PATHIAM SYSTEM WITH ISCAN FOR P53 AND KI-67
Device Facts
| Record ID | K092333 |
|---|---|
| Device Name | PATHIAM SYSTEM WITH ISCAN FOR P53 AND KI-67 |
| Applicant | Bioimagene, Inc. |
| Product Code | NQN · Hematology |
| Decision Date | Oct 27, 2010 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 864.1860 |
| Device Class | Class 2 |
Intended Use
The PATHIAM System is intended as an aid to the pathologist to detect, count, and classify cells of clinical interest based on recognition of cellular objects of particular color, size, and shape, using appropriate controls to assure the validity of the scores. The p53 application is intended for use as an aid to the pathologist to quantify the percentage of positively stained nuclei in formalin fixed paraffin embedded breast tissue specimens stained with Dako mouse monoclonal anti-human p53 antibody, clone DO7and visualized with DAB chromogen, to detect both wild-type and mutant p53, a nuclear protein, as specified in the instructions for these reagents. It is the responsibility of a qualified pathologist to employ appropriate morphological studies and controls as specified in the instructions for Dako p53 to assure the validity of the PATHIAM-assisted p53 assessment. The Ki-67 application is intended as an aid to the pathologist to quantify the percentage of positively stained nuclei in formalin-fixed paraffin embedded normal and neoplastic breast tissue specimens immunohistochemically stained with Dako mouse monoclonal anti-human Ki-67 antigen, clone MIB1 visualized with DAB chromogen as specified in the instructions for these reagents. It is the responsibility of a qualified pathologist to employ appropriate morphological studies and controls as specified in the instructions for Dako Ki-67 to assure the validity of the PATHIAM-assisted Ki-67 assessment.
Device Story
PATHIAM System is a web-based digital pathology solution for quantitative assessment of protein expression in IHC-stained histologic sections. Input: formalin-fixed, paraffin-embedded tissue slides scanned by iScan (Olympus 20x objective, LED illumination). Operation: Pathologist selects fields of view (FOVs) on digital images; software performs image analysis (segmentation of epithelial cell nuclei based on color, size, shape; classification as stained/non-stained); outputs quantitative percent positivity. Used in clinical labs; operated by pathologists. Output assists pathologist in interpretation; pathologist retains final authority to accept or override scores. Benefits: provides consistent, reproducible quantitative data to aid clinical decision-making.
Clinical Evidence
Bench testing and comparative studies performed. Study compared manual microscopy vs. PATHIAM-assisted scoring on 120 archived breast carcinoma TMA cores for p53 and Ki-67. Concordance between manual and PATHIAM-assisted scoring exceeded 75% for all clinical cut-offs (>1%, >5%, >10%). Inter-pathologist and intra-pathologist reproducibility using PATHIAM exceeded 75% concordance. Intra- and inter-system precision/reproducibility studies (n=3 systems) showed low %CV, confirming system consistency.
Technological Characteristics
System includes iScan slide scanner (Olympus 20x/0.50 Plan Fluor objective, 0.46 µm/pixel resolution, LED illumination), computer, monitor, and web-based software. Connectivity: Networked/web-based. Image format: JPEG 2000. Software performs automated image quality assessment, segmentation, and classification of epithelial cell nuclei. No specific ASTM material standards cited.
Indications for Use
Indicated for identification of p53 accumulation in human neoplasias and assessment of proliferative activity in normal and neoplastic breast tissue. For use by qualified pathologists in conjunction with clinical history and other diagnostic tests. Requires pathologist verification of PATHIAM scores.
Regulatory Classification
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.
Special Controls
(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.
