Visuwell® Reagin II is an enzyme-linked immunosorbent assay for the in vitro qualitative detection of non-treponemal (reagin) antibodies as a screening test in syphilis serology. It is not intended for use in screening blood or plasma donors.

Device Description

Visuwell® Reagin II is an enzyme-linked immunosorbent assay for the in vitro qualitative detection of non-treponemal (reagin) antibodies in syphills serology. In this device, serum is incubated with a mixture of cardiolipin, lecithin, cholesterol dried to a polystyrene solid phase. Antilipid antibodies react with the lipoidal antigen to form an immune complex. The presence of non-treponemal complexed antibodies is detected with a monoclonal anti-human lgG-peroxidase conjugate. The presence of bound conjugate is detected by the addition of enzyme substrate and subsequent development of colour. The reaction is stopped by the addition of acid and colour intensity is determined spectrophotometrically at 450 nm. Test results are interpreted relative to a floating cutoff based on the negative control. Positive and negative controls are used for establishing test validity.

AI/ML Overview

Acceptance Criteria and Device Performance Study for Visuwell® Reagin II

1. Table of Acceptance Criteria and Reported Device Performance

Acceptance Criteria Category	Acceptance Criteria (Reference Non-Treponemal Tests Performance)	Visuwell® Reagin II Reported Performance	Met Acceptance Criteria?
Specificity	99.5%	97.1%	Substantially equivalent
Sensitivity (Untreated Syphilis)	95.8%	92.2%	Substantially equivalent
Sensitivity (Treatment Status Unknown)	82.4%	93.2%	Substantially equivalent (Exceeded)
Sensitivity (Treated Syphilis)	90.2%	75.4%	Lower reactivity, but considered substantially equivalent for untreated syphilis detection. Suggests potential for monitoring therapy.
Predictive Value of Positive (STD Population)	99.4%	97.4%	Substantially equivalent
Predictive Value of Negative (All Sites)	99.5%	99.0%	Substantially equivalent
Specificity in Cross-Reactivity (Non-Syphilitic Conditions)	91.9%	86.8%	Substantially equivalent
Overall Agreement	Not explicitly stated as a single number (comparison to reference tests)	96.5%	Substantially equivalent

Note on "Substantially equivalent": The report explicitly states that Visuwell® Reagin II was "substantially equivalent" in performance to the reference tests despite some numerical differences. For example, for sensitivity in treated syphilis, Visuwell® Reagin II showed lower reactivity (75.4% vs 90.2%), but this was interpreted as potentially beneficial for therapy monitoring, and the device was still deemed substantially equivalent for its primary intended use of detecting non-treponemal antibody in untreated syphilis.

2. Sample Sizes Used for the Test Set and Data Provenance

Specificity Comparison: 10,738 specimens from random, low-risk, and high-risk populations.
Sensitivity Comparison:
- 306 patients with untreated syphilis
- 74 patients with unknown treatment status
- 325 patients with treated syphilis
Predictive Values:
- Predictive value of positive calculated for the Sexually Transmitted Disease (STD) population.
- Predictive value of negative calculated with data from "all sites."
Cross-Reactivity: 151 specimens from individuals with various bacterial, viral, and auto-immune disorders, including syphilis biological false-positives, pregnancy, and drug abuse.
Overall Agreement: 11,443 total sera (presumably the aggregate of relevant specificity and sensitivity samples).

Data Provenance: The document does not explicitly state the country of origin or whether the data was retrospective or prospective. It refers to "various populations" and "all sites," suggesting a multicenter study, but lacks specific details on geographical location or study design.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications

The document does not provide information on the number of experts used or their qualifications for establishing ground truth. The comparison is made against "legally marketed reference non-treponemal tests" (VDRL, RPR, RST), implying that the results from these established tests were considered the ground truth.

4. Adjudication Method for the Test Set

The document does not describe any specific adjudication method (e.g., 2+1, 3+1). The nature of the study involves comparing the Visuwell® Reagin II results directly to the results obtained from established reference non-treponemal tests. The interpretation of these reference tests (VDRL, RPR, RST) is described as "subjective... according to the presence or absence of flocculation," which implies expert interpretation of the reference test results themselves, but no explicit adjudication process for disagreements is mentioned.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No Multi-Reader Multi-Case (MRMC) comparative effectiveness study was mentioned. The study focused on the performance of the Visuwell® Reagin II device compared to existing non-treponemal tests, not on human reader performance with or without AI assistance.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance)

Yes, this was a standalone performance study. Visuwell® Reagin II is an "enzyme-linked immunosorbent assay," and its results are "objectively spectrophotometrically interpreted." This indicates an automated or semi-automated process where the device's output (color intensity) is directly converted into a result relative to a floating cutoff, without human-in-the-loop interpretation being the primary focus of the comparison with reference methods.

7. Type of Ground Truth Used

The ground truth was established by comparison to existing, legally marketed reference non-treponemal tests (Venereal Disease Research Laboratory (VDRL) Slide Test, Rapid Plasma Reagin (RPR) Card Test, Reagin Screen Test (RST)). These tests are implied to be the standard of care for detecting non-treponemal antibodies in syphilis serology. Clinical diagnosis of syphilis (e.g., "patients with untreated syphilis") was also used to categorize some samples for sensitivity calculations.

8. Sample Size for the Training Set

The document does not provide specific details about a dedicated "training set" or its size for the Visuwell® Reagin II device development. The information presented pertains to a performance study evaluating the final device's performance against reference methods.

