The Pathwork® Tissue of Origin Test is intended to measure the degree of similarity between the RNA expression pattern in a patient's fresh-frozen tumor and the RNA expression patterns in a database of tumor samples (poorly differentiated, undifferentiated and metastatic cases) that were diagnosed according to then current clinical and pathological practice. The database contains examples of RNA expression patterns for fifteen common malignant tumor types: bladder, breast, colorectal, gastric, hepatocellular, kidney, non-small cell lung, ovarian, pancreatic, prostate, and thyroid carcinomas, melanoma, testicular germ cell tumor, non-Hodgkins lymphoma (not otherwise specified), and soft tissue sarcoma (not otherwise specified). The Pathwork® Tissue of Origin Test result is intended for use in the context of the patient's clinical history and other diagnostic tests evaluated by a qualified clinician.

Limitations: The Pathwork Tissue of Origin Test is not intended to establish the origin of tumors that cannot be diagnosed according to current clinical and pathological practice. (e.g. carcinoma of unknown primary). It is not intended to subclassify or modify the classification of tumors that can be diagnosed by current clinical and pathological practice, nor to predict disease course or survival or treatment efficacy, nor to distinguish primary from metastatic tumor. Tumor types not in the Pathwork Tissue of Origin Test database may have RNA expression patterns that are similar to RNA expression patterns in tumor types in the database, leading to indeterminate results or misclassifications,

Device Description

The Pathwork® Tissue of Origin Test is a microarray and analytics "kit" that quantifies the similarity of tumor specimens to 15 cancer types representing 60 morphologies. Frozen biopsy specimens are processed by the clinical laboratory as described in the User Guide. In brief, mRNA is extracted, amplified, labeled and hybridized to the Pathchip® microarray, which is then scanned using one of the instrument systems validated for use with this test. The resulting data file is transmitted via secure internet transfer protocol to the Pathwork® System Software for data quality control and analysis. Test results are available for clinical interpretation via a secure password protected website.

Components included in the kit:
Microarray: Pathchip microarrays, packaged in boxes of 5 or 10.
Tissue of Origin Test Report produced by the Pathwork System Software (by licensed agreement): The Pathwork® System Software receives data from the scanned Pathchip™ microarray and performs data quality control and analysis. The System Software then generates a Pathwork® Tissue of Origin Test Report which provides a Similarity Score for each of the 15 tissues on the test panel. The test report is accessible for clinical interpretation via a secure password protected website.
Tissue of Origin Test Reagents: Reagents for specimen processing and RNA extraction.

AI/ML Overview

Here's a breakdown of the acceptance criteria and study details for the Pathwork® Tissue of Origin Test, based on the provided document:

Acceptance Criteria and Reported Device Performance

Acceptance Criteria Category	Acceptance Criteria (Implicit)	Reported Device Performance
Accuracy (Positive Percent Agreement)	High Positive Percent Agreement (Specific threshold not explicitly stated but generally expected above 85-90%)	89.4% (487/545) across all 15 tissues
Accuracy (Negative Percent Agreement)	High Negative Percent Agreement (Specific threshold not explicitly stated but generally expected above 95%)	99.6% (507/509) across all 15 tissues
Precision (Site-to-site concordance)	High inter-site concordance (Specific threshold not explicitly stated but generally expected above 90%)	Approximately 93% overall site-to-site concordance
Interfering Substances	No significant impact on performance from common interfering substances in biopsy specimens (e.g., adipose tissue, fibrous tissue, necrotic tissue). Adequate performance with pancreas-related specimens despite known RNase levels.	No effect from high levels of adipose tissue, fibrous tissue, or necrotic tissue (up to 20% of biopsy specimen). Adequate performance with pancreas-related specimens, though performance is lower due to elevated RNases.

