The GenASIs HiPath IHC Family provides image capture, management, analysis, and viewing of specific immunohistochemically stained slides. 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 GenASIs HiPath IHC Family for HER2 (4B5) is for image capture and analysis applications. This particular system is intended for use as an aid to the pathologist in the detection and semi-quantitative measurement of HER2 protein in formalin-fixed, paraffin-embedded breast cancer tissue. This device is an accessory to Ventana Medical Systems, Inc. PATHWAY® anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody. The PATHWAY® anti-HER2/ neu (4B5) Rabbit Monoclonal Primary Antibody is indicated for use as an aid in the assessment of breast cancer patients for whom HERCEPTIN® (Trastuzumab) treatment is being considered.

NOTE: The GenASIs HiPath IHC Family for HER2 (4BS) image capture and analysis applications are adjunctive computer-assisted methodologies for the qualified pathologist in the acquisition and semi-quantitative measurement of images from microscope glass slides of breast cancer specimens stained for the presence of HER-2/neu receptor protein. The pathologist should verify agreement with the Image Analysis software application score by reviewing the glass slide under the microscope. The accuracy of the test results on the quality of the immuchistochemical staining. It is the responsibility of a qualified pathologist to employ appropriate morphological studies and controls as specified in the instructions for the PATHWAY® anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody assay used to assure the validity of the GenASIs HiPath IHC Family for HER2 (4B5) image capture and analysis scores. The actual correlation of PATHWAY® anti-HER-2/neu (4B5) to clinical outcome has not been established.

The GenASIs HiPath IHC Family for PR (1E2) is for image capture and analysis applications. This particular system is intended for use as an aid to the pathologist in the detection and qualitative measurement of progesterone receptor (PR) protein in formalin-fixed, paraffin-embedded breast cancer tissue. This device is an accessory to Ventana Medical Systems, Inc. CONFIRMTM anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody assay. The CONFIRMTM anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody assay is indicated for use as an aid in the assessment of breast cancer patients for whom endocrine treatment is being considered (but is not the sole basis for treatment).

Note: The GenASIs HiPath IHC for PR (1E2) image capture and analysis applications are adjunctive computer-assisted methodologies for the qualified pathologist in the acquisition and qualitative measurement of images from microscope glass slides of breast cancer specimens stained for the presence of PR protein. The pathologist should verify agreement with the Image Analysis software application score by reviewing the glass slide under the microscope. 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-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody used to assure the validity of the GenASIs HiPath IHC Family for PR (1E2) image capture and analysis scores. The actual correlation of CONFIRMTM anti-PR antibody to clinical outcome has not been established.

The GenASIs HiPath IHC Family for ER (SP1) is for image capture and analysis applications. The particular system is intended for use as an aid to the pathologist in the detection and qualitative measurement of ER (SP1): protein in formalin-fixed, paraffin-embedded breast cancer tissue. This device is an accessory to the Ventana Medical Systems, Inc. CONFIRMTM anti-Estrogen Receptor (ER) (SP1) Rabbit Monoclonal Primary Antibody. The Ventana Medical Systems, Inc. CONFIRMTM anti-Estrogen Receptor (ER) (SP1) Rabbit Monoclonal Primary Antibody is indicated for use as an aid in the assessment of ER status in breast cancer patients (but is not the sole basis for treatment).

Note: The GenASIs HiPath IHC Family for ER (SP1) image capture and analysis applications are adjunctive computerassisted methodologies for the qualified pathologist in the acquisition and qualitative measurement of images from microscope glass slides of breast cancer specimens stained for the protein. The pathologist should verify agreement with the Image Analysis software application score by reviewing the glass slide under the microscope. The accuracy of the test results depends on the immuohistochemical 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-Estrogen Receptor (ER) (SP1) Rabbit Monoclonal Primary Antibody to assure the validity of the GenASIs HiPath IHC Family for ER (SP1) image capture and analysis scores. The actual correlation of CONFIRMTM anti-Estrogen Receptor (ER) (SP1) Rabbit Monoclonal Primary Antibody to clinical outcome has not been established.

The GenASIs HiPath IHC Family for Ki67 (30-9) is for image capture and analysis applications. The particular system is intended for use as an aid to the pathologist in the detection and qualitative measurement of Ki67 (30-9): protein in formalin-fixed, paraffin-embedded breast cancer tissue. This device is an accessory to the Ventana Medical Systems, Inc. CONFIRMTM anti-Ki67 (30-9) Rabbit Monoclonal Primary Antibody assay. The Ventana Medical Systems, Inc. CONFIRMTM anti-Ki67 (30-9) assay is indicated for use in assessing the activity of breast cancer tissue. When used with this assay, the GenASIs HiPath IHC Family for Ki67 (30-9) is indicated for use as an aid in the assessment of Ki-67 status in breast cancer patients (but is not the sole basis for treatment).

Note: The GenASIs HiPath IHC Family for Ki67 (30-9) image capture and analysis applications are adjunctive computerassisted methodologies for the qualified pathologist in the acquisition and qualitative measurement of images from microscope glass slides of breast cancer stained for the presence of Ki67 protein. The pathologist should verify agreement with the Image Analysis software application score by reviewing the glass slide under the microscope. The accuracy of the test results depends on the immunohistochemical staining. It is the responsibility of a qualified pathologist to employ appropriate morphological studies and controls as specified in the instructions for the CONFIRMTM anti-Ki67 (30-9) Rabbit Monoclonal Primary Antibody assay to assure the validity of the GenASIs HiPath IHC Family for Ki67 (30-9) image capture and analysis scores. The actual correlation of CONFIRMTM anti-Ki67 (30-9) Rabbit Monoclonal Primary antibody assay to clinical outcome has not been established.

Device Description

The GenASIs HiPath IHC Family, including software is designed to assist the qualified pathologist in the consistent assessment in inmmohistochemnically stained histologic sections from formalin-fixed, paraffin-embedded breast cancer tissues. The device consists of a slide capture camera, Microscope, computer, monitor, keyboard, mouse, image analysis algorithms for specific immunohistochemical markers, and software with a Graphic User Interface (GUI).

The GenASIs HiPath IHC Family is an intranet-based, end-to-end, digital pathology software solution that allows pathology laboratories, to acquire, manage, view, analyze, share, and report test results of pathology specimens. Using the GenASIs HiPath IHC Family software the pathologist can view captured images, add annotations, make measurements, perform image analysis and generate reports.

Hardware: A camera based acquisition device designed to captures bright-field microscope digital images of formalin-fixed, paraffin-embedded tissues that are suitable for storage and viewing. The device includes a digital slide acquisition camera, X-Y Stage with holder adaptor for loading glass slides on a microscope and a workstation including a computer, keyboard, mouse and monitor.

Software: The GenASIs HiPath IHC Family software is designed to complement the routine workflow of a qualified pathologist in the review of immunohistochemically stained histologic slides. It allows the user to select fields of view (FOVs) in the digital image for analysis and provides quantitative data on these FOVs to assist with interpretation. The software makes no independent interpretations of the data and requires competent human intervention for all steps in the analysis process.

