PATHIAM IMAGING SOFTWARE FOR HER2/NEU

K062756 · Bioimagene, Inc. · NOT · Feb 20, 2007 · Hematology

Device Facts

• Record ID: K062756
• Device Name: PATHIAM IMAGING SOFTWARE FOR HER2/NEU
• Applicant: Bioimagene, Inc.
• Product Code: NOT · Hematology
• Decision Date: Feb 20, 2007
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 864.1860
• Device Class: Class 2
• Attributes: Software as a Medical Device

Intended Use

The imaging software is intended to detect and classify cells of clinical interest by analyzing digitized images of microscope slides based on recognition of cellular objects of particular color, size and shape. The software can be used with a computer and image digitizer with features specified in the labeling. BioImagene PATHIAM is intended for use as an accessory to the Dako HercepTest® to aid a pathologist in semi-quantitative measurement of HER2/neu (c-erbB-2) in Formalin-fixed, paraffin-embedded breast cancer tissue. When used with the Dako HercepTest it is indicated as an aid in the assessment of breast cancer patients for whom Herceptin® (Trastuzumab) treatment is being considered. NOTE: The actual correlation of the Dako HercepTest to Herceptin clinical outcome has not been established.

Device Story

PATHIAM is standalone software for semi-quantitative assessment of Her2/neu staining in breast cancer tissue. Input: digital images (JPEG, BMP, TIFF) of IHC-stained slides acquired via microscope/camera or digital slide scanner. Operation: pathologist selects representative tumor fields; software automatically differentiates tumor cells from stromal cells/artifacts using morphological features; calculates total positively/unstained tumor cells, median intensity, extent, and thickness of membrane staining. Output: semi-quantitative score (0 to 3) displayed alongside digital image for pathologist review. Used in clinical laboratory settings by pathologists to aid interpretation of Her2/neu expression levels. Benefits: provides standardized, reproducible semi-quantitative data to assist clinical decision-making regarding Trastuzumab therapy.

Clinical Evidence

Bench testing only. Study evaluated 176 breast cancer specimens stained with Dako HercepTest. Agreement between manual scoring and PATHIAM raw scores, and manual scoring vs. PATHIAM-assisted pathologist scores, was assessed across three sites using different imaging hardware. Percent agreement between manual and PATHIAM-assisted scores ranged from 81.25% to 84.09%. Reproducibility across different imaging setups showed high consistency (93.67% to 95.45% agreement for raw scores).

Technological Characteristics

Standalone software; requires Windows 2000+, 2.4 GHz processor, 512MB RAM. Supports TIFF, JPEG, JPEG 2000, BMP formats. Uses colorimetric pattern recognition for object identification based on size, shape, color, and intensity. Operates on digitized images from standard microscope/camera or digital slide scanners.

Indications for Use

Indicated for use as an accessory to Dako HercepTest® to aid pathologists in semi-quantitative measurement of HER2/neu in formalin-fixed, paraffin-embedded breast cancer tissue for patients being considered for Herceptin® (Trastuzumab) treatment.

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

• ChromaVision Medical Systems, Inc. Automated Cellular Imaging System (ACIS) for Her2/neu (K032113)

Submission Summary (Full Text)

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KO62756

FEB 2 0 2007

## 510(K) SUMMARY OF SAFETY AND EFFECTIVENESS

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: BioImagene, Inc. 1601 S. De Anza Blvd. Suite 212 Cupertino, CA 95014 United States

Contact Person Anna Longwell Longwell and Associates 1900 Embarcadero Road, Suite 107 Palo Alto. CA 94303 Tel [phone] FAX [phone] anna.longwell(@fdclaw.com

Date Summary Prepared: 25 August 2006 Date Summary Revised: 11 January 2007

Trade Name: PATHIAM Image Analysis Software for Her2/neu

Classification Name: Unknown

Device Description:

PATHIAM software is a standalone software application that will work on a system with the following features required but not provided:

# Computer

- . Processor: 2.4 GHz, Pentium IV equivalent
- Memory: 512 MB RAM .
- Operating System: Windows 2000 or later .
- Hard Drive: minimum 100MB for software installation, 20GB for image . storage
- . LAN connectivity, minimum 100 MBPS (recommended), support for USB interface, support for HTTP, TCP/IP protocols (using the Operating system)
- High Speed Graphic Accelerator Card (1024 X 768) .
- 17" High resolution display monitor .
- 24 bit color depth .
- Font Setting: Small font (DPI setting: 96 DPI) .