9. How the Ground Truth for the Training Set Was Established

As no specific training set is described in the provided text, there is no information on how its ground truth was established. The focus of this submission is on the validation of the device, comparing its performance to established methods in various clinical populations.

Summary

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MAY 2 3 1996 510(k) SUMMARY VISUWELL® REAGIN II

This 510(k) summary of safety and effectiveness information is being submitted in accordance with the requirements of the Safety Medical Devices Act of 1990.

Submitter:

BIOMIRA Diagnostics Inc. 30 Meridian Rd. Rexdale, Ontario M9W 4Z7 Contact: Ms. Althea R. Lawrence, Director, Quality/Regulatory

Date Submitted:

June 16, 1995

Device Name:

Trade Name: Visuwell® Reagin II

Common Name:

Syphilis non-treponemal antibody detection kit

Classification Name: Treponemal pallidum non-treponemal test reagent, Class II

Device Description:

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Antilipid antibodies react with the lipoidal antigen to form an immune complex. The presence of non-treponemal complexed antibodies is detected with a monoclonal anti-human lgG-peroxidase conjugate. The presence of bound conjugate is detected by the addition of enzyme substrate and subsequent development of colour. The reaction is stopped by the addition of acid and colour intensity is determined spectrophotometrically at 450 nm.

Test results are interpreted relative to a floating cutoff based on the negative control. Positive and negative controls are used for establishing test validity.

Intended Use

Substantial Equivalence Claim

Visuwell® Reagin II was demonstrated to be substantially equivalent in performance to the following legally marketed reference non-treponemal tests:

Venereal Disease Research Laboratory (VDRL) Slide Test Rapid Plasma Reagin (RPR) Card Test Reagin Screen Test (RST)

Visuwell® Reagin II has the same intended use for screening in svphilis serology but different technological characteristics than the above mentioned reference tests. These tests employ lipoidal antigen comprised of cardiolipin, lecithin and cholesterol.

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Results in the reference tests are interpreted subjectively according to the presence or absence of flocculation as opposed to the objective spectrophotometric interpretation of results using Visuwell® Reagin II.

To demonstrate substantial equivalence, Visuwell® Reagin was compared to the reference tests in specificity, sensitivity, predictive values, cross-reactivity and overall agreement of test results.

Specificity Comparison

Specificity results were obtained from 10,738 specimens in random, low-risk and high-risk populations. The specificity of Visuwell® Reagin II was 97.1% compared to the 99.5% specificity of the reference non-treponemal tests. Visuwell® Reagin II is substantially equivalent to non-treponemal reference tests in specificity.

Sensitivity Comparison

Sensitivity results were obtained from the specimens of 306 patients with untreated syphilis, 74 patients whose treatment status was unknown and 325 patients with treated syphilis.

Visuwell® Reagin II was reactive with 92.2% of specimens from patients with untreated syphilis as compared to 95.8% of specimens with the reference tests. Where treatment status of the patients was unknown, Visuwell® Reagin II was reactive with 93.2% of the specimens as compared to 82.4% of the specimens with the reference tests. Visuwell® Reagin II was reactive with 75.4% of specimens from patients with treated syphilis as compared to 90.2% of the specimens with the reference tests.

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Therefore, Visuwell® Reagin II is substantially equivalent to reference nontreponemal tests in the detection of non-treponemal antibody in sera of patients with untreated syphilis. Visuwell® Reagin II shows lower reactivity with sera from patients with treated syphilis which may suggest potential for monitoring response to therapy.

Predictive Values

The predictive values of positive for syphilis in Visuwell® Reagin II and the reference tests were determined for the Sexually Transmitted Disease (STD) population. The predictive values of negative were determined with data from all sites. The predictive value of positive for Visuwell® Reagin II was 97.4% as compared to 99.4% for the reference tests. The predictive value of negative for Visuwell® Reagin II was 99.0% as compared to 99.5% for the reference tests.

Consequently, Visuwell® Reagin II is substantially equivalent to reference tests in predictive value of positive for STD populations and predictive value of negative.

Cross-Reactivity

Cross-Reactivity results were obtained from 151 specimens consisting of specimens from individuals with a variety of bacterial, viral and auto-immune disorders. Specimens identified as syphilis biological false-positives and specimens from conditions frequently associated with false reactivity in nontreponemal screen tests such as pregnancy and drug abuse were included in these results.

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The specificity of Visuwell® Reagin II in the clinical population characterized by non-syphilitic diseases or conditions was 86.8% as compared to 91.9% with the reference tests. These results indicate that the performance of Visuwell® Reagin II is substantially equivalent to the reference tests for specimens that have potential for interference.

Overall Agreement

The overall agreement between the Visuwell® Reagin II and the reference tests results for all sera (11,443 specimens) was 96.5%. Visuwell® Reagin II is substantially equivalent to non-treponemal reference tests in overall agreement of test results.

Conclusion

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The safety and effectiveness of Visuwell® Reagin II is substantially equivalent to legally marketed non-treponemal reference tests (VDRL, RPR, RST) as demonstrated in the comparison of the performance of Visuwell® Reagin to these tests.

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Regulation Number and Section

§ 866.3820

Treponema pallidum nontreponemal test reagents.(a)
Identification. Treponema pallidum nontreponemal test reagents are devices that consist of antigens derived from nontreponemal sources (sources not directly associated with treponemal organisms) and control sera (standardized sera with which test results are compared) used in serological tests to identify reagin, an antibody-like agent, which is produced from the reaction of treponema microorganisms with body tissues. The identification aids in the diagnosis of syphilis caused by microorganisms belonging to the genusTreponema and provides epidemiological information on syphilis.(b)
Classification. Class II (performance standards).