Predicate Devices
- Ventana Image Analysis System (VIAS) p53 application (K062428)
- Ventana Image Analysis System (VIAS) Ki-67 application (K053520)
Related Devices
- K121516 — VIRTUOSO SYSTEM FOR IHC HER2 (4B5) · Ventana Medical Systems, Inc. · Sep 26, 2013
- K080910 — PATHIAM SYSTEM FOR HER2/NEU IMMUNOHISTOCHEMISTRY REAGENTS & KITS · Bioimagene, Inc. · Feb 4, 2009
- K111755 — VIRTUOSO SYSTEM FOR IHC KI-67 (30-9) · Ventana Medical Systems, Inc. · Feb 22, 2012
Submission Summary (Full Text)
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K092333
OCT 2 7 2010
# SECTION 3 – 510(k) SUMMARY OF SAFETY AND EFFECTIVENESS
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T 2 7 2010
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of 21 CFR §807.92(c)
Submitted by: Indu Lakshman, Director of Quality & Regulatory Affairs BioImagene, Inc 919 Hermosa Ct. Sunnyvale, CA 94085 United States
Date summary prepared: June, 2009 Date summary updated: Oct, 2009
Trade Name: PATHIAM™ System with iScan for p53 and Ki-67
Classification Name: Microscope, automated, image analysis, immunohistochemistry, operator intervention, nuclear intensity & percent positivity.
#### Device Description:
The PATHIAM™ System is an instrument and software system designed to assist the qualified pathologist in the consistent quantitative 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. PATHIAM is a web-based, end-toend digital pathology software solution that allows pathology labs to acquire, manage, view, analyze, share, and report on digital images of pathology specimens. Using the PATHIAM software, the pathologist can view digital images, add annotations, make measurements, perform image analysis, and generate reports.
The iScan slide scanning device captures digital images of formalin-fixed, Hardware: 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.
The PATHIAM software is designed to complement the routine workflow of a Software: 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 at all steps in the analysis process.
#### Indications for Use:
The p53 results provided by the PATHIAM System are indicated for use on is a useful tool for the identification of p53 accumulation in human neoplasias when used with IVD reagents marketed for this indication. Interpretation should be made within the context of the patient's
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clinical history and other diagnostic tests by a qualified pathologist. The pathologist must verify agreement with the PATHIAM score.
Ki-67 results provided by the PATHIAM System are indicated for use to assess proliferative activity when used with in vitro diagnostic reagents marketed for this indication. Interpretation should be made within the context of the patient's clinical history and other diagnostic tests by a qualified pathologist. The pathologist must verify agreement with the PATHIAM score.
Predicate Device: Tripath Imaging, Inc. Ventana® Image Analysis System (VIASTM) K062428 - VIAS p53 application K053520 - VIAS Ki-67 application Regulation: 21 CFR §864.1860, Immunohistochemistry Reagents and Kits Product Code: NON Panel: Pathology
#### Performance:
#### PATHIAM System Comparison Studies (Inter and Intra Pathologist Studies)
Inter pathologist study
#### Round 1 Manual Scoring:
Slides were scored by a qualified pathologist at each site manually. The three pathologists read randomly selected 120 stained tissue test samples manually on a microscope and assigned a score to each specimen (test sample) according to the scoring categories.
#### Round 2 PATHIAM Assisted Scoring:
PATHIAM assisted scoring took place after a minimum of one week passed since manual slide reading. The order that the test samples were accessed (randomized) for scoring was presented to the pathologists at the time the testing was administered and was different from the order presented in Round 1 to further reduce the possibility that the manual scoring influenced the scoring using the PATHIAM system. The same three pathologists reviewed the digital images of the test samples presented by the software on the computer monitor (PATHIAM system). The the toot only is the ability to navigate freely around the images at various magnifications (as in a microscope), select field of views for scoring, and determine the score for each specimen (test sample) with the assistance of the Pathiam system according to the scoring categories.
The above two steps (Round 1 and Round 2) were performed with three investigators on the same set of test samples.