Digitizing Equipment: Camera

- Resolution: at least 2048 x 1536 pixels .
- . Frame rate: 20 fps@1200 x 768 resolution (6 fps @ 2048 x 1536 resolution)
- . Sampling Frequency of 6.26 square/um

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- . Compression format: JPEG 2000, BMP, TIFF, JPEG
- Color: 24-bit (R. G. B) .
- Connection to computer

Digitizing Equipment: Digital Side Scanner

- Input Format: 25X75mm microscope slides .
- . Resolution: 54,000 pixel/inch with 20X objective
- . Method: Line-scanning
- . File Format: TIFF/JPEG2000; compliant with TIFF 6.0 standard.
- . Color: 24-bit (R.G. B)
- Connectivity: 100/1000 MBPS Ethernet .
- . Compression format: JPEG 2000, BMP, TIFF, JPEG

The software allows both archiving of the digital image, and semi quantitative analysis of extent and intensity of stained tissue, providing the pathologist with an aid to interpretation of level of expression of Her2/neu in breast cancer tissue. The pathologist is presented with a digital image of the tissue section and a suggested staining score (0 to 3). The pathologist then makes an assessment of the digital image and reports his/her score.

## Indications for Use:

BioImagene PATHIAM is intended for use as an accessory to the Dako HercepTest® to aid a pathologist in semi-quantitative measurement of HER2/neu (c-erbB-2) in Formalin-fixed, paraffin-embedded breast cancer tissue. When used with the Dako HercepTest it is indicated as an aid in the assessment of breast cancer patients for whom Herceptin® (Trastuzumab) treatment is being considered.

NOTE: The actual correlation of the Dako HercepTest to Herceptin clinical outcome has not been established.

# Predicate Devices:

Software Her2/neu application of ChromaVision Medical Systems, Inc. Automated Cellular Imaging System (ACIS) for Her2/neu, K032113

#### Performance

- a. Between laboratory reproducibility: PATHIAM software was tested by three different pathologists, who analyzed images of the same set of 176 stained breast cancer tissue specimens using three different imaging systems in three different laboratories located at three different sites in the US. One laboratory used a microscope with a camera, and two used different models of digital whole slide scanners. The score distribution for these samples, as determined initially, was 1/6 of samples score 0, 1/3 of samples score 1, 1/3 of samples score 2, and 1/6 of samples score 3.
Overall agreement for the PATHIAM values between labs ranged from 94% to 95% (Table 1). For pathologist assisted by PATHIAM, overall agreement

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between labs was 81% to 96% (Table 2). Overall agreement between laboratories for a manual (microscope assessment only) value ranged from 76% to 97% (Table 3).

| Lab # vs. Lab# | % Overall<br>Agreement | 95% Confidence Interval<br>(Exact) |
|----------------|------------------------|------------------------------------|
| 1 v 2 | 95 | 91-98 |
| 1 v 3 | 94 | 89-96 |
| 2 v 3 | 94 | 89-97 |

Table 1. Between-Lab Agreement for Raw PATHIAM- Scores, HercepTest®stained Breast Tissue

Table 2. Between-Lab Agreement for Pathologist Assisted by PATHIAM Scores, HercepTest-stained Breast Tissue

| Lab # vs. Lab# | % Overall<br>Agreement | 95% Confidence Interval<br>(Exact) |
|----------------|------------------------|------------------------------------|
| 1 v 2 | 96 | 92-98 |
| 1 v 3 | 81 | 75-87 |
| 2 v 3 | 81 | 74-89 |

Table 3. Between-Lab Agreement for Manual Scores, HercepTest-stained Breast Tissue

| Lab # vs. Lab # | % Overall<br>Agreement | 95% Confidence Interval<br>(Exact) |
|-----------------|------------------------|------------------------------------|
| 1 v 2 | 97 | 93-99 |
| 1 v 3 | 76 | 69-82 |
| 2 v 3 | 78 | 71-84 |

- b. Comparison with manual (microscope assessment only) Her2-neu scores were obtained for those same breast cancer tissues from a review of PATHIAM values by the same three trained pathologists, who viewed both the digital images and the score provided by the software, and then selected an appropriate Her2-neu tissue score (0 to 3). One week later, the same pathologist read the same slides manually, using an optical microscope. The table shows the comparison.

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| Lab # | % Overall<br>Agreement | 95% Confidence Interval<br>(Exact) |
|-------|------------------------|------------------------------------|
| 1 | 81 | 75-87 |
| 2 | 84 | 78-89 |
| 3 | 82 | 76-88 |

Table 4. Percent Agreement Between PATHIAM-Assisted and Manual Scores, HercepTest®-stained Breast Tissue

| | Table 5. Percent Agreement between PATHIAM raw scores and Manual Scores, |
|----------------------------------|--------------------------------------------------------------------------|
| HercepTest-stained breast Tissue | |

| Lab # | % Overall<br>Agreement | 95% Confidence Interval<br>(Exact) |
|-------|------------------------|------------------------------------|
| 1 | 81 | 74-86 |
| 2 | 83 | 77-88 |
| 3 | 78 | 71-84 |