Study Information

Sample size used for the test set and the data provenance:
- Sample Size: 545 frozen specimens.
- Data Provenance: Not explicitly stated, but the study was performed at "four laboratory sites," implying multi-center data collection. It is likely retrospective as the samples were "diagnosed according to then current clinical and pathological practice" and stored as "frozen specimens."
Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- Number of Experts: Not specified.
- Qualifications: Ground truth was established by "the available diagnosis" based on "current clinical and pathological practice." This suggests diagnosis by qualified pathologists and clinicians, but specific numbers and their years of experience are not detailed.
Adjudication method for the test set:
- Not explicitly stated. The document refers to "the available diagnosis," indicating that the clinical diagnoses were used as the reference standard without mentioning an adjudication process for discrepancies in the test set.
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:
- No MRMC comparative effectiveness study was done or reported in this document. The study focuses purely on the device's standalone performance against a diagnostic ground truth.
If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
- Yes, a standalone study was performed. The reported accuracy (positive and negative percent agreement) refers to the performance of the Pathwork® Tissue of Origin Test itself in identifying the tissue of origin. The device generates "Similarity Scores" and a "Test Report" for clinical interpretation, but the performance metrics provided are for the algorithm's output.
The type of ground truth used:
- Clinical and Pathological Diagnosis: The ground truth for the test set was established based on "the available diagnosis" from "current clinical and pathological practice." This refers to established clinical and histopathological diagnoses for the tumor samples.
The sample size for the training set:
- The document states that the test "quantifies the similarity of tumor specimens to 15 cancer types representing 60 morphologies" against "RNA expression patterns in a database of tumor samples." However, it does not explicitly state the sample size of this database used for training the algorithm. It only mentions the database contains examples of RNA expression patterns.
How the ground truth for the training set was established:
- The ground truth for the samples in the database (which would have been used for training) was established by samples "diagnosed according to then current clinical and pathological practice." This implies standard clinical and pathological evaluations of the source tumor samples in the database.

Summary

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1196 Borregas Avenue Suite 200 Sunnyvale, CA 94089

JUL 30 2008

SECTION 6 510(k) SUMMARY

This 510(k) Summary is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.

This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.

The assigned 510(k) number is K080896

807.92 (a)(1):	Name:	Pathwork® Diagnostics, Inc
	Address:	1196 Borregas AvenueSuite 200Sunnyvale, CA 94089
	Phone:Contact:	408-400-0828 x103Glenda G. AndersonFounder and CTO

807.92 (a)(2): Device Name - trade name and common name, and classification

Trade name:	Pathwork® Tissue of Origin Test
Common name:	Microarray and software system kit for gene expression-baseddiagnostics
Classification:	21 CFR § 862.3100, Amphetamine Test SystemClass II, Product Code NVI (diagnostic software)

Identification of the legally marketed predicate device 807.92 (a)(3): The Tissue of Origin Test is substantially equivalent to the BioPlex 2200 Medical Decision Support software (MDSS) on the BioPlex 2200 Multi-Analyte Detection System, (Bio-Rad Laboratories, Hercules, CA), cleared under premarket notification K043341 on October 27, 2005.

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Image /page/1/Picture/0 description: The image shows the logo for Pathwork Diagnostics. The logo consists of a stylized black and white image of a winding road on the left, followed by the word "Pathwork" in a bold, sans-serif font. Below "Pathwork" is the word "Diagnostics" in a smaller font.

807.92 (a)(4): Device Description

Components included in the kit

Microarray: Pathchip microarrays, packaged in boxes of 5 or 10.

Tissue of Origin Test Report produced by the Pathwork System Software (by licensed agreement): The Pathwork® System Software receives data from the scanned Pathchip™ microarray and performs data quality control and analysis. The System Software then generates a Pathwork® Tissue of Origin Test Report which provides a Similarity Score for each of the 15 tissues on the test panel. The test report is accessible for clinical interpretation via a secure password protected website.

Tissue of Origin Test Reagents: Reagents for specimen processing and RNA extraction.

807.92 (a)(5): Intended Use

Indications for Use: The Pathwork® Tissue of Origin Test is intended to measure the degree of similarity between the RNA expression pattern in a patient's fresh-frozen tumor and the RNA expression patterns in a database of tumor samples (poorly differentiated, undifferentiated and metastatic cases) that were diagnosed according to then current clinical and pathological practice. The database contains examples of RNA expression patterns for fifteen common malignant tumor types: bladder, breast, colorectal, gastric, hepatocellular, kidney, non-small cell lung, ovarian, pancreatic, prostate, and thyroid carcinomas, melanoma, testicular germ cell tumor, non-Hodgkins lymphoma (not otherwise specified), and soft tissue sarcoma (not otherwise specified). The Pathwork® Tissue of Origin Test result is intended for use in the context of the patient's clinical history and other diagnostic tests evaluated by a qualified clinician.