AI/ML Overview

Here's a breakdown of the acceptance criteria and the study details for the GenASIs HiPath IHC Family device, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implied by the "Overall Agreement," "Positive Agreement," and "Negative Agreement" percentages. These percentages represent the agreement between the device's analysis and manual pathological analysis.

HER2/neu (4B5)

Metric	Acceptance Criteria (Implied)	Reported Device Performance
Overall Agreement	High agreement (e.g., >95%)	97%
Positive Agreement	High agreement (e.g., >95%)	98%
Negative Agreement	High agreement (e.g., >95%)	97%

PR (1E2)

Metric	Acceptance Criteria (Implied)	Reported Device Performance
Overall Agreement	High agreement (e.g., >95%)	99%
Positive Agreement	High agreement (e.g., >95%)	98%
Negative Agreement	High agreement (e.g., >95%)	100%

ER (SP1)

Metric	Acceptance Criteria (Implied)	Reported Device Performance
Overall Agreement	High agreement (e.g., >95%)	100%
Positive Agreement	High agreement (e.g., >95%)	99%
Negative Agreement	High agreement (e.g., >95%)	100%

Ki67 (30-9)

Metric	Acceptance Criteria (Implied)	Reported Device Performance
Overall Agreement	High agreement (e.g., >95%)	96%
Positive Agreement	High agreement (e.g., >90%)	93%
Negative Agreement	High agreement (e.g., >95%)	97%

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

The study was conducted across three clinical sites. The data provenance is not explicitly stated (e.g., country of origin), nor is it specified whether the data was retrospective or prospective. However, it involved "stained samples," implying real patient data.

HER2/neu (4B5): 357 stained samples
PR (1E2): 385 stained samples
ER (SP1): 427 stained samples
Ki67 (30-9): 373 stained samples

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

Number of Experts: Three (3) pathologists.
Qualifications: "Pathologist that followed the recommendations of the Ventana user insertions for the different panel antibodies." This implies they are qualified experts in immunohistochemical analysis. Specific experience levels (e.g., years of experience) are not provided.

4. Adjudication Method for the Test Set

The ground truth was established by manual evaluation through microscope eyepieces performed by three different pathologists. The document refers to "comparison to the measures of agreement test of conventional manual evaluation through the microscope eyepieces, performed by pathologist." It then presents "Pooled Results; Frequency distribution of agreement of Manual versus GenASIs HiPath IHC Family." This indicates that the manual reads by the three pathologists were likely combined to form a consensus or reference standard, against which the device's results were compared. An explicit adjudication method like "2+1" or "3+1" is not detailed, but the pooling of results suggests a form of consensus was used to derive the "Manual analysis" column in the tables.

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

The document describes a comparison study where "manual evaluation through the microscope eyepieces, performed by pathologist" was compared to the device's analysis. However, it does not present a MRMC comparative effectiveness study in the sense of evaluating how much human readers improve with AI vs without AI assistance. Instead, it evaluates the agreement between the standalone AI device and the human readers' manual interpretations. There is no mention of human readers using the AI as assistance and then assessing their improved performance.

6. Standalone Performance Study

Yes, a standalone performance study was conducted. The "Analytical Performance" section details the "agreement rates of the comparison between manual and GenASIs HiPath IHC Family system statistical test results." This directly presents the device's performance in categorizing samples (Negative/Positive) against the ground truth established by manual pathological analysis, without human-in-the-loop during the device's diagnostic output generation.

7. Type of Ground Truth Used

Expert Consensus: The ground truth for the test set was established through "conventional manual evaluation through the microscope eyepieces, performed by pathologist that followed the recommendations of the Ventana user insertions for the different panel antibodies." This indicates that the ground truth was based on the consensus or established interpretations of qualified pathologists.

8. Sample Size for the Training Set

The document does not explicitly state the sample size used for the training set. The "Analytical Performance" section focuses on the validation study (test set).

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

As the training set sample size is not specified, neither is the method for establishing its ground truth. However, given the context of a medical device submission, it would be expected that if a machine learning model was developed, the training data would also be expert-annotated.

Summary

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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

December 10, 2015

Applied Spectral Imaging Ltd. Ilan Sharon P.O. Box 4414 (A-109) Caesarea,30889 Isreal

Re: K140957

Trade/Device Name: GenASIs HiPath IHC Family Regulation Number: 21 CFR §864.1860 Regulation Name: Immunohistochemistry reagents and kits Regulatory Class: Class II Product Code: NON, NOT Dated: 12/11/2014 Received: 12/16/2014

Dear Ilan Sharon:

This letter corrects our substantially equivalent letter of January 15, 2015.

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. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. 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

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medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

If you desire specific advice for your device on our labeling regulation (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR 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 Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely yours,

Reena Philip -S

Reena Philip, Ph.D. Director Division of Molecular Genetics and Pathology Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

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Indications for Use

510(k) Number (if known) K140957

Device Name

GenASIs HiPath IHC Family

Indications for Use (Describe)

The GenASIs HiPath IHC Family for HER2 (4B5) is for image capture and analysis applications. This particular system is intended for use as an aid to the pathologist in the detection and semi-quantitative measurement of HER2 protein in formalin-fixed, paraffin-embedded breast cancer tissue. This device is an accessory to Ventana Medical Systems, Inc. PATHWAY® anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody. The PATHWAY® anti-HER2/ neu (4B5) Rabbit Monoclonal Primary Antibody is indicated for use as an aid in the assessment of breast cancer patients for whom HERCEPTIN® (Trastuzumab) treatment is being considered.

The GenASIs HiPath IHC Family for PR (1E2) is for image capture and analysis applications. This particular system is intended for use as an aid to the pathologist in the detection and qualitative measurement of progesterone receptor (PR) protein in formalin-fixed, paraffin-embedded breast cancer tissue. This device is an accessory to Ventana Medical Systems, Inc. CONFIRMTM anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody assay. The CONFIRMTM anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody assay is indicated for use as an aid in the assessment of breast cancer patients for whom endocrine treatment is being considered (but is not the sole basis for treatment).

The GenASIs HiPath IHC Family for ER (SP1) is for image capture and analysis applications. The particular system is intended for use as an aid to the pathologist in the detection and qualitative measurement of ER (SP1): protein in formalin-fixed, paraffin-embedded breast cancer tissue. This device is an accessory to the Ventana Medical Systems, Inc. CONFIRMTM anti-Estrogen Receptor (ER) (SP1) Rabbit Monoclonal Primary Antibody. The Ventana Medical Systems, Inc. CONFIRMTM anti-Estrogen Receptor (ER) (SP1) Rabbit Monoclonal Primary Antibody is indicated for use as an aid in the assessment of ER status in breast cancer patients (but is not the sole basis for treatment).

