(28 days)
No
The document describes "image analysis algorithms" but explicitly states the software "makes no independent interpretations of the data and requires competent human intervention for all steps in the analysis process." There is no mention of AI, ML, or related terms, nor is there a description of training or test sets typical for ML model development.
No
The device is described as an aid to the pathologist for analysis and assessment of tissues and cells, and not for directly treating or diagnosing patients.
Yes
The "Intended Use / Indications for Use" section explicitly states that the device is "intended for in vitro diagnostic use as an aid to the pathologist." It further specifies its use in the "detection and semi-quantitative measurement of p53 (DO-7) protein" in tissues, which is a diagnostic activity.
No
The device description explicitly states that the Virtuoso™ System is an "instrument-plus-software system" and lists hardware components including a slide scanner (iScan), computer, monitor, keyboard, and mouse.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use Statement: The "Intended Use / Indications for Use" section explicitly states: "It is intended for in vitro diagnostic use as an aid to the pathologist..." This is a clear declaration of its IVD purpose.
- Clinical Context: The device is intended to be used with a specific IVD assay (Ventana Medical Systems, Inc. CONFIRM™ anti-p53 (DO-7) Mouse Monoclonal Primary Antibody assay) to aid in the assessment of p53 status in breast cancer patients. This places it firmly within a clinical diagnostic workflow.
- Analysis of Biological Specimens: The system analyzes digital images of formalin-fixed, paraffin-embedded normal and neoplastic tissue, which are biological specimens.
- Aid to Diagnosis: The device is intended to "aid to the pathologist in the display, detection, counting, review and classification of tissues and cells of clinical interest" and "aid to the pathologist in the detection and semi-quantitative measurement of p53 (DO-7) protein". This function directly supports the diagnostic process.
The device description and performance studies further reinforce its role as an IVD by detailing its use in a pathology laboratory setting for analyzing stained tissue samples and providing data to assist pathologists in their interpretations.
N/A
Intended Use / Indications for Use
The Virtuoso system provides automated digital slide creation, management, analysis, and viewing. It is intended for in vitro diagnostic use as an aid to the pathologist in the display, detection, counting, review and classification of tissues and cells of clinical interest based on particular morphology, color, intensity, size, pattern and shape.
The 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 (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.
Product codes
NOT, NQN, OEO
Device Description
The Virtuoso™ System is an instrument-plus-software system designed to assist the qualified pathologist in the consistent assessment of protein expression in immunohistochemically stained histologic sections from formalin-fixed, 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 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.
Mentions image processing
Yes
Mentions AI, DNN, or ML
Not Found.
Input Imaging Modality
Brightfield microscopy (digital images of immunohistochemically stained histologic sections).
Anatomical Site
Formalin-fixed, paraffin-embedded normal and neoplastic tissue. Specifically breast cancer specimens.
Indicated Patient Age Range
Not Found.
Intended User / Care Setting
Qualified pathologist, pathology laboratories.
Description of the training set, sample size, data source, and annotation protocol
Not Found.
Description of the test set, sample size, data source, and annotation protocol
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.
For performance with a secondary stainer (Benchmark ULTRA), 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.
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
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.
Agreement/Concordance (Virtuoso Digital Read vs Manual Method - Benchmark XT stainer):
Sample Size: Site 1 (n = 119), Site 2 (n = 119), Site 3 (n = 117), Site 4 (n = 114)
Overall agreements across the four sites were: 93%, 95%, 94%, and 82%, respectively.
Negative % Agreement: Site 1 (100%), Site 2 (93%), Site 3 (95%), Site 4 (74%)
Positive % Agreement: Site 1 (83%), Site 2 (100%), Site 3 (93%), Site 4 (97%)
Agreement/Concordance (Virtuoso Image Analysis vs Manual Method - Benchmark XT stainer):
Sample Size: Site 1 (n = 119), Site 2 (n = 119), Site 3 (n = 117), Site 4 (n = 105)
Overall agreements across the four sites were: 92%, 97%, 91% and 90%, respectively.
