COPALIS TREPONEMAL ANTIGEN TOTAL ANTIBODY ASSAY by DIASORIN, INC.

The Copalis Treponemal Antibody Assay uses Coupled Particle Light Scattering (Copalis®) technology in a microparticle agglutination-based immunoassay for the qualitative detection of total antibodies (IgG and IgM) to recombinant Treponema pallidum antigens in human serum using the Copalis I Immunoassay System. The presence of antibodies is indicative of current or prior infection with T. pallidum. The assay is indicated as an aid in the confirmation of syphilis disease following a positive result with a nontreponemal screening test. This assay has not been FDA cleared or approved for the screening of blood or plasma donors.

Device Description

The Copalis® Treponemal Antigen Total Antibody Assay is based on Coupled Particle Light Scattering (Copalis) technology which provides a rapid method for the measurement of antibodies to specific pathogens.

The assay is a microparticle agglutination test using the Copalis light scattering technology. Polystyrene microparticles are coated with recombinant antigen derived from T. pallidum and are contained within a special covered reaction well in the test cup. The dried reagent is reconstituted with a reaction buffer on the instrument at the start of the assay. Patient sample is added to the reaction mixture and incubated for 10 minutes. The presence of antibodies specific to T. pallidum in the patient sample results in agglutination of the monomer microparticles to form aggregrates. The reaction mixture is passed through a flow cell and the instrument uses light scattering technology to measure the monomer concentration. The decrease in the monomer population resulting from agglutination is related to the amount of antibody in the sample. The residual monomer concentration in each reaction mixture is compared to a cutoff value to determine sample reactivity and nonreactivity.

AI/ML Overview

Here's a summary of the acceptance criteria and study details for the Copalis Treponemal Antigen Total Antibody Assay based on the provided text:

Acceptance Criteria and Device Performance

The document does not explicitly state pre-defined acceptance criteria with specific thresholds (e.g., "sensitivity must be >95%"). Instead, it presents the device's performance across various clinical scenarios and compares it to established predicate devices. The implicit acceptance criteria are the satisfactory performance across these categories benchmarked against the predicate devices (FTA-ABS and TP-PA).

The reported device performance, which implies the acceptance criteria were met by these reported values, are:

Metric / Stage	Treatment Status	Copalis Performance (with 95% CI where provided)	Notes
Clinical Sensitivity: RPR + FTA +	Primary (Untreated)	100% (15.8-100%)
	Primary (Treated)	100% (75.3-100%)
	Secondary (Untreated)	100% (86.3-100%)
	Secondary (Treated)	100% (88.1-100%)
	Latent (Treated)	97.8% (92.2-99.7%)
	Late, Cardiovascular	100% (29.2-100%)
	Congenital	100%* (15.8-100%)	*Excludes 1 equivocal result
Clinical Sensitivity: RPR - FTA +	Primary (Treated)	66.7% (22.2-95.7%)
	Secondary (Treated)	100% (2.5-10%)	Note the narrow confidence interval, likely due to a very small sample size in this specific sub-category.
	Latent (Treated)	100% (66.4-100%)
	Late, Cardiovascular	100% (2.5-100%)
	Congenital	100% (15.8-100%)
Clinical Specificity: RPR +/- FTA -	Primary (Untreated)	100% (2.5-100%)
	Primary (Treated)	100% (2.5-100%)
Agreement - RPR positive samples	N/A	96.3% (944/980)	25 samples were equivocal. These were RPR positive samples sent to hospital laboratories for confirmation.
Prevalence - Apparently healthy adults	Copalis	3.2% (32/1002)	Compared to FTA = 2.2% (22/1002)
Agreement - Obstetric; Pediatric >18 months	N/A	100% (34/34)	1 Copalis equivocal/FTA negative sample
Agreement - CDC Panel	N/A	90% (18/20)
Agreement - Commercial syphilis mixed titer panel	N/A	100% (25/25)
Reproducibility: Total %CV (across sites)	Negative Control	1.4	Tested in duplicate once a day for 5 days using 6 samples spanning the assay's CTRs at 3 sites.
	Positive Control	8.7
	RP1	1.9
	RP2	18.0
	RP3	1.8
	RP4	16.7
	RP5	16.7
	RP6	13.3

