PATHIAM SYSTEM FOR HER2/NEU IMMUNOHISTOCHEMISTRY REAGENTS & KITS

K080910 · Bioimagene, Inc. · NOT · Feb 4, 2009 · Hematology

Device Facts

• Record ID: K080910
• Device Name: PATHIAM SYSTEM FOR HER2/NEU IMMUNOHISTOCHEMISTRY REAGENTS & KITS
• Applicant: Bioimagene, Inc.
• Product Code: NOT · Hematology
• Decision Date: Feb 4, 2009
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 864.1860
• Device Class: Class 2

Intended Use

PATHIAM-Assisted Scoring: Intended for clinical laboratory use as an accessory to the DAKO HercepTest to aid in the detection and semi-quantitative measurement of Her2/neu in formalin fixed, paraffin-embedded normal and neoplastic tissue. When used with the DAKO HercepTest, Pathiam Assisted Scoring is indicated for use as an aid in the assessment of breast cancer patients for whom HERCEPTIN (Trastuzumab) treatment is being considered. The pathologist should verify agreement with the PATHIAM System score. HER2/neu results are indicated for use as an aid in the management, prognosis and predication of therapy outcomes of breast cancer. Note: The actual correlation of the DAKO HercepTest to Herceptin® clinical outcome has not been established.

Device Story

PATHIAM System is an automated digital image analysis tool for pathologists. Input: digitized images of immunohistochemically stained (DAKO HercepTest) breast tissue slides captured by BioImagene iScan slide scanner. Operation: pathologist selects area of interest; software performs semi-quantitative analysis of staining extent and intensity; system suggests staining score (0 to 3). Output: digital image and suggested score displayed on monitor. Usage: clinical laboratory setting; operated by qualified pathologist. The system provides quantitative data to assist reproducibility of slide interpretation; pathologist makes final assessment and reports score. Benefits: improved consistency and data recording in HER2/neu assessment.

Clinical Evidence

Bench testing only. Study compared PATHIAM-assisted scoring to manual HercepTest scoring across 176 breast tissue specimens at three sites. Overall percent agreement between PATHIAM and manual scores ranged from 77% to 88%. Inter-site reproducibility for PATHIAM scores ranged from 89% to 92%. Scanner precision (repeatability) was 97%; inter-system reproducibility was 100%. No clinical outcome data provided.

Technological Characteristics

System includes BioImagene iScan slide scanner, Intel-based PC (dual core, dual Xeon), monitor, keyboard, mouse, and PATHIAM software. Digitizes formalin-fixed, paraffin-embedded tissue slides. Software performs object identification based on intensity, shape, size, and color. No specific ASTM materials cited. Software requires human intervention; no independent interpretation.

Indications for Use

Indicated for clinical laboratory use as an accessory to DAKO HercepTest for semi-quantitative measurement of HER2/neu in formalin-fixed, paraffin-embedded breast tissue to aid in assessing breast cancer patients being considered for HERCEPTIN (Trastuzumab) therapy.

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

• PATHIAM Imaging Software for HER2/neu (K062756)

Submission Summary (Full Text)

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Ko809/0

# 510(k) SUMMARY OF SAFETY AND EFFECTIVENESS

FEB - 4 2009

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: Indu Lakshman BioImagene 1601 S. De Anza Blvd. Suite 212 Cupertino, CA 95014 Tel [phone] FAX [phone]

[e-mail]

Date summary prepared: March 31, 2008 Date summary updated: October 2, 2008

Trade Name: PATHIAM™ System with iScan for HER2/neu

Classification Name: Microscope, Automated Image Analysis, Operator Intervention (NOT), primary and Automated Digital Image Manual Interpretation. Microscope (OEO) secondary.

#### Device Description:

The PATHIAMIM System is an instrument (iScan) and image analysis software system designed to assist the qualified pathologist in the consistent quantitative assessment of marker expression in immunohistochemically stained histological sections digital images. The sample tissue is breast tissue prepared using the DAKO HercepTest Reagent Kit. The PATHIAM system consists of the BioImagene iScan slide scanner, computer with the PATHIAM Software, monitor, keyboard and mouse.

The PATHIAM System digitizes formalin-fixed, paraffin embedded normal and neoplastic tissue and provides semi-quantitative analysis of extent and intensity of stained tissue, providing the pathologist with an aid to interpretation of the 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

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assessment of the digital image and reports his/her score. Alternately, the pathologist can simply use the digitized image to perform his interpretation of the level of expression, without employing the software.