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microscope glass slides of breast cancer specimens stained for the protein. The pathologist should verify agreement with the Image Analysis software application score by reviewing the glass slide under the microscope. The accuracy of the test results depends on the immuohistochemical 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-Estrogen Receptor (ER) (SP1) Rabbit Monoclonal Primary Antibody to assure the validity of the GenASIs HiPath IHC Family for ER (SP1) image capture and analysis scores. The actual correlation of CONFIRMTM anti-Estrogen Receptor (ER) (SP1) Rabbit Monoclonal Primary Antibody to clinical outcome has not been established. 4. The GenASIs HiPath IHC Family for Ki67 (30-9) is for image capture and analysis applications. The particular system is intended for use as an aid to the pathologist in the detection and qualitative measurement of Ki67 (30-9): protein in formalin-fixed, paraffin-embedded breast cancer tissue. This device is an accessory to the Ventana Medical Systems, Inc. CONFIRMTM anti-Ki67 (30-9) Rabbit Monoclonal Primary Antibody assay. The Ventana Medical Systems, Inc. CONFIRMTM anti-Ki67 (30-9) assay is indicated for use in assessing the activity of breast cancer tissue. When used with this assay, the GenASIs HiPath IHC Family for Ki67 (30-9) is indicated for use as an aid in the assessment of Ki-67 status in breast cancer patients (but is not the sole basis for treatment). Note: The GenASIs HiPath IHC Family for Ki67 (30-9) image capture and analysis applications are adjunctive computerassisted methodologies for the qualified pathologist in the acquisition and qualitative measurement of images from microscope glass slides of breast cancer stained for the presence of Ki67 protein. The pathologist should verify agreement with the Image Analysis software application score by reviewing the glass slide under the microscope. The accuracy of the test results depends on the immunohistochemical staining. It is the responsibility of a qualified pathologist to employ appropriate morphological studies and controls as specified in the instructions for the CONFIRMTM anti-Ki67 (30-9) Rabbit Monoclonal Primary Antibody assay to assure the validity of the GenASIs HiPath IHC Family for Ki67 (30-9) image capture and analysis scores. The actual correlation of CONFIRMTM anti-Ki67 (30-9) Rabbit Monoclonal Primary antibody assay to clinical outcome has not been established.

Type of Use (Select one or both, as applicable)

ال Prescription Use (Part 21 CFR 801 Subpart D)

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

PLEASE DO NOT WRITE BELOW THIS LINE - CONTINUE ON A SEPARATE PAGE IF NEEDED.

FOR FDA USE ONLY

Concurrence of Center for Devices and Radiological Health (CDRH) (Signature)

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Image /page/4/Picture/0 description: The image contains the logo for Applied Spectral Imaging (ASI). The logo features the letters 'ASI' in a stylized font, with a green arc above the letters. Below the letters, the words 'Applied Spectral Imaging' are written in green, followed by the tagline 'Bringing Details to Light' in blue.

510(k) Summar As required by section 807.92(c).

January 15, 2015

510(K) Number A.

K140957

B. Purpose for Submission

The proposed ASI's GenASIs HiPath IHC Family, including GenASIs HiPath IHC Family for HER2 (4B5), PR (1E2), ER (SP1) and Ki67 (30-9), is an IVD image capture and image analysis score accessory for assist the qualified pathologist in the consistent assessment of protein expression in immunohistochemical stained histological sections from formalinfixed, paraffin embedded breast cancer tissue.

ASI is hereby preparing this traditional 510(K) submission to show that the proposed ASI's GenASIs HiPath IHC Family is substantially equivalent to the legally marketed predicate devices referred to in paragraph H.

C. Manufacturer and Instrument Name

C.1. Device Name

GenASIs HiPath IHC Family

C.2. Submitter's name

Name: Applied Spectral Imaging Ltd. 2 Ha Carmel St, New Industrial Zone, Yokneam 20691, Israel Tel: (972) 4 6547567, Fax: (972) 4 6547507

C.3. Submission contact person

Ilan Sharon P.O.B. 4414 (A-109), Caesarea 30889, Israel TEL: 972-52-8704904

Type of Test or Tests Performed D.

The GenASIs HiPath IHC Family provides image capture, management, analysis, and viewing of specific immunohistochemically stained slides. 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 and is intended for use as an aid to the pathologist in the detection and qualitative measurement of the following tests:

HER2 protein in formalin-fixed, paraffin-embedded breast cancer tissue. This device is an accessory to Ventana Medical Systems, Inc. PATHWAY® anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody. The PATHWAY® anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody is indicated for use as an aid in the assessment of breast cancer patients for whom HERCEPTIN® (Trastuzumab) treatment is being considered.

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Progesterone receptor (PR) protein in formalin-fixed, paraffin-embedded breast cancer tissue. This device is an accessory to Ventana Medical Systems, Inc. CONFIRM 114 anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody assay. The CONFIRM 110 anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody assay is indicated for use as an aid in the assessment of breast cancer patients for whom endocrine treatment is being considered (but is not the sole basis for treatment). 3. ER (SP1): protein in formalin-fixed, paraffin-embedded breast cancer tissue. This device is an accessory to the Ventana Medical Systems, Inc. CONFIRM™ anti-Estrogen Receptor (ER) (SP1) Rabbit Monoclonal Primary Antibody. The Ventana Medical Systems, Inc. CONFIRM™ anti-Estrogen Receptor (ER) (SP1) Rabbit Monoclonal Primary Antibody is indicated for use as an aid in the assessment of ER status in breast cancer patients (but is not the sole basis for treatment).
Ki67 (30-9): protein in formalin-fixed, paraffin-embedded breast cancer tissue. This device is an accessory to the Ventana Medical Systems, Inc. CONFIRM™ anti-Ki67 (30-9) Rabbit Monoclonal Primary Antibody assay. The Ventana Medical Systems, Inc. CONFIRM " anti-Ki67 (30-9) assay is indicated for use in assessing the proliferative activity of breast cancer tissue. When used with this assay, the GenASIs HiPath IHC Family for Ki67 (30-9) is indicated for use as an aid in the assessment of Ki-67 status in breast cancer patients (but is not the sole basis for treatment).

E. System Descriptions

Device description:

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F. Regulatory Information

Device Classification

Product Code:	NQN, NOT
CFR section:	21 CFR §864.1860
Regulation name:	Immunohistrochemistry reagents and kits
Trade Name:	GenASIs HiPath IHC Family
Common Name:	Immunohistrochemistry reagents and kits
Classification:	Class II

Intended Use G.

The GenASIs HiPath IHC Family for HER2 (4B5) is for image capture and analysis applications. This particular system is intended for use as an aid to the pathologist in the detection and semi-quantitative measurement of HER2 protein in formalin-fixed, paraffinembedded breast cancer tissue. This device is an accessory to Ventana Medical Systems, Inc. PATHWAY® anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody. The PATHWAY® anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody is indicated for use as an aid in the assessment of breast cancer patients for whom HERCEPTIN® (Trastuzumab) treatment is being considered.

NOTE: The GenASIs HiPath IHC Family for HER2 (4B5) image capture and analysis applications are adjunctive computer-assisted methodologies for the qualified pathologist in the acquisition and semi-quantitative measurement of images from microscope glass slides of breast cancer specimens stained for the presence of HER-2/neu receptor protein. The pathologist should verify agreement with the Image Analysis software application score by reviewing the glass slide under the microscope. The accuracy of the test results depends on the quality of the immuohistochemical staining. It is the responsibility of a qualified pathologist to employ appropriate morphological studies and controls as specified in the instructions for the PATHWAY® anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody assay used to assure the validity of the GenASIs HiPath IHC Family for HER2 (4B5) image capture and analysis scores. The actual correlation of PATHWAY® anti-HER-2/neu (4B5) to clinical outcome has not been established.

