K Number

Device Name

UROVYSION BLADDER CANCER RECURRENCE KIT

Manufacturer

VYSIS

Date Cleared

2002-02-08

(86 days)

Product Code

MMW

Regulation Number

866.6010

Intended Use

The UroVysion Bladder Cancer Recurrence Kit (UroVysion Kit) is designed to detect aneuploidy for chromosomes 3, 7, 17, and loss of the 9p21 locus via fluorescence in situ hybridization (FISH) in urine specimens from subjects with transitional cell carcinoma of the bladder. Results from the UroVysion Kit are intended for use as a noninvasive method for monitoring for turnor recurrence in conjunction with cystoscopy in patients previously diagnosed with bladder cancer.

Device Description

The UroVysion Kit is based upon fluorescence in situ hybridization (FISH) DNA probe technology. The UroVysion probes are fluorescently labeled nucleic acid probes for use in in situ hybridization assays on urine specimens fixed on slides. . The UroVysion Kit consists of a 4-color, four-probe mixture of DNA probe sequences homologous to specific regions on chromosomes 3, 7, 9, and 17. The UroVysion probe mixture consists of Chromosome Enumeration Probe (CEP®) 3 SpectrumRed™, CEP 7 SpectrumGreen™, CEP 17 SpectrumAqua™, and Locus Specific Identifier (LSI®) 9p21 SpectrumGold TM .

More Information

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Type

Center

Panel

Date Received

Product Code

Subsequent Product Codes

Applicant Name (Manufacturer)

Device Name

Decision

Street 1

Street 2

City

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ZIP

Postal Code

Class Advise Committee

SSP Indicator

Third Party Reviewed

Expedited Review

Predicate Devices

Bard® (Bion) BTAstat™ Test

Reference Devices

Not Found

AI/ML (Artificial Intelligence / Machine Learning)

No
The device description and performance studies focus on traditional FISH technology and qualitative visual analysis, with no mention of AI or ML.

Therapeutic

No
The device is used for monitoring tumor recurrence and diagnosis, not for treating a condition or disease.

Diagnostic

Yes
The device is described as a "Bladder Cancer Recurrence Kit" and its "Intended Use" is for "monitoring for turnor recurrence" which is a diagnostic purpose. It determines the presence of aneuploidy related to cancer, indicating a diagnostic function.

SaMD (Software as a Medical Device)

The device is a kit based on fluorescence in situ hybridization (FISH) DNA probe technology, which involves physical reagents and laboratory procedures, not solely software.

IVD (In Vitro Diagnostic)

Yes, this device is an IVD (In Vitro Diagnostic).

Here's why:

Intended Use: The "Intended Use / Indications for Use" section explicitly states that the kit is "designed to detect aneuploidy... in urine specimens". It also mentions that the results are "intended for use as a noninvasive method for monitoring for tumor recurrence in conjunction with cystoscopy in patients previously diagnosed with bladder cancer." This clearly indicates that the device is used to examine specimens derived from the human body (urine) to provide information for diagnostic purposes (monitoring for tumor recurrence).
Device Description: The description details the use of "fluorescence in situ hybridization (FISH) DNA probe technology" on "urine specimens fixed on slides." This further confirms that the device is used to analyze biological samples.
Performance Studies: The document describes clinical studies using "urine specimens" from patients to evaluate the device's performance (specificity, agreement with standard of care).

These points align directly with the definition of an In Vitro Diagnostic device, which is used to examine specimens from the human body to provide information for the diagnosis, prevention, or treatment of a disease or condition.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

Product codes

MMW

Device Description

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Not Found

Anatomical Site

Bladder

Indicated Patient Age Range

The clinical study included unique patients with an age range of 36 - 98 years and an average age of 71 years.

Intended User / Care Setting

Not Found

Description of the training set, sample size, data source, and annotation protocol

Not Found

Description of the test set, sample size, data source, and annotation protocol

Specificity Study:

Sample Size: 309 usable office visits, resulting in 230 informative specimens on the first attempt, and a total of 275 patient specimens yielding informative results (representing 357 data points due to some patients having multiple conditions).
Data Source: Multi-center, prospective study conducted on urine from healthy volunteers and urology patients without prior history or clinical evidence of bladder cancer.
Annotation Protocol: The UroVysion test's specificity was established by comparing results to the absence of prior history or clinical evidence of bladder cancer. Patients with medical conditions falling into multiple categories and/or multiple conditions within the same category were counted for each individual condition. Specificity was also calculated on "unique cases," where each patient was counted only once.

Performance vs. Standard of Care Study:

Sample Size: 251 usable office visits, resulting in 234 informative results, representing 176 unique patients.
Data Source: Multi-center, prospective, longitudinal study on patients previously diagnosed with bladder cancer.
Annotation Protocol: Performance was compared relative to cystoscopy followed by histology, which served as the comparative reference. For recurrence, the first positive visit was used; for non-recurring patients, the last negative visit was used. A positive cystoscopy without a biopsy was considered positive.

Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)

Specificity Study:

Study Type: Multi-center, prospective study.
Sample Size: 309 usable office visits (resulting in 357 data points from 275 unique patients).
Standalone Performance: Overall specificity of 93.0% (332/357). Specificity among unique cases was 94.5% (260/275). Specificity among healthy patients was 100% (59/59).
Key Results: The test demonstrated high specificity in the patient group, indicating that FISH does not generate artificial aneuploidy determinations.

Performance vs. Standard of Care Study:

Study Type: Multi-center, prospective, longitudinal study.
Sample Size: 251 usable office visits (representing 176 unique patients).
Standalone Performance:
- Agreement of (+) results = 71.0% (95% CI = 58.1% - 81.8%)
- Agreement of (-) results = 65.8% (95% CI = 56.3% - 74.4%)
- Overall Agreement = 67.6% (95% Cl = 60.2% - 74.5%)
Key Results: The UroVysion Kit showed greatest agreement of positive results (100%) among the most severe tumors (T2 and Tis) when compared to cystoscopy/histology.

Substantial Equivalence vs. BTAstat Test:

Study Type: Comparative study within the clinical study described above.
Sample Size: Urine specimens from each of the 176 unique patients (first positive, last negative office visit).
Key Results: The UroVysion test showed greater percent agreement of positive results for all tumor stages compared to BTAstat, including 100% agreement for T2 and Tis tumors. The criteria for substantial equivalence to the BTAstat test were met, as the 95% CIs for UroVysion were greater than the BTAstat scores minus 15% for agreement of positive, negative, and overall results. Concordance between UroVysion and BTAstat was 61.9%.

Longitudinal Study:

Study Type: Continuation of the multi-center prospective study.
Sample Size: Office visit information collected from 105 of 114 eligible patients, resulting in 299 usable office visits, representing 104 unique patients.
Key Results: The results showed recurrence in a greater percentage of patients in the FISH positive, cystoscopy/histology negative group (41.67%) than in the FISH negative, cystoscopy/histology negative group (19.12%). The difference was statistically significant (p=0.014). Kaplan-Meier analysis showed a statistical difference in recurrence-free survival between the FISH+ /cysto:histo - and FISH- /cysto:histo - groups.

Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)

Specificity Study:

Overall Specificity: 93.0% (332/357)
Specificity (Unique Patients): 94.5% (260/275)
Specificity (Healthy): 100% (59/59)
Specificity (Non-Healthy): 93.1% (201/216)
Specificity (Smokers): 95.2% (40/42)
Specificity (Non-Smokers): 94.7% (234/247)

Performance vs. Standard of Care:

Agreement of (+) results = 71.0% (95% CI = 58.1% - 81.8%)
Agreement of (-) results = 65.8% (95% CI = 56.3% - 74.4%)
Overall Agreement = 67.6% (95% Cl = 60.2% - 74.5%)
(+) Predictive Value = 53.0% (95% Cl = 41.7%-64.1%)
(-) Predictive Value = 80.6% (95% CI = 71.1% - 88.1%)
Prevalence = 35.2% (95% Cl = 28.2% - 42.8%)
p =

Regulation Number and Section

§ 866.6010 Tumor-associated antigen immunological test system.

(a)
Identification. A tumor-associated antigen immunological test system is a device that consists of reagents used to qualitatively or quantitatively measure, by immunochemical techniques, tumor-associated antigens in serum, plasma, urine, or other body fluids. This device is intended as an aid in monitoring patients for disease progress or response to therapy or for the detection of recurrent or residual disease.(b)
Classification. Class II (special controls). Tumor markers must comply with the following special controls: (1) A guidance document entitled “Guidance Document for the Submission of Tumor Associated Antigen Premarket Notifications (510(k)s) to FDA,” and (2) voluntary assay performance standards issued by the National Committee on Clinical Laboratory Standards.

Summary

K013785

Image /page/0/Picture/1 description: The image shows a date, "FEB 0 8 2002". The month is February, the day is the 8th, and the year is 2002. The text is in a bold, sans-serif font. The background is white.

Vysis, Inc. 3100 Woodcreek Dr. Downers Grove, IL 60515 Tel: 630 271-7040 Fax: 630 271-7438 Contact: Russel K. Enns, Ph.D.