The iScan slide scanning device captures digital images of Hardware: formalin-fixed, paraffin-embedded tissues that are suitable for storage, viewing and visual analysis. The device includes a digital slide scanner, racks for loading glass slides, an Intel based PC, dual core, dual Xeon processor, PATHIAM Software, and a monitor.

The PATHIAM Software requires competent human Software: intervention at all steps in the analysis process. The system is designed to complement the routine workflow of a qualified pathologist screening the immunohistochemically stained histological slides with additional quantitative data to assist the reproducibility of the slide interpretation. It allows the user to select the area of interest on the breast tissue image. The user marks the area of interest for the analysis. The system software makes no independent interpretations of the data. The software will act as a tool for the user, to improve consistency and data recording. The image produced digitally may also be used independent of the software, by allowing the pathologist to count from the digital image, rather than from the microscope.

#### Indications for Use:

When used with the DAKO HercepTest, it is indicated for use as aid in the assessment of breast cancer patients for whom HERCEPTIN® (Trastuzumab) treatment is being considered. The pathologist should verify agreement with the PATHIAM score.

Predicate Device: PATHIAM Imaging Software for HER2/neu, K062756 Regulation: 21 CFR §864.1860 Product Code: NOT Panel: Pathology

# Performance:

- a. Reproducibility Study between Pathologists and PATHIAM Systems The PATHIAM System was tested by analyzing images of the same set of 176 stained tissue specimens by three pathologists at three sites. Pathologists recorded their estimation of the score from the score provided by the PATHIAM System plus their review of the digital images provided by the software. Concordance for the PATHIAM System values between labs ranged from 89% to 92%.

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# b. Comparison with Manual HercepTest method

Values for staining intensity were obtained from a review of PATHIAM values by trained pathologists at three sites, who viewed both the digital images and the score provided by the software, and then selected an appropriate tissue score (0 to 3). The same pathologists read the same slides manually using the DAKO HercepTest package insert. The manual assessments took place 7 days before the experiments with the PATHIAM System were completed at the site.

Tables 1-3 - Concordance Between the PATHIAM System and Manual Scores of HercepTest® stained Breast Tissue,

| Site 1 | Manual 0-1+ | Manual 2+ | Manual 3+ |
|--------------|-------------|-----------|-----------|
| PATHIAM 0-1+ | 71 | 17 | 4 |
| PATHIAM 2+ | 0 | 25 | 19 |
| PATHIAM 3+ | 0 | 1 | 39 |

# Table 1. Site 1. Manual vs PATHIAM

Percent Agreement =135/176 X 100 = 77% Overall % agreement (95% EXACT CI): 77% (70% - 83%)

## Table 2. Site 2. Manual vs PATHIAM

| Site 2 | Manual 0-1+ | Manual 2+ | Manual 3+ |
|--------------|-------------|-----------|-----------|
| PATHIAM 0-1+ | 80 | 4 | 0 |
| PATHIAM 2+ | 13 | 37 | 0 |
| PATHIAM 3+ | 0 | 16 | 26 |

Percent Agreement =143/176 X 100 = 81% Overall % agreement (95% EXACT CI): 81% (75% - 87%)

#### Table 3. Site 3. Manual vs PATHIAM

| Site 3 | Manual 0-1+ | Manual 2+ | Manual 3+ |
|--------------|-------------|-----------|-----------|
| PATHIAM 0-1+ | 86 | 7 | 0 |
| PATHIAM 2+ | 3 | 28 | 9 |
| PATHIAM 3+ | 0 | 2 | 41 |

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Percent Agreement =155/176 X 100 = 88% Overall % agreement (95% EXACT CI): 88% (82% - 92%)

Tables 4-6 - Comparison Manual Scoring between Sites

Table 4. Site 1 vs 2. Manual vs Manual

| Site 1 vs. 2 | Manual 0-1+ | Manual 2+ | Manual 3+ |
|--------------|-------------|-----------|-----------|
| Manual 0-1+ | 70 | 1 | 0 |
| Manual 2+ | 21 | 22 | 0 |
| Manual 3+ | 2 | 34 | 26 |

Percent Agreement = 118/176 X 100 = 67% Overall % agreement (95% EXACT CI): 67% (60% - 74%)