The GenASIs HiPath IHC Family for PR (1E2) is for image capture and analysis applications. This particular system is intended for use as an aid to the pathologist in the detection and qualitative measurement of progesterone receptor (PR) protein in formalinfixed, paraffin-embedded breast cancer tissue. This device is an accessory to Ventana Medical Systems. Inc. CONFIRMTM anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody assay. The CONFIRMTM anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody assay is indicated for use as an aid in the

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assessment of breast cancer patients for whom endocrine treatment is being considered (but is not the sole basis for treatment).

The GenASIs HiPath IHC Family for ER (SP1) is for image capture and analysis applications. The particular system is intended for use as an aid to the pathologist in the detection and qualitative measurement of ER (SP1): protein in formalin-fixed, paraffinembedded breast cancer tissue. This device is an accessory to the Ventana Medical Systems, Inc. CONFIRMTM anti-Estrogen Receptor (ER) (SP1) Rabbit Monoclonal Primary Antibody. The Ventana Medical Systems, Inc. CONFIRMTM anti-Estrogen Receptor (ER) (SP1) Rabbit Monoclonal Primary Antibody is indicated for use as an aid in the assessment of ER status in breast cancer patients (but is not the sole basis for treatment).

Note: The GenASIs HiPath IHC Family for ER (SP1) image capture and analysis applications are adjunctive computer-assisted methodologies for the qualified pathologist in the acquisition and qualitative measurement of images from microscope glass slides of breast cancer specimens stained for the presence of ER protein. The pathologist should verify agreement with the Image Analysis software application score by reviewing the glass slide under the microscope. The accuracy of the test results depends on the quality of the immuohistochemical 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-Estrogen Receptor (ER) (SP1) Rabbit Monoclonal Primary Antibody to assure the validity of the GenASIs HiPath IHC Family for ER (SP1) image capture and analysis scores. The actual correlation of CONFIRMTM anti-Estrogen Receptor (ER) (SP1) Rabbit Monoclonal Primary Antibody to clinical outcome has not been established.

The GenASIs HiPath IHC Family for Ki67 (30-9) is for image capture and analysis applications. The particular system is intended for use as an aid to the pathologist in the detection and qualitative measurement of Ki67 (30-9): protein in formalin-fixed, paraffinembedded breast cancer tissue. This device is an accessory to the Ventana Medical Systems, Inc. CONFIRMTM anti-Ki67 (30-9) Rabbit Monoclonal Primary Antibody assay. The Ventana Medical Systems, Inc. CONFIRMTM anti-Ki67 (30-9) assay is indicated for use in assessing the proliferative activity of breast cancer tissue. When used with this assay, the GenASIs HiPath IHC Family for Ki67 (30-9) is indicated for use as an aid in the assessment of Ki-67 status in breast cancer patients (but is not the sole basis for treatment).

