Biolmagene 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.

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.

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
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.

AI/ML Overview

Here's a breakdown of the acceptance criteria and study details for the BioImagene PATHIAM Image Analysis Software for Her2/neu, based on the provided 510(k) summary:

Acceptance Criteria and Reported Device Performance

The acceptance criteria for the PATHIAM software are implicitly defined by comparison to the established predicate device (ACIS Her2/neu software component) and through performance studies demonstrating inter-laboratory and inter-reader agreement. While explicit numerical acceptance criteria for overall agreement are not stated as "target thresholds," the demonstrated high levels of agreement strongly support the device's performance.

Criterion	Acceptance Criteria (Implied)	Reported Device Performance
Between-laboratory reproducibility for PATHIAM raw scores (Automated analysis only)	High overall agreement across different labs/imaging systems.	94% - 95% Overall Agreement (95% CI: 89-98%) among three different labs. (Table 1)
Between-laboratory reproducibility for Pathologist Assisted by PATHIAM Scores	High overall agreement across different labs with pathologist assistance.	81% - 96% Overall Agreement (95% CI: 74-98%) among three different labs. (Table 2)
Comparison of PATHIAM-Assisted vs. Manual Scores (Intra-lab agreement)	High agreement between a pathologist's score with and without PATHIAM assistance from the same lab.	81% - 84% Overall Agreement (95% CI: 75-89%) for each of the three labs. (Table 4)
Comparison of PATHIAM raw scores vs. Manual Scores (Intra-lab agreement)	High agreement between the raw algorithm score and a pathologist's manual score from the same lab.	78% - 83% Overall Agreement (95% CI: 71-88%) for each of the three labs. (Table 5)
Substantial Equivalence to Predicate Device	Similar intended use, indications for use, specimen type, image analysis system, method of cell detection, hardware components, and assay used.	The device is compared favorably to the predicate (ACIS Her2/neu software component) across these attributes, indicating substantial equivalence. (Table 6)

Study Details

Sample sizes used for the test set and the data provenance:
- Test Set Sample Size: 176 stained breast cancer tissue specimens.
- Data Provenance: The study was conducted in the US at three different sites. There is no explicit mention of the data being retrospective or prospective, but the description of "analyzed images of the same set of 176 stained breast cancer tissue specimens" suggests a retrospective analysis of existing samples.
Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- Number of Experts: Three different pathologists.
- Qualifications: They are referred to as "trained pathologists," but no specific experience levels (e.g., years of experience, board certifications) are provided.
Adjudication method (e.g. 2+1, 3+1, none) for the test set:
- The study involved multiple pathologists providing scores, and comparisons were made between their scores. However, there is no explicit mention of an adjudication method to establish a single, definitive ground truth score for each case through consensus or a tie-breaker. Instead, the study focuses on agreement between the individual scores of the device, manual readers, and device-assisted readers across different labs.
If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:
- Yes, implicitly, an MRMC comparative effectiveness study was performed in the sense that multiple readers (pathologists) evaluated multiple cases with and without the PATHIAM assistance, and across different laboratory setups.
- Effect Size of Improvement:
  - Manual Scores (Inter-lab agreement): 76% - 97% overall agreement (Table 3).
  - Pathologist Assisted by PATHIAM Scores (Inter-lab agreement): 81% - 96% overall agreement (Table 2).
  - The summary states: "Consistency is improved when the PATHIAM score assists the pathologist in their interpretation (Table 2)."
  - While not quantified as a single "effect size" number, comparing Table 3 (Manual Scores) to Table 2 (PATHIAM-Assisted Scores) suggests an improvement in agreement. For instance, Lab 1 vs Lab 3 manual agreement was 76%, while with PATHIAM assistance, it was 81%. Lab 2 vs Lab 3 manual agreement was 78%, and with PATHIAM assistance, it was also 81%. This indicates a trend towards improved inter-reader consistency with AI assistance.
If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
- Yes, a standalone performance assessment was conducted. This is evidenced by the "Between-Lab Agreement for Raw PATHIAM- Scores" (Table 1), which shows the consistency of the algorithm's output across different laboratories without direct pathologist modification of the software's initial score. The study also compared "PATHIAM raw scores and Manual Scores" (Table 5), which is a comparison of the algorithm's output against human interpretation.
The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- The primary "ground truth" or reference for comparison in this study is the pathologist's interpretation, both manual (microscopic assessment) and PATHIAM-assisted. The study focuses on agreement between these interpretations rather than against an external, independent gold standard like pathology results or clinical outcomes. The device is an aid to a pathologist, implying its performance is assessed by how well it aligns with or improves human expert interpretation.
The sample size for the training set:
- The document does not provide information on the sample size used for the training set. The performance data presented relates exclusively to the test set used for validation.
How the ground truth for the training set was established:
- Since the training set size and details are not provided, it is also not stated how the ground truth for any potential training set was established.

Summary

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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 650.213.9162 FAX 650.213.9164 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

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#	% OverallAgreement	95% Confidence Interval(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#	% OverallAgreement	95% Confidence Interval(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 #	% OverallAgreement	95% Confidence Interval(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 #	% OverallAgreement	95% Confidence Interval(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 #	% OverallAgreement	95% Confidence Interval(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 softwarecomponent	PATHIAM
Intended use	The imaging software isintended to detect andclassify cells of clinicalinterest by analyzing digitalimages of microscope slidesbased on objectidentification of cellular	Same
Indications for use	objects of particularintensity, shape, size andcolor. The software can beused with a computer andimage digitizer withfeatures specified in thelabelingAs an accessory to an assaywhich is indicated as an aidin the assessment of breastcancer patients for whomHerceptin® treatment isconsidered	As an accessory to the DakoHercepTest® to aid apathologist in semi-quantitative measurement ofHER2/neu (c-erbB-2) inFormalin-fixed, paraffin-embedded breast cancertissue.When used with the DakoHercepTest it is indicated asan aid in the assessment ofbreast cancer patients forwhom Herceptin®(Trastuzumab) treatment isbeing considered.
Specimen Type	Formalin-fixed, paraffin-embedded specimensstained byimmunohistochemistryreagent for Her2/neu	Same
Image Analysis System	Histologic observation by apathologist through acontrolledmicroscope/digital cameracombination	Histologic observation by apathologist through aspecified microscope/digitalcamera combination or slidescanner
Method of Cell Detection	Colorimetric patternrecognition by microscopicexamination of preparedcells by size, shape, hueand intensity as observed bya computer-assistedmicroscope and by visualobservation by a health careprofessional	Object identification of adigitized field of view of apathology slide, using size,shape, color and intensity asobserved by a software andby visual observation of thedigitized image by a healthcare professional.
Hardware components	Computer, microscope,color monitor, keyboard,automatic storage ofacquired images	Required but not provided:computer, eithermicroscope with digitizingcamera or slide scanner,
		keyboard, mouse, hi-resolution color monitor,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 (240) 276-0450. 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 (800) 638-2041 or (240) 276-3150 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

Division Sian-Off

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Office of In Vitro Dlagnostic Device Evaluation and Safety

510(k) Ko 627356

15 2/12/07

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.