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Image /page/2/Picture/0 description: The image shows the logo for Pathwork Diagnostics. The logo consists of a stylized image of a path on the left, followed by the word "Pathwork" in a bold, sans-serif font. Below "Pathwork" is the word "Diagnostics" in a smaller font.

1 1 96 Borregas Avenue Suite 200 Sunnyvale, CA 94089

807.92 (a)(6): Technological Similarities and Differences to Predicate

	Tissue of Origin TestK080896	Bioplex 2200 Medical DecisionSupport SoftwareK043341
CHARACTERISTIC
Intended Use	Indications for Use: The Pathwork®Tissue of Origin Test is intended tomeasure the degree of similarity betweenthe RNA expression pattern in a patient'sfresh-frozen tumor and the RNAexpression patterns in a database oftumor samples (poorly differentiated,undifferentiated and metastatic cases)that were diagnosed according to thencurrent clinical and pathological practice.The database contains examples of RNAexpression patterns for fifteen commonmalignant tumor types: bladder, breast,colorectal, gastric, hepatocellular,kidney, non-small cell lung, ovarian,pancreatic, prostate, and thyroidcarcinomas, melanoma, testicular germcell tumor, non-Hodgkins lymphoma(not otherwise specified), and soft tissuesarcoma (not otherwise specified). ThePathwork® Tissue of Origin Test resultis intended for use in the context of thepatient's clinical history and otherdiagnostic tests evaluated by a qualifiedclinician.	The Bioplex 2200 Medical DecisionSupport Software (MDSS), used inconjunction with the ANA Screen, is anoptional laboratory tool that associatespatient antibody results with predefinedMDSS profiles that have been correlatedwith the following systemic autoimmunediseases: SLE, Mixed Connective TissueDisease, Sjogren's Syndrome,Scleroderma, and Polymyositis
Principle of Operation	The frozen biopsy specimen is processedby the clinical laboratory and is thenhybridized to the Pathchip microarray.The Pathchip is scanned and theresulting intensity data file is processedby the Pathwork System Software. Theresults are presented to the laboratory asa Pathwork Tissue of Origin Test Report(secure internet access; pdf file) thatquantifies the similarity of the RNAexpression pattern found in a tumorspecimen (poorly or un-differentiatedprimary tumors, as well as metastatictumors) to expression patterns found intumor specimens from 15 known tissuesof origin.	The autoantibody results from thechemistry assay are compared tothe MDSS database that contain resultsfor over 1,400 sera/plasma, representingtest results from patients with systemicautoimmune diseases and from healthyindividuals. If one or more results areobtained from a serum or plasma sample,the results are associated with the mostappropriate MDSS profiles. When theMDSS result is positive, the MDSSproduces two outputs that BioPlex2200 can display in its User Interface.The first output is a text result containingthe specific disease association(s) results.The second output is a graph of thespecific disease association(s) and thepatient's analyte results.
	Tissue of Origin TestK080896	Bioplex 2200 Medical DecisionSupport SoftwareK043341
CHARACTERISTIC
Sample Preparation	Frozen biopsy tissues	Serum or plasma
Required Platform	Affymetrix GeneChip® ScannerGCS3000Dx, or equivalent	BioPlex 2200 Multi-Analyte DetectionSystem
Output	Similarity of RNA expression patternsfound in tumor specimens to 15 knowntissues of origin	Results of MDSS analysis fall into oneof three categories: Negative, NoAssociation, or Association with Disease
Testing Environment	Professional use, CLIA HighComplexity Laboratory	Professional use, CLIA HighComplexity Laboratory
Precision	Reproducibly studies were conducted atfour sites with multiple specimens (n = 3or n = 6) from all 15 tissue types offeredon the Pathwork Tissue of Origin Testpanel (n = 60 specimens across all tissuetypes). Aliquots from each specimenwere processed, scanned, and interpretedby all four sites, and each site wascompared to each other. The overall site-to-site concordance among the four sitesfor Tissue of Origin Test results wasapproximately 93%.	Reproducibly studies were conducted atthree sites with 11 eleven panel samplesand three lots of reagents. Each samplewas tested in duplicate, two "runs" perday for 10 days. The data were analyzedfor intra-assay precision and inter-assayprecision. For intra-assay precision, thepercent coefficients of variation (%CVs)ranged from 1.7% to 11.1% across thethree sites. For inter-assay precision, the%CVs ranged from 2.8% to 12.8%across the three sites.
Accuracy	The accuracy, defined as positive andnegative percent agreement against theavailable diagnosis was as follows. Thepositive percent agreement across all 15tissues was approximately 90% Thenegative percent agreement across all 15tissues was approximately 99%.	Percent agreements of the MDSS outputswhen a specific positive antibody waspresent, to the available diagnosis,ranged from 71% to 100%.
Interfering Substances	Studies were conducted that evaluatedthe effect from potential interferingsubstances found in biopsy specimens,such as adipose tissue, RNases, fibroustissue, and necrotic tissue. The datashowed that there was no effect fromhigh levels of adipose tissue (as found inbreast specimens), fibrous tissue (asfound in skin specimens), or necrotictissue, when up to 20% of the biopsyspecimen. The test demonstratedadequate performance with pancreas-related specimens, although performanceis lower than for other tissues on thepanel. The lower performance isostensibly due to elevated levels ofRNases in these specimens.	No significant interference was foundfrom the following substances whenchallenges were made at highconcentrations:Substance ConcentrationHemoglobin ≤500 mg/dlBilirubin(unconjugated) ≤ 20 mg/dlTriglycerides ≤ 3000 mg/dlProtein (total) ≤ 12 g/dlCholesterol ≤ 500 mg/dlRed blood cells ≤ 0.4% concentrateGamma-globulin ≤2.5 g/dlAscorbic acid ≤ 3.0 mg/dl