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## Table 1: Concordance Results for p53 Scoring
| p53 Cut-Off<br>Threshold | Manual vs PATHIAM-assisted<br>Substantial Equivalence<br>Concordance Range for 3<br>Pathologists | PATHIAM-assisted vs<br>PATHIAM-assisted<br>Reproducibility<br>Concordance Range for<br>3 Pathologists | Manual vs Manual<br>Reproducibility<br>Concordance Range for<br>3 Pathologists |
|--------------------------|--------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------|
| >1% | 82% - 90% | 88% - 93% | 78% - 95% |
| >5% | 77% - 85% | 90% - 93% | 78% - 88% |
| >10% | 83% - 89% | 93% - 97% | 86% - 90% |
## Table 2: Concordance Results for Ki-67 Scoring
| Ki-67 Cut-Off Threshold | Manual vs. PATHIAM-<br>assisted Substantial<br>Equivalence<br>Concordance Range for<br>3 Pathologists | PATHIAM-assisted vs.<br>PATHIAM-assisted<br>Reproducibility<br>Concordance Range for<br>3 Pathologists | Manual vs. Manual<br>Reproducibility<br>Concordance Range for<br>3 Pathologists |
|-------------------------|-------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------|
| >1% | 88%-93% | 92%-94% | 86%-91% |
| >5% | 87%-93% | 90%-93% | 85%-89% |
| >10% | 81%-89% | 88%-95% | 80%-91% |
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## PATHIAM System Reproducibility and Precision Study (Inter and Intra System Studies)
The intra system (PATHIAM system with iScan) study was performed on five sets of images (one set = eight test samples) produced by one scanner and scored on one computer system (consisting of a computer, monitor, keyboard, p53 & Ki-67 image analysis algorithms, MS Windows web browser and a mouse). This study was repeated on a total of three different scanners and computer systems. Test samples were pre-selected (field of views) by a qualified pathologist. See the data analysis tables below.
## p53 System Study Precision (between run) Results:
| Sample ID | Mean | SD | %CV |
|-----------|-------|------|------|
| A7 | 0.00 | 0.00 | - |
| E3 | 0.00 | 0.00 | - |
| C9 | 42.90 | 0.02 | 0.06 |
| B5 | 2.82 | 0.08 | 2.67 |
| E3 | 73.50 | 0.05 | 0.07 |
| B9 | 16.44 | 0.01 | 0.09 |
| D4 | 22.14 | 0.07 | 0.32 |
| B3 | 24.05 | 0.06 | 0.23 |
Table 5: Intra-system Precision Study - System I for p53
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| Sample ID | Mean | SD | %CV |
|-----------|-------|------|------|
| A7 | 0.00 | 0.00 | - |
| E3 | 0.00 | 0.00 | - |
| C9 | 42.74 | 0.02 | 0.05 |
| B5 | 2.57 | 0.01 | 0.58 |
| E3 | 72.89 | 0.04 | 0.06 |
| B9 | 16.51 | 0.04 | 0.24 |
| D4 | 22.44 | 0.04 | 0.17 |
| B3 | 22.68 | 0.06 | 0.25 |
Table 6: Intra system Precision Study – System II for p53
Table 7: Intra system Precision Study – System III for p53
| Sample ID | Mean | SD | %CV |
|-----------|-------|------|------|
| A7 | 0.00 | 0.00 | - |
| E3 | 0.00 | 0.00 | - |
| C9 | 42.60 | 0.05 | 0.11 |
| B5 | 2.71 | 0.02 | 0.78 |
| E3 | 74.07 | 0.13 | 0.18 |
| B9 | 16.49 | 0.03 | 0.18 |
| D4 | 24.42 | 0.01 | 0.05 |
| B3 | 24.90 | 0.10 | 0.40 |
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## Ki-67 System Study Precision (between run) Results:
| | Sample<br>ID | Mean | SD | %CV |
|------------------------------------------|--------------|-------|------|------|
| Ki67 Precision Study -<br>System 1 (n=5) | A2 | 31.78 | 0.10 | 0.31 |
| | E2 | 64.53 | 0.25 | 0.39 |
| | A3 | 15.45 | 0.15 | 0.99 |
| | D4 | 17.82 | 0.09 | 0.50 |
| | E7 | 9.76 | 0.02 | 0.22 |
| | D6 | 4.85 | 0.02 | 0.40 |
| | E5 | 9.13 | 0.12 | 1.35 |
| | A1 | 0.88 | 0.02 | 1.78 |
Table 8: Intra system Precision Study – System I for Ki-67
Table 9: Intra system Precision Study – System II for Ki-67
| | Sample<br>ID | Mean | SD | %CV |
|------------------------------------------|--------------|-------|------|------|
| Ki67 Precision Study - System 2<br>(n=5) | A2 | 32.77 | 0.37 | 1.13 |
| | E2 | 63.29 | 0.08 | 0.12 |
| | A3 | 15.76 | 0.17 | 1.09 |
| | D4 | 17.91 | 0.04 | 0.23 |
| | E7 | 9.41 | 0.04 | 0.44 |
| | D6 | 4.87 | 0.14 | 2.90 |
| | E5 | 9.27 | 0.04 | 0.42 |
| | A1 | 0.85 | 0.01 | 0.89 |
