training set of the Virtuoso system's image analysis algorithms.
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.

Summary

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Image /page/0/Picture/0 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. Below the word "VENTANA" is the text "A Member of the Roche Group" in a smaller, serif font.

SECTION 7 510(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 K111872.

807.92 (a)(1): Name:	Ventana Digital Pathology
Address:	919 Hermosa Court
	Sunnyvale, 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 forimmunochemistry-stained slides
Classifications:	21 CFR § 864.1860- Immunohistochemistry reagents and kit

Product Codes: NOT, NON, OEO

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

The Virtuoso System for IHC p53 (DO-7) is substantially equivalent to BioImagene's PATHIAM™ 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 p53 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

Page 1 of 8

APR 1 9 2012

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VENTANA

A Member of the Roche Group

(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.

Additional Materials Required:

Ventana CONFIRM™ P53 (DO-7) mouse 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 (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

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A Member of the Roche Group

VENTANA

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

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™ antip53 (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).

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Image /page/3/Picture/0 description: The image shows the logo for Ventana Medical Systems, Inc. The logo consists of a stylized sun-like symbol on the left, followed by the word "VENTANA" in bold, uppercase letters. To the right of the word "VENTANA" is a superscripted registered trademark symbol. Below the logo is the text "A Member of the Roche Group" in a smaller font size.

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

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

Characteristic	Virtuoso™ IHC p53 (DO-7)	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 p53 (DO-7) Digital Read andImage Analysis applications are intendedfor use as an aid to the pathologist in thedetection and semi-quantitativemeasurement of p53 protein in formalin-fixed, paraffin-embedded normal andneoplastic tissue. When used with VentanaMedical Systems, Inc. CONFIRM™ anti-p53 (DO-7) Mouse 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	Biolmagene (now Ventana) iScan slidescanner, computer, color monitor,proprietary software for p53 (DO-7)	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™ p53 (DO-7)(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 p53 (DO-7) was clinically validated via two studies. The first (primary) study evaluated overall system performance across four sites in terms of: (1) agreement between the reference manual method (with a traditional microscope) and both the digital read (DR) and image analysis (IA) applications of of the Virtuoso system, (2) intra-pathologist/inter-day reproducibility of the two Virtuoso applications (3 sessions), and (3) interpathologist reproducibility (3 sites) of the two Virtuoso applications.

In the second study, scanner precision was evaluated in an isolated fashion via a cross-over design from the primary study. In this second study, a subset of the clinical cases (n = 40) was scanned two more times with two different scanners at two separate locations. This study evaluated scanner precision of the image analysis application only for both inter-scanner precision and intrascanner/inter-day precision, as the image analysis application is the more objective of the two applications and is not affected by memory bias as would be the case with human interpretations. 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% 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) around the agreements are shown below.

Confusion Matrix		Site 1(n = 119)		Site 2(n = 119)		Site 3(n = 117)		Site 4(n = 114)
		Digital
		Neg	Pos	Neg	Pos	Neg	Pos	Neg	Pos
Manual	Neg (≤10%)	73	0	82	6	71	4	56	20
	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%)

Agreement: Digital Read vs Manual (manual = true score) n53 (DO-7)

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· Ventana Digital Pathology | 919 Hermosa Court, Sunnyvale, CA 94085 |T: 408 207 4299 www.ventanadigitalpathology.com| powered by Biolmagene

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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, is presented below.

	Image Analysis
Confusion Matrix		Site 1(n = 119)		Site 2(n = 119)		Site 3(n = 117)		Site 4(n = 105)
		Neg	Pos	Neg	Pos	Neg	Pos	Neg	Pos
Manual	Neg (≤10%)	72	1	84	4	71	4	61	6
	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%)

Agreement: Image Analysis vs Manual (manual = true score) p53 (DO-7)

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 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
Session1	Neg	27	26	1	25	2	25	15
	Pos	13	0	13	0	13
Session2	Neg	26					24	2
	Pos	14					1	13
% Agreement			98%		95%		93%
(95% CI)			(87% -	100%)	(83% -	99%)	(80% -	97%)

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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 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
			26	14	25	ો રે	ટર	ો રે
Session	Neg	25	24		24
1 .	Posl	। રે	2	13		14
Session	Negl	26					25
2	Pos	14					0	14
% Agreement			93%		વે રેજી જેવી સવલતો પ્રાપ્ય થયેલી છે. આ ગામનાં લોકોનો મુખ્ય વ્યવસાય ખેતી, ખેતમજૂરી તેમ જ પશુપાલન છે. આ ગામમાં પ્રાથમિક શાળા, પંચાયતઘર, આંગણવાડી તેમ જ દૂધની ડેરી જેવી સવલતો પ્		98%
(95% CI)			(80% -	97%)	(83% -		99%) (187% -	100%)

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

Manual Read

The three manual readings across three pathologists were compared to each other. The agreements ranged from 87% to 92%, indicating some human variation among the three pathologists.

Inter-Pathologist Manual
Confusion Matrix			Site 2		Site 3		Site 3
			Neg	Pos	Neg	Pos	Neg	Pos
Site 1	Neg	74	88	31	76	42	76	42
	Pos	46	73	0	70	3
Site 2	Neg		15	31	6	39
	Pos		88				76	11
			31				0	31
% Agreement			87%		92%		91%
(95% CI)			(80% - 92%)		(86% - 96%)		(84% - 95%)

Ventana Digital Pathology | 919 Hermosa Court, Sunnyvale, CA 94085 |T: 408 207 4299 www.ventanadigitalpathology.com | powered by BioImagene

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Digital Read

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

Inter-Pathologist Digital
Confusion Matrix			Site 2		Site 3		Site 3
			Neg	Pos	Neg	Pos	Neg	Pos
Site 1	Neg	81	81	0	74	6
	Pos	38	1	37	1	37
Site 2	Neg	82					75	6
	Pos	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
Confusion Matrix			Site 2		Site 3		Site 3
			Neg	Pos	Neg	Pos	Neg	Pos
Site 1	Neg	81	81	0	76	4
	Pos	38	3	35	3	35
Site 2	Neg	84					79	4
	Pos	35					0	35
% Agreement				97%		94%		97%
(95% CI)			(93% -	99%)	(88% -	97%)	(92% -	99%)

Scanner Precision

When the iScan scanner was evaluated for inter-site and intra-site/inter-day precision, the percent agreements for three image analysis filed of views were 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 p53 (DO-7). The test system was shown to be safe and 'effective for its intended use.

Ventana Digital Pathology | 919 Hermosa Court, Sunnyvale, CA 94085 |T: 408 207 4299 www.ventanadigitalpathology.com | powered by Biolmagene

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DEPARTMENT OF HEALTH & HUMAN SERVICES

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Public Health Service

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

APR 1 9 2012

Re: K111872

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: NON, NOT, OEO Dated: April 3, 2012 Received: April 4, 2012

Dear Mr. Quander:

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 or any I vith 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 requirements as over marketing your device as described in your Section 510(k) premarket

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Page 2 - Mr. Troy Quander

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.

Maria M Chan

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):

K111872

Virtuoso™ System for IHC p53 (DO-7) Device Name:

Indications for Use

Note: The IHC p53 (D0-7) 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.

Over-The-Counter Use AND/OR Prescription Use X (21 CFR 801 Subpart C) (Part 21 CFR 801 Subpart D) Olvision Sign-Office of In Vitro Diagnostic Device Evaluation and Safety K111872

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

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

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.