510(k) Summary: Safety and Effectiveness Information for the UroVvsion™ Bladder Cancer Recurrence Kit

January 28, 2002

Trade Name Vysis™ UroVysion™ Bladder Cancer Recurrence Kit

Common or Usual Name Fluorescence in situ hybridization (FISH) reagents

Classification Name Class II IVD Device

Predicate Legally Marketed Device Bard® (Bion) BTAstat™ Test

Description of the Device

Intended Use

Different Technological Characteristics

Both the UroVysion Kit and the BTAstat test use the same specimen collection and preparation techniques in clinical practice. Thus, no new issues of safety with respect to patient care are introduced by the FISH technique; both the UroVysion Kit and the BTAstat test start with the same patient specimen (i.e., voided urine).

The major differences between the two tests are that they detect different substances and use different detection methods. Briefly, the UroVysion Kit uses DNA probes for specific regions on chromosomes 3, 7, 9 and 17 that bind to the target chromosomes by the DNA hybridization reaction. The actual binding mechanism of the UroVysion Kit is via specific complementary base pairing. In contrast, the BTAstat test is a lateral flow assay that detects the presence of bladder tumor associated antigen through antigen-specific antibodies. Also, the necessary visual interpretation of the results of the UroVysion Kit and of the BTAstat test is different. For the BTAstat test, urine is allowed to react with a colloidal gold-conjugated antibody and the results are determined qualitatively by the presence or absence of a line on the test stick. For the UroVysion Kit, the analyst visually recognizes chromosomes 3, 7 and 17, and the 9p21 locus by the fluorescent signal carried by the DNA probe mixture.

Even though the technological characteristics are different between the BTAstat test (antigen test) and the UroVysion test (DNA probe test), both test are intended for use to monitor for the recurrence of bladder cancer from voided urine specimens. The overall performance of the UroVysion test was demonstrated to be substantially equivalent.

Safety and effectiveness issues evaluated for the UroVysion Kit included the following: prospective, comparative methods evaluation for monitoring bladder cancer recurrence; specificity evaluation in healthy and unhealthy patients (without previous diagnosis of bladder cancer); interference assessment; and reproducibility studies.

Non-Clinical Parameters

Hybridization Efficiency

On the ProbeChek™ quality control slides run in conjunction with the clinical trials, 1.5% (4/261) of the targets failed due to lack of hybridization. These slides are prepared from cultured human bladder carcinoma (positive target) and normal lymphoblast (neqative target) cell lines, and represent the best-case scenario for hybridization efficiency. Thus, under these conditions, the hybridization efficiency was found to be 98.5%, with 275 for individual disease categories. 3Non-GU cancers included breast (1), colon (1), and leukemia (1)

Based on the patient population in this study, the UroVysion test demonstrated an overall specificity of 93.0% (332/357), with a 100% specificity (59/59) among healthy patients. The specificity among unique cases was 94.5% (260/275). The false positive results found in 15 patients represented the following categories (note that some patients had health conditions falling into multiple disease categories); non

genitourinary (GU) benign diseases (3), non-GU cancer (2), GU diseases (15), and GU cancer (5). These results indicate that the test is highly specific in this patient group, which reinforces the fact that FISH does not generate artificial aneuploidy determinations; the FISH probes react only with the intended chromosomes.

Performance vs. Standard of Care

Study Summary

A multi-center, prospective, longitudinal study was conducted to further define the performance characteristics of the UroVysion Kit relative to cystoscopy followed by histology, the standard of care for monitoring for disease recurrence in patients previously diagnosed with bladder cancer. The comparative reference used for all percent agreement calculations was cystoscopy with histology confirmation for positive or suspicious cystoscopies. If a patient had a positive cystoscopy but histology was absent (e.g., the lesion was fulgurated), then the specimen was considered positive for bladder cancer. If a test had a suspicious cystoscopy but histology was absent, then the case was omitted from analysis. A total of 309 patient visits were conducted at 21 investigation sites, resulting in 251 usable office visits. The 58 unusable visits included 17 that did not meet the eligibility criteria, 16 with insufficient urine volume, 10 with suspicious cvstoscopies but no histology, and in 15 cases urine was not sent to the testing. laboratories. Urine processing and analysis were conducted at one centralized testing laboratory. FISH assay and analysis on the 251 usable office visits in the resulted in 234 informative results, representing 176 unique patients. For patients who experienced a recurrence during the trial (as determined by is a cystoscopy and/or histology), the first positive visit was used (i.e., the visit at which the diagnosis of recurrence was established). For the non-recurring patients, the last negative visit was used for those patients with more than one visit. The demographics for the 176 unique patients are summarized in Table 5.

Table 5
Patient Demographics
Sex
Male	132
Female	44
Race
Caucasian	153
African American	3
Hispanic	3
Other	13
Unknown	4
Age
Range	36 - 98 years
Average	71 years

Technical Performance: Informative vs. Non-Informative Results FISH assays on 70% (175/251) of the eligible study specimens were informative on the first attempt. Of the 76 specimens that failed to yield informative results on the first attempt, only 26 were due to hybridization failures. The hybridization efficiency for the first assay attempt was 87%. The remaining non-informative assays were the result of poor specimen quality (e.g., insufficient number of cells) or technical error (e.q., broken slide).