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| | Sample<br>ID | Mean | SD | %CV |
|------------------------------------------|--------------|-------|------|------|
| Ki67 Precision Study - System 3<br>(n=5) | A2 | 31.53 | 0.19 | 0.59 |
| | E2 | 62.11 | 0.23 | 0.36 |
| | A3 | 15.05 | 0.12 | 0.78 |
| | D4 | 17.66 | 0.02 | 0.14 |
| | E7 | 9.81 | 0.07 | 0.72 |
| | D6 | 4.95 | 0.03 | 0.68 |
| | E5 | 9.43 | 0.02 | 0.24 |
| | A1 | 0.86 | 0.00 | 0.35 |
Table 10: Intra system Precision Study - System III for Ki-67
## Reproducibility (between Run/Inter System) Study
The data from the above three intra-system studies were used to understand the inter-system comparison.
Table 11: Inter system Reproducibility Study - p53
| Sample<br>ID | Mean | SD | %CV |
|--------------|-------|------|------|
| A7 | 0.00 | 0.00 | - |
| E3 | 0.00 | 0.00 | - |
| C9 | 42.75 | 0.13 | 0.30 |
| B5 | 2.70 | 0.12 | 4.32 |
| E3 | 73.49 | 0.50 | 0.68 |
| B9 | 16.48 | 0.04 | 0.25 |
| D4 | 23.00 | 1.05 | 4.55 |
| B3 | 23.88 | 0.95 | 3.97 |
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| Ki67 Inter-System Reproducibility - System 1, 2, 3 (n=3x5) | | | | | |
|------------------------------------------------------------|-----------|-------|------|------|--|
| Line Item # | Sample ID | Mean | SD | %CV | |
| TMA 3<br>2007 | A2 | 32.03 | 0.60 | 1.87 | |
| TMA 3<br>2007 | E2 | 63.31 | 1.04 | 1.65 | |
| TMA 3<br>2007 | A3 | 15.42 | 0.33 | 2.14 | |
| TMA 4<br>2007 | D4 | 17.79 | 0.12 | 0.66 | |
| TMA 3<br>2007 | E7 | 9.66 | 0.19 | 1.95 | |
| TMA 5<br>2007 | D6 | 4.89 | 0.09 | 1.84 | |
| TMA 3<br>2007 | E5 | 9.28 | 0.14 | 1.53 | |
| TMA 2<br>2007 | A1 | 0.86 | 0.02 | 2.07 | |
Table 12: Inter system Reproducibility Study – Ki67
## Substantial Equivalence
Table 13: Comparison to Predicate Devices to Support Substantial Equivalence Determination for p53 Image Analysis Systems
| Attribute | PATHIAM System for p53 | Tripath (VIAS p53)<br>K062428 |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use | This device is intended for in vitro<br>diagnostic (IVD) use. | This antibody is intended for in vitro<br>diagnostic (IVD) use. |
| | The PATHIAM System is intended<br>as an aid to the pathologist to detect,<br>count, and classify cells of clinical<br>interest based on recognition of<br>cellular objects of particular color,<br>size, and shape, using appropriate<br>controls to assure the validity of the<br>scores.<br><br>The p53 application is intended for | Ventana® Medical Systems<br>(Ventana) CONFIRM anti-p53 (DO-<br>7) primary antibody<br>is a mouse monoclonal antibody<br>(IgG1, kappa) directed against<br>human p53. The antibody is<br>intended for laboratory use to<br>qualitatively identify by light<br>microscopy wild type and mutant<br>p53 in sections of formalin fixed, |
| Attribute | PATHIAM System for p53 | Tripath (VIAS p53)<br>K062428 |
| use as an aid to the pathologist to<br>quantify the percentage of positively<br>stained nuclei in formalin fixed<br>paraffin embedded breast tissue<br>specimens stained with Dako mouse<br>monoclonal anti-human p53<br>antibody, clone DO7and visualized<br>with DAB chromogen, to detect both<br>wild-type and mutant p53, a nuclear<br>protein, as specified in the<br>instructions for these reagents. It is<br>the responsibility of a qualified<br>pathologist to employ appropriate<br>morphological studies and controls<br>as specified in the instructions for<br>Dako p53 to assure the validity of<br>the PATHIAM-assisted p53<br>assessment. | paraffin embedded tissue on a<br>Ventana automated slide stainer. | |
| Indications for<br>use | The p53 results provided by the<br>PATHIAM System are indicated for<br>use for the identification of p53<br>accumulation in human neoplasias<br>when used with IVD reagents<br>marketed for this indication.<br>Interpretation should be made within<br>the context of the patient's clinical<br>history and other diagnostic tests by<br>a qualified pathologist. The<br>pathologist must verify agreement<br>with the PATHIAM score. | The Ventana Image Analysis<br>System (VIASTM) is an adjunctive<br>computer-assisted image analysis<br>system functionally connected to an<br>interactive microscope. It is intended<br>for use as an aid to the pathologist in<br>the detection, classification and<br>counting of cells of interest 2 based<br>on marker intensity, size and shape<br>using appropriate controls to assure<br>the validity<br>of the VIAS scores. |