Similarities/Differences between the Tissue of Origin Test and the Predicate

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1196 Borregas Avenue Suite 200 Sunnyvale, CA 94089

Similarities/Differences (continued)

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Image /page/4/Picture/0 description: The image shows the logo for Pathwork Diagnostics. The logo consists of a stylized graphic of a winding road or path on the left, followed by the word "Pathwork" in a bold, sans-serif font. Below "Pathwork" is the word "Diagnostics" in a smaller font size.

1196 Borregas Avenue Suite 200 Sunnwale, CA 94089

807.92 (b)(1): Brief Description of Non-clinical data

Studies were conducted that evaluated the effect from potential interfering substances found in biopsy specimens, such as adipose tissue, RNases, fibrous tissue, and necrotic tissue. The data showed that there was no effect from high levels of adipose tissue (as found in breast specimens), fibrous tissue (as found in skin specimens), or necrotic tissue up to 20% of the biopsy specimen. The Tissue of Origin Test demonstrates adequate performance with pancreas-related specimens, although performance is lower than for other tissues on the TOO panel. The lower performance is ostensibly due to elevated levels of RNases in these specimens.

Reproducibly studies were conducted at four sites with multiple specimens (n = 3 or n = 6) from all 15 tissue types offered on the Pathwork Tissue of Origin Test panel (n = 60 specimens across all tissue types). Aliquots from each specimen were processed, scanned, and interpreted by all four sites, and each site was compared to each other. The overall site-to-site concordance among the four sites for Tissue of Origin Test results was approximately 93%.

807.92 (b)(2): Brief Description of Clinical Data

The clinical study was performed at four laboratory sites and included 545 frozen specimens. The accuracy, defined as positive and negative percent agreement against the available diagnosis was as follows. The positive percent across all 15 tissues was 89.4 (487/545), with a confidence interval of 86.5% to 91.8%. The negative percent agreement across all 15 tissues was 99.6% (507/509) with a confidence interval of 98.6% to 100.0%.

807.92 (b)(3): Conclusions from Clinical Testing

The results of the clinical validation demonstrated that the Pathwork Tissue of Origin Test is safe and effective for its intended use.

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Public Health Service

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Pathwork Diagnostics, Inc. c/o Ms Erika B. Ammirati Regulatory Consultant 1196 Borregas Ave, Suite 200 Sunnyvale, CA 94089

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Re: K080896

Trade/Device Name: Pathwork® Tissue of Origin Test Regulation Number: 21 CFR 862.3100 Regulation Name: Amphetamine test system Regulatory Class: II Product Code: OIW Dated: July 21, 2008 Received: July 22, 2008

JUL 30 ...