Note: The GenASIs HiPath IHC Family for Ki67 (30-9) image capture and analysis

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

H. Substantial Equivalence Information

#	Comparisonparameter	Proposed device:ASI GenASIs HiPath IHC Family	Predicate device:VirtuosoTM System
1	Owner	Applied Spectral Imaging Ltd.	Ventana Digital Pathology
2	LegallydistributionclearanceNo.	K..........Subject to this submission	K111543 - VirtuosoTM System for IHC HER2 (4B5)K111869 - VirtuosoTM System for IHC PR (1E2)K130515 - VirtuosoTM System for IHC ER (SP1)K111755 - VirtuosoTM System for IHC Ki67 (30-9)
3	Intended useandindicationsfor use.	The GenASIs HiPath IHC Family providesimage capture, management, analysis, andviewing of specific immunohistochemicallystained slides. It is intended for in vitrodiagnostic use as an aid to the pathologist inthe display, detection, counting, review andclassification of tissues and cells of clinicalinterest based on particular morphology,color, intensity, size, pattern and shape:1. The GenASIs HiPath IHC Family forHER2 (4B5) is for image capture andanalysis applications. This particular systemis intended for use as an aid to thepathologist in the detection and semi-quantitative measurement of HER2 proteinin formalin-fixed, paraffin-embedded breastcancer tissue. This device is an accessory toVentana Medical Systems, Inc.PATHWAY® anti-HER2/neu (4B5) RabbitMonoclonal Primary Antibody. ThePATHWAY® anti-HER2/neu (4B5) RabbitMonoclonal Primary Antibody is indicatedfor use as an aid in the assessment of breastcancer patients for whom HERCEPTIN®(Trastuzumab) treatment is beingconsidered.NOTE: The GenASIs HiPath IHC Family	K111543 - VirtuosoTM System for IHC HER2 (4B5)The Virtuoso system provides automatic digitalslide creation, management, analysis, andviewing. It is intended for in vitro diagnostic useas an aid to the pathologist in the display,detection, counting, review and classification oftissues and cells of clinical interest based onparticular morphology, color, intensity, size,pattern and shape:The VirtuosoTM System for HER2 (4B5) is fordigital read and image analysis applications.This particular system is intended for use as anaid to the pathologist in the detection and semi-quantitative measurement of HER2 protein informalin-fixed, paraffin-embedded normal andneoplastic tissue. This device is an accessory toVentana Medical Systems, Inc. PATHWAY®anti-HER2/neu (4B5) Rabbit MonoclonalPrimary Antibody. The PATHWAY® anti-HER2/neu (4B5) Rabbit Monoclonal PrimaryAntibody is indicated for use as an aid in theassessment of breast cancer patients for whomHERCEPTIN® (Trastuzumab) treatment isbeing considered.NOTE: The IHC System for HER2 (4B5) digitalread and image analysis applications areadjunctive computer-assisted methodologies forthe qualified pathologist in the acquisition and
#	Comparisonparameter	Proposed device:ASI GenASIs HiPath IHC Family	Predicate device:Virtuoso™ System
		for HER2 (4B5) image capture and analysisapplications are adjunctive computer-assisted methodologies for the qualifiedpathologist in the acquisition and semi-quantitative measurement of images frommicroscope glass slides of breast cancerspecimens stained for the presence of HER-2/neu receptor protein. The pathologistshould verify agreement with the ImageAnalysis software application score byreviewing the glass slide under themicroscope. The accuracy of the test resultsdepends on the quality of theimmuohistochemical staining. It is theresponsibility of a qualified pathologist toemploy appropriate morphological studiesand controls as specified in the instructionsfor the PATHWAY® anti-HER-2/neu(4B5) Rabbit Monoclonal Primary Antibodyassay used to assure the validity of theGenASIs HiPath IHC Family for HER2(4B5) image capture and analysis scores.The actual correlation of PATHWAY®anti-HER-2/neu (4B5) to clinical outcomehas not been established.	measurement of images from microscope glassslides of breast cancer specimens stained for thepresence of HER-2/neu receptor protein. Thepathologist should verify agreement with theImage Analysis software application score. Theaccuracy of the test results depends on thequality of the immunohistochemical staining. Itis the responsibility of a qualified pathologist toemploy appropriate morphological studies andcontrols as specified in the instructions for thePATHWAY® anti-HER-2/neu (4B5) RabbitMonoclonal Primary Antibody assay used toassure the validity of the iScan System for HER24B5 digital read and image analysis scores. Theactual correlation of PATHWAY® anti-HER-2/neu (4B5) to clinical outcome has not beenestablished.
	2.	The GenASIs HiPath IHC Family for PR(1E2) is for image capture and analysisapplications. This particular system isintended for use as an aid to the pathologistin the detection and qualitativemeasurement of progesterone receptor (PR)protein in formalin-fixed, paraffin-embedded breast cancer tissue. This deviceis an accessory to Ventana MedicalSystems, Inc. CONFIRMTM anti-Progesterone Receptor (PR) (1E2) RabbitMonoclonal Primary Antibody assay. TheCONFIRMTM anti-Progesterone Receptor(PR) (1E2) Rabbit Monoclonal PrimaryAntibody assay is indicated for use as an aidin the assessment of breast cancer patientsfor whom endocrine treatment is beingconsidered (but is not the sole basis fortreatment).Note: The GenASIs HiPath IHC for PR(1E2) image capture and analysisapplications are adjunctive computer-assisted methodologies for the qualifiedpathologist in the acquisition and qualitativemeasurement of images from microscopeglass slides of breast cancer specimensstained for the presence of PR protein. The	K111869 - Virtuoso™ System for IHC PR (1E2)The Virtuoso system provides automatic digitalslide creation, management, analysis, andviewing. It is intended for in vitro diagnostic useas an aid to the pathologist in the display,detection, counting, review and classification oftissues and cells of clinical interest based onparticular morphology, color, intensity, size,pattern and shape:The VirtuosoTM System for PR (1E2) is fordigital read and image analysis applications.This particular system is intended for use as anaid to the pathologist in the detection and semi-quantitative measurement of progesteronereceptor (PR) protein in formalin-fixed, paraffin-embedded normal and neoplastic tissue. Thisdevice is an accessory to Ventana MedicalSystems, Inc. CONFIRMTM anti-ProgesteroneReceptor (PR) (1E2) Rabbit MonoclonalPrimary Antibody assay. The CONFIRMTM anti-Progesterone Receptor (PR) (1E2) RabbitMonoclonal Primary Antibody assay is indicatedfor use as an aid in the assessment of breastcancer patients for whom endocrine treatment isbeing considered (but is not the sole basis fortreatment).Note: The IHC PR (1E2) digital read and imageanalysis applications are adjunctive computer-
#	Comparisonparameter	Proposed device:ASI GenASIs HiPath IHC Family	Predicate device:Virtuoso™ System
		pathologist should verify agreement withthe Image Analysis software applicationscore by reviewing the glass slide under themicroscope. The accuracy of the test resultsdepends on the quality of theimmunohistochemical staining. It is theresponsibility of a qualified pathologist toemploy appropriate morphological studiesand controls as specified in the instructionsfor the CONFIRM™ anti-ProgesteroneReceptor (PR) (1E2) Rabbit MonoclonalPrimary Antibody used to assure thevalidity of the GenASIs HiPath IHC Familyfor PR (1E2) image capture and analysisscores. The actual correlation ofCONFIRM™ anti-PR antibody to clinicaloutcome has not been established.	assisted methodologies for the qualifiedpathologist in the acquisition and measurementof images from microscope glass slides of breastcancer specimens stained for the presence of PRprotein. The pathologist should verify agreementwith the Image Analysis software applicationscore. The accuracy of the test results dependson the quality of the immunohistochemicalstaining. It is the responsibility of a qualifiedpathologist to employ appropriate morphologicalstudies and controls as specified in theinstructions for the CONFIRM™ anti-Progesterone Receptor (PR) (1E2) RabbitMonoclonal Primary Antibody used to assure thevalidity of the Virtuoso System for PR (1E2)digital read and image analysis scores. Theactual correlation of CONFIRM™ anti-PRantibody to clinical outcome has not beenestablished.
		3. The GenASIs HiPath IHC Family for ER(SP1) is for image capture and analysisapplications. The particular system isintended for use as an aid to the pathologistin the detection and qualitativemeasurement of ER (SP1): protein informalin-fixed, paraffin-embedded breastcancer tissue. This device is an accessory tothe Ventana Medical Systems, Inc.CONFIRM™ anti-Estrogen Receptor (ER)(SP1) Rabbit Monoclonal PrimaryAntibody. The Ventana Medical Systems,Inc. CONFIRM™ anti-Estrogen Receptor(ER) (SP1) Rabbit Monoclonal PrimaryAntibody is indicated for use as an aid inthe assessment of ER status in breast cancerpatients (but is not the sole basis fortreatment).	K130515 - Virtuoso™ System for IHC ER (SP1)The Virtuoso system provides automated digitalslide creation, management, analysis, andviewing. It is intended for in vitro diagnostic useas an aid to the pathologist in the display,detection, counting, review and classification oftissues and cells of clinical interest based onparticular morphology, color, intensity, size,pattern and shape.The Virtuoso™ System for IHC ER (SP1) is fordigital read and image analysis applications.This particular Virtuoso system is intended foruse as an aid to the pathologist in the detectionand semi-quantitative measurement of estrogenreceptor (ER) protein in formalin-fixed, paraffin-embedded neoplastic tissue. This device is anaccessory to Ventana Medical Systems, Inc.CONFIRM™ anti-Estrogen Receptor (ER)(SF1) Rabbit Monoclonal Primary Antibodyassay. The CONFIRM™ anti- ER (SF1) RabbitMonoclonal Primary Antibody assay is indicatedfor use as an aid in the assessment of breastcancer patients for whom endocrine treatment isbeing considered (but is not the sole basis fortreatment).