| Specimen Type | Formalin-fixed, paraffin embedded<br>breast cancer specimens stained by<br>immunohistochemistry reagent for<br>p53 | Same |
| Image Analysis<br>System | Histologic observation by a<br>pathologist through the<br>BioImagene's PATHIAM image<br>analysis system with iScan slide<br>scanner. | Histologic observation by a<br>pathologist through a specified<br>interactive microscope/digital<br>camera with image analysis<br>software. |
| Hardware and<br>Software | PATHIAM software, BioImagene<br>iScan slide scanner, computer, | VIAS with software, computer,<br>microscope, motorized stage, digital |
| Attribute | PATHIAM System for p53 | Tripath (VIAS p53)<br>K062428 |
| Components | mouse, keyboard, windows web<br>browser and monitor. | color video camera, mouse,<br>keyboard, and monitor. |
| Assay used | The tissues were stained using the<br>Dako p53, clone DO7TM monoclonal<br>antibody. | Ventana ConfirmTM anti-p53 (DO-7) |
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Table 14: Comparison to Predicate Devices to Support Substantial Equivalence Determination for Ki-67 Image Analysis Systems
| Attribute | PATHIAM System for Ki-67 | Tripath (VIAS Ki-67)<br>K053520 |
|--------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use | This device is intended for in vitro diagnostic (IVD) use.<br><br>The PATHIAM System is intended as an aid to the pathologist to detect, count, and classify cells of clinical interest based on recognition of cellular objects of particular color, size, and shape, using appropriate controls to assure the validity of the scores.<br><br>The Ki-67 application is intended as an aid to the pathologist to quantify the percentage of positively stained nuclei in formalin-fixed paraffin embedded normal and neoplastic breast tissue specimens immunohistochemically stained with Dako mouse monoclonal anti-human Ki-67 antigen, clone MIB1 visualized with DAB chromogen as specified in the instructions for these reagents. It is the responsibility of a qualified pathologist to employ appropriate morphological studies and controls as specified in the instructions for Dako Ki-67 to assure the validity of the | This device is intended for in vitro diagnostic (IVD) use.<br><br>The Ventana Image Analysis System (VIAS) is an adjunctive computer-assisted image analysis system functionally connected to an interactive microscope. It is intended for use as an aid to the pathologist in the detection, classification and counting of cells of interest based on marker intensity, size and shape using appropriate controls to assure the validity of the VIAS scores. In this application, the VIAS is intended to aid a qualified pathologist in the acquisition and measurement of images to quantify the percentage of positively stained nuclei in paraffin embedded breast cancer tissue specimens immunohistochemically stained for the presence of Ki-67 proteins using Ventana's reagents and nuclear hematoxylin. It is indicated for use in assessing the proliferative activity of normal and neoplastic breast tissue when used with in vitro |
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| Attribute | PATHIAM System for Ki-67 | Tripath (VIAS Ki-67)<br>K053520 |
|----------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| | PATHIAM-assisted Ki-67<br>assessment. | diagnostic reagents marketed for<br>these indications. |
| Indications for<br>use | Ki-67 results provided by the<br>PATHIAM System are indicated for<br>use to assess proliferative activity<br>when used with in vitro diagnostic<br>reagents marketed for this<br>indication. Interpretation should be<br>made within the context of the<br>patient's clinical history and other<br>diagnostic tests by a qualified<br>pathologist. The pathologist must<br>verify agreement with the<br>PATHIAM score. | It is indicated for use in assessing<br>the proliferative activity of normal<br>and neoplastic breast tissue when<br>used with in vitro diagnostic<br>reagents marketed for these<br>indications |