Table 5. Site 2 vs 3. Manual vs Manual

| Site 2 vs. 3 | Manual 0-1+ | Manual 2+ | Manual 3+ |
|--------------|-------------|-----------|-----------|
| Manual 0-1+ | 86 | 7 | 0 |
| Manual 2+ | 3 | 30 | 24 |
| Manual 3+ | 0 | 0 | 26 |

Percent Agreement = 142/176 X 100 = 81% Overall % agreement (95% EXACT CI): 81% (74% - 86%)

Table 6. Site 3 vs 1. Manual vs Manual

| Site 3 vs. 1 | Manual 0-1+ | Manual 2+ | Manual 3+ |
|--------------|-------------|-----------|-----------|
| Manual 0-1+ | 69 | 20 | 0 |
| Manual 2+ | 2 | 22 | 13 |
| Manual 3+ | 0 | 1 | 49 |

Percent Agreement =140 /176 X 100 = 80% Overall % agreement (95% EXACT CI): 80% (73% - 85%)

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Tables 7-9 - Comparison PATHIAM Scoring between Sites

| Site 1 vs. 2 | PATHIAM 0-1+ | PATHIAM 2+ | PATHIAM 3+ |
|--------------|--------------|------------|------------|
| PATHIAM 0-1+ | 83 | 9 | 0 |
| PATHIAM 2+ | 1 | 40 | 3 |
| PATHIAM 3+ | 0 | 1 | 39 |

# Table 7. Site 1 vs 2. PATHIAM vs PATHIAM

Percent Agreement =162/176 X 100 = 92% Overall % agreement (95% EXACT CI): 92% (87% - 96%)

# Table 8. Site 2 vs 3. PATHIAM vs PATHIAM

| Site 2 vs. 3 | PATHIAM 0-1+ | PATHIAM 2+ | PATHIAM 3+ |
|--------------|--------------|------------|------------|
| PATHIAM 0-1+ | 82 | 2 | 0 |
| PATHIAM 2+ | 11 | 35 | 4 |
| PATHIAM 3+ | 0 | 3 | 39 |

Percent Agreement =156/176 X 100 = 89% Overall % agreement (95% EXACT CI): 89% (83% - 93%)

# Table 9. Site 3 vs 1. PATHIAM vs PATHIAM

| Site 3 vs. 1 | PATHIAM 0-1+ | PATHIAM 2+ | PATHIAM 3+ |
|--------------|--------------|------------|------------|
| PATHIAM 0-1+ | 88 | 5 | 0 |
| PATHIAM 2+ | 4 | 34 | 2 |
| PATHIAM 3+ | 0 | 5 | 38 |

Percent Agreement =160/176 X 100 = 91% Overall % agreement (95% EXACT CI): 91% (86% - 95%)

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- c. BioImagene iScan Slide Scanner Reproducibility
- 1. iScan Slide Scanner Precision

Eight samples, two each with manual scores of 0, 1+, 2+ and 3+ were scanned 5 times on the iScan slide scanner. The precision was calculated to be 97%.

- 2. Inter-run/Inter System Reproducibility
Eight samples, two each with manual scores of 0, 1+, 2+ and 3+ were scanned 5 times on 3 different iScan slide scanners. The agreement between the PATHIAM System scores for different scans is 100% and for different iScan slide scanners was 100%.

- d. Substantial Equivalence
Table 13: Comparison to Predicate Devices to Support Substantial Equivalence Determination

| Attribute | PATHIAM Software<br>(predicate) | PATHIAM System |
|---------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use | The imaging software is<br>intended to detect and<br>classify cells of clinical<br>interest by analyzing<br>digitized images of<br>microscope slides based on<br>object identification of<br>cellular objects of<br>particular intensity, shape,<br>size and color. The<br>software can be used with a<br>computer and image<br>digitizer with features<br>specified in the labeling. | The PATHIAM<br>System consists of the<br>PATHIAM Software,<br>the BioImagene iScan<br>Slide Scanner,<br>computer, keyboard,<br>monitor and mouse<br>intended to detect and<br>classify cells of<br>clinical interest by<br>analyzing digitized<br>images of microscope<br>slides based on object<br>identification of<br>cellular objects of<br>particular intensity,<br>shape, size and color. |
| Indications for use | When used with the DAKO<br>HercepTest, it is indicated<br>for use as an aid in the<br>assessment of breast cancer<br>patients for whom<br>HERCEPTIN® | Same |