Negative % Agreement: Site 1 (99%), Site 2 (95%), Site 3 (95%), Site 4 (91%)
Positive % Agreement: Site 1 (80%), Site 2 (100%), Site 3 (83%), Site 4 (89%)
Reproducibility (Intra-Pathologist/Inter-Day Digital Read - Benchmark XT stainer):
Agreements between each of three comparisons across three sessions with the same pathologist ranged from 90% to 95%.
Session 1 vs Session 2: 98%
Session 1 vs Session 3: 95%
Session 2 vs Session 3: 93%
Reproducibility (Intra-Pathologist/Inter-Day Image Analysis - Benchmark XT stainer):
Agreements between each of the three comparisons across three sessions with the same pathologist ranged from 80% to 93%.
Session 1 vs Session 2: 93%
Session 1 vs Session 3: 95%
Session 2 vs Session 3: 98%
Reproducibility (Inter-Pathologist/Site Digital Read - Benchmark XT stainer):
Agreements ranged from 94% to 99%.
Site 1 vs Site 2: 99%
Site 1 vs Site 3: 94%
Site 2 vs Site 3: 95%
Reproducibility (Inter-Pathologist/Site Image Analysis - Benchmark XT stainer):
Agreements ranged from 94% to 97%.
Site 1 vs Site 2: 97%
Site 1 vs Site 3: 94%
Site 2 vs Site 3: 97%
Performance with a Secondary Stainer (Benchmark ULTRA):
Sample Size: 120 cases
Study type: Concordance study comparing manual score to digital read and image analysis.
Digital Read vs Manual (Negative= 0-10%; Positive= >10%):
Positive Percent Agreement (PPA): 100.0% (34/34) (95% CI: 89.8-100.0)
Negative Percent Agreement (NPA): 83.7% (72/86) (95% CI: 74.5-90.0)
Overall Percent Agreement (OPA): 88.3% (106/120) (95% CI: 81.4-92.9)
Image Analysis vs Manual (Negative= 0-10%; Positive= >10%):
Positive Percent Agreement (PPA): 94.1% (32/34) (95% CI: 80.9-98.4)
Negative Percent Agreement (NPA): 95.3% (82/86) (95% CI: 88.6-98.2)
Overall Percent Agreement (OPA): 95.0% (114/120) (95% CI: 89.5-97.7)
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
See "Summary of Performance Studies" for positive percent agreement, negative percent agreement, and overall percent agreement, along with associated 95% confidence intervals.
Predicate Device(s)
Reference Device(s)
Not Found.
Predetermined Change Control Plan (PCCP) - All Relevant Information
Not Found.
§ 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.
0
510(k) Summary
| 807.92 (a)(1): Name: | Ventana Digital Pathology | JUN - 1 2012 |
|---|---|---|
| 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 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
1
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.
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.
2
807.92 (a)(5): Intended Use
· The Virtuoso system provides automated digital slide creation, management, analysis, and viewing. It is intended for in vitro diagnostic use as an aid to the pathologist in the display, detection, counting, review and classification of tissues and cells of clinical interest based on particular morphology, color, intensity, size, pattern and shape.
The Virtuoso™ System for 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 (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.
- 3 -
3
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 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. | SAME |
| Intended
Use/Indications
for 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™ 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). | SAME |
| Specimen Type | Formalin-fixed, paraffin-embedded tissue
stained by immunohistochemical technique | Same |
| System Operation
(Digital Read and
Image Analysis) | Histologic observation by a pathologist
through the viewer and image analysis
systems | Same |
| Hardware and
Software | Ventana iScan slide scanner, computer, color
monitor, 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 |
| Ancillary
Reagents/Stainers | DAB universal chromogen kits,
Slides stained with Benchmark ULTRA
stainer | DAB universal chromogen kits,
Slides stained with Benchmark XT
stainer |
| Localization of
IHC positive stain | Nucleus | Same |
| Interpretation | Interpretation is performed by the pathologist. | Same |
The following chart describes similarities and differences hetween the two test systems
4
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.
5
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.
5
| 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) -
6
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%.
7
| 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.
8
| 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
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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
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 (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)
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)
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