| Specimen Type | Formalin-fixed, paraffin embedded<br>specimens stained by<br>immunohistochemistry reagent for<br>Ki-67 | Same |
| Image Analysis<br>System | Histologic observation by a<br>pathologist through the<br>BioImagene's PATHIAM image<br>analysis system with/ iScan slide<br>scanner. | Histologic observation by a<br>pathologist through a specified<br>interactive microscope/digital<br>camera with image analysis<br>software. |
| Hardware and<br>Software<br>Components | PATHIAM software, BioImagene<br>iScan slide scanner, computer,<br>mouse, keyboard, windows web<br>browser and monitor. | VIAS with software, computer,<br>microscope, motorized stage, digital<br>color video camera, mouse,<br>keyboard, and monitor. |
| Assay used | The tissues were stained using Dako<br>Ki-67, clone MIB1 antibody. | Per Ventana Ki-67 kit product insert<br>(Catalogue Number 790-2910) |
## Standards Employed
None under Section 514
r
## FDA Guidance
Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices, May 11, 2005
... . . . . .
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# SECTION 4 – DEVICE DESCRIPTION
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#### General Description
The PATHIAM™ System is an instrument and software system designed to assist the qualified pathologist in the consistent quantitative 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. PATHIAM is a web-based, end-toend digital pathology software solution that allows pathology labs to acquire, manage, view, analyze, share, and report on digital images of pathology specimens. Using the PATHIAM software, the pathologist can view digital images, add annotations, make measurements, perform image analysis, and generate reports.
The iScan slide scanning device captures digital images of formalin-fixed, Hardware: 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 PATHIAM 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 at all steps in the analysis process.
Additional materials required:
- Dako p53, clone DO7TM monoclonal antibody .
- Dako Ki-67, clone MIB1 monoclonal antibody .
- Reagents for visualization, such as DAB chromagen .
- Associated materials for completing immunohistochemical staining according to the . appropriate package insert
- . Color printer if user wishes to print out color copies
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#### 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 either Ki-67 or p53 primary antibodies. Slides are visualized using DAB. Prepared slides are loaded into the PATHIAM 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 PATHIAM software. The PATHIAM software produces a "percent positive" result for the specific immunohistochemical study (Ki-67 or p53), and the pathologist has the choice of accepting the result or entering his/her own score.
#### Principal of Operation
After the initial image quality check, the algorithm goes through the following steps before generating the analysis results:
- 1. Field of View (FOV) identification: The algorithm separates the tissue area from the background such that only the tissue area is processed in the following steps.
- 2. Preprocessing: The algorithm generates two images after preprocessing. One of them is a contrast stretched image, and the other is an image with each of the tissue AOI pixels classified as stained or non-stained.
- 3. Segmentation: This processing step consists of extracting the objects of interest from the image. In the current applications, the objects of interest are epithelial cell nuclei. These are separated out from the rest of the identified objects using morphological properties, such as size and shape.
- 4. Classification: The segmented nuclei are classified as stained cells or non-stained cells based on the percentage of stained pixels within them.
