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 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 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.

Hardware: The iScan slide scanning device captures digital images of 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.

Software: The PATHIAM Software requires competent human 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.

AI/ML Overview

The provided document outlines the performance study for the PATHIAM™ System with iScan for HER2/neu, primarily focusing on its agreement with manual HercepTest methods and reproducibility.

Here's an analysis of the acceptance criteria and study details:

1. Table of Acceptance Criteria and Reported Device Performance:

Acceptance Criteria Category	Acceptance Criteria	Reported Device Performance
Agreement with Manual HercepTest Method	While explicit numerical acceptance criteria for agreement between the PATHIAM System and manual scores are not stated as "acceptance criteria," the study aimed to demonstrate acceptable levels of concordance. Implicitly, the observed percentage agreements in each site were considered acceptable for the claim of aiding pathologists.	Site 1: 77% Overall Agreement (95% CI: 70% - 83%) Site 2: 81% Overall Agreement (95% CI: 75% - 87%) Site 3: 88% Overall Agreement (95% CI: 82% - 92%)
Reproducibility Between Pathologists and PATHIAM Systems (Inter-site with PATHIAM assistance)	Implicitly, good concordance was desired. The study reported "Concordance for the PATHIAM System values between labs ranged from 89% to 92%." This suggests that the system-assisted readings were highly reproducible across sites.	Site 1 vs. 2: 92% Overall Agreement (95% CI: 87% - 96%) Site 2 vs. 3: 89% Overall Agreement (95% CI: 83% - 93%) Site 3 vs. 1: 91% Overall Agreement (95% CI: 86% - 95%)
Manual HercepTest Reproducibility (Inter-site without PATHIAM assistance)	While not an acceptance criterion for the device itself, this serves as a baseline for comparison. The goal would likely be to show the PATHIAM system-assisted readings are at least as reproducible or better than manual readings.	Site 1 vs. 2: 67% Overall Agreement (95% CI: 60% - 74%) Site 2 vs. 3: 81% Overall Agreement (95% CI: 74% - 86%) Site 3 vs. 1: 80% Overall Agreement (95% CI: 73% - 85%)
iScan Slide Scanner Precision	Not explicitly stated as a numerical acceptance criterion, but "precision was calculated to be 97%."	97%
Inter-run/Inter System Reproducibility (iScan)	Not explicitly stated as a numerical acceptance criterion, but the study implies a high degree of agreement was expected.	100% agreement between PATHIAM System scores for different scans and for different iScan slide scanners.

2. Sample size used for the test set and the data provenance:

Sample Size: 176 stained tissue specimens.
Data Provenance: The document does not explicitly state the country of origin. The study appears to be prospective in the sense that the pathologists performed readings specifically for this study, first manually and then with the PATHIAM System. There is no indication of retrospective analysis of existing clinical data.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

Number of Experts: Three pathologists.
Qualifications of Experts: The document states "trained pathologists" without specifying years of experience or sub-specialization.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set:

Adjudication Method: Not explicitly stated. For the "Comparison with Manual HercepTest method," pathologists observed digital images and the suggested score, then selected an appropriate tissue score. This suggests the pathologist made the final judgment for the PATHIAM System assisted score. For the manual scores, they read the slides manually. There's no mention of a consensus process or arbitration for discrepant scores.

5. 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:

MRMC Study: Yes, a form of MRMC study was conducted. Three pathologists (multiple readers) assessed 176 cases (multiple cases) both with and without the AI assistance (manual vs. PATHIAM-assisted).
Effect Size of Improvement: The study demonstrates improved inter-reader reproducibility with AI assistance compared to manual reading.
- Manual Inter-reader Agreement: Ranged from 67% to 81%.
- PATHIAM-assisted Inter-reader Agreement: Ranged from 89% to 92%.
- This represents an improvement in inter-reader agreement of 8% to 22% when using the PATHIAM system compared to manual reading alone (e.g., 92% vs 67% for Site 1 vs 2 comparison, an improvement of 25 percentage points; 89% vs 81% for Site 2 vs 3, an improvement of 8 percentage points; 91% vs 80% for Site 3 vs 1, an improvement of 11 percentage points). The "effect size" here is the increase in percentage agreement between pathologists.

6. If a standalone (i.e. algorithm only without human-in-the loop performance) was done:

Standalone Performance: No, a standalone performance study of the algorithm without human-in-the-loop was not performed. The device description explicitly states: "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..." and "The software will act as a tool for the user, to improve consistency and data recording." The "PATHIAM System values" are derived from the pathologist's review of the digital images and the software's suggested score.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc):

Ground Truth: The "ground truth" for evaluating the PATHIAM System's performance was the manual assessment by trained pathologists using the DAKO HercepTest package insert. This is implicitly assumed to be the "gold standard" against which the system-assisted readings are compared. The reproducibility study between pathologists also uses their independent assessments as the reference.

8. The sample size for the training set:

Training Set Sample Size: The document does not provide information on the training set size or how the algorithm was developed. The studies described are performance validation studies.

9. How the ground truth for the training set was established:

Training Set Ground Truth: As with the training set size, information on how the ground truth for any potential training set was established is not provided in this summary.

Summary

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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 408-207-4242 FAX 408-207-4299

ilakshman@bioimagene.com

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:

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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%.

1. 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(predicate)	PATHIAM System
Intended Use	The imaging software isintended to detect andclassify cells of clinicalinterest by analyzingdigitized images ofmicroscope slides based onobject identification ofcellular objects ofparticular intensity, shape,size and color. Thesoftware can be used with acomputer and imagedigitizer with featuresspecified in the labeling.	The PATHIAMSystem consists of thePATHIAM Software,the BioImagene iScanSlide Scanner,computer, keyboard,monitor and mouseintended to detect andclassify cells ofclinical interest byanalyzing digitizedimages of microscopeslides based on objectidentification ofcellular objects ofparticular intensity,shape, size and color.
Indications for use	When used with the DAKOHercepTest, it is indicatedfor use as an aid in theassessment of breast cancerpatients for whomHERCEPTIN®	Same

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Attribute	PATHIAM Software(predicate)	PATHIAM System
Specimen Type	Formalin-fixed, paraffinembedded specimensstained byimmunohistochemistryreagent for HER2/neu	Same
Image AnalysisSystem	Histologic observation by apathologist through aspecifiedmicroscope/digital cameracombination or slidescanner.	Histologic observationby a pathologistthrough theBioImagene iScanslide scanner.
Method of CellDetection	Object identification of adigitized field of view of apathology slide, using size,shape, color and intensityas observed by a software,and by visual observationof the digitized image by ahealth care professional.	Same
HardwareComponents	Computer, eithermicroscope with digitizingcamera or slide scanner,keyboard, mouse, highresolution color monitor,and hard drive for storage.	PATHIAM Software,BioImagene iScanslide scanner,computer, andmonitor.
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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1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 -

and the comments of the comments of the comments of

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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 (240) 276-0450. 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 (240) 276-3474. For questions regarding the reporting of device adverse events (Medical Device Reporting (MDR)), please contact the Division of Surveillance Systems at (240) 276-3464. 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 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:

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

Page 1 of 1

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.