		Note: The GenASIs HiPath IHC Family forER (SP1) image capture and analysisapplications are adjunctive computer-assisted methodologies for the qualifiedpathologist in the acquisition and qualitativemeasurement of images from microscopeglass slides of breast cancer specimensstained for the presence of ER protein. Thepathologist should verify agreement withthe Image Analysis software applicationscore by reviewing the glass slide under themicroscope. The accuracy of the test resultsdepends on the quality of theimmunohistochemical staining. It is theresponsibility of a qualified pathologist toemploy appropriate morphological studiesand controls as specified in the instructions	Note: The IHC ER (SP1) Digital Read and ImageAnalysis applications are adjunctive computer-assisted methodologies for the qualifiedpathologist in the acquisition and measurementof images from microscope glass slides of breastcancer specimens stained for the presence of ERprotein. The pathologist should verify agreementwith the Image Analysis software application
#	Comparison	Proposed device:	Predicate device:
	parameter	ASI GenASIs HiPath IHC Family	Virtuoso"M System
		for the CONFIRMTM anti-Estrogen	score. The accuracy of the test results depends
		Receptor (ER) (SP1) Rabbit Monoclonal	on the quality of the immuohistochemical
		Primary Antibody to assure the validity of	staining. It is the responsibility of a qualified
		the GenASIs HiPath IHC Family for ER	pathologist to employ appropriate morphological
		(SP1) image capture and analysis scores.	studies and controls as specified in the
		The actual correlation of CONFIRMTM	instructions for the CONPIRM™ anti-Estrogen
		anti-Estrogen Receptor (ER) (SP1) Rabbit	Receptor (ER) (SP3) Rabbit MonoclonalPrimary Antibody used to assure the validity of
		Monoclonal Primary Antibody to clinicaloutcome has not been established.	the Virtuoso System for IHC ER Digital Read
			and Image Analysis scores. The actual
		4. The GenASIs HiPath IHC Family for	correlation of CONFIRM™ anti-Estrogen
		Ki67 (30-9) is for image capture and	Receptor (ER)(SPI) Rabbit Monoclonal
		analysis applications. The particular system	Antibody to clinical outcome has not been
		is intended for use as an aid to the	established.
		pathologist in the detection and qualitative
		measurement of Ki67 (30-9): protein in	K111755 - Virtuoso™ System for IHC Ki67 (30-9)
		formalin-fixed. paraffin-embedded breast	The Virtuoso system provides automatic digital
		cancer tissue. This device is an accessory to	slide creation, management, analysis, and
		the Ventana Medical Systems, Inc.CONFIRMTM anti-Ki67 (30-9) Rabbit	viewing. It is intended for in vitro diagnostic use
		Monoclonal Primary Antibody assay. The	as an aid to the pathologist in the display,
		Ventana Medical Systems, Inc.	detection, counting, review and classification of
		CONFIRMTM anti-Ki67 (30-9) assay is	tissues and cells of clinical interest based on
		indicated for use in assessing the	particular morphology, color, intensity, size,
		proliferative activity of breast cancer tissue.	pattern and shape:
		When used with this assay, the GenASIs	The Virtuoso™ System for Ki67 (30-9) is for
		HiPath IHC Family for Ki67 (30-9) is	digital read and image analysis applications. The
		indicated for use as an aid in the assessment	particular system is intended for use as an aid to
		of Ki-67 status in breast cancer patients (but	the pathologist in the detection and semi-quantitative measurement of Ki67 (30-9):
		is not the sole basis for treatment).	protein in formalin-fixed, paraffin-embedded
		Note: The GenASIs HiPath IHC Family for	normal and neoplastic tissue. This device is an
		Ki67 (30-9) image capture and analysis	accessory to the Ventana Medical Systems, Inc.
		applications are adjunctive computer-	CONFIRM™ anti-Ki67 (30-9) Rabbit
		assisted methodologies for the qualified	Monoclonal Primary Antibody assay. The
		pathologist in the acquisition and qualitative	Ventana Medical Systems, Inc. CONFIRMTM
		measurement of images from microscope	anti-Ki67 (30-9) assay is indicated for use in
		glass slides of breast cancer specimens	assessing the proliferative activity of normal and
		stained for the presence of Ki67 protein.	neoplastic breast tissue. When used with this
		The pathologist should verify agreementwith the Image Analysis software	assay, the Virtuoso™ System for Ki67 (30-9) is
		application score by reviewing the glass	indicated for use as an aid in the assessment of
		slide under the microscope. The accuracy of	Ki-67 status in breast cancer patients (but is notthe sole basis for treatment).
		the test results depends on the quality of the	Note: The IHC Family for Ki67 (30-9) digital
		immunohistochemical staining. It is the	read and image analysis applications are
		responsibility of a qualified pathologist to	adjunctive computer-assisted methodologies for
		employ appropriate morphological studies	the qualified pathologist in the acquisition and
		and controls as specified in the instructions	measurement of images from microscope glass
		for the CONFIRMTM anti-Ki67 (30-9)	slides of breast cancer specimens stained for the
		Rabbit Monoclonal Primary Antibody assay	presence of Ki67 protein. The pathologist should
		to assure the validity of the GenASIs HiPath	verify agreement with the Image Analysis
		IHC Family for Ki67 (30-9) image capture	software application score. The accuracy of the
		and analysis scores. The actual correlation	test results depends on the quality of the
		of CONFIRMTM anti-Ki67 (30-9) Rabbit	inunmohistochemnical staining. It is the
#	Comparison	Proposed device:	Predicate device:
	parameter	ASI GenASIs HiPath IHC Family	Virtuoso™ System
		Monoclonal Primary antibody assay toclinical outcome has not been established	responsibility of a qualified pathologist toemploy appropriate morphological studies andcontrols as specified in the instructions for theCONFIRM™ anti-Ki67 (30-9) RabbitMonoclonal Primary Antibody assay to assurethe validity of the Virtuoso "M System for Ki67(30-9) digital read and image analysis scores.The actual correlation of CONFIRM 104 anti-Ki67 (30-9) Rabbit Monoclonal Primaryantibody assay to clinical outcome has not beenestablished.
4	Application:IHC HER2(4B5)	Detection and semi-quantitativemeasurement of HER2 protein in formalin-fixed, paraffin-embedded breast cancertissue	Detection and semi-quantitative measurement ofHER2 protein in formalin-fixed, paraffin-embedded normal and neoplastic tissue
5	Application:IHC PR (1E2)	Detection and qualitative measurement ofprogesterone receptor (PR) protein informalin-fixed, paraffin-embedded breastcancer tissue.	Detection and semi-quantitative measurement ofprogesterone receptor (PR) protein in formalin-fixed, paraffin-embedded normal and neoplastictissue.
б	Application:IHC ER (SP1)	Detection and qualitative measurement ofEstrogen Receptor (ER) protein in formalin-fixed, paraffin-embedded breast cancertissue.	Detection and semi-quantitative measurement ofEstrogen Receptor (ER) protein in formalin-fixed, paraffin-embedded normal and neoplastictissue.
7	Application:IHC Ki67 (30-9)	Detection and qualitative measurement ofKi67 (30-9): protein in formalin-fixed,paraffin-embedded breast cancer tissue.	Detection and semi-quantitative measurement ofKi67 (30-9): protein in formalin-fixed, paraffin-embedded normal and neoplastic tissue.
8	SpecimenIdentification	By the pathologist, according the singleslide label.	Identified by slide label or barcode.
9	Calibration	Camera White Balance	Tests must be run with nine custom slidescalibrated for the module which can be obtainedfrom the sponsor.
10	OualityControl	Performed by the operator as part of thestandard operation procedures using slideswith sub-optimal images.	Performed by the operator before releasing theimages to the pathologist for review. Slides withsub-optimal images will be rescanned
11	Slideacquisition/Capture	CCD high resolution color camera and racksfor loading the glass slides.Images to be processed selected viamicroscope's eyepiece.	Digital slide bright field scanner (Ventana iScan)and racks for loading glass slides.Images to be processed selected from the screendigital read image.
12	DeviceComponents	Microscope, CCD color camera, PC,keyboard, Mouse, Color Monitor, X-Y stageand rack for loading 1 glass slide.	Digital slide scanner, PC, keyboard, Mouse,colorMonitor, racks for loading up to 160 glass slides.