Study Details:

Sample sizes used for the test set and the data provenance:
- Syphilis Patients: 188 samples from patients with a diagnosis of syphilis.
- Other disease/health states:
  - RPR positive samples for confirmation: 1005 samples
  - Apparently healthy adults: 1002 samples
  - Obstetric; Pediatric (>18 months old): 35 samples
  - CDC Panel: 20 samples
  - Commercial syphilis mixed titer panel: 25 samples
- Data Provenance: Clinical trials were conducted at four sites: 2 clinical laboratories, 1 reference laboratory, and DiaSorin Inc.'s laboratory. The origin of the patient samples (e.g., country) is not specified, but the diverse site locations suggest a possible mix of sources within the US. The data appears to be prospective in nature, as it describes a clinical trial process to evaluate the assay's performance.
Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- The document implies ground truth was established by comparison to predicate devices (Zeus Scientific Inc. FTA-ABS assay and FUJIREBIO Inc. TP-PA), which are described as confirmatory tests for syphilis.
- For the "Samples from patients with diagnosis of syphilis," the diagnosis itself would typically be made by medical professionals, likely physicians, based on a combination of clinical symptoms and laboratory results (including RPR and FTA-ABS). However, the number and qualifications of these specific "experts" (e.g., infectious disease specialists or pathologists) who established the original patient diagnoses are not explicitly stated in the provided text. The study primarily uses the results of existing confirmatory tests as its gold standard for evaluating the new device.
Adjudication method (e.g. 2+1, 3+1, none) for the test set:
- The document does not detail an adjudication method beyond referencing the results of the predicate confirmatory tests (FTA-ABS and TP-PA) and RPR. There's no mention of multiple experts independently reviewing cases and then adjudicating discrepancies.
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. This is an immunoassay device, not an imaging AI diagnostic. Therefore, an MRMC study and human reader improvement with AI assistance are not applicable in this context. The device directly measures antibodies, and human "readers" (in the sense of interpreting images) are not involved in its primary function.
If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
- Yes, this is a standalone device. The Copalis Treponemal Antigen Total Antibody Assay is an automated immunoassay that uses Coupled Particle Light Scattering technology to detect antibodies. It generates a result (reactive/non-reactive) based on its intrinsic algorithm and measurement. While a human interprets the final result, the assay performance itself is standalone in generating the raw data and comparison to a cutoff value. It does not involve human users actively interpreting complex patterns that AI might augment.
The type of ground truth used (expert consensus, pathology, outcomes data, etc):
- The primary ground truth appears to be based on results from predicate confirmatory tests (Zeus Scientific Inc. FTA-ABS assay and FUJIREBIO Inc. TP-PA), which are established methods for confirming syphilis. For the "diagnosis of syphilis" patient group, this would represent a form of expert consensus implicitly, as the diagnosis would have been made by clinicians using established diagnostic criteria and confirmatory testing. For the panels, the ground truth was "characterized commercial syphilis mixed titer panel" and CDC panel, indicating pre-determined reference results.
The sample size for the training set:
- The document does not explicitly state a dedicated "training set" sample size. For immunoassay development, there isn't typically a distinct "training set" in the same way an AI model would have. The assay's parameters (like cutoff values) are established during the development and optimization phases, which would involve testing a variety of samples, but these are not usually quantified or presented as a formal "training set" within a 510(k) summary for such a device. The data provided focuses on the validation (test) set performance.
How the ground truth for the training set was established:
- As no formal training set is described, the method for establishing its ground truth is also not described. The assay's design and cutoff values would have been determined through internal validation and optimization against known positive and negative samples, but the specifics are not provided in this regulatory document.