- c. Conclusion: It can be seen that the agreement of the manual scores compared to the PATHIAM raw scores (Table 5) is more consistent than the inter-pathologist comparison of manual scores (Table 3). Consistency is improved when the PATHIAM score assists the pathologist in their interpretation (Table 2). The comparison of PATHIAM raw scores across the three different setups in three different laboratories is very good (Table 1). Differences may be due to the selection by the pathologists of different fields of view for the analyses.
- d. Specificity, sensitivity and interferences are described in the HercepTest package insert.
- Substantial equivalence: Table 6 shows a comparison of attributes between e. PATHIAM and the predicate

| Attribute | ACIS Her2/neu software<br>component | PATHIAM |
|--------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended use | The imaging software is<br>intended to detect and<br>classify cells of clinical<br>interest by analyzing digital<br>images of microscope slides<br>based on object<br>identification of cellular | Same |
| Indications for use | objects of particular<br>intensity, shape, size and<br>color. The software can be<br>used with a computer and<br>image digitizer with<br>features specified in the<br>labeling<br>As an accessory to an assay<br>which is indicated as an aid<br>in the assessment of breast<br>cancer patients for whom<br>Herceptin® treatment is<br>considered | As an accessory to the Dako<br>HercepTest® to aid a<br>pathologist in semi-<br>quantitative measurement of<br>HER2/neu (c-erbB-2) in<br>Formalin-fixed, paraffin-<br>embedded breast cancer<br>tissue.<br>When used with the Dako<br>HercepTest it is indicated as<br>an aid in the assessment of<br>breast cancer patients for<br>whom Herceptin®<br>(Trastuzumab) treatment is<br>being considered. |
| Specimen Type | Formalin-fixed, paraffin-<br>embedded specimens<br>stained by<br>immunohistochemistry<br>reagent for Her2/neu | Same |
| Image Analysis System | Histologic observation by a<br>pathologist through a<br>controlled<br>microscope/digital camera<br>combination | Histologic observation by a<br>pathologist through a<br>specified microscope/digital<br>camera combination or slide<br>scanner |
| Method of Cell Detection | Colorimetric pattern<br>recognition by microscopic<br>examination of prepared<br>cells by size, shape, hue<br>and intensity as observed by<br>a computer-assisted<br>microscope and by visual<br>observation by a health care<br>professional | Object identification of a<br>digitized field of view of a<br>pathology slide, using size,<br>shape, color and intensity as<br>observed by a software and<br>by visual observation of the<br>digitized image by a health<br>care professional. |
| Hardware components | Computer, microscope,<br>color monitor, keyboard,<br>automatic storage of<br>acquired images | Required but not provided:<br>computer, either<br>microscope with digitizing<br>camera or slide scanner, |
| | | keyboard, mouse, hi-<br>resolution color monitor,<br>and hard drive for storage. |
| Assay used | DAKO HercepTest | Same |

Table 6. Comparison to Predicate Devices to Support Substantial Equivalence Determination

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- f. Standards Employed: None under Section 514
- EDA Guidance Guidance for the Content of Premarket Submissions for Software g. contained in Medical Devices, May 11, 2005

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#### DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/6/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a circular seal with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES (USA)" arranged around the perimeter. Inside the circle is a stylized symbol featuring three parallel lines that curve and flow together, resembling a human figure or a flame.

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

BioImagene, Inc. c/o Ms. Anna Longwell Longwell and Associates 1900 Embarcadero Rd Suite 107 Palo Alto, CA 94303

FEB 2 0 2007

Re: k062756

Trade/Device Name: PATHIAMTM Imaging Software for Her2/neu Regulation Number: 21 CFR 864.1860 Regulation Name: Immunohistochemistry Reagents and Kits Regulatory Class: Class II Product Code: NOT Dated: February 12, 2007 Received: February 13, 2007

Dear Ms. Longwell:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food. Drug. and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to such 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 Part 801); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820). This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The

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Page 2 -

FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.

If you desire specific information about the application of labeling requirements to your device, or questions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at [phone]. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number [phone] or [phone] or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html.

Sincerely yours.

Robert H. Becker/

Robert L. Becker, Jr., M.D., Ph.D. Director Division of Immunology and Hematology Devices Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health

Enclosure

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# Indications for Use

#### 510(k) Number (if known): K062756

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Device Name: PATHIAM™ Imaging software for Her2/neu

Biolmagene PATHIAM is intended for use as an accessory to Indications For Use: the Dako HercepTest® to aid a pathologist in semi-quantitative measurement of HER2/neu (c-erbB-2) in Formalin-fixed, paraffin-embedded breast cancer tissue. When used with the Dako HercepTest it is indicated as an aid in the assessment of breast cancer patients for whom Herceptin® (Trastuzumab) treatment is being considered. NOTE: The actual correlation of the Dako HercepTest to Herceptin clinical outcome has not been established.

The imaging software is intended to detect and classify cells of Intended Use: clinical interest by analyzing digitized images of microscope slides based on recognition of cellular objects of particular color, size and shape. The software can be used with a computer and image digitizer with features specified in the labeling.

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

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

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

Concurrence of CDRH, Office of Device Evaluation (ODE)

Mana mchan

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Division Sian-Off

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Office of In Vitro Dlagnostic Device Evaluation and Safety

510(k) Ko 627356

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