Dear Ms. Ammirati:

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). You may, therefore, market the device, subject to the general controls provisions of the Act and the limitations described below. 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.

The Office of In Vitro Diagnostic Device Evaluation and Safety has determined that there is a reasonable likelihood that this device will be used for an intended use not identified in the proposed labeling and that such use could cause harm. Therefore, in accordance with Section 513(i)(1)(E) of the Act, the following limitation must appear under the Indications for Use section of the device's labeling and the patient test report:

The Pathwork® Tissue of Origin Test is not intended to establish the origin of tumors (e.g. carcinoma of unknown primary) that cannot be diagnosed according to current clinical and pathological practice. It is not intended to subclassify or modify the classification of tumors that can be diagnosed by current clinical and pathological practice, nor to predict disease course or survival or treatment efficacy, not to distinguish primary from metastatic tumor. Tumor types not in the Pathwork® Tissue of Origin Test database may have RNA expression patterns that are similar to patterns in the database.

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Please note that the above labeling limitations are required by Section 513(i)(1)(E) of the Act. Therefore, a new 510(k) is required before these limitations are modified in any way or removed from the device's labeling.

The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and permits your device to nroceed to the market. This letter will allow you to begin marketing your device as described in your Scction 510(k) premarket notification if the limitation statement described above is added to your labeling.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations (CFR), Title 21, Parts 800 to 895. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).

If you desire specific information about the application of other 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). 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.

Dame Zurch for

$teven I. Gutman, M.D., M.B.A. Director 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): K080896 Device Name: Pathwork® Tissue of Origin Test

FDA's Statement of the Indications For Use for device:

The Pathwork® Tissue of Origin Test is intended to measure the degree of similarity between the RNA expression pattern in a patient's fresh-frozen tumor and the RNA expression patterns in a database of tumor samples (poorly differentiated, undifferentiated and metastatic cases) that were diagnosed according to then current clinical and pathological practice. The database contains examples of RNA expression patterns for fifteen common malignant tumor types: bladder, breast, colorectal, gastric, hepatoccllular, kidney, non-small cell lung, ovarian, pancreatic, prostate and thyroid cancinominas, melanoma, testicular germ cell tumor, non-Hodgkins lymphoma (not otherwise specified), and soft tissue sarcoma (not otherwise specified). The Pathwork® Tissue of Origin Test result is intended for use in the context of the patient's clinical history and other diagnostic tests evaluated by a qualified clinician.

Limitations:

The Pathwork® Tissue of Origin Test is not intended to establish the origin of tumors (e.g. carcinoma of unknown primary) that cannot be diagnosed according to current clinical and pathological practice. It is not intended to subclassify or modify the classification of tumors that can be diagnosed by current clinical and pathological practice, nor to predict disease course or survival or treatment efficacy, not to distinguish primary from metastatic tumor. Tumor types not in the Pathwork®Tissue of Origin Test database may have RNA expression patterns that are similar to patterns in the database.

Prescription Use _ كما (Part 21 CFR 801 Subpart D)

AND/OR

Over-The-Counter Use (21 CFR 807 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 (OIVD)

Mana Mchon

Division Sign-Off

Office of In Vitro Diagno Device Evaluation and Sa

510(k) K080896

Regulation Number and Section

§ 862.3100 Amphetamine test system.

(a)
Identification. An amphetamine test system is a device intended to measure amphetamine, a central nervous system stimulating drug, in plasma and urine. Measurements obtained by this device are used in the diagnosis and treatment of amphetamine use or overdose and in monitoring levels of amphetamine to ensure appropriate therapy.(b)
Classification. Class II (special controls). An amphetamine test system is not exempt if it is intended for any use other than employment or insurance testing or is intended for Federal drug testing programs. The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 862.9, provided the test system is intended for employment and insurance testing and includes a statement in the labeling that the device is intended solely for use in employment and insurance testing, and does not include devices intended for Federal drug testing programs (e.g., programs run by the Substance Abuse and Mental Health Services Administration (SAMHSA), the Department of Transportation (DOT), and the U.S. military).