1. Comparison of Predicate devices:

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2. Substantial Equivalence discussion

Similarities:

Intended Use:

The proposed GenASIs HiPath IHC Family and the legally cleared Virtuoso "14 Systems (K111543, K111869, K130515 and K111755) have the same intended use and indications for use for the following: Acquisition, image capture, management, analysis, and viewing. The proposed GenASIs HiPath IHC Family and the legally cleared Virtuoso "" Systems are 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 proposed GenASIs HiPath IHC Family and the legally cleared Virtuoso™ Systems are indicated as an aid to pathologists in the assessment of HER2, PR, ER and Ki67 (30-9) status in breast cancer patients.

Performance:

The proposed GenASIs HiPath IHC Family and the legally cleared Virtuoso™ Systems are designed for the same IVD applications (H1 sections 3 - 6) using similar hardware and software components and similar analysis tools, the pathologist has to select the ROI for the scoring algorithm (H1 sections 7, 8) and calibration and quality control has to be performed to make sure that scoring results are stable (Table 4.3 sections 10, 11).

Technology:

The proposed GenASIs HiPath IHC Family and the legally cleared Virtuoso™ Systems are using similar hardware and software components, designed to complement the routine workflow of a qualified pathologist in the review of IHC stained histological slides (H1 section 12).

Differences:

Intended Use: No difference

Performance:

The legally cleared Virtuoso " Systems are using slide scanner for generating the digital slide while the proposed GenASIs HiPath IHC Family is using a color camera to capture and convert the microscope's image to a digital image.
Images to be processed selected from Vituoso's screen digital read image, while in the proposed GenASIs HiPath IHC Family images for processing are selected via microscope's eyepiece (H1 section 11).
Calibration and quality control processes are different in both systems (H1 sections 10, 11). 4. Legally cleared Virtuoso 100 Systems are designed for multi slide automatic loading, slide label or automatic barcode for specimen identification method must be used while the GenASIs HiPath IHC Family glass slide loading is manual and the pathologist is responsible for the slide identification (H1 section 9).

The effectiveness of the proposed GenASIs HiPath IHC Family calibration and quality control processes were verified and validated during the clinical studies.

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Technology:

The legally cleared Virtuoso "" Systems use a slide scanner for generating the digital slide while the proposed GenASIs HiPath IHC Family use a color camera to capture and convert the microscope's image to a digital image.
Acquisition control software and illumination light sources are different and optimized to the acquisition flow and process (H1, sections 10 - 11).
The Virtuoso "10 System have additional hardware components; automatic multi slides loader, slides identifier and slide scanner, as opposed to the proposed GenASIs HiPath IHC Family that is using a magnifying microscope for manual slide capture (H1. section 12).

I. Special Control/ Guidance Document Referenced (if applicable)

The following Special Control and guidance documents are used in the preparation of the 510(K) submission:

Guidance for Industry "Guidance for Submission of Immunohistochemistry Applications to the FDA", dated June 3 1998.
CLSI I/LA28-A2Q:2009 - uality assurance for design control and implementation of immunohistochemistry assays; approved guidelines-second edition. (InVitro Diagnostics).
Guidance for Industry and FDA Staff: "Statistical Guidance on Reporting Results from Studies Evaluating Diagnostic Tests"; March 2007.
"Guidance for the Content of Premarket Submission for Software Contained in Medical Device", CDRH, May 2005.
Guidance for Industry, Clinical Investigators, Institutional Review Boards and Food and Drug Administration Staff, Doc. 1776 dated November 2013

J. Performance Characteristics

The following information of the device performance characteristics are based on ASI testing and experiments, using the following Ventana Medical Systems, Inc probe kits:

PATHWAY® anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody .
CONFIRM™ anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary ● Antibody assay
CONFIRM™ anti-Estrogen Receptor (ER) (SP1) Rabbit Monoclonal Primary . Antibody
CONFIRM™ anti-Ki67 (30-9) Rabbit Monoclonal Primary antibody assay ●

The user must use the staining process described in Ventana's user instructions for the above mentioned assay kits. Additionally, clinical sensitivity, clinical specificity and clinical cut-off are also related to the above mentioned assay kits (as per user instructions).

The operators shall be aware of limitations derived from the following performance characteristics:

a. Analytical Performance:

The clinical studies were based on comparison to the measures of agreement test of conventional manual evaluation through the microscope eyepieces, performed by

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pathologist that followed the recommendations of the Ventana user insertions for the different panel antibodies and test analysis performed with the proposed GenASIs HiPath IHC Family system, using the same stained slides.

The comparison study was conducted in three clinical sites, by three different pathologists, according to Applied Spectral Imaging's protocol. The study included a total of:

· HER2/neu (4B5) - 357 stained samples.
· PR (1E2) · · · · - 385 stained samples.
· ER (SP1) · - 427 stained samples
Ki67 (30-9) - 373 stained samples

The agreement rates of the comparison between manual and GenASIs HiPath IHC Family system statistical test results when pooling all three sites tests are:

HER2/neu (4B5)

Pooled Results; Frequency distribution of agreement of Manual versus GenASIs HiPath IHC Family:

		Manual analysis
GenASIs HiPathIHC analysis		Negative (0, 1+)	Positive (2+, 3+)	Total
	Negative (0, 1+)	185	5	190
	Positive (2+, 3+)	4	163	167
	Total	189	168	357
Overall Agreement		97%
Positive Agreement		98%
Negative Agreement		97%

PR (1E2)

Pooled Results; Frequency distribution of agreement of Manual versus GenASIs HiPath IHC Family:

		Manual analysis
GenASIs HiPathIHC analysis		Negative (<1%)	Positive (≥1%)	Total
	Negative (<1%)	161	1	162
	Positive (≥1%)	3	220	223
	Total	164	221	385
Overall Agreement		99%
Positive Agreement		98%
Negative Agreement		100%

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ER (SP1)

Pooled Results; Frequency distribution of agreement of Manual versus GenASIs HiPath IHC Family:

		Manual analysis
GenASIs HiPathIHC analysis		Negative (<1%)	Positive (≥1%)	Total
	Negative (<1%)	151	1	152
	Positive (≥1%)	1	274	275
	Total	152	275	427
Overall Agreement		100%
Positive Agreement		99%
Negative Agreement		100%

Ki67 (30-9)

Pooled Results; Frequency distribution of agreement of Manual versus GenASIs HiPath IHC Family:

		Manual analysis
GenASIs HiPathIHC analysis		Negative (≤10%)	Positive (>10%)	Total
	Negative (≤10%)	132	6	138
	Positive (>10%)	10	225	235
	Total	142	231	373
Overall Agreement		96%
Positive Agreement		93%
Negative Agreement		97%

Precision/Reproducibility: b.