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| Attribute | PATHIAM Software<br>(predicate) | PATHIAM System |
|-----------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------|
| Specimen Type | Formalin-fixed, paraffin<br>embedded specimens<br>stained by<br>immunohistochemistry<br>reagent for HER2/neu | Same |
| Image Analysis<br>System | Histologic observation by a<br>pathologist through a<br>specified<br>microscope/digital camera<br>combination or slide<br>scanner. | Histologic observation<br>by a pathologist<br>through the<br>BioImagene iScan<br>slide scanner. |
| Method of Cell<br>Detection | Object identification of a<br>digitized field of view of a<br>pathology slide, using size,<br>shape, color and intensity<br>as observed by a software,<br>and by visual observation<br>of the digitized image by a<br>health care professional. | Same |
| Hardware<br>Components | Computer, either<br>microscope with digitizing<br>camera or slide scanner,<br>keyboard, mouse, high<br>resolution color monitor,<br>and hard drive for storage. | PATHIAM Software,<br>BioImagene iScan<br>slide scanner,<br>computer, and<br>monitor. |
| Assay used | DAKO HercepTest™ | Same |

Standards Employed

None under Section 514

# FDA Guidance

Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices, May 11, 2005

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/8/Picture/1 description: The image shows the logo for the Department of Health & Human Services USA. The logo consists of a stylized eagle with three stripes forming its body and wings. The eagle is facing right. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES USA" is arranged in a circular fashion around the eagle.

#### Public Health Service

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

# FEB - 4 2009

BioImagene, Inc. c/o Mr. Indu Lakshman Director of QA & RA 1601 South De Anza Blvd., Suite 212 Cupertino, CA 95014

Re: k080910

Trade/Device Name: PATHIAM System with iScan for HER2/neu Regulation Number: 21 CFR 864.1860 Regulation Name: Immunohistochemistry Reagents and Kits Regulatory Class: Class II Product Code: NOT Dated: January 16, 2009 Received: January 21, 2009

Dear Mr. Lakshman:

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 devoce that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Noss mail Act (Act) that do not require approval of a premarket approval application (PMA). You ocay, 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 levenest good manufacturing practice, labeling, and prohibitions against misbranding and adulterotion.

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 Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. In addition, IDAo way 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 0art) (207); labeling (21 CFR Parts 801 and 809); and good manufacturing practice requirements as set for in the quality systems (QS) regulation (21 CFR Part 820). This letter will allow your to begin marketing your device as described in your Section 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.

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#### Page 2 - Mr. Indu Lakshman

If you desire specific advice for your device on our labeling regulation (21 CFR Part 801), 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" (21CFR Part 807.97). For questions regarding postmarket surveillance, please contact CDRH's Office of Surveillance and Biometric's (OSB's) Division of Postmarket Surveillance at [phone]. For questions regarding the reporting of device adverse events (Medical Device Reporting (MDR)), please contact the Division of Surveillance Systems at [phone]. 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 vours.

Maria M. Chan

Maria M. Chan, Ph.D.

Acting Division 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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## 510(k) Number (if known): K080910

## Device Name: PATHIAM System with iScan for HER2/neu

#### Indication For Use:

PATHIAM-Assisted Scoring: Intended for clinical laboratory use as an accessory to the DAKO HercepTest to aid in the detection and semi-quantitative measurement of Her2/neu in formalin fixed, paraffin-embedded normal and neoplastic tissue. When used with the DAKO HercepTest, Pathiam Assisted Scoring is indicated for use as an aid in the assessment of breast cancer patients for whom HERCEPTIN (Trastuzumab) treatment is being considered. The pathologist should verify agreement with the PATHIAM System score.

HER2/neu results are indicated for use as an aid in the management, prognosis and predication of therapy outcomes of breast cancer. Note: The actual correlation of the DAKO HercepTest to Herceptin® clinical outcome has not been established.

Prescription Use X And/Or (21 CFR Part 801 Subpart D)

Over the Counter Use (21 CFR Part 801 Subpart C)

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

Concurrence of CDRH, Office of In Vitro Diagnostic Device Evaluation and Safety (OVD)

Josephine Bartlett

Division/Sign-Off Office of In Vitro Diagnostic Device Evaluation and Safety

510(k) K080910

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