Repeat assays were conducted on 70 specimens; six of the 76 specimens had insufficient volume remaining to repeat the assay. Of the 70 repeat assays, 59 yielded informative results, leaving 17 specimens classified as "non-informative" (including the 6 cases with insufficient volume for repeat assay). In summary, over 93% of the cases vielded an informative result on the first or second attempt.

Performance vs. Standard of Care

Of the eligible patients with informative FISH results, 62 were positive by cystoscopy/histology. A breakdown of the number of tumors by stage and grade is shown in Table 6.

Number of Tumors, by Stage and Grade
Tumor				Tumor Grade
Stage :		ND - 1 -		: 2 . : 3 . 3	Unknown	Total
ND		11 : 0 ::		1: 00 : 0 : 000	0 ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------	11 .
Ta	0	20	6	റ	0	32
11	0	O	2	3		ರ
T2	0	0	0	1
Tis	0	O	()		0
Unknown	O	2		. O	0
Total	11	22	g	18	2	62

Table 6

ND = not assigned or no biopsy

Table 7 shows the performance of the UroVysion Kit, relative to cystoscopy / histology, by tumor stage and grade for all cases with biopsy information available. The UroVysion Kit showed greatest agreement of positive results (100%) among the most severe tumors (T2 and Tis), when compared to cystoscopy/histology.

Table 7
Comparison of UroVysion vs. Cystoscopy/Histology for Detection
of Bladder Cancer Recurrence by Tumor Stage and Grade*
Agreement of (+) Results (%)

Stage:
All	36/48 (75.0%)
Ta, Grade 1	11/20 (55.0%)
Ta, Grade 2,3	10/12 (83.3%)
T1	5/6 (83.3%)
T2	3/3 (100%)
Tis	7/7 (100%)
Grade:
All	36/49 (73.5%)
1	12/22 (54.5%)
2	7/9 (77.8%)
3	17/18 (94.4%)

*Biopsy was not performed in 11 cases. In addition, no stage was assigned in 3 cases and no grade in 2.

Table 8 shows a comparison of the performance of the UroVysion Kit relative to cystoscopy followed by histology. Overall, FISH analysis with the ========================================================================================================= UroVysion Kit demonstrated a percent agreement of positive results of 71.0% and a percent agreement of negative results of 65.8% when compared to the results of cystoscopy, followed by histology in the case of positive or suspicious cystoscopy (Note: A positive cystoscopy without a biopsy was considered positive in this analysis).

Table 8 Comparison of UroVysion vs. Cystoscopy/Histology for Detection of Bladder Cancer Recurrence

	Cysto/Histo
FISH	+	-	Total
+	44	39	83
-	18	75	93
Total	62	114	176
Agreement of (+) results = 71.0% (95% CI = 58.1% - 81.8%)

Agreement of (-) results = 65.8% (95% CI = 56.3% - 74.4%) Overall Agreement = 67.6% (95% Cl = 60.2% - 74.5%) (+) Predictive Value = 53.0% (95% Cl = 41.7%-64.1%) (-) Predictive Value = 80.6% (95% CI = 71.1% - 88.1%) Prevalence = 35.2% (95% Cl = 28.2% - 42.8%) p = Trade Name: UroVysion™ Bladder Cancer Recurrence Kit Regulation Number: 21 CFR § 866.6010 Regulation Name: Tumor-associated antigen immunological test system Regulatory Class: Class II Product Code: MMW Dated: November 13, 2001 Received: November 14, 2001

FEB 0 8 2002

Dear Dr. Enns:

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); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

Page 2 -

This letter will allow you to begin marketing your device as described in your 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.

If you desire specific advice for your device on our labeling regulation (21 CFR Part 801 and t additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at (301) 594-4588. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 443-6597 or at its internet address "http://www.fda.gov/odrh/dsma/dsmamain.html".

Sincerely yours,

Steven Butman

Steven I. Gutman, M.D., M.B.A. Director Division of Clinical Laboratory-Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure

510(k) Number (IF KNOWN): | DJ3285

DEVICE NAME: Vysis™, Inc. UroVysion™ Bladder Cancer Recurrence Kit

INDICATIONS FOR USE:

Note: No change from the current, cleared, indications for use (K011031)

Sousan. S. Altare

(Division Sign-Off)
Division of Clinical Laboratory Devices
510(k) Number. K013785

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

Concurrence of CDRH, Office of Device Evaluation (ODE)

Prescription Use (Per 21 CFR 801.109)

Over-The-Counter-Use (Optimal Format 1-2-96)