Summary

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DEC I 6 1999

K992552

December 10, 1999

510(K) SUMMARY

SUBMITTED BY:	Judith J. SmithVice President,Worldwide Regulatory Affairs and Quality Systems
NAME OF DEVICES:
Trade Name:	Copalis Treponemal Antigen Total Antibody Assay
Common Names/Descriptions:	Immunoassay for the Detection of Total Antibodiesto Treponema pallidum
Classification Names:	Treponema pallidum treponemal test
PREDICATE DEVICES:	Zeus Scientific Inc. FTA-ABS and FUJIREBIO INC.SERODIA® TP-PA

DEVICE DESCRIPTION:

INTENDED USE: The Copalis Treponemal Antibody Assay uses Coupled Particle Light Scattering (Copalis®) technology in a microparticle agglutination-based immunoassay for the qualitative detection of total antibodies (IgG and IgM) to recombinant Treponema pallidum antigens in human serum using the Copalis I Immunoassay System. The presence of antibodies is indicative of current or prior infection with T. pallidum. The assay is indicated as an aid in the confirmation of syphilis disease following a positive result with a nontreponemal screening test. This assay has not been FDA cleared or approved for the screening of blood or plasma donors.

KIT DESCRIPTION: The Copalis® Treponemal Antigen Total Antibody Assay is based on Coupled Particle Light Scattering (Copalis) technology which provides a rapid method for the measurement of antibodies to specific pathogens.

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PERFORMANCE DATA:

Clinical Correlation: Clinical trials were conducted at four sites (2 clinical laboratories, 1 reference laboratory and the laboratory located at DiaSorin Inc.) to evaluate the performance of the Copalis Treponemal Antibody Assay in detecting antibodies to Treponema pallidum on the Copalis I Immunoassay System. The assay performance was compared to the Zeus Scientific Inc. FTA-ABS assay and the FUJIREBIO Inc. TP-PA, both of which are confirmatory tests.

Samples from 188 patients with diagnosis of syphilis were analyzed using the Copalis® Treponemal Antigen Total Antibody Assay. These samples were characterized by disease state and treatment status. The clinical sensitivity of the assay is shown below.

Stage	TreatmentStatus	CopalisSensitivityRPR + FTA +	CopalisSensitivityRPR - FTA +	CopalisSpecificityRPR +/- FTA -
Primary	Untreated	100%(15.8-100%)	--	100%(2.5-100%)
	Treated	100%(75.3-100%)	66.7%(22.2-95.7%)	100%(2.5-100%)
Secondary	Untreated	100%(86.3-100%)	--	--
	Treated	100%(88.1-100%)	100%(2.5-10%)	--
Latent	Treated	97.8%(92.2-99.7%)	100%(66.4-100%)	100%(15.8-100%)
Late,		100%(29.2-100%)	100%(2.5-100%)	--
Cardiovascular		100%*(15.8-100%)	100%(15.8-100%)	--
Congenital

Clinical Sensitivity and 95% Confidence Limits From Syphilitic Sera:

*excludes 1 equivocal result

In addition, 2086 sera from a variety of diseases and 45 CDC or commercial panel samples were tested. The results are summarized below.

Category	Number	Agreement
RPR positive samples sent to hospitallaboratories for confirmation of disease	1005	96.3%(944/980)(25 equivocal)
Apparently healthy adults	1002	Prevalence:Copalis = 3.2%(32/1002)FTA = 2.2%(22/1002)
Other (Obstetric; Pediatric >18 monthsold)	35	100%(34/34)(1 Copalis eq/FTA -)

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Category	Number	Agreement
CDC Panel	20	90%(18/20)
Characterized commercial syphilismixed titer panel	25	100%(25/25)

Reproducibility: Reproducibility studies were performed at the 3 sites using one lot of reagents. Assay reproducibility was determined by testing 6 samples that spanned the range of the assay's CTRs. Samples were tested in duplicate once a day for 5 days. The results are summarized below.