- 5. Scoring / Grading: Based on the classification, an overall score for the image is computed using the numbers of stained cells, non-stained cells and total cells for the calculations.
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Table 15 - BioImagene iScan Slide Scanner Specifications
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| Input Format | 1 x 3 inch (25 x 75mm) microscope slides |
|-----------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Slide Capacity | 1 to 160 slides using 8 integrated standard<br>Sakura racks |
| Microscope Objective | Olympus 20x/0.50 Plan Fluor (Nikon 20x/0.50<br>Plan Fluor) |
| Scanning Resolution | 0.46 $\mu$ m/pixel @ 20x |
| Camera Frame Size | 1392x1032 |
| Light Source (Illumination) | Integrated LED |
| Auto-Scan | Automated barcode reading, tissue<br>identification, autofocus, scanning and JPEG<br>2000 compression for up to 160 slides |
| Manual Scan | User selects scan area for single or batched<br>slides in automatic or manual mode |
| Throughput | ~ 4 minutes/slide in batch mode (15 x 15mm<br>scan area @ 20x)<br>- Time To View (defined as total pre-<br>processing time, scanning time and encoding<br>time) |
| Scan Viewing | 24-bit true color |
| Slide Storage Format | JPEG 2000 |
| Compression | 1:1 - 20:1 (range) |
| Barcode Capability | 1D and 2D option |
| Dimensions | Approximately 18 x 18 x 17 high inches (45 x<br>45 x 41 high mm) |
| Weight | 75 lbs (23 kg) |
| Power | 110-240 VAC, 50/60 Hz |
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# SECTION 5 – COMPARATIVE INFORMATION
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## Substantial Equivalence
## Table 16: Comparison to Predicate Devices to Support Substantial Equivalence Determination
| Attribute | PATHIAM System | Tripath (VIAS p53)<br>K062428 |
|----------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use | This device is intended for in vitro<br>diagnostic (IVD) use. | This antibody is intended for<br>in vitro diagnostic (IVD) use. |
| | The PATHIAM System is intended<br>as an aid to the pathologist to<br>detect, count, and classify cells of<br>clinical interest based on<br>recognition of cellular objects of<br>particular color, size, and shape,<br>using appropriate controls to assure<br>the validity of the scores.<br>The p53 application is intended for<br>use as an aid to the pathologist to<br>quantify the percentage of<br>positively stained nuclei in<br>formalin fixed paraffin embedded<br>breast tissue specimens stained<br>with Dako mouse monoclonal anti-<br>human p53 antibody, clone<br>DO7and visualized with DAB<br>chromogen, to detect both wild-<br>type and mutant p53, a nuclear<br>protein, as specified in the<br>instructions for these reagents. It<br>is the responsibility of a qualified<br>pathologist to employ appropriate<br>morphological studies and controls<br>as specified in the instructions for<br>Dako p53 to assure the validity of<br>the PATHIAM-assisted p53<br>assessment. | Ventana® Medical Systems<br>(Ventana) CONFIRM anti-<br>p53 (DO-7) primary antibody<br>is a mouse monoclonal<br>antibody (IgG1, kappa)<br>directed against human p53.<br>The antibody is intended for<br>laboratory use to qualitatively<br>identify by light microscopy<br>wild type and mutant p53 in<br>sections of formalin fixed,<br>paraffin embedded tissue on a<br>Ventana automated slide<br>stainer. |
| Indications for use | The p53 results provided by the<br>PATHIAM System are indicated<br>for use for the identification of p53<br>accumulation in human neoplasias | The Ventana Image Analysis<br>System (VIASTM) is an<br>adjunctive computer-assisted<br>image analysis system |
| Attribute | PATHIAM System | Tripath (VIAS p53)<br>K062428 |
| | when used with IVD reagents<br>marketed for this indication.<br>Interpretation should be made<br>within the context of the patient's<br>clinical history and other<br>diagnostic tests by a qualified<br>pathologist. The pathologist must<br>verify agreement with the<br>PATHIAM score. | functionally connected to an<br>interactive microscope. It is<br>intended for use as an aid to<br>the pathologist in the<br>detection, classification and<br>counting of cells of interest<br>based on marker intensity,<br>size and shape using<br>appropriate controls to assure<br>the validity of the VIAS<br>scores. |