Repeatability and reproducibility (R&R) studies were conducted to evaluate the variation in the performance of the automatic system between different runs of the same system and same day, between days of the same system and between systems located on different sites. Separate tests were performed for HER2/neu, ER, PR and Ki-67. For each antibody, forty (40) slides were selected, aiming to cover the samples result categories of the intended population.

The one hundred and sixty (160) slides were selected from a known pool as follows:

· For ER & PR slides were selected from positive, negative and around-cutoff slides to cover the entire clinically relevant range
· For Ki67 slides were selected from positive, negative slides to cover the entire clinically relevant range
· For HER2/neu slides were selected from the 4 classes of 0,1+,2+,3+.

All slides were labeled by slide index and antibody type.

Slides were evaluated by three independent pathologists and than were repeatedly evaluated

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by the GenASIs HiPath IHC family device.

A minimal washout time between manual and GenASIs HiPath analysis was 7 days. The precision of manual and system results is reported separately.

The following factors were used for testing GenASIs HighPath family precision:

Run Each slide is re-evaluated three times on a same system and on a same day. i)
ii) Day - Each slide is re-evaluated three times on non-consecutive days (at least 5 days apart) on a same system.
iii) System Each slide is re-evaluated three times using different systems (at least 7 days apart).

HER2/neu (4B5)

The study includes forty (40) sample slides for each antibody, which represent the range of the intended use.

The R&R agreements for positive and negative sample slides analysis were:

	Average Positive Agreement(2+, 3+)	Average Negative Agreement(0, 1+)
Run 1 vs Run 2	97.6%	97.5%
Run 1 vs Run 3	95.0%	95.0%
Run 2 vs Run 3	97.6%	97.5%

Between-Run. Within-Day. Within-System:

Between-Day, Within-System:

	Average Positive Agreement(2+, 3+)	Average Negative Agreement(0, 1+)
Day 1 vs Day 2	100%	100%
Day 1 vs Day 3	97.6%	97.5%
Day 2 vs Day 3	97.6%	97.5%

Between-Systems:

	Average Positive Agreement(2+, 3+)	Average Negative Agreement(0, 1+)
Sys 1 vs Syst 2	97.6%	97.5%
Sys 1 vs Sys 3	97.5%	97.6%
Sys 2 vs Sys 3	95.2%	95.2%

PR (1E2)

The study include forty (40) sample slides for each antibody, which represent the range of the intended use.

The R&R agreements for positive and negative sample slides analysis were:

Between-Run, Within-Day, Within-System:

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	Average Positive Agreement(≥ 1%)	Average Negative Agreement(<1%)
Run 1 vs Run 2	100.0%	100.0%
Run 1 vs Run 3	100.0%	100.0%
Run 2 vs Run 3	100.0%	100.0%

Between-Day, Within-System:

	Average Positive Agreement(≥ 1%)	Average Negative Agreement(<1%)
Day 1 vs Day 2	97.9%	97.1%
Day 1 vs Day 3	97.9%	97.1%
Day 2 vs Day 3	95.8%	93.8%

Between-Systems:

	Average Positive Agreement(≥ 1%)	Average Negative Agreement(<1%)
Sys 1 vs Sys 2	97.9%	97.1%
Sys 1 vs Sys 3	97.9%	97.1%
Sys 2 vs Sys 3	100.0%	100.0%

ER (SP1)

The study include forty (40) sample slides for each antibody, which represent the range of the intended use.

The R&R agreements for positive and negative sample slides analysis were:

Between-Run, Within-Day, Within-System:
-----------------------------------------	--	--	--

	Average Positive Agreement(≥ 1%)	Average Negative Agreement(<1%)
Run 1 vs Run 2	100.0%	100.0%
Run 1 vs Run 3	100.0%	100.0%
Run 2 vs Run 3	100.0%	100.0%

Between-Day, Within-System:

	Average Positive Agreement(≥1%)	Average Negative Agreement(<1%)
Day 1 vs Day 2	100.0%	100.0%
Day 1 vs Day 3	100.0%	100.0%
Day 2 vs Day 3	100.0%	100.0%

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Between-Systems:

	Average Positive Agreement	Average Negative Agreement
	(≥ 1%)	(<1%)
Sys 1 vs Sys 2	100.0%	100.0%
Sys 1 vs Sys 3	100.0%	100.0%
Sys 2 vs Sys 3	100.0%	100.0%

Ki67 (30-9)

The study includes forty (40) sample slides for each antibody, which represent the range of the intended use.

The R&R agreement for positive and negative sample slides analysis was:

Between-Run, Within-Day, Within-System:

	Average Positive Agreement(>10%)	Average Negative Agreement(≤10%)
Run 1 vs Run 2	97.9%	97.1%
Run 1 vs Run 3	89.4%	84.9%
Run 2 vs Run 3	91.3%	88.2%

Between-Day, Within-System:

	Average Positive Agreement(>10%)	Average Negative Agreement(≤10%)
Day 1 vs Day 2	95.8%	93.8%
Day 1 vs Day 3	95.8%	93.8%
Day 2 vs Day 3	95.8%	93.8%

Between-Systems:

	Average Positive Agreement	Average Negative Agreement
	(>10%)	(<10%)
Sys 1 vs Sys 2	95.8%	93.8%
Sys 1 vs Sys 3	97.9%	97.1%
Sys 2 vs Sys 3	97.9%	97.1%

c. Linearity

Not applicable

d. Carryover:

Not applicable

e. Interfering Substances:

Not applicable

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3. Other Supportive Instrument Performance Data Not Covered Above:

Not applicable

K. Proposed Labeling

Labeling was prepared in accordance with the requirements of 21 CFR Part 809.10.

L. Conclusion

Based on the above, it is Applied Spectral Imaging's opinion that the proposed GenASIs HiPath IHC Family is substantially equivalent in terms of design, principles, and performance characteristics and is shown to be safe & effective for its intended use.

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.

1. Table of Acceptance Criteria and Reported Device Performance

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

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

4. Adjudication Method for the Test Set

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

6. Standalone Performance Study

7. Type of Ground Truth Used

8. Sample Size for the Training Set

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

Reena Philip -S

Indications for Use

Indications for Use (Describe)

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510(K) Number A.

B. Purpose for Submission

C. Manufacturer and Instrument Name

C.1. Device Name

C.2. Submitter's name

C.3. Submission contact person

Type of Test or Tests Performed D.

E. System Descriptions

Device description:

F. Regulatory Information

Intended Use G.

H. Substantial Equivalence Information

1. Comparison of Predicate devices:

2. Substantial Equivalence discussion

Similarities:

Intended Use:

Performance:

Technology:

Differences:

Performance:

I. Special Control/ Guidance Document Referenced (if applicable)

J. Performance Characteristics

a. Analytical Performance:

HER2/neu (4B5)

PR (1E2)

ER (SP1)

Ki67 (30-9)

Precision/Reproducibility: b.

HER2/neu (4B5)

PR (1E2)

Between-Day, Within-System:

Between-Systems:

ER (SP1)

Ki67 (30-9)

3. Other Supportive Instrument Performance Data Not Covered Above:

K. Proposed Labeling

L. Conclusion

§ 864.1860 Immunohistochemistry reagents and kits.

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