COPALIS TREPONEMAL ASSAY REPRODUCIBILITY RESULTS COMBINED SITES CTR

SAMPLE	MEAN CTR	WITHINRUN %CV	TOTAL%CV
Negative Control	101	-	1.4
Positive Control	171	-	8.7
RP1	103	1.4	1.9
RP2	1470	16.2	18.0
RP3	101	1.5	1.8
RP4	280	13.1	16.7
RP5	1068	12.9	16.7
RP6	172	7.6	13.3

The Copalis TTA Quality Control procedures include the running of a negative and a positive control at least every 24 hours of use. This procedure was followed by all sites during the clinical trials. A summary of the control data is presented here.

CONTROL RESULTS, SITES COMBINED

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DEC I 6 1999

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Ms. Judith J. Smith Vice President Worldwide Regulatory Affairs and Quality Systems DiaSorin, Inc. 9175 Guilford Road Quarry Park Place, Suite 100 Columbia, Maryland 21046

Re: K992552
Trade Name: DiaSorin Copalis™ Treponemal Antigen Total Antibody Assay Regulatory Class: II Product Code: LIP Dated: October 20, 1999 Received: October 25, 1999

Dear Ms. Smith:

We have reviewed your Section 510(k) notification of intent to market the device referenced above and we 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. 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 (Premarket Approval), 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 895. A substantially equivalent determination assumes compliance with the Current Good Manufacturing Practice requirements, as set forth in the Quality System Regulation (QS) for Medical Devices: General regulation (21 CFR Part 820) and that, through periodic QS inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP regulation may result in regulatory action. In addition, FDA may publish further announcements concerning your device in the Federal Register. Please note: this response to your premarket notification submission does not affect any obligation you might have under sections 531 through 542 of the Act for devices under the Electronic Product Radiation Control provisions, or other Federal laws or regulations.

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Page 2

Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), this device may require a CLIA complexity categorization. To determine if it does, you should contact the Centers for Disease Control and Prevention (CDC) at (770)488-7655.

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 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" (21 CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers Assistance at its toll free number (800) 638-2041 or at (301) 443-6597 or at its internet address "http://www.fda.gov/cdrh/dsmamain.html"

Sincerely yours,

Steven Autman

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

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510(k) Number (if known): K992552

Device Name: DiaSorin Copalis®Treponemal Antigen Total Antibody Assay

Indications For Use:

The Copalis Treponemal Antibody Assay uses Coupled Particle Light Scattering (Copalis®) technology in a microparticle agglutination-based immunoassay for the qualitative detection of total antibodies (IgG and IgM) to recombinant Treponema pallidum antigens in human serum using the Copalis I Immunoassay System. The presence of antibodies is indicative of current or prior infection with T. pallidum. The assay is indicated as an aid in the serological confirmation of syphilis disease following a positive result with a nontreponemal screening test. This assay has not been FDA cleared or approved for the screening of blood or plasma donors.

NOTE: The Copalis Treponemal Antibody Assav has not been evaluated as an initial or single test for the serodiagnosis of syphilis. The predictive value of a positive Copalis Treponemal Antibody Assay result has not been determined with RPR negative specimens.

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

Concurrence of CDRH, Office of Device Evaluation (ODE)

Woody Dubois

vision of Clinical Laboratory Devices K 992552 510(k) Number ...

Prescription Use (Per 21 CFR 801.109)

Over-The-Counter Use

(Optional Format 1-2-96)

Regulation Number and Section

§ 866.3830

Treponema pallidum treponemal test reagents.(a)
Identification. Treponema pallidum treponemal test reagents are devices that consist of the antigens, antisera and all control reagents (standardized reagents with which test results are compared) which are derived from treponemal sources and that are used in the fluorescent treponemal antibody absorption test (FTA-ABS), theTreponema pallidum immobilization test (T.P.I.), and other treponemal tests used to identify antibodies toTreponema pallidum directly from infecting treponemal organisms in serum. The identification aids in the diagnosis of syphilis caused by bacteria belonging to the genusTreponema and provides epidemiological information on syphilis.(b)
Classification. Class II (performance standards).