| Specimen Type | Formalin-fixed, paraffin embedded<br>breast cancer specimens stained by<br>immunohistochemistry reagent for<br>p53 | Same |
| Image Analysis<br>System | Histologic observation by a<br>pathologist through BioImagene's<br>PATHIAM image analysis system<br>with iScan slide scanner. | Histologic observation by a<br>pathologist through a<br>specified interactive<br>microscope/digital camera<br>with image analysis software. |
| Hardware and<br>Software<br>Components | PATHIAM software, BioImagene<br>iScan slide scanner, computer,<br>mouse, keyboard, windows web<br>browser and monitor. | VIAS with software,<br>computer, microscope,<br>motorized stage, digital color<br>video camera, mouse,<br>keyboard, and monitor. |
| Assay used | Dako p53, clone DO7TM<br>monoclonal antibody | Ventana ConfirmTM anti-p53<br>(DO-7) |
{18}------------------------------------------------
Table 17: Comparison to Predicate Devices to Support Substantial Equivalence Determination
| Attribute | PATHIAM System | Tripath (VIAS Ki-67)<br>K053520 |
|----------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use | This device is intended for in<br>vitro diagnostic (IVD) use. | This device is intended for in<br>vitro diagnostic (IVD) use. |
| Intended Use | The PATHIAM System is<br>intended as an aid to the<br>pathologist to detect, count, and<br>classify cells of clinical interest<br>based on recognition of cellular<br>objects of particular color, size,<br>and shape, using appropriate<br>controls to assure the validity of | The Ventana Image Analysis<br>System (VIAS) is an adjunctive<br>computer-assisted image<br>analysis system functionally<br>connected to an interactive<br>microscope. It is intended for<br>use as an aid to the pathologist in<br>the detection, classification and |
| Attribute | PATHIAM System | Tripath (VIAS Ki-67)<br>K053520 |
| | the scores. | counting of cells of interest based<br>on marker intensity, size and<br>shape using appropriate controls<br>to assure the validity of the VIAS<br>scores. |
| | The Ki-67 application is intended<br>as an aid to the pathologist to<br>quantify the percentage of<br>positively stained nuclei in<br>formalin-fixed paraffin embedded<br>normal and neoplastic breast<br>tissue specimens<br>immunohistochemically stained<br>with Dako mouse monoclonal<br>anti-human Ki-67 antigen,<br>clone MIB1 visualized with DAB<br>chromogen as specified in the<br>instructions for these reagents. It<br>is the responsibility of a qualified<br>pathologist to employ appropriate<br>morphological studies and<br>controls as specified in the<br>instructions for Dako Ki-67 to<br>assure the validity of the<br>PATHIAM-assisted Ki-67<br>assessment. | In this application, the VIAS is<br>intended to aid a qualified<br>pathologist in the acquisition<br>and measurement of images to<br>quantify the percentage of<br>positively stained nuclei in<br>paraffin embedded breast cancer<br>tissue specimens<br>immunohistochemically stained<br>for the presence of Ki-67 proteins<br>using Ventana's reagents and<br>nuclear hematoxylin. It is<br>indicated for use in assessing the<br>proliferative activity of normal<br>and neoplastic breast<br>tissue when used with in vitro<br>diagnostic reagents marketed for<br>these indications. |
| Indications for<br>use | Ki-67 results provided by the<br>PATHIAM System are indicated<br>for use to assess proliferative<br>activity when used with in vitro<br>diagnostic reagents marketed for<br>this indication. Interpretation<br>should be made within the<br>context of the patient's clinical<br>history and other diagnostic tests<br>by a qualified pathologist. The<br>pathologist must verify<br>agreement with the PATHIAM<br>score. | It is indicated for use in assessing<br>the proliferative activity of<br>normal and neoplastic breast<br>tissue when used with in vitro<br>diagnostic reagents marketed for<br>these indications |
| Specimen Type | Formalin-fixed, paraffin<br>embedded specimens stained by<br>immunohistochemistry reagent